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Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

The site-specific introduction of unnatural amino acids (UAAs) has been demonstrated to be a useful tool in protein engineering. Moreover, the incorporation of a UAA into a protein has become feasible with the increased commercial availability of UAAs and robust expression plasmids. In addition to the ease of incorporation, the concepts utilized in the incorporation of a UAA are ideal to illustrate key concepts involved in protein translation and structure-function relationships. Consequently, a novel experiment has been developed for the incorporation of various UAAs into the GFP fluorophore to alter spectral properties. This experiment provides students with a hands-on approach for transformation, protein expression and purification, and structure-function analysis.

Ring annuloplasty (Ring) and suture bicuspidization annuloplasty (Suture-bicuspidization) are 2 techniques for tricuspid valve repair. With the emergence of transcatheter tricuspid valve repair technologies that mimic these conventional surgical techniques, we compared their midterm outcomes and longitudinal echocardiographic profiles. From 2002 to 2016, 650 patients underwent tricuspid valve repair (324 Ring and 326 Suture-bicuspidization) for primary or functional tricuspid regurgitation (TR). Concomitant aortic valve, mitral valve, or coronary artery bypass graft procedures were included but tricuspid valve replacement, concomitant aortic procedures, heart transplantation or ventricular assist device placement procedures were excluded. Tricuspid valve event-free survival was estimated using Kaplan-Meier competing risk analysis. Freedom from TR recurrence (defined as at least moderate TR) and freedom from tricuspid valve reoperation were also assessed. There were no statistical differences in terms of age, gender, and most baseline comorbidities (P >.05). In-hospital outcomes also did not significantly differ between groups (P >.05). However, Suture-bicuspidization was associated with significantly lower tricuspid valve event-free survival, and freedom from TR recurrence and tricuspid valve reoperation compared with Ring at 1, 5, and 8 years (all P <.05). After adjusting for significant confounders, Suture-bicuspidization continued to be associated with significantly decreased tricuspid valve event-free survival (hazard ratio = 2.13; 95% confidence interval, 1.3-3.4). The superiority of Ring over Suture-bicuspidization annuloplasty for tricuspid valve repair appeared to be evident in terms of event-free survival and freedom from tricuspid valve insufficiency and reoperation. These findings raise concern in the context of emerging transcatheter technologies that mimic the bicuspidization technique. [ABSTRACT FROM AUTHOR]

Adverse repercussions associated with the current opioid epidemic have been documented in many surgical specialties. This study evaluated the impact of opioid use disorder (OUD) on in-hospital cardiac surgery outcomes by using a large national database. Using the National Inpatient Sample, this study isolated patients undergoing coronary artery bypass grafting, valve repair, or valve replacement from 2009 to 2014. Patients were stratified by OUD status. Multivariable analysis was performed to evaluate the association between opioid use and postoperative outcomes. Patients were further stratified by surgery type. Overall, 1,743,161 patients underwent cardiac surgery, and 6960 patients had OUD (0.4%). Mean age was 47.2 and 65.8 years among those with and without OUD, respectively. Although in-hospital mortality did not differ among these groups, patients with OUD had a significantly higher incidence of stroke (8.3% vs 2.8%) and acute kidney injury (21.4% vs 16.2%), longer hospital stays (18 days vs 10 days), and higher hospitalization costs ($81,238 vs $58,654; all P <.01). However, after adjusting for patient and hospital-level factors, OUD was associated only with a longer hospital length of stay (2.2 days; 95% confidence interval, 1.19 to 3.20) compared with non-opioid users. OUD among cardiac surgery patients is associated with prolonged hospitalization and increased risk of postoperative morbidity, mainly driven by the patient's preoperative risk factors. Strategies to minimize these risk factors at the prehospitalization level is warranted to curb the opioid epidemic and improve overall outcomes in this vulnerable population. [ABSTRACT FROM AUTHOR]

Tested causal model of academic self-efficacy in faculty of research university. Data from Measure of Self-Efficacy in Academic Tasks instrument showed that being female contributed indirectly to feeling less efficacious about research tasks. Feeling nourished and rewarded by department and being male contributed to service self-efficacy. Teaching self-efficacy was not explained by model. (Author/NB)

Investigated the ability of the Wechsler Scale for Children-Revised (WISC-R) subtest scores to distinguish between three groups of behaviorally disordered boys and a control group. Results suggest that although WISC-R subtest scores were able to distinguish between the groups, their use as a classification metric could be highly misleading. (Author)

Background: The terms "Hernia Center" (HC) and Hernia Surgeon" (HS) have gained more and more popularity in recent years. Nevertheless, there is lack of protocols and methods for certification of their activities and results. The Italian Society of Hernia and Abdominal Wall Surgery proposes a method for different levels of certification.Methods: The national board created a commission, with the task to define principles and structure of an accreditation program. The discussion of each topic was preceded by a Systematic Review, according to PRISMA Guidelines and Methodology. In case of lack or inadequate data from literature, the parameter was fixed trough a Commission discussion.Results: The Commission defined a certification process including: "FLC - First level Certification": restricted to single surgeon, it is given under request and proof of a formal completion of the learning curve process for the basic procedures and an adequate year volume of operations. "Second level certification": Referral Center for Abdominal Wall Surgery. It is a public or private structure run by at least two already certified and confirmed FLC surgeons. "Third level certification": High Specialization Center for Abdominal Wall Surgery. It is a public or private structure, already confirmed as Referral Centers, run by at least three surgeons (two certified and confirmed with FLC and one research fellow in abdominal wall surgery). Both levels of certification have to meet the Surgical Requirements and facilities criteria fixed by the Commission.Conclusion: The creation of different types of Hernia Centers is directed to create two different entities offering the same surgical quality with separate mission: the Referral Center being more dedicated to clinical and surgical activity and High Specialization Centers being more directed to scientific tasks. [ABSTRACT FROM AUTHOR]

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic peroxisome biogenesis disorder with a reported incidence of 1 in 100 000 live births. The 3 genetic subtypes of RCDP are acquired by an autosomal recessive inheritance pattern. RCDP type 1 accounts for greater than 90% of all aggregate cases. Differentiating between the 3 subtypes of RCDP, as well as disorders characterized by similar punctate cartilaginous changes, is essential to guide an appropriate postnatal plan of care. Management strategies are focused toward associated clinical manifestations and require an interdisciplinary approach including ophthalmology, cardiovascular, endocrine, physical and occupational therapy, and neurology. Purposeful and frequent collaboration among all members of the neonatal/pediatric interdisciplinary team is necessary to optimize outcomes for the neonate and the family unit. The purpose of this article is to anticipate the needs of both patients with known and prenatal diagnosis of RCDP type 1 and patients with suspected clinical diagnosis of RCDP type 1 in the immediate neonatal period and to guide the appropriate plan of care. This article presents a case report of type I RCDP, as well as describes genetic influences, symptoms, diagnosis, management, and prognosis. [ABSTRACT FROM AUTHOR]