DNA Adductomics by mass tag prelabeling.

RATIONALE: As a new approach to DNA adductomics, we directly reacted intact, double-stranded (ds)-DNA under warm conditions with an alkylating mass tag followed by analysis by liquid chromatography/mass spectrometry. This method is based on the tendency of adducted nucleobases to locally disrupt the DNA structure (forming a "DNA bubble") potentially increasing exposure of their nucleophilic (including active hydrogen) sites for preferential alkylation. Also encouraging this strategy is that the scope of nucleotide excision repair is very broad, and this system primarily recognizes DNA bubbles. METHODS: A cationic xylyl (CAX) mass tag with limited nonpolarity was selected to increase the retention of polar adducts in reversed-phase high-performance liquid chromatography (HPLC) for more detectability while maintaining resolution. We thereby detected a diversity of DNA adducts (mostly polar) by the following sequence of steps: (1) react DNA at 45°C for 2 h under aqueous conditions with CAX-B (has a benzyl bromide functional group to label active hydrogen sites) in the presence of triethylamine; (2) remove residual reagents by precipitating and washing the DNA (a convenient step); (3) digest the DNA enzymatically to nucleotides and remove unlabeled nucleotides by nonpolar solid-phase extraction (also a convenient step); and (4) detect CAX-labeled, adducted nucleotides by LC/MS2 or a matrix-assisted laser desorption/ionization (MALDI)-MS technique. RESULTS: Examples of the 42 DNA or RNA adducts detected, or tentatively so based on accurate mass and fragmentation data, are as follows: 8-oxo-dGMP, ethyl-dGMP, hydroxyethyl-dGMP (four isomers, all HPLC-resolved), uracil-glycol, apurinic/apyrimidinic sites, benzo[a]pyrene-dGMP, and, for the first time, benzoquinone-hydroxymethyl-dCMP. Importantly, these adducts are detected in a single procedure under a single set of conditions. Sensitivity, however, is only defined in a preliminary way, namely the latter adduct seems to be detected at a level of about 4 adducts in 109 nucleotides (S/N ~30). CONCLUSIONS: CAX-Prelabeling is an emerging new technique for DNA adductomics, providing polar DNA adductomics in a practical way for the first time. Further study of the method is encouraged to better characterize and extend its performance, especially in scope and sensitivity.

Serious Inhalation Injuries From Military Operations in Afghanistan, Iraq, and Syria.

OBJECTIVE: To characterize serious inhalation injuries seen during recent military operations, and assess whether bronchoscopic severity findings were associated with clinical presentation and outcomes. METHODS: Service members who suffered inhalation injuries while deployed to Iraq, Afghanistan, or Syria from 2001-2018 were identified using ICD-9 and 10 codes from the Expeditionary Medical Encounter Database (EMED), which is abstracted from patient records in forward-deployed medical facilities. Further information including demographics, mechanism of injury, mortality, total burn surface area (TBSA), degree of facial burn, total Injury Severity Score (ISS), and first post-injury bronchoscopy notes were collected. Patients were excluded with ISS less than 16 or without sufficient details regarding bronchoscopy. Injuries were grouped based on bronchoscopic Abbreviated Injury Scores (AIS) into low-grade (AIS of 1), moderate-grade (AIS of 2), or high-grade (AIS of 3 or 4). RESULTS: 91 patients met inclusion criteria, with no significant differences in age, gender, paygrade, or service branch between degrees of injury. There were no statistical correlations between grade of injury and battle versus non-battle injury, blast versus non-blast mechanism, TBSA, or degree of facial burn. High-grade injuries had significantly higher ISS than low or moderate-grade injuries. After adjusting for ISS, the odds ratio of death was 10.4 (95% CI 1.47 to 74.53) for those with high-grade and 3.7 (95% CI 0.45 to 32.30) for those with moderate-grade compared to low-grade injuries. CONCLUSION: In this cohort of deployed military members with inhalation injuries, initial bronchoscopic severity findings are strongly associated with mortality even after adjusting for ISS. The AIS may be an important prognostic tool in all of those with serious inhalation injuries.

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival.

PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

PaSD-qc: quality control for single cell whole-genome sequencing data using power spectral density estimation.

Single cell whole-genome sequencing (scWGS) is providing novel insights into the nature of genetic heterogeneity in normal and diseased cells. However, the whole-genome amplification process required for scWGS introduces biases into the resulting sequencing that can confound downstream analysis. Here, we present a statistical method, with an accompanying package PaSD-qc (Power Spectral Density-qc), that evaluates the properties and quality of single cell libraries. It uses a modified power spectral density to assess amplification uniformity, amplicon size distribution, autocovariance and inter-sample consistency as well as to identify chromosomes with aberrant read-density profiles due either to copy alterations or poor amplification. These metrics provide a standard way to compare the quality of single cell samples as well as yield information necessary to improve variant calling strategies. We demonstrate the usefulness of this tool in comparing the properties of scWGS protocols, identifying potential chromosomal copy number variation, determining chromosomal and subchromosomal regions of poor amplification, and selecting high-quality libraries from low-coverage data for deep sequencing. The software is available free and open-source at https://github.com/parklab/PaSDqc.

Comparative cost of transoral robotic surgery and radiotherapy (IMRT) in early stage tonsil cancer.

PURPOSE: To compare treatment costs and cost-effectiveness for transoral robotic surgery (TORS) and definitive intensity-modulated radiotherapy (IMRT) in managing early stage tonsil cancer. MATERIALS AND METHODS: Direct treatment costs for surgery and IMRT were calculated from SEER-Medicare data for a cohort with clinically early stage (cT1/2N0) p16+ tonsillar squamous cell carcinoma from Kaiser Permanente Southern California Health Plan between 2012 and 2017. A Markov decision tree model with a 5-year time horizon was then applied to the cohort which incorporated costs associated with treatment, surveillance, and recurrence. RESULTS: IMRT cost up to $19,000 more (35%) than TORS in direct treatment costs. When input into the Markov model, TORS dominated IMRT with lower cost and better effectiveness over a range of values. CONCLUSION: TORS is a more cost-effective treatment method than IMRT in early stage (cT1/2N0) tonsil cancer.

Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination.

Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2's isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development.

METTL23, a transcriptional partner of GABPA, is essential for human cognition.

Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.

Abrogation of ß-catenin signaling in oligodendrocyte precursor cells reduces glial scarring and promotes axon regeneration after CNS injury.

When the brain or spinal cord is injured, glial cells in the damaged area undergo complex morphological and physiological changes resulting in the formation of the glial scar. This scar contains reactive astrocytes, activated microglia, macrophages and other myeloid cells, meningeal cells, proliferating oligodendrocyte precursor cells (OPCs), and a dense extracellular matrix. Whether the scar is beneficial or detrimental to recovery remains controversial. In the acute phase of recovery, scar-forming astrocytes limit the invasion of leukocytes and macrophages, but in the subacute and chronic phases of injury the glial scar is a physical and biochemical barrier to axonal regrowth. The signals that initiate the formation of the glial scar are unknown. Both canonical and noncanonical signaling Wnts are increased after spinal cord injury (SCI). Because Wnts are important regulators of OPC and oligodendrocyte development, we examined the role of canonical Wnt signaling in the glial reactions to CNS injury. In adult female mice carrying an OPC-specific conditionally deleted ß-catenin gene, there is reduced proliferation of OPCs after SCI, reduced accumulation of activated microglia/macrophages, and reduced astrocyte hypertrophy. Using an infraorbital optic nerve crush injury, we show that reducing ß-catenin-dependent signaling in OPCs creates an environment that is permissive to axonal regeneration. Viral-induced expression of Wnt3a in the normal adult mouse spinal cord induces an injury-like response in glia. Thus canonical Wnt signaling is both necessary and sufficient to induce injury responses among glial cells. These data suggest that targeting Wnt expression after SCI may have therapeutic potential in promoting axon regeneration.

Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.

Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.

Human babesiosis, Maine, USA, 1995-2011.

We observed an increase in the ratio of pathogenic Babesia microti to B. odocoilei in adult Ixodes scapularis ticks in Maine. Risk for babesiosis was associated with adult tick abundance, Borrelia burgdorferi infection prevalence, and Lyme disease incidence. Our findings may help track risk and increase the focus on blood supply screening.

Hypoglossal Nerve Stimulator in the Active Duty Population: Military Readiness and Satisfaction.

INTRODUCTION: Because inadequate sleep impairs mission performance, the U.S. Army regards sleep as a core pillar of soldier readiness. There is an increasing incidence of obstructive sleep apnea (OSA) among active duty (AD) service members, which is a disqualifying condition for initial enlistment. Moreover, a new diagnosis of OSA in the AD population often prompts a medical evaluation board, and if symptomatic OSA proves refractory to treatment, this may result in medical retirement. Hypoglossal nerve stimulator implantation (HNSI) is a newer implantable treatment option, which requires minimal ancillary equipment to function and may provide a useful treatment modality to support AD service members while maintaining readiness in appropriate candidates. Because of a perception among AD service members that HNSI results in mandatory medical discharge, we aimed to evaluate the impact of HNSI on military career progression, maintenance of deployment readiness, and patient satisfaction. METHODS: The Department of Research Programs at the Walter Reed National Military Medical Center provided institutional review board approval for this project. This is a retrospective, observational study and telephonic survey of AD HNSI recipients. Military service information, demographics, surgical data, and postoperative sleep study results were collected from each patient.Additional survey questions assessed each service member's experience with the device. RESULTS: Fifteen AD service members who underwent HNSI between 2016 and 2021 were identified. Thirteen subjects completed the survey. The mean age was 44.8 years (range 33-61), and all were men. Six subjects (46%) were officers. All subjects maintained AD status following HNSI yielding 14.5 person-years of continued AD service with the implant. One subject underwent formal assessment for medical retention. One subject transferred from a combat role to a support role. Six subjects have since voluntarily separated from AD service following HNSI. These subjects spent an average of 360 (37-1,039) days on AD service. Seven subjects currently remain on AD and have served for an average of 441 (243-882) days. Two subjects deployed following HNSI. Two subjects felt that HSNI negatively affected their career. Ten subjects would recommend HSNI to other AD personnel. Following HNSI, of the eight subjects with postoperative sleep study data, five achieved surgical success defined as >50% reduction of apnea-hypopnea index and absolute apnea-hypopnea index value of <20. CONCLUSIONS: Hypoglossal nerve stimulator implantation for AD service members offers an effective treatment modality for OSA, which generally allows for the ability to maintain AD status, however: The impact on deployment readiness should be seriously considered and tailored to each service member based on their unique duties before implantation. Seventy-seven percent of HNSI patients would recommend it to other AD service members suffering from OSA.

Closed-loop modulation of remote hippocampal representations with neurofeedback.

Humans can remember specific events without acting on them and can influence which memories are retrieved based on internal goals. However, current animal models of memory typically present sensory cues to trigger retrieval and assess retrieval based on action 1-5 . As a result, it is difficult to determine whether measured patterns of neural activity relate to the cue(s), the retrieved memory, or the behavior. We therefore asked whether we could develop a paradigm to isolate retrieval-related neural activity in animals without retrieval cues or the requirement of a behavioral report. To do this, we focused on hippocampal "place cells." These cells primarily emit spiking patterns that represent the animal's current location (local representations), but they can also generate representations of previously visited locations distant from the animal's current location (remote representations) 6-13 . It is not known whether animals can deliberately engage specific remote representations, and if so, whether this engagement would occur during specific brain states. So, we used a closed-loop neurofeedback system to reward expression of remote representations that corresponded to uncued, experimenter-selected locations, and found that rats could increase the prevalence of these specific remote representations over time; thus, demonstrating memory retrieval modulated by internal goals in an animal model. These representations occurred predominately during periods of immobility but outside of hippocampal sharp-wave ripple (SWR) 13-15 events. This paradigm enables future direct studies of memory retrieval mechanisms in the healthy brain and in models of neurological disorders.

Spyglass: a framework for reproducible and shareable neuroscience research.

Scientific progress depends on reliable and reproducible results. Progress can also be accelerated when data are shared and re-analyzed to address new questions. Current approaches to storing and analyzing neural data typically involve bespoke formats and software that make replication, as well as the subsequent reuse of data, difficult if not impossible. To address these challenges, we created Spyglass, an open-source software framework that enables reproducible analyses and sharing of data and both intermediate and final results within and across labs. Spyglass uses the Neurodata Without Borders (NWB) standard and includes pipelines for several core analyses in neuroscience, including spectral filtering, spike sorting, pose tracking, and neural decoding. It can be easily extended to apply both existing and newly developed pipelines to datasets from multiple sources. We demonstrate these features in the context of a cross-laboratory replication by applying advanced state space decoding algorithms to publicly available data. New users can try out Spyglass on a Jupyter Hub hosted by HHMI and 2i2c: https://spyglass.hhmi.2i2c.cloud/.

The neural basis of mental navigation in rats.

A brain-machine interface demonstrates volitional control of hippocampal activity.

Dysphagia Outcomes Following Surgical Management of Unilateral Vocal Fold Immobility: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess dysphagia outcomes following surgical management of unilateral vocal fold immobility (UVFI) in adults. DATA SOURCES: Ovid MEDLINE, Embase, Web of Science, and Cochrane Central. REVIEW METHODS: A structured literature search was utilized, and a 2-researcher systematic review was performed following PRISMA guidelines. Extractable data were pooled, and a quantitative analysis was performed with a random effects model to analyze treatment outcome and complications by procedure. RESULTS: A total of 416 publications were screened and 26 met inclusion criteria. Subjects encompassed 959 patients with UVFI who underwent 916 procedures (n = 547, injection laryngoplasty; n = 357, laryngeal framework surgery; n = 12, laryngeal reinnervation). An overall 615 were identified as having dysphagia as a result of UVFI and had individually extractable outcome data, which served as the basis for a quantitative meta-analysis. In general, dysphagia outcomes after all medialization procedures were strongly positive. Quantitative analysis demonstrated a success rate estimate of 90% (95% CI, 75%-100%) for injection laryngoplasty and 92% (95% CI, 87%-97%) for laryngeal framework surgery. The estimated complication rate was 7% (95% CI, 2%-13%) for injection laryngoplasty and 15% (95% CI, 10%-20%) for laryngeal framework surgery, with minor complications predominating. Although laryngeal reinnervation could not be assessed quantitatively due to low numbers, qualitative analysis demonstrated consistent benefit for a majority of patients for each procedure. CONCLUSION: Dysphagia due to UVFI can be improved in a majority of patients with surgical procedures intended to improve glottal competence, with a low risk of complications. Injection laryngoplasty and laryngeal framework surgery appear to be efficacious and safe, and laryngeal reinnervation may be a promising new option for select patients.

The Quality of Otolaryngology- Head and Neck Surgery Literature over the Last Decade.

OBJECTIVE: To describe the changes in the quality of the Otolaryngology-Head and Neck Surgery (OTOHNS) literature over the last decade, and compare it to other surgical-based fields. METHODS: Based on impact factors, the top eight clinical U.S. OTOHNS journals were selected, and articles were analyzed from 2020 (Oto 2020) and compared to 2010 (Oto 2010). This was done similarly for Neurosurgery, Orthopedic, Ophthalmology, and General Surgery journals in 2020 (non-Oto). To limit bias and account for random variability, the first 10 research articles from each journal in each group were included. Data regarding the study type, level of evidence, use of confidence intervals, and funding source were collected. RESULTS: Based on an a priori power analysis, 160 articles were analyzed for Oto 2010 and Oto 2020. Compared to Oto 2020, Oto 2010 had more level 1 and 2 evidence (12 vs. 4; p = 0.032) and less reporting of confidence intervals (10 vs. 32; p < 0.001). Comparing the top 160 articles from 2020 from Non-Oto and OTOHNS (Oto), Non-Oto had more level 1 and 2 evidence (19 vs. 6; p = 0.0047), more randomized controlled trials (8 vs. 1; p = 0.016), and less reporting of confidence intervals (42 vs. 58; p = 0.009). CONCLUSION: High quality studies remain relatively scarce in the OTOHNS literature. Although reporting of confidence intervals has improved over the last decade, aggregate levels of evidence and extramurally funded studies lag behind other surgical-based fields. Better study design will provide stronger evidence basis, in hopes of improving clinical care. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:1853-1856, 2023.

Laryngotracheal and pharyngoesophageal traumatic injuries from US military operations in Iraq and Afghanistan, 2003-2017.

INTRODUCTION: Laryngotracheal and pharyngo-oesophageal trauma present military providers with especially difficult, life-threatening challenges. Although effective treatment strategies are crucial, there is no clear consensus. This study of combat injuries from Iraq and Afghanistan describes initial treatment outcomes. METHODS: US service members who sustained 'laryngotracheal' and 'pharyngoesophageal' injuries while deployed in military operations from 2003 to 2017 were identified from the Expeditionary Medical Encounter Database. Those with inhalation or ingestion injuries and an Injury Severity Score (ISS) <16 were excluded. Data on demographics, survival, mechanism and type of injury and diagnostic and therapeutic intervention were recorded. RESULTS: A total of 111 service members met inclusion criteria. Nearly one-third (32.4%) were killed in action (KIA) or died of wounds (DoW). Fatality was not significantly associated with age, theatre of operation, type of injury or mechanism of injury, but was associated with a higher ISS and those in the Marines. Although survival rates were not significantly different, the frequency of these injuries decreased after the introduction of cervical collar protection in 2007. Of those who DoW or survived, 41.1% required a surgical airway. Tracheobronchoscopy was performed in 25.6%, oesophagoscopy in 20.0% and oesophagram in 6.7%. Of the 85 with penetrating neck injuries, 43 (50.6%) underwent neck exploration, in which 31 (72.1%) required intervention. CONCLUSIONS: Severe laryngotracheal and pharyngo-oesophageal injuries have a high fatality rate and demand prompt treatment from skilled providers. Further work will elucidate preventive measures and clear management algorithms to optimise outcomes.

Dysphagia Outcomes Following Surgical Management of Unilateral Vocal Fold Immobility in Children: A Systematic Review.

OBJECTIVE: To assess dysphagia outcomes following surgical management of unilateral vocal fold immobility in children. DATA SOURCES: Ovid Medline, Embase, Web of Science, and CENTRAL databases. REVIEW METHODS: A systematic review of the medical literature was performed following the PRISMA guidelines. An a priori protocol was defined to identify all articles that presented quantifiable outcome data in children aged <18 years who underwent surgical treatment to improve glottal competence for dysphagia. Two authors independently determined references meeting the inclusion criteria, extracted data, and assigned levels of evidence. Data were pooled via a random effects model where possible. The quality of studies was graded with the MINORS criteria. RESULTS: An overall 398 publications were screened, with 9 meeting inclusion criteria. A total of 115 patients were included. Of these, 75% had preoperative swallowing symptoms. Surgical intervention for dysphagia included 61 injection laryngoplasties, 11 medialization laryngoplasties, and 10 reinnervations (ansa cervicalis to recurrent laryngeal nerve). The articles consistently reported success in improving dysphagia symptoms, and limited meta-analysis demonstrated a mean improvement after surgical intervention in 79% (95% CI, 67%-91%) of children. The reported rate of minor and major complications was 15% (95% CI, 1%-29%). The MINORS scores ranged from 5 to 12. CONCLUSION: Surgical management of unilateral vocal fold immobility in properly selected children can be an effective treatment for dysphagia when symptoms are present. Selection of surgical modalities relies on patient- and surgeon-related factors, and the rate of success is high across different interventions in treating these complex children.

Chromosomal microarray testing influences medical management.

PURPOSE: Chromosomal microarray (CMA) testing provides the highest diagnostic yield for clinical testing of patients with developmental delay (DD), intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). Despite improved diagnostic yield and studies to support cost-effectiveness, concerns regarding the cost and reimbursement for CMA have been raised because it is perceived that CMA results do not influence medical management. METHODS: We conducted a retrospective chart review of CMA testing performed during a 12-month period on patients with DD/ID, ASD, and congenital anomalies to determine the proportion of cases where abnormal CMA results impacted recommendations for clinical action. RESULTS: Among 1792 patients, 13.1% had clinically relevant results, either abnormal (n = 131; 7.3%) or variants of possible significance (VPS; n = 104; 5.8%). Abnormal variants generated a higher rate of recommendation for clinical action (54%) compared with VPS (34%; Fisher exact test, P = 0.01). CMA results influenced medical care by precipitating medical referrals, diagnostic imaging, or specific laboratory testing. CONCLUSIONS: For all test indications, CMA results influenced medical management in a majority of patients with abnormal variants and a substantial proportion of those with VPS. These results support the use of CMA as a clinical diagnostic test that influences medical management for this patient population.