AGPAT3 Deficiency Impairs Adipocyte Differentiation and Leads to a Lean Phenotype in Mice.

Acylglycerophosphate acyltransferases (AGPATs) catalyze the de novo formation of phosphatidic acid to synthesize glycerophospholipids and triglycerides. AGPATs demonstrate unique physiological roles despite a similar biochemical function. AGPAT3 is highly expressed in the testis, kidney, and liver, with intermediate expression in adipose tissue. Loss of Agpat3 is associated with reproductive abnormalities and visual dysfunction. However, the role of AGPAT3 in adipose tissue and whole-body metabolism has not been investigated. We found that male Agpat3-KO mice exhibited reduced body weights with decreased white and brown adipose tissue mass. Such changes were less pronounced in the female Agpat3-KO mice. Agpat3-KO mice have reduced plasma insulin growth factor 1 (IGF1) and insulin levels and diminished circulating lipid metabolites. They manifested intact glucose homeostasis and insulin sensitivity despite a lean phenotype. Agpat3-KO mice maintained an energy balance with normal food intake, energy expenditure, and physical activity, except for increased water intake. Their adaptive thermogenesis was also normal despite reduced brown adipose mass and triglyceride content. Mechanistically, Agpat3 was elevated during mouse and human adipogenesis and enriched in adipocytes. Agpat3-knockdown 3T3-L1 cells and Agpat3-deficient mouse embryonic fibroblasts (MEFs) have impaired adipogenesis in vitro. Interestingly, pioglitazone treatment rescued the adipogenic deficiency in Agpat3 deficient cells. We conclude that AGPAT3 regulates adipogenesis and adipose development. It is possible that adipogenic impairment in Agpat3 deficient cells potentially leads to reduced adipose mass. Findings from this work support the unique role of AGPAT3 in adipose tissue.

A comparison of endoscopic endonasal versus open approaches for skull base chordoma: a comprehensive National Cancer Database analysis.

OBJECTIVE: The authors of this study aimed to investigate independent prognostic factors of survival with a particular focus on comparing the safety and efficacy of endoscopic endonasal versus open approaches in the surgical management of skull base chordoma. METHODS: A retrospective National Cancer Database review of skull base chordoma patients was performed to capture resection cases from 2010 to 2020, evaluating overall survival (OS), early postoperative mortality, readmission rates, and hospital length of stay (LOS) between surgical approaches and the independent prognostication of death utilizing Cox multivariate regression analysis. RESULTS: Among the 736 patients included in the cohort, 456 patients (62.0%) and 280 patients (38.0%) underwent endoscopic endonasal and open resection, respectively. These values represent a rate of change over the study period of +4.1 versus -0.14 cases per year, respectively. Gross-total resection was achieved in 32.5% of cases. A positive margin status was found in 51.8% of cases. There was no association between extent of resection and surgical approach (p = 0.257). There was no difference in OS (p = 0.562), 30- and 90-day mortality (p = 0.209 and 0.126, respectively), and 30-day readmission (p = 0.438) between the two surgical groups. The mean LOS was reduced by 2.1 days in the endoscopic cohort (p = 0.013) compared with the open approach cohort. Finally, multivariate analysis revealed a tumor size ≥ 4 cm (HR 4.03, p = 0.005) and public insurance (HR 2.76, p = 0.004) as negative predictors of survival and treatment at an academic center (HR 0.36, p = 0.043) as a positive prognosticator of survival. CONCLUSIONS: The endoscopic endonasal approach has been increasingly utilized over time and touts noninferiority with respect to safety and efficacy with a marked improvement in LOS, which carries substantial implications for both healthcare costs and enhanced patient recovery. Future prospective studies are necessary to further delineate trends and surgical outcomes for skull base chordoma.

Special Considerations in Pediatric Endoscopic Skull Base Surgery.

Originally pioneered in adults, endoscopic endonasal approaches for skull base pathology are being increasingly applied as a minimally invasive alternative for young children. Intrinsic anatomic differences between these patient populations have sparked discussions on the feasibility, safety, and efficacy of these techniques in pediatric patients. This work aims to serve as a primer for clinicians engaged in the rapidly evolving field of pediatric endoscopic skull base surgery. A succinct overview of relevant embryology, sinonasal anatomy, and diagnostic workup is presented to emphasize key differences and unique technical considerations. Additional discussions regarding select skull base lesions, reconstructive paradigms, potential surgical complications, and postoperative care are also highlighted in the setting of multidisciplinary teams.

A Modified Single-Stage Endoscopic Repair for Bilateral Choanal Atresia.

The work illustrates a step-by-step surgical approach to demonstrate technical feasibility of a single-stage endoscopic repair for bilateral choanal atresia with adjuvant bioabsorbable steroid-eluting stent placement to safely mitigate unique perioperative challenges in the pediatric population. Laryngoscope, 2024.

Evaluating the Distribution, Quality, and Educational Value of Videos Related to Knee Instability Exercises on the Social Media Platform TikTok.

Introduction TikTok, a globally popular short-form video platform, offers a unique space for healthcare professionals to share advice, particularly under common conditions such as knee pain or instability. Despite its popularity, doubts persist regarding the reliability of medical information disseminated on TikTok. This study aimed to evaluate the quality of TikTok videos as a source of patient information on knee instability, recognizing the need for a comprehensive assessment of potential misinformation on this influential social media platform. Methods A search for "knee stability exercises" on TikTok yielded 448 videos, of which 187 met the inclusion criteria. These videos were categorized by source and evaluated using the Knee Exercise Education Scoring Tool (KEEST) and an information analysis questionnaire, DISCERN. Results General user videos (69.84%) had notably lower DISCERN scores than healthcare professional videos (29.1%) across all categories (P < 0.001, P = 0.282, P = 0.131, and P = 0.010). The DISCERN scores were inversely linked to video metrics (views, likes, comments, favorites, and shares). General user videos were largely of poor quality (66.4%), whereas healthcare professional videos spanned poor (61.8%), fair (28.2%), good (9.1%), and excellent (1.8%) categories. Both general users (12.31/25) and healthcare professionals (12.18/25) exhibited average quality according to KEEST standards (P = 0.809), with an intriguing inverse correlation between video popularity and DISCERN score. Conclusion Healthcare professionals demonstrated superior evidence-based content (DISCERN), whereas both groups were comparatively educated on treatment plans and effects (KEEST). TikTok's prevalent knee instability videos lack quality, proper sourcing, treatment risk information, and explanation. Moreover, popularity is inversely correlated with quality, and healthcare professionals appear to offer better evidence-based content. TikTok's role in healthcare highlights the importance of ensuring accurate information and implementing content quality regulations.

Single-Stage Endoscopic Repair of Pediatric Basal Encephalocele: A Comprehensive Multimedia Case Report.

BACKGROUND AND IMPORTANCE: Basal encephaloceles are the result of a concomitant cranial and dural defect that allows for inferior displacement of cerebral tissue, meninges, and cerebrospinal fluid into the paranasal sinuses and outside the cranial vault. This work illustrates a step-by-step surgical approach of a successful single-stage, endoscopic repair of a congenital basal encephalocele in a 10-year-old child, using a free mucosal middle turbinate graft that provided effective results without utilization of traditional open reconstructive techniques or vascularized flaps. CLINICAL PRESENTATION: A previously healthy 10-year-old male with a history of unilateral clear rhinorrhea was admitted as an inpatient because of an acute episode of nausea, vomiting, and confusion, accompanied by fever, diplopia, and bilateral abducens nerve palsies. Preoperative imaging revealed a 2-cm right-sided intranasal mass accompanied by a subcentimeter skull base defect spanning the lateral lamella. After completing a course of intravenous antibiotic therapy for 1 week after a negative lumbar puncture to ensure clearance of intracranial infection, the decision was made to proceed with definitive endoscopic skull base repair to obviate recurrent bacterial meningitis episodes and potential neurological complications. CONCLUSION: This study demonstrates technical feasibility of a single-stage endoscopic endonasal approach for pediatric basal encephalocele resection and repair which minimizes craniofacial morbidity associated with traditional open approaches and sinonasal morbidity associated with local pedicle-based flaps for small cranial base defects in this unique patient population.

Biologic Therapy in Pediatric Chronic Rhinosinusitis: A Systematic Review.

OBJECTIVE: Provide clinicians with current evidence for biologic therapy in children with chronic rhinosinusitis with nasal polyposis (CRSwNP). DATA SOURCES: PubMed, MEDLINE, Cochrane, and clinical trial registries. REVIEW METHODS: Key search terms related to biologic therapy in pediatric CRSwNP were identified via a structured query of current medical literature and clinical trial databases. CONCLUSIONS: There is a dearth of active clinical trials and research studies for biologics targeting pediatric CRSwNP. There is an ongoing compassionate-use clinical trial involving Dupilumab for children with nasal polyps as well as only 1 published work specifically focused on Dupilumab for pediatric CRSwNP in the setting of aspirin-exacerbated respiratory disease. IMPLICATIONS FOR PRACTICE: For children with atopic dermatitis, asthma, and chronic idiopathic urticaria, biologic therapies such as Omalizumab, Dupilumab, and Mepolizumab have gained Food and Drug Administration approval. The role of biologic therapy in pediatric CRSwNP demonstrates significant promise in the comprehensive management of the unified airway. Additional Phase III trials are necessary to broaden clinical indications for children with comorbid conditions and complex sinonasal disease.

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.

Surgical Complexity and Physician Workload in Craniofacial Surgery: Do RVUs Need to be Adjusted?

RVU valuations need to be revisited regularly as procedure complexity and patient care pathways continue to evolve. The NSQIP-P database was queried for craniofacial procedures performed in North America between 2012 and 2019. Multivariate regression was performed to determine correlation coefficients of perioperative variables deemed to reflect procedure severity, including procedure duration, blood transfusion, length of stay, serious adverse events, related readmission, and related reoperation. CPT 21159 Le Fort III with forehead advancement remains the craniofacial procedure with the highest RVUs using our model at 33.93 units. The most underestimated procedure is CPT 42235 Repair of anterior palate, including vomer flap, with a suggested change of +8.27 units, which is a 194% increase from current compensation. Adjusted RVUs based on quantitative and nationally representative perioperative variables that reflect procedure severity might be a better alternative for procedure valuation over current survey methods to determine appropriate insurance compensation.

ECPELLA: Beyond a Left Ventricular Venting Strategy When to Unload the Left Ventricle and How to Decide.

Left ventricular (LV) unloading has been shown to improve survival for patients requiring veno-arterial extracorporeal membrane oxygenation (VA ECMO) support for cardiogenic shock. A mortality benefit has been shown for ECMO and concomitant placement of a transcatheter unloading LV pump such as an Impella device (colloquially referred to as ECPELLA or ECMELLA) for patients resuscitated with VA ECMO after a short period of cardiac arrest. Despite the described benefit of LV unloading with VA ECMO for cardiopulmonary resuscitation, it remains unclear as to what criteria should be used and what other diagnostic and therapeutic adjuncts may be useful. We describe here the successful utilization of concomitant VA ECMO and Impella in a 43 year old male with acute heart failure and cardiac arrest. Distinguishing itself from the currently reported methods, our methodology incorporates transesophageal echocardiography (TEE) in the emergency department for rapid decision-making in addition to an automatic chest compression device, the Lund University Cardiac Assist System (LUCAS) device (Stryker, Portage, MI) as a bridge to LV unloading in a hybrid operating suite.

Cardiometabolic risk factors and neurodegeneration: a review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer's disease.

A growing body of evidence suggests that cardiometabolic risk factors play a significant role in Alzheimer's disease (AD). Diabetes, obesity and hypertension are highly prevalent and can accelerate neurodegeneration and perpetuate the burden of AD. Insulin resistance and enzymes including insulin degrading enzymes are implicated in AD where breakdown of insulin is prioritised over amyloid-ß. Leptin resistance and inflammation demonstrated by higher plasma and central nervous system levels of interleukin-6 (IL-6), IL-1ß and tumour necrosis factor-α, are mechanisms connecting obesity and diabetes with AD. Leptin has been shown to ameliorate AD pathology and enhance long-term potentiation and hippocampal-dependent cognitive function. The renin-aldosterone angiotensin system, involved in hypertension, has been associated with AD pathology and neurotoxic reactive oxygen species, where angiotensin binds to specific angiotensin-1 receptors in the hippocampus and cerebral cortex. This review aims to consolidate the evidence behind putative processes stimulated by obesity, diabetes and hypertension, which leads to increased AD risk. We focus on how novel knowledge can be applied clinically to facilitate recognition of efficacious treatment strategies for AD.

Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma.

Expression of the serine/threonine kinase never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is essential for entry into mitosis via its role in facilitating centrosome separation. Its overactivity can lead to tumorigenesis and drug resistance through the activation of several oncogenic pathways, including AKT. Although the cancer-enabling activities of NEK2 are documented in many malignancies, including correlations with poor survival in myeloma, breast, and non-small cell lung cancer, little is known about the role of NEK2 in lymphoma. Here, in tumors from patients with diffuse large B-cell lymphoma (DLBCL), the most common, aggressive non-Hodgkin lymphoma, we found a high abundance of NEK2 mRNA and protein associated with an inferior overall survival. Using our recently developed NEK2 inhibitor, NBI-961, we discovered that DLBCL cell lines and patient-derived cells exhibit a dependency on NEK2 for their viability. This compromised cell fitness was directly attributable to efficient NEK2 inhibition and proteasomal degradation by NBI-961. In a subset of particularly sensitive DLBCL cells, NBI-961 induced G2/mitosis arrest and apoptosis. In contrast, an existing indirect NEK2 inhibitor, INH154, did not prevent NEK2 autophosphorylation, induce NEK2 proteasomal degradation, or affect cell viability. Global proteomics and phospho-proteomics revealed that NEK2 orchestrates cell-cycle and apoptotic pathways through regulation of both known and new signaling molecules. We show the loss of NEK2-sensitized DLBCL to the chemotherapy agents, doxorubicin and vincristine, and effectively suppressed tumor growth in mice. These studies establish the oncogenic activity of NEK2 in DLBCL and set the foundation for development of anti-NEK2 therapeutic strategies in this frequently refractory and relapse-prone cancer.

Endoscopic pediatric endonasal retrieval of transorbital projectile: An illustrative multimedia report.

Air guns, particularly BB (ball-bearing or bullet ball) guns, have gained significant power and velocity over the last few decades. More than 145,000 pediatric patients suffered injuries attributed to air guns in the United States between 2001 and 2011, and approximately 22,000 pediatric emergency department visits are attributed to air gun-related injuries annually (Hyak et al., 2020 [1]). This study aims to describe an effective surgical technique in addressing maxillofacial injuries caused by BB gun projectiles in the pediatric population. We present a detailed surgical approach for endoscopic endonasal retrieval of a transorbital projectile in a 13-year-old male who sustained a maxillofacial BB gun injury, with the goal of restoring sinonasal function in a minimally invasive fashion.

Nasal Epistaxis Balloons: A Comprehensive MAUDE Database Analysis.

BACKGROUND: While nasal epistaxis balloons are generally seen as safe and routinely utilized by both surgical and nonsurgical providers, the complication profile related to this type of device has not been well defined. OBJECTIVE: The objective of this study was to utilize the FDA MAUDE (Manufacturer and User Facility Device Experience) database to better assess adverse events (AE) related to use of nasal epistaxis balloons. Reports were individually tabulated and events were categorized with special attention to AEs. METHODS: The FDA MAUDE database was queried for all medical device reports (MDR) related to nasal epistaxis balloon devices from January 2012 to November 2022. RESULTS: 19 MDRs met inclusion criteria. 5 MDRs were classified as device related (26.3 %); two events were reported for balloon leak and deflation, two events were reported for device breakage, and one device related event was unknown. 14 MDRs (73.7 %) were classified as patient related. Two documented MDRs were patient deaths due to exsanguination. Additional serious AEs included balloon ingestion and subsequent small bowel perforation (n = 1), cerebrospinal fluid leak (n = 1), skull base violation and intracranial placement of the device (n = 1), and respiratory distress (n = 3). CONCLUSION: Though epistaxis control with nasal balloons is generally seen as a safe procedure, there have been several concerning AEs reported. While two reports of death due to exsanguination were the most severe AEs, multiple other life-threatening AEs were also documented. Increased awareness of associated complications can be used to better counsel patients during the informed consent process as well as providers in their clinical decision making.

Chordoma: A Comprehensive Systematic Review of Clinical Trials.

This systematic review aims to characterize ongoing clinical trials and therapeutic treatment options for chordoma, a rare notochordal remnant tumor that primarily affects the cranial base, mobile spine, and sacrum. While radical surgical resection remains the cornerstone for chordoma management, unique technical challenges posed by its proximity to critical neurovascular structures confer a tendency towards disease recurrence which often requires additional treatment modalities. In an attempt to better understand the current treatment landscape, a systematic review was designed to identify clinical trials directed at chordoma. A total of 108 chordoma trials were identified from four clinical trial databases; fifty-one trials were included in the final analysis, of which only 14 were designated as completed (27.5%). Aggregate data suggests most chordoma interventions are repurposed from other neoplasms that share common molecular pathways, with a recent emphasis on combination therapeutics within and across drug classes. Naturally, the publication and dissemination of clinical trial results remain a concern (n = 4, 28.6%), highlighting the need for enhanced reporting and transparency measures. Active clinical trial efforts are quite promising, with a renewed focus on novel biotherapeutic targets and deciphering the natural history, as well as survivorship of this complex disease.

Integrative multiomics analysis of neointima proliferation in human saphenous vein: implications for bypass graft disease.

Introduction: Human saphenous veins (SV) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima proliferation (NP). NP involves complex interplay between vascular smooth muscle cells (VSMC) and fibroblasts. Little is known, however, regarding the transcriptomic and proteomic dynamics of NP. Here, we performed multi-omics analysis in an ex vivo tissue culture model of NP in human SV procured for CABG surgery. Methods and results: Histological examination demonstrated significant elastin degradation and NP (indicated by increased neointima area and neointima/media ratio) in SV subjected to tissue culture. Analysis of data from 73 patients suggest that the process of SV adaptation and NP may differ according to sex and body mass index. RNA sequencing confirmed upregulation of pro-inflammatory and proliferation-related genes during NP and identified novel processes, including increased cellular stress and DNA damage responses, which may reflect tissue trauma associated with SV harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics detected transdifferentiating VSMC in the intima on the day of harvesting and highlighted dynamic alterations in fibroblast and VSMC phenotype and behavior during NP. Specifically, we identified new cell subpopulations contributing to NP, including SPP1 + , LGALS3 + VSMC and MMP2 + , MMP14 + fibroblasts. Conclusion: Dynamic alterations of gene and protein expression occur during NP in human SV. Identification of the human-specific molecular and cellular mechanisms may provide novel insight into SV bypass graft disease.

A Lost Bullet in the Coronary Sinus: A Cautionary Tale.

We present a case of venous bullet embolism to the right atrium following a gunshot wound (GSW) to the abdomen. A 53-year-old male presented after a GSW to the abdomen. His workup included a computed tomography (CT) scan demonstrating an aortic injury with aortocaval fistula. A radio-opaque object consistent with a bullet was visualized in the right atrium. First, this case details an important decision, choice of surgery versus an interventional approach. After repair of the aortocaval fistula, the patient underwent a planned attempt to extract the bullet through a right lateral thoracotomy approach utilizing cardiopulmonary bypass to facilitate a right atriotomy. Intraoperatively, the team was not able to localize the bullet in the right atrium despite fluoroscopic evaluation. A postoperative CT scan demonstrated that the bullet had migrated into the coronary sinus. Lastly, this case demonstrates successful positioning maneuvers to dislodge the bullet out of the heart and into the inferior vena cava, allowing for the endovascular extraction of the bullet.

Cortisol as a Target for Treating Mental Disorders: A Promising Avenue for Therapy.

Cortisol, commonly known as the "stress hormone," plays a critical role in the body's response to stress. Elevated cortisol levels have been associated with various mental disorders, including anxiety, depression, and post-traumatic stress disorder. Consequently, researchers have explored cortisol modulation as a promising avenue for treating these conditions. However, the availability of research on cortisol as a therapeutic option for mental disorders is limited, and existing studies employ diverse methodologies and outcome measures. This review article aimed to provide insights into different treatment approaches, both pharmacological and non-pharmacological, which can effectively modulate cortisol levels. Pharmacological interventions involve the use of substances, such as somatostatin analogs, dopamine agonists, corticotropin-releasing hormone antagonists, and cortisol synthesis inhibitors. Additionally, non-pharmacological techniques, including cognitivebehavioral therapy, herbs and supplements, transcranial magnetic stimulation, lifestyle changes, and surgery, have been investigated to reduce cortisol levels. The emerging evidence suggests that cortisol modulation could be a promising treatment option for mental disorders. However, more research is needed to fully understand the effectiveness and safety of these therapies.