Citations

Abstract Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus to understand ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglial-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

ABSTRACT Infections due to nontuberculous mycobacteria (NTM) continue to increase in prevalence, leading to problematic clinical outcomes. Omadacycline (OMC) is an aminomethylcycline antibiotic with FDA orphan drug and fast-track designations for pulmonary NTM infections, including Mycobacteroides abscessus (MAB). This multicenter retrospective study across 16 U.S. medical institutions from January 2020 to March 2023 examined the long-term clinical success, safety, and tolerability of OMC for NTM infections. The cohort included patients aged ≥18 yr, who were clinically evaluable, and` had been treated with OMC for ≥3 mo without a previous diagnosis of cystic fibrosis. The primary outcome was 3 mo clinical success, with secondary outcomes including clinical improvement and mortality at 6- and 12 mo, persistence or reemergence of infection, adverse effects, and reasons for OMC utilization. Seventy-five patients were included in this analysis. Most patients were female (48/75, 64.0%) or Caucasian (58/75, 77.3%), with a median (IQR) age of 59 yr (49–67). Most had NTM pulmonary disease (33/75, 44.0%), skin and soft tissue disease (19/75, 25.3%), or osteomyelitis (10/75, 13.3%), and Mycobacterium abscessus (60/75, 80%) was the most commonly isolated NTM pathogen. The median (IQR) treatment duration was 6 mo ( 4 – 14 ), and the most commonly co-administered antibiotic was azithromycin (33/70, 47.1%). Three-month clinical success was observed in 80.0% (60/75) of patients, and AEs attributable to OMC occurred in 32.0% (24/75) of patients, leading to drug discontinuation in 9.3% (7/75).

Abstract AIMS High-grade glioma continues to have dismal survival with current standard-of-care treatment, owing in part to its intra- and inter-patient heterogeneity. Typical diagnostic biopsies are taken from the dense tumor core to determine the presence of abnormal cells and the status of a few key genes (e.g. IDH1, MGMT). However, the tumor core is typically resected, leaving behind possibly genetically, transcriptomically and/or phenotypically distinct invasive margins that repopulate the disease. As these remaining populations are the ones ultimately being treated, it is important to know their compositional differences from the tumor core. We aim to identify the phenotypic niches defined by the relative composition of key cellular populations and understand their variation amongst patients. METHOD We have established an image-localized research biopsy study, that samples from both the invasive margin and tumor core. From this protocol, we currently have 202 samples from 58 patients with available bulk RNA-Seq, collected between Mayo Clinic and Barrow Neurological Institute. Using a single-cell reference dataset from our collaborators at Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell states for each sample. RESULTS We find that these cell state abundances connect to patient survival and show regional differences. For example, proneural glioma states were higher in invasive regions, whereas proliferative and mesenchymal states were higher in the tumor core. CONCLUSIONS Our analysis demonstrates a need to characterize the residual tissue following glioma resection to better understand the recurrent disease.

Purpose To develop a machine learning model capable of identifying subscapularis tears before surgery based on imaging and physical examination findings. Methods Between 2010 and 2020, 202 consecutive shoulders underwent arthroscopic rotator cuff repair by a single surgeon. Patient demographics, physical examination findings (including range of motion, weakness with internal rotation, lift/push‐off test, belly press test, and bear hug test), and imaging (including direct and indirect signs of tearing, biceps status, fatty atrophy, cystic changes, and other similar findings) were included for model creation. Results Sixty percent of the shoulders had partial or full thickness tears of the subscapularis verified during surgery (83% of these were upper third). Using only preoperative imaging‐related parameters, the XGBoost model demonstrated excellent performance at predicting subscapularis tears (c‐statistic, 0.84; accuracy, 0.85; F1 score, 0.87). The top 5 features included direct signs related to the presence of tearing as evidenced on magnetic resonance imaging (MRI) (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. Conclusions In this study, machine learning was successful in predicting subscapularis tears by MRI alone in 85% of patients, and this accuracy did not decrease by isolating the model to the top features. The top five features included direct signs related to the presence of tearing as evidenced on MRI (changes in tendon morphology and signal), as well as the quality of the MRI and biceps pathology. Last, in advanced modeling, the addition of physical examination or patient characteristics did not make a significant difference in the predictive ability of this model. Level of Evidence Level III, diagnostic case‐control study.

Abstract Background Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology‐based topics spanning the field. Methods In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence‐Based Review with Recommendations, Evidence‐Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses format, and completed sections underwent a thorough and iterative consensus‐building process. The final document underwent rigorous synthesis and review prior to publication. Results The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology‐based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. Conclusion As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

ABSTRACTCoccidioidesspp. are dimorphic fungi that are capable of infecting human and non-human mammals and can cause diverse manifestations of coccidioidomycosis or Valley fever (VF). In combination with clinical symptoms and radiographic findings, antibody-based diagnostic tests are often used to diagnose and monitor patients with VF. Chitinase 1 (CTS1) has previously been identified as the seroreactive antigen used in these diagnostic assays to detect anticoccidial IgG. Here, an indirect enzyme-linked immunosorbent assay to detect IgG to CTS1 demonstrated 165 of 178 (92.7%) patients with a positive result by immunodiffusion (ID) and/or complement fixation (CF) had antibodies to the single antigen CTS1. We then developed a rapid antibody lateral flow assay (LFA) to detect anti-CTS1 antibodies. Out of 143 samples tested, the LFA showed 92.9% positive percent agreement [95% confidence interval (CI), 84.3%–96.9%] and 97.7% negative percent agreement (95% CI, 87.9%–99.6%) with ID and CF assays. Serum or plasma from canines, macaques, and dolphins was also tested by the CTS1 LFA. Test line densities of the CTS1 LFA correlated in a linear manner with the reported CF and ID titers for human and non-human samples, respectively. This 10-min point-of-care test for the rapid detection of anti-coccidioidal antibodies could help to inform healthcare providers in real-time, potentially improving the efficiency of healthcare delivery.

Background: Patients with fungal pneumonias sometimes progress to acute respiratory distress syndrome (ARDS). Mortality has been reported as high as 60% to 90% in this group. Venovenous extracorporeal membrane oxygenation (VV-ECMO) can be used to support such patients, however, outcomes are not well understood. Patients and Methods: This was a retrospective study across the four adult ECMO centers in Minnesota for one decade (2012–2022). The outcomes of interest were duration of ECMO, survival rate, and complications. Data were extracted from the electronic medical record and analyzed using descriptive statistics. Results: Fungal pneumonia was the etiology of ARDS in 22 of 422 (5%) adults supported with VV-ECMO during the 10-year study period. Median patient age was 43 years (interquartile range [IQR], 35–56) and 68% were male. By type of fungal infection, 16 (72%) had blastomycosis, five (22%) had pneumocystis, and one (5%) had cryptococcus. Of the 16 patients with blastomycosis two were immunosuppressed whereas all five of the pneumocystis patients were immunosuppressed. The overall survival rate was 73%; most patients with blastomycosis (67%) and pneumocystis (80%) survived to hospital discharge. The duration of ECMO support was greater for the pneumocystis group (median, 30 days; IQR, 21–43) compared with blastomycosis (median, 10 days; IQR, 8–18). Conclusions: Our findings support the use of VV-ECMO for ARDS caused by fungal pneumonias in select immunocompetent and immunocompromised patients. Although survival was high, patients with pneumocystis required longer ECMO runs.

Background: Meniscal allograft transplantation (MAT) has been shown to provide clinical benefits in patients with symptomatic meniscal deficiency in the short term and midterm. There is, however, a paucity of data regarding long-term outcomes after MAT using fresh-frozen allografts and the bridge-in-slot technique. Purpose: To report clinical outcomes and revision rates after primary MAT with fresh-frozen allografts and the bridge-in-slot technique in a large case series of patients at a 10-year minimum follow-up. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review of prospectively collected data was performed on patients undergoing primary MAT between 2001 and 2012. Lysholm, International Knee Documentation Committee subjective form, and Knee injury and Osteoarthritis Outcome Score subscales were collected preoperatively and at 1-, 2-, 5-, and minimum 10-year follow-ups. Cox proportional hazards modeling was used to identify variables associated with reoperation and failure, defined as revision MAT or conversion to arthroplasty. Reoperation was defined as a subsequent surgical intervention on the transplanted meniscus, including partial or total meniscectomy, meniscal repair, or failure as defined in the previous sentence. Results: A total of 174 patients undergoing MAT met the inclusion criteria and were followed for a mean of 12.7 ± 2.7 years (range, 10.0-21.0 years). The mean age at surgery was 28.3 ± 10.1 years. The patients were predominantly female (n = 92; 53%), and medial MAT was the most commonly performed procedure (n = 91; 52%). Concomitant procedures were performed in 115 patients (66%), with the most common procedure being osteochondral allograft transplantation (n = 59; 34%). Patients demonstrated statistically significant postoperative improvements at all time points for all patient-reported outcome measures ( P ≤ .0001). A total of 65 patients (37%) underwent a meniscal reoperation at a mean time of 6.6 ± 5.5 years (range, 0.3-16.7 years) postoperatively. A total of 40 patients (23%) met the criteria for failure at a mean time of 7.3 ± 5.0 years (range, 1.0-17.4 years) after MAT, with 22 of these patients having undergone a previous meniscal reoperation. At the final follow-up, 13 patients (7%) had undergone revision MAT and 27 (15%) had converted to arthroplasty. The MAT survival rates free of meniscal reoperation and failure were 73% and 85% at 10 years and 60% and 72% at 15 years, respectively. At the time of the final follow-up, 86% of patients reported that they were satisfied with their overall postoperative condition. Conclusion: Primary MAT demonstrates efficacy and durability with high rates of patient satisfaction at a minimum 10-year follow-up. Patients should be counseled that although reoperation rates may approach 40% at 15 years, rates of overall revision MAT and conversion to arthroplasty remain low at long-term follow-up.