Update on using buccal myomucosal flaps for patients with cleft palate and velopharyngeal insufficiency: primary and secondary interventions.

PURPOSE OF REVIEW: This review aims to examine the indications and anatomical circumstances for when to optimally incorporate buccal myomucosal flaps (BMFs) into palatal surgical reconstruction. RECENT FINDINGS: Studies examining outcomes following primary cleft palate repair with incorporation of BMF have demonstrated excellent speech outcomes and low rates of fistula. Furthermore, some reports cite an association of buccal flap use with reduced midface hypoplasia and the need for later orthognathic surgery. When used for secondary speech surgery, BMFs have been shown to lead to speech improvements across multiple outcome measures. Advantages of BMF techniques over conventionally described pharyngeal flap and pharyngoplasty procedures include significant lengthening of the velum, favorable repositioning of the levator muscular sling, and lower rates of obstructive sleep apnea. SUMMARY: Although the published data demonstrate excellent outcomes with use of BMFs for primary and secondary palatal surgery, there are limited data to conclude superiority over the traditional, more extensively investigated surgical techniques. The authors of this review agree with the evidence that BMF techniques can be useful in primary palatoplasty for congenitally wide clefts, secondary speech surgery for large velopharyngeal gaps, and/or in individuals with a predisposition for airway obstruction from traditional approaches.

Tympanostomy Tube Otorrhea: Microbiological Differences Between Children with and Without Cleft Palate.

OBJECTIVE: To characterize and compare microbiological profiles in tympanostomy tube otorrhea for children with and without cleft palate. DESIGN: Retrospective cohort study. SETTING: Pediatric otolaryngology and multidisciplinary cleft/craniofacial clinic at a single tertiary care center. PATIENTS: Children with and without cleft palate <18 years of age who underwent tympanostomy tube placement between 2017-2021. MAIN OUTCOME MEASURES: Otopathogen profiles and antibiotic resistance patterns in ear culture specimens obtained in children presenting for treatment of recalcitrant post-tympanostomy tube otorrhea. RESULTS: Of the 886 children with tympanostomy tubes placed between 2017-2021, 345 (38.9%) had clinically significant otorrhea defined as requiring at least one otolaryngology visit for treatment. Children with cleft palate had higher rates of otorrhea (50.0% versus 35.7%; P < .01). In the 128 cultures obtained, Staphylococcus aureus was the most common organism in both groups present in 39.8% of cultures; 49% were methicillin-resistant (MRSA). Pseudomonas aeruginosa was also frequently isolated (20.0% versus 23.4%, P = .69) in children with and without cleft palate. Collectively, fluoroquinolone resistance was observed in 68.6% and 27.6% of the S. aureus and P. aeruginosa isolates, respectively, however, no differences in fluoroquinolone resistance were observed between cleft and non-cleft cohorts. Corynebacterium species were isolated more frequently in children with cleft palate (26.7% versus 6.1%, P < .01), a finding of unclear significance. CONCLUSIONS: Recalcitrant post-tympanostomy tube otorrhea is more common in children with cleft palate. MRSA was the most common isolate, which was commonly resistant to first-line fluoroquinolone therapy.

Perspectives on the state of cleft lip and cleft palate patient care in Africa.

PURPOSE OF REVIEW: Patients with cleft lip -palate (CLP) experience morbidity and social stigma, particularly in low-income and middle-income countries (LMICs) such as those of sub-Saharan Africa (SSA). Delays in treatment secondary either to lack of awareness, skills, equipment and consumables; poor health infrastructure, limited resources or a combination of them, has led to SSA having the highest rates of death and second highest rates of disability-adjusted life years in patients with CLP globally. Here we review current perspectives on the state of comprehensive cleft lip and palate repair in Africa. RECENT FINDINGS: To bridge gaps in government health services, nongovernmental organizations (NGOs) have emerged to provide care through short-term surgical interventions (STSIs). These groups can effect change through direct provision of care, whereas others strengthen internal system. However, sustainability is lacking as there continue to be barriers to achieving comprehensive and longitudinal cleft care in SSA, including a lack of awareness of CLP as a treatable condition, prohibitive costs, poor follow-up, and insufficient surgical infrastructure. With dedicated local champions, a comprehensive approach, and reliable partners, establishing sustainable CLP services is possible in countries with limited resources. SUMMARY: The replacement of CLP 'missions' with locally initiated, internationally supported capacity building initiatives, integrated into local healthcare systems will prove sustainable in the long-term.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Transcriptional cartography integrates multiscale biology of the human cortex.

The cerebral cortex underlies many of our unique strengths and vulnerabilities, but efforts to understand human cortical organization are challenged by reliance on incompatible measurement methods at different spatial scales. Macroscale features such as cortical folding and functional activation are accessed through spatially dense neuroimaging maps, whereas microscale cellular and molecular features are typically measured with sparse postmortem sampling. Here, we integrate these distinct windows on brain organization by building upon existing postmortem data to impute, validate, and analyze a library of spatially dense neuroimaging-like maps of human cortical gene expression. These maps allow spatially unbiased discovery of cortical zones with extreme transcriptional profiles or unusually rapid transcriptional change which index distinct microstructure and predict neuroimaging measures of cortical folding and functional activation. Modules of spatially coexpressed genes define a family of canonical expression maps that integrate diverse spatial scales and temporal epochs of human brain organization - ranging from protein-protein interactions to large-scale systems for cognitive processing. These module maps also parse neuropsychiatric risk genes into subsets which tag distinct cyto-laminar features and differentially predict the location of altered cortical anatomy and gene expression in patients. Taken together, the methods, resources, and findings described here advance our understanding of human cortical organization and offer flexible bridges to connect scientific fields operating at different spatial scales of human brain research.

Evidence-Based Performance Measures for Reconstruction after Skin Cancer Resection: A Multidisciplinary Performance Measure Set.

BACKGROUND: The American Society of Plastic Surgeons commissioned the multidisciplinary Performance Measure Development Work Group on Reconstruction after Skin Cancer Resection to identify and draft quality measures for the care of patients undergoing skin cancer reconstruction. Included stakeholders were the American Academy of Otolaryngology-Head and Neck Surgery, the American Academy of Facial Plastic and Reconstructive Surgery, the American Academy of Dermatology, the American Society of Dermatologic Surgery, the American College of Mohs Surgery, the American Society for Mohs Surgery, and a patient representative. METHODS: Two outcome measures and five process measures were identified. The outcome measures included the following: (1) patient satisfaction with information provided by their surgeon before their facial procedure, and (2) postprocedural urgent care or emergency room use. The process measures focus on antibiotic stewardship, anticoagulation continuation and/or coordination of care, opioid avoidance, and verification of clear margins. RESULTS: All measures in this report were approved by the American Society of Plastic Surgeons Quality and Performance Measures Work Group and Executive Committee, and the stakeholder societies. CONCLUSION: The work group recommends the use of these measures for quality initiatives, Continuing Medical Education, Continuous Certification, Qualified Clinical Data Registry reporting, and national quality reporting programs.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort.

Importance: Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). Objective: To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). Design, Setting, and Participants: A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. Exposures: PGSs for EXT, depression, schizophrenia, and suicide attempt. Main Outcomes and Measures: Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Results: Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Conclusions and Relevance: Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy.

BACKGROUND: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. METHODS: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-ß/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. RESULTS: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CONCLUSION: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

The molecular genetic landscape of human brain size variation.

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease.

Characterizing the phenotypic and genetic structure of psychopathology in UK Biobank.

Mental conditions exhibit a higher-order transdiagnostic factor structure which helps to explain the widespread comorbidity observed in psychopathology. However, the phenotypic and genetic structures of psychopathology may differ, raising questions about the validity and utility of these factors. Here, we study the phenotypic and genetic factor structures of ten psychiatric conditions using UK Biobank and public genomic data. Although the factor structure of psychopathology was generally genetically and phenotypically consistent, conditions related to externalizing (e.g., alcohol use disorder) and compulsivity (e.g., eating disorders) exhibited cross-level disparities in their relationships with other conditions, plausibly due to environmental influences. Domain-level factors, especially thought disorder and internalizing factors, were more informative than a general psychopathology factor in genome-wide association and polygenic index analyses. Collectively, our findings enhance the understanding of comorbidity and shared etiology, highlight the intricate interplay between genes and environment, and offer guidance for psychiatric research using polygenic indices.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Metabolic Heterogeneity, Plasticity, and Adaptation to "Glutamine Addiction" in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase-ω-Amidase (Glutaminase II)] Pathway.

Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as "l-glutamine addiction", this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the "glutamine transaminase-ω-amidase (GTωA)" pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.

Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.

Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.