Lipidic drug delivery systems are responsive to the human microbiome.

In vitro and in vivo tests for therapeutic agents are typically conducted in sterile environments, but many target areas for drug delivery are home to thousands of microbial species. Here, we examine the behaviour of lipidic nanomaterials after exposure to representative strains of four bacterial species found in the gastrointestinal tract and skin. Small angle X-ray scattering measurements show that the nanostructure of monoolein cubic and inverse hexagonal phases are transformed, respectively, into inverse hexagonal and inverse micellar cubic phases upon exposure to a strain of live Staphylococcus aureus often present on skin and mucosa. Further investigation demonstrates that enzymatic hydrolysis and cell membrane lipid transfer are both likely responsible for this effect. The structural responses to S. aureus are rapid and significantly reduce the rate of drug release from monoolein-based nanomaterials. These findings are the first to demonstrate how a key species in the live human microbiome can trigger changes in the structure and drug release properties of lipidic nanomaterials. The effect appears to be strain specific, varies from patient to patient and body region to body region, and is anticipated to affect the bioapplication of monoglyceride-based formulations.

Spinal Injuries and Spine Care in the US Military Health System (2001-Present).

STUDY DESIGN: Literature Review. OBJECTIVE: The goal of this study was to provide a comprehensive outline of spinal injuries that may transpire over the course of military service from traumatic to repetitive stress injuries and chronic sequalae. We considered studies that assessed spinal injuries in the combat and non-combat settings as reported in the literature over the last 15-20 years. SUMMARY OF BACKGROUND DATA: Military service places servicemembers under substantial physical demands, while also exposing them to dangerous, unpredictable environments. As a result, servicemembers are at an increased risk of spinal injuries from combat-related trauma and other causes. They may have different care needs and recovery profiles when compared to civilians with spinal disorders. METHODS: We performed a review of the available literature on spinal injuries and spinal care in the Military Health System from 2001-present. RESULTS: The studies discussed in this review were primarily focused on the conflicts in both Iraq and Afghanistan from over ten years ago and do not fully capture the present-day advancements in military technology that may have an impact on the potential for spinal injuries. The long-term effects of sustained military service and the relative influence of high demand versus sedentary military occupations on the development of spinal disorders remains poorly understood. Given the changing nature of military service, both with respect to the demographic in uniform and the ever-evolving nature of modern combat, we believe that only a long-term prospective observational study dedicated to the surveillance of spinal problems could effectively answer these questions. CONCLUSION: Further research into the present-day characterization of spinal injuries is warranted given the advancements in both military technology and spine care that have occurred over the last ten years.

Structure, biosynthesis and activity of indolactam alkaloids.

Indolactam alkaloids are a family of aromatic toxins produced by various actinobacteria and the cyanobacterium, Moorena producens. The best characterized examples include the teleocidins, lyngbyatoxins, olivoretins, blastmycetins, and pendolmycins, which share a nine-membered lactam core, comprised from l-tryptophanol and l-valine. Contact with indolactam alkaloids has been linked to severe dermatitis (swimmers itch), while accidental ingestion may lead to illness and fatalities. Indolactam alkaloids are also potent tumor promotors, due to their activation of protein kinase C isozymes. This chapter reviews the current literature on indolactam alkaloids, from their discovery in the early 1960s up to 2024. Topics covered include the isolation, structural elucidation, biosynthesis, bioactivity, and total synthesis of the indolactam alkaloid core.

Scheduled intravenous ketorolac is safe and reduces narcotic use after robotic-assisted simple prostatectomy.

We sought to examine whether scheduled intravenous (IV) ketorolac decreased post-operative narcotic utilization and changed peri-operative outcomes (including complications) in patients undergoing robotic-assisted simple prostatectomy (RASP). An IRB-approved, retrospective chart review was performed of all patients undergoing RASP at a single institution from November 2017 to July 2019. Patient demographic, peri-operative, and post-operative data, including morphine equivalent use (MEU), were collected. Scheduled ketorolac use was implemented at the surgeon's discretion for up to 5 days post-operatively. The primary outcome was MEU in the post-operative stay. Two hundred seven men underwent RASP during the study period, of which 143 (69%) received scheduled ketorolac. No differences in patient demographics, prostate size, prior opioid utilization, or operative characteristics were identified between groups. Median MEU was significant less (5 vs 15, p < 0.001) in patients receiving scheduled ketorolac. Significantly more patients receiving scheduled ketorolac did not require the use of any narcotic during hospitalization (30% vs 11%, p = 0.005). On multivariable linear regression adjusted for age, BMI, prior opioid use, and length of stay, ketorolac use independently associated with decreased narcotic use (p = 0.003). No significant difference in transfusion rates were identified (3.5% vs. 1.6%, p = 0.44). Scheduled ketorolac is effective in reducing post-operative, in-hospital opioid utilization without increasing morbidity after RASP. Almost a third of patients on scheduled ketorolac did not require any opioids post-operatively.

Activation of Heme Metabolism Promotes Tissue Health After Intraarticular Injury or Surgical Exposure.

Posttraumatic osteoarthritis (PTOA) is a well-recognized public health burden without any disease modifying treatment. This occurs despite noted advances in surgical care in the past 50 years. Mitochondrial oxidative damage pathways initiate PTOA after severe injuries like intraarticular fracture that often require surgery and contribute to PTOA after less severe injuries that may or may not require surgery like meniscal injuries. When considering the mitochondrial and redox environment of the injured joint, we hypothesized that activation of heme metabolism, previously associated with healing in many settings, would cause prototypic mitochondrial reprogramming effects in cartilage ideally suited for use at the time of injury repair. Activation of heme metabolism can be accomplished through the gasotransmitter carbon monoxide (CO), which activates hemeoxygenase-1 (HO1) and subsequent heme metabolism. In this study, we employed unique carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolism in vitro and in vivo . Doxycycline-inducible, chondrocyte-specific HO1 overexpressing transgenic mice show similar mitochondrial reprogramming after induction compared to COF. CO is retained at least 24 h after COF injection into stifle joints and induces sustained increases in heme metabolism. Lastly, intraarticular injection of COF causes key redox outcomes without any adverse safety outcomes in rabbit stifle joints ex vivo and in vivo . We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes chondrocyte mitochondrial metabolism and restores redox homeostasis.

Psychopathology and the Validity of Gastrointestinal Symptom Reporting as Revealed Through Cluster Analyses of MMPI-2-RF Results.

BACKGROUND: Psychological state, self-reported gut symptoms, and somatic complaints are recognized relationships that can impact health assessment and subsequent treatment. AIM: To investigate the impact of psychological state and personality on symptom self-reporting and somatization. METHODS: Sixty-two (62) participants from the Hunter region of NSW (Australia) undertook a survey of health and lifestyle along with an MMPI-2-RF assessment of personality, psychopathology, and test-taking attitude. Participants also completed the Rome Criteria to assess functional gastrointestinal disorders (FGIDs). To assist the interpretation of MMPI-2-RF results, clustering was applied to identify similar responses and sub-cohort profiles of reporting. RESULTS: Cluster analysis revealed four sub-cohorts, stratified by psychopathology, gut-related symptoms, and the validity of self-reported somatic complaints. Sample clustering identified one sub-cohort defined by high rates of negative affectivity and suicidal ideation. Apart from these differences, clusters were uniform for age, sex, smoking, mental health diagnoses, as well as for gut-related conditions. CONCLUSION: Results provide further evidence of the interaction of the gut-brain axis and its relationship to serious mental health conditions. It also points to the need to assess the veracity of self-reported symptomatology that may be both pathognomonic for psychopathology but might also be a consequence of gut dysbiosis. Clustering assisted these investigations by defining distinct sub-cohorts based on participant MMPI-2-RF responses.

The utility of disc space and vertebral body specimens cell count differential for the diagnosis of native vertebral osteomyelitis: a prospective cohort study.

BACKGROUND: Diagnostic methods for native vertebral osteomyelitis (NVO) often yield inconclusive results. Image-guided spine biopsies for culture are specific but diagnose NVO in only 50% of cases. Pre-exposure to antimicrobials further reduces diagnostic yield. Our study assesses the value of neutrophil percentage in disc space fluid and vertebral body (DS/VB) samples for diagnosing NVO. METHODS: Adults referred for spine biopsy at Mayo Clinic from August 2022 to September 2023 were consented and enrolled at the time of biopsy. Following routine specimen collection, the biopsy needle was rinsed in saline into an EDTA tube for cell analysis. NVO diagnosis required organism identification in spine tissue or blood and/or positive histopathology, and consistent symptoms and imaging. RESULTS: Sixty-eight patients were prospectively enrolled, comprising 14 with NVO and 54 with alternative diagnoses. The median biopsy sample polymorphonuclear (PMN) percentage for NVO patients was 80.5% (IQR 72.5-85.2), compared to 64.5% (IQR 54.0-69.0) for those without NVO (p < 0.001). Nine (64.3%) NVO patients received antibiotics within 10 days prior to spine biopsy. As a continuous measure, PMN differential showed a moderately strong ability in classifying NVO status with an area under ROC curve of 0.795; an optimal point on the curve of 71.5% corresponded to a sensitivity of 78.6%, specificity of 79.6%, negative predictive value of 93.5% and positive predictive value of 50.0%. CONCLUSION: PMN differential in DS/VB biopsies may serve as an effective diagnostic tool in the evaluation of patients with NVO particularly in ambiguous cases with an initially negative spine biopsy. Future efforts will aim to implement these findings within routine clinical practice.

Detection of interstellar 1-cyanopyrene: A four-ring polycyclic aromatic hydrocarbon.

Polycyclic aromatic hydrocarbons (PAHs) are organic molecules containing adjacent aromatic rings. Infrared emission bands show that PAHs are abundant in space, but only a few specific PAHs have been detected in the interstellar medium. We detect 1-cyanopyrene, a cyano-substituted derivative of the related four-ring PAH pyrene, in radio observations of the dense cloud TMC-1 using the Green Bank Telescope. The measured column density of 1-cyanopyrene is [Formula: see text], from which we estimate that pyrene contains up to 0.1% of the carbon in TMC-1. This abundance indicates that interstellar PAH chemistry favors the production of pyrene. We suggest that some of the carbon supplied to young planetary systems is carried by PAHs that originate in cold molecular clouds.

Pediatric sporadic Burkitt lymphoma of the head and neck: A case series and analysis of national trends.

OBJECTIVE: Burkitt lymphoma (BL) is an aggressive form of non-Hodgkin lymphoma with the sporadic subtype being predominant in North America. The clinical presentations and outcomes of pediatric BL within the head and neck were assessed using both an institutional case series and the Surveillance, Epidemiology, and End Results (SEER) Cancer database. METHODS: The electronic medical record at our quaternary children's hospital was queried over a 22-year period (2000-2022) for BL patients with head and neck manifestations. Demographics, clinical presentation, staging, treatment, and outcomes data were collected and analyzed. A corresponding review of the SEER database from 1975 to 2022 was also performed. RESULTS: Our institutional case series identified 48 sporadic BL patients with a mean age of 8.7 years, the majority of whom were male (79 %) and white (74 %). The most common primary sites were the cervical lymph nodes (38 %) and (or) palatine tonsils (23 %). Thirty-five patients (73 %) were treated initially for a presumed inflammatory or infectious process before undergoing malignancy work-up, which did not significantly delay time to diagnosis (31.5 vs. 38.8 days, p = 0.27). The SEER database analysis identified 78 cases, 43.5 % of whom were 5-9 years of age, with a similar male (66 %) and Caucasian (76.9 %) predominance. Cervical lymph nodes were also the most common subsite (67 %), followed by the palatine tonsils (13 %). Remission rates were similar, 93.7 % and 94.8 %, respectively, in both the institutional and SEER database cohorts. CONCLUSION: Unilateral cervical lymphadenopathy and asymmetric tonsillar hypertrophy are the most common presentations in sporadic BL in the head and neck. Clinical presentation in patients with BL is often similar to common, insidious pediatric otolaryngology symptoms and a majority of patients initially undergo treatment for presumed infectious or inflammatory disease. Although overall BL disease-free survival is high even for disseminated BL, the prognosis is better for local/regional disease, and minimizing time to diagnosis and treatment should remain a priority.

Sensitivity analysis of aromatic chemistry to gas-phase kinetics in a dark molecular cloud model.

The increasingly large number of complex organic molecules detected in the interstellar medium necessitates robust kinetic models that can be relied upon for investigating the involved chemical processes. Such models require rate coefficients for each of the thousands of reactions; the values of these are often estimated or extrapolated, leading to large uncertainties that are rarely quantified. We have performed a global Monte Carlo and a more local one-at-a-time sensitivity analysis on the gas-phase rate coefficients in a 3-phase dark cloud model. Time-dependent sensitivities have been calculated using four metrics to determine key reactions for the overall network as well as for the cyanonaphthalene molecule in particular, an important interstellar species that is severely under-produced by current models. All four metrics find that reactions involving small, reactive species that initiate hydrocarbon growth have large effects on the overall network. Cyanonaphthalene is most sensitive to a number of these reactions as well as ring-formation of the phenyl cation (C6H5+) and aromatic growth from benzene to naphthalene. Future efforts should prioritize constraining rate coefficients of key reactions and expanding the network surrounding these processes. These results highlight the strength of sensitivity analysis techniques to identify critical processes in complex chemical networks, such as those often used in astrochemical modeling.

Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.

ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.

Physicochemical Properties of Seed Oil Blends and Their Potential for the Creation of Synthetic Oleosomes with Modulated Polarities.

There is an increasing demand within the pharmaceutical and cosmetic industries for biofriendly lipid-based active ingredient delivery systems. Micelles, liposomes, and lipid nanoparticles are currently the most used systems despite their limitations. Oleosomes, also known as lipid droplets, are promising alternatives to the existing strategies. Oleosomes are typically found in plant cells and are characterized by a nonpolar triacylglycerol core surrounded by a phospholipid monolayer punctuated with the protein oleosin. Producing oleosomes synthetically allows the customization of their lipid content, size, protein content, and oil core characteristics, expanding their versatility. Herein we demonstrate a proof of concept for the use of synthetic oleosomes to sequester polar molecules by modulating their core polarity with blends of sunflower and castor oils. The physical properties (density, refractive index, and permittivity) of the oil blends are characterized and demonstrate ideal mixing of the oils, which is supported by molecular dynamics simulations. Spectroscopic examination of the oil blends using fluorescent probes shows that the polarity of oil blends increases as the fraction of castor oil increases. Finally, we show that the uptake of a polar fluorescent probe (NBD-glucose) into synthetic oleosomes is enhanced by increasing the polarity of the oil core, but large charged molecules are excluded from the core regardless of polarity. These experiments show that synthetic oleosomes with tunable oil cores can expand the range of molecules that can be loaded into a biofriendly package as desired for biotechnology applications.

Comparison of a Novel Posterior Integrated Transfixation Sacroiliac Joint Fusion Approach to the Posterolateral and Lateral Approaches: A Cadaveric Biomechanical and Computational Analysis of the Fixation, Invasiveness, and Fusion Area.

Purpose: To concurrently assess and compare the fixation efficacy, invasiveness, and fusion potential of a posterior integrated transfixation cage system to the posterolateral threaded implant and lateral triangular rod systems, in a cadaveric model. Methods and Materials: Twelve (12) cadaveric sacroiliac joint specimens were utilized and tested within the single-leg stance multidirectional pure moment bending model. Each specimen was tested in the intact, destabilized, treated (using posterior, posterolateral, and lateral systems), and post-fatigue conditions by applying 0 to ± 7.5 Nm of moment in flexion-extension, axial rotation, and lateral bending while measuring the angular range of motion between the sacrum and ilium. Computational models were reconstructed from Computed Tomography (CT) scans and manufacturer surgical technique guides. The models were utilized to quantify the volume of bone removed during implantation and the surface area available for fusion. Results: The posterior integrated transfixation cage system and the lateral triangular rods produced equivalent motion reduction in all motion planes (P > 0.583). The posterolateral cylindrical threaded implant produced less motion reductions than the posterior and lateral implants in flexion-extension (6% ± 3% vs 37% ± 10% and 33% ± 11%, respectively, P <0.05). The posterior system removed 22%-60% less bone volume from the sacrum and ilium (P<0.10), introduced 200%-270% more implant surface to the joint space (P<0.01) and decorticated 75%-375% more joint surface area (P<0.01). Conclusion: The posterior integrated transfixation single-implant cage system is superior to the posterolateral cylindrical threaded single-implant system. Its performance in osteopenic bone is equivalent to the lateral triangular rod system in healthy bone; however, the posterior integrated transfixation cage system requires a single implant, while the lateral triangular rod system requires three. The posterior implant removes the least bone volume and has the most surface area for fusion, providing a significantly better opportunity for robust sacroiliac joint arthrodesis.

B7-H3 is widely expressed in soft tissue sarcomas.

PURPOSE: Targeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS. PATIENTS AND METHODS: This retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature. RESULTS: Specimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93-0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61-0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1. CONCLUSION: These data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Liver iron stores and effectors of ferroptosis are dependent on age and sex.

Ferroptosis is a form of cell death characterized by a pro-oxidative cellular milieu and iron-dependent lipid peroxidation. Ferroptosis has been implicated in various forms of liver injury, in keeping with the major role of the liver in iron metabolism. Limited research has addressed potential differences in ferroptosis mediators with age and sex, especially in an in vivo model. The goal of this investigation was to evaluate hepatic labile iron and mediators of ferroptosis with ageing in both sexes. Because female animals generally display greater antioxidant defences than males, we hypothesized that females would display a phenotype resistant to ferroptosis. Here, we determined iron contents, protein expression of ferroptosis mediators and measures of oxidative injury in liver samples from 12- and 24-month-old male and female Fischer 344 rats. In comparison to males, the livers of female rats at both ages contained more non-haem iron, which was associated with greater ferritin heavy chain expression and attenuated expression of transferrin receptor-1. In female rats, the 24-month-old group had higher contents of thiobarbituric acid reactive substances compared with their 12-month-old counterparts, yet similar contents of labile iron. These results suggest a disconnect between labile iron contents and oxidative injury with age. Female animals also displayed greater expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), a modulator of ferroptosis, and greater abundance of high molecular weight 4-hydroxnonenal-modified proteins. These results demonstrate clear differences in iron and ferroptosis mediators between sexes and suggest that female rats of this strain might be more susceptible to ferroptosis.

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.

BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. METHODS: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. RESULTS: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. CONCLUSIONS: P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

Chaotropic Agent-Assisted Supported Lipid Bilayer Formation.

Supported lipid bilayers (SLBs) are useful structures for mimicking cellular membranes, and they can be integrated with a variety of sensors. Although there are a variety of methods for forming SLBs, many of these methods come with limitations in terms of the lipid compositions that can be employed and the substrates upon which the SLBs can be deposited. Here we demonstrate the use of an all-aqueous chaotropic agent exchange process that can be used to form SLBs on two different substrate materials: SiO2, which is compatible with traditional SLB formation by vesicle fusion, and Al2O3, which is not compatible with vesicle fusion. When examined with a quartz crystal microbalance with dissipation monitoring, the SLBs generated by chaotropic agent exchange (CASLBs) have similar frequency and dissipation shifts to SLBs formed by the vesicle fusion technique. The CASLBs block nonspecific protein adsorption on the substrate and can be used to sense protein-lipid interactions. Fluorescence microscopy was used to examine the CASLBs, and we observed long-range lateral diffusion of fluorescent probes, which confirmed that the CASLBs were composed of a continuous, planar lipid bilayer. Our CASLB method provides another option for forming planar lipid bilayers on a variety of surfaces, including those that are not amenable to the widely used vesicle fusion method.

Wide variability of the definitions used for native vertebral osteomyelitis: walking the path for a unified diagnostic framework with a meta-epidemiological approach.

BACKGROUND CONTEXT: Native Vertebral Osteomyelitis (NVO) has seen a rise in incidence, yet clinical outcomes remain poor with high relapse rates and significant long-term sequelae. The 2015 IDSA Clinical Practice Guidelines initiated a surge in scholarly activity on NVO, revealing a patchwork of definitions and numerous synonyms used interchangeably for this syndrome. PURPOSE: To systematically summarize these definitions, evaluate their content, distribution over time, and thematic clustering. STUDY DESIGN/SETTING: Meta-epidemiological study with a systematic review of definitions. PATIENTS SAMPLE: An extensive search of multiple databases was conducted, targeting trials and cohort studies dating from 2005 to present, providing a definition for NVO and its synonyms. OUTCOME MEASURES: Analysis of the diagnostic criteria that composed the definitions and the breaking up of the definitions in the possible combinations of diagnostic criteria. METHODS: We pursued a thematic synthesis of the published definitions with Boolean logic, yielding single or multiple definitions per included study. Using 8 predefined diagnostic criteria, we standardized definitions, focusing on the minimum necessary combinations used. Definition components were visualized using Sankey diagrams. RESULTS: The literature search identified 8,460 references, leading to 171 studies reporting on 21,963 patients. Of these, 91.2% were retrospective, 7.6% prospective, and 1.2% RCTs. Most definitions originated from authors, with 29.2% referencing sources. We identified 92 unique combinations of diagnostic criteria across the literature. Thirteen main patterns emerged, with the most common being clinical features with imaging, followed by clinical features combined with imaging and microbiology, and lastly, imaging paired with microbiology. CONCLUSIONS: Our findings underscore the need for a collaborative effort to develop standardized diagnostic criteria. We advocate for a future Delphi consensus among experts to establish a unified diagnostic framework for NVO, emphasizing the core components of clinical features and MRI while incorporating microbiological and histopathological insights to improve both patient outcomes and research advancements.