γ-Secretase Modulator BPN15606 Reduced Aß42 and Aß40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome.

OBJECTIVES: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aß42 and Aß40 peptides. METHODS: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months. RESULTS: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aß40 and Aß42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-ß were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits. INTERPRETATION: Our findings point to the involvement of increased levels of Aß42 and/or Aß40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aß42 and/or Aß40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404.

Correlation of Orthognathic Surgical Movements to Perception of Facial Appearance in Patients With Cleft Lip and Palate.

STUDY DESIGN: Cephalometric scans were compared before and after surgery to assess the degree of correction. Correlations between skeletal movements and survey outcomes were determined using multivariate regression analysis. OBJECTIVE: This study aims to identify relationships between subjective observer-reported improvements in esthetics and emotional appearance with specific surgical movements. METHODS: Ten patients at a single tertiary institution (average age: 18.1 ± 0.8), 9 males and 1 female, underwent orthognathic repair and had comprehensive cephalometric records. Standardized anterior posterior and lateral pre and postoperative photographs of patients were included in a survey to clinicians to assess noncognitive domains on a Likert Scale (1-10). CLEFT-Q was administered to gauge patient satisfaction in categories of appearance, speech, and quality of life. RESULTS: Per clinicians, multiple domains increased including facial attractiveness (4.1 ± 0.7 versus 7.3 ± 0.7, P < 0.001), friendliness (4.5 ± 0.4 versus 7.3 ± 0.5, P < 0.001), confidence (4.1 ± 0.4 versus 7.1 ± 0.4, P < 0.001), and recommendation for surgery decreased (8.9 ± 0.1 versus 3.6 ± 0.5, P < 0.001). Speech distress decreased with increased SNA and convexity, whereas Psychological and Social scores decreased with an increased ANB. Functional eating and drinking scores increased with maxillary depth. CONCLUSIONS: Orthognathic surgery improves many noncognitive domains in patients with cleft lip and palate as assessed by both patients and clinicians on all aspects of facial attractiveness and perception. These findings demonstrate objective bases of skeletal adjustments for perceived improvements in facial appearance and emotion.

Use it or Lose it: Predictors of Compliance and Satisfaction With Postoperative Nasal Stent Therapy After Primary Cleft Lip Repair.

OBJECTIVE: Postoperative nasal stents (NSs) are used to improve esthetic outcomes after primary or secondary cleft lip repair (CLR). Prior studies have utilized anthropometric measurements or physician assessment to determine the efficacy of NS, but data on caregiver-reported outcomes is limited. This study aims to assess caregiver compliance and satisfaction with postoperative NS. METHODS: The authors designed a survey to collect parent-reported postoperative NS usage outcomes. Parents of infants with cleft lip (CL) who used postoperative NS after primary CLR were approached through social media to complete the survey. Data were analyzed to determine factors impacting compliance, satisfaction, and parent-reported outcomes. RESULTS: Eighty-five parents completed the questionnaire, and 60% reported noncompliance with NS. Parents with male children (odds ratio: 5.08, P = 0.019) and patients with incomplete CL (odds ratio: 5.72, P = 0.006) were more likely to be non-compliant with NS for over a week. Complete CL and use of presurgical molding therapy were each associated with better overall experience with postoperative NS ( P = 0.002 and P = 0.037), higher appearance ratings ( P = 0.005 and P = 0.0008), and greater satisfaction with nostril shape after surgery ( P = 0.016 and P = 0.001). CONCLUSIONS: Despite limited literature related to caregiver-reported outcomes after postoperative NS for primary CLR, the authors' results align with what has been published regarding this topic. These results can help guide surgeons in counseling patients preoperatively. Larger, multi-institutional studies are needed to better delineate and address factors associated with compliance and satisfaction after NS therapy.

Implementation of Mandibular Distraction Osteogenesis for Patients With Pierre Robin Sequence in a Developing Country Through International Collaboration: A Paradigm for Success.

OBJECTIVE: Though it has made significant strides, Vietnam remains a resource-constrained country of 98 million people. Vietnam National Children's Hospital (VNCH) provides tertiary care to a catchment of 40 million people and is the sole national children's hospital. As such, it is one of the few referral centers in the country equipped to take care of patients diagnosed with Pierre Robin sequence (PRS) as this requires pulmonary, critical care, otolaryngology, and plastic surgery expertise. Before 2015, the only surgical options were tongue lip adhesion or tracheostomy. Only 20% of patients successfully avoided tracheostomy, mechanical ventilation, or death. From 2015 to 2019, mandibular distraction osteogenesis (MDO) was introduced by visiting international surgeons on a short-term basis. Since 2020, local surgeons at VNCH have refined their technique and widely use MDO independently. This report seeks to capitulate their experience and identify factors leading to success. METHODS: A retrospective review was conducted of patients diagnosed with PRS at VNCH from 2015 to 2022. Paper records were digitized, translated, and reviewed for inclusion criteria, including demographics, indications, hospital course, and postoperative outcomes. RESULTS: Complete records satisfying inclusion criteria were available for 53 patients with a diagnosis of PRS who underwent MDO from 2020 to 2022. From 2015 to 2019, there were 19 cases of MDO, though records were incomplete. The median age at the time of MDO was 50 ± 43 days. Forty patients (75.5%) had isolated PRS and 13 (24.5%) were syndromic. Forty-four patients (83%) had a cleft palate. Fifty-one (96.2%) of patients required preoperative supplemental oxygen or mechanical ventilation. The active distraction and consolidation phase was 4.8 ± 1.3 months. The median days to discharge after surgery was 19.0 ± 8.3 days. Median weight at birth, at the time of surgery, and at the time of device removal were 6.8 ± 1.2, 7.7 ± 1.9, and 14.8 ± 2.8 pounds, respectively. Fifty-two patients (98.1%) had obstructive sleep apnea preoperatively with an average Apnea Hypopnea Index of 25.0 ± 10.6. Post-MDO, only 4 (7.5%) had obstructive sleep apnea and the average Apnea Hypopnea Index was 5.2 ± 0.6. No patients (0) required a tracheostomy for a 100% success rate. CONCLUSIONS: The tremendous success of the implementation of MDO by local surgeons in Vietnam after its introduction by visiting international surgeons illustrates a paradigm for capacity-enhancing global surgical endeavors. Mandibular distraction osteogenesis has replaced tongue lip adhesion as the surgical treatment of choice for PRS patients at VNCH. Surgical techniques can be transferred to operating environments with basic infrastructure through collaboration and resource optimization. These results demonstrate that global surgical engagement may be scalable and repeatable with direct benefits for patients in lower-middle-income countries.

Postoperative Radiologic Imaging in Secondary Alveolar Bone Grafting for Cleft Lip and Palate: A Systematic Review and Meta-Analysis.

INTRODUCTION: Radiographs (XRs), computed tomography (CT) scans, and cone-beam CT (CBCT) scans are utilized for assessment of secondary alveolar bone graft (SABG) in patients with cleft lip and palate (CLP). However, the optimal choice for imaging modality remains unclear. This study compares the image fidelity and safety profile for XR, CT, and CBCT in the assessment of patients with CLP who have undergone SABG. METHODS: Articles from MEDLINE and Elsevier Embase were screened. The primary outcome was graft success rate. Secondary outcomes were percent-by-volume of graft maintained and patient safety, defined by radiation exposure. A random effects model was used to calculate the pooled outcomes for each imaging modality. Chi-squared analysis was used to compare pooled outcomes between different imaging modalities. RESULTS: Of the 149 articles identified initially, 14 were included. Computed tomography exhibited a significantly higher image fidelity demonstrated by a lower graft success rate (62.0%) compared with both XR (72.6%, P<0.01) and CBCT (69.8%, P<0.01). Cone-beam CT had the lowest reported percent-by-volume of graft maintained (32.1%). Computed tomography had a higher mean radiation dosage (39.7 milligray) than what has been reported for both XR and CBCT. CONCLUSION: Computed tomography demonstrated lower graft success rates than both XR and CBCT, possibly indicating a higher image fidelity. However, compared with CBCT, CT may have a higher radiation exposure. Randomized trials and longitudinal studies are necessary to perform a direct comparison between CT and CBCT and to correlate the image fidelity of these modalities with clinical outcomes.

Artificial Intelligence Methods for the Argenta Classification of Deformational Plagiocephaly to Predict Severity and Treatment Recommendation.

INTRODUCTION: Deformational plagiocephaly (DP) can be classified into 5 severity types using the Argenta scale (AS). Patients with type III or higher require referral to craniofacial surgery for management. Primary care pediatricians (PCPs) are often the first to encounter patients with DP, but current screening methods are subjective, increasing the risk of bias, especially for clinicians with little exposure to this population. The authors propose the use of artificial intelligence (AI) to classify patients with DP using the AS and to make recommendations for referral to craniofacial surgery. METHODS: Vertex photographs were obtained for patients diagnosed with unilateral DP from 2019 to 2020. Using the photographs, an AI program was created to characterize the head contour of these infants into 3 groups based on the AS. The program was trained using photographs from patients whose DP severity was confirmed clinically by craniofacial surgeons. To assess the accuracy of the software, the AS predicted by the program was compared with the clinical diagnosis. RESULTS: Nineteen patients were assessed by the AI software. All 3 patients with type I DP were correctly classified by the program (100%). In addition, 4 patients with type II were correctly identified (67%), and 7 were correctly classified as type III or greater (70%). CONCLUSIONS: Using vertex photographs and AI, the authors were able to objectively classify patients with DP based on the AS. If converted into a smartphone application, the program could be helpful to PCPs in remote or low-resource settings, allowing them to objectively determine which patients require referral to craniofacial surgery.

Subgaleal and Epidural Hematomas Secondary to Calvarial Infarcts: An Uncommon Presentation of Sickle Cell Disease.

We present the case of a 13-year-old male with sickle cell disease (SCD) who presented to the emergency department with a severe headache secondary to calvarial infarcts with associated epidural and subgaleal hematomas. This case was complicated by external compression of the superior sagittal sinus by the hematomas as seen on magnetic resonance imaging. Management included supportive treatment of pain and swelling. This case emphasizes skull infarctions with associated hematomas as a possible differential diagnosis for patients with SCD presenting with headaches and scalp swellings.

The BC Radon Data Repository (BCRDR) and BC Radon Map: Integrating disparate data sources for improved public health communication.

SETTING: The potential for exposure to indoor radon varies dramatically across British Columbia (BC) due to varied geology. Individuals may struggle to understand their exposure risk and agencies may struggle to understand the value of population-level programs and policies to mitigate risk. INTERVENTION: The BC Centre for Disease Control (BCCDC) established the BC Radon Data Repository (BCRDR) to facilitate radon research, public awareness, and action in the province. The BCRDR aggregates indoor radon measurements collected by government agencies, industry professionals and organizations, and research and advocacy groups. Participation was formalized with a data sharing agreement, which outlines how the BCCDC anonymizes and manages the shared data integrated into the BCRDR. OUTCOMES: The BCRDR currently holds 38,733 measurements from 18 data contributors. The repository continues to grow with new measurements from existing contributors and the addition of new contributors. A prominent use of the BCRDR was to create the online, interactive BC Radon Map, which includes regional concentration summaries, risk interpretation messaging, and health promotion information. Anonymized BCRDR data are also available for external release upon request. IMPLICATIONS: The BCCDC leverages existing radon measurement programs to create a large and integrated database with wide geographic coverage. The development and application of the BCRDR informs public health research and action beyond the BCCDC, and the repository can serve as a model for other regional or national initiatives.

RéSUMé: LIEU: Le potentiel d'exposition au radon à l'intérieur des bâtiments varie beaucoup d'une région à l'autre de la Colombie-Britannique en raison de la géologie variée. Les particuliers peuvent avoir du mal à comprendre leur risque d'exposition, et les organismes, à comprendre l'utilité des programmes et des politiques populationnels pour atténuer le risque. INTERVENTION: Le BC Centre for Disease Control (« le Centre ¼) a créé un organe d'archivage, le BC Radon Data Repository (BCRDR), pour faciliter la recherche, l'information, la sensibilisation du public et l'action liées au radon dans la province. Le BCRDR totalise les relevés du radon à l'intérieur des bâtiments pris par les organismes gouvernementaux, les professionnels et les organismes de l'industrie, ainsi que les groupes de recherche et de revendication. La participation est officialisée par un accord de partage de données qui décrit comment le Centre anonymise et gère les données communes du BCRDR. RéSULTATS: Le BCRDR contient actuellement 38 733 relevés de 18 contributeurs de données. Il continue de croître, avec de nouveaux relevés venant de contributeurs existants et l'ajout de nouveaux contributeurs. Il a servi, entre autres, à créer une carte du radon interactive en ligne pour la Colombie-Britannique, avec des résumés des concentrations régionales, des messages d'interprétation du risque et des informations de promotion de la santé. Sur demande, les données anonymisées du BCRDR sont également disponibles pour diffusion externe. CONSéQUENCES: Le Centre a exploité les programmes de prise de relevés du radon existants pour créer une grande base de données intégrée ayant une vaste couverture géographique. Le développement et les applications du BCRDR éclairent la recherche et l'action en santé publique au-delà du Centre, et l'organe d'archivage peut servir de modèle pour d'autres initiatives régionales ou nationales.

The Lawnmower and the Pediatric Lower Extremity: A Catastrophic Combination.

Background: Lower extremity (LE) trauma within the pediatric population may be debilitating and have different implications and etiologies than in adults. Specifically, lawnmower injuries can cause catastrophic sequelae to the lower extremities, often requiring complex reconstruction or resulting in amputation. This study aims to present our experience with pediatric LE lawnmower injuries at one of the busiest level 1 trauma centers in the United States. Methods: An IRB-approved retrospective analysis was performed studying pediatric patients (age <18 years) who experienced LE trauma due to a lawnmower injury over a 5-year period (2012-2017). Patient demographics, perioperative data, and types of reconstruction were reviewed. Univariate analysis of the data was performed to examine trends in exposure and management of pediatric LE lawnmower injuries. Results: Twenty-three patients were identified with pediatric LE lawnmower injuries, of whom 82.6% were male. The patients had a median age of 6 years and a median Injury Severity Score (ISS) of 4. Over one-third (34.8%) of this cohort required immediate amputation. Additionally, 26.1% and 8.7% required local and free flap reconstruction, respectively. In comparison, only 3.6% and 2.3% of all traumatic pediatric LE injuries from the same time frame required local and free flaps, respectively. Conclusions: Lawnmower injuries to the LE can be devastating, causing long-term physical, emotional, and psychosocial consequences for pediatric patients and their families. The data in this study suggest that pediatric LE injuries from lawnmowers more often require complex reconstruction than other traumatic LE injuries. Rapid and effective decision-making by experienced surgeons is necessary to optimize the potential for limb salvage in pediatric LE lawnmower injuries. An algorithm of recommendations on when to transfer these types of injuries to more experienced tertiary centers is provided. Additional resources should be dedicated toward improving public awareness and industrial safety features to help prevent lawnmower injuries in pediatric patients.