Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome.

BACKGROUND: Opitz G/BBB syndrome is a heterogeneous disorder characterised by variable expression of midline defects including cleft lip and palate, hypertelorism, laryngealtracheoesophageal anomalies, congenital heart defects, and hypospadias. The X-linked form of the condition has been associated with mutations in the MID1 gene on Xp22. The autosomal dominant form has been linked to chromosome 22q11.2, although the causative gene has yet to be elucidated. METHODS AND RESULTS: In this study, we performed whole exome sequencing on DNA samples from a three-generation family with characteristics of Opitz G/BBB syndrome with negative MID1 sequencing. We identified a heterozygous missense mutation c.1189A>C (p.Thr397Pro) in SPECC1L, located at chromosome 22q11.23. Mutation screening of an additional 19 patients with features of autosomal dominant Opitz G/BBB syndrome identified a c.3247G>A (p.Gly1083Ser) mutation segregating with the phenotype in another three-generation family. CONCLUSIONS: Previously, SPECC1L was shown to be required for proper facial morphogenesis with disruptions identified in two patients with oblique facial clefts. Collectively, these data demonstrate that SPECC1L mutations can cause syndromic forms of facial clefting including some cases of autosomal dominant Opitz G/BBB syndrome and support the original linkage to chromosome 22q11.2.

Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

Inhibition of the Wnt/ß-catenin pathway enhances antitumor immunity in ovarian cancer.

BACKGROUND: The Wnt/ß-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models. METHODS: Human ovarian cancer cells were treated with WNT974 in vitro. RNAseq libraries were constructed and differences in gene expression patterns between responders and nonresponders were compared to The Cancer Genome Atlas (TCGA). Mice with subcutaneous or intraperitoneal ID8 ovarian cancer tumors were treated with WNT974, paclitaxel, combination, or control. Tumor growth and survival were measured. Flow cytometry and ß-TCR repertoire analysis were used to determine the immune response. RESULTS: Gene expression profiling revealed distinct signatures in responders and nonresponders, which strongly correlated with T cell infiltration patterns in the TCGA analysis of ovarian cancer. WNT974 inhibited tumor growth, prevented ascites formation, and prolonged survival in mouse models. WNT974 increased the ratio of CD8+ T cells to T regulatory cells (Tregs) in tumors and enhanced the effector functions of infiltrating CD4+ and CD8+ T cells. Treatment also decreased the expression of inhibitory receptors on CD8+ T cells. Combining WNT974 with paclitaxel further reduced tumor growth, prolonged survival, and expanded the T cell repertoire. CONCLUSIONS: These findings suggest that inhibiting the Wnt/ß-catenin pathway may have a potent immunomodulatory effect in the treatment of ovarian cancer, particularly when combined with paclitaxel.

Head Start children's lifestyle behaviors, parental perceptions of weight, and body mass index.

This study examined lifestyle behaviors (food intake, active play, and screen time), parental perception of children's weight, and body mass index (BMI) of children enrolled in Head Start. Ninety-six parent-child dyads participated. Obesity prevalence (15.6%) was higher than the national average (10.4%); however, most parents (86.5%) of obese children did not perceive their children as obese. Regardless of BMI, food intake and active play levels generally did not meet recommended guidelines. Further, children who were less active were more likely to eat snacks (chi(2) = 6.24, p < or = .04). The role of pediatric nurses in counseling and referring Head Start families is explored.

Being overweight and obese: Black children ages 2-5 years.

Obesity in children is a significant public health concern. The prevalence of obesity in Black preschoolers (ages 2-5 years) is slightly higher than in whites. However, by age 6, Black children experience higher obesity prevalence. The consequences to health throughout childhood and into adulthood have both medical and economic cost to individuals and society. Factors associated with obesity in preschool children are lifestyle behaviors such as diet, level of activity, culture, environment, and parental perceptions. Programs should target young Black children and their families to reduce the incidence of obesity and promoting healthy behaviors could aid in eliminating health disparities and improving quality of life. Nurses need to provide comprehensive culturally appropriate strategies at community and individual/family levels to prevent overweight and obesity in children.

Achieving Guideline-Driven High-Intensity Statin Dose in Cardiac Rehabilitation Patients With Coronary Artery Disease.

PURPOSE: The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high-intensity statin therapy in patients aged ≤75 y with clinical coronary artery disease (CAD). The effectiveness of cardiac rehabilitation (CR) in lipid management and guideline adherence is unknown. The purpose of this study is to determine whether CR participation affects guideline-driven achievement for statin use. METHODS: This multicenter retrospective study evaluated statin utilization in patients pre- and post-CR between January 1, 2014, and August 31, 2015. Records for patients with known CAD who completed 18 or more CR sessions were reviewed for statin-drug use and dose before and after CR and documented statin intolerance. RESULTS: Of the total 468 patients, 76% were male with mean age ± SD = 66.0 ± 10.8 y and range of 32 to 89 y. Patients aged ≤75 y (n = 375) showed a modest but statistically significant increase (P = .0006) in high-intensity statin use post-CR (56.3%-61.1%). Males demonstrated a significant increase in high-intensity statin use (P = .0005). Of the 146 patients aged ≤75 y not on high-intensity statins post-CR, only 21 had history of statin intolerance. Of the subjects aged >75 y (n = 93), 91% were already on high- or moderate-intensity statins with no significant change during CR. CONCLUSIONS: Patients aged ≤75 y following CR completion increased high-intensity statin use but only by 4.8% and 33% of subjects were inadequately treated. The updated 2013 treatment recommendations simplified statin use, yet substantial data continue to reveal that guideline achievement even post-CR remains limited.

Reverse Engineering: Strategy to Teach Evidence-Based Practice to Online RN-to-BSN Students.

This article describes an innovative approach to introducing RN-to-BSN students to nursing research and evidence-based practice (EBP). Reverse engineering updates an existing EBP project to better emphasize the role of research and evidence to practicing RNs enrolled in an RN-to-BSN program. Reverse engineering of a nursing practice guideline offers a method for teaching an appreciation of research and supporting nursing practice with best evidence.

Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies.

OBJECTIVE: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. METHODS: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. RESULTS: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation. CONCLUSIONS: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.

Interprofessional education and prelicensure baccalaureate nursing students: an integrative review.

Interprofessional education is increasingly being used in nursing education. After presenting their integrative literature review of intervention studies of interprofessional education among baccalaureate nursing students, the authors conclude with a discussion of implications for nursing education practice and research.

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

An integrative review of obesity prevention in African American children.

The obesity epidemic disproportionately affects African American children ages 2 to 18 years of age. The author performed an integrative review of the literature pertaining to African American childhood obesity prevention. The 28 research articles that met the inclusion criteria for this integrative review were primarily comprised of descriptive studies, targeted primarily middle-school children and only six were intervention studies. Most intervention studies were pilot studies, had insufficient power related to small sample size, and had short-term interventions and no follow-up. These studies are promising as they test innovative and cultural specific interventions targeting children's lifestyle behaviors aimed at reducing obesity among African Americans.