Integration of Chronological Age Does Not Improve the Performance of a Mixed-Effect Model Using Comorbidity Burden and Frailty to Predict 90-Day Readmission After Surgery for Degenerative Scoliosis.

OBJECTIVE: We evaluated the contributions of chronological age, comorbidity burden, and/or frailty in predicting 90-day readmission in patients undergoing degenerative scoliosis surgery. METHODS: Patients were identified through the Healthcare Cost and Utilization Project Nationwide Readmissions Database. Frailty was assessed using the Johns Hopkins Adjusted Clinical Groups frailty-defining indicator. Comorbidity was assessed using the Elixhauser Comorbidity Index (ECI). Generalized linear mixed-effects models were created to predict readmission using age, frailty, and/or ECI. Area under the curve (AUC) was compared using DeLong's test. RESULTS: A total of 8104 patients were identified. Readmission rate was 9.8%, with infection representing the most common cause (3.5%). Our first model utilized chronological age, ECI, and/or frailty as primary predictors. The combination of ECI + frailty + age performed best, but the inclusion of chronological age did not significantly improve performance compared to ECI + frailty alone (AUC 0.603 vs. 0.599, P = 0.290). A second model using only chronological age and frailty as primary predictors performed better, however the inclusion of chronological age worsened performance when compared to frailty alone (AUC 0.747 vs. 0.743, P = 0.043). CONCLUSIONS: These data support frailty as a predictor of 90-day readmission within a nationally representative sample. Frailty alone performed better than combinations of ECI and age. Interestingly, the integration of chronological age did not dramatically improve the model's performance. Limitations include the use of a national registry and a single frailty index. This provides impetus to explore biological age, rather than chronological age, as a potential tool for surgical risk assessment.

A Greater Platelet Dose May Yield Better Clinical Outcomes for Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Systematic Review.

PURPOSE: To determine whether the platelet dose administered during a platelet-rich plasma (PRP) injection for knee osteoarthritis (OA) affects clinical outcomes. METHODS: A systematic review was performed by searching PubMed, Cochrane Library, and Embase for randomized controlled trials with at least 1 study arm using PRP for knee OA. Only studies that provided a platelet count, concentration, or dose with a minimum of 6-month outcome scores were included. Studies in which the PRP group had statistically significant positive outcomes were separated from those without statistical significance. The average platelet doses for studies with positive outcomes in the PRP group were compared with those without positive outcomes. RESULTS: After exclusion criteria were applied, 29 studies were analyzed. Of the 29, there were 31 arms that used PRP as a treatment method, of which 28 had statistically significant positive outcomes at 6 months compared with the control group. The mean platelet dose in the 28 with a positive outcome was 5,500 ± 474 × 106, whereas the 3 that had no positive difference had a mean platelet dose of 2,302 ± 437 × 106 (P < .01). There were 18 studies with 12-month outcomes, with 16 of 18 having positive outcomes. The positive studies had an average platelet dose of 5,464 ± 511, whereas the studies that had no statistical difference had an average platelet dose of 2,253 ± 753 × 106 (P < .05). CONCLUSIONS: Improved clinical outcomes from PRP injections for knee OA may be related to a greater platelet dose. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

Methicillin Resistance Elements in the Canine Pathogen Staphylococcus pseudintermedius and Their Association with the Peptide Toxin PSM-mec.

Staphylococcus pseudintermedius is a frequent cause of infections in dogs. Infectious isolates of this coagulase-positive staphylococcal species are often methicillin- and multidrug-resistant, which complicates therapy. In staphylococci, methicillin resistance is encoded by determinants found on mobile genetic elements called Staphylococcal Chromosome Cassette mec (SCCmec), which, in addition to methicillin resistance factors, sometimes encode additional genes, such as further resistance factors and, rarely, virulence determinants. In this study, we analyzed SCCmec in a collection of infectious methicillin-resistant S. pseudintermedius (MRSP) isolates from predominant lineages in the United States. We found that several lineages characteristically have specific types of SCCmec elements and Agr types and harbor additional factors in their SCCmec elements that may promote virulence or affect DNA uptake. All isolates had SCCmec-encoded restriction-modification (R-M) systems of types I or II, and sequence types (STs) ST84 and ST64 had one type II and one type I R-M system, although the latter lacked a complete methylation enzyme gene. ST68 isolates also had an SCCmec-encoded CRISPR system. ST71 isolates had a psm-mec gene, which, in all but apparently Agr-dysfunctional isolates, produced a PSM-mec peptide toxin, albeit at relatively small amounts. This study gives detailed insight into the composition of SCCmec elements in infectious isolates of S. pseudintermedius and lays the genetic foundation for further efforts directed at elucidating the contribution of identified accessory SCCmec factors in impacting SCCmec-encoded and thus methicillin resistance-associated virulence and resistance to DNA uptake in this leading canine pathogen.

Native Circular RNA Pulldown Method to Simultaneously Profile RNA and Protein Interactions.

Circular RNAs (circRNAs) are a widespread, cell-, tissue-, and disease-specific class of largely non-coding RNA transcripts. These single-stranded, covalently-closed transcripts arise through non-canonical splicing of pre-mRNA, a process called back-splicing. Back-splicing results in circRNAs which are distinguishable from their cognate mRNA as they possess a unique sequence of nucleic acids called the backsplice junction (BSJ). CircRNAs have been shown to play key functional roles in various cellular contexts and achieve this through their interaction with other macromolecules, particularly other RNA molecules and proteins. To elucidate the molecular mechanisms underlying circRNA function, it is necessary to identify these interacting partners. Herein, we present an optimized strategy for the simultaneous purification of the circRNA interactome within eukaryotic cells, allowing the identification of both circRNA-RNA and circRNA-protein interactions.

Top 25 Most-Cited Articles on Robotic-Assisted Lumbar Spine Surgery.

BACKGROUND: Robot-guided lumbar spine surgery has evolved rapidly with evidence to support its utility and feasibility compared with conventional freehand and fluoroscopy-based techniques. The objective of this study was to assess trends among the top 25 most-cited articles pertaining to robotic-guided lumbar spine surgery. METHODS: An "advanced document search" using Boolean search operator terms was performed on 16 November 2022 through the Web of Science and SCOPUS citation databases to determine the top 25 most-referenced articles on robotic lumbar spine surgery. The articles were compiled into a directory and hierarchically organized based on the total number of citations. RESULTS: Cumulatively, the "Top 25" list for robot-assisted navigation in lumbar spine surgery received 2240 citations, averaging 97.39 citations annually. The number of citations ranged from 221 to 40 for the 25 most-cited articles. The most-cited study, by Kantelhardt et al, received 221 citations, averaging 18 citations per year. CONCLUSIONS: As utilization of robot-guided modalities in lumbar spine surgery increases, this review highlights the most impactful studies to support its efficacy and implementation. Practical considerations such as cost-effectiveness, however, need to be better defined through further longitudinal studies that evaluate patient-reported outcomes and cost-utility. CLINICAL RELEVANCE: Through an overview of the top 25 most-cited articles, the present review highlights the rising prominence and technical efficacy of robotic-guided systems within lumbar spine surgery, with consideration to pragmatic limitations and need for additional data to facilitate cost-effective applications.

Versatile toolkit for highly-efficient and scarless overexpression of circular RNAs.

Circular RNAs (circRNAs) are a class of single-stranded, covalently closed RNA that contain a unique back-splice junction (bsj) sequence created by the ligation of their 5' and 3' ends via spliceosome-catalyzed back-splicing. A key step in illuminating the cellular roles of specific circRNAs is via increasing their expression. This is frequently done by transfecting cells with plasmid DNA containing cloned exons from which the circRNA is transcribed, flanked by sequences that promote back-splicing. We observed that commonly used plasmids lead to the production of circRNAs with molecular scars at the circRNA bsj. Stepwise redesign of the cloning vector corrected this problem, ensuring bona fide circRNAs are produced with their natural bsj at high efficiency. The fidelity of circRNAs produced from this new construct was validated by RNA sequencing and also functionally validated. To increase the utility of this modified resource for expressing circRNA, we developed an expanded set of vectors incorporating this design that (i) enables selection with a variety of antibiotics and fluorescent proteins, (ii) employs a range of promoters varying in promoter strength and (iii) generated a complementary set of lentiviral plasmids for difficult-to-transfect cells. These resources provide a novel and versatile toolkit for high-efficiency and scarless overexpression of circular RNAs that fulfill a critical need for the investigation of circRNA function.

Prevalence of Moral Injury, Burnout, Anxiety, and Depression in Healthcare Workers 2 Years in to the COVID-19 Pandemic.

ABSTRACT: COVID-19 has led to marked increases in healthcare worker distress. Studies of these phenomena are often limited to a particular element of distress or a specific subset of healthcare workers. We administered the Moral Injury Symptom Scale for Healthcare Professionals, Copenhagen Burnout Inventory, Patient Health Questionnaire-9, and Generalized Anxiety Disorder-7 via online survey to 17,000 employees of a large academic medical center between December 2021 and February 2022. A total of 1945 participants completed the survey. Across all roles, the prevalence of moral injury, burnout, depression, and anxiety were 40.9%, 35.3%-60.6%, 25.4%, and 24.8%, respectively. Furthermore, 8.1% had been bothered by thoughts that they would be better off dead or of hurting themselves for "several days" or more frequently. Healthcare workers across all roles and practice settings are experiencing unsustainable levels of distress, with 1 in 12 regularly experiencing thoughts of self-harm.

The association between the amino acid transporter LAT1, tumor immunometabolic and proliferative features and menopausal status in breast cancer.

L-type Amino Acid Transporter 1 (LAT1) facilitates the uptake of specific essential amino acids, and due to this quality, it has been correlated to worse patient outcomes in various cancer types. However, the relationship between LAT1 and various clinical factors, including menopausal status, in mediating LAT1's prognostic effects remains incompletely understood. This is particularly true in the unique subset of tumors that are both obesity-associated and responsive to immunotherapy, including breast cancer. To close this gap, we employed 6 sets of transcriptomic data using the Kaplan-Meier model in the Xena Functional Genomics Explorer, demonstrating that higher LAT1 expression diminishes breast cancer patients' survival probability. Additionally, we analyzed 3'-Deoxy-3'-18F-Fluorothymidine positron emission tomography-computed tomography (18F-FLT PET-CT) images found on The Cancer Imaging Archive (TCIA). After separating all patients based on menopausal status, we correlated the measured 18F-FLT uptake with various clinical parameters quantifying body composition, tumor proliferation, and immune cell infiltration. By analyzing a wealth of deidentified, open-access data, the current study investigates the impact of LAT1 expression on breast cancer prognosis, along with the menopausal status-dependent associations between tumor proliferation, immunometabolism, and systemic metabolism.

Extensive remodelling of the cell wall during the development of Staphylococcus aureus bacteraemia.

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

Cite-seeing and reviewing: A study on citation bias in peer review.

Citations play an important role in researchers' careers as a key factor in evaluation of scientific impact. Many anecdotes advice authors to exploit this fact and cite prospective reviewers to try obtaining a more positive evaluation for their submission. In this work, we investigate if such a citation bias actually exists: Does the citation of a reviewer's own work in a submission cause them to be positively biased towards the submission? In conjunction with the review process of two flagship conferences in machine learning and algorithmic economics, we execute an observational study to test for citation bias in peer review. In our analysis, we carefully account for various confounding factors such as paper quality and reviewer expertise, and apply different modeling techniques to alleviate concerns regarding the model mismatch. Overall, our analysis involves 1,314 papers and 1,717 reviewers and detects citation bias in both venues we consider. In terms of the effect size, by citing a reviewer's work, a submission has a non-trivial chance of getting a higher score from the reviewer: an expected increase in the score is approximately 0.23 on a 5-point Likert item. For reference, a one-point increase of a score by a single reviewer improves the position of a submission by 11% on average.

Understanding mechanisms of virulence in MRSA: implications for antivirulence treatment strategies.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen, often causing recurrent and deadly infections in the hospital and community. Many S. aureus virulence factors have been suggested as potential targets for antivirulence therapy to decrease the threat of diminishing antibiotic availability. Antivirulence methods hold promise due to their adjunctive and prophylactic potential and decreased risk for selective pressure. AREAS COVERED: This review describes the dominant virulence mechanisms exerted by MRSA and antivirulence therapeutics that are currently undergoing testing in clinical or preclinical stages. We also discuss the advantages and downsides of several investigational antivirulence approaches, including the targeting of bacterial transporters, host-directed therapy, and quorum-sensing inhibitors. For this review, a systematic search of literature on PubMed, Google Scholar, and Web of Science for relevant search terms was performed in April and May 2023. EXPERT OPINION: Vaccine and antibody strategies have failed in clinical trials and could benefit from more basic science-informed approaches. Antivirulence-targeting approaches need to be set up better to meet the requirements of drug development, rather than only providing limited results to provide 'proof-of-principle' translational value of pathogenesis research. Nevertheless, there is great potential of such strategies and potential particular promise for novel probiotic approaches.

Circular RNAs drive oncogenic chromosomal translocations within the MLL recombinome in leukemia.

The first step of oncogenesis is the acquisition of a repertoire of genetic mutations to initiate and sustain the malignancy. An important example of this initiation phase in acute leukemias is the formation of a potent oncogene by chromosomal translocations between the mixed lineage leukemia (MLL) gene and one of 100 translocation partners, known as the MLL recombinome. Here, we show that circular RNAs (circRNAs)-a family of covalently closed, alternatively spliced RNA molecules-are enriched within the MLL recombinome and can bind DNA, forming circRNA:DNA hybrids (circR loops) at their cognate loci. These circR loops promote transcriptional pausing, proteasome inhibition, chromatin re-organization, and DNA breakage. Importantly, overexpressing circRNAs in mouse leukemia xenograft models results in co-localization of genomic loci, de novo generation of clinically relevant chromosomal translocations mimicking the MLL recombinome, and hastening of disease onset. Our findings provide fundamental insight into the acquisition of chromosomal translocations by endogenous RNA carcinogens in leukemia.

A review of the impact of energy balance on triple-negative breast cancer.

Cancer cells cannot proliferate without sufficient energy to generate biomass for rapid cell division, as well as to fuel their functions at baseline. For this reason, many recent observational and interventional studies have focused on increasing energy expenditure and/or reducing energy intake during and after cancer treatment. The impact of variance in diet composition and in exercise on cancer outcomes has been detailed extensively elsewhere and is not the primary focus of this review. Instead, in this translational, narrative review we examine studies of how energy balance impacts anticancer immune activation and outcomes in triple-negative breast cancer (TNBC). We discuss preclinical, clinical observational, and the few clinical interventional studies on energy balance in TNBC. We advocate for the implementation of clinical studies to examine how optimizing energy balance-through changes in diet and/or exercise-may optimize the response to immunotherapy in people with TNBC. It is our conviction that by taking a holistic approach that includes energy balance as a key factor to be considered during and after treatment, cancer care may be optimized, and the detrimental effects of cancer treatment and recovery on overall health may be minimized.

Extensive re-modelling of the cell wall during the development of Staphylococcus aureus bacteraemia.

The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen Staphylococcus aureus manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, tcaA, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in tcaA are selected for during bacteraemia, this protein positively contributes to the virulence of S. aureus through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

The impact of variance in carnitine palmitoyltransferase-1 expression on breast cancer prognosis is stratified by clinical and anthropometric factors.

CPT1A is a rate-limiting enzyme in fatty acid oxidation and is upregulated in high-risk breast cancer. Obesity and menopausal status' relationship with breast cancer prognosis is well established, but its connection with fatty acid metabolism is not. We utilized RNA sequencing data in the Xena Functional Genomics Explorer, to explore CPT1A's effect on breast cancer patients' survival probability. Using [18F]-fluorothymidine positron emission tomography-computed tomography images from The Cancer Imaging Archive, we segmented these analyses by obesity and menopausal status. In 1214 patients, higher CPT1A expression is associated with lower breast cancer survivability. We confirmed a previously observed protective relationship between obesity and breast cancer in pre-menopausal patients and supported this data using two-sided Pearson correlations. Taken together, these analyses using open-access databases bolster the potential role of CPT1A-dependent fatty acid metabolism as a pathogenic factor in breast cancer.

Rank-One Prior: Real-Time Scene Recovery.

Scene recovery is a fundamental imaging task with several practical applications, including video surveillance and autonomous vehicles, etc. In this article, we provide a new real-time scene recovery framework to restore degraded images under different weather/imaging conditions, such as underwater, sand dust and haze. A degraded image can actually be seen as a superimposition of a clear image with the same color imaging environment (underwater, sand or haze, etc.). Mathematically, we can introduce a rank-one matrix to characterize this phenomenon, i.e., rank-one prior (ROP). Using the prior, a direct method with the complexity O(N) is derived for real-time recovery. For general cases, we develop ROP + to further improve the recovery performance. Comprehensive experiments of the scene recovery illustrate that our method outperforms competitively several state-of-the-art imaging methods in terms of efficiency and robustness.

Meningitis in the Guise of Dementia: Lyme-Induced Normal Pressure Hydrocephalus.

While the cause of altered mentation in the elderly may be multifactorial, infectious etiologies may be missed. This case report aims to detail an account of a patient with dementia, found to have Lyme meningitis in the setting of a normal pressure hydrocephalus (NPH). The patient smelled of urine and presented with ambulatory dysfunction, fitting the "wet, wacky, and wobbly" triad of NPH while also having subjective chills and leukocytosis. Non-contrast brain CT scan showed dilated ventricles. Cerebrospinal fluid (CSF) studies suggested aseptic meningitis. Serum studies using a modified two-tiered algorithm confirmed the diagnosis of Lyme disease. Treatment of the underlying condition with a prolonged course of doxycycline improved symptoms and clinical course. Review of the literature on the association between Lyme meningitis and NPH reveals that few cases of Lyme-related NPH have been reported worldwide and further research into the pathophysiology, diagnostic approach, treatment modalities, and management of NPH secondary to Lyme meningitis may be warranted.

Identification and characterization of the pathogenic potential of phenol-soluble modulin toxins in the mouse commensal Staphylococcus xylosus.

In contrast to the virulent human skin commensal Staphylococcus aureus, which secretes a plethora of toxins, other staphylococci have much reduced virulence. In these species, commonly the only toxins are those of the phenol-soluble modulin (PSM) family. PSMs are species-specific and have only been characterized in a limited number of species. S. xylosus is a usually innocuous commensal on the skin of mice and other mammals. Prompted by reports on the involvement of PSMs in atopic dermatitis (AD) and the isolation of S. xylosus from mice with AD-like symptoms, we here identified and characterized PSMs of S. xylosus with a focus on a potential involvement in AD phenotypes. We found that most clinical S. xylosus strains produce two PSMs, one of the shorter α- and one of the longer ß-type, which were responsible for almost the entire lytic and pro-inflammatory capacities of S. xylosus. Importantly, PSMα of S. xylosus caused lysis and degranulation of mast cells at degrees higher than that of S. aureus δ-toxin, the main PSM previously associated with AD. However, S. xylosus did not produce significant AD symptoms in wild-type mice as opposed to S. aureus, indicating that promotion of AD by S. xylosus likely requires a predisposed host. Our study indicates that non-specific cytolytic potency rather than specific interaction underlies PSM-mediated mast cell degranulation and suggest that the previously reported exceptional potency of δ-toxin of S. aureus is due to its high-level production. Furthermore, they suggest that species that produce cytolytic PSMs, such as S. xylosus, all have the capacity to promote AD, but a high combined level of PSM cytolytic potency is required to cause AD in a non-predisposed host.

Use of Casirivimab and Imdevimab for the Treatment of COVID-19.

The authors present three cases of unvaccinated coronavirus disease 2019 (COVID-19) patients who exhibited symptoms of fever, sore throat, nausea, diarrhea, congestion, and headache. Although they refused COVID-19 vaccination, they presented for the casirivimab and imdevimab monoclonal antibody cocktail, which resulted in the resolution of all symptoms. The authors describe the mechanisms and importance of monoclonal antibody treatment for high-risk and unvaccinated patients infected with SARS-CoV-2.