Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes.

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

Buffering Mitigates Chondrocyte Oxidative Stress, Metabolic Dysfunction, and Death Induced by Normal Saline: Formulation of a Novel Arthroscopic Irrigant.

For decades, surgeons have utilized 0.9% normal saline (NS) for joint irrigation to improve visualization during arthroscopic procedures. This continues despite mounting evidence that NS exposure impairs chondrocyte metabolism and compromises articular cartilage function. We hypothesized that chondrocyte oxidative stress induced by low pH is the dominant factor driving NS toxicity, and that buffering NS to increase its pH would mitigate these effects. Effects on chondrocyte viability, reactive oxygen species (ROS) production, and overall metabolic function were assessed. Even brief exposure to NS caused cell death, ROS overproduction, and disruption of glycolysis, pentose phosphate, and tricarboxylic acid (TCA) cycle pathways. NS also stimulated ROS overproduction in synovial cells that could adversely alter the synovial function and subsequently the entire joint health. Buffering NS with 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) significantly increased chondrocyte viability, reduced ROS production, and returned metabolite levels to near control levels while also reducing ROS production in synovial cells. These results confirm that chondrocytes and synoviocytes are vulnerable to insult from the acidic pH of NS and demonstrate that adding a buffering agent to NS averts many of its most harmful effects.

Incision Closure for Direct Anterior Total Hip Arthroplasty: Is There a Difference in the Rate of Superficial Wound Complications With Suture Versus Staples?

Background Direct anterior total hip arthroplasty (DA-THA) has increased in popularity over recent decades. However, DA-THA has been reported to have a higher incidence of superficial wound complications, including infection and incisional dehiscence, compared to other surgical approaches to hip arthroplasty. While this indicates a need for optimal wound closure, little research exists on the preferred method of skin closure following DA-THA. This study aimed to determine if there was any difference in rates of superficial infection, wound dehiscence, or overall wound complications with skin closure using a running subcuticular 3-0 Monocryl® suture compared to surgical staples following DA-THA.  Methods Records of patients who underwent DA-THA at our institution between July 2017 to July 2022 were retrospectively reviewed. Data were abstracted on patient demographics, comorbidities, skin closure method, and wound complications from the electronic medical record. Superficial infection and wound dehiscence were classified based on explicit diagnosis in post-operative records and incision photographs taken during follow-up visits. Overall wound complications were classified in patients who experienced either superficial infection, incisional dehiscence, or both complications following surgery. Descriptive statistics and chi-squared measures were obtained from post-operative patient data, and significance was set at p [Formula: see text] 0.05. Results A total of 365 DA-THAs were completed in 349 patients. A running subcuticular 3-0 Monocryl® suture closed 207 surgeries (56.7%), while surgical staples closed 158 surgeries (43.3%). There was no significant difference in independent rates of superficial infection (p = 0.076) or wound dehiscence (p = 0.118) between suture and staple cohorts; however, suture closure (10, 2.7%) was associated with a significantly higher rate of overall wound complications compared to staple closure (1, 0.3%) (p = 0.020). Conclusion DA-THA carries the risk of overall wound complications, including superficial infection and wound dehiscence. Our findings suggest superficial skin closure with staples may be preferred over sutures due to lower rates of overall wound complications. Further studies are needed to determine the optimal method of skin closure following DA-THA.

The impact of the distal ureteral diameter ratio, bladder volume at onset of vesicoureteral reflux, and/or grade in predictive models of clinical outcomes in children with vesicoureteral reflux.

PURPOSE: Vesicoureteral reflux (VUR) grade has been used as a primary factor in assessing a child's risk of clinical outcomes. Unfortunately, grade has poor inter-observer reliability. We hypothesized that more objective and reliable VCUG parameters including the distal ureteral diameter ratio (UDR) and volume at onset of VUR (Vol) may either augment or replace the current grading system to provide more reliable prediction of clinical outcomes. MATERIALS AND METHODS: Multivariate clinical outcome models were analyzed to assess the impact on predictive accuracy by the addition of voiding cystourethrogram (VCUG) data including grade, UDR, and Vol, alone or in combinations. Clinical variables from retrospective review of 841 children's records included age, gender, presentation, VUR laterality, bowel and bladder dysfunction, history of febrile urinary tract infection (UTI), and number of UTIs. The primary outcomes assessed included VUR resolution or persistence and need for operative intervention. RESULTS: Grade, UDR, and Vol were independent predictors of resolution and operative intervention. Vol increased predictive accuracy in resolution models with grade or UDR alone; however, no significant difference occurred in models with the substitution of grade with UDR. CONCLUSIONS: A more reliable classification system for VUR, with improved predictive accuracy regarding clinical outcomes, may be developed incorporating UDR and Vol. Whether VUR grade can be completely replaced by Vol and UDR measurements requires further evaluation with larger number of patients.