Author Correction: Complete biosynthesis of cannabinoids and their unnatural analogues in yeast.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dissecting the energetic architecture within an RNA tertiary structural motif via high-throughput thermodynamic measurements.

Structured RNAs and RNA/protein complexes perform critical cellular functions. They often contain structurally conserved tertiary contact "motifs," whose occurrence simplifies the RNA folding landscape. Prior studies have focused on the conformational and energetic modularity of intact motifs. Here, we turn to the dissection of one common motif, the 11nt receptor (11ntR), using quantitative analysis of RNA on a massively parallel array to measure the binding of all single and double 11ntR mutants to GAAA and GUAA tetraloops, thereby probing the energetic architecture of the motif. While the 11ntR behaves as a motif, its cooperativity is not absolute. Instead, we uncovered a gradient from high cooperativity amongst base-paired and neighboring residues to additivity between distant residues. As expected, substitutions at residues in direct contact with the GAAA tetraloop resulted in the largest decreases to binding, and energetic penalties of mutations were substantially smaller for binding to the alternate GUAA tetraloop, which lacks tertiary contacts present with the canonical GAAA tetraloop. However, we found that the energetic consequences of base partner substitutions are not, in general, simply described by base pair type or isostericity. We also found exceptions to the previously established stability-abundance relationship for 11ntR sequence variants. These findings of "exceptions to the rule" highlight the power of systematic high-throughput approaches to uncover novel variants for future study in addition to providing an energetic map of a functional RNA.

Complete biosynthesis of cannabinoids and their unnatural analogues in yeast.

Cannabis sativa L. has been cultivated and used around the globe for its medicinal properties for millennia1. Some cannabinoids, the hallmark constituents of Cannabis, and their analogues have been investigated extensively for their potential medical applications2. Certain cannabinoid formulations have been approved as prescription drugs in several countries for the treatment of a range of human ailments3. However, the study and medicinal use of cannabinoids has been hampered by the legal scheduling of Cannabis, the low in planta abundances of nearly all of the dozens of known cannabinoids4, and their structural complexity, which limits bulk chemical synthesis. Here we report the complete biosynthesis of the major cannabinoids cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, cannabidiolic acid, Δ9-tetrahydrocannabivarinic acid and cannabidivarinic acid in Saccharomyces cerevisiae, from the simple sugar galactose. To accomplish this, we engineered the native mevalonate pathway to provide a high flux of geranyl pyrophosphate and introduced a heterologous, multi-organism-derived hexanoyl-CoA biosynthetic pathway5. We also introduced the Cannabis genes that encode the enzymes involved in the biosynthesis of olivetolic acid6, as well as the gene for a previously undiscovered enzyme with geranylpyrophosphate:olivetolate geranyltransferase activity and the genes for corresponding cannabinoid synthases7,8. Furthermore, we established a biosynthetic approach that harnessed the promiscuity of several pathway genes to produce cannabinoid analogues. Feeding different fatty acids to our engineered strains yielded cannabinoid analogues with modifications in the part of the molecule that is known to alter receptor binding affinity and potency9. We also demonstrated that our biological system could be complemented by simple synthetic chemistry to further expand the accessible chemical space. Our work presents a platform for the production of natural and unnatural cannabinoids that will allow for more rigorous study of these compounds and could be used in the development of treatments for a variety of human health problems.

The Biochemical Impact of Extracting an Embedded Adenylate Kinase Domain Using Circular Permutation.

Adenylate kinases (AKs) have evolved AMP-binding and lid domains that are encoded as continuous polypeptides embedded at different locations within the discontinuous polypeptide encoding the core domain. A prior study showed that AK homologues of different stabilities consistently retain cellular activity following circular permutation that splits a region with high energetic frustration within the AMP-binding domain into discontinuous fragments. Herein, we show that mesophilic and thermophilic AKs having this topological restructuring retain activity and substrate-binding characteristics of the parental AK. While permutation decreased the activity of both AK homologues at physiological temperatures, the catalytic activity of the thermophilic AK increased upon permutation when assayed >30 °C below the melting temperature of the native AK. The thermostabilities of the permuted AKs were uniformly lower than those of native AKs, and they exhibited multiphasic unfolding transitions, unlike the native AKs, which presented cooperative thermal unfolding. In addition, proteolytic digestion revealed that permutation destabilized each AK in differing manners, and mass spectrometry suggested that the new termini within the AMP-binding domain were responsible for the increased proteolysis sensitivity. These findings illustrate how changes in contact order can be used to tune enzyme activity and alter folding dynamics in multidomain enzymes.

Racial disparities in the management and outcomes of primary osseous neoplasms of the spine: a SEER analysis.

PURPOSE: Primary osseous neoplasms of the spine, including Ewing's sarcoma, osteosarcoma, chondrosarcoma, and chordoma, are rare tumors with significant morbidity and mortality. The present study aims to identify the prevalence and impact of racial disparities on management and outcomes of patients with these malignancies. METHODS: The 2000 to 2020 Surveillance, Epidemiology, and End Results (SEER) Registry, a cancer registry, was retrospectively reviewed to identify patients with Ewing's sarcoma, osteosarcoma, chondrosarcoma, or chordoma of the vertebral column or sacrum/pelvis. Study patients were divided into race-based cohorts: White, Black, Hispanic, and Other. Demographics, tumor characteristics, treatment variables, and mortality were assessed. RESULTS: 2,415 patients were identified, of which 69.8% were White, 5.8% Black, 16.1% Hispanic, and 8.4% classified as "Other". Tumor type varied significantly between cohorts, with osteosarcoma affecting a greater proportion of Black patients compared to the others (p < 0.001). A lower proportion of Black and Other race patients received surgery compared to White and Hispanic patients (p < 0.001). Utilization of chemotherapy was highest in the Hispanic cohort (p < 0.001), though use of radiotherapy was similar across cohorts (p = 0.123). Five-year survival (p < 0.001) and median survival were greatest in White patients (p < 0.001). Compared to non-Hispanic Whites, Hispanic (p < 0.001) and "Other" patients (p < 0.001) were associated with reduced survival. CONCLUSION: Race may be associated with tumor characteristics at diagnosis (including subtype, size, and site), treatment utilization, and mortality, with non-White patients having lower survival compared to White patients. Further studies are necessary to identify underlying causes of these disparities and solutions for eliminating them.

Double lumen endobronchial tube intubation: lessons learned from anatomy.

BACKGROUND: Double lumen endobronchial tubes (DLTs) are frequently used to employ single lung ventilation strategies during thoracic surgical procedures. Placement of these tubes can be challenging even for experienced clinicians. We hypothesized that airway anatomy, particularly of the glottis and proximal trachea, significantly impacts the ease or difficulty in placement of these tubes. METHODS: Images from 24 randomly selected Positron Emission Tomography - Computed Tomography (PET-CT) scans were evaluated for several anatomic aspects of the upper airway, including size and angulation of the glottis and proximal tracheal using calibrated CT measurements and an online digital protractor. The anatomic issues identified were confirmed in cadaveric anatomic models. RESULTS: Proximal tracheal diameter measurements in PET-CT scans demonstrated a mean ± standard deviation of 20.4 ± 2.5 mm in 12 males and 15.5 ± 0.98 mm in 12 females (p < 0.001), and both were large enough to accommodate 39 French and 37 French DLTs in males and females, respectively. Subsequent measurements of the posterior angulation of the proximal trachea revealed a mean angle of 40.8 ± 5.7 degrees with no sex differences. By combining the 24 individual posterior tracheal angles with the 16 angled distal tip measurements DLTs (mean angle 24.9 ± 2.1 degrees), we created a series of 384 patient intubation angle scenarios. This data clearly showed that DLT rotation to a full 180 degrees decreased the mean intubation angle between the DLT and the proximal trachea from a mean of 66.6 ± 5.9 to only 15.8 ± 5.9 degrees. CONCLUSIONS: Rotation of DLTs a full 180 instead of the recommended 90 degrees facilitates DLT intubations.

High-throughput dissection of the thermodynamic and conformational properties of a ubiquitous class of RNA tertiary contact motifs.

Despite RNA's diverse secondary and tertiary structures and its complex conformational changes, nature utilizes a limited set of structural "motifs"-helices, junctions, and tertiary contact modules-to build diverse functional RNAs. Thus, in-depth descriptions of a relatively small universe of RNA motifs may lead to predictive models of RNA tertiary conformational landscapes. Motifs may have different properties depending on sequence and secondary structure, giving rise to subclasses that expand the universe of RNA building blocks. Yet we know very little about motif subclasses, given the challenges in mapping conformational properties in high throughput. Previously, we used "RNA on a massively parallel array" (RNA-MaP), a quantitative, high-throughput technique, to study thousands of helices and two-way junctions. Here, we adapt RNA-MaP to study the thermodynamic and conformational properties of tetraloop/tetraloop receptor (TL/TLR) tertiary contact motifs, analyzing 1,493 TLR sequences from different classes. Clustering analyses revealed variability in TL specificity, stability, and conformational behavior. Nevertheless, natural GAAA/11ntR TL/TLRs, while varying in tertiary stability by ∼2.5 kcal/mol, exhibited conserved TL specificity and conformational properties. Thus, RNAs may tune stability without altering the overall structure of these TL/TLRs. Furthermore, their stability correlated with natural frequency, suggesting thermodynamics as the dominant selection pressure. In contrast, other TL/TLRs displayed heterogenous conformational behavior and appear to not be under strong thermodynamic selection. Our results build toward a generalizable model of RNA-folding thermodynamics based on the properties of isolated motifs, and our characterized TL/TLR library can be used to engineer RNAs with predictable thermodynamic and conformational behavior.

Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.

Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

Directed Evolution of Aptamer Discovery Technologies.

Although antibodies are a powerful tool for molecular biology and clinical diagnostics, there are many emerging applications for which nucleic acid-based aptamers can be advantageous. However, generating high-quality aptamers with sufficient affinity and specificity for biomedical applications is a challenging feat for most research laboratories. In this Account, we describe four techniques developed in our laboratory to accelerate the discovery of high-quality aptamer reagents that can achieve robust binding even for challenging molecular targets. The first method is particle display, in which we convert solution-phase aptamers into aptamer particles that can be screened via fluorescence-activated cell sorting (FACS) to quantitatively isolate individual aptamer particles based on their affinity. This enables the efficient isolation of high-affinity aptamers in fewer selection rounds than conventional methods, thereby minimizing selection biases and reducing the emergence of artifacts in the final aptamer pool. We subsequently developed the multiparametric particle display (MPPD) method, which employs two-color FACS to isolate aptamer particles based on both affinity and specificity, yielding aptamers that exhibit excellent target binding even in complex matrixes such as serum. The third method is an alkyne-azide chemistry ("click chemistry")-based particle display (click-PD) that enables the generation and screening of "non-natural" aptamers with a wide range of base modifications. We have shown that these base-modified aptamers can achieve robust affinity and specificity for targets that have proven challenging or inaccessible with natural nucleotide-based aptamer libraries. Finally, we describe the non-natural aptamer array (N2A2) platform in which a modified benchtop sequencing instrument is used to characterize base-modified aptamers in high throughput, enabling the efficient identification of molecules with excellent affinity and specificity for their targets. This system first generates aptamer clusters on the flow-cell surface that incorporate alkyne-modified nucleobases and then performs a click reaction to couple those nucleobases to an azide-modified chemical moiety. This yields a sequence-defined array of tens of millions of base-modified sequences, which can then be characterized for affinity and specificity in a high-throughput fashion. Collectively, we believe that these advancements are helping to make aptamer technology more accessible, efficient, and robust, thereby enabling the use of these affinity reagents for a wider range of molecular recognition and detection-based applications.

Atlantoaxial instability associated with ALDH18A1 mutation.

We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.

A current review of spinal meningiomas: epidemiology, clinical presentation and management.

PURPOSE: To provide an up-to-date review of the epidemiology, histopathology, molecular biology, and etiology of spinal meningiomas, as well as discuss the clinical presentation, clinical evaluation, and most recent treatment recommendations for these lesions. METHODS: PubMed and Google Scholar search was performed for studies related to meningiomas of the spine. The terms "meningioma," "spinal meningioma," "spine meningioma," "meningioma of the spine," "benign spinal tumors," and "benign spine tumors," were used to identify relevant studies. All studies, including primary data papers, meta-analyses, systematic reviews, general reviews, case reports, and clinical trials were considered for review. RESULTS: Eighty-four studies were identified in the review. There were 22 studies discussing adverse postoperative outcomes, 21 studies discussing tumor genetics, 19 studies discussing epidemiology and current literature, 9 studies discussing radiation modalities and impact on subsequent tumor development, 5 studies on characteristic imaging findings, 5 studies discussing hormone use/receptor status on tumor development, 2 discussing operative techniques and 1 discussing tumor identification. CONCLUSION: Investigations into spinal meningiomas generally lag behind that of intracranial meningiomas. Recent advancements in the molecular profiling of spinal meningiomas has expanded our understanding of these tumors, increasing our appreciation for their heterogeneity. Continued investigation into the defining characteristics of different spinal meningiomas will aid in treatment planning and prognostication.

Effect of race, sex, and socioeconomic factors on overall survival following the resection of intramedullary spinal cord tumors.

INTRODUCTION: Intramedullary spinal cord tumors (IMSCTs) account for 2-4% of all primary CNS tumors. Given their low prevalence and the intricacy of their diagnosis and management, it is critical to address the surrounding racial and socioeconomic factors that impact the care of patients with IMSCTs. This study aimed to investigate the association between race and socioeconomic factors with overall 5 year mortality following the resection of IMSCTs. METHODS: The study used the National Cancer Database to retrospectively analyze patients who underwent resection of IMSCTs from 2004 to 2017. Patients were divided into four cohorts by race/ethnicity, facility type, insurance, median income quartiles, and living area. The primary outcome of interest was 5 year survival, and secondary outcomes included postoperative length of stay and 30 day readmission. Descriptive and multivariable analyses were used to identify independent factors associated with mortality, with statistical significance assessed at a 2-sided p < 0.05. RESULTS: We evaluated the patient characteristics and outcomes for 8,028 patients who underwent surgical treatment for IMSCTs between 2004 and 2017. Most patients were white males (52.4%) with a mean age of 44 years where 7.17% of patients were Black, 7.6% were Hispanic, and 3% were Asian. Most were treated in an academic/research program (72.4%) and had private insurance (69.2%). Black patients had a higher odd of 5 year mortality (OR 1.4; 95% CI 1.1 to 1.77; p = 0.04) compared to white patients, while no significant differences in mortality were observed among other races. Factors associated with lower odds of mortality included being female (OR 0.89; 95% CI 0.78 to 1.02; p < 0.01), receiving treatment in an academic/research program (OR 0.51; 95% CI 0.33 to 0.79; p = 0.04), having private insurance (OR 0.65; 95% CI 0.45 to 0.93; p = 0.02), and having higher income quartiles (OR 0.77; 95% CI 0.62 to 0.96; p = 0.02). CONCLUSION: Our study sheds light on the healthcare disparities that exist in the surgical management of IMSCTs. Our findings indicate that race, sex, socioeconomic status, and treatment facility are independent predictors of 5 year mortality, with Black patients, males, those with lower socioeconomic status, and those treated at non-academic centers experiencing significantly higher mortality rates. These alarming disparities underscore the urgent need for policymakers and researchers to address the underlying factors contributing to these discrepancies and provide equal access to high-quality surgical care for patients with IMSCTs.

Twelve-month results of the ADAPT randomized controlled trial: Reproducibility and sustainability of advanced hybrid closed-loop therapy outcomes versus conventional therapy in adults with type 1 diabetes.

AIMS: To reassess the 6-month efficacy and to assess the 12-month sustained efficacy of the MiniMed™ 780G advanced hybrid closed-loop automated insulin delivery (AID) system compared to multiple daily injections plus intermittently scanned glucose monitoring (MDI+isCGM) in people with type 1 diabetes not meeting glucose targets. METHODS: The ADAPT study was a prospective, multicentre, open-label, randomized control trial in people with type 1 diabetes, with a glycated haemoglobin (HbA1c) concentration of at least 8.0% (64 mmol/mol), on MDI+isCGM therapy. After a 6-month study phase, participants randomized at baseline to MDI+isCGM switched to AID (SWITCH) while the others continued AID therapy (SUSTAIN) for an additional 6 months. The primary endpoint of this continuation phase was the within-group change in mean HbA1c between 6 and 12 months, with superiority in the SWITCH group and noninferiority in the SUSTAIN group (ClinicalTrials.gov: NCT04235504). RESULTS: A total of 39 SWITCH and 36 SUSTAIN participants entered the continuation phase. In the SWITCH group, HbA1c was significantly decreased by -1.4% (95% confidence interval [CI] -1.7% to -1.1%; P < 0.001) from a mean ± SD of 8.9% ± 0.8% (73.9 ± 8.6 mmol/mol) at 6 months to 7.5% ± 0.6% (58.5 ± 6.9 mmol/mol) at 12 months. Mean HbA1c increased by 0.1% (95% CI -0.05% to +0.25%), from 7.3% ± 0.6% (56.5 ± 6.7 mmol/mol) to 7.4% ± 0.8% (57.7 ± 9.1 mmol/mol) in the SUSTAIN group, meeting noninferiority criteria. Three severe hypoglycaemia events occurred in two SWITCH participants during the continuation phase. CONCLUSION: ADAPT study phase glycaemic improvements were reproduced and sustained in the continuation phase, supporting the early adoption of AID therapy in people with type 1 diabetes not meeting glucose targets on MDI therapy.

Gross total resection of spinal chondrosarcoma is associated with improved locoregional relapse-free survival and overall survival.

BACKGROUND: Spinal chondrosarcomas are rare malignant osseous tumors. The low incidence of spinal chondrosarcomas and the complexity of spine anatomy have led to heterogeneous treatment strategies with varying curative and survival rates. The goal of this study is to investigate prognostic factors for locoregional recurrence-free survival (LRFS) and overall survival (OS) comparing en bloc vs. piecemeal resection for the management of spinal chondrosarcoma. METHODS: We retrospectively identified patients who underwent curative-intent resection of primary and metastatic spinal chondrosarcoma over a 25-year period. Univariate and multivariate survival analyses were conducted with LRFS as primary endpoint and OS as secondary endpoint. LRFS and OS were modeled using the Kaplan-Meier method and assessed using Cox regression analysis. RESULTS: For 72 patients who underwent first resection, the median follow-up time was 5.1 years (95% CI 2.2-7.0). Thirty-three patients (45.8%) had en bloc resection, and 39 (54.2%) had piecemeal resection. Of the 68 patients for whom extent of resection was known, 44 patients had gross total resection (GTR) and 24 patients had subtotal resection. In survival analyses, both LRFS and OS showed statistically significant difference based on the extent of resection (p = 0.001; p = 0.04, respectively). However, only LRFS showed statistically significant difference when assessing the type of resection (p = 0.02). In addition, higher tumor grade and more invasive disease were associated with worse LRFS and OS rates. CONCLUSION: Although in our study en bloc and GTR were associated with improved survival, heterogenous and complex spinal presentations may limit total resection. Therefore, the surgical management should be tailored individually to ensure the best local control and maximum preservation of function.

The prognostic nutritional index (PNI) is independently associated with 90-day and 12-month mortality after metastatic spinal tumor surgery.

INTRODUCTION: Estimated postoperative survival is an important consideration during the decision-making process for patients with spinal metastases. Nutritional status has been associated with poor outcomes and limited survival in the general cancer population. The objective of this study was to evaluate the predictive utility of the prognostic nutritional index (PNI) for postoperative mortality after spinal metastasis surgery. METHODS: A total of 139 patients who underwent oncologic surgery for spinal metastases between April 2012 and August 2022 and had a minimum 90-day follow-up were included. PNI was calculated using preoperative serum albumin and total lymphocyte count, with PNI < 40 defined as low. The mean PNI of our cohort was 43 (standard deviation: 7.7). The primary endpoint was 90-day mortality, and the secondary endpoint was 12-month mortality. Multivariate logistic regression analyses were performed. RESULTS: The 90-day mortality was 27% (37/139), and the 12-month mortality was 56% (51/91). After controlling for age, ECOG performance status, total psoas muscle cross-sectional area (TPA), and primary cancer site, the PNI was associated with 90-day mortality [odds ratio 0.86 (95% confidence interval 0.79-0.94); p = 0.001]. After controlling for ECOG performance status and primary cancer site, the PNI was associated with 12-month mortality [OR 0.89 (95% CI 0.82-0.97); p = 0.008]. Patients with a low PNI had a 50% mortality rate at 90 days and an 84% mortality rate at 12 months. CONCLUSION: The PNI was independently associated with 90-day and 12-month mortality after metastatic spinal tumor surgery, independent of performance status, TPA, and primary cancer site.

Association of frailty with healthcare resource utilization after open thoracic/thoracolumbar posterior spinal fusion for adult spinal deformity.

PURPOSE: The Hospital Frailty Risk Score (HFRS) is a frailty-identifying metric developed using ICD-10-CM codes. While other studies have examined frailty in adult spinal deformity (ASD), the HFRS has not been assessed in this population. The aim of this study was to utilize the HFRS to investigate the impact of frailty on outcomes in ASD patients undergoing posterior spinal fusion (PSF). METHODS: A retrospective study was performed using the 2016-2019 National Inpatient Sample database. Adults with ASD undergoing elective PSF were identified using ICD-10-CM codes. Patients were categorized into HFRS-based frailty cohorts: Low (HFRS < 5) and Intermediate-High (HFRS ≥ 5). Patient demographics, comorbidities, intraoperative variables, and outcomes were assessed. Multivariate regression analyses were used to determine whether HFRS independently predicted extended length of stay (LOS), non-routine discharge, and increased cost. RESULTS: Of the 7500 patients identified, 4000 (53.3%) were in the Low HFRS cohort and 3500 (46.7%) were in the Intermediate-High HFRS cohort. On average, age increased progressively with increasing HFRS scores (p < 0.001). The frail cohort experienced more postoperative adverse events (p < 0.001), greater LOS (p < 0.001), accrued greater admission costs (p < 0.001), and had a higher rate of non-routine discharge (p < 0.001). On multivariate analysis, Intermediate-High HFRS was independently associated with extended LOS (OR: 2.58, p < 0.001) and non-routine discharge (OR: 1.63, p < 0.001), though not increased admission cost (OR: 1.01, p = 0.929). CONCLUSION: Our study identified HFRS to be significantly associated with prolonged hospitalizations and non-routine discharge. Other factors that were found to be associated with increased healthcare resource utilization include age, Hispanic race, West hospital region, large hospital size, and increasing number of AEs.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Predictors of time in target glucose range in real-world users of the MiniMed 780G system.

AIM: Automated insulin delivery systems have improved glycaemic control in people with type 1 diabetes mellitus. The analysis investigated predictors of improved sensor glucose time-in-range (TIR; 70-180 mg/dl) based on real-world use of the MiniMed 780G advanced hybrid closed-loop (AHCL) system. METHODS: Data uploaded by MiniMed 780G system users from August 2020-July 2021 were analysed using univariate and multivariable models to identify baseline, demographic and system use characteristics associated with TIR after AHCL initiation (post-AHCL). System settings associated with improved TIR post-AHCL were identified and their impact on time below range (TBR, <70 mg/dl) post-AHCL was explored. RESULTS: In total, 12 870 users were included, of which 2977 had baseline sensor glucose data. Baseline TIR and time in AHCL (defined as the percentage of time the system was in Auto-mode) were positively associated with TIR post-AHCL with larger values predicting greater mean TIR post-AHCL. Characteristics inversely associated with TIR post-AHCL included the percentage of daily basal insulin dose, daily autocorrection dose, number of daily AHCL exits triggered by the system and number of daily alarms, wherein larger values of these characteristics predicted lower mean TIR post-AHCL. System settings that predicted the largest mean TIR post-AHCL were active insulin time of 2 h and glucose target of 100 mg/dl. Active insulin time was not associated with TBR post-AHCL. CONCLUSION: Modifiable factors, including optimized pump settings, can allow users to achieve glycaemic targets with >80% TIR. The findings from this analysis will potentially guide the optimal use of the MiniMed 780G system and facilitate meaningful improvements in safe glycaemic control.

Comparison of MiniMed 780G system performance in users aged younger and older than 15 years: Evidence from 12 870 real-world users.

AIM: To investigate real-world glycaemic outcomes and goals achieved by users of the MiniMed 780G advanced hybrid closed loop (AHCL) system aged younger and older than 15 years with type 1 diabetes (T1D). MATERIALS AND METHODS: Data uploaded by MiniMed 780G system users from 27 August 2020 to 22 July 2021 were aggregated and retrospectively analysed based on self-reported age (≤15 years and >15 years) for three cohorts: (a) post-AHCL initiation, (b) 6-month longitudinal post-AHCL initiation and (c) pre- versus post-AHCL initiation. Analyses included mean percentage of time spent in AHCL and at sensor glucose ranges, insulin delivered and the proportion of users achieving recommended glucose management indicator (GMI < 7.0%) and time in target range (TIR 70-180 mg/dl > 70%) goals. RESULTS: Users aged 15 years or younger (N = 3211) achieved a GMI of 6.8% ± 0.3% and TIR of 73.9% ± 8.7%, while spending 92.7% of time in AHCL. Users aged older than 15 years (N = 8874) achieved a GMI of 6.8% ± 0.4% and TIR of 76.5% ± 9.4% with 92.3% of time in AHCL. Time spent at less than 70 mg/dl was within the recommended target of less than 4% (3.2% and 2.3%, respectively). Similar outcomes were observed for each group (N = 790 and N = 1642, respectively) in the first month following AHCL initiation, and were sustained over the 6-month observation period. CONCLUSIONS: This real-world analysis shows that more than 75% of users with T1D aged 15 years or younger using the MiniMed 780G system achieved international consensus-recommended glycaemic control, mirroring the achievements of the population aged older than 15 years.