Systematic Review of Postoperative Velopharyngeal Insufficiency: Incidence and Association With Palatoplasty Timing and Technique.

Cleft palate is among the most common congenital disorders worldwide and is correctable through surgical intervention. Sub-optimal surgical results may cause velopharyngeal insufficiency (VPI). When symptomatic, VPI can cause hypernasal or unintelligible speech. The postoperative risk of VPI varies significantly in the literature but may be attributed to differences in study size, cleft type, surgical technique, and operative age. To identify the potential impact of these factors, a systematic review was conducted to examine the risk of VPI after primary palatoplasty, accounting for operative age and surgical technique. A search of PubMed, Embase, and Web of Science was completed for original studies that examined speech outcomes after primary palatoplasty. The search identified 4740 original articles and included 35 studies that reported mean age at palatoplasty and VPI-related outcomes. The studies included 10,795 patients with a weighted mean operative age of 15.7 months (range: 3.1-182.9 mo), and 20% (n=2186) had signs of postoperative VPI. Because of the heterogeneity in reporting of surgical technique across studies, small sample sizes, and a lack of statistical power, an analysis of the VPI risk per procedure type and timing was not possible. A lack of data and variable consensus limits our understanding of optimal timing and techniques to reduce VPI occurrence. This paper presents a call-to-action to generate: (1) high-quality research from thoughtfully designed studies; (2) greater global representation; and (3) global consensus informed by high-quality data, to make recommendations on optimal technique and timing for primary palatoplasty to reduce VPI.

Genome Analysis Using Whole-Exome Sequencing of Non-Syndromic Cleft Lip and/or Palate from Malagasy Trios Identifies Variants Associated with Cilium-Related Pathways and Asian Genetic Ancestry.

BACKGROUND: Orofacial clefts (OFCs) are common congenital disabilities that can occur as isolated non-syndromic events or as part of Mendelian syndromes. OFC risk factors vary due to differences in regional environmental exposures, genetic variants, and ethnicities. In recent years, significant progress has been made in understanding OFCs, due to advances in sequencing and genotyping technologies. Despite these advances, very little is known about the genetic interplay in the Malagasy population. METHODS: Here, we performed high-resolution whole-exome sequencing (WES) on non-syndromic cleft lip with or without palate (nCL/P) trios in the Malagasy population (78 individuals from 26 families (trios)). To integrate the impact of genetic ancestry admixture, we computed both global and local ancestries. RESULTS: Participants demonstrated a high percentage of both African and Asian admixture. We identified damaging variants in primary cilium-mediated pathway genes WNT5B (one family), GPC4 (one family), co-occurrence in MSX1 (five families), WDR11 (one family), and tubulin stabilizer SEPTIN9 (one family). Furthermore, we identified an autosomal homozygous damaging variant in PHGDH (one family) gene that may impact metabiotic activity. Lastly, all variants were predicted to reside on local Asian genetic ancestry admixed alleles. CONCLUSION: Our results from examining the Malagasy genome provide limited support for the hypothesis that germline variants in primary cilia may be risk factors for nCL/P, and outline the importance of integrating local ancestry components better to understand the multi-ethnic impact on nCL/P.

The effect of short-term preoperative nutritional intervention for cleft surgery eligibility.

BACKGROUND: Children with orofacial clefts are highly susceptible to malnutrition, with severe malnutrition restricting their eligibility to receive safe surgery. Ready-to-use therapeutic foods (RUTF) are an effective treatment for malnutrition; however, the effectiveness has not been demonstrated in this patient population prior to surgery. We studied the effectiveness of short-term RUTF use in transitioning children with malnutrition, who were initially ineligible for surgery, into surgical candidates. METHODS: A cohort of patients from Ghana, Honduras, Malawi, Madagascar, Nicaragua, and Venezuela enrolled in a nutrition program were followed by Operation Smile from June 2017 to January 2020. Age, weight, and length/height were tracked at each visit. Patients were included until they were sufficiently nourished (Z > = -1) with a secondary outcome of receiving surgery. The study was part of a collaborative program between Operation Smile (NGO), Birdsong Peanuts (peanut shellers and distributors), and MANA Nutrition (RUTF producer). RESULTS: A total of 556 patients were recruited between June 2017 and January 2020. At baseline 28.2% (n = 157) of patients were diagnosed with severe, 21.0% (n = 117) moderate, and 50.7% (n = 282) mild malnutrition. 324 (58.3%) presented for at least one return visit. Of those, 207 (63.7%) reached optimal nutrition status. By visit two, the mean z-score increased from -2.5 (moderate) to -1.7 (mild) (p < 0·001). The mean time to attain optimal nutrition was 6 weeks. There was a significant difference in the proportion of patients who improved by country(p < 0.001). CONCLUSION: Malnutrition prevents many children with orofacial clefts in low- and middle-income countries from receiving surgical care even when provided for free. This creates an even larger disparity in access to surgery. In an average of 6 weeks with an approximate cost of $25 USD per patient, RUTF transitioned over 60% of patients into nutritionally eligible surgical candidates, making it an effective, short-term preoperative nutritional intervention. Through unique partnerships, the expansion of cost-effective, large-scale nutrition programs can play a pivotal role in ensuring those at the highest risk of living with unrepaired orofacial clefts receive timely and safe surgical care.

High prevalence of deleterious mutations in concomitant nonsyndromic cleft and outflow tract heart defects.

Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole-blood-based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt-signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients.

Cleft Lip and Palate Research in Low- and Middle-income Countries: A Scientometric Analysis.

Cleft lip and palate (CLP) comprise over 90% of the world's congenital anomalies and cause significant disability worldwide, while disproportionally burdening low- and middle-income countries (LMICs). Research can help inform strategies that reduce disparities in accessing CLP care. We performed a scientometric analysis of CLP research in LMICs to identify influential contributors and themes. METHODS: The authors searched seven citation databases accessed via Web of Science, from inception to March 2, 2021. Social network analysis was done using VOSviewer. The Kruskal-Wallis test and linear regression were used. RESULTS: In total, 1561 articles authored by 6414 researchers affiliated with 2113 organizations in 119 countries were included. Most authors (n = 6387, 99.6%) had published two or more articles. The USA (454 articles), Brazil (211 articles), China (175 articles), and India (127 articles) published the most. The most prolific institutions were the University of Sao Paulo (94 articles), the University of Pittsburgh (57 articles), and the University of Iowa (55 articles). Marazita ML (33 articles), Shi B (27 articles), and Murray JC (22 articles) had the highest number of publications. An estimated 510 articles (32.7%) were focused on epidemiology, 240 (15.4%) on management, and 54 (3.5%) on global plastic surgery for CLP. CONCLUSIONS: LMICs are disproportionally burdened by CLP, but research is limited and often produced by high-income countries. This study elucidates partnership and health system strengthening opportunities to improve LMIC research capacity and ultimately informs the management and outcomes for patients with CLP.

The influence of an all-female healthcare environment on mentorship and empowerment of female healthcare professionals.

Low- and middle-income countries (LMICs) have the greatest need for additional healthcare providers, and women outside the workforce help address the need. Women in healthcare need more mentorship and leadership training to advance their careers due to systemic barriers. This study evaluates how women working together on a medical team influences mentorship, leadership and empowerment. A single all-female volunteer team participating in a cleft surgery mission in Oujda, Morocco were surveyed before and after the mission. Statistical analysis with student's t-test or chi-squared were performed. 95 female volunteers from 23 countries participated on this team and 85% completed surveys. Volunteers from high-income countries (32%) and LMICs (68%) had similar mission roles (p = 0.58). Experience as a mission volunteer (p = 0.47), team leader (p = 0.28), and educator (p = 0.18) were equivalent between cohorts. 73% of women had previously received mentorship but 98% wanted more. 75% had previously mentored others, but 97% wanted to be mentors. 73% of volunteers who had no prior mentorship found their first mentor during the mission. All participants found a long-term peer relationship and felt motivated to mentor women at home. 95% were inspired to pursue leadership positions, advance professionally, and continue working with other women. This population of female healthcare professionals overwhelmingly desired more mentorship than is felt to be available. An all-female healthcare environment appears to provide opportunities for mentorship and create lasting motivation to teach, lead, and advance professionally. Findings raise the potential that increasing visibility of female professionals may effectively empower women in healthcare.

Predictors of Complication Following Cleft Lip and Palate Surgery in a Low-Resource Setting: A Prospective Outcomes Study in Nicaragua.

BACKGROUND: Higher rates of postoperative complication following cleft lip or palate repair have been documented in low resource settings, but their causes remain unclear. This study sought to delineate patient, surgeon, and care environment factors in cleft complications in a low-income country. DESIGN: Prospective outcomes study. SETTING: Comprehensive Cleft Care Center. PATIENTS: Candidate patients presenting for cleft lip or palate repair or revision. INTERVENTIONS: Patient anthropometric, nutritional, environmental and peri- and post-operative care factors were collected. Post-operative evaluation occurred at standard 1-week and 2-month postoperative intervals. MAIN OUTCOME MEASURES: Complication was defined as fistula, dehiscence and/or infection. RESULTS: Among 408 patients enrolled, 380 (93%) underwent surgery, of which 208 (55%) underwent lip repair (124) or revision (84), and 178 (47%) underwent palate repair (96) or revision (82). 322 (85%) were evaluated 1 week and 166 (44%) 2 months postoperatively. 50(16%) complications were identified, including: 25(8%) fistulas, 24(7%) dehiscences, 17(5%) infections. Mid-upper arm circumference (MUAC) ≤12.5 cm was associated with dehiscence after primary lip repair (OR = 28, p = 0.02). Leukocytosis ≥11,500 on pre-operative evaluation was associated with dehiscence (OR = 2.51, p = 0.04) or palate revision fistula (OR = 64, p < 0.001). Surgeons who performed fewer previous-year palate repairs had higher likelihood of palate complications, (OR = 3.03, p = 0.01) although there was no difference in complication rate with years of surgeon experience or duration of surgery. CONCLUSIONS: Multiple patient, surgeon, and perioperative factors are associated with higher rates of complication in a low-resource setting, and are potentially modifiable to reduce complications following cleft surgery.

The International Family Study of Nonsyndromic Orofacial Clefts: Design and Methods.

BACKGROUND: The majority of research to understand the risk factors of nonsyndromic orofacial clefts (NSOFCs) has been conducted in high-income populations. Although patients with NSOFCs in low- and middle-income countries (LMICs) are at the highest risk of not receiving care, global health infrastructure allows innovative partnerships to explore the etiologic mechanisms of cleft and targets for prevention unique to these populations. METHODS: The International Family Study (IFS) is an ongoing case-control study with supplemental parental trio data designed to examine genetic, environmental, lifestyle, and sociodemographic risk factors for NSOFCs in 8 LMICs (through August 2020). Interview and biological samples are collected for each family. The interview includes demographics, family history of cleft, diet and water sources, maternal pregnancy history, and other lifestyle and environmental factors. RESULTS: Seven of 8 countries are currently summarized (2012-2017) for a total of 2955 case and 2774 control families with 11 946 unique biological samples from Vietnam, Philippines, Honduras, Madagascar, Morocco, Democratic Republic of the Congo, and Nicaragua. The phenotype distribution was 1641 (55.5%) cases with cleft lip and palate, 782 (26.5%) with cleft lip (CL), and 432 (14.6%) with cleft palate (CP). DISCUSSION: The International Family Study is the largest case set of NSOFCs with an associated biobank in LMICs currently assembled. The biobank, family, and case-control study now include samples from 8 LMICs where local health care infrastructure cannot address the surgical burden of cleft or investigate causal mechanisms. The International Family Study can be a source of information and may collaborate with local public health institutions regarding education and interventions to potentially prevent NSOFCs.

The Smile Index: Part 3. A Simple, Prognostic Severity Scale for Unilateral Cleft Palate.

BACKGROUND: Unilateral cleft palates have a large spectrum of variability. Key morphologic factors such as cleft width and palatal length are not represented in current classification systems. Palate length and velopharyngeal port size are clinically linked to speech outcomes, as the soft palate must close the posterior pharynx for proper phonation. This study investigates the relationship between objective preoperative measures and postoperative velopharyngeal port size, to define a reproducible severity scale. METHODS: Surgical data were prospectively collected from unilateral cleft palate patients in Morocco, Bolivia, Vietnam, and Madagascar. Key measurements were cleft width and palate width at the hard-soft palate junction, alveolar cleft width, vertical alveolar discrepancy, velopharyngeal port size. Cleft width ratio (CWR) was defined as the width of the cleft at the hard-soft junction, divided by the palate width. RESULTS: Seventy-six patients were evaluated. Thirty-one had complete clefts and average age at surgical repair was 2.9 years. Mean CWR was 0.50 ± 0.12. Palate length was increased by an average of 2.2 mm (11%) after palatoplasty. Multivariate analysis determined greater CWR and larger preoperative velopharyngeal ports were significantly correlated with a smaller percent change in palate length after palatoplasty (P < 0.01). CONCLUSIONS: A wider palatal cleft decreases the surgeon's ability to decrease velopharyngeal port size through palatoplasty. Given the ease of measurement even in low-resource settings, CWR may be a valuable tool for setting expectations for speech results, modifying surgical technique, and correlating future speech outcomes in evidence-based cleft care.

Convolutional Neural Network Models for Automatic Preoperative Severity Assessment in Unilateral Cleft Lip.

BACKGROUND: Despite the wide range of cleft lip morphology, consistent scales to categorize preoperative severity do not exist. Machine learning has been used to increase accuracy and efficiency in detection and rating of multiple conditions, yet it has not been applied to cleft disease. The authors tested a machine learning approach to automatically detect and measure facial landmarks and assign severity grades using preoperative photographs. METHODS: Preoperative images were collected from 800 unilateral cleft lip patients, manually annotated for cleft-specific landmarks, and rated using a previously validated severity scale by eight expert reviewers. Five convolutional neural network models were trained for landmark detection and severity grade assignment. Mean squared error loss and Pearson correlation coefficient for cleft width ratio, nostril width ratio, and severity grade assignment were calculated. RESULTS: All five models performed well in landmark detection and severity grade assignment, with the largest and most complex model, Residual Network, performing best (mean squared error, 24.41; cleft width ratio correlation, 0.943; nostril width ratio correlation, 0.879; severity correlation, 0.892). The mobile device-compatible network, MobileNet, also showed a high degree of accuracy (mean squared error, 36.66; cleft width ratio correlation, 0.901; nostril width ratio correlation, 0.705; severity correlation, 0.860). CONCLUSIONS: Machine learning models demonstrate the ability to accurately measure facial features and assign severity grades according to validated scales. Such models hold promise for the creation of a simple, automated approach to classifying cleft lip morphology. Further potential exists for a mobile telephone-based application to provide real-time feedback to improve clinical decision making and patient counseling.

Factors Associated With Delay in Cleft Surgery at a Tertiary Children's Hospital in a Major US Metropolitan City.

OBJECTIVE: To identify factors associated with late cleft repair at a US tertiary children's hospital. DESIGN: Retrospective study of children with CL/P using Children's Hospital Los Angeles (CHLA) records. SETTING: US tertiary children's hospital. PATIENTS/PARTICIPANTS: Patients undergoing primary CL or CP repair at CHLA from 2009 to 2018. MAIN OUTCOME MEASURES: Proportion of children who had delayed primary CL repair or CP repair using CHLA and American Cleft Palate-Craniofacial Association (ACPA) guidelines and factors associated with late surgery. RESULTS: In total, 805 patients-503 (62.5%) who had CL repair, 302 (37.5%) CP repair-were included. Using CHLA protocol, 14.3% of patients seeking CL repair had delayed surgery. Delay was significantly associated with female gender, non-Hispanic ethnicity, Spanish primary language, government insurance, bilateral cleft, cleft lip and palate (CLP), and syndromic diagnosis. Using ACPA guidelines, 5.4% had delayed surgery. Female gender and syndromic diagnosis were significantly associated with delay and remained significant after adjustment for confounders in multivariate models. For CP repair, 60.3% of patients had delayed surgery using CHLA protocol. Cleft lip and palate diagnosis, complete cleft, syndromic diagnosis, and longer travel distance were significantly associated with delay. Using ACPA guidelines, 28.5% had delayed surgery; however, significant association with patient variables was not consistently observed. CONCLUSIONS: Delay in cleft surgery occurs most often for patients seeking CP repair and is associated with female gender, non-Hispanic ethnicity, Spanish language, government insurance, and bilateral CL, CLP, or syndromic diagnoses. Initiatives should aim to optimize cleft surgery delivery for these subpopulations.

The Use of Crowdsourcing Technology to Evaluate Preoperative Severity in Patients With Unilateral Cleft Lip in a Multiethnic Population.

ABSTRACT: Crowd sourcing has been used in multiple disciplines to quickly generate large amounts of diverse data. The objective of this study was to use crowdsourcing to grade preoperative severity of unilateral cleft lip phenotype in a multiethnic cohort with the hypothesis that crowdsourcing could efficiently achieve similar rankings compared to expert surgeons. Deidentified preoperative photos were collected for patients with primary, unilateral cleft lip with or without cleft palate (CL ±â€ŠP). A platform was developed with C-SATS for pairwise comparisons utilizing Elo rankings by crowdsource workers through Amazon Mechanical Turk. Images were independently ranked by 2 senior surgeons for comparison. Seventy-six patients with varying severity of unilateral (CL ±â€ŠP) phenotype were chosen from Operation Smile missions in Bolivia, Madagascar, Vietnam, and Morocco. Patients were an average of 1.2 years' old, ranging from 3 months to 3.3 years. Each image was compared with 10 others, for a total of 380 unique pairwise comparisons. A total of 4627 total raters participated with a median of 12 raters per pair. Data collection was completed in <20 hours. The crowdsourcing ranking and expert surgeon rankings were highly correlated with Pearson correlation coefficient of R = 0.77 (P = 0.0001). Crowdsourcing provides a rapid and convenient method of obtaining preoperative severity ratings, comparable to expert surgeon assessment, across multiple ethnicities. The method serves as a potential solution to the current lack of rating systems for preoperative severity and overcomes the difficulty of acquiring large-scale assessment from expert surgeons.

The Local Mission: Improving Access to Surgical Care in Middle-Income Countries.

BACKGROUND: Billions of people lack access to quality surgical care. Short-term missions are used to supplement the delivery of surgical care in regions with poor access to care. Traditionally known for using international teams, Operation Smile has transitioned to using a local mission model, where surgical service is delivered to areas of need by teams originating within that country. This study investigates the proportion and location of Operation Smile missions that use the local mission model. METHODS: A retrospective review was performed of the Operation Smile mission database for fiscal years 2014 to 2019. Missions were classified into local or international missions. Countries were also classified by their income levels as well as their specialist surgical workforce (SAO) density. As no individual patient or provider data was recorded, ethics board approval was not warranted. RESULTS: Between 2014 and 2019, Operation Smile held an average of 144.8 (range 135-154) surgical missions per year. Local missions accounted for 97 ± 5.6 (67%) of the missions. Of the 34 program countries, 26 (76%) used local missions. Of the countries that had only international missions, six (75%) were low-income countries and the average SAO density was 1.54 (range 0.19-5.88) providers per 100,000 people. Of the countries with local missions, 24 (92%) were middle-income, and the average SAO density was 30.9 (range 3.4-142.4). CONCLUSION: International investments may assist in the creation of local surgical teams. Once teams are established, local missions are a valuable way to provide specialized surgical care within a country's own borders.

The experiences of female surgeons around the world: a scoping review.

INTRODUCTION: The Lancet Commission for Global Surgery identified an adequate surgical workforce as one indicator of surgical care accessibility. Many countries where women in surgery are underrepresented struggle to meet the recommended 20 surgeons per 100,000 population. We evaluated female surgeons' experiences globally to identify strategies to increase surgical capacity through women. METHODS: Three database searches identified original studies examining female surgeon experiences. Countries were grouped using the World Bank income level and Global Gender Gap Index (GGGI). RESULTS: Of 12,914 studies meeting search criteria, 139 studies were included and examined populations from 26 countries. Of the accepted studies, 132 (95%) included populations from high-income countries (HICs) and 125 (90%) exclusively examined populations from the upper 50% of GGGI ranked countries. Country income and GGGI ranking did not independently predict gender equity in surgery. Female surgeons in low GGGI HIC (Japan) were limited by familial support, while those in low income, but high GGGI countries (Rwanda) were constrained by cultural attitudes about female education. Across all populations, lack of mentorship was seen as a career barrier. HIC studies demonstrate that establishing a critical mass of women in surgery encourages female students to enter surgery. In HICs, trainee abilities are reported as equal between genders. Yet, HIC women experience discrimination from male co-workers, strain from pregnancy and childcare commitments, and may suffer more negative health consequences. Female surgeon abilities were seen as inferior in lower income countries, but more child rearing support led to fewer women delaying childbearing during training compared to North Americans and Europeans. CONCLUSION: The relationship between country income and GGGI is complex and neither independently predict gender equity. Cultural norms between geographic regions influence the variability of female surgeons' experiences. More research is needed in lower income and low GGGI ranked countries to understand female surgeons' experiences and promote gender equity in increasing the number of surgical providers.

The role of smoke from cooking indoors over an open flame and parental smoking on the risk of cleft lip and palate: A case- control study in 7 low-resource countries.

BACKGROUND: Cleft is one of the most common birth defects globally and the lack of access to surgery means millions are living untreated. Smoke exposure from cooking occurs infrequently in developed countries but represents a high-proportion of smoke exposure in less-developed regions. We aimed to study if smoke exposure from cooking is associated with an increased risk in cleft, while accounting for other smoke sources. METHODS: We conducted a population-sampled case-control study of children with cleft lip and/or palate and healthy newborns from Vietnam, Philippines, Honduras, Nicaragua, Morocco, Congo, and Madagascar. Multivariable regression models were used to assess associations between maternal cooking during pregnancy, parental smoking, and household tobacco smoke with cleft. RESULTS: 2137 cases and 2014 controls recruited between 2012-2017 were included. While maternal smoking was uncommon (<1%), 58.3% case and 36.1% control mothers cooked over an open fire inside. Children whose mothers reported cook smoke exposure were 49% (95% confidence interval (CI) = 1.2-1.8) more likely to have a child with a cleft. This was consistent in five of seven countries. No significant associations were found for any other smoke exposure. CONCLUSIONS: Our finding of maternal cook smoke and cleft in low-resource countries, similar to maternal tobacco smoke in high-resource countries, may reflect a common etiology. This relationship was present across geographically diverse countries with variable socioeconomic statuses and access to care. Exposures specific to low-resource settings must be considered to develop public health strategies that address the populations at increased risk of living with cleft and inform the mechanisms leading to cleft development.

A Synonymous Exonic Splice Silencer Variant in IRF6 as a Novel and Cryptic Cause of Non-Syndromic Cleft Lip and Palate.

Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 (IRF6) have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband's grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of IRF6 (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5' of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants.

Congenital Heart Disease in Patients With Cleft Lip/Palate and Its Impact on Cleft Management.

OBJECTIVE: To evaluate characteristics of congenital heart disease (CHD) in patients with cleft lip and/or palate (CL/P) and assess potential associations with cleft outcomes. DESIGN: Retrospective review of all patients with CL/P who underwent primary cleft treatment from 2009 to 2015. SETTING: Children's Hospital Los Angeles, a tertiary hospital. PATIENTS: Exclusion criteria included microform cleft lip diagnosis, international patients, and patients presenting for secondary repair or revision after primary repair at another institution. MAIN OUTCOMES MEASURED: Patient demographics, prenatal and birth characteristics, CL/P characteristics, syndromic status, postoperative complications, and other outcomes were analyzed relative to CHD diagnoses and management. Patients with CL/P with (+CHD) were compared to those without (-CHD) CHD using χ2 tests and analysis of variance. RESULTS: Among 575 patients with CL/P, 83 (14.4%) had CHD. Congenital heart disease rates were significantly higher in patients with cleft palate (CP) compared to other cleft types (χ2, P = .009). Eighty-one (97.6%) out of 83 +CHD patients were diagnosed prior to initial CL/P surgical assessment. Twenty-three (27.7%) +CHD patients required surgical repair of 10 cardiac anomalies prior to cleft care. Congenital heart disease was associated with delayed CP repair and increased rates of fistula in isolated patients with CP. CONCLUSIONS: Congenital heart disease is known to be more prevalent in patients with CL/P. These data suggest the condition is particularly increased in patients with CP. Severe forms of CHD are diagnosed and treated prior to cleft care however postoperative fistula may be more common in patients with CHD. Therefore, careful attention is required for patient optimization and palatal flap dissection in patients with coexisting CHD and CL/P.

Pilot Evaluation of the Impact of a Mission-Based Surgical Training Rotation on the Plastic Surgery Skills and Competencies Development of General Surgery Residents in Rwanda.

OBJECTIVE: Increasing subspecialty surgical capacity in Rwanda requires innovative approaches to augment the skills of pre-existing surgical providers. Short-term, high-intensity training programs can be effective for surgical education, however, few studies have investigated the quality of skills acquired through a condensed surgical experience. This study aims to determine the efficacy of a 3-week surgical training rotation (STR) to teach plastic surgery skills to general surgery residents in Rwanda. DESIGN: A survey-based, prospective observational study of general surgery residents and volunteer plastic surgery educators participating in an Operation Smile STR. Resident self-assessment scores of surgical capabilities at the beginning and end of the rotation were compared to surgeon evaluation of resident performance. Progression of resident performance and change in inter-rater reliability between residents and educators were analyzed. Student's t test with significance at p < 0.05 was used to confirmed statistical significance. SETTING: This study took place during the Operaiton Smile STR at the Rwinkwavu District Hospital, a primary level hospital in Rwinkwavu, Rwanda. PARTICIPANTS: All residents (5) and surgeon evaluators (4) who participated in the STR were included in this study. All study participants completed all study surveys. RESULTS: Residents reported a significant increase in confidence with the majority of procedures performed by the end of the rotation. Surgeons identified significant improvement in all resident skills by 2 weeks (p < 0.05). Resident ability to perform self-assessment improved, as determined by a significant decrease in inter-rater error margin from -0.61 to -0.10 over the course of the rotation (p < 0.01). CONCLUSIONS: In this pilot study, a 3 week rotation improved surgical competencies and technical skills of general surgery residents learning plastic surgery. These findings support using the short-term STR as a method for task-sharing education. Further studies are needed to determine durability of skills transfer and long-term impact on surgical capacity.

The Smile Index: Part 2. A Simple, Prognostic Severity Scale for Unilateral Cleft Lip.

BACKGROUND: There is no universally accepted classification system for unilateral cleft lip that objectively quantifies the spectrum of disease, making it difficult to evaluate postoperative outcomes in the context of preoperative severity. METHODS: Anthropometric measurements and photographs were prospectively collected from unilateral cleft lip patients in Morocco, Bolivia, Vietnam, and Madagascar. Columellar angle, cleft width, nostril widths, vertical lip heights, and horizontal vermillion lengths were measured preoperatively and postoperatively. "Unacceptable" postoperative outcomes were defined as those with a cleft-side/non-cleft-side vertical lip height discrepancy greater than 3 mm, based on previous sociologic and cleft outcome studies. RESULTS: Of the 147 patients studied, 22 had unacceptable outcomes. Univariate logistic and multivariate logistic stepwise models showed that among preoperative characteristics, cleft width ratio (preoperative cleft width divided by commissure width) was the most significant predictor for unacceptable outcomes, controlling for surgeon experience. Cleft width ratio was normally distributed. Two severity categories were created based on iterative data and regression analysis: "severe" (cleft width ratio >0.5) and "not-severe" (cleft width ratio <0.5). Severe patients had a higher likelihood of unacceptable outcomes versus not-severe patients (OR, 2.9; 95 percent CI, 1.1 to 7.7; p = 0.029; 27 percent versus 11 percent). The probability of having unacceptable outcomes for severe individuals was higher versus not-severe individuals (positive predictive value, 73 percent versus 89 percent). CONCLUSIONS: Preoperative cleft width ratio greater than 0.5 is associated with having an unacceptable surgical outcome. The authors propose a simple, objective, and clinically reproducible scale to unify the language of unilateral cleft lip severity, as a step toward improving algorithms of care, directing surgical technique, guiding patient/family discussions, and optimizing patient outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.