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OBJECTIVES: To transfer sterile medical devices (SMD), infusion bags (IB), ampoules (A), injection vials (V) and infusion bottles (B) into a laminar airflow cabinet (LAF) or safety cabinet (SC) with a surface bioburden as low as possible.METHODS: Surface bioburden of the outer layer of SMD, IB, A, V and B was determined by contact plates. Surface bioburden determination of critical spots on A, V and B (ampoule necks and stoppers) was determined by high-recovery swabs and contact plates. Particle emission from white cardboard boxes was determined by a particle counter.RESULTS: The chances of a contaminated outer layer of SMD is negligible as long as they stay in their original boxes. The outer layer of double-packed IB can contain a considerable number of micro-organisms. As found in previous studies, the surface bioburden of A, V and B is low as long as they stay in their original cardboard boxes. Particle emission from white boxes is low. The necessity of a final disinfection step inside LAF/SC of critical sspots of A, V and B cannot be proven. SmallSMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised. Tohave materials with a low chance of contamination in LAF/SC, transfer bypresentation for SMD and IB and using a sterile tray for disinfected materialsis an effective procedure. Wiping of ampoule necks and stoppers inside LAF/SC isadvised based on risk assessment.Small SMD, ampoules and injection vials can be transferred into the background areain their original white boxes. Other materials have to be unpacked in front ofthe lock while the operator wear disposable gloves. Disinfection of the outerlayer of IB, before transfer trough the lock, is advised.CONCLUSION: When SMD, ampoules, injection vials and infusion bottles stay in their original boxes as long as possible, the aseptic transfer and the disinfection procedure can be maintained effectively and efficiently.

OBJECTIVES: To improve the disinfection methods for materials with a non-sterile surface to be used in aseptic handling.METHODS: The surface bioburden on ampoules (A) and injection vials (IV) is determined by contact plates and total immersion. The occurrence of spore-forming bacteria is determined by strain colouring and matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The disinfection procedures of non-sterile materials in 10 hospital pharmacies are judged by observing.RESULTS: After wiping according to local disinfection methods, the mean surface bioburden determined by contact plates in 10 hospital pharmacies is 0.36 (plastic A), 0.50 (glass A) and 0.29 colony-forming unit (cfu) (IV). The observers found great differences in accuracy of wiping and degree of wetting the sterile gauzes.After improved wiping with commercially available alcohol impregnated sterile wipes and a two-towel technique (one-step TT disinfection), the mean surface bioburden determined by contact plates is 0.03 (plastic A), 0.2 (glass A) and 0.13 cfu (IV). Further improvement can be reached by submerging A and IV in ethanol 70% followed by improved wiping (two-step TT disinfection), but still micro-organisms will remain (mean surface bioburden determined by total immersion is 0 (plastic A) and 0.3 cfu (IV); glass A not determined). Two-step TT disinfection is more labour intensive. Spilling of alcohol is another disadvantage. However, we presume one-step TT disinfection is effective enough in daily practice. Routine surface bioburden determinations have to prove this.The effectiveness of the combination of spray and wipe is not examined because we observed a quick disappearance of alcohols from vertical as well as horizontal surfaces, which shortens the contact time to far below the advised 2 min.Spore-forming bacteria disappear as quickly as other micro-organisms during disinfection by alcohols.CONCLUSION: Local disinfection procedures can be improved. Complete removal of micro-organisms from materials with a non-sterile surface, even after two-step TT disinfection, is impossible. Routine surface bioburden determinations have to prove if one-step TT disinfection is effective enough.

Objectives To develop methods for surface bioburden determination of ampoules and vials to be used in the validation of the disinfection procedures and in routine monitoring of ampoules and vials. Methods The surface bioburdens of ampoules and vials are determined before and after disinfection by contact plates and total immersion. Results The mean surface bioburdens of non-disinfected ampoules and vials taken straight from the original boxes are 2.4 and 5.01 cfu (total immersion; n = 20), and 0.97 and 0.94 cfu (contact plates; n = 60). The mean surface bioburdens of ampules and vials after disinfection by wiping are 1.15 and 7.50 cfu (total immersion; n = 20), and 0.12 and 0.10 cfu (contact plates; n = 60). The high number of cfu on vials (total immersion) indicate hidden cfu around the neck not removable by wiping and not detected by contact plates. Total immersion needs special laboratory facilities and is expensive (about €50 a sample). Therefore, it is less appropriate for use in routine monitoring. However, because of the high recovery, it is the method of choice for the validation of the disinfection procedure. Surface bioburden determination by contact plates is relatively simple. Non-flat surfaces cannot be reached, but the recovery from the touched flat part of the surface is high (around 50%). The recovery from swabs is low (around 10%). Another disadvantage of swabs is the laboratory work after sampling. We therefore advise contact plates for routine monitoring. To get a reliable value of the mean surface bioburden at least 30 samples need to be examined. Conclusion Total immersion is the method of choice for the determination of the effectiveness of a disinfection procedure for ampoules and vials. Contact plate is the method of choice for routine monitoring of the surfaces of ampoules and vials.

Publisher's version (útgefin grein)., Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., 23Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA. 24Research Unit-Genetic Epidemiology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria. 25Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15260, USA. 26Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA. 27Department of Radiology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands. 28Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto M4G 1R8, Canada. 29Departments of Psychology and Psychiatry, University of Toronto, Toronto M5S 1A1, Canada.

Background Craniofacial dysmorphic features are morphological changes of the face and skull which are associated with syndromic conditions. Moyamoya angiopathy is a rare cerebral vasculopathy that can be divided into Moyamoya syndrome, which is associated or secondary to other diseases, and into idiopathic Moyamoya disease. Facial dysmorphism has been described in rare genetic syndromes with associated Moyamoya syndrome. However, a direct relationship between idiopathic Moyamoya disease with dysmorphic facial changes is not known yet. Methods Landmarks were manually placed on frontal photographs of the face of 45 patients with bilateral Moyamoya disease and 50 matched controls. After procrustes alignment of landmarks a multivariate, penalized logistic regression (elastic-net) was performed on geometric features derived from landmark data to classify patients against controls. Classifiers were visualized in importance plots that colorcode importance of geometric locations for the classification decision. Results The classification accuracy for discriminating the total patient group from controls was 82.3% (P-value = 6.3×10−11, binomial test, a-priori chance 50.2%) for an elastic-net classifier. Importance plots show that differences around the eyes and forehead were responsible for the discrimination. Subgroup analysis corrected for body mass index confirmed a similar result. Discussion Results suggest that there is a resemblance in faces of Caucasian patients with idiopathic Moyamoya disease and that there is a difference to matched controls. Replication of findings is necessary as it is difficult to control all residual confounding in study designs such as ours. If our results would be replicated in a larger cohort, this would be helpful for pathophysiological interpretation and early detection of the disease.

Background In rheumatoid arthritis treatment, targeted treatment has shown to improve disease outcomes including the option of drug tapering and discontinuation. In non-systemic juvenile idiopathic arthritis (nsJIA) this has not been tried in a trial. Objectives To investigate which of three treatment strategies, targeting at drug-free inactive disease, is most effective and safe in recent onset DMARD-naive nsJIA. Methods We conducted a randomised, multicenter, treatment strategy study with 24 months of follow up. Patients, 2–16 years old with symptom duration Results 94 children (67% girls) with a median (InterQuartile Range) age of 9.1 (4.6–12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. Eleven had oligo-articular JIA, n=73 polyarticular JIA and n=8 juvenile psoriatic arthritis, 37% were ANA positive. At baseline VAS physician was median (IQR) 50 39–58 mm, VAS patient 54 37–70 mm, ESR 6 (2–14) mm/hr, active joints 8, 5–12 limited joints 2.5 (1–5), and CHAQ score 0.9 (0.6–1.5). After 24 months 61% (arm 1), 63% (arm 2) and 61% (arm 3) of patients had inactive disease and 45% (arm 1) 31% (arm 2) and 38% (arm 3) had stopped all DMARD(s). Time to inactive disease (median 9.0 (6.0–12.0) months) was not significantly different between arms, nor was time to flare (18.0 (15.0–21.0) months). Adapted ACRpedi-scores were comparably high between arms. Functional ability improved and remained almost normal. Toxicity reports showed mild events in similar rates across all arms. Results after 24 months by GEE. Conclusions Treatment to target drug free inactive disease is feasible in recent onset non-systemic JIA, resulting, regardless of initial treatment, in over 60% of patients in inactive disease and 38% drug free. Disclosure of Interest None declared

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci, among which 17 were previously unpublished. A multi-ethnic replication study in 7,917 individuals confirmed 13 loci including 8 unpublished ones. Allele frequencies at the face-associated loci were significantly more differentiated among populations than genome background, supporting a role of nature selection in shaping genetic differentiation underlying facial variation. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities at INTU, PAX3, RPGRIP1L. Knocking-out two face-associated genes TBX15 and PAX1 in mice resulted in craniofacial dysmorphology. These results substantially advance our understanding of the genetic and functional basis of human facial variation.

In a protein C deficient family, we recently identified a candidate gene, CADM1, which interacted with protein C deficiency in increasing the risk of venous thrombosis (VT). This study aimed to determine whether CADM1 variants also interact with protein C pathway abnormalities in increasing VT risk outside this family.We genotyped over 300 CADM1 variants in the population-based MEGA case-control study. We compared VT risks between cases with low protein C activity (n=194), low protein S levels (n=23), high factor VIII activity (n=165) or factor V Leiden carriers (n=580), and all 4004 controls. Positive associations were repeated in all 3496 cases and 4004 controls.We found 22 variants which were associated with VT in one of the protein C pathway risk groups. After mutual adjustment, six variants remained associated with VT. The strongest evidence was found for rs220842 and rs11608105. For rs220842, the odds ratio (OR) for VT was 3.2 (95% CI 1.2-9.0) for cases with high factor VIII activity compared with controls. In addition, this variant was associated with an increased risk of VT in the overall study population (OR: 1.5, 95% CI 1.0-2.2). The other variant, rs11608105, was not associated with VT in the overall study population (OR: 1.0, 95% CI 0.8-1.1), but showed a strong effect on VT risk (OR: 21, 95% CI 5.1-88) when combined with low protein C or S levels.In a population-based association study, we confirm a role for CADM1 variants in increasing the risk of VT by interaction with protein C pathway abnormalities.

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 x 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P-0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity. European Journal of Human Genetics (2011) 19, 1192-1197; doi:10.1038/ejhg.2011.110; published online 22 June 2011

Genome wide association studies for complex diseases are typically followed by more focused characterization of the identified genetic region. We propose a latent class model to evaluate a candidate region with several measured markers using observations on families. The main goal is to estimate linkage disequilibrium (LD) between the observed markers and the putative true but unobserved disease locus in the region. Based on this model, we estimate the joint distribution of alleles at the observed markers and the unobserved true disease locus, and a penetrance parameter measuring the impact of the disease allele on disease risk. A family specific random effect allows for varying baseline disease prevalences for different families. We present a likelihood framework for our model and assess its properties in simulations. We apply the model to an Alzheimer data set and confirm previous findings in the ApoE region.

Digital image analysis of faces has been demonstrated to be effective in a small number of syndromes. In this paper we investigate several aspects that help bringing these methods closer to clinical application. First, we investigate the impact of increasing the number of syndromes from 10 to 14 as compared to an earlier study. Second, we include a side-view pose into the analysis and third, we scrutinize the effect of geometry information. Picture analysis uses a Gabor wavelet transform, standardization of landmark coordinates and subsequent statistical analysis. We can demonstrate that classification accuracy drops from 76% for 10 syndromes to 70% for 14 syndromes for frontal images. Including side-views achieves an accuracy of 76% again. Geometry performs excellently with 85% for combined poses. Combination of wavelets and geometry for both poses increases accuracy to 93%. In conclusion, a larger number of syndromes can be handled effectively by means of image analysis.

Clinical evaluation of children with developmental delay continues to present a challenge to the clinicians. In many cases, the face provides important information to diagnose a condition. However, database support with respect to facial traits is limited at present. Computer-based analyses of 2D and 3D representations of faces have been developed, but it is unclear how well a larger number of conditions can be handled by such systems. We have therefore analysed 2D pictures of patients each being affected with one of 10 syndromes (fragile X syndrome; Cornelia de Lange syndrome; Williams-Beuren syndrome; Prader-Willi syndrome; Mucopolysaccharidosis type III; Cri-du-chat syndrome; Smith-Lemli-Opitz syndrome; Sotos syndrome; Microdeletion 22q11.2; Noonan syndrome). We can show that a classification accuracy of >75% can be achieved for a computer-based diagnosis among the 10 syndromes, which is about the same accuracy achieved for five syndromes in a previous study. Pairwise discrimination of syndromes ranges from 80 to 99%. Furthermore, we can demonstrate that the criteria used by the computer decisions match clinical observations in many cases. These findings indicate that computer-based picture analysis might be a helpful addition to existing database systems, which are meant to assist in syndrome diagnosis, especially as data acquisition is straightforward and involves off-the-shelf digital camera equipment.

In this analysis, we investigate the contributions that linkage-based methods, such as identical-by-descent mapping, can make to association mapping to identify rare variants in next-generation sequencing data. First, we identify regions in which cases share more segments identical-by-descent around a putative causal variant than do controls. Second, we use a two-stage mixed-effect model approach to summarize the single-nucleotide polymorphism data within each region and include them as covariates in the model for the phenotype. We assess the impact of linkage disequilibrium in determining identical-by-descent states between individuals by using markers with and without linkage disequilibrium for the first part and the impact of imputation in testing for association by using imputed genome-wide association studies or raw sequence markers for the second part. We apply the method to next-generation sequencing longitudinal family data from Genetic Association Workshop 18 and identify a significant region at chromosome 3: 40249244-41025167 (p-value = 2.3 × 10(-3)).

It is hypothesized that certain alleles can have a protective effect not only when inherited by the offspring but also as noninherited maternal antigens (NIMA). To estimate the NIMA effect, large samples of families are needed. When large samples are not available, we propose a combined approach to estimate the NIMA effect from ascertained nuclear families and twin pairs. We develop a likelihood-based approach allowing for several ascertainment schemes, to accommodate for the outcome-dependent sampling scheme, and a family-specific random term, to take into account the correlation between family members. We estimate the parameters using maximum likelihood based on the combined joint likelihood (CJL) approach. Simulations show that the CJL is more efficient for estimating the NIMA odds ratios as compared to a families-only approach. To illustrate our approach, we used data from a family and a twin study from the United Kingdom on rheumatoid arthritis, and confirmed the protective NIMA effect, with an odds ratio of 0.477 (95% CI 0.264-0.864).

Computer systems play an important role in clinical genetics and are a routine part of finding clinical diagnoses but make it difficult to fully exploit information derived from facial appearance. So far, automated syndrome diagnosis based on digital, facial photographs has been demonstrated under study conditions but has not been applied in clinical practice. We have therefore investigated how well statistical classifiers trained on study data comprising 202 individuals affected by one of 14 syndromes could classify a set of 91 patients for whom pictures were taken under regular, less controlled conditions in clinical practice. We found a classification accuracy of 21% percent in the clinical sample representing a ratio of 3.0 over a random choice. This contrasts with a 60% accuracy or 8.5 ratio in the training data. Producing average images in both groups from sets of pictures for each syndrome demonstrates that the groups exhibit large phenotypic differences explaining discrepancies in accuracy. A broadening of the data set is suggested in order to improve accuracy in clinical practice. In order to further this goal, a software package is made available that allows application of the procedures and contributions toward an improved data set.

Item does not contain fulltext A great number of case reports on concordant and discordant twins with oculo-auriculo-vertebral spectrum (OAVS) suggest that there might be an association between reproductive abnormalities, twinning and OAVS. The etiology of OAVS is unknown, but may involve epigenetic dysregulation of the oocyte or early embryo. We collected data on fertility and pregnancy outcome of 72 parents of patients with sporadic OAVS. We also evaluated prospective follow-up data on 3.372 fetuses and children conceived by intracytoplasmatic sperm injection (ICSI). Parental age, duration of menstrual cycle and the incidence of spontaneous abortion was not different when compared to the German population. However, there is an excess of parents who have used assisted reproductive techniques (ART; retrospective P = 0.038, prospective P = 0.023) and an excess of twins among naturally conceived patients with OAVS (P = 0.0025). An excess of ART conceptions and monozygotic twinning in OAVS is compatible with the concept of overripeness ovopathy as proposed by Jongbloet (Maandschr Kindergeneeskd 36:352-367, 1968).

Waldenström macroglobulinemia (WM), a distinctive subtype of non-Hodgkin lymphoma that features overproduction of immunoglobulin M (IgM), clearly has a familial component; however, no susceptibility genes have yet been identified. We performed a genomewide linkage analysis in 11 high-risk families with WM that were informative for linkage, for a total of 122 individuals with DNA samples, including 34 patients with WM and 10 patients with IgM monoclonal gammopathy of undetermined significance (IgM MGUS). We genotyped 1,058 microsatellite markers (average spacing 3.5 cM), performed both nonparametric and parametric linkage analysis, and computed both two-point and multipoint linkage statistics. The strongest evidence of linkage was found on chromosomes 1q and 4q when patients with WM and with IgM MGUS were both considered affected; nonparametric linkage scores were 2.5 (P=.0089) and 3.1 (P=.004), respectively. Other locations suggestive of linkage were found on chromosomes 3 and 6. Results of two-locus linkage analysis were consistent with independent effects. The findings from this first linkage analysis of families at high risk for WM represent important progress toward identifying gene(s) that modulate susceptibility to WM and toward understanding its complex etiology.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications., Author Summary Monozygotic twins look more alike than dizygotic twins or other siblings, and siblings in turn look more alike than unrelated individuals, indicating that human facial morphology has a strong genetic component. We quantitatively assessed human facial shape phenotypes based on statistical shape analyses of facial landmarks obtained from three-dimensional magnetic resonance images of the head. These phenotypes turned out to be highly promising for studying the genetic basis of human facial variation in that they showed high heritability in our twin data. A subsequent genome-wide association study (GWAS) identified five candidate genes affecting facial shape in Europeans: PRDM16, PAX3, TP63, C5orf50, and COL17A1. In addition, our data suggest that genetic variants associated with NSCL/P also influence normal facial shape variation. Overall, this study provides novel and confirmatory links between common DNA variants and normal variation in human facial morphology. Our results also suggest that the high heritability of facial phenotypes seems to be explained by a large number of DNA variants with relatively small individual effect size, a phenomenon well known for other complex human traits, such as adult body height.