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Item does not contain fulltext All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

Item does not contain fulltext BACKGROUND: Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. METHODS: We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. FINDINGS: Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20-29 and simplified acute physiology score [SAPS 2] 35-58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1.13 (95% CI 0.98-1.31). The overall daily risk of discharge after ventilator-associated pneumonia was 0.74 (0.68-0.80), leading to an overall cumulative risk for dying in the ICU of 2.20 (1.91-2.54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2.97, 95% CI 2.24-3.94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2.49 [1.81-3.44] for patients with APACHE scores of 20-29 and 2.72 [1.95-3.78] for those with SAPS 2 scores of 35-58). INTERPRETATION: The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. FUNDING: None.

Objective: The stepped wedge design is increasingly being used in cluster randomized trials (CRTs). However, there is not much information available about the design and analysis strategies for these kinds of trials. Approaches to sample size and power calculations have been provided, but a simple sample size formula is lacking. Therefore, our aim is to provide a sample size formula for cluster randomized stepped wedge designs.Study Design and Setting: We derived a design effect (sample size correction factor) that can be used to estimate the required sample size for stepped wedge designs. Furthermore, we compared the required sample size for the stepped wedge design with a parallel group and analysis of covariance (ANCOVA) design.Results: Our formula corrects for clustering as well as for the design. Apart from the cluster size and intracluster correlation, the design effect depends on choices of the number of steps, the number of baseline measurements, and the number of measurements between steps. The stepped wedge design requires a substantial smaller sample size than a parallel group and ANCOVA design.Conclusion: For CRTs, the stepped wedge design is far more efficient than the parallel group and ANCOVA design in terms of sample size. (c) 2013 Elsevier Inc. All rights reserved.

Item does not contain fulltext OBJECTIVES: In early stages of development of new medical technologies, there are conceptually separate but related societal decisions to be made concerning adoption, further development (i.e., technical improvement), and research (i.e., clinical trials) of new technologies. This article presents a framework to simultaneously support these three decisions from a societal perspective. The framework is applied to the 70-gene signature, a gene-expression profile for breast cancer, deciding which patients should receive adjuvant systemic therapy after surgery. The "original" signature performed on fresh frozen tissue (70G-FFT) could be further developed to a paraffin-based signature (70G-PAR) to reduce test failures. METHODS: A Markov decision model comparing the "current" guideline Adjuvant Online (AO), 70G-FFT, and 70G-PAR was used to simulate 20-year costs and outcomes in a hypothetical cohort in The Netherlands. The 70G-PAR strategy was based on projected data from a comparable technology. Incremental net monetary benefits were calculated to support the adoption decision. Expected net benefit of development for the population and expected net benefit of sampling were calculated to support the development and research decision. RESULTS: The 70G-PAR had the highest net monetary benefit, followed by the 70G-FFT. The population expected net benefit of development amounted to euro91 million over 20 years (assuming euro250 development costs per patient receiving the test). The expected net benefit of sampling amounted to euro61 million for the optimal trial (n = 4000). CONCLUSIONS: We presented a framework to simultaneously support adoption, development, and research decisions in early stages of medical technology development. In this case, the results indicate that there is value in both further development of 70G-FFT into 70G-PAR and further research.

Item does not contain fulltext Oculopharyngeal muscular dystrophy (OPMD) is caused by trinucleotide repeat expansion mutations in Poly(A) binding protein 1 (PABPN1). PABPN1 is a regulator of mRNA stability and is ubiquitously expressed. Here we investigated how symptoms in OPMD initiate only at midlife and why a subset of skeletal muscles is predominantly affected. Genome-wide RNA expression profiles from Vastus lateralis muscles human carriers of expanded-PABPN1 at pre-symptomatic and symptomatic stages were compared with healthy controls. Major expression changes were found to be associated with age rather than with expression of expanded-PABPN1, instead transcriptomes of OPMD and elderly muscles were significantly similar (P

Item does not contain fulltext PURPOSE: The clinical relevance of and risk factors associated with errors related to medication administration time were studied. METHODS: In this explorative study, 66 medication administration rounds were studied on two wards (surgery and neurology) of a hospital. Data on medication errors were collected using the blister collection method. The emptied packaging material of medication was collected after each round and compared with each patient's medication orders. Administration time errors were defined as medication administration (actual intake) occurring more than one hour before or after the prescribed time. Generalized estimating equations analysis was performed to study the correlation between medication administration errors and risk factors. RESULTS: Data from 129 patients were included in the study. Among these 129 patients, 2874 opportunities for error were recorded. The majority of opportunities for error occurred during the 7 a.m. round. Within the 2874 opportunities for errors, 10 administration time errors occurred for medications that might interact with food or another medication. Time of administration (noon and 3 p.m.), route of administration (injection or infusion), and frequency of administration (if necessary) had significant protective effects against the occurrence of administration time errors. The rectal route of administration was associated with a significant increase in the frequency of administration time errors compared with the oral route. A clinically relevant administration time error occurred in 2 cases (0.07%). CONCLUSION: Analysis of medication administration rounds found time errors to be the most common medication error.

Item does not contain fulltext BACKGROUND: Depression in nursing-home residents is often under-recognised. We aimed to establish the effectiveness of a structural approach to its management. METHODS: Between May 15, 2009, and April 30, 2011, we undertook a multicentre, stepped-wedge cluster-randomised trial in four provinces of the Netherlands. A network of nursing homes was invited to enrol one dementia and one somatic unit per nursing home. In enrolled units, nursing-home staff recruited residents, who were eligible as long as we had received written informed consent. Units were randomly allocated to one of five groups with computer-generated random numbers. A multidisciplinary care programme, Act in Case of Depression (AiD), was implemented at different timepoints in each group: at baseline, no groups were implenting the programme (usual care); the first group implemented it shortly after baseline; and other groups sequentially began implementation after assessments at intervals of roughly 4 months. Residents did not know when the intervention was being implemented or what the programme elements were; research staff were masked to intervention implementation, depression treatment, and results of previous assessments; and data analysts were masked to intervention implementation. The primary endpoint was depression prevalence in units, which was the proportion of residents per unit with a score of more than seven on the proxy-based Cornell scale for depression in dementia. Analyses were by intention to treat. This trial is registered with the Netherlands National Trial Register, number NTR1477. FINDINGS: 16 dementia units (403 residents) and 17 somatic units (390 residents) were enrolled in the course of the study. In somatic units, AiD reduced prevalence of depression (adjusted effect size -7.3%, 95% CI -13.7 to -0.9). The effect was not significant in dementia units (0.6, -5.6 to 6.8) and differed significantly from that in somatic units (p=0.031). Adherence to depression assessment procedures was lower in dementia units (69% [SD 19%]) than in somatic units (82% [15%]; p=0.045). Adherence to treatment pathways did not differ between dementia units (43% [SD 33%]) and somatic units (38% [40%]; p=0.745). INTERPRETATION: A structural approach to management of depression in nursing homes that includes assessment procedures can reduce depression prevalence in somatic units. Improvements are needed in depression screening in dementia units and in implementation of nursing-home treatment protocols generally. FUNDING: The Netherlands Organization for Health Research and Development.

Item does not contain fulltext OBJECTIVES: Estimation of the effectiveness of human papillomavirus (HPV) vaccination in the open population on the basis of published data from various sources. METHODS: A Bayesian approach was used to reanalyze the data underlying a guidance by the Dutch National Health Insurance Board about the quadrivalent HPV vaccine Gardasil. Several studies document the vaccine's effectiveness in preventing cases in different subpopulations. None of these (sub)populations, however, is representative of the actual target population that the vaccination program will be applied to. We used a Bayesian approach for restructuring the data by means of reweighting the subpopulations by using HPV prevalence data, to estimate the effectiveness that can be expected in the actual target population. RESULTS: The original data show an effectiveness of 44% in the entire population and an effectiveness of 98% for women who were compliant and were HPV-free at the start of the study. In the study population, the HPV prevalence was below 4%. In the relevant target population, however, the actual prevalence could be very different. In fact, some publications find an HPV prevalence of around 10%. We used Bayesian techniques to estimate the effectiveness in the actual target population. We found a mean effectiveness of 25%, and the probability that the effectiveness in the target population exceeds 50% is virtually zero. The results are very sensitive to the HPV prevalence that is used. CONCLUSIONS: A supplementary analysis can put together the bits and pieces of information to arrive at more relevant answers. A Bayesian approach allows for integrating all the evidence into one model in a straightforward way and results in very intuitive probability statements.

Objective This pilot study aimed to understand cultural perspectives on cleft anomalies in the community of Hyderabad, India, and its rural outskirts. Design Interviews focusing on perceptions of cleft lip and palate were conducted using a 21-item interview guide approved by the director of the Gosla Srinivas Reddy Institute of Craniofacial Surgery (GSR). Settings Interviews were conducted at GSR, a specialty surgical center located in Hyderabad, India. Patients and Participants All patients who presented to GSR with either cleft lip, cleft palate, or cleft lip and palate at the time of this study were included. Results Of the 23 families interviewed, 12 mothers believed the cleft was caused by an eclipse, and two believed the scientific explanation their physician offered. Fourteen families were offered no explanation for the cleft lip and/or palate at the time of their first physician visit. No families practiced non-Western methods for treatment of the cleft. One family identified beliefs held in the community that their child with a cleft lip was bad luck. Conclusion A commonly held belief in this community in India is that cleft lip, cleft palate, or cleft lip and palate are caused by an eclipse. Physicians appear to be providing families with insufficient education on cleft impairments. Data generated from studies similar to this can be used to design educational protocols that address this gap in community understanding of orofacial clefting.

Item does not contain fulltext BACKGROUND: Improving hand hygiene compliance is still a major challenge for most hospitals. Innovative approaches are needed. OBJECTIVE: We tested whether an innovative, theory based, team and leaders-directed strategy would be more effective in increasing hand hygiene compliance rates in nurses than a literature based state-of-the-art strategy. DESIGN AND SETTING: A cluster randomised controlled trial called HELPING HANDS was conducted in 67 nursing wards of three hospitals in the Netherlands. PARTICIPANTS: All affiliated nurses of the nursing wards. Wards were randomly assigned to either the team and leaders-directed strategy (30 wards) or the state-of-the-art strategy (37 wards). METHODS: The control arm received a state-of-the-art strategy including education, reminders, feedback and targeting adequate products and facilities. The experimental group received all elements of the state-of-the-art strategy supplemented with interventions based on social influence and leadership, comprising specific team and leaders-directed activities. Strategies were delivered during a period of six months. We monitored nurses' HH compliance during routine patient care before and directly after strategy delivery, as well as six months later. Secondary outcomes were compliance with each type of hand hygiene opportunity, the presence of jewellery and whether the nurses wore long-sleeved clothes. The effects were evaluated on an intention-to-treat basis by comparing the post-strategy hand hygiene compliance rates with the baseline rates. Multilevel analysis was applied to compensate for the clustered nature of the data using mixed linear modelling techniques. RESULTS: During the study, we observed 10,785 opportunities for appropriate hand hygiene in 2733 nurses. The compliance in the state-of-the-art group increased from 23% to 42% in the short term and to 46% in the long run. The hand hygiene compliance in the team and leaders-directed group improved from 20% to 53% in the short term and remained 53% in the long run. The difference between both strategies showed an Odds Ratio of 1.64 (95% CI 1.33-2.02) in favour of the team and leaders-directed strategy. CONCLUSIONS: Our results support the added value of social influence and enhanced leadership in hand hygiene improvement strategies. The methodology of the latter also seems promising for improving team performance with other patient safety issues. TRIAL REGISTRATION: ClinicalTrials.gov [NCT00548015].

Contains fulltext : 118394.pdf (Publisher’s version ) (Closed access) BACKGROUND: Revision antireflux surgery and large hiatal hernia repair require extensive dissection at the gastroesophageal junction. This may lead to troublesome symptoms due to delayed gastric emptying, eventually requiring gastrectomy. The aim of this study was to evaluate the outcome of gastrectomy for severely delayed gastric emptying after large hiatal hernia repair or redo antireflux surgery. METHODS: Eleven patients were treated between 1995 and 2010 and entered in the study. Preoperative and operative data were retrospectively collected. Standardized questionnaires were sent to all of the patients to evaluate symptomatic outcome. RESULTS: The primary intervention was Nissen fundoplication in nine patients, Toupet fundoplication in one, and cruroplasty in another. The repairs were for refractory gastroesophageal reflux disease in five patients and a symptomatic large hiatal hernia in six. Subsequent gastrectomy was partial in four patients, subtotal in six, and total in one. There was one minor postoperative complication. After a mean (+/-SD) duration of 102 +/- 59 months, nine patients were available for symptomatic follow-up. Eight patients experienced daily symptoms related to dumping. Daily symptoms indicative of delayed gastric emptying were present in seven patients at follow-up. Mean general quality of life was increased from 3.8 +/- 2.2 before gastrectomy to 5.4 +/- 1.8 at follow-up. Eight patients reported gastrectomy as worthwhile. CONCLUSION: Gastrectomy after previous antireflux surgery or large hiatal hernia repair is safe with the potential to improve quality of life. Although upper gastrointestinal symptoms tend to persist, gastrectomy can be considered a reasonable, last-resort surgical option for alleviating upper gastrointestinal symptoms after this kind of surgery.

Item does not contain fulltext Interest is rising in measuring subjective health outcomes, such as treatment outcomes that are not directly quantifiable (functional disability, symptoms, complaints, side effects and health-related quality of life). Health economists in particular have applied probabilistic choice models in the area of health evaluation. They increasingly use discrete choice models based on random utility theory to derive values for healthcare goods or services. Recent attempts have been made to use discrete choice models as an alternative method to derive values for health states. In this article, various probabilistic choice models are described according to their underlying theory. A historical overview traces their development and applications in diverse fields. The discussion highlights some theoretical and technical aspects of the choice models and their similarity and dissimilarity. The objective of the article is to elucidate the position of each model and their applications for health-state valuation.

Item does not contain fulltext BACKGROUND: Caesarean section rates are increasing worldwide, and the long-term effects are unknown. OBJECTIVE: To evaluate the risk of subsequent ectopic pregnancy in women with a previous caesarean section, compared with vaginal delivery. SEARCH STRATEGY: Systematic review of the literature using CINAHL, the Cochrane Library, Embase, Medline, PubMed, SCOPUS and Web of Knowledge, published from 1945 until 17 July 2011. SELECTION CRITERIA: Cohort and case-control designs reporting on the mode of delivery and subsequent ectopic pregnancy. Two reviewers independently assessed the titles, abstracts, and full articles to identify eligible studies, using a standardised data collection form, and also assessed the study quality. Reference lists of the studies included were also cross-checked. DATA COLLECTION AND ANALYSIS: Odds ratios (ORs) were combined using a random-effect model to estimate the overall association between caesarean section delivery and the risk of subsequent ectopic pregnancy. MAIN RESULTS: Thirteen studies were included, which recruited a total of 61,978 women. Five studies reported adjustment for confounding factors, and the pooled OR of subsequent ectopic pregnancy following a caesarean section was 1.05 (95% CI 0.51-2.15). The removal of one study that reported outlier results yielded a pooled OR of 0.82 (95% CI 0.42-1.61). The pooled crude OR for all 13 studies was 1.36 (95% CI 0.99-1.88). AUTHOR'S CONCLUSIONS: This review found no evidence of an association between prior caesarean section delivery and the occurrence of a subsequent ectopic pregnancy, but the studies included were of poor or variable quality, and only a small number adjusted for potential confounding factors. Further research of a higher methodological quality is required to assess any potential association between mode of delivery and subsequent ectopic pregnancy.

Summary Objective To evaluate the correlation between symmetry of the craniofacial skeleton and aesthetics of the nose and upper lip in children with complete unilateral cleft lip and palate (CUCLP). Material and methods Craniofacial symmetry was evaluated on postero-anterior (PA) cephalograms of 54 children (37 boys and 17 girls; mean age = 11.0 years, SD 1.6) with CUCLP repaired with a one-stage closure ( Cleft group). Treated subjects were age- and gender-matched with 54 untreated subjects taken from the University of Michigan Growth Study ( Control group). Fourteen coefficients of asymmetry (CAs) were calculated and four angles were measured. Four raters assessed the nasolabial appearance on cropped facial and profile photographs with the 5-grade aesthetic index of Asher-McDade (grade 1 means the most aesthetic and grade 5 the least aesthetical outcome) in the Cleft group only. Independent t -tests were used to evaluate the inter-group differences for CAs. Pearson's correlation coefficients were calculated to examine a relationship between particular components of the aesthetical index and CAs. Multiple regression analyses were carried out to explain the nasolabial aesthetics on the basis of craniofacial symmetry. Results In the Cleft group, most cephalometric variables demonstrated asymmetry not exceeding 10%. The Cleft and Control groups differed regarding three angular measurements ( Se , Ism , and ANS ) and 1 CA ( Mo-V ). Three of the four nasolabial components demonstrated correlation with some cephalometric variables. However, the correlation coefficients were low (range: –0.309 to 0.305). Conclusions There is a weak correlation between craniofacial skeletal symmetry and aesthetics of the nose and upper lip in children with CUCLP.

Item does not contain fulltext To investigate the so-called "drift" with generic-generic drug substitution, a single-dose, four-way crossover comparative bioavailability study was performed involving 24 healthy subjects and three generic and one branded formulation of a tablet containing 800 mg gabapentin as test medication. The results showed that the 90% confidence intervals (CIs) for the area under the drug concentration-time curve (AUC0-t) and for the peak drug concentration (Cmax) were within the acceptance range of 80-125% for all comparisons. The safety profiles of the different gabapentin formulations were comparable. To conclude, all three generic formulations of gabapentin were found to be bioequivalent with the branded formulation and with each other, indicating that the formulations are interchangeable. These results strongly indicate the absence of "drift" with gabapentin generic-generic substitution.Clinical Pharmacology & Therapeutics (2013); 94 4, 519-524. doi:10.1038/clpt.2013.108.

Item does not contain fulltext OBJECTIVE AND METHODS: In the diagnostic work-up of patients suspected of a dural arteriovenous fistula (dAVF), imaging has a key role in order to diagnose the dAVF, assess its bleeding risk and choose optimal treatment strategy. Digital subtraction angiography (DSA) is the gold standard for the most detailed image of a dAVF. Nowadays four-dimensional CT angiography (4D-CTA) could possibly be an additional first-line tool in the work-up of a patient suspected of a dAVF. We describe three cases clinically suspected of a dAVF which had a diagnostic work-up with 4D-CTA as well as DSA. We evaluated the angioarchitecture of the dAVF both on 4D-CTA and DSA, with emphasis on the patterns of venous drainage as this is important in assessing the bleeding risk of a dAVF. RESULTS AND CONCLUSION: 4D-CTA identified the dAVF, revealed its angioarchitecture and correctly differentiated different patterns of venous drainage (Borden type I, II and III) as confirmed on DSA. Although DSA has the advantage of higher spatial and temporal resolution, 4D-CTA seems to be a new useful non-invasive tool in the diagnostic work-up of a patient suspected of a dAVF.

Item does not contain fulltext Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans. (c) 2013 Wiley Periodicals, Inc.

Contains fulltext : 119214.pdf (Publisher’s version ) (Closed access)

The aim of this study was to design mandibular ramal height growth curves for patients with HFM and compare those with the curves for a Dutch reference population. Two hundred fifty-one pre-operative orthopantomograms (OPTs) from 84 patients with unilateral HFM were used in conjunction with a control set of 2260 OPTs from 329 healthy individuals from the Nijmegen Growth Study (NGS) to determine mandibular ramal distances. For grades I/IIa and IIb/III, and for both sides, growth curves were constructed for mandibular ramal height with a linear curve-fitting procedure. This procedure revealed a significant difference between HFM patients and the NGS control group (p < 0.001); both in the mild and severe group mandibular ramal height differed significantly between the affected and non-affected side (p < 0.001). Growth was similar between HFM patients and the NGS control group. HFM patients therefore start with a smaller mandible and end with a smaller mandible, but experience growth similar to the Dutch normal population. These growth curves may aid the timing and determination of the combined surgical orthodontic treatment plan for HFM patients. (C) 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Item does not contain fulltext Postural instability, recurrent falls and fear of falling are common in advanced Parkinson's disease (PD). We examined the impact of fall frequency, fear of falling, balance confidence and objectively measured balance impairment (using Tinetti's Mobility Index) on health-related quality of life (HrQoL) in PD. In 74 subjects HrQoL was assessed using the 39-item Parkinson's disease Quality of Life Questionnaire [PDQ-39]. Patients were interviewed using a validated falls questionnaire, addressing fall history, consequences of falls and fear of falling. Neurological examination included Hoehn and Yahr scale, the Unified Parkinson's disease Rating Scale and Tinetti's Mobility Index. Disease severity, age and gender explained 43% of the differences in HrQoL across patients (R2 = 0.43). The combination of these factors and each of the factors fear of falling, balance confidence and fall frequency lead to 55%, 50% and 45% of explained variation, respectively. The standardised regression coefficients of these risk factors were 0.34 (fear of falling), 0.28 (balance confidence) and 0.13 (fall frequency). This suggests that fear of falling is a more important determinant of HrQoL than actual falling. These results emphasise the importance of addressing fear of falling in the clinical management of PD, and the need for development of strategies to reduce fear of falling in intervention programs.

Item does not contain fulltext BACKGROUND: Tumour necrosis factor (TNF)-inhibiting therapy increases the risk of serious infections in rheumatoid arthritis (RA). However, it is not clear whether this risk differs between TNF inhibitors. OBJECTIVE: To analyse whether the risk of serious infections in patients with RA treated with an anti-TNF inhibitor is different for adalimumab, infliximab and etanercept. METHODS: Data from the Dutch RA monitoring registry were used. Incidence rates were calculated from the observed number of first serious infections and follow-up time up to 5 years. A Cox proportional hazards model with time-to-first-serious infection was used to estimate risk differences among the anti-TNF treatment groups, with correction for confounders. RESULTS: The unadjusted incidence rate of a first serious infection in patients with RA per 100 patient-years was 2.61 (95% CI 2.21 to 3.00) for adalimumab, 3.86 (95% CI 3.33 to 4.40) for infliximab and 1.66 (95% CI 1.09 to 2.23) for etanercept. Age, year of starting anti-TNF therapy, comorbidities at baseline and disease activity score 28 over time were included as confounders. No difference in risk for serious infections was found between adalimumab and infliximab with an adjusted HR (adjHR) of 0.90 (95% CI 0.55 to 1.48). The risk of serious infections was significantly lower in etanercept than in both infliximab (adjHR=0.49 (95% CI 0.29 to 0.83)) and adalimumab (adjHR=0.55 (95% CI 0.44 to 0.67)). CONCLUSIONS: The risk of serious infections in patients with RA treated with adalimumab or infliximab was similar, while the risk of serious infections in patients with RA treated with etanercept was lower than with both adalimumab and infliximab.

Contains fulltext : 117935.pdf (Publisher’s version ) (Closed access) OBJECTIVE: : To estimate whether a strategy of immediate surgery was noninferior to a strategy based on discordant urodynamic findings followed by individually tailored therapy in women with stress urinary incontinence (SUI). METHODS: : A multicenter diagnostic cohort study with an embedded noninferiority randomized controlled trial was conducted in six academic and 24 nonacademic Dutch hospitals. Women with predominant SUI eligible for surgical treatment based on clinical assessment were included between January 2009 and November 2010. All patients underwent urodynamics. In patients in whom urodynamics were discordant with clinical assessment, participants were randomly allocated to receive either immediate surgery or individually tailored therapy based on urodynamics. The primary outcome was clinical improvement assessed by the Urogenital Distress Inventory 12 months after baseline. Analysis was by intention to treat; a difference in mean improvement of 5 points or less was considered noninferior. RESULTS: : Five hundred seventy-eight women with SUI were studied, of whom 268 (46%) had discordant findings. One hundred twenty-six patients gave informed consent for randomization and were allocated to receive immediate surgery (n=64) or individually tailored therapy (n=62). The mean improvement measured with the Urogenital Distress Inventory after 1 year was 44 points (+/-24) in the group receiving immediate surgery and 39 (+/-25) points in the group receiving individually tailored treatment. The difference in mean improvement was 5 points in favor of the group receiving immediate surgery (95% confidence interval -infinity to 5). There were no differences with respect to cure or complication rate. CONCLUSION: : In women with uncomplicated SUI, an immediate midurethral sling operation is not inferior to individually tailored treatment based on urodynamic findings. CLINICAL TRIAL REGISTRATION: : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00814749. LEVEL OF EVIDENCE: : I.

Item does not contain fulltext Dental development does not end with the shedding of the deciduous dentition. Partly as a result of the continuing facial growth up to adulthood, adaptations in the position of the teeth and the occlusion occur after the second phase of eruption. The dissertation Gebissentwicklung und Gesichtswachstum in der Adoleszenz, from 1988, was concerned with research into tooth development, facial growth and their interrelationship during the first decade after the second phase of tooth eruption. Changes in the dental arches go together with changes in the occlusion. These physiological changes in the dentition can largely be attributed to the shift of the mandibular dental arch to a more ventral position, with respect to the maxillary dental arch. Facial growth and changes in the morphology of the craniofacial skeleton up to adulthood are especially a result of adaptations which take place under the floor of the nose and as a result of the enlargement of the mandible. Later research in patients up to the age of approximately 40 years, revealed that these dental and skeletal changes continued to occur.

Contains fulltext : 119123.pdf (Publisher’s version ) (Open Access) OBJECTIVE: This study evaluates whether a sedentary lifestyle is an independent predictor for increased mortality after elective cardiac surgery. METHODS: Three thousand one hundred fifty patients undergoing elective cardiac surgery between January 2007 and June 2012 completed preoperatively the Corpus Christi Heart Project questionnaire concerning physical activity (PA). Based on this questionnaire, 1815 patients were classified as active and 1335 patients were classified as sedentary. The endpoints of the study were hospital mortality and early mortality. RESULTS: The study population had a mean age of 69.7 +/- 10.1 (19-95) years and a mean logistic EuroSCORE risk of 5.1 +/- 5.6 (0.88-73.8). Sedentary patients were significantly older (p = 0.001), obese (p = 0.001), had a higher EuroSCORE risk (p = 0.001), and a higher percentage of complications. Hospital mortality (1.1 % versus 0.4 % (p = 0.014)) and early mortality (1.5 % versus 0.6 % (p = 0.006)) were significantly higher in the sedentary group compared with the active group. However, a sedentary lifestyle was not identified as an independent predictor for hospital mortality (p = 0.61) or early mortality (p = 0.70). CONCLUSION: Sedentary patients were older, obese and had a higher EuroSCORE risk. They had significantly more postoperative complications, higher hospital mortality and early mortality. Despite these results, sedentary behaviour could not be identified as an independent predictor for hospital or early mortality.

Item does not contain fulltext Background: To increase effectiveness of standard adalimumab treatment 40 mg every other week (EOW) for patients with psoriasis, dose escalation to 40 mg every week or addition of methotrexate (MTX) are possible strategies. Methods: Daily practice data about adalimumab treatment were extracted from a prospective observational cohort. We analyzed all patients with insufficient efficacy of adalimumab EOW who received 1) adalimumab dose escalation, 2) addition of MTX to adalimumab EOW, or 3) both. Effectiveness was analyzed after 12 and 24 weeks using PASI50, PASI75, and mean differences in PASI. Results: Forty-seven treatment episodes (TE) of adalimumab dose escalations, 11 of MTX addition and six combinations were analyzed. After a first episode of adalimumab dose escalation, 25% and 35% achieved PASI50 after 12 and 24 weeks, respectively. After MTX introduction to adalimumab EOW, 9% and 18% achieved PASI50 after 12 and 24 weeks, respectively. No related serious adverse events were reported. Conclusions:Twenty-five percent of first TE with adalimumab dose escalation induced a PASI50 response after 12 weeks and 35% after 24 weeks. Addition of MTX to adalimumab EOW resulted in PASI50 in 9% after 12 weeks and 18% after 24 weeks. Defining patient-groups that will benefit from these interventions is important.

Contains fulltext : 118928.pdf (Publisher’s version ) (Closed access) BACKGROUND: Primary vitreous floaters can be highly bothersome in some patients. In the case of persistently bothersome floaters, pars plana vitrectomy may be the most effective treatment. The aim of this study is to evaluate the incidence of complications, and patient satisfaction, after pars plana vitrectomy for disabling primary vitreous opacities. METHODS: We included a total of 110 eyes that underwent pars plana vitrectomy between February 1998 and August 2010. Fifty-seven eyes (51.8%) underwent 20-gauge vitrectomy, whereas 53 eyes (48.2%) underwent 23-gauge vitrectomy. In a retrospective manner, we assessed intraoperative and postoperative complications. There was a considerable range of time between surgery and questionnaire (range: 4-136 months). Patient satisfaction was assessed by a questionnaire based on a modified NEI VFQ-25 questionnaire. RESULTS: A retinal detachment occurred in 10.9% of cases, and the incidence did not differ significantly between the 20-gauge and 23-gauge vitrectomy groups. In 4.5% of the eyes, a retinal detachment developed within the first 3 months, and 6.4% occurred later in the postoperative period. Cystoid macular edema occurred in 5.5%, and an epiretinal membrane was seen postoperatively in 3.6% of cases. Development of glaucoma requiring glaucoma surgery, a macular hole, and postoperative scotoma, each occurred in 0.9% of cases. No cases of endophthalmitis occurred. Eighty-five percent of patients were satisfied or very satisfied with the results of the vitrectomy. Eighty-four percent of all patients were completely cured from their troublesome vitreous floaters, and an additional 9.3% of patients were less troubled by vitreous floaters. Ten patients (9.3%) were dissatisfied, and six of these patients (5.6%) had a serious complication that resulted in permanent visual loss. CONCLUSIONS: Pars plana vitrectomy is an effective approach to treat primary vitreous floaters, resulting in a high rate of patient satisfaction. Postoperative complications may be more frequent than previously reported, so patients should be well-informed about the complication rate before reaching informed consent about this surgical intervention. Additional preventive measures should be considered to reduce this complication rate.

Contains fulltext : 117870.pdf (Publisher’s version ) (Closed access) BACKGROUND: To warrant the adoption or rejection of health care interventions in daily practice, it is important to establish the point at which the available evidence is considered sufficiently conclusive. This process must avoid bias resulting from multiple testing and take account of heterogeneity across studies. The present paper addresses the issue of whether the available evidence may be considered sufficiently conclusive to continue or discontinue the current practice of postoperative abdominal drainage after pancreatic resection. METHODS: A systematic review was conducted of randomized and non-randomized studies comparing outcomes after routine intra-abdominal drainage with those after no drainage after pancreatic resection. Studies were retrieved from the PubMed, Cochrane Central Trial Register and EMBASE databases and meta-analysed cumulatively, adjusting for multiple testing and heterogeneity using the iterated logarithm method. RESULTS: Three reports, describing, respectively, one randomized and two non-randomized studies with a comparative design, met the inclusion criteria predefined for primary studies reporting on drain management and complications after pancreatic resection. These studies included 89, 179 and 226 patients, respectively. The absolute differences in rates of postoperative complications in these studies were -6.4%, -9.5% and -6.3%, respectively, in favour of the no-drain groups. The cumulative risk difference in major complications, adjusted for multiple testing and heterogeneity, was -7.8%, with a 95% confidence interval of -20.2% to 4.7% (P = 0.214). CONCLUSIONS: The routine use of abdominal drains after pancreatic resection may result in a higher risk for major complications, but the evidence is inconclusive.

Item does not contain fulltext BACKGROUND: The purpose of this study is to assess the valgus and varus laxity of the unlinked version of the Latitude total elbow prosthesis and the effects of radial head preservation or replacement. METHODS: Biomechanical analysis of the valgus and varus laxity of the unlinked Latitude was performed in fourteen upper limb specimens in the following conditions: (1) native elbow, (2) native elbow after the surgical approach and closing all layers again, (3) elbow with humeral and ulnar component implanted, unlinked, with the native radial head preserved, (4) elbow with humeral and ulnar component implanted, unlinked, with the native radial excised, (5) elbow with humeral, ulnar, and radial head component implanted. FINDINGS: After implantation of the Latitude total elbow prosthesis both the valgus and varus laxity slightly increase from mid to maximal flexion when compared to the native elbow after surgical approach. The unlinked Latitude total elbow prosthesis provides both valgus and varus stability in elbows with intact ligamentous constraints. With intact ligamentous constraints the radial head component only slightly contributes to the stability of the elbow after implantation of the unlinked Latitude total elbow prosthesis. INTERPRETATION: The unlinked Latitude total elbow prosthesis provides both valgus and varus stability in elbows with intact ligamentous constraints. The radial head component contributes only slightly to the stability. 01 juni 2013

Item does not contain fulltext OBJECTIVE: To evaluate the effectiveness of primary stapes surgery with and without a vein graft in patients with otosclerosis and to determine the differences in the postoperative gain in air-bone gap (ABG) and air-conduction (AC). STUDY DESIGN: A nonrandomized multicenter clinical evaluation. SETTING: Two tertiary referral centers in The Netherlands and France. PATIENTS: Otosclerosis patients that underwent primary stapedotomy surgery. INTERVENTION: Primary stapedotomy surgery without a vein graft (n = 939, first center) compared with primary stapedotomy surgery with a vein graft (n = 3691, second center). MAIN OUTCOME MEASURES: Preoperative and postoperative audiometric results were compared. An analysis of variance was performed to evaluate differences in postoperative ABG and AC gains between surgeries with and without a vein graft, adjusted for potential confounders. RESULTS: The postoperative ABG was 10 dB or lesser in 72.1% of the patients without a vein graft and in 93.2% of patients with a vein graft. After adjustments for differences at baseline, the mean gain in ABG was 18.6 dB (95% CI, 18.1-19.1) in the group without vein graft, compared with 24.2 dB (95% CI, 23.9-24.6) in the group with vein graft (mean difference, 5.6 dB; 95% CI, 5.0-6.2). The mean gain in AC was 19.5 dB (95% CI, 18.7-20.3) in the group without vein graft, compared with 24.3 dB (95% CI, 23.7-24.7) in the group with vein graft (mean difference, 4.8 dB; 95% CI, 3.8-5.7). CONCLUSION: Patients with otosclerosis undergoing primary stapes surgery may benefit more from a vein graft interposition. LEVEL OF EVIDENCE: 2B.

To determine the incidence of bowel injury in operations requiring adhesiolysis and to assess the impact of adhesiolysis on the incidence of surgical complications, postoperative morbidity, and costs.Morbidity of adhesiolysis during abdominal surgery seems an important health care problem, but the direct impact of adhesiolysis on inadvertent organ damage, morbidity, and costs is unknown.In a prospective cohort study, detailed data on adhesiolysis were gathered by direct observation during elective abdominal surgery. Comparison was made between surgical procedures with and without adhesiolysis on the incidence of inadvertent bowel defects. Secondary outcomes were the effect of adhesiolysis and bowel injury on surgical complications, other morbidity, and costs.A total of 755 (out of 844) surgeries in 715 patients were included. Adhesiolysis was required in 475 (62.9%) of operations. Median adhesiolysis time was 20 minutes (range: 1-177). Fifty patients (10.5%) undergoing adhesiolysis inadvertently incurred bowel defect, compared with 0 (0%) without adhesiolysis (P0.001). In univariate and multivariate analyses, adhesiolysis was associated with an increase of sepsis incidence [odds ratio (OR): 5.12; 95% confidence interval (CI): 1.06-24.71], intra-abdominal complications (OR: 3.46; 95% CI: 1.49-8.05) and wound infection (OR: 2.45; 95% CI: 1.01-5.94), longer hospital stay (2.06 ± 1.06 days), and higher hospital costs [$18,579 (15,204-21,954) vs $14,063 (12,471-15,655)]. Mortality after adhesiolysis complicated by a bowel defect was 4 out of 50 (8%), compared with 7 out of 425 (1.6%) after uncomplicated adhesiolysis (OR: 5.19; 95% CI: 1.47-18.41).Adhesiolysis and inadvertent bowel injury have a large negative effect on the convalescence after abdominal surgery. The awareness of adhesion-related morbidity during reoperation and the prevention of postsurgical adhesion deserve priority in research and clinical practice.

Background Chronic abdominal pain is common in chronic pancreatitis (CP) and may involve altered central pain processing. This study evaluated the relationship between pain processing and pain outcome after pancreatic duct decompression and/or pancreatic resection in patients with CP. Methods Patients with CP underwent quantitative sensory testing. Pain processing was measured via electrical pain detection (ePDT) and electrical pain tolerance (ePTT) thresholds in dermatomes C5 and L4. Inhibitory descending pain control mechanisms were assessed using the conditioned pain modulation (CPM) paradigm. Healthy controls and patients with CP were compared, and patients with CP and a poor pain outcome (visual analogue scale (VAS) score greater than 30) were compared with those with a good pain outcome (VAS score 30 or less). Results Forty-eight patients with CP had lower ePDT, ePTT and CPM responses compared with values in 15 healthy controls (P < 0·030). The sum of ePDT values was lower in patients with a poor pain outcome than in those with a good outcome (median 7·1 versus 11·2 mA; P = 0·008). There was a correlation with the VAS score and the sum of ePDT values (rs = −0·45, P = 0·016) and ePTT values (rs = −0·46, P = 0·011), and CPM response (rs = −0·43, P = 0·006) in patients with CP. Conclusion After pain-relieving pancreatic surgery, patients with CP exhibit altered central pain processing compared with that in healthy controls. Poor pain outcomes are associated with more central sensitization and more pronociceptive descending pain modulation, and this should be considered when managing persistent pain after pain-relieving surgery for CP. Presented in part to the 7th Alpine Liver and Pancreatic Surgery Meeting, Madonna di Campiglio, Italy, January 2012, and the American Pancreatic Association/International Association of Pancreatology Joint Annual Meeting, Miami, Florida, USA, October–November 2012; published in abstract form as Pancreas 2012; 41: 1350

Background Ileal pouch–anal anastomosis (IPAA) is considered the surgical treatment of choice for patients with ulcerative colitis. Quality of life (QoL) and health status are the most important patient-related outcomes. Studies investigating QoL are often cross-sectional and focus on health status. This longitudinal study evaluated QoL and health status after IPAA for ulcerative colitis and compared these with reference data from a healthy population. Methods Patients with ulcerative colitis who underwent a pouch operation between 2003 and 2008 completed validated questionnaires for QoL and health status. Questionnaires were completed before pouch surgery, and 6, 12, 24 and 36 months after operation. The effect of IPAA on QoL and health status was analysed, and data were compared with reference values from the healthy Dutch population. Results Data were obtained for 30 of the 32 patients. Six months after IPAA, QoL was at least comparable with that of the reference population in four of six domains. Twelve months after IPAA, overall QoL had improved, supported by findings in three QoL domains. Six months after IPAA, health status was comparable to that of the reference population in three of eight dimensions, and after 3 years it was at least comparable in five dimensions. Conclusion QoL and health status increased after IPAA and reached levels comparable with those of the healthy reference population in a majority of domains and dimensions. QoL was restored first after IPAA, followed by health status.

Item does not contain fulltext Mechanical ventilation is frequently used in patients under general anesthesia during invasive procedures. Invasive animal experiments similarly require the maintenance of normal hemodynamic and pulmonary parameters during long-term general anesthesia. The authors describe a method for mechanical ventilation of mice. Mice were ventilated and monitored for up to 8 h of general anesthesia during surgery. Hemodynamic and pulmonary parameters remained within the normal ranges. The authors believe that this ventilation technique can be of great value for experimental procedures in mice that require general anesthesia.

Item does not contain fulltext OBJECTIVE: Our aim was to assess cost-effectiveness of mindfulness-based cognitive therapy (MBCT) compared with enhanced usual care (EUC) in treating patients with persistent medically unexplained symptoms(MUS). METHODS: A full economic evaluation with a one year time horizon was performed from a societal perspective. Costs were assessed by prospective cost diaries. Health-related Quality of Life was measured using SF-6D. Outcomes were costs per Quality-Adjusted Life Year (QALY). Bootstrap simulations were performed to obtain mean costs, QALY scores and incremental cost-effectiveness ratios (ICERs). RESULTS: MBCT participants (n=55) had lower hospital costs and higher mental health care costs than patients who received EUC (n=41). Mean bootstrapped costs for MBCT were euro6269, and euro5617 for EUC (95% uncertainty interval for difference: -euro1576; euro2955). QALYs were 0.674 for MBCT and 0.663 for EUC. MBCT was on average more effective and more costly than EUC, resulting in an ICER of euro56,637 per QALY gained. At a willingness to pay of euro80,000 per QALY, the probability that MBCT is cost-effective is 57%. CONCLUSION: Total costs were not statistically significantly different between MBCT and EUC. However, MBCT seemed to cause a shift in the use of health care resources as mental health care costs were higher and hospital care costs lower in the MBCT condition. Due to the higher drop-out in the EUC condition the cost-effectiveness of MBCT might have been underestimated. The shift in health care use might lead to more effective care for patients with persistent MUS. The longer-term impact of MBCT for patients with persistent MUS needs to be further studied.

Item does not contain fulltext The scientific literature is sparse on reports that evaluate facial asymmetry after mandibular reconstructive surgery objectively. The aim of this study is to introduce and validate a new method, using three dimensional (3D) stereophotogrammetry, that quantifies soft-tissue facial asymmetry in patients who have undergone mandibular reconstruction. To validate the new method, two observers applied the method on 3D photographs of five patients and five controls. An inter-observer difference of 0.04 mm (-0.08 to 0.17) was found with a measurement error of 0.13 mm. 15 3D photographs of the mandibular reconstructed patients were compared with 24 3D photographs of healthy controls. A significant difference (1.19 mm) in asymmetry was found between patients and controls. It is concluded that this new measuring method is a valid, fast and clinically applicable technique to quantify soft-tissue facial asymmetry. It is concluded that facial symmetry in patients is not restored to the level of the control group with the mandibular reconstruction method applied.

Contains fulltext : 127317.pdf (Publisher’s version ) (Closed access) Dysphagia is reported in advanced stages of Duchenne muscular dystrophy (DMD). The population of DMD is changing due to an increasing survival. We aimed to describe the dysphagia in consecutive stages and to assess the underlying mechanisms of dysphagia in DMD, in order to develop mechanism based recommendations for safe swallowing. In this cross-sectional study, participants were divided into: early and late ambulatory stage (AS, n = 6), early non-ambulatory stage (ENAS, n = 7), and late non-ambulatory stage (LNAS, n = 11). Quantitative oral muscle ultrasound was performed to quantify echo intensity. Swallowing was assessed with a video fluoroscopic swallow study, surface electromyography (sEMG) of the submental muscle group and tongue pressure. Differences in outcome parameters among the three DMD stages were tested with analysis of variance. Oral muscles related to swallowing were progressively affected, starting in the AS with the geniohyoid muscle. Tongue (pseudo) hypertrophy was found in 70 % of patients in the ENAS and LNAS. Oral phase problems and post-swallow residue were observed, mostly in the LNAS with solid food. sEMG and tongue pressure data of swallowing solid food revealed the lowest sEMG amplitude, the longest duration and lowest tongue pressure in the LNAS. In case of swallowing problems in DMD, based on the disturbed mechanisms of swallowing, it is suggested to (1) adjust meals in terms of less solid food, and (2) drink water after meals to clear the oropharyngeal area.

Item does not contain fulltext OBJECTIVE: The introduction of effective treatment strategies in the past two decades has changed the management of RA dramatically. The objective was to analyse the changes in disease activity, function, joint damage and incidence of orthopaedic surgery over a period of 20 years (1989-2009) for patients with RA. METHODS: Data acquired from 1989 to 2008 inclusive from the Nijmegen RA inception cohort were studied. By repeated measures analysis the course of the population mean disease activity score (DAS28) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) corrected for age, gender, RF and disease duration was determined. Orthopaedic interventions were analysed as incidence rates with a Poisson distribution. We calculated the prevalence of the various therapies that patients were receiving. RESULTS: By 2009, 992 patients with RA had been included and 273 had been excluded. From 1989 onwards, the proportion of patients using MTX increased from 5% (8 of 164) to 62% (486 of 780), and biologic response modifiers from 0% to 22% (168 of 780) in 2008. The average MTX dosage increased to 16.1 +/- 5.5 mg/week in 2008. The mean DAS28 (3.1) and HAQ-DI (0.47) were least (P < 0.008) in 2008 compared with previous years. There was a significant trend towards lower incidence rates of orthopaedic intervention in the period 2006-2008 than in almost all previous years. CONCLUSION: Treatment strategy changed in a large inception cohort of patients with RA which coincided with decreased disease activity, increased functional ability and fewer orthopaedic interventions since the early 1990s.

Contains fulltext : 118353.pdf (Publisher’s version ) (Closed access) 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. (c) 2012 Movement Disorder Society.

Item does not contain fulltext During the last phase of spermatogenesis, called spermiogenesis, the nucleosome-based chromatin structure is replaced by a protamine-based DNA packaging. Not much is known about the chromatin remodelling involved in humans and animals. Here, we have investigated initiation of chromatin remodelling over seven probands of which five were diagnosed with non-obstructive azoospermia (NOA) and two with obstructive azoospermia (OA) (failed vaso-vasostomy patients with proven fertility prior to vasectomy, Johnsen scores >/=9). Chromatin remodelling was studied evaluating the presence of nucleosomes, histone H3, pre-protamine 2 and protamine 1. This approach was feasible since the local initiation of nucleosome eviction in the sub acrosomal domain, which was visible in alkaline nuclear spread preparations. The patterns of nucleosome and H3 loss were largely congruent. Nucleus wide incorporation of protamine 1 could already be observed at the late round spermatid stage. Both for nucleosome loss and for protamine 1 incorporation, there was distinct variation within and between probands. This did not relate to the efficiency of sperm production per meiocyte. Pre-protamine 2 was always confined to the subacrosomal domain, confirming the role of this area in chromatin remodelling.

Item does not contain fulltext This study aimed to assess the effects of bone-borne and tooth-borne surgically assisted rapid maxillary expansion on the volumes of the nose and nasal airway 2 yr after maxillary expansion. This prospective cohort study included 32 patients with transverse maxillary hypoplasia. Expansion was performed with a tooth-borne distractor (Hyrax) in 19 patients and with a bone-borne distractor [transpalatal distractor (TPD)] in the remaining 13. Cone beam computed tomography scans and three-dimensional (3D) photographs of the face were acquired before treatment and 22 +/- 7 months later, and were used to evaluate the volumes of the nose and nasal airway. Nasal volume increased by 1.01 +/- 1.6% in the Hyrax group and by 2.39 +/- 2.4% in the TPD group. Nasal airway volume increased by 9.7 +/- 5.6% in the Hyrax group and by 12.9 +/- 12.7% in the TPD group. Changes in the nasal volume and in the nasal airway volume between the pre- and post-treatment measurements were statistically significant, whereas differences between the treatment groups were not; 22 months after surgically assisted rapid maxillary expansion, the increases in the nasal volume and in the nasal airway volume were comparable between tooth-borne and bone-borne devices.

Background and Purpose— In patients harboring intracranial aneurysms, the major goal in treatment is to prevent bleeding. A new generation of an endoluminal device (Surpass Flow Diverter [Surpass]) was developed to reconstruct parent artery and occlude the aneurysm. We present our clinical and angiographic single-center experience. Methods— Patients with a wide range of complex unruptured aneurysms were treated with the Surpass placed in the parent artery and bridging the aneurysm. Clinical and angiographic follow-up were performed at 6 months. Data were prospectively collected. Results— Thirty seven patients (mean age, 56 years; range, 32–79), harboring 49 unruptured aneurysms were treated at our center. All except 1 patient were treated with a single device. Successful delivery of the device was achieved in all patients. All 35 nonbifurcation aneurysm necks were covered completely, whereas 14 bifurcation aneurysms were only partially covered. There was no major periprocedural morbidity or mortality. During follow-up, 4 patients (10.4%) experienced transient neurological deficit. One patient (3%) developed a minor stroke at 4-month follow-up with persistent neurological deficit. Twelve patients had neurological symptoms related to their aneurysm and 7 showed improvement of these symptoms during follow-up. At 6-month follow-up, 29 of 31 aneurysms studied that had complete neck coverage showed a complete occlusion (94%) including 1 case with a 95% to 100% occlusion, whereas 5 of the 10 bifurcation aneurysms were occluded. Conclusions— Our study shows high safety and efficacy profile of a new generation endoluminal device in treatment of complex intracranial aneurysms. Long-term studies of treated bifurcation aneurysms are needed.

Item does not contain fulltext The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain-reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006-2008) and (b) afterwards (2009-2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV-related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality.Bone Marrow Transplantation advance online publication, 10 June 2013; doi:10.1038/bmt.2013.84.

In the past decade, orthodontists have added cone-beam computed tomography (CBCT) to their armamentarium to visualize the craniofacial complex in three dimensions. A search in PubMed indicates that the number of publications on CBCT applications is growing weekly. However, the number of publications concerning orthodontic applications is limited compared to publications that deal with applications in the field of maxillofacial surgery. Two systematic reviews and several narrative reviews have been published that give an overview of the evidence for the use of CBCT for orthodontic purposes. The SEDENTEXCT Consortium has formulated evidence-based guidelines on the use of CBCT in dental and maxillofacial radiology. Ten of these guidelines concern orthodontic applications. The purpose of this paper is to review the use of CBCT in orthodontics.

Item does not contain fulltext AIM: Sentinel lymph node (SLN) biopsy is an accepted alternative to axillary lymph node dissection to assess the axillary tumour status in breast cancer patients. Memorial Sloan-Kettering Cancer Center (MSKCC) developed a nomogram to predict the likelihood of SLN metastases in breast cancer patients. Nomogram performance was tested on a Dutch population. METHODS: Data of 770 breast cancer patients who underwent successful SLN biopsy were collected. SLN metastases were present in 222 patients. A receiver operating characteristic (ROC) curve was drawn and the area under the curve was calculated to assess the discriminative ability of the MSKCC nomogram. A calibration plot was drawn to compare actual versus nomogram-predicted probabilities. RESULTS: The area under the ROC curve for the predictive nomogram was 0.67 (95% confidence interval 0.63-0.72) as compared to 0.75 in the original population. The nomogram was well-calibrated in the Dutch population. CONCLUSIONS: In a Dutch population, the MSKCC nomogram estimated risk of sentinel node metastases in breast cancer patients well (i.e. calibration) with reasonable discrimination (area under ROC curve). Nomogram performance on core needle biopsy data has to be evaluated prospectively.

Item does not contain fulltext Neurosensory status and craniomandibular function of 19 patients (mean age 35.2 years, range 17.8-58.8 years) treated by combined surgical orthodontic treatment with distraction osteogenesis of the mandibular anterior alveolar process (DO group) was compared with that in 41 orthodontically treated patients (mean age 22.9 years, range 15.1-49.0 years; control group). Clinical examination took place on average 5.9 years (DO group) and 5.4 years (control group) after treatment ended. Neurosensory status was determined by two-point discrimination (2-pd) and the pointed and blunt test. Lateral cephalograms evaluated advancement of the mandibular alveolar process and possible relapse. There was no significant difference in craniomandibular function and neurosensory status between the groups. Age was significantly correlated with 2-pd at the lips (DO: p=0.01, R=0.575; control group: p=0.039, R=0.324) and chin (DO: p=0.029, R=0.501; control group: p=0.008, R=0.410). Younger patients had smaller 2-pd values. Gender, age, the amount of advancement, and relapse at point B or incision inferior show no correlation with craniomandibular function and neurosensory impairment. DO of the mandibular anterior alveolar process is a valuable and safe method with minor side effects regarding neurosensory impairment.

Item does not contain fulltext BACKGROUND: A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care. METHODS: We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehorigen-kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791. FINDINGS: We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1.3 points, 95% CI -2.1 to 2.8; corresponding raw logit score difference 0.1, 95% CI 0.003 to 0.2) as was the average PDQL score (difference 3.0 points, 0.4 to 5.6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0.9 points, 95% CI -0.6 to 2.4; corresponding raw logit score difference 0.1, -0.02 to 0.3) or PDQL (difference 1.7 points, -1.2 to 4.6). Secondary outcomes did not differ between groups (UPDRS III score difference 0.6 points, 95% CI -1.4 to 2.6; BELA-A-k score difference 0.8 points, -0.2 to 1.8; cost difference euro742, -euro489 to euro1950). INTERPRETATION: This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits. FUNDING: NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation.

Item does not contain fulltext BACKGROUND: Presently, 2 types of elbow prostheses are used: unlinked and linked. The Latitude total elbow prosthesis allows the surgeon to decide during the implantation whether the prosthesis is placed unlinked or linked, and whether the native radial head is retained, resected, or replaced. The purpose of this study is to assess and to compare the varus and valgus laxity of the unlinked and linked version of the latitude total elbow prosthesis with: (1) the native radial head preserved, (2) the native radial head excised, and (3) the native radial head replaced by a radial head component. METHODS: Biomechanical testing was performed on 14 fresh-frozen upper limb specimens. RESULTS: Linking the prosthesis predominantly influences the valgus laxity of the elbow. DISCUSSION/CONCLUSION: Linking the Latitude total elbow prosthesis results in increased valgus stability. In the linked version of the total elbow prosthesis, the radial head only plays a small part in both valgus and varus stability. An unlinked situation is not advised in absence of a native radial head or in case of inability to replace the radial head.

Item does not contain fulltext OBJECTIVE: To answer 2 research questions: what are the learning curve patterns of novices on the da Vinci skills simulator parameters and what parameters are appropriate for criterion-based robotic training. MATERIALS AND METHODS: A total of 17 novices completed 2 simulator sessions within 3 days. Each training session consisted of a warming-up exercise, followed by 5 repetitions of the "ring and rail II" task. Expert participants (n = 3) performed a warming-up exercise and 3 repetitions of the "ring and rail II" task on 1 day. We analyzed all 9 parameters of the simulator. RESULTS: Significant learning occurred on 5 parameters: overall score, time to complete, instrument collision, instruments out of view, and critical errors within 1-10 repetitions (P

BackgroundThe Lichtenstein technique is the treatment of first choice according to guidelines for primary inguinal hernia treatment. Postoperative chronic pain has been reported as complication in 15–40 % after Lichtenstein’s repair. The postoperative effects on health status after open preperitoneal hernia repair have hardly been examined. Development of an open technique that combines the safe anterior approach of the Lichtenstein with the ‘promising’ preperitoneal soft mesh position was done; the transinguinal preperitoneal (TIPP) mesh repair. A double-blind prospective randomized controlled trial (TULIP trial, ISRCTN93798494) was conducted to compare different outcome parameters after TIPP or Lichtenstein, one parameter is topic of evaluation in this paper; the health status after TIPP and Lichtenstein for inguinal hernia repair.MethodsThe study protocol has been published. It was hypothesized that the health status of inguinal hernia patients would be better after the TIPP repair compared with the Lichtenstein technique. The size of this study was based on chronic pain as primary outcome measure. Three hundred and two patients were randomized. Patients and the outcome assessors were blinded. Follow-up was scheduled after 14 days, 3 months, and 1 year. The three dimensions of possible errors were warranted.ResultsWith regard to health status, significant differences were found in the dimensions ‘physical pain’ [difference: 6.1 (95 % CI 2.3–9.9, p = 0.002)] and ‘physical functioning’ [difference: 3.5 (95 % CI 0.5–6.7, p = 0.023)], favoring the TIPP patients after 1 year.ConclusionIn conclusion, the SF-36 ‘physical function’ and ‘physical pain’ dimensions after TIPP show significant better patient outcomes at 1 year compared with the Lichtenstein patients in this trial. These differences are in line with reported significant differences in less patients with postoperative chronic pain after TIPP compared with Lichtenstein at 1 year.Keywords: Inguinal hernia, Preperitoneal, TIPP, Lichtenstein, Health status

Contains fulltext : 127294.pdf (Publisher’s version ) (Closed access) OBJECTIVE: A subgroup of patients with Chronic Fatigue Syndrome (CFS) has cognitive impairments, reflected by deviant neuropsychological test performance. However, abnormal test scores can also be caused by suboptimal effort. We hypothesized that worse neuropsychological test performance and underperformance were related to each other and to a smaller reduction in fatigue, functional impairments, physical limitations and higher dropout rates following cognitive behavior therapy (CBT) for CFS. METHODS: Data were drawn from a previous trial, in which CFS patients were randomized to two conditions; 1) guided self-instruction and additional CBT (n=84) or 2) waiting period followed by regular CBT for CFS (n=85). Underperformance was assessed using the Amsterdam Short Term Memory Test (