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At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction. To identify regulators of postsynaptic function, we conducted a genome-wide RNAi screen for genes required for proper response to levamisole, a pharmacological agonist of ionotropic LAChRs at the Caenorhabditis elegans NMJ. A total of 117 gene knockdowns were found to cause levamisole hypersensitivity, while 18 resulted in levamisole resistance. Our screen identified conserved genes important for muscle function including some that are mutated in congenital myasthenic syndrome, congenital muscular dystrophy, congenital myopathy, myotonic dystrophy, and mitochondrial myopathy. Of the genes found in the screen, we further investigated those predicted to play a role in endocytosis of cell surface receptors. Loss of the Epsin homolog epn-1 caused levamisole hypersensitivity and had opposing effects on the levels of postsynaptic L-AChRs and GABAA receptors, resulting in increased and decreased abundance, respectively. We also examined other genes that resulted in a levamisolehypersensitive phenotype when knocked down including gas-1, which functions in Complex I of the mitochondrial electron transport chain. Consistent with altered ATP synthesis impacting levamisole response, treatment of wild-type animals with levamisole resulted in L-AChR– dependent depletion of ATP levels. These results suggest that the paralytic effects of levamisole ultimately lead to metabolic exhaustion. [ABSTRACT FROM AUTHOR]

The 22q11.2 duplication syndrome (22q11.2DupS) is characterized by phenotypic heterogeneity, from seemingly asymptomatic to severely affected patients. Our study sought to detail the cardiac phenotype associated with 22q11.2DupS, the prevalence of aortic arch anomalies and aortic root dilation in 22q11.2DupS, and to assess how frequently new congenital heart disease (CHD) is diagnosed at outpatient cardiac evaluation following genetic diagnosis. In our cohort of 85 patients, 20.0% had CHD, with a wide range of phenotypes. Sixty‐eight patients had complete cardiac evaluations detailing aortic arch sidedness and branching pattern, of which 5 (7.4%) had an aortic arch anomaly, all of whom had concurrent intracardiac CHD. Of 53 patients without CHD who had complete cardiac evaluations, only 3 (5.7%) had evidence of aortic root dilation. Of 46 patients who underwent outpatient cardiac evaluation following diagnosis of 22q11.2DupS, only one (2.2%) was found to have CHD, an isolated bicuspid aortic valve without stenosis. Therefore, the CHD phenotype in 22q11.2DupS, when present, is heterogeneous. Aortic arch anomalies are uncommon, and no patient in our cohort had one in isolation. Isolated aortic root dilation is also uncommon. Finally, outpatient cardiac evaluation following genetic diagnosis without previously known CHD infrequently identified minor cardiac malformations. [ABSTRACT FROM AUTHOR]

Ozone is a highly reactive compound composed of three oxygen atoms that acts as an oxidant and oxidizer. It exists at the ground level as an air pollutant and a constituent of urban smog, as well as in the Earth's upper atmosphere as a protective layer from ultraviolet rays. Healthy cells contain antioxidants such as vitamins C and E to protect against ozone oxidization. However, pathogens such as bacteria contain very trace amounts of antioxidants in their membranes, which make them susceptible to ozone and destroy the cell membrane. This review explores the history, composition, and use of ozone worldwide in dentistry. Ozone therapy has thus far been utilized with wound healing, dental caries, oral lichen planus, gingivitis and periodontitis, halitosis, osteonecrosis of the jaw, post-surgical pain, plaque and biofilms, root canals, dentin hypersensitivity, temporomandibular joint disorders, and teeth whitening. The utility of ozone will undoubtedly grow if studies continue to show positive outcomes in an increasing number of dental conditions. [ABSTRACT FROM AUTHOR]

Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient is often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence., Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas (TCGA) across 33 cancer types, we estimated background rates of co-occurrence rates of mutations between discrete pairs of samples across cancers and by cancer type. We developed a mutational profile similarity score (MPS) that uses a large background database to produce confidence estimates that two tumors share a unique, related molecular profile. The MPS algorithm was applied to randomly paired tumor profiles, including patients who underwent repeat solid tumor biopsies sequenced with MSK-IMPACT (n=53,113). We also evaluated the MPS in sample pairs from single patients with multiple cancers (n=2,012), as well as patients with plasma and solid-tumor variant profiles (n=884 patients)., Results: In unrelated tumors, nucleotide-specific variants are shared in 1.3% (cancer-type agnostic) and in 10-13% (cancer-type specific) of cases. The mutational profile similarity (MPS) method contextualized shared variants to specify whether patients had a single cancer versus multiple distinct cancers. When multiple tumors were compared from the same patient, and an initial clinicopathologic diagnosis was discordant with molecular findings, the MPS anticipated future diagnosis changes in 28% of examined cases., Conclusions: Use of a novel shared variant framework can provide information to clarify the molecular relationship between compared biospecimens with minimal required input.

Background and Objectives: The "July Effect" hypothesizes increased morbidity and mortality after the addition of inexperienced physicians at the beginning of an academic year. However, the impact of newer members on neurosurgical teams managing patients with traumatic brain injury (TBI) has yet to be examined. This study conducted a nationwide analysis to evaluate the existence of the "July Effect" in the setting of patients with TBI., Methods: The Healthcare Cost and Utilization Project Central Distributor's National Inpatient Sample data set was queried for patients with TBI using International Classification of Diseases (ICD)-9 and ICD-10 codes. Discharges were included for diagnoses of traumatic epidural, subdural, or subarachnoid hemorrhages. Only patients treated at teaching hospitals were included to ensure resident involvement in care. Patients were grouped into July admission and non-July admission cohorts. A subgroup of patients with neurotrauma undergoing any form of cranial surgery was created. Perioperative variables were recorded. Rates of different complications were assayed. Groups were compared using χ2 tests (qualitative variables) and t-tests or Mann-Whitney U-tests (quantitative variables). Logistic regression was used for binary variables. Gamma log-linked regression was used for continuous variables., Results: The National Inpatient Sample database yielded a weighted average of 3 160 452 patients, of which 312 863 (9.9%) underwent surgical management. Patients admitted to the hospital in July had a 5% decreased likelihood of death (P = .027), and a 5.83% decreased likelihood of developing a complication (P < .001) compared with other months of the year. July admittance to a hospital showed no significant impact on mean length of stay (P = .392) or routine discharge (P = .147). Among patients with TBI who received surgical intervention, July admittance did not significantly affect the likelihood of death (P = .053), developing a complication (P = .477), routine discharge (P = .986), or mean length of stay (P = .385)., Conclusion: The findings suggested that there is no "July Effect" on patients with TBI treated at teaching hospitals in the United States., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Rationale: Acute cellular rejection (ACR) after lung transplant is a leading risk factor for chronic lung allograft dysfunction. Prior studies have demonstrated dynamic microbial changes occurring within the allograft and gut that influence local adaptive and innate immune responses. However, the lung microbiome's overall impact on ACR risk remains poorly understood. Objectives: To evaluate whether temporal changes in microbial signatures were associated with the development of ACR. Methods: We performed cross-sectional and longitudinal analyses (joint modeling of longitudinal and time-to-event data and trajectory comparisons) of 16S rRNA gene sequencing results derived from lung transplant recipient lower airway samples collected at multiple time points. Measurements and Main Results: Among 103 lung transplant recipients, 25 (24.3%) developed ACR. In comparing samples acquired 1 month after transplant, subjects who never developed ACR demonstrated lower airway enrichment with several oral commensals (e.g., Prevotella and Veillonella spp.) than those with current or future (beyond 1 mo) ACR. However, a subgroup analysis of those who developed ACR beyond 1 month revealed delayed enrichment with oral commensals occurring at the time of ACR diagnosis compared with baseline, when enrichment with more traditionally pathogenic taxa was present. In longitudinal models, dynamic changes in α-diversity (characterized by an initial decrease and a subsequent increase) and in the taxonomic trajectories of numerous oral commensals were more commonly observed in subjects with ACR. Conclusions: Dynamic changes in the lower airway microbiota are associated with the development of ACR, supporting its potential role as a useful biomarker or in ACR pathogenesis.

Introduction: The internet is an essential resource for patients and their loved ones to understand their medical conditions, and professional medical organizations have taken great strides to develop educational material targeting patients. The average American reads at a seventh to eighth grade reading level, hence it is important to understand the readability of this medical information to ensure patients comprehend what is being presented., Methods: In January 2023, online patient education material was downloaded from major cerebrovascular healthcare organizations and assessed using eight assessments, including Bormuth Cloze Mean, Bormuth Grade Placement, Coleman-Liau (grade levels), Coleman-Liau (predictive cloze scores), Flesch Reading Ease (FRE), and Fry., Results: A total of 32 files were extracted from six organizations and analyzed across 15 readability measures. None of the organizations met the federal government guidelines for grade-level readability. This held constant across all measured tests. Two organizations had above a postgraduate level. The FRE graphs do not identify any organizations with material below a ninth grade reading level, while the American Association of Neurological Surgeons (AANS) and the Society of Interventional Radiology (SIR) have a postgraduate readability level. The Fry graphs show similar results, with AANS/CNS Cerebrovascular Section, Society of NeuroInterventional Surgery (SNIS), SIR, and AANS having college-level readability. The lowest readability across all measures is only at an early seventh grade reading level., Conclusions: Current health literacy content for cerebrovascular patients is far above the recommended readability level. We provide straightforward suggestions for how major professional organizations should improve their informational material on cerebrovascular diseases to improve patient understanding., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Chromophores with zwitterionic excited-state intramolecular proton transfer (ESIPT) have been shown to have larger Stock shifts and red-shifted emission wavelengths compared to the conventional π-delocalized ESIPT molecules. However, there is still a dearth of design strategies to expand the current library of zwitterionic ESIPT compounds. Herein, a novel zwitterionic excited-state intramolecular proton transfer system is reported, enabled by addition of 1,4,7-triazacyclononane (TACN) fragments on a dicyanomethylene-4H-pyran (DCM) scaffold. The solvent-dependent steady-state photophysical studies, pKa measurements, and computational analysis strongly support that the ESIPT process is more efficient with two TACN groups attached to the DCM scaffold and not affected by polar protic solvents. Impressively, compound DCM-OH-2-DT exhibits a near-infrared (NIR) emission at 740 nm along with an uncommonly large Stokes shift. Moreover, DCM-OH-2-DT shows high affinity towards soluble amyloid β (Aβ) oligomers in vitro and in 5xFAD mouse brain sections, and we have successfully applied DCM-OH-2-DT for the in vivo imaging of Aβ aggregates and demonstrated its potential use as an early diagnostic agent for AD. Overall, this study can provide a general molecular design strategy for developing new zwitterionic ESIPT compounds with NIR emission in vivo imaging applications., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer's disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit selective binding toward Aβ oligomers. These amphiphilic compounds can also label the Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu 2+ -Aβ induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target Aβ oligomers and modulate the Aβ oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Malnutrition is quite common in patients with esophageal cancer, and can be secondary to tumor related dysphagia or treatment side effects. Traditionally, open feeding jejunostomy tube was performed in all patients undergoing surgical treatment of esophageal cancer. With the advent of minimally invasive approaches, placement of the jejunostomy tube can be currently accomplished with either robotic or laparoscopic assistance. Here, we discuss the technical aspects as well as the pros and cons of a minimally invasive jejunostomy feeding tube placement., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.