Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.

The Association of Guideline-Concordant Sentinel Lymph Node Biopsy for Melanoma at Minority-Serving Hospitals.

BACKGROUND: Minority-serving hospitals (MSHs) have been associated with lower guideline adherence and worse outcomes for various cancers. However, the relationship among MSH status, concordance with sentinel lymph node biopsy (SLNB) guidelines, and overall survival (OS) for patients with cutaneous melanoma is not well studied. METHODS: The National Cancer Database was queried for patients diagnosed with T1a*, T2, and T3 melanoma between 2012 and 2017. MSHs were defined as the top decile of institutions ranked by the proportion of minorities treated for melanoma. Based on National Comprehensive Cancer Network guidelines, guideline-concordant care (GCC) was defined as not undergoing SLNB if thickness was < 0.76 mm without ulceration, mitosis ≥ 1/mm2, or lymphovascular invasion (T1a*), and performing SLNB for patients with intermediate thickness melanomas between 1.0 and 4.0 mm (T2/T3). Multivariable logistic regressions examined associations with GCC. The Kaplan-Meier method and log-rank tests were used to evaluate OS between MSH and non-MSH facilities. RESULTS: Overall, 5.9% (N = 2182/36,934) of the overall cohort and 37.8% of minorities (n = 199/527) were managed at MSHs. GCC rates were 89.5% (n = 33,065/36,934) in the overall cohort and 85.4% (n = 450/527) in the minority subgroup. Patients in the overall cohort (odds ratio [OR] 0.85; p = 0.02) and the minority subgroup (OR 0.55; p = 0.02) were less likely to obtain GCC if they received their care at MSHs compared with non-MSHs. Minority patients receiving care at MSHs had a decreased survival compared with those treated at non-MSHs (p = 0.002). CONCLUSIONS: Adherence to SLNB guidelines for melanoma was lower at MSHs. Continued focus is needed on equity in melanoma care for minority patients in the United States.

A Systematic Review and Meta-Analysis to Assess the Impact of Pre-existing Comorbidities on the 30-Day Readmission after Lower Extremity Bypass Surgery for Peripheral Artery Occlusive Disease.

BACKGROUND: Unplanned hospital readmissions after surgical operations are considered a marker for suboptimal care during index hospitalizations and are associated with poor patient outcomes and increased healthcare resource utilization. Patients undergoing lower extremity bypass (LEB) operations for severe peripheral arterial disease (PAD) have one of the highest readmission rates, among all the vascular and nonvascular surgical operations. This review is meant to evaluate the impact of pre-existing comorbidities (diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), hypertension (HTN), and coronary artery disease (CAD))-on the 30-day readmission rates among patients who underwent LEB for severe PAD. METHODS: The review protocol was registered to the PROSPERO database (CRD42021261067). A systematic review of the English literature was performed using PubMed, Scopus, and the Cochrane Library databases from inception till April 2022. The review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and included only studies reporting on 30-day readmission following LEB for occlusive PAD. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach and was reported as high, moderate, or low. The risk of bias was evaluated utilizing the Risk of Bias in Nonrandomized Studies - of Interventions (ROBINS-I) tool. A pooled odds ratio (OR) for each study was computed, and a P-value of <0.05 was designated as statistically significant. Interstudy heterogeneity was evaluated by Q-metric and quantified using Higgins I2 statistics. RESULTS: Five studies reported data on 30-day readmission after LEB for occlusive PAD. A total of 19,739 patients were included. Readmission occurred among 3,559 (18%) patients. DM and COPD were reported by all 5 selected studies, and CHF and HTN were reported by 4 studies. CAD was least reported among the selected 5 pre-existing conditions, with only 2 studies mentioning it. HTN (OR, 1.35; 95% confidence interval (CI), 1.10-1.64; P ≤ 0.001; I2 = 52.20%), DM (OR, 1.52; 95% CI, 1.30-1.79; P ≤ 0.001; I2 = 74.51%), and CHF (OR, 1.85; 95% CI, 1.51-2.25; P ≤ 0.001; I2 = 50.48%) were all found to be associated with an increased risk of 30-day readmission, while the presence of COPD (OR, 1.16; 95% CI, 0.98-1.36; P = 0.09; I2 = 61.93%) and CAD (OR, 1.30; 95% CI, 0.94-1.78; P = 0.11; I2 = 51.01%) was not associated with early readmission on meta-analysis of the available studies. CONCLUSIONS: The pre-existing comorbidities HTN, DM, and CHF increase the risk of 30-day readmission after LEB for occlusive PAD. The identification of these risk factors can help stratify the patients and further guide in understanding the variety of factors that contribute in hospital readmissions.

The Impact of Interpretation Services Training on Contact Tracing Efforts During the COVID-19 Pandemic.

There is limited research regarding interpretation services training and its benefit in contact tracing programs. This study seeks to assess the impact of optional formal interpretation services training on contact tracers and identify specific barriers tracers face when contacting patients with limited English proficiency, who have been disproportionately impacted by the COVID-19 pandemic.

Defining the clinical characteristics of mammary analog secretory carcinoma of the salivary gland: Analysis of the National Cancer Database.

Objectives: Mammary analog secretory carcinoma (MASC) is a classification of salivary gland tumors, recently included within the term secretory carcinoma. Previous descriptions of this diagnosis have largely consisted of case reports and case series with few studies investigating its clinical characteristics as compared to non-MASC tumors. Our objective was to use a large patient database to compare the clinical characteristics of mammary analog secretory carcinoma vs. non-mammary analog secretory carcinoma salivary gland tumors. Methods: The National Cancer Database was queried between September and October 2022 for histological diagnosis of mammary analog secretory carcinoma and non-MASC salivary tumors. Patients diagnosed with mammary analog secretory carcinoma and non-mammary analog secretory carcinoma salivary tumors between the period of 2004 through 2019 were included in this analysis. Various demographic and clinical variables were abstracted from the database and compared using Wilcoxon rank sum and chi-square tests. Survival was compared between cohorts using Cox proportional hazards regression. Results: Overall, compared to non-mammary analog secretory carcinoma diagnoses (n = 47668), mammary analog secretory carcinoma tumors (n = 384) affected younger individuals, displayed favorable pathologic staging and tumor grade, and were less likely to invade surrounding tissues. Patients with mammary analog secretory carcinoma tumors also received treatment more quickly following diagnosis compared to patients with non-mammary analog secretory carcinoma tumors. The risk of death was 4.3 times greater for non-mammary analog secretory carcinoma diagnoses when adjusted for patient variables (hazard ratio = 4.3, 95% confidence interval [2.37-7.71], p < 0.001). Conclusions: Clinically, mammary analog secretory carcinoma salivary tumors have a more indolent course compared to other salivary cancers. Additional studies are needed to determine the natural history of this tumor type.

Can magnetic resonance imaging replace computed tomography scans in the evaluation of pediatric post-appendectomy abscess?

BACKGROUND: Computed tomography scans have been used when cross-axial imaging is required to evaluate pediatric post-appendectomy abscesses. To reduce a source of radiation exposure, our institution converted to using contrast-enhanced magnetic resonance imaging to replace computed tomography scans in this clinical context. Our aim is to evaluate the performance of magnetic resonance imaging compared to computed tomography scans and associated clinical outcomes in this patient population. METHODS: A contrast-enhanced comprehensive magnetic resonance imaging protocol was implemented to evaluate a post-appendectomy abscess in 2018. A retrospective chart review was performed from 2015 to 2022 for pediatric patients (<18 years old) with prior appendectomy and subsequent cross-sectional imaging to evaluate for an intraabdominal abscess. Patient characteristics and clinical parameters between the 2 modalities were abstracted and compared using standard univariate statistics. RESULTS: There were a total of 72 post-appendectomy patients who received cross-axial imaging, which included 43 computed tomography scans and 29 magnetic resonance imaging during the study interval. Patient demographics were comparable between cohorts and rates of perforated appendicitis at the index operation (computed tomography: 79.1% vs magnetic resonance imaging: 86.2%). Missed abscess rate, abscess size, management technique, drainage culture results, readmission, and reoperation were similar between imaging modalities. Median request to scan time was longer for magnetic resonance imaging than computed tomography (191.5 vs 108 minutes, P = .04). The median duration of a comprehensive magnetic resonance imaging scan was 32 minutes (interquartile range 28-50.5 minutes). CONCLUSION: Contrast-enhanced magnetic resonance imaging provides an alternative cross-sectional imaging modality to computed tomography scans to evaluate pediatric post-appendectomy abscesses.

Surgical management in pediatric neuroblastoma diagnosis and treatment: a 20-year, single-center experience.

BACKGROUND: The currently utilized International Neuroblastoma Risk Group (INRG) staging system developed in 2009 uses image-defined risk factors as a measure of surgical risk, separating resectable neuroblastoma from those best preceded by chemotherapy. The previous International Neuroblastoma Staging System was based primarily on surgical findings. We hypothesized there would be a change to the role of the surgeon in neuroblastoma treatment in the more recent decade. METHODS: This is a single center 20-year retrospective analysis of 104 patients with International Classification of Diseases-9 and -10 codes for neuroblastoma. Patient demographics, tumor site, cancer treatment modality, survival, biopsy technique, surgical intervention, and pathology staging were collected. Data was analyzed by analysis of variance (ANOVA) and Student's t test. RESULTS: There was a decrease in open surgeries for extra-adrenal neuroblastomas in the later decade (77%, 31%, P = 0.01). There was a narrowing of the time interval to surgery in the later cohort, likely as a result of uniformity in surgical timing on treatment protocols relying on INRG staging. CONCLUSIONS: Our findings mirror changes in practice patterns globally. We found an increase in minimally invasive approaches but did not find a difference in the role of the surgeon under the INRG staging system.

Uncovering a Failed Pediatric Patient Population in Rural America: A Statewide Analysis of Over 1,000 Dog Bite Injuries.

Pediatric dog bites are prevalent and often devastating. Population-based data on these injuries can aid public health intervention efforts. However, most existing literature comes from single institutions in urban settings. We assess a statewide cohort to compare injury characteristics in urban and rural regions and find predictors for inter-hospital transfer. Data from 1,007 injuries from 2000 to 2015 were analyzed. Patients in rural areas were younger, more likely to be white and low-income, and more likely to receive delayed patient care. Injuries occurring in public settings as opposed to the private residence were more likely to involve males, occur in low-income areas, and involve non-white patients. Patients who required inter-hospital transfer were more likely to require a surgical subspecialist and operative repair. Our population analysis reveals children living in rural areas as a previously unidentified vulnerable patient population that may be suitable targets for public health interventions.

COVID-19 Contact Tracing Highlights Disparities: Household Size and Low-English Proficiency.

Although it is known that coronavirus disease 2019 (COVID-19) disproportionately affects racial and ethnic minorities, our study characterizes the connection between COVID-19 susceptibility and both limited English proficiency (LEP) and large household size. We examined demographic and social data for 1130 individuals who tested positive for or were exposed to COVID-19. Analysis revealed that LEP persons were 3.2 times as likely to report difficulty obtaining supplies for quarantine. Individuals in large households were 1.9 times as likely to report difficulty obtaining supplies for quarantine and 2.0 times as likely to report inability to quarantine. This study, therefore, informs interventions targeted to these populations.

Securing the Airway in Maxillofacial Trauma Patients: A Systematic Review of Techniques.

STUDY DESIGN: The present study is a systematic review of the literature. OBJECTIVE: The goal of this study is to review our experience and the current literature on airway management techniques in maxillofacial trauma. METHODS: Independent searches of the PubMed and MEDLINE databases were performed from January 1, 2019 to February 1, 2019. Articles from the period of 2008 to 2018 were collected. All studies which described both airway management and maxillofacial trauma using the Boolean method and relevant search term combinations, including "maxillofacial," "trauma," and "airway," were considered. RESULTS: A total of 452 relevant articles in total were identified. Articles meeting inclusion criteria by abstract review included 68 total articles, of which 16 articles were focused on airway management techniques for maxillofacial trauma in the general population and were deemed appropriate for inclusion in the literature review. CONCLUSIONS: Establishing an effective and stable airway in patients with maxillofacial trauma is of paramount concern. In both the acute setting and during delayed reconstruction, special considerations must be taken when securing a reliable airway in this patient population. The present article provides techniques for securing the airway and algorithms for utilization of these techniques, including both during the initial evaluation and the definitive operative management.

TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model.

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.

Inside human and other animal cells, filaments known as microtubules help support the shape of the cell and move proteins to where they need to be. Defects in microtubules may lead to disease. For example, genetic mutations affecting a microtubule component called TUBB4A cause a rare brain disease in humans known as H-ABC. Individuals with H-ABC display many symptoms including abnormal walking, speech defects, impaired swallowing, and several cognitive defects. Abnormalities in several areas of the brain, including the cerebellum and striatum contribute to these defects. . In these structures, the neurons that carry messages around the brain and their supporting cells, known as oligodendrocytes, die, which causes these parts of the brain to gradually waste away. At this time, there are no therapies available to treat H-ABC. Furthermore, research into the disease has been hampered by the lack of a suitable "model" in mice or other laboratory animals. To address this issue, Sase, Almad et al. generated mice carrying a mutation in a gene which codes for the mouse equivalent of the human protein TUBB4A. Experiments showed that the mutant mice had similar physical symptoms to humans with H-ABC, including an abnormal walking gait, poor coordination and involuntary movements such as twitching and reduced reflexes. H-ABC mice had smaller cerebellums than normal mice, which was consistent with the wasting away of the cerebellum observed in individuals with H-ABC. The mice also lost neurons in the striatum and cerebellum, and oligodendrocytes in the brain and spinal cord. Furthermore, the mutant TUBB4A protein affected the behavior and formation of microtubules in H-ABC mice. The findings of Sase, Almad et al. provide the first mouse model that shares many features of H-ABC disease in humans. This model provides a useful tool to study the disease and develop potential new therapies.

Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine.

Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressive-like brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1ß, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure led to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased Ih currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and Ih currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.