Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer.

Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.

Radiographic severity is associated with worse executive function in metopic craniosynostosis.

BACKGROUND: Children with metopic synostosis have been found to have more neurocognitive and behavioral difficulties. The variables that may affect future neurodevelopmental outcomes, including presenting morphologic severity, have not been fully studied. In the largest study to date, we aimed to assess what portends worse neurocognitive and behavioral outcomes at school age. METHODS: Children 6-18 years old with surgically corrected metopic nonsyndromic craniosynostosis underwent neurocognitive testing. Parents completed behavior rating surveys about their child: Conners-3 (ADHD), Social Responsiveness Scale-2 (autism spectrum disorder), Behavior Rating Inventory of Executive Function-2 (BRIEF-2: executive function), and Child's Behavior Checklist (overall behavior). The endocranial bifrontal angle (EBA), adjusted EBA (aEBA), frontal angle (FA), and AI-derived metopic severity score (MSS) were determined on pre-operative CT images. Multivariate linear regressions were used to evaluate the association of age at surgery and severity. RESULTS: There were 87 children who underwent neurocognitive testing (average age 10.9 ± 3.3 years) of whom 67 also completed behavioral assessments. Greater phenotypical severity of metopic synostosis (lower FA, aEBA, and EBA) was associated with worse scores on the subscales of the BRIEF-2 (executive function) and executive subscale of the Conners-3. Increasing age at surgery was associated with worse executive function subscale scores of the Conners-3 when controlling for each severity measurement and sociodemographic risk. CONCLUSION: Children with greater phenotypic severity of metopic synostosis have worse executive function at school age. The majority of children with metopic synostosis have signs of ADHD. Later surgeries (greater than 12 months) may impact executive functioning, regardless of the degree of severity. Future research should aim at identifying the direct structural changes to the brain.

Severity of Mandibular Dysmorphology in Treacher Collins Syndrome for Stratification of Perioperative Airway Risk.

BACKGROUND: Patients with Treacher Collins syndrome (TCS) and attendant airway dysmorphology may be predisposed to airway complications in the perioperative period. However, limited data correlates severity of mandibular hypoplasia and airway status. This study aims to improve risk stratification for perioperative airway insufficiency in TCS by using a previously proposed mandibular severity index. METHODS: Patient demographics, perioperative airway status, difficulty of intubation, and Cormack Lehane grade were collected and compared using a TCS mandibular hypoplasia severity grading scale in patients with TCS treated between 2000 and 2022. RESULTS: Twenty-six patients underwent 222 procedures with institutional mandibular severity gradings as follows: 23% Grade I, 31% Grade II, 39% Grade III, 8% Grade IV. Our severity index was associated with intubation difficulty ( P <0.001) and difficult airway status ( P <0.001), with 72% of difficult airways found in grade III and grade IV patients. Mandibular retrusion and ramal hypoplasia subscores were positively correlated with measures of airway severity ( P <0.001), whereas the gonial angle was negatively correlated ( P <0.001). Age was negatively correlated with difficult visualization for endotracheal intubation ( P =0.02) but had no association with difficult airway status ( P =0.2). CONCLUSIONS: This study found a positive correlation between severity of maxillomandibular dysmorphology and perioperative airway difficulty in TCS patients. Our findings suggest that severely affected patients require heightened vigilance throughout life, as difficult airways may not completely resolve with aging. Given the risk of morbidity and mortality associated with airway complications, proper identification and preparation for challenging airways is critical for TCS patients.

Changes in Ventricular Volume After Posterior Vault Distraction Osteogenesis in Patients With Syndromic and Nonsyndromic Craniosynostosis.

OBJECTIVE: Little is known about the response of the ventricular system to cranial vault surgery in patients with craniosynostosis. This study aims to evaluate the changes in the cerebral ventricular system in response to posterior vault distraction osteogenesis (PVDO) in patients with syndromic and nonsyndromic craniosynostosis. METHODS: A single-institution retrospective review of all patients with craniosynostosis undergoing PVDO from 2000 to 2022 was completed. Patients were included for analysis if they had pre and postoperative cranial computed tomography scans. Ventricular volume (VV) and intracranial volume (ICV) were calculated using segmentation software. RESULTS: Both patients with syndromic synostosis and nonsyndromic synostosis (NSS) experienced a significant increase in ICV after PVDO, but only patients with NSS experienced a significant VV change ( P = 0.004). After normalization by ICV, total, lateral, and third VV changes retained significance with percentage increases of 114%, 117%, and 89%, respectively ( P < 0.05 for all). CONCLUSION: The differing results between cohorts reinforce the concept that the intracranial milieu is different between patients with syndromic synostosis and NSS. The results of the NSS cohort suggest that these patients may exist in a compensated state in which a reduction in cerebral blood flow and VV allows for the maintenance of parenchymal health to prevent the development of intracranial hypertension. Further studies may explore VV as a surrogate marker of ICP elevation, and the utility of cranial vault remodeling on nonsynostotic pathologies with cephalocranial disproportion.

LeFort III Versus Monobloc Frontofacial Advancement: A Comparative Analysis of Soft Tissue Changes.

INTRODUCTION: The LeFort III and monobloc are commonly used midface advancement procedures for patients with syndromic craniosynostosis with well characterized postoperative skeletal changes. However, the differential effects of these procedures on facial soft tissues are less understood. The purpose of this study was to critically analyze and compare the effects of these 2 procedures on the overlying soft tissues of the face. METHODS: Frontal and lateral preoperative and postoperative photographs of patients undergoing monobloc or LeFort III were retrospectively analyzed using ImageJ to measure soft tissue landmarks. Measurements included height of facial thirds, nasal length and width, intercanthal distance, and palpebral fissure height and width. Facial convexity was quantified by calculating the angle between sellion (radix), subnasale, and pogonion on lateral photographs. RESULTS: Twenty-five patients with an average age of 6.7 years (range 4.8-14.5) undergoing monobloc (n=12) and LeFort III (n=13) were identified retrospectively and analyzed preoperatively and 6.4±3.6 months postoperatively. Patients undergoing LeFort III had a greater average postoperative increase in facial convexity angle acuity (28.2°) than patients undergoing monobloc (17.8°, P =0.021). Patients in both groups experience postoperative increases in nasal width ( P <0.001) and decreases in palpebral fissure height ( P <0.001). CONCLUSIONS: Both subcranial LeFort III advancements and monobloc frontofacial advancements resulted in significant changes in the soft tissues. Patients undergoing LeFort III procedures achieved greater acuity of the facial convexity angle, likely because the nasion is not advanced with the LeFort III segment.

Validating the Supraorbital Notch-Nasion-Supraorbital Notch Angle as a Marker for Metopic Craniosynostosis Severity.

OBJECTIVE: Metopic craniosynostosis (MCS) can be difficult to differentiate from metopic ridge (MR) or normal frontal morphology. This study assess whether the supraorbital notch-nasion-supraorbital notch (SNS) angle can help identify MCS. METHODS: Records of 212 patients with preoperative three-dimensional computed tomography scans were examined. The SNS angles, surgeon craniofacial dysmorphology rankings, and CranioRate metopic severity scores (MSSs) were compared with the Spearman rank correlation coefficient. Receiver operating characteristic (ROC) curves with Youden J-statistic and cross-validation of regression models assessed the ability of these measures to predict surgery. RESULTS: A total of 212 patients were included, consisting of 78 MCS, 37 MR, and 97 controls. Both the mean SNS angle (MCS: 111.7 ± 10.7 degrees, MR: 126.0 ± 8.2 degrees, controls: 130.7 ± 8.8 degrees P < 0.001) and MSS (MCS: 5.9 ± 2.0, MR: 1.4 ± 1.9, controls: 0.2 ± 1.9, P < 0.001) were different among the cohorts. The mean SNS angle (111.5 ± 10.7 versus 129.1 ± 8.8, P < 0.001) was lower in those who had surgery and CranioRate score (5.9 ± 2.1 versus 0.8 ± 2.2, P < 0.001) was higher in those who underwent surgery. SNS angles were positively correlated with surgeon craniofacial dysmorphology rankings ( r = 0.41, P < 0.05) and CranioRate MSS ( r = 0.54, P < 0.05). The ROC curve requiring high sensitivity revealed an SNS angle of 124.8 degrees predicted surgery with a sensitivity of 88.7% and a specificity of 71.3%. A ROC curve using the CranioRate MCC values ≥3.19 predicted surgery with 88.7% sensitivity and 94.7% specificity. CONCLUSION: Orbital dysmorphology in patients with MCS is well captured by the supraorbital-nasion angle. Both the SNS angle and CranioRate MSS scores accurately predict surgical intervention.

Multi-Omics Analysis Identified Drug Repurposing Targets for Chronic Obstructive Pulmonary Disease.

Despite recent advances in chronic obstructive pulmonary disease (COPD) research, few studies have identified the potential therapeutic targets systematically by integrating multiple-omics datasets. This project aimed to develop a systems biology pipeline to identify biologically relevant genes and potential therapeutic targets that could be exploited to discover novel COPD treatments via drug repurposing or de novo drug discovery. A computational method was implemented by integrating multi-omics COPD data from unpaired human samples of more than half a million subjects. The outcomes from genome, transcriptome, proteome, and metabolome COPD studies were included, followed by an in silico interactome and drug-target information analysis. The potential candidate genes were ranked by a distance-based network computational model. Ninety-two genes were identified as COPD signature genes based on their overall proximity to signature genes on all omics levels. They are genes encoding proteins involved in extracellular matrix structural constituent, collagen binding, protease binding, actin-binding proteins, and other functions. Among them, 70 signature genes were determined to be druggable targets. The in silico validation identified that the knockout or over-expression of SPP1, APOA1, CTSD, TIMP1, RXFP1, and SMAD3 genes may drive the cell transcriptomics to a status similar to or contrasting with COPD. While some genes identified in our pipeline have been previously associated with COPD pathology, others represent possible new targets for COPD therapy development. In conclusion, we have identified promising therapeutic targets for COPD. This hypothesis-generating pipeline was supported by unbiased information from available omics datasets and took into consideration disease relevance and development feasibility.

Incomes to Outcomes: A Global Assessment of Disparities in Cleft and Craniofacial Treatment.

OBJECTIVE: Recent investigations focused on health equity have enumerated widespread disparities in cleft and craniofacial care. This review introduces a structured framework to aggregate findings and direct future research. DESIGN: Systematic review was performed to identify studies assessing health disparities based on race/ethnicity, payor type, income, geography, and education in cleft and craniofacial surgery in high-income countries (HICs) and low/middle-income countries (LMICs). Case reports and systematic reviews were excluded. Meta-analysis was conducted using fixed-effect models for disparities described in three or more studies. SETTING: N/A. PATIENTS: Patients with cleft lip/palate, craniosynostosis, craniofacial syndromes, and craniofacial trauma. INTERVENTIONS: N/A. RESULTS: One hundred forty-seven articles were included (80% cleft, 20% craniofacial; 48% HIC-based). Studies in HICs predominantly described disparities (77%,) and in LMICs focused on reducing disparities (42%). Level II-IV evidence replicated delays in cleft repair, alveolar bone grafting, and cranial vault remodeling for non-White and publicly insured patients in HICs (Grades A-B). Grade B-D evidence from LMICs suggested efficacy of community-based speech therapy and remote patient navigation programs. Meta-analysis demonstrated that Black patients underwent craniosynostosis surgery 2.8 months later than White patients (P < .001) and were less likely to undergo minimally-invasive surgery (OR 0.36, P = .002). CONCLUSIONS: Delays in cleft and craniofacial surgical treatment are consistently identified with high-level evidence among non-White and publicly-insured families in HICs. Multiple tactics to facilitate patient access and adapt multi-disciplinary case in austere settings are reported from LMICs. Future efforts including those sharing tactics among HICs and LMICs hold promise to help mitigate barriers to care.

Sociodemographic Factors Predict Long-Term Attrition from Multidisciplinary Cleft Clinic.

OBJECTIVE: Identify and describe factors associated with retention and attrition of patients during longitudinal follow-up at multidisciplinary cleft clinic. DESIGN: Retrospective cohort study. SETTING: Single, tertiary care center. PATIENTS, PARTICIPANTS: Patients born between 1995 and 2007 with a diagnosis of cleft palate with or without cleft lip attending multidisciplinary cleft clinic. INTERVENTIONS: None tested, observational study. MAIN OUTCOME MEASURE(S): Age at last clinical appointment with a multidisciplinary cleft team provider. Attrition was defined as absence of an outpatient appointment following 15 years of age. RESULTS: Six hundred seventy-eight patients were included. The average age at last appointment across the entire cohort was 13.1 years (IQR 6.6-17.2). Patients who were Black (HR 1.60, 95% CI 1.10-2.32, p = 0.014) and other races (HR 1.90, 95% CI 1.22-2.98, p = 0.004) were more likely to be lost to follow-up compared to white patients. Publicly insured patients were more likely to experience attrition than those who were privately insured (HR 1.30, 95% CI 1.03-1.65, p = 0.030). Estimated income was not significantly associated with length of follow-up (p = 0.259). Those whose residence was in the fourth quartile of driving distance from our center experienced loss to follow-up significantly more than those who lived the closest (HR 2.04, 95% CI 1.50-2.78, p < 0.001). CONCLUSIONS: There is a high degree of follow-up attrition among patients with cleft lip and palate. Race, insurance status, and driving distance to our center were associated with attrition in a large, retrospective cohort of patients who have reached the age of cleft clinic graduation.

Psychosocial Status and Self-Perception in Patients with Cleft Lip and/or Palate.

OBJECTIVE: To describe how the psychosocial status of patients with cleft lip and/or palate (CL/P) relates to patient-reported outcomes (PROs). DESIGN: Cross-sectional retrospective chart review. SETTING: Tertiary care pediatric hospital. PATIENTS/PARTICIPANTS: Patients aged 8 to 29 years attending cleft team evaluations during a 1-year period. MAIN OUTCOME MEASURES: CLEFT-Q. RESULTS: Patients (N = 158) with isolated or syndromic CL/P and mean age 13.4 ± 3.0 years were included. Fifteen (9%) patients had siblings who also had CL/P. Of 104 patients who met with the team psychologist, psychosocial concerns were identified in 49 (47%) patients, including 25 (24%) with Attention-Deficit/Hyperactivity Disorder or behavior concerns, 28 (27%) with anxiety, and 14 (13%) with depression or mood concerns. Younger age and having siblings with cleft were associated with better PROs, while psychosocial concerns were associated with worse PROs on Speech, Psychosocial, and Face Appearance scales. CONCLUSIONS: Patient perception of cleft outcomes is linked to psychosocial factors.

Effects of light- vs. heavy-load squat training on velocity, strength, power, and total mechanical work in recreationally trained men and women.

The purpose of this study was to investigate the effects of light and heavy loads in the squat exercise on kinematics and mechanical variables in recreationally trained men and women. Twenty-two men and sixteen women were assigned to 4 groups: 40% and 80% one-repetition maximum (1RM) male (M40 and M80) and female (F40 and F80). Over 6 weeks, participants performed twice a week the full back-squat (SQ) exercise with initially equated relative volume load (Sets*Repetitions/Set*%1RM). All groups performed different amounts of work (p < 0.05), while relative work (work/1RM) only differed between load groups (p < 0.001). There was no significant Time*Sex*Load interaction. Based on the magnitude of effect sizes: M80 achieved small improvements in the SQ maximum isometric force (MIF; ES = 0.43, 95% CI [0.16, 0.81]); small gains in squat estimated 1RM strength were observed in the 80%-1RM groups (M80: 0.42 [0.18, 0.77]; F80: 0.44 [0.26, 0.76]) and the F40 group (0.42 [0.17, 0.81]); all groups made moderate to large gains in the average velocity attained against heavy loads (> 60%1RM; F40: 1.20 [0.52, 2.27]; F80: 2.20 [1.23, 3.93]; M40: 0.85 [0.29, 1.59]; M80: 1.03 [0.55, 1.77]), as well as small to moderate improvements in the average velocity against light loads (< 60%1RM; F40: 0.49[-0.24, 1.68]; F80: 1.10 [0.06, 3.16]; M40: 0.80 [0.41, 1.35]; M80: 0.93 [0.25, 1.84]). Lastly, only the F40 group showed small improvements in countermovement jump (CMJ) height (ES = 0.65 [0.14, 1.37]). In conclusion, light and heavy loads produced similar strength gains in men and women when initially equated by relative volume load, although the standardized mean differences suggest nuances depending on the sample and task.

Task Shifting and Task Sharing to Strengthen the Surgical Workforce in Sub-Saharan Africa: A Systematic Review of the Existing Literature.

BACKGROUND: A major constraint to surgical care delivery in low-resource settings is inadequate workforce availability. Surgical task shifting (TShifting) and task sharing (TSharing), in which non-surgeon clinicians (NSCs) are trained to perform select surgical procedures, have been proposed as one solution. However, patterns of safety and efficacy of surgical TShifting/TSharing are not well-established. This study aims to summarize the current literature and assess clinical outcomes and impact of surgical TShifting/TSharing in sub-Saharan Africa. METHODS: A two-tiered systematic, PRISMA-adherent literature review of surgical TShifting/TSharing in sub-Saharan Africa was conducted. Collected data included healthcare settings; types of surgeries performed; attitudes toward NSCs; and categories, training, capacity, clinical outcomes, safety, retention, cost-effectiveness, and supervision of NSCs. A random effects meta-analysis of morbidity and mortality rates between NSCs and surgeons was conducted. RESULTS: Among the 659 abstracts screened, 31 studies met inclusion criteria and were integrated in the final analysis. Eighteen studies (58%) report on the capacity and aptitude of NSCs, 16 (52%) on clinical outcomes and safety, and seven (23%) on attitudes. NSCs performed 1999 (61%) of 3304 total surgical cases studied. The most common operations reported were hernia repair (n = 12, 57%), acute abdominal (n = 12, 57%), and orthopedic procedures (n = 6, 29%). No differences were found between NSC and surgeon case morbidity [315 (16%) vs. 224 (17%); p > 0.05] and mortality [44 (2.2%) vs. 33 (2.5%); p > 0.05] rates. CONCLUSION: NSCs are increasingly performing surgical tasks in regions of sub-Saharan Africa deficient in trained surgeons and appear to have non-inferior safety outcomes in select programs.

Prior fronto-orbital advancement associated with complications from transcranial midface surgery in patients with syndromic craniosynostosis.

PURPOSE: Our center adopted posterior vault distraction osteogenesis (PVDO) as a first-line intervention for cranial expansion in syndromic craniosynostosis in 2008, and we have a growing cohort of patients undergoing transcranial midface advancement who have not had prior fronto-orbital advancement (FOA). The purpose of this study was to evaluate whether a history of FOA influences the risk profile of transcranial midface advancement in patients with syndromic craniosynostosis. METHODS: Patients undergoing transcranial fronto-facial advancement from 2000 to 2022 were retrospectively divided into cohorts based on preceding history of fronto-orbital advancement (FOA- and FOA+). Perioperative outcomes including operative time, length of stay, intraoperative dural injury, and complications (Clavien-Dindo score) were compared between groups with appropriate statistics. RESULTS: Thirty-eight patients were included (15 in FOA- group and 23 in FOA+ group). The overall complication rate was 47% (10% minor, 37% major). Compared to the FOA- group, the FOA+ group had a higher incidence of dural tears (65% v 20%, p = 0.006) and major complications (48% v 13%, p = 0.028). These findings were recapitulated in multivariate logistic regression controlling for other predictors. CONCLUSIONS: Prior FOA is associated with increased rates of major complications and dural tears in patients with syndromic craniosynostosis undergoing fronto-facial surgery. Options for cranial vault expansion that avoid the frontal region, such as PVDO, may favorably alter the risk profile of fronto-facial advancement.

Oxycephaly-systematic review, case presentation, and diagnostic clarification.

PURPOSE: Oxycephaly is a specific phenotype of multi-suture craniosynostosis that is often misrepresented. This study aims to review the relevant literature, clarify the diagnostic criteria, and present an alternate approach to its management. METHODS: Published literature regarding oxycephaly was reviewed from 1997, when the largest series was published, until 2022. All cases at a single institution were then retrospectively reviewed. RESULTS: Over the last 25 years, four studies met the inclusion criteria, none of which specifically defined oxycephaly. One case, in one study, was potentially consistent with the phenotype. An institutional review yielded two patients who met the original diagnostic criteria set forth by Renier and Marchac. Both patients had unexplained speech delays, mild retinal nerve fiber layer thickening, and diffuse inner table scalloping, along with the characteristic oxycephalic phenotype. One patient also had a direct intracranial pressure (ICP) measurement of 25 mmHg, and the other had a Chiari I malformation. Both were treated with posterior vault distraction osteogenesis (PVDO) to alleviate the cephalo-cranial disproportion while simultaneously allowing for turricephaly correction. CONCLUSIONS: Oxycephaly presents with late onset multi-suture fusion. Patients have patent sutures at birth. Midface hypoplasia and known syndromic associations are absent. Patients demonstrate supraorbital recession, an obtuse fronto-nasal angle, and turricephaly without substantial brachycephaly. Over 60% of patients have symptomatic ICP elevation, the presentation of which ranges from headaches to rapidly progressive blindness. This rare form of craniosynostosis is particularly virulent and likely often missed due to diagnostic ambiguity and its relatively mild phenotype.

Associations Between Medicaid Expansion and Timely Repair of Cleft Lip and Palate.

The expansion of Medicaid under the Affordable Care Act (ACA) increased access to health care for many low-income children. However, the impact of this expansion on the timing of primary cleft lip and palate repair remains unclear. This study aimed to evaluate whether Medicaid expansion improved access to timely cleft lip and palate repair and whether it reduced preexisting ethnoracial disparities. Using a quasi-experimental design, the study analyzed data from 44 pediatric surgical centers across the United States. The results showed that Medicaid expansion was associated with a 9.0 percentage-point increase in delayed cleft lip repairs, resulting in an average delay of 16 days. Non-White patients were disproportionately affected by this delay, experiencing a 14.8 percentage-point increase compared with a 4.9 percentage-point increase for White patients. In contrast, Medicaid expansion had no significant effect on the timing of palate repair or on ethnoracial disparities in palate repair. The study underscores the importance of monitoring unintended consequences of large-scale health system changes, especially those affecting disadvantaged populations. Delayed cleft lip repair can lead to worse outcomes for patients, and the disproportionate impact on non-White patients is concerning. Further research is needed to identify the reasons for this delay and to mitigate its effects. Overall, the study highlights the need for ongoing vigilance to ensure that health care policies and interventions do not inadvertently worsen health disparities.

Genetic Subtypes of Apert Syndrome Are Associated With Differences in Airway Morphology and Early Upper Airway Obstruction.

BACKGROUND: Apert syndrome is predominantly caused by 2 paternally inherited gain-of-function mutations in the FGFR2 gene, Pro253Arg, and Ser252Trp. Studies comparing phenotypic features between these 2 mutations have established differences in syndactyly severity and incidence of cleft palate. Obstructive sleep apnea can be debilitating in a subset of patients with Apert syndrome, yet is not well understood. This study aims to determine whether FGFR2 mutations impart differential effects on airway physiology and morphology. METHODS: Patients with Apert syndrome and confirmatory molecular testing were reviewed for polysomnography, nasal endoscopy, microlaryngoscopy and bronchoscopy, and computed tomography imaging. Obstructive apnea-hypopnea index and oxygen saturation nadir, nasal airway volumes, choanal cross-sectional area, and midfacial cephalometric dimensions were compared across mutation types. RESULTS: Twenty-four patients (13 Ser252Trp, 11 Pro253Arg) were included. Severe obstructive sleep apnea (obstructive apnea-hypopnea index>10) occurred in 8 (62%) patients with Ser252Trp mutations compared with 1 (9%) patient with Pro253Arg mutations ( P =0.009). Computed tomography imaging at 1 year of age demonstrated that nasopharyngeal airway volumes were 5302±1076 mm 3 in the Ser252Trp group and 6832±1414 mm 3 in the Pro253Arg group ( P =0.041). Maxillary length (anterior nasal spine-posterior nasal spine, P =0.026) and basion-anterior nasal spine ( P =0.007) were shorter in patients with Ser252Trp mutations. CONCLUSIONS: The findings suggest that the Ser252Trp mutation in Apert syndrome is associated with higher severity obstructive sleep apnea and decreased nasopharyngeal airway volume. Heightened clinical awareness of these associations may inform treatment planning and family counseling.

Novel Isoform DTX3c Associates with UBE2N-UBA1 and Cdc48/p97 as Part of the EphB4 Degradation Complex Regulated by the Autocrine IGF-II/IRA Signal in Malignant Mesothelioma.

EphB4 angiogenic kinase over-expression in Mesothelioma cells relies upon a degradation rescue signal provided by autocrine IGF-II activation of Insulin Receptor A. However, the identity of the molecular machinery involved in EphB4 rapid degradation upon IGF-II signal deprivation are unknown. Using targeted proteomics, protein-protein interaction methods, PCR cloning, and 3D modeling approaches, we identified a novel ubiquitin E3 ligase complex recruited by the EphB4 C tail upon autocrine IGF-II signal deprivation. We show this complex to contain a previously unknown N-Terminal isoform of Deltex3 E3-Ub ligase (referred as "DTX3c"), along with UBA1(E1) and UBE2N(E2) ubiquitin ligases and the ATPase/unfoldase Cdc48/p97. Upon autocrine IGF-II neutralization in cultured MSTO211H (a Malignant Mesothelioma cell line that is highly responsive to the EphB4 degradation rescue IGF-II signal), the inter-molecular interactions between these factors were enhanced and their association with the EphB4 C-tail increased consistently with the previously described EphB4 degradation pattern. The ATPase/unfoldase activity of Cdc48/p97 was required for EphB4 recruitment. As compared to the previously known isoforms DTX3a and DTX3b, a 3D modeling analysis of the DTX3c Nt domain showed a unique 3D folding supporting isoform-specific biological function(s). We shed light on the molecular machinery associated with autocrine IGF-II regulation of oncogenic EphB4 kinase expression in a previously characterized IGF-II+/EphB4+ Mesothelioma cell line. The study provides early evidence for DTX3 Ub-E3 ligase involvement beyond the Notch signaling pathway.

Characterizing Interventions and Family Assistance of a Nurse Navigation Program in Orofacial Cleft Care.

OBJECTIVE: Characterize the interventions and assistance employed by a cleft nurse navigator (CNN) which have mediated improvement in care equity at our institution. DESIGN: Retrospective study. SETTING: Academic tertiary care center. PATIENTS, PARTICIPANTS: Patients presenting with cleft lip and/or cleft palate presenting between August 2020 and August 2021 with exclusions for syndromic diagnosis, Pierre-Robin sequence, late (> 6 months) presentation, and prior cleft surgery at outside institutions. INTERVENTIONS: Multidisciplinary cleft nurse navigator program. MAIN OUTCOME MEASURE(S): Family interactions with the CNN by phone, text, and email across the first year of life including feeding support, nasoalveolar molding (NAM) assistance, appointment scheduling, financial assistance, addressing perioperative concerns, and facilitating physician consults. Patient weight and surgical timing were also recorded. RESULTS: Sixty-nine patients were included with a total of 639 interactions between the CNN and families. Scheduling support (30%), addressing perioperative concerns (22%), and feeding support (20%) were the most common interactions. Feeding support and NAM assistance were heavily distributed in the first 3 months of life compared to after 3 months (P < .001). Median age at first contact was 1 week (range: 22 weeks gestation-14 weeks). There was no difference in the proportion of families receiving feeding support, NAM assistance, or scheduling assistance based on insurance status or race (P > .05 for all). CONCLUSIONS: Scheduling assistance, addressing perioperative concerns, and feeding support are the predominant methods by which the CNN interacts with and assists families of patients with cleft conditions. CNN service distribution is largely equitable between demographic groups.

Long-Term Patient-Reported Outcomes in Internationally Adopted Children with Cleft Lip and Palate.

OBJECTIVE: To compare patient-reported outcomes (PROs) in internationally adopted patients with cleft lip and palate to those in non-adopted peers. DESIGN: Cross-sectional study. SETTING: Multidisciplinary cleft team at tertiary care hospital. PATIENTS: Patients aged ≥ 8 with cleft lip and palate attending routine cleft team evaluations September 2021 - September 2022. MAIN OUTCOME MEASURE: CLEFT-Q PRO scores. RESULTS: Sixty-four internationally adopted patients and 113 non-adopted patients with a mean age of 13 years were included. Compared to non-adopted peers, adopted patients demonstrated worse satisfaction with face appearance (mean 59 vs. 66, p = .044), speech function (mean 69 vs. 78, p = .005), and speech distress (mean 80 vs. 84, p = .032). No significant differences were observed on the nose, nostrils, teeth, lips, lip scar, jaws, psychological function, or social function scales (p > .05). Objective clinical evaluation corroborated these findings, with adopted patients demonstrating worse Pittsburgh Weighted Speech scores (mean 3.0 vs 1.9, p = .027) and greater incidence of articulation errors (64% vs 46%, p = .021). No significant differences were observed in rates of mood, anxiety, or behavior concerns identified on psychosocial assessment (p = .764). Among adopted patients, undergoing palatoplasty prior to adoption was associated with worse satisfaction with speech, appearance, school, and social function (p < .05). CONCLUSIONS: Patient-reported outcomes among internationally adopted adolescents and young adults with cleft lip and palate show slightly lower satisfaction with facial appearance and speech but otherwise demonstrate similar results to non-adopted peers on most appearance and psychosocial measures. PRO data correlated well with objective speech assessment and did not portend worse psychosocial function.

Does Dedicated Research Time During Residency Predict Resident Academic Productivity and a Future Academic Career?

OBJECTIVE: Dedicated research time is a component of certain plastic surgery programs, and yet, there is limited research examining its impact on academic productivity and career outcomes. This study aimed to assess the effect of dedicated research time on the academic productivity of residents and the likelihood of pursuing an academic career. METHODS: We conducted a cross-sectional study that examined bibliometric indices of integrated plastic surgery residency graduates from 2010 to 2020. Academic productivity was determined by the number of peer-reviewed publications and h-index 1 year after residency graduation. Results were analyzed using descriptive statistics, χ2 test, t test, and logistic regression. RESULTS: Data on plastic surgery residency graduates were analyzed (N = 490 from 46 programs). The mean numbers of publications and h-index per research track graduate were 26.1 and 8.23, respectively. The mean numbers of publications and h-index per nonresearch track graduate were 15.9 and 5.97, respectively. After controlling for the University of Alabama research ranking through multilinear regression analysis, we found that pursuing dedicated research time was an independent predictor of increased h-index and publication output, although it did not predict an increased likelihood of pursuing an academic career. CONCLUSIONS: Participating in dedicated research during residency increases academic productivity, irrespective of the residency program's research rank. Given this finding, offering research years can help support the mission of fostering academic opportunities within plastic surgery.