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Abstract We explored the existence and application of standard operating procedures (SOPs) for pain management (PM) in German neonatal intensive care units (NICUs), and identified the factors associated with their application in practice. This study was part of the Safety4NICU project, a cross‐sectional survey conducted from 2015 to 2016. All 224 German NICUs were invited to participate, providing written consent from the head neonatologist and head nurse. We distributed questionnaires to the head neonatologist, the head nurse, and the NICU staff (physicians and nurses). We asked the head neonatologist whether written SOPs for PM existed, and we asked the staff whether these SOPs were applied in their daily routine. We received evaluable responses from 468 physicians and 1251 nurses from 76 NICUs. Of these 76 NICUs, the head neonatologists from 54 NICUs (71.1%) reported that written SOPs for PM exist. However, only 48.5% of the physicians and 53.7% of the nurses declared that these existing SOPs were also applied. We found various predictors for the existing SOPs as being applied, depending on the profession. For physicians, clinical training was important (OR: 2.482, p ≤ 0.05), while for nurses their working experience was a decisive predictor (OR: 1.265, p ≤ 0.05). For both, a high level of perceived cooperative norms between physicians and nurses increased the probability that SOPs for PM were applied, whereas a high bed turnover rate decreased that probability. According to the responses from head neonatologists, written SOPs for PM were common in German NICUs. However, if management strategies on pain existed, this did not mean that these were directly applied in the daily routine. Clinical training of the staff, the promotion of adequate interprofessional cooperation, as well as allowing time to deal with these SOPs might be all essential measures to strengthen the application.

Abstract Aim To analyse the associations between a nurse's psychological safety and her/his additional training. Design A cross‐sectional survey conducted between September 2015 and August 2016. Methods A multi‐level modelling approach was used considering unit membership. We used data from 1,239 questionnaires completed by nurses on 75 different German neonatal intensive care units, and 75 questionnaires completed by the corresponding leading nurse. Results We found the additional managerial training as a charge nurse to be a positive predictor for psychological safety (β = .346, p ≤ .05). Surprisingly, the additional clinical training in paediatric intensive care is negatively associated with psychological safety (β = −.192, p ≤ .01). Our model estimates that this negative association can be inhibited if the team's share of nurses with an additional clinical training increases (β = .313, p ≤ .05).

Background: Nonsyndromic cleft with or without cleft palate (nsCL/P) is a common birth defect. Although genome-wide association studies (GWAS) have identified numerous risk variants, a considerable fraction of the genetic heritability remains unknown. The aim of the present study was to replicate a previous finding that de novo deletions in a 62 kb region of chromosome 7p14 are a risk factor for nsCL/P, using an independent cohort., Methods: Data from a published case-control GWAS cohort of 399 patients and 1318 controls were used. Copy number variant (CNV) detection in the 62 kb candidate region of 7p14 was performed using QuantiSNP. Putative CNVs in probands were verified and validated by quantitative polymerase chain reaction. Segregation analyses were performed in family members for whom DNA was available., Results: Within the 62 kb candidate region, a deletion of 7.4 kb showed association with nsCL/P (13/387 cases, 20/1300 controls, plowest = 0.024, odds ratio = 2.22). In all families with a sporadic case (n = 3), the deletion occurred de novo. In multiplex families, both incomplete segregation and incomplete penetrance were observed., Conclusion: The present data support the hypothesis that deletions at 7p14 are a common risk factor for nsCL/P. Genome-wide CNV analyses in nsCL/P cohorts are warranted to explore the functional relevance of these deletions and their contribution to nsCL/P, and to determine exact breakpoints. Birth Defects Research (Part A) 106:767-772, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population., Methods: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios., Results: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT  = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT  = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations., Conclusion: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment., (© 2015 Wiley Periodicals, Inc.)

Background: The genes Gremlin-1 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL/P etiology., Methods: The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case-control sample (n = 96, respectively). For rare variants observed in cases, segregation analyses were performed., Results: In NOG, four rare sequence variants (minor allele frequency < 1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated., Conclusion: Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements., (© 2014 Wiley Periodicals, Inc.)

Background: Nonsyndromic orofacial clefting (nsOFC) is among the most common of all congenital disorders and has a genetically complex etiology. Based on embryological and epidemiological data, the phenotype can be differentiated into nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only, with nsCL/P being the most frequent form. Recent genetic research, predominantly performed in populations from Europe and Asia, has identified numerous genetic susceptibility loci for nsCL/P. As only few data are available concerning genetic susceptibility to nsCL/P in Arab populations, we investigated a newly recruited nsOFC sample from Yemen., Methods: For each of the 15 currently known nsCL/P risk loci, the top single-nucleotide polymorphism (plus nine back-up variants) were genotyped in 242 nsCL/P cases and 420 healthy controls., Results: Single-marker association analysis revealed significant associations for four loci (8q24, 9q22, 10q25, 13q31). The strongest association was for the European high risk locus at 8q24 (Pcorrected  = 5.09 × 10(-4) ; heterozygous odds ratio = 1.74 (1.22-2.47), homozygous odds ratio = 2.47 (1.55-3.93). Five additional loci (1q32.2, 3q12, 8q21, 17q22, 20q12) showed nominal significance that did not withstand correction for multiple testing. Although the six remaining loci (1p22, 1p36, 2p21, 3p11, 15q22, 17p13) failed to reach nominal significance, the risk alleles were in the same direction as in the discovery studies., Conclusion: The results suggest that four of the 15 analyzed nsCL/P risk loci which were identified in European and Asian ethnicities significantly confer risk for nsCL/P in Arab populations., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is among the most frequently occurring congenital malformations worldwide. The number of genetic loci identified as being involved in NSCL/P etiology was recently increased by a large genome-wide meta-analysis of European and Asian samples. This meta-analysis confirmed all six previously recognized genetic susceptibility loci and identified six novel ones., Methods: To investigate which of these 12 loci contribute to NSCL/P risk in an independent sample of distinct ethnicity, we performed a case-control association analysis in a sample of the Mesoamerican population. A total of 153 individuals with NSCL/P (cases) and 337 unaffected controls were included. Top single-nucleotide polymorphisms (SNPs) at 8 of the 12 loci (1p22.1, 1p36, 2p21, 3p11.1, 8q21.3, 13q31.1, 15q22, and 20q12) were analyzed using mass spectroscopy and restriction-length-fragment polymorphism analyses. In a previous study, we had analyzed the remaining four NSCL/P susceptibility regions (IRF6, 8q24, 10q25, and 17q22) in the same sample., Results: Single-marker association analyses applying allelic, dominant, and recessive models revealed nominal significant associations for four of the eight loci, with two additional loci showing at least a trend of association in the hypothesized direction., Conclusion: In combination with results from our previous study using the same sample, our data suggest that the majority of the known NSCL/P susceptibility regions identified to date also confer risk for this malformation in the Mesoamerican population. Birth Defects Research (Part A) 100:43-47, 2014. © 2013 Wiley Periodicals, Inc., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P., Methods: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level., Results: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees., Conclusion: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all birth defects. NSCL/P has a multifactorial etiology that includes both genetic and environmental factors. The IRF6 gene and three further susceptibility loci at 8q24, 10q25, and 17q22, which were identified by a recent genome-wide association scan (GWAS), are confirmed genetic risk factors for NSCL/P in patients of European descent., Methods: A case-control association study was performed to investigate whether these four risk loci contribute to NSCL/P in a Mesoamerican population using four single nucleotide polymorphisms to represent IRF6 and the three novel susceptibility loci. A total of 149 NSCL/P patients and 303 controls of Mayan origin were included., Results: Single marker analysis revealed a significant association between NSCL/P and risk variants in IRF6 and the 8q24 and 10q25 loci. In contrast to previous findings, the association at the 8q24 locus was driven solely by homozygote carriers of the risk allele. This suggests that this locus might act in a recessive manner in the Mayan population. No evidence for association was found at the 17q22 locus. This may have been attributable to the limited power of the sample., Conclusion: These results suggest that IRF6 and the 10q25 and 8q24 loci confer a risk for the development of NSCL/P in persons of Mayan origin., (2010 Wiley-Liss, Inc.)