Critical Degree of Orbital Floor Displacement Drives Operative Repair of Zygomaticomaxillary Complex Fractures: Findings from a 10-Year Retrospective Study.

Among zygomaticomaxillary complex (ZMC) fractures presenting to a tertiary urban academic center, the authors hypothesized the presence of both clinical and radiographic predictors of operative management. The investigators conducted a retrospective cohort study of 1,914 patients with facial fractures managed at an academic medical center in New York City between 2008 and 2017. The predictor variables were based on both clinical data and features of pertinent imaging studies, and the outcome variable was an operative intervention. Descriptive and bivariate statistics were computed and the p-value was set at 0.05. In total, 196 patients sustained ZMC fractures (5.0%) and 121 (61.7%) ZMC fractures were treated surgically. All patients who presented with globe injury, blindness, retrobulbar injury, restricted gaze, or enophthalmos and a concurrent ZMC fracture were managed surgically. The most common surgical approach was the gingivobuccal corridor (31.9% of all approaches), and there were no significant immediate postoperative complications. Younger patients (38.9 ± 18 years vs. 56.1 ± 23.5 years, p < 0.0001) and patients with greater than or equal to 4 mm of orbital floor displacement were more likely to receive surgical treatment than observation (82 vs. 56%, p = 0.045), as were patients with comminuted orbital floor fractures (52 vs. 26%, p = 0.011). In this cohort, patients more likely to undergo surgical reduction were young patients with ophthalmologic symptoms on presentation and at least 4 mm displacement of the orbital floor. Low kinetic energy ZMC fractures may warrant surgical management as often as high-energy ZMC fractures. While orbital floor comminution has been shown to be a predictor for operative reduction, in this study we also demonstrated a difference in the rate of reduction based on the severity of orbital floor displacement. This may have significant implications in both the triage and selection of patients most suitable for operative repair.

PSD-95 in CA1 Area Regulates Spatial Choice Depending on Age.

Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the reward corner during the spatial choice task. Moreover, training decreased the correlation between PSD-95 expression and the size of dendritic spines. Furthermore, PSD-95 depletion did not impair place choice or reward preference in old mice. Thus, our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices, old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment.SIGNIFICANCE STATEMENT It remains poorly understood how aging affects behavioral and molecular processes that support cognitive functions. It is, however, essential to understand these processes to develop therapeutic interventions that support successful cognitive aging. Our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices (i.e., choices that require spatial information), old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment. Second, the contribution of PSD-95-dependent synaptic functions in spatial choice changes with age.

Telemedicine lessons learned during the COVID-19 pandemic: The augmented outpatient otolaryngology teleconsultation.

PURPOSE: Telemedicine use in otolaryngology waxed and waned during the COVID-19 pandemic outbreak in the U.S. Assessing the patterns of telemedicine use and its perceived limitations during the COVID-19 outbreak in 2020 allows identification and correction of impediments to consistent telemedicine use by otolaryngologists. MATERIALS AND METHODS: Full-time faculty of 2 academic otolaryngology departments in New York City were surveyed regarding their telemedicine use from March through August 2020 during the "first wave" of the COVID-19 pandemic. Based on these findings, a method of "augmented outpatient otolaryngology teleconsultation" designed to enhance the quality of the physical examination was developed and employed from August to December 2020. Patients receiving this augmented teleconsult were anonymously surveyed about their telemedical experience. RESULTS: Telemedicine use by faculty was minimal prior to the pandemic, but as total outpatient volume decreased 65-84% across subspecialties, it was used by all otolaryngologists during COVID-19. Physicians were less confident in making a telemedical diagnosis at all phases of the study in all subspecialties. Patients who had an augmented otolaryngology teleconsultation were satisfied with it, believed it facilitated earlier care, limited the time and cost of travel to the physician's office and felt their physician was able to perform a sufficient physical examination. CONCLUSIONS: During the COVID-19 crisis, physicians utilized teleotolaryngology to provide care but were less satisfied with their ability to make an accurate diagnosis. Inexpensive direct-to-consumer digital otoscopes can improve the quality of the physical examination provided and can address both patient and physician needs.

Injury Patterns in Pediatric Facial Fractures Unique to an Urban Environment.

This study aimed to define better the clinical presentation, fracture patterns, and features predictive of associated injuries and need for surgery in pediatric facial trauma patients in an urban setting. Charts of patients 18 years or younger with International Classification of Disease 9th and 10th revision (ICD-9/ICD-10) codes specific for facial fractures (excluding isolated nasal fractures) at NY-Presbyterian/Weill Cornell Medical Center between 2008 and 2017 were retrospectively reviewed. Of 204 patients, most were referred to the emergency department by a physician's office or self-presented. Children (age 0-6 years) were most likely to have been injured by falls, while more patients 7 to 12 years and 13 to 18 years were injured during sporting activities (p < 0.0001). Roughly half (50.5%) of the patients had a single fracture, and the likelihood of surgery increased with greater numbers of fractures. Older patients with either orbital or mandibular fractures were more likely to undergo surgery than younger ones (p = 0.0048 and p = 0.0053, respectively). Cranial bone fractures, CSF leaks, and intracranial injuries were more common in younger patients (p < 0.0001) than older patients and were more likely after high energy injuries; however, 16.2% of patients sustaining low energy injuries also sustained cranial bone, CSF leak, or intracranial injury. In an urban environment, significant pediatric facial fractures and associated injuries may occur after nonclassic low kinetic energy traumatic events. The age of the patient impacts both the injuries sustained and the treatment rendered. It is essential to maintain a high index of suspicion for associated injuries in all pediatric facial trauma patients.

Effects of oxytocin-family peptides and substance P on locomotor activity and filial preferences in visually naïve chicks.

Nonapeptides from the vasopressin/oxytocin family have been implicated in a wide variety of social behaviours across vertebrates. Experimental manipulations that alter nonapeptide levels or receptor function in the brain have provided evidence for understanding how nonapeptides influence responses to social stimuli in adults. While behaviours in adults have been extensively studied, much less in known about roles of nonapeptides in early life and the development of affiliative social behaviours. We examined an experience-independent preference (social predisposition) that is present at hatching and is characterized by the tendency of visually naïve chicks (Gallus gallus) to prefer to approach a stuffed hen stimulus over a control stimulus in a choice test. Among chicks that show the social predisposition preference, bilateral intracranial mesotocin injections resulted in higher mean hen preference scores compared with saline-injected controls. Equimolar doses of mesotocin and vasotocin injections had different effects on locomotor activity: vasotocin, but not mesotocin, resulted in hypoactivity. We also tested whether intraperitoneal substance P had an effect on hen preference scores because previous research has proposed that vasotocin effects on social approach are mediated by peripheral release of substance P, but found no significant effect. All together, our data suggest that mesotocin signalling may be important for social predispositions and can potentially enhance the perceived salience of social stimuli soon after hatching. Specifically, mesotocin release and signalling in the brain may regulate the ability to recognize naturalistic stimuli and/or to act on the motivation to approach naturalistic stimuli.

Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in "intermediate" CD14++CD16+ monocytes and an activated subpopulation of CD14+ monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.

Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation.

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack threonine-286 autophosphorylation of αCaMKII have shown that hippocampal LTM can be formed despite absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typically two presynaptic inputs. PSD-95 overexpression is sufficient for MIS generation and depends on mTOR signaling. LTM that involves MIS generation appears less modifiable upon retrieval in comparison to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting negative feedback CaMKII signaling at the synapse.

Mechanism for long-term memory formation when synaptic strengthening is impaired.

Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.

Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) is a stress-induced actin bundling factor that modulates synaptic efficacy and cognition.

Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition.

Elective Surgery Trends and Outcomes of Nonagenarians and Centenarians in Otolaryngology-Head and Neck Surgery: A NSQIP Study.

OBJECTIVE: To describe types and outcomes of elective otolaryngological surgeries undergone by patients ≥90 years of age and to assess whether very old age is an independent risk factor for postsurgical complications and death. METHODS: The National Surgical Quality Improvement Program, a validated national prospective surgical outcomes database, was used to identify all patients aged 65 years and older who underwent elective otolaryngological procedures from 2011 to 2020. Study outcomes included minor complications, major life-threatening complications, and 30-day mortality. Predictors of outcomes, including frailty, were identified using univariable analyses and age was added into the final logistic regression models with stepwise selection. RESULTS: A total of 40,723 patients met inclusion criteria; 629 (1.5%) patients were ≥90 years of age. Of the 63,389 procedures, head and neck (67.6%) and facial plastics and reconstructive (15.0%) procedures were most common. The overall incidence of major life-threatening complications, minor complications, and death was 2.0%, 3.5%, and 0.4%, respectively. Age ≥90 was significantly associated with an increased risk for 30-day mortality, but not with major or minor postoperative complications. A high modified frailty index was significantly associated with an increased risk for major postoperative complications and death amongst patients ≥90 years. CONCLUSIONS: Elective otolaryngological surgery can be safe in relatively healthy nonagenarians and centenarians, though there is a small increased risk of 30-day mortality. Although older age can predispose patients to other comorbidities, age alone should not deter surgeons and patients from considering elective otolaryngological procedures. Frailty may be a better predictor for surgical outcomes. LEVEL OF EVIDENCE: Level IV Laryngoscope, 2024.

How to be a good reviewer: A step-by-step guide for approaching peer review of a scientific manuscript.

Objectives: The peer review process is critical to maintaining quality, reliability, novelty, and innovation in the scientific literature. However, the teaching of scientific peer review is rarely a component of formal scientific or clinical training, and even the most experienced peer reviewers express interest in continuing education. The objective of this review article is to summarize the collective perspectives of experienced journal editors about how to be a good reviewer in a step-by-step guide that can serve as a resource for the performance of peer review of a scientific manuscript. Methods: This is a narrative review. Results: A review of the history and an overview of the modern-day peer review process are provided with attention to the role played by the reviewer, including important reasons for involvement in scientific peer review. The general components of a scientific peer review are described, and a model for how to structure a peer review report is provided. These concepts are also summarized in a reviewer checklist that can be used in real-time to develop and double-check one's reviewer report before submitting it. Conclusions: Peer review is a critically important service for maintaining quality in the scientific literature. Peer review of a scientific manuscript and the associated reviewer's report should assess specific details related to the accuracy, validity, novelty, and interpretation of a study's results. We hope that this article will serve as a resource and guide for reviewers of all levels of experience in the performance of peer review of a scientific manuscript.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology.

An increasing body of data has shown that matrix metalloproteinase-9 (MMP-9), an extracellularly acting, Zn(2+)-dependent endopeptidase, is important not only for pathologies of the central nervous system but also for neuronal plasticity. Here, we use three independent experimental models to show that enzymatic activity of MMP-9 causes elongation and thinning of dendritic spines in the hippocampal neurons. These models are: a recently developed transgenic rat overexpressing autoactivating MMP-9, dissociated neuronal cultures, and organotypic neuronal cultures treated with recombinant autoactivating MMP-9. This dendritic effect is mediated by integrin ß1 signalling. MMP-9 treatment also produces a change in the decay time of miniature synaptic currents; however, it does not change the abundance and localization of synaptic markers in dendritic protrusions. Our results, considered together with several recent studies, strongly imply that MMP-9 is functionally involved in synaptic remodelling.

An NCAM mimetic, FGL, alters hippocampal cellular morphometry in young adult (4 month-old) rats.

The neural cell adhesion molecule, NCAM, is ubiquitously expressed within the CNS and has roles in development, cognition, neural plasticity and regulation of the immune system. NCAM is thus potentially an important pharmacological target for treatment of brain diseases. A cell adhesion mimetic FGL, a 15 amino-acid peptide derived from the second fibronectin type-III module of NCAM, has been shown to act as a neuroprotective agent in experimental disease and ageing models, restoring hippocampal/cognitive function and markedly alleviating deleterious changes in the CNS. However, the effects of FGL on the hippocampus of young healthy rats are unknown. The present study has examined the cellular neurobiological consequences of subcutaneous injections of FGL, on hippocampal cell morphometry in young (4 month-old) rats. We determined the effects of FGL on hippocampal volume, pyramidal neuron number/density (using unbiased quantitative stereology), and examined aspects of neurogenesis (using 2D morphometric analyses). FGL treatment reduced total volume of the dorsal hippocampus (associated with a decrease in total pyramidal neuron numbers in CA1 and CA3), and elevated the number of doublecortin immunolabeled neurons in the dentate gyrus, indicating a likely influence on neurogenesis in young healthy rats. These data indicate that FGL has a specific age dependent effect on the hippocampus, differing according to the development and maturity of the CNS.

Demographic Disparities in the Federal Drug Approval Process for Allergic Rhinitis Medications.

OBJECTIVE: Demographic minorities are underrepresented in clinical trials. For the approval of new drug applications (NDAs), the Food and Drug Administration (FDA) has asserted that clinical trial enrollment should represent the demographics of patients likely to receive the trial drug. The aim of this study is to assess the demographics of clinical trials included in NDAs and biologics license applications (BLAs) approved by the FDA since 1990 for allergic rhinitis (AR), a condition whose demographic prevalence mirrors the US population. METHODS: Federal Freedom of Information Act requests were submitted to the US government to obtain documents related to all relevant NDAs and BLAs. The Drugs@FDA database was queried for all clinical trial documentation. Demographic data were extracted from clinical trials used to inform FDA approval for AR pharmacotherapies. Demographics were analyzed relative to national US Census data. RESULTS: Since 1990, 22 drugs have been approved for AR. The racial, ethnic, and sex composition of all included study populations differed significantly (p < 0.05) from the demographics of AR and from US Census data. Most NDAs and BLAs included overrepresentation of White participants and underrepresentation of Black, Asian, Pacific Island, Native American, and Hispanic participants. CONCLUSION: The patients enrolled in clinical trials used to inform FDA approval for AR pharmacotherapeutics do not represent the demographics of the United States or the demographics of AR. The clinical significance of unrepresentative demography between study and treatment populations has been examined for several medical disorders, but has not been studied for AR. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:755-763, 2023.

Impact of Medicaid Expansion on Rhinologic Cancer Presentation, Treatment, and Outcomes.

OBJECTIVE: The United States Patient Protection and Affordable Care Act allocated funds for states to expand Medicaid coverage. However, several states declined expansion. We aim to determine whether Medicaid expansion is associated with healthcare coverage, cancer stage at diagnosis, treatment, and survival among patients with rhinologic cancer. Rhinologic cancer was defined to include cancer of the nasal cavity, paranasal sinus, nasopharynx, or olfactory nerve. STUDY DESIGN: Cohort study. METHODS: Patients diagnosed with primary rhinologic malignancies between 2007 to 2016 were extracted from the National Cancer Institute Surveillance, Epidemiology, End Results (SEER) registry. Patients were grouped by diagnosis before and after 2014 (when Medicaid expansion became effective) and whether their state had expanded Medicaid. Multivariable logistic regression controlling for age, sex, race, ethnicity, and income/education was utilized to examine associations between Medicaid expansion/insurance status and stage at diagnosis, treatment, and survival. Overall and disease-specific survival were examined using Kaplan-Meier analysis. RESULTS: Analysis included 10,164 patients. The proportion of uninsured patients decreased after 2014 (2.4%) compared to before 2014 (4.8%, P < .001). After 2014, patients in nonexpanded states were more likely to be diagnosed with advanced stage disease compared to patients in expanded states (N = 2,364; OR = 1.27, 95% CI 1.01-1.60). Being uninsured in any state was associated with advanced stage disease at diagnosis (OR = 1.75, 95% CI 1.41-2.22) and increased risk of disease-specific death (HR = 1.54, 95% CI 1.32-1.82). Survival measures were not associated with diagnosis before versus after 2014 or Medicaid expansion. CONCLUSIONS: Patients lacking insurance or residing in nonexpanded states may be more likely to present with advanced stage rhinologic cancer. Longitudinal studies should validate these findings. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:43-50, 2023.

Lysate-to-grid: Rapid Isolation of Native Complexes from Budding Yeast for Cryo-EM Imaging.

Single-particle electron cryo-microscopy (cryo-EM) is an effective tool to determine high-resolution structures of macromolecular complexes. Its lower requirements for sample concentration and purity make it an accessible method to determine structures of low-abundant protein complexes, such as those isolated from native sources. While there are many approaches to protein purification for cryo-EM, attaining suitable particle quality and abundance is generally the major bottleneck to the typical single-particle project workflow. Here, we present a protocol using budding yeast ( S. cerevisiae ), in which a tractable immunoprecipitation tag (3xFLAG) is appended at the endogenous locus of a gene of interest (GOI). The modified gene is expressed under its endogenous promoter, and cells are grown and harvested using standard procedures. Our protocol describes the steps in which the tagged proteins and their associated complexes are isolated within three hours of thawing cell lysates, after which the recovered proteins are used directly for cryo-EM specimen preparation. The prioritization of speed maximizes the ability to recover intact, scarce complexes. The protocol is generalizable to soluble yeast proteins that tolerate C-terminal epitope tags. Graphical abstract Overview of lysate-to-grid workflow. Yeast cells are transformed to express a tractable tag on a gene of interest. Following cell culture and lysis, particles of interest are rapidly isolated by co-immunoprecipitation and prepared for cryo-EM imaging (created with BioRender.com).

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.