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Objective: To determine whether palatoplasty technique affects the resolution of eustachian tube dysfunction and postoperative speech outcomes in children with cleft palate (CP)., Design: Retrospective cohort., Setting: Multidisciplinary cleft and craniofacial clinic at a tertiary care center., Patients: Seventy-three patients with nonsyndromic CP who underwent palatoplasty between 2005 and 2019. Inclusion criteria included soft palate repair with Furlow technique or intravelar veloplasty (IVV) and Veau classifications I-III., Interventions: Either Furlow or IVV repair was performed based on the surgeon's clinical judgment. All patients had bilateral ear tubes placed prior to or at the time of palate repair, with postpalatoplasty ear tubes placed at the ENT surgeon's discretion. Patients received routine follow-up care for over 5 years. Data were analyzed with Wilcoxon tests, χ 2 tests, and negative binomial regression., Main Outcome Measures: Number of postpalatoplasty ear tubes placed, rates of velopharyngeal insufficiency, and speech surgery after palatoplasty in each group., Results: Furlow repair patients required a similar number of postpalatoplasty ear tubes ( P  = .321) and underwent additional sets at similar rates compared to those who underwent IVV repair. Negative binomial regression found no covariates (age, race, Veau, repair type, speech surgery, fistula repair) that predicted additional ear tube requirements., Conclusion: Furlow repair patients required postpalatoplasty ear tubes at a similar rate compared to IVV repair patients. While the palatoplasty techniques differ, patients may still need the same amount of time for resolution of their eustachian tube dysfunction., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mitomycin C is an alkylating agent with the ability to suppress fibroblast proliferation and activity, making it a powerful antifibrotic. It has therefore become popular in glaucoma filtering surgeries, used both intraoperatively during bleb formation and postoperatively as an adjunct to bleb needling. This report presents a rare but serious risk of bleb needling with Mitomycin C at the slit lamp, where inadvertent movement of the patient resulted in an orbital injection. The patient quickly developed focal tissue inflammation and necrosis, presenting one day after the procedure with complete ptosis, ophthalmoplegia, and a palpable orbital mass. After appropriate imaging and an excisional biopsy to exclude infectious, infiltrative, and neoplastic causes, this was managed with close observation and continued improvement, and resolution of most orbital sequelae., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Eating disorders (EDs) are a group of debilitating mental illnesses characterized by maladaptive eating behaviors and severe cognitive-emotional dysfunction, directly affecting 1-3% of the population. Standard treatments are not effective in approximately one third of ED cases, representing the need for scientific advancement. There is emerging evidence for the safety and efficacy of psilocybin-assisted psychotherapy (PAP) to improve treatment outcomes in individuals with EDs. However, the limited knowledge of the neurobiological mechanisms underlying the therapeutic effects of PAP restricts the ability to confirm its clinical utility. This narrative review presents an overview of methodologies used to elucidate the pathophysiological mechanisms of EDs or the effects of psilocybin that could be employed to probe the neurobiological correlates of PAP in EDs, including magnetic resonance imaging and molecular neuroimaging techniques, electrophysiological approaches, and neuroplasticity markers. Finally, the implications of these methodologies are described in relation to the unique features of the psychedelic study design, challenges, limitations, and future directions to advance the field. This paper represents a valuable resource for scientists during study conceptualization and design phases and stimulates advancement in the identification of effective therapeutic interventions for EDs., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor., Competing Interests: Declaration of interests A pending patent application has been filed by Escient Pharmaceuticals that includes compounds EP-2825 and EP-3945. B.L.R. is on the scientific advisory board of Escient Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Gastrointestinal nematode (GIN) parasites are a major constraint to goat production. GIN parasite control has relied primarily on the use of anthelmintic drugs. A major issue in goat operations globally, including in the United States (U.S.), is that GIN populations have developed widespread resistance to current anthelmintic drugs. Widespread anthelmintic resistance is a major concern to U.S. goat producers, but there currently remains limited information on what goat production practices are used nationally to combat GIN infections and prevent anthelmintic resistance. The current practices used by goat producers to control GIN parasites and reduce anthelmintic resistance on their operations were evaluated as part of the 2019 National Animal Health Monitoring System (NAHMS) study, which was conducted by the U.S. Department of Agriculture (USDA). The study aims were to determine GIN parasite burden at both the individual animal- and operation-level, investigate geographic patterns of GIN parasitism, and identify risk factors associated with infection prevalence and intensity. The study covered 24 U.S. states, representing 80.4 % of U.S. goats on operations with ≥ 5 goats and 75.8 % of operations with ≥ 5 goats. Data from fecal samples submitted for fecal egg count (FEC) analysis and individual goat- and operation-level questionnaires were collected from 9879 goats across 623 operations. The estimated, weighted mean operation- and animal-level FEC for goats was 658 and 651 eggs per gram, respectively. Across all goats tested, parasite burden was found to be over-dispersed, with the top 24.1 % of animals contributing to 80 % of the total FEC. Geographically, lungworm prevalence was significantly lower in the Southwest region compared with the Northeast, Northwest, and Southeast regions. For GIN FEC values, the highest operation-level counts were found in the Northeast and Southeast region, and the highest animal-level counts were found in the Southeast region by univariate analysis and the Northeast and Southeast regions by multiple regression analysis. Univariate analysis revealed that primary operation production type, primary land/facility management type, primary grazing/browsing management, FAMACHA© card usage, body condition categorization, and month of sample collection were significant factors impacting mean FEC at both the operation- and animal-level. U.S. regionality, goat type, breed, FAMACHA© score, and browsing schedule were found to be significant at the animal-level. Multiple regression analysis at the operation-level revealed that deworming frequency in the previous 12 months, pasture housing practices, and the interaction between region and sample collection date were significant factors that impacted the mean FEC. Multiple regression analysis at the animal-level revealed that goat type, FAMACHA© score, body condition categorization, primary grazing/browsing management, primary operation production type, the interaction between region and multiple species grazing, and the interaction between region and sample collection date, were significant factors that impacted mean FEC. This study provides valuable information to help guide future GIN research and regionally specific control practices., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Parathyroid gland (PG) auto-transplantation is performed to preserve the function of de-vascularized or unintentionally removed PGs, however, little has been published about the technique and outcomes in children. In our study, we aimed to present the results of PG auto-transplantation in children undergoing thyroidectomy or parathyroidectomy at a tertiary single institution. A retrospective review identified 14 patients (<18 years of age) who underwent PG auto-transplantation from January 2000 to December 2022. 57.1% (8/14) had transient postoperative hypocalcemia and 14.3% (2/14) had permanent postoperative hypocalcemia. Eight patients had transient hypoparathyroidism, correlating with the rate of transient hypocalcemia. The most common reimplantation site was the sternocleidomastoid (11/14) and it was significantly associated with normalized calcium levels 6 months after auto-transplantation (p=0.033). Bilateral central neck dissection and surgical indication of cancer had a statistically significant association with transient hypocalcemia (p=0.03 and p=0.005, respectively). Our study provides valuable insights into the outcomes of PG auto-transplantation in pediatric patients, highlighting the potential for successful engraftment and factors associated with hypocalcemia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Lithium-rich iron sulphide, Li 2 FeS 2 , exhibits reversible charge-storage via both cationic and anionic sites, storing nearly 400 mA h g -1 , but its synthesis is limited to solid-state methods that result in large primary particles. We describe an alternate solution-based, redox-mediated method to lithiate pyrite FeS 2 , ultimately forming nanoscale Li 2 FeS 2 .

Background The use of automatic external defibrillators (AEDs) by lay rescuers can reduce the time to defibrillation and improve survival in out-of-hospital cardiac arrest (OHCA). AEDs use voice prompts to guide users through the defibrillation process, creating a potential barrier for deaf and hard-of-hearing (HoH) individuals. The objective of this study is to assess familiarity with and concerns regarding AED use among members of these communities. Methods A 19-question Qualtrics survey was distributed to adults in the United States who self-identified as deaf or HoH. The questions included seven demographics, eight yes/no/unsure, three Likert scales, and one multiple-response question. Quantitative analysis was performed using 95% confidence intervals to compare familiarity with and concerns about AED use among deaf, HoH, and combined groups of respondents. Results Of the responses, 500 met the inclusion criteria; 130 (26%) self-identified as deaf, and 370 (74%) self-identified as HoH. Around 460 (92%) were in the 18-40 age group. AED recognition was high among both deaf (90.77%) and HoH (84.59%) respondents, though deaf respondents were less likely than HoH respondents to have seen an AED in a public place (p=0.03) or know how to safely use one (p=0.001). In both the deaf and HoH groups, the top concern regarding AED use was that AEDs were too technical or complicated (61.86% and 56.8%). Of all respondents, 36.4% reported that AEDs were not user-friendly (p=0.034). All participants identified some concerns regarding AED use in emergencies. In addition, 56.15% of deaf and 39.19% of HoH respondents were concerned that AED use is potentially dangerous (p<0.001). There was no statistically significant difference between the two groups in knowing when to use an AED or where to find more information about AEDs.  Conclusion Deaf and HoH people have specific concerns about AEDs, including the safety and complexity of operating an AED and the accessibility (user-friendliness). In this study, the deaf population is less familiar with using an AED than the HoH population. Possible interventions to address concerns of the deaf and HoH communities include AED training given in American Sign Language (ASL) and updating AED designs with improved visual and non-verbal directions., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. University of Arizona Human Subjects Protection Program issued approval 2103565368. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: $100 donation from Dr. Karl Kern for Amazon Gift Cards distributed to randomly selected participants during the study. . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Yee et al.)

Purpose: Precision oncology in non-small cell lung cancer (NSCLC) relies on biomarker testing for clinical decision making. Despite its importance, challenges like the lack of genomic oncology training, nonstandardized biomarker reporting, and a rapidly evolving treatment landscape hinder its practice. Generative artificial intelligence (AI), such as ChatGPT, offers promise for enhancing clinical decision support. Effective performance metrics are crucial to evaluate these models' accuracy and their propensity for producing incorrect or hallucinated information. We assessed various ChatGPT versions' ability to generate accurate next-generation sequencing reports and treatment recommendations for NSCLC, using a novel Generative AI Performance Score (G-PS), which considers accuracy, relevancy, and hallucinations., Methods: We queried ChatGPT versions for first-line NSCLC treatment recommendations with an Food and Drug Administration-approved targeted therapy, using a zero-shot prompt approach for eight oncogenes. Responses were assessed against National Comprehensive Cancer Network (NCCN) guidelines for accuracy, relevance, and hallucinations, with G-PS calculating scores from -1 (all hallucinations) to 1 (fully NCCN-compliant recommendations). G-PS was designed as a composite measure with a base score for correct recommendations (weighted for preferred treatments) and a penalty for hallucinations., Results: Analyzing 160 responses, generative pre-trained transformer (GPT)-4 outperformed GPT-3.5, showing higher base score (90% v 60%; P < .01) and fewer hallucinations (34% v 53%; P < .01). GPT-4's overall G-PS was significantly higher (0.34 v -0.15; P < .01), indicating superior performance., Conclusion: This study highlights the rapid improvement of generative AI in matching treatment recommendations with biomarkers in precision oncology. Although the rate of hallucinations improved in the GPT-4 model, future generative AI use in clinical care requires high levels of accuracy with minimal to no room for hallucinations. The GP-S represents a novel metric quantifying generative AI utility in health care compared with national guidelines, with potential adaptation beyond precision oncology.

Background: Branchial cleft cysts are pediatric congenital anomalies that can present as sinus tracts to the neck. Intraoperative methylene blue dye with fibrin glue has been suggested as an effective tool for tracking the tract's depth to help definitively excise. In this large retrospective study of 118 patients spanning a decade, we aim to elucidate outcomes of branchial cleft anomaly excision without methylene blue dye., Methods: A retrospective review was conducted with patients who received branchial cleft anomaly (BCA) with sinus tract excision at Monroe Carrell Jr. Children's Hospital from June 2012 to June 2022. We collected demographic variables, BCA characteristics, perioperative care variables (ie, prior drainage, imaging, and concurrent procedure), and perioperative outcomes (ie, intra- and post-operative complications). Median and interquartile range (IQR) were calculated for continuous demographic variables, and average and standard deviation (SD) were calculated for sinus tract length. Two-tailed Chi-square or Fisher's exact tests were performed to compare categorical samples where applicable with a statistical significance threshold set a priori at P  < .05, and multivariable logistic regression assessed significant associations., Results: The sample included 118 patients with an average tract length of 3.3 cm (SD = 1.7 cm). Incision/drainage was performed before definitive excision in 16 (13.6%) patients and was associated with age above the median (aOR = 5.29, 95% CI = 1.39-20.09, P  = .015) and female sex (aOR = 3.81, 95% CI = 1.12-13.01, P  = .032). Most patients (N = 85, 72.0%) did not receive imaging. Among 118 cases, 2 (1.7%) required return to the operating room for surgical site complications. No patients experienced intra-operative complications or tract recurrence necessitating revision surgery., Conclusion: Patients with branchial cleft sinus tracts that were surgically excised without intraoperative dye achieved definitive resection with no recurrence and limited post-operative complications. While not a direct comparison, these results suggest that using intraoperative dye may be associated with unnecessary costs without benefit in outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Nickel-based catalysts are widely studied for water-gas shift (WGS), a key intermediate step in hydrogen production from carbon-based feedstocks. Their viability under practical conditions is limited at high temperatures when Ni aggregates and converts CO to methane, an undesirable side product. Because experimental and computational studies identify undercoordinated Ni step sites as most active toward CH 4 formation, we eliminate Ni step sites by atomically dispersing Ni into networked, nanoparticulate CeO 2 aerogels. The mesoporous catalyst with 2.5 atomic % Ni in CeO 2 is highly active for WGS, converting near-equilibrium levels of CO at 350°C, while no CH 4 is detected at the limit of detection (<2 parts per million). In contrast, supporting low weight percentages of Ni clusters or nanoparticles on CeO 2 aerogels leads to methanation. The CH 4 yield produced by the atomically dispersed Ni-substituted CeO 2 aerogel is over an order of magnitude lower than previously reported Ni-based catalysts claiming methane suppression, marking an important advance in the development of WGS catalysts.

We present a genome assembly from an individual male Myotis mystacinus (whiskered bat; Chordata; Mammalia; Chiroptera; Vespertilionidae). The genome sequence has a total length of 2,081.20 megabases. Most of the assembly (97.52%) is scaffolded into 23 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 16.93 kilobases in length., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Ryan H et al.)

The pupil is modulated by luminance, arousal, bottom-up sensory, and top-down cognitive signals, and has increasingly been used to assess these aspects of brain functioning in health and disease. However, changes in pupil dynamics across the lifespan have not been extensively examined, hindering our ability to fully utilize the pupil in probing these underlying neural processes in development and aging in healthy and clinical cohorts. Here, we examined pupil responses during the interleaved pro-/anti-saccade task (IPAST) in healthy participants across the lifespan ( n  = 567, 5-93 years of age). Based on the extracted measurements of pupil dynamics, we demonstrated age-related changes in pupil measures and task modulation. Moreover, we characterized the underlying factors and age-related effects in components of pupil responses that may be attributed to developmental and aging changes in the associated brain regions. Finally, correlations between factors of pupil dynamics and saccade behaviors revealed evidence of shared neural processes in the pupil and saccade control circuitries. Together, these results demonstrate changes in pupil dynamics as a result of development and aging, providing a baseline with which altered pupil responses due to neurological deficits at different ages can be studied., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huang, Smorenburg, Yep, Riek, Calancie, Kirkpatrick, Brien, Coe, Wang and Munoz.)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of vaccines to prevent Ebola virus disease in people who have been, or have potentially been, exposed to Ebola virus., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: A commonly adopted intervention to help to reduce wait times for hospital treatment is administrative validation, where administrators write to patients to check if a procedure is still required. The did not return (DNR) rate to validation letters is substantial. We tested whether the DNR rate was reduced by introducing nudges to validation letters., Methods: Participants from eight public hospitals (N = 2855; in 2017) in Ireland were randomized to receive an existing (control group) or a redesigned validation letter including nudges (intervention group)., Results: Participants in the intervention group were less likely not to return it than those in the control group, OR = .756, SE = .069, p = .002. Control and intervention group DNR rates were 23.97% and 19.24%. This is equivalent to 1 in 5 non-responders changing their behaviour because of the redesigned letter., Conclusions: The redesigned letter increased patient compliance with the validation process. The redesign has subsequently been adopted by public hospitals in Ireland., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diffuse-type gastric cancer (DGC) accounts for approximately one-third of gastric cancer diagnoses but is a more clinically aggressive disease with peritoneal metastases and inferior survival compared with intestinal-type gastric cancer (IGC). The understanding of the pathogenesis of DGC has been relatively limited until recently. Multiomic studies, particularly by The Cancer Genome Atlas, have better characterized gastric adenocarcinoma into molecular subtypes. DGC has unique molecular features, including alterations in CDH1, RHOA, and CLDN18-ARHGAP26 fusions. Preclinical models of DGC characterized by these molecular alterations have generated insight into mechanisms of pathogenesis and signaling pathway abnormalities. The currently approved therapies for treatment of gastric cancer generally provide less clinical benefit in patients with DGC. Based on recent phase II/III clinical trials, there is excitement surrounding Claudin 18.2-based and FGFR2b-directed therapies, which capitalize on unique biomarkers that are enriched in the DGC populations. There are numerous therapies targeting Claudin 18.2 and FGFR2b in various stages of preclinical and clinical development. Additionally, there have been preclinical advancements in exploiting unique therapeutic vulnerabilities in several models of DGC through targeting of the focal adhesion kinase (FAK) and Hippo pathways. These preclinical and clinical advancements represent a promising future for the treatment of DGC., Competing Interests: Declarations Funding LWW is supported by the NIH/NCI Molecular Oncology Training Program (5T32CA203703-09), and RHM is supported by grants from the NIH (K08CA263304) and Gastric Cancer Foundation. This publication is supported by NIH/NCI Cancer Center Support Grant P30CA013696. Conflict of interest Lawrence W. Wu, Sung Joo Jang, Cameron Shapiro, Ladan Fazlollahi, and Timothy C. Wang have no relevant conflicts of interest to declare that may be relevant to the contents of this article. Sandra W. Ryeom has undertaken consulting work for AttisLab and has received research support from ImmPACT Bio. Ryan H. Moy has undertaken consulting work for Puretech Health, served on the Advisory Board for IDEAYA Biosciences and Nimbus Therapeutics, and has received research funding, paid to the institution, from Nimbus Therapeutics and Repare Therapeutics. Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication All authors consent to the publication of this article. Availability of data and material No datasets were generated or analyzed during this study. Code availability Not applicable. Authors’ contributions LWW and RHM proposed the review topic. LWW wrote the original draft of this article. LF provided representative images of diffuse-type and intestinal-type gastric cancer. All authors have reviewed, revised, and provided critical feedback on the manuscript, and provided final approval of the manuscript., (© 2024. The Author(s).)

Objective: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children., Methods: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children., Results: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%., Conclusions: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children., (© 2024 The Author(s). Cytopathology published by John Wiley & Sons Ltd.)

A 68-year-old woman was seen in oculoplastic consultation with a medial canthal lesion initially diagnosed as an atypical fibroxanthoma. On excisional biopsy, she was found to have a spindle cell carcinoma, which is a rare and reportedly more aggressive form of squamous cell carcinoma. The authors highlight the surgical technique of biopsy and reconstruction, the detailed histologic and immunohistochemical analysis required for accurate diagnosis, considerations for adjuvant treatment, and suggestions for systemic workup and surveillance. This case adds to the small body of available literature on primary spindle cell carcinoma of the ocular surface and ocular adnexa, which the authors have summarized. They hope that as more data become available, there will be clearer diagnostic and treatment algorithms for this uncommon presentation., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Background and Aims: Hepatitis C virus (HCV) burden is higher among people in prison given high prevalence of injecting drug use. This study evaluated direct-acting antiviral (DAA) treatment outcome in prisons., Methods: The Surveillance and Treatment of Prisoners with hepatitis C (SToP-C) study enrolled individuals incarcerated in four Australian prisons (2017-2019). Participants with detectable HCV RNA were offered sofosbuvir-velpatasvir for 12 weeks. Sustained virological response (SVR) was assessed in intention-to-treat (ITT; participants commencing treatment and due for SVR assessment before study close) and per-protocol (PP; participants with documented treatment completion and SVR assessment) populations., Results: Among 799 participants with HCV, 324 (41%) commenced treatment (94% male; median age, 32 years; median duration of incarceration, 9 months). In ITT population (n = 310), 201 had documented treatment completion (65% [95% CI: 59-70]), and 137 achieved SVR (ITT-SVR: 44% [95% CI: 39-50]). In PP population (n = 143), 137 achieved SVR (PP-SVR: 96% [95% CI: 91-98]). Six participants had quantifiable HCV RNA at SVR assessment from treatment failure (n = 2) or reinfection (n = 4). Release or inter-prison transfer was common reasons for no documented treatment completion (n = 106/109 [97%]) and no SVR assessment (n = 57/58 [98%]). In ITT analysis, longer incarceration was associated with increased SVR (adjusted OR per month 1.03 [95% CI: 1.01-1.04])., Conclusion: Among participants who completed DAA treatment and were assessed for SVR, treatment outcome was consistent with non-prison clinical studies. However, most individuals did not complete treatment or lacked study-documented treatment outcome due to release or transfer. Strategies to accommodate dynamic prisoner populations are required to ensure continuity of HCV care, including treatment completion and post-treatment care., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Cystic fibrosis (CF) is an autosomal recessive disease characterized by microbial infection and progressive decline in lung function, leading to significant morbidity and mortality. The bitter taste receptor T2R14 is a chemosensory receptor that is significantly expressed in airways. Using a combination of cell-based assays and T2R14 knockdown in bronchial epithelial cells from CF and non-CF individuals, we observed that T2R14 plays a crucial role in the detection of bacterial and fungal signals and enhances host innate immune responses. Expression of Gαi protein is enhanced in CF bronchial epithelial cells and T2R14-Gαi specific signaling leads to increased calcium mobilization. Knockdown of T2R14 leads to reduced innate immune activation by bacterial strains deficient in quorum sensing. The results demonstrate that T2R14 helps protect against microbial infection and thus may play an important role in the innate immune defense of the CF airway epithelium., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.

An 11-year-old boy presented in distress with tachypnea, holosystolic murmur, and a gallop. Echocardiography revealed mitral valve thickening and severe regurgitation. He required valve replacement with pathology consistent with acute on chronic valvulitis. This case underscores the importance of considering rheumatic heart disease, despite no preceding suspicious history., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo , we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP + CXCR4 hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8 + T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4 + LOX-1 + subset are inversely correlated with the TFF2 level and CD8 + T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

Objectives/hypothesis: To evaluate costs associated with perioperative gastrostomy tube (G-tube) placement for neonates with Robin sequence (PRS) that undergo mandibular distraction osteogenesis (MDO)., Methods: Retrospective chart review was performed to examine the medical records of neonates with RS who received treatment at our institution between 2012 and 2021. Patients under 6 months of age that underwent MDO for RS were included. Billing records of hospital costs over a 2-year period were analyzed., Results: The study included 26 total patients with 11 in the MDO-only group, 9 in G-tube after MDO group, and 6 in G-tube before MDO group. There was a significant difference (p < 0.001) in total hospital costs between groups with MDO-only group averaging $119,532 (SD ± $$ \pm $$ 33,503), the G-tube after MDO group averaging $245,315 (SD ± $$ \pm $$ 102,327), and G-tube before MDO group averaging $252,300 (SD ± $$ \pm $$ 84,990). Multiple linear regression was performed controlling for genetic syndrome and birth weight, which still showed a statistically significant difference in total cost between the MDO-only group and G-tube after MDO (p = 0.006), and between the MDO-only group and G-tube prior to MDO (p = 0.01). There was a significant difference in costs between all three groups for total inpatient/outpatient costs with MDO-only group averaging $78,502 (SD ± $$ \pm $$ 30,953), the G-tube after MDO group averaging $176,125 (SD ± $$ \pm $$ 84,315), and the G-tube prior to MDO group averaging $156,309 (SD ± $$ \pm $$ 95,746)., Conclusions: MDO performed without perioperative G-tube placement may reduce charges by >$100,000. The associated improvement of dysphagia after MDO surgery and potential for avoiding a G-tube has tremendous downstream cost and social benefits for families., Level of Evidence: NA Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of psychedelic molecules. With a focus on the 5-HT 2A receptor subtype, a G-protein coupled receptor known to be the primary target of psychedelics, we refer to several X-ray and cryoEM structures, with a variety of ligands bound, to illustrate the underlying atomistic basis for some of the known pharmacological observations of psychedelic drug actions., (© 2024 British Pharmacological Society.)

Objectives: Although parotid gland malignancies are uncommon, they nevertheless represent a cause of morbidity and mortality in the pediatric population. Few studies have sought to identify disparities related to their presentation, treatment, and survival. There is a need to understand these variations to improve care for historically underrepresented groups., Study Design: Retrospective Cohort Study., Setting: Surveillance, Epidemiology, and End Results (SEER) Program Database., Methods: Analysis of pediatric patients with parotid gland malignancies between 2000 and 2019. Race and ethnicity were classified as Non-Hispanic White, Non-Hispanic Black, Asian, and Hispanic for multivariable analysis. Outcomes included tumor size and stage at diagnosis, survival, and need for facial nerve sacrifice. Kaplan-Meier analysis was used to analyze survival. Multivariable logistic regression was conducted to identify predictors of outcomes., Results: 149 patients met the criteria for inclusion. Stratified by race/ethnicity, Non-Hispanic Black (Median 23 mm, IQR 15-33), Asian (30 mm, 14-32), and Hispanic (23 mm, 20-28) patients had larger tumors at presentation than Non-Hispanic White patients (18 mm, 12-25, p = 0.017). Disease-specific survival differed by time-to-treatment (log-rank, p = 0.01) and overall survival differed by income (p < 0.001). On multivariable analysis, Hispanic patients were more likely to experience facial nerve sacrifice (OR 3.71, 95%CI 1.25-11.6, p = 0.020), and Non-Hispanic Black (OR 3.37, 0.95-11.6, = 0.053) and Asian (OR 5.67, 1.46-22.2, p = 0.011) patients presented with larger tumors compared to Non-Hispanic White patients., Conclusions: Variations in presentation and treatment exist across race and ethnicity in pediatric parotid cancer. Identifying these disparities may help improve access and outcomes for underserved patient populations., Level of Evidence: III., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose: Rahul K. Sharma, MD – None. Shreyas G. Krishnapura, MD – None. John Ceremsak, MD – None. Jean-Nicolas Gallant, MD PhD – None. Daniel J. Benedetti MD MA – None. Scott C. Borinstein MD PhD - None. Ryan H Belcher, MD MPH - None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To characterize the onset and prevalence of conductive hearing loss (CHL) in pediatric patients with cleft palate (CP) prior to palatoplasty with an enhanced audiologic protocol., Design: Retrospective cohort study., Setting: Multidisciplinary cleft and craniofacial clinic at a tertiary care center., Patients: Patients with CP who received audiologic workup pre-operatively. Patients with bilateral permanent hearing loss, expiration prior to palatoplasty, or no pre-operative data were excluded., Interventions: Patients with CP born February 2019 to November 2019 who passed newborn hearing screening (NBHS) received audiologic testing at 9 months of age (standard protocol). Patients born December 2019 to September 2020 underwent testing prior to 9 months of age (enhanced protocol)., Main Outcome Measures: Age of identification of CHL in patients after implementation of the enhanced audiologic protocol., Results: The number of patients who passed their NBHS in the standard protocol (n = 14, 54%) and the enhanced protocol (n = 25, 66%) did not differ. Infants who passed their NBHS, but demonstrated hearing loss on subsequent audiologic testing did not differ between enhanced (n = 25, 66%) and standard cohort (n = 14, 54%). Of patients who passed NBHS in the enhanced protocol, 48% (n = 12) had CHL identified by 3 months, and 20% (n = 5) by 6 months of age. With the enhanced protocol, patients who did not undergo additional testing post NBHS significantly dropped from 44.9% (n = 22) to 4.2% (n = 2) ( P  < .0001)., Conclusion: Even with passed NBHS, CHL is still present for infants with CP pre-operatively. Earlier and more frequent testing for this population is recommended., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. This retrospective cohort study was approved by the Vanderbilt University institutional Review Board (#190840).

Gold standard detection of SARS-CoV-2 by reverse transcription quantitative PCR (RT-qPCR) can achieve ultrasensitive viral detection down to a few RNA copies per sample. Yet, the lengthy detection and labor-intensive protocol limit its effectiveness in community screening. In view of this, a structural switching electrochemical aptamer-based biosensor (E-AB) targeting the SARS-CoV-2 nucleocapsid (N) protein was developed. Four N protein-targeting aptamers were characterized on an electrochemical cell configuration using square wave voltammetry (SWV). The sensor was investigated in an artificial saliva matrix optimizing the aptamer anchoring orientation, SWV interrogation frequency, and target incubation time. Rapid detection of the N protein was achieved within 5 min at a low nanomolar limit of detection (LOD) with high specificity. Specific N protein detection was also achieved in simulated positive saliva samples, demonstrating its feasibility for saliva-based rapid diagnosis. Further research will incorporate novel signal amplification strategies to improve sensitivity for early diagnosis.

The potential weakening of the Atlantic Meridional Overturning Circulation (AMOC) in response to anthropogenic forcing, suggested by climate models, is at the forefront of scientific debate. A key AMOC component, the Florida Current (FC), has been measured using submarine cables between Florida and the Bahamas at 27°N nearly continuously since 1982. A decrease in the FC strength could be indicative of the AMOC weakening. Here, we reassess motion-induced voltages measured on a submarine cable and reevaluate the overall trend in the inferred FC transport. We find that the cable record beginning in 2000 requires a correction for the secular change in the geomagnetic field. This correction removes a spurious trend in the record, revealing that the FC has remained remarkably stable. The recomputed AMOC estimates at ~26.5°N result in a significantly weaker negative trend than that which is apparent in the AMOC time series obtained with the uncorrected FC transports., (© 2024. The Author(s).)

Industrial activities on the banks of waterways can degrade both the waterbody and the surrounding area and continue to exert pressure on the environment even after the closure of the industries involved. An assessment was undertaken to determine concentration, distribution, mobility and ecological risk of potentially toxic elements (PTE) from legacy contamination in sediments of the Forth and Clyde Canal, UK. Concentrations of PTE, determined by ICP-MS following aqua regia digestion, were 5.54-219 mg kg -1 for As, < 0.025-11.0 mg kg -1 for Cd, 44.8-883 mg kg -1 for Cr, 39.3-618 mg kg -1 for Cu, 35.8-72.1 g kg -1 for Fe, 720-4460 mg kg -1 for Mn, 42.0-154 mg kg -1 for Ni, 93.9-2740 mg kg -1 for Pb, 5.36-122 mg kg -1 for Sn and 288-3640 mg kg -1 for Zn. With the exception of Fe and Mn, higher levels were observed at urban locations than at rural. Enhanced Cr, Pb and Sn content at suburban locations could be attributed to historical industrial activities on the canal bank, while widespread distribution of As and Pb was consistent with atmospheric deposition. In the inner-city area, sediment quality was severely deteriorated, and the potential ecological risk was very high. Fractionation patterns, determined using the modified BCR sequential extraction, indicated a particularly high risk of mobilization for Cd, Mn and Zn, and the highest exchangeable fraction risk from Zn. The research highlights the need to assess and, where necessary, manage legacy contaminated sites in line with the UN 2030 Agenda for Sustainable Development., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Chordomas are rare tumors that originate from undifferentiated remnants of the notochord. Currently, there are no established guidelines regarding the choice of adjuvant radiation modality for patients surgically treated for chordomas. Using a nationwide, multicenter database, the authors aimed to compare long-term survival outcomes associated with the use of proton or photon adjuvant therapy for the management of chordomas of skull base and spine., Methods: The National Cancer Database (NCDB) was queried for chordoma cases from 2004 to 2017. Patient, tumor, and treatment characteristics were extracted from the database. The primary outcome was overall survival (OS). Kaplan-Meier survival analyses were conducted to investigate differences in outcome on propensity score-matched cohorts of patients treated with proton or photon adjuvant radiotherapy., Results: Of the 3490 patients available, 424 met the inclusion criteria for this study. In the prematching analysis, patients receiving adjuvant photon therapy were significantly older (median age 57.0 vs 45.0 years, p < 0.001) and were more commonly male (61% vs 43%, p < 0.001) compared with those receiving proton therapy. Races were equally distributed among radiotherapy modalities (p = 0.64). Patients with chordomas of the mobile spine or sacrum were less likely to receive proton compared with photon therapy (37% vs 58%). Patients receiving proton therapy were more often represented among private insurance holders (69% vs 52%, p < 0.001) as well as in the highest income quartile (52% vs 40%, p = 0.008). Patients traveled farther to receive proton, as opposed to photon, therapy (median 59.0 vs 34.9 miles, p < 0.001). On postmatching Kaplan-Meier analysis encompassing all chordoma cases, no difference in OS between photon and proton therapy was revealed (HR 0.75, 95% CI 0.39-1.44; p = 0.39). A Kaplan-Meier analysis only including patients with skull base chordomas reached similar results (HR 0.83, 95% CI 0.31-2.22; p = 0.71). In patients with spine chordomas, however, a significant difference was found, as proton therapy exhibited a superior OS over photon therapy (HR 0.28, 95% CI 0.09-0.81; p = 0.012)., Conclusions: Based on this nationwide analysis, patients with private insurance and higher income were more likely to receive proton adjuvant radiotherapy, while those with spinal or sacral chordomas were less likely to receive this modality. Despite this disparity, an OS benefit was observed in patients with chordomas of the spine and sacrum who received adjuvant proton therapy, in comparison with a matched cohort of patients treated with photon therapy. Conversely, this advantageous outcome was not evident in cases of chordomas located at the skull base.

Competing Interests: None declared.

Background: The oculomotor circuit spans many cortical and subcortical areas that have been implicated in psychiatric disease. This, combined with previous findings, suggests that eye tracking may be a useful method to investigate eating disorders. Therefore, this study aimed to assess oculomotor behaviors in youth with and without an eating disorder., Methods: Female youth with and without an eating disorder completed a structured task involving randomly interleaved pro-saccade (toward at a stimulus) and anti-saccade (away from stimulus) trials with video-based eye tracking. Differences in saccades (rapid eye movements between two points), eye blinks and pupil were examined., Results: Youth with an eating disorder (n = 65, M age = 17.16 ± 3.5 years) were compared to healthy controls (HC; n = 65, M age = 17.88 ± 4.3 years). The eating disorder group was composed of individuals with anorexia nervosa (n = 49), bulimia nervosa (n = 7) and other specified feeding or eating disorder (n = 9). The eating disorder group was further divided into two subgroups: individuals with a restrictive spectrum eating disorder (ED-R; n = 43) or a bulimic spectrum eating disorder (ED-BP; n = 22). In pro-saccade trials, the eating disorder group made significantly more fixation breaks than HCs (F(1,128) = 5.33, p = 0.023). The ED-BP group made the most anticipatory pro-saccades, followed by ED-R, then HCs (F(2,127) = 3.38, p = 0.037). Groups did not differ on rate of correct express or regular latency pro-saccades. In anti-saccade trials, groups only significantly differed on percentage of direction errors corrected (F(2, 127) = 4.554, p = 0.012). The eating disorder group had a significantly smaller baseline pupil size (F(2,127) = 3.60, p = 0.030) and slower pro-saccade dilation velocity (F(2,127) = 3.30, p = 0.040) compared to HCs. The ED-R group had the lowest blink probability during the intertrial interval (ITI), followed by ED-BP, with HCs having the highest ITI blink probability (F(2,125) = 3.63, p = 0.029)., Conclusions: These results suggest that youth with an eating disorder may have different oculomotor behaviors during a structured eye tracking task. The oculomotor behavioral differences observed in this study presents an important step towards identifying neurobiological and cognitive contributions towards eating disorders., (© 2024. The Author(s).)

Recent advances in active materials and fabrication techniques have enabled the production of cyclically self-deployable metamaterials with an expanded functionality space. However, designing metamaterials that possess continuously tunable mechanical properties after self-deployment remains a challenge, notwithstanding its importance. Inspired by push puppets, we introduce an efficient design strategy to create reversibly self-deployable metamaterials with continuously tunable post-deployment stiffness and damping. Our metamaterial comprises contracting actuators threaded through beads with matching conical concavo-convex interfaces in networked chains. The slack network conforms to arbitrary shapes, but when actuated, it self-assembles into a preprogrammed configuration with beads gathered together. Further contraction of the actuators can dynamically tune the assembly's mechanical properties through the beads' particle jamming, while maintaining the overall structure with minimal change. We show that, after deployment, such metamaterials exhibit pronounced tunability in bending-dominated configurations: they can become more than 35 times stiffer and change their damping capability by over 50%. Through systematic analysis, we find that the beads' conical angle can introduce geometric nonlinearity, which has a major effect on the self-deployability and tunability of the metamaterial. Our work provides routes towards reversibly self-deployable, lightweight, and tunable metamaterials, with potential applications in soft robotics, reconfigurable architectures, and space engineering.

Background: Despite recent advances in lung cancer therapeutics and improving overall survival, disparities persist among socially disadvantaged populations. This study aims to determine the effects of neighborhood deprivation indices (NDI) on lung cancer mortality. This is a multicenter retrospective cohort study assessing the relationship between NDI and overall survival adjusted for age, disease stage, and DNA methylation among biopsy-proven lung cancer patients. State-specific NDI for each year of sample collection were computed at the U.S. census tract level and dichotomized into low- and high-deprivation., Results: A total of 173 non small lung cancer patients were included, with n = 85 (49%) and n = 88 (51%) in the low and high-deprivation groups, respectively. NDI was significantly higher among Black patients when compared with White patients (p = 0.003). There was a significant correlation between DNA methylation and stage for HOXA7, SOX17, ZFP42, HOXA9, CDO1 and TAC1. Only HOXA7 DNA methylation was positively correlated with NDI. The high-deprivation group had a statistically significant shorter survival than the low-deprivation group (p = 0.02). After adjusting for age, race, stage, and DNA methylation status, belonging to the high-deprivation group was associated with higher mortality with a hazard ratio of 1.81 (95%CI: 1.03-3.19)., Conclusions: Increased neighborhood-level deprivation may be associated with liquid biopsy DNA methylation, shorter survival, and increased mortality. Changes in health care policies that consider neighborhood-level indices of socioeconomic deprivation may enable a more equitable increase in lung cancer survival., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

As many as 30% of the patients with non-small cell lung cancer harbor oncogenic KRAS mutations, which leads to extensive remodeling of the tumor immune microenvironment. Although co-mutations in several genes have prognostic relevance in KRAS-mutated patients, their effect on tumor immunogenicity are poorly understood. In the present study, a total of 189 patients with non-small cell lung cancer underwent a standardized analysis including IHC, whole-exome DNA sequencing, and whole-transcriptome RNA sequencing. Patients with activating KRAS mutations demonstrated a significant increase in PDL1 expression and CD8+ T-cell infiltration. Both were increased in the presence of a co-occurring TP53 mutation and lost with STK11 co-mutation. Subsequent genomic analysis demonstrated that KRAS/TP53 co-mutated tumors had a significant decrease in the expression of glycolysis-associated genes and an increase in several genes involved in lipid metabolism, notably lipoprotein lipase, low-density lipoprotein receptor, and LDLRAD4. Conversely, in the immune-excluded KRAS/STK11 co-mutated group, we observed diminished lipid metabolism and no change in anaerobic glycolysis. Interestingly, in patients with low expression of lipoprotein lipase, low-density lipoprotein receptor, or LDLRAD4, KRAS mutations had no effect on tumor immunogenicity. However, in patients with robust expression of these genes, KRAS mutations were associated with increased immunogenicity and associated with improved overall survival. Our data further suggest that the loss of STK11 may function as a metabolic switch, suppressing lipid metabolism in favor of glycolysis, thereby negating KRAS-induced immunogenicity. Hence, this concept warrants continued exploration, both as a predictive biomarker and potential target for therapy in patients receiving ICI-based immunotherapy., Significance: In patients with lung cancer, we demonstrate that KRAS mutations increase tumor immunogenicity; however, KRAS/STK11 co-mutated patients display an immune-excluded phenotype. KRAS/STK11 co-mutated patients also demonstrated significant downregulation of several key lipid metabolism genes, many of which were associated with increased immunogenicity and improved overall survival in KRAS-mutated patients. Hence, alteration to lipid metabolism warrants further study as a potential biomarker and target for therapy in patients with KRAS-mutated lung cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background/aim: Allostatic load (AL) is a measure of chronic stress that is associated with worse cancer outcomes. The purpose of this retrospective cohort study was to investigate the relationship between AL and uveal melanoma (UM) clinical features., Patients and Methods: AL score was calculated as a composite of ten biomarkers in 111 patients with UM from the University of Illinois Hospital. One point was assigned to an AL score for each biomarker based on predetermined cutoff values. Linear and logistic regression analyses evaluated the relationship between AL score and several tumor clinical characteristics., Results: High AL score had a significant relationship with extraocular extension (p=0.015). There was also a significant difference in mean blood glucose levels between the different tumor size groups (p=0.029). Higher AL scores also had a trend of being associated with a smaller tumor size (p=0.069)., Conclusion: AL score was significantly associated with the presence of extraocular extension for uveal melanoma, while the smallest tumor size group was associated with the highest blood glucose level. No other significant correlations were found between AL and other clinical features of UM. The relationship between AL score and extraocular extension warrants further investigation. Additional research is needed to evaluate socioeconomic factors and their effect on the relationship between chronic stress and the clinical features of UM., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Hemithyroidectomy is often performed in the pediatric population for indeterminate or benign thyroid nodules. Prior studies confirmed the safety of same-day discharge for adults undergoing hemithyroidectomy or total thyroidectomy, but this has not been studied thoroughly in the pediatric population. Our goal was to determine differences in pediatric patients undergoing hemithyroidectomy who were admitted versus discharged for complications or factors to support same-day discharge., Study Design: Retrospective cohort., Setting: Pediatric tertiary care hospital., Methods: This was a retrospective study of pediatric patients (0-18 years of age) undergoing hemithyroidectomy at a pediatric tertiary care hospital from 2003 to 2022. Perioperative variables and outcomes were gathered via manual chart review., Results: One hundred five pediatric patients who underwent hemithyroidectomy were identified. Ninety (86%) patients were admitted postoperatively, and 15 (14%) were discharged the same day. There were no differences in patient demographics, including age (P = 0.29) distance from the hospital (P = 0.08) or benign versus malignant pathology (P = 0.93). Surgical time in same-day discharges was significantly shorter (P = 0.0001; 138.6 minutes, SD = 66.0) versus admitted patients (204.2 minutes, SD = 48.6) Hemostatic agents were used more in same-day discharges at 53.3% versus 4.5% (P = 0.0001). Perioperative complications occurred in 2 (2.2%) admitted patients compared to none in the same-day discharge (P = 1.0). There were no readmissions within 30 days for same-day discharges., Conclusion: In pediatric patients undergoing uncomplicated hemithyroidectomy, same-day discharge appears appropriate for those with shorter surgical times and intraoperative use of hemostatic agents with no readmissions or complications in those discharged the same day., (© 2024 The Authors. Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

With recent gains in telehealth access across health sectors, this editorial explores adolescent-specific health issues where innovative use of virtual care is improving outcomes and access for adolescents. These include contraception, obesity, gender-affirming care, mental health, and eating disorder care. Clinicians caring for adolescents should be aware of advances in this field to maximize opportunities for their patients to receive evidence-based care in a manner that supports health equity and confidentiality concerns while understanding the evolving regulatory landscape of telehealth., Competing Interests: Disclosure The authors have no relevant financial or non-financial relationships to disclose relating to the content of this activity. The views expressed in this presentation are those of the author and do not necessarily reflect the official policy or position of the Department of Defense, the United States Air Force, or the US Government., (Published by Elsevier Inc.)

The SARS-CoV-2 main protease (M pro ) is initially synthesized as part of polyprotein precursors that undergo autoproteolysis to release the free mature M pro . To investigate the autoprocessing mechanism in transfected mammalian cells, we examined several fusion precursors, with the mature SARS-CoV-2 M pro along with the flanking amino acids (to keep the native substrate sequences) sandwiched between different tags. Our analyses revealed differential proteolysis kinetics at the N- and C-terminal cleavage sites. Particularly, N-terminal processing is differentially influenced by various upstream fusion tags (GST, sGST, CD63, and Nsp4) and amino acid variations at the N-terminal P1 position, suggesting that precursor catalysis is flexible and subject to complex regulation. Mutating Q to E at the N-terminal P1 position altered both precursor catalysis and the properties of the released M pro . Interestingly, the wild-type precursors exhibited different enzymatic activities compared to those of the released M pro , displaying much lower susceptibility to known inhibitors targeting the mature form. These findings suggest the precursors as alternative targets for antiviral development. Accordingly, we developed and validated a high-throughput screening (HTS)-compatible platform for functional screening of compounds targeting either the N-terminal processing of the SARS-CoV-2 M pro precursor autoprocessing or the released mature M pro through different mechanisms of action.

Cellular responses to environmental stimuli are typically thought to be governed by genetically encoded programs. We demonstrate that melanoma cells can form and maintain cellular memories during the acquisition of therapy resistance that exhibit characteristics of cellular learning and are dependent on the transcription factor AP-1. We show that cells exposed to a low dose of therapy adapt to become resistant to a high dose, demonstrating that resistance was not purely selective. The application of therapy itself results in the encoding of transient gene expression into cellular memory and that this encoding occurs for both transiently induced and probabilistically arising expression. Chromatin accessibility showed concomitant persistence. A two-color AP-1 reporter system showed that these memories are encoded in cis , constituting an example of activating cis epigenetics. Our findings establish the formation and maintenance of cellular memories as a critical aspect of gene regulation during the development of therapy resistance., Competing Interests: Declaration of interests A.R. receives royalties related to Stellaris RNA FISH probes. A.R. serves on the scientific advisory board of Spatial Genomics. All other authors declare no competing interests.

Objective: Diabetic retinopathy is a complication of diabetes mellitus with the potential for significant patient morbidity. Although changes to intraocular inflammatory cytokines are integral to disease pathogenesis, studies have been inconsistent about which exact cytokines are associated with diabetic retinopathy. We aimed to quantitatively summarize proangiogenic and proinflammatory cytokines in nonproliferative diabetic retinopathy (NPDR), given its frequency among those with diabetes mellitus., Methods: A systematic literature search without year limitation to February 21, 2022, identified 59 studies assessing vitreous or aqueous cytokine levels in NPDR, encompassing 1378 eyes with NPDR and 1288 eyes from nondiabetic controls. Effect sizes were generated as standardized mean differences (SMD) of cytokine concentrations between patients with NPDR and controls., Results: Concentrations (SMD, 95% confidence interval, and p value) of aqueous interleukin-6 (IL-6) (2.58, 1.17‒3.99; p = 0.0003), IL-8 (1.56, 0.39‒2.74; p = 0.009), IL-17 (13.55, 7.50‒19.59; p < 0.001), transforming growth factor beta (TGF-β) (2.44, 1.02‒3.85; p = 0.0007) and vascular endothelial growth factor (VEGF) (1.35, 0.76‒1.93; p < 0.00001), and vitreous VEGF (1.49, 0.60‒2.37; p = 0.001) were significantly higher in patients with NPDR when compared with those of healthy controls., Conclusions: These cytokines may serve as disease markers of the biochemical alterations seen in NPDR and may guide interventions, as we move into an era of more targeted therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Background: Current protocols generate highly pure human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro that recapitulate characteristics of mature in vivo cardiomyocytes. Yet, a risk of arrhythmias exists when hiPSC-CMs are injected into large animal models. Thus, understanding hiPSC-CM maturational mechanisms is crucial for clinical translation. Forkhead box (FOX) transcription factors regulate postnatal cardiomyocyte maturation through a balance between FOXO and FOXM1. We also previously demonstrated that p53 activation enhances hiPSC-CM maturation. Here, we investigate whether p53 activation modulates the FOXO/FOXM1 balance to promote hiPSC-CM maturation in 3-dimensional suspension culture., Methods and Results: Three-dimensional cultures of hiPSC-CMs were treated with Nutlin-3a (p53 activator, 10 μM), LOM612 (FOXO relocator, 5 μM), AS1842856 (FOXO inhibitor, 1 μM), or RCM-1 (FOXM1 inhibitor, 1 μM), starting 2 days after onset of beating, with dimethyl sulfoxide (0.2% vehicle) as control. P53 activation promoted hiPSC-CM metabolic and electrophysiological maturation alongside FOXO upregulation and FOXM1 downregulation, in n=3 to 6 per group for all assays. FOXO inhibition significantly decreased expression of cardiac-specific markers such as TNNT2. In contrast, FOXO activation or FOXM1 inhibition promoted maturational characteristics such as increased contractility, oxygen consumption, and voltage peak maximum upstroke velocity, in n=3 to 6 per group for all assays. Further, by single-cell RNA sequencing of n=2 LOM612-treated cells compared with dimethyl sulfoxide, LOM612-mediated FOXO activation promoted expression of cardiac maturational pathways., Conclusions: We show that p53 activation promotes FOXO and suppresses FOXM1 during 3-dimensional hiPSC-CM maturation. These results expand our understanding of hiPSC-CM maturational mechanisms in a clinically-relevant 3-dimensional culture system.

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro , these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo , tissue features, such as regions of necrosis, can influence which resistant fate is adopted., Competing Interests: Declaration of interests A.R. receives royalties related to Stellaris RNA FISH probes. J.A.W. is an inventor on US patent application no. PCT/US17/53.717 submitted by the University of Texas MD Anderson Cancer Center, which covers methods to enhance immune checkpoint blockade responses by modulating the microbiome. J.A.W. reports compensation for the speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Exelixis and Bristol Myers Squibb; and has served as a consultant and/or advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol Myers Squibb, Micronoma, OSE therapeutics, Merck and Everimmune. J.A.W. receives stock options from Micronoma and OSE therapeutics. All other authors declare no competing interests.