Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only.

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signalswithin this high-density datasetare enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinementapproach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.Clefts of the lip and palate are common birth defects, and require long-term multidisciplinary management. Their etiology involves genetic factors and environmental influences and/or a combination of both, however, these interactions are poorly defined. Moreover, although clefts of the lip may or may not involve the palate, the determinants predisposing to specific subphenotypes are largely unknown. Here we demonstrate that variations in the non-coding region near the GREM1 gene show a highly significant association with a particular phenotype in which cleft lip and cleft palate co-occ

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions

Robot-assisted early mobilization of intensive care patients : a feasibility study protocol

Background: Early mobilization positively infuences the outcome of critically ill patients, yet in clinical practice, the implementation is sometimes challenging. In this study, an adaptive robotic assistance system will be used for early mobilization in intensive care units. The study aims to evaluate the experience of the mobilizing professionals and the general feasibility of implementing robotic assistance for mobilization in intensive care as well as the efects on patient outcomes as a secondary outcome. Methods: The study is single-centric, prospective, and interventional and follows a longitudinal study design. To evaluate the feasibility of robotic-assisted early mobilization, the number of patients included, the number of performed VEM (very early mobilization) sessions, and the number and type of adverse events will be collected. The behavior and experience of mobilizing professionals will be evaluated using standardized observations (n > 90) and episodic interviews (n > 36) before implementation, shortly after, and in routine. Patient outcomes such as duration of mechanical ventilation, loss of muscle mass, and physical activity will be measured and compared with a historical patient population. Approximately 30 patients will be included. Discussion: The study will provide information about patient outcomes, feasibility, and the experience of mobilizing professionals. It will show whether robotic systems can increase the early mobilization frequency of critically ill patients. Within ICU structures, early mobilization as therapy could become more of a focus. Efects on the mobilizing professionals such as increased motivation, physical relief, or stress will be evaluated. In addition, this study will focus on whether current structures allow following the recommendation of mobilizing patients twice a day for at least 20 mi

Frühmobilisation auf der Intensivstation : sind robotergestützte Systeme die Zukunft?

'''Hintergrund:''' Bei etwa 43% aller Überlebenden der Intensivmedizin wird ein erworbenes Syndrom an Muskelschwäche beobachtet, welches Überleben und Lebensqualität vermindert. Da kausale Therapieoptionen bisher fehlen, stehen die Vermeidung der bekannten Risikofaktoren und Frühmobilisation im Vordergrund. Robotische Unterstützungssysteme werden vermehrt in der Mobilisation erprobt. '''Ziel der Arbeit:''' In diesem Übersichtsartikel wird die aktuelle Evidenz von Frühmobilisation von kritisch Kranken zusammengefasst und der Stellenwert robotischer Assistenzsysteme für Mobilisation diskutiert. '''Ergebnisse:''' Mobilisation sollte auf der Intensivstation nachMöglichkeit früh begonnen werden. Hierunter wird der Beginn in den ersten 72 h nach der Aufnahme auf die Intensivstation verstanden. Physiotherapeutische Interventionen während des Intensivaufenthalts zeigen positive Effekte auf die Lebensqualität von PatientInnen, auf die Dauer von invasiver Beatmung, Intensivaufenthalt und Delir. Strukturierte Behandlungsprotokolle führen zu mehr aktiver Mobilisation, höherer Mobilität und häufigerer funktioneller Unabhängigkeit bei Entlassung aus dem Krankenhaus. Nach Schlaganfällen erhöhen zusätzliche robotergestützte Therapieeinheiten insbesondere bei stärker eingeschränkten PatientInnen die Rate an Rückkehrern zum selbstständigen Gehen, scheinen sicher und verbesserten in kleinen Studien Muskelkraft und Lebensqualität. '''Schlussfolgerung:''' Frühmobilisation verbessert das Outcome von kritisch Erkrankten. Robotische Systeme unterstützen das Gangtraining nach einem Schlaganfall und werden auf der Intensivstation in ersten Studien zu Vertikalisierung und Frühmobilisation untersucht

Evaluation of effects of robot-assisted early mobilization on critically ill patients, on the mobilization behaviour and experience of the mobilizing professionals and the organizational processes in an intensive care unit -a clinical intervention study : study protocol

'''Background:''' Early mobilization positively influences the outcome of critically ill patients, yet in the clinical practice the implementation is sometimes challenging. In this study, an adaptive robotic assistance system will be used for early mobilization in intensive care units. The study aims to evaluate the experience of the mobilizing professionals, the effects on patient outcomes, and the general feasibility of implementing robotic assistance for mobilization in intensive care. '''Methods:''' The study is monocentric, prospective, interventional, and has multiple time points for data collection. To evaluate the feasibility of robotic-assisted early mobilization, the number of patients included, the number of performed VEM (very early mobilization) sessions, as well as the number and type of adverse events will be collected. The behavior and experience of mobilizing professionals will be evaluated using standardized observations (n>90) and episodic interviews (n>36) before implementation, shortly after, and in routine. Patient outcomes such as duration of mechanical ventilation, loss of muscle mass and physical activity will be measured and compared with a historical patient population. Approximately 30 patients will be included. '''Discussion:''' The study will provide information about patient outcomes, feasibility, and the experience of mobilizing professionals. It will show whether robotic systems can increase early mobilization frequency of critically ill patients. Within ICU structures, early mobilization as therapy could become more of a focus. Effects on the mobilizing professionals such as increased motivation, physical relief, or stress will be evaluated. In addition, this study will focus on whether current structures allow following the recommendation of mobilizing patients twice a day for at least 20 minutes. The aim of this study is to evaluate the implementation of a new standard of robotic-assisted early mobilization in the intensive care setting and whether it can be utilized permanently within the current framework. '''Trial registration:''' (clinicaltrials.org TRN: NCT05071248, Date: 2021/10/21) URL https://clinicaltrials.gov/ct2/show/NCT0507124

Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, similar to 5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 x 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (p(combined) = 2.63 x 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 x 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO

Sample overview.

<p>Sample overview.</p