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Magnetic particle imaging (MPI) is an emerging ionizing radiation-free biomedical tracer imaging technique that directly images the intense magnetization of superparamagnetic iron ...oxide nanoparticles (SPIOs). MPI offers ideal image contrast because MPI shows zero signal from background tissues. Moreover, there is zero attenuation of the signal with depth in tissue, allowing for imaging deep inside the body quantitatively at any location. Recent work has demonstrated the potential of MPI for robust, sensitive vascular imaging and cell tracking with high contrast and dose-limited sensitivity comparable to nuclear medicine. To foster future applications in MPI, this new biomedical imaging field is welcoming researchers with expertise in imaging physics, magnetic nanoparticle synthesis and functionalization, nanoscale physics, and small animal imaging applications.
Background:
Multiple sclerosis (MS) is a neuroinflammatory disease with debilitating manifestations that may predispose patients to hip fracture and osteoarthritis, and may affect recovery from total ...hip arthroplasty (THA). With increased longevity of MS patients and growth in demand for arthroplasty in this population, it is important to understand outcomes of THA in patients with MS.
Aim:
We sought to compare outcomes of THA among persons with MS and without MS.
Methods:
International Classification of Diseases, Ninth Revision Procedure Coding System (ICD-9-PCS) codes for hip arthroplasty (815.1) were used to identify all patients in the New York Statewide Planning and Research Cooperative System (SPARCS) database who underwent THA between 2000 and 2014. Patients with MS, the primary exposure, were identified using ICD-9-Clinical Modification (CM) code 340. The study outcomes of length of stay (days), discharge disposition, index admission mortality, 90-day readmission, 1-year revision arthroplasty, and 1-year all-cause mortality were evaluated using multivariable regression analyses inclusive of basic demographics, admission source, disposition, payer, comorbidity, and socioeconomic status (SES).
Results:
Compared to patients without MS, those with MS had marginally longer lengths of stay (mean ratio MR 1.05; 95% confidence interval CI, 1.01–1.10; p = 0.0142), higher risk for institutional discharge disposition (odds ratio OR 2.03; 95% CI, 1.54–2.70; p < 0.0001) and higher risk of readmission for revision hip arthroplasty (OR 2.60; 95% CI, 1.07–6.35; p = 0.035). However, MS patients had similar risk for 90-day readmission and one-year all-cause mortality as compared with non-MS patients.
Conclusions:
Although patients with MS who underwent THA had a 90-day complication risk that was similar to those without MS, the risk for requiring revision surgery was more than 2-fold higher. Additional studies are needed to understand the reasons for revision surgery and for developing strategies to mitigate the risk of complications.
Purpose
Patients with acute pulmonary embolism (PE) can quickly deteriorate and the condition has high mortality due to right ventricular (RV) failure. Immediately available predictors of adverse ...outcome are of major interest to the treating physician in the acute setting. The purpose of the present study was to evaluate if easily attainable measurements of RV function from the diagnostic computed tomography pulmonary angiography (CTPA) provide information for fast risk stratification in patients with acute PE.
Methods
We retrospectively evaluated images from CTPA in 261 patients (age median 60 years, 50% females) enrolled in a prospective study. RV and left ventricular (LV) diameters and their ratio, the presence of septal bowing, contrast reflux in the inferior vena cava, and the diameter of the central pulmonary arteries (PA) were measured. The composite outcome was 5-day severe adverse events including death, acute decompensation, or need for emergent treatment. We used Wilcoxon rank sum test and Fischer’s exact test to test between groups and multivariate logistic regression for prediction.
Results
In multivariate analysis, increased diameter of the main PA (OR = 1.08 per 1 mm increase,
p
= 0.047) and the presence of septal bowing (OR = 2.23,
p
= 0.055) were associated with severe adverse events. RV/LV > 1 did not predict severe outcomes (OR = 0.73,
p
= 0.541).
Conclusions
Two easily attainable parameters of RV function on CTPA, septal bowing and main PA diameter, are associated with short-term adverse outcomes in patients with acute PE. Further study is required to determine whether these findings can be incorporated into clinical treatment algorithms.
Uncorrected superior glenoid wear in patients managed with reverse total shoulder arthroplasty (rTSA) can result in increased complications, including baseplate failure. The present study quantifies ...the clinical and radiographic outcomes of patients with Favard type-E1, E2, and E3 glenoid deformity who were managed with rTSA with use of a superior or superior/posterior augmented glenoid baseplate.
We retrospectively reviewed the records for 68 patients with shoulder arthritis and Favard type-E1, E2, or E3 glenoid deformity who were managed with primary rTSA and a 10° superior augmented or 10° superior/8° posterior augmented baseplate. The mean duration of follow-up was 40 months (range, 24 to 85 months). Outcomes were assessed preoperatively and at the latest follow-up with shoulder range of motion and use of outcome scores including the Simple Shoulder Test (SST), University of California Los Angeles (UCLA) score, American Shoulder and Elbow Surgeons (ASES) score, Constant score, and Shoulder Pain and Disability Index (SPADI) score. Radiographs were evaluated preoperatively and at the time of the latest follow-up. Differences in preoperative and postoperative range of motion and outcome metrics were assessed with use of a 2-tailed Student t test.
The majority of patients experienced clinically meaningful improvements in terms of pain and function following rTSA with a superior or superior/posterior augment, with 94% of patients rating themselves as "much better" (73.5%) or "better" (20.5%) at the time of the latest follow-up. At least 88% of the patients exceeded the minimum clinically important difference (MCID) threshold, and 75% of patients exceeded the substantial clinical benefit (SCB) threshold, for each of the clinical outcome metrics and range of motion. Five complications were reported (prevalence, 7.4%), including acromial stress fracture (2 patients), posttraumatic scapular neck fracture (1 patient), chronic shoulder pain (1 patient), and aseptic glenoid loosening (1 patient).
The present short-term clinical and radiographic study demonstrated that shoulder arthropathy with superior glenoid wear patterns (Favard types E1, E2, and E3) can be successfully treated with rTSA with a superior or superior/posterior augmented baseplate. Longer-term clinical and radiographic follow-up is necessary to confirm that these promising short-term results are durable.
Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Loss of inflammatory effector function, such as cytokine production and proliferation, is a fundamental driver of failure in T cell therapies against solid tumors. Here, we used CRISPR/Cas9 to ...genetically disrupt ZFP36, an RNA binding protein that regulates the stability of mRNAs involved in T cell inflammatory function, such as the cytokines IL2 and IFNγ, in human T cells engineered with a clinical-stage mesothelin-targeting CAR to determine whether its disruption could enhance antitumor responses. ZFP36 disruption slightly increased antigen-independent activation and cytokine responses but did not enhance overall performance in vitro or in vivo in a xenograft tumor model with NSG mice. While ZFP36 disruption does not reduce the function of CAR-T cells, these results suggest that singular disruption of ZFP36 is not sufficient to improve their function and may benefit from a multiplexed approach.
A high flow of air applied by large bore nasal cannulae has been suggested to improve symptoms of chronic respiratory insufficiency. In pediatric patients, nasal high-flow (nHF) ventilation was ...similarly effective compared to noninvasive ventilation with a face mask.
The aim of this study was to describe changes in respiratory parameters.
We measured pressure amplitudes during the respiratory cycle and mean pressures in patients with idiopathic pulmonary fibrosis (IPF) and COPD. In order to achieve tidal volume and minute volume measurements, we used a polysomnography device. Capillary blood was taken for blood gas analysis before and after nHF breathing (8 h).
nHF led to an increase in pressure amplitude and mean pressure in healthy volunteers and in patients with COPD and IPF in comparison with spontaneous breathing. In COPD, nHF increased tidal volume, while no difference in tidal volume was observed in patients with IPF. Interestingly, tidal volume decreased in healthy volunteers. Breathing rates and minute volumes were reduced in all groups. Capillary pCO2 decreased in patients with IPF and COPD.
nHF resulted in significant effects on respiratory parameters in patients with obstructive and restrictive pulmonary diseases. The rise in pressure amplitude and mean pressure and the decrease in breathing rate and minute volume will support inspiratory efforts, helps to increase effectiveness of ventilation and will contribute to a reduction in the work of breathing. A CO2 wash-out effect in the upper airway part of the anatomical dead space may contribute to the beneficial effects of the nHF instrument.
This article reports a novel impedance-driven flow apparatus and its applicability for studying magnesium degradation under flow versus static conditions. Magnesium has potential to be an effective ...biomaterial for use inside the human body due to its biodegradability and biocompatibility.Magnesium undergoes degradation reactions in aqueous solutions such as body fluids, leading to mass loss and pH increase of the surrounding fluid. To compare the degradation process of magnesium under flow versus static conditions, a novel flow apparatus consisting of an impedance pump and a flow chamber was designed and constructed. In addition to low-cost, this apparatus is flexible to be sterilized and assembled, and is small enough for use inside an incubator, making it appealing for measuring and comparing magnesium degradation in vitro under flow versus static conditions. The average flow rate in this flow apparatus was 2.8 ml/s, mimicking the flow rate(2.6 ml/s) in coronary artery. In a simulated body fluid(SBF), magnesium samples lost their mass at a much faster rate under the flow condition than that under the static condition. Starting with a pH of 7.4, the SBF showed a pH increase to 8.5 under the flow condition within 96 h due to the degradation of magnesium, greater than the pH increase under the static condition.The results of this study demonstrated the effects of fluid flow on magnesium degradation using the impedance-driven flow apparatus, providing useful design guidelines for magnesium-based implants that may be exposed to body fluid flow.
BackgroundCAR-T cell therapy has demonstrated remarkable success in hematological malignancies but displays limited efficacy in solid tumors, which comprise most cancer cases. Recent studies suggest ...that CAR-T cell failure via T cell exhaustion is characterized by decreased surface CAR expression, cytotoxicity, and Th1 cytokine production, leading to reduced antitumor functionality.1 2 3 To address these issues, studies have turned to genetically knocking out or overexpressing targets associated with an exhaustion or effector phenotype, such as PD-1 knockout (KO) and c-Jun overexpression, among other candidates that are typically receptors or transcription factors.4 5 6 However, there are other underexplored factors that mediate various aspects of immune regulation. While genome-wide CRISPR screens may discover such factors, they are unlikely to reveal phenotypes for genes whose function is partially redundant, therefore promising candidates may be missed. Such candidates include post-transcriptional regulators (PTRs) that coordinate immune responses, which are less well-studied in the context of CAR-T cell function. We hypothesized that KO of these PTRs may increase CAR-T cell cytokine activity, phenotype, and persistence, potentially under long-term or exhaustion-inducing conditions, leading to increased tumor control. Ultimately, disruption of negative immune regulators could produce CAR-T cells with enhanced activity and persistence, narrowing the gap between efficacy in hematological and solid tumors.MethodsTo explore whether the disruption of two target PTRs improves solid tumor efficacy, we used CRISPR-Cas9 to genetically delete one or both PTRs in mesothelin-targeting human CAR-T cells and assayed their function in vitro and in vivo in NSG mice.ResultsWe show successful genetic deletion of these genes in post-thymic human T cells and that their disruption does not affect primary expansion (figure 1) or transduction efficiency (figure 2). These KO CAR-T cells display increased expression of co-stimulatory receptors and various cytokines (figure 3). While KO CAR-T cells are functionally similar to WT CAR-T cells in in vitro assays (figure 4), KO CAR-T cells demonstrate superior activity in vivo and can clear large, established tumors compared to WT CAR-T cells at low dose (figure 5).Abstract 131 Figure 1Expansion kinetics of KO CAR-T cellsAbstract 131 Figure 2Transduction efficiency and baseline phenotype of KO CAR-T cellsAbstract 131 Figure 3Costimulatory receptor and cytokine expression of KO CAR-T cellsAbstract 131 Figure 4In vitro cytotoxicity of KO CAR-T cellsAbstract 131 Figure 5In vivo activity of KO CAR-T cellsConclusionsThese results indicate that KO of our target PTRs may improve the potency of CAR-T cells in solid tumors and may have important implications on the development of effective solid-tumor cell therapies.ReferencesJE Wherry and M Kurachi, Molecular and cellular insights into T cell exhaustion, Nature Reviews Immunology 2015;15:486–499.EW Weber, et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 2021;372:6537.S Kuramitsu et al. Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment. Cell, in revision.BD Choi et al, CRISPR-Cas9 disruption of PD-1 enhances activity of university EGFRvIII CAR T cells in a preclinical model of human glioblastoma. Journal for ImmunoTherapy of Cancer 2019;7:304.RC Lynn et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 2019;576:293–300.LJ Rupp et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific Reports 2017;7:737.
To evaluate the cost-effectiveness of nonoperative management, primary SLAP repair, and primary biceps tenodesis for the treatment of symptomatic isolated type II SLAP tear.
A microsimulation Markov ...model was constructed to compare 3 strategies for middle-aged patients with symptomatic type II SLAP tears: SLAP repair, biceps tenodesis, or nonoperative management. A failed 6-month trial of nonoperative treatment was assumed. The principal outcome measure was the incremental cost-effectiveness ratio in 2017 U.S. dollars using a societal perspective over a 10-year time horizon. Treatment effectiveness was expressed in quality-adjusted life-years (QALY). Model results were compared with estimates from the published literature and were subjected to sensitivity analyses to evaluate robustness.
Primary biceps tenodesis compared with SLAP repair conferred an increased effectiveness of 0.06 QALY with cost savings of $1,766. Compared with nonoperative treatment, both biceps tenodesis and SLAP repair were cost-effective (incremental cost-effectiveness ratio values of $3,344/QALY gained and $4,289/QALY gained, respectively). Sensitivity analysis showed that biceps tenodesis was the preferred strategy in most simulations (52%); however, for SLAP repair to become cost-effective over biceps tenodesis, its probability of failure would have to be lower than 2.7% or the cost of biceps tenodesis would have to be higher than $14,644.
When compared with primary SLAP repair and nonoperative treatment, primary biceps tenodesis is the most cost-effective treatment strategy for type II SLAP tears in middle-aged patients. Primary biceps tenodesis offers increased effectiveness when compared with both primary SLAP repair and nonoperative treatment and lower costs than primary SLAP repair.
Level III, economic decision analysis.
BackgroundThere is limited literature evaluating the impact of isolated cannabis use on outcomes for patients following spinal surgery. This study sought to compare 90-day complication, 90-day ...readmission, as well as 2-year revision rates between baseline cannabis users and non-users following thoracolumbar spinal fusion (TLF) for adult spinal deformity (ASD). MethodsThe New York Statewide Planning and Research Cooperative System (SPARCS) database was queried between January 2009 and September 2013 to identify all patients who underwent TLF for ASD. Inclusion criteria were age ≥18 years and either minimum 90-day (for complications and readmissions) or 2-year (for revisions) follow-up surveillance. Cohorts were created and propensity score-matched based on presence or absence of isolated baseline cannabis use. Baseline demographics, hospital-related parameters, 90-day complications and readmissions, and two-year revisions were retrieved. Multivariate binary stepwise logistic regression identified independent outcome predictors. Results704 patients were identified (n=352 each), with comparable age, sex, race, primary insurance, Charlson/Deyo scores, surgical approach, and levels fused between cohorts (all, p>0.05). Cannabis users (versus non-users) incurred lower 90-day overall and medical complication rates (2.4% vs. 4.8%, p=0.013; 2.0% vs. 4.1%, p=0.018). Cohorts had otherwise comparable complication, revision, and readmission rates (p>0.05). Baseline cannabis use was associated with a lower risk of 90-day medical complications (OR=0.47, p=0.005). Isolated baseline cannabis use was not associated with 90-day surgical complications and readmissions, or two-year revisions. ConclusionIsolated baseline cannabis use, in the absence of any other diagnosed substance abuse disorders, was not associated with increased odds of 90-day surgical complications or readmissions or two-year revisions, though its use was associated with reduced odds of 90-day medical complications when compared to non-users undergoing TLF for ASD. Further investigations are warranted to identify the physiologic mechanisms underlying these findings. Level of Evidence: III.
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