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Background Immune checkpoint inhibitors (ICIs) are standard treatments for advanced non-small cell lung cancer and have expanded use in small cell lung cancer. Although generally better tolerated than traditional chemotherapy, immune-related adverse events, such as immune checkpoint inhibitor-related pneumonitis (ICI-P), remain poorly understood toxicities that limit ICI treatment and can result in considerable morbidity. In this retrospective case-control study, we assessed a lung cancer cohort to identify ICI-P risk factors. Research Question What are the risk factors, clinical presentations, radiographic findings, and outcomes for ICI-P in a real-world lung cancer cohort? Do chronic pulmonary diseases confer increased risk for ICI-P? Study Design and Methods Medical records from lung cancer patients receiving nivolumab, pembrolizumab, or combination ipilimumab and nivolumab at six centers in North Carolina were reviewed (January 2004-July 2017). Patients with ICI-P and control participants were characterized, and logistic regression was used to assess for ICI-P risk factors. Results Three hundred fifteen lung cancer patients who predominantly received nivolumab (76.5%) or pembrolizumab (22%) were included. The incidence of ICI-P was 9.5%, with a median time to diagnosis of 52.5 days. Most patients with ICI-P had cases of high severity, and eight patients (27%) died with ongoing ICI-P treatment. Development of ICI-P was independently associated with the presence of baseline fibrosis on chest CT scan (adjusted OR [aOR], 6.61; 95% CI, 2.48-17.7), a composite measure of obstructive lung disease (aOR, 2.79; 95% CI, 1.07-7.29), and treatment with pembrolizumab (aOR, 2.57; 95% CI, 1.08-6.11). Interpretation In this cohort, ICI-P was more common and severe than previously reported and carried an unexpectedly high mortality rate. Risk for ICI-P was shown to be independently associated with several chronic pulmonary diseases, which may account for the higher incidence of ICI-P in patients with lung cancer.

Complement is known to play a role in ischemia and reperfusion injury (IRI). A general paradigm is that complement is activated by self-reactive natural IgM antibodies (nAbs), after they engage postischemic neoepitopes. However, a role for nAbs in lung transplantation (LTx) has not been explored. Using mouse models of LTx, we investigated the role of two postischemic neoepitopes, modified annexin IV (B4) and a subset of phospholipids (C2), in LTx. Antibody deficient Rag1−/−recipient mice were protected from LTx IRI. Reconstitution with either B4 or C2nAb restored IRI, with C2 significantly more effective than B4 nAb. Based on these information, we developed/ characterized a novel complement inhibitor composed of single-chain antibody (scFv) derived from the C2 nAb linked to Crry (C2scFv-Crry), a murine inhibitor of C3 activation. Using an allogeneic LTx, in which recipients contain a full nAb repertoire, C2scFv-Crry targeted to the LTx, inhibited IRI, and delayed acute rejection. Finally, we demonstrate the expression of the C2 neoepitope in human donor lungs, highlighting the translational potential of this approach.

Background Diffusion MRI estimates of the apparent diffusion coefficient (ADC) have been shown to be useful in predicting treatment response in patients with glioblastoma (GBM), with ADC elevations indicating tumor cell death. We aimed to investigate whether the ADC values measured before and after treatment with immune checkpoint inhibitors (ICIs) and the changes in these ADC values could predict overall survival (OS) in patients with recurrent IDH wild-type GBM. Methods Forty-four patients who met the following inclusion criteria were included in this retrospective study: (i) diagnosed with recurrent IDH wild-type GBM and treated with either pembrolizumab or nivolumab and (ii) availability of diffusion data on pre- and post-ICI MRI. Tumor volume and the median relative ADC (rADC) with respect to the normal-appearing white matter within the enhancing tumor were calculated. Results Median OS among all patients was 8.1 months (range, 1.0–22.5 months). Log-rank test revealed that higher post-treatment rADC was associated with a significantly longer OS (median, 10.3 months for rADC ≥ 1.63 versus 6.1 months for rADC < 1.63; P = .02), whereas tumor volume, pretreatment rADC, and changes in rADC after treatment were not significantly associated with OS. Cox regression analysis revealed that post-treatment rADC significantly influenced OS (P = .02, univariate analysis), even after controlling for age and sex (P =.01, multivariate analysis), and additionally controlling for surgery after ICI treatment (P = .045, multivariate analysis). Conclusions Elevated post-treatment rADC may be an early imaging biomarker for OS benefits in GBM patients receiving ICI treatment.

Objective: Aim of the present study was the optimization of the sustained release (SR) layer of isosorbide dinitrate (ISDN) 40 mg and compressed with the immediate-release (IR) layer of hydralazine hydrochloride (HHC) 25 mg to decrease the dosing frequency and development of a novel b. i. d dosage form. Methods: Drug excipients compatibility study was carried out by FT-IR and a preliminary study was conducted for screening of polymer. The amount of HPMC K100M (X1) and the amount of Polyoxtm WSR303 (X2) were chosen as independent variables in 32full factorial designs. While % cumulative drug releases at 1 h (Q1) (Y1), % cumulative drug release at 2 h (Q2) (Y2), % cumulative drug release at 4 h (Q4) (Y3) and % cumulative drug release at 6 h (Q6) (Y4), were taken as dependent variables and statistically evaluation by using sigma plot 13.0. In the present study, according to the U. S. P. 2007 the following constraints were used for the selection of an optimized batch: Q1=15% to 30%, Q2=50% to 70%, Q4=65% to 85% and Q6>75%. To validate the evolved mathematical models, a checkpoint batch was selected from its desirability value. Results: FT-IR spectra show that the drug and excipients were compatible with each other. The calculated F values found for Q1, Q2, Q4, and Q6 were 084.583, 038.188, 057.719, and 118.396, respectively. All Calculated F values are greater than the tabulated value for all dependent variables. Prepared checkpoint batch selected from its desirability value 1 and it gives a 93.40±1.29 % drug release within 6 h. Conclusion: This bilayer formulation of anti-hypertensive drugs decreases the dosing frequency of HHC and ISDN.

Transjugular intrahepatic portosystemic shunt (TIPS) is used to treat complications of portal hypertension, such as ascites and variceal bleeding (VB). While liver doppler ultrasound (DUS) is used to assess TIPS patency, trans-shunt venography (TSV) is the gold standard.To determine the accuracy of DUS to assess TIPS dysfunction and for need for revision.Retrospective review of patients referred for TIPS revision from 2008-2021. Demographics, DUS parameters at baseline and at the DUS preceding TIPS revision, TSV data were collected. Receiver operating characteristics curves, sensitivity, specificity, performance for doppler to predict need for revision were performed. Univariate and multivariate analyses were used to predict clinical factors associated with need for TIPS revision.The cohort consisted of 89 patients with cirrhosis (64% men, 76% white, 31% alcohol as etiology); median age 59 years. Indication for initial TIPS were VB (41%), refractory ascites (51%), and other (8%). TIPS was revised in 44%. On univariate analysis, factors associated with need for TIPS revision were male (DUS has poor overall sensitivity and specificity in predicting need for TIPS revision. Non-invasive methods of predicting TIPS dysfunction are needed since those needing TIPS revision had better survival.

Background: There are limited data on differences in angiographic distribution of peripheral artery disease and endovascular revascularization strategies in patients presenting with intermittent claudication (IC) and critical limb ischemia (CLI). We aimed to compare anatomic features, treatment strategies, and clinical outcomes between patients with IC and CLI undergoing endovascular revascularization. Methods: We examined 3326 patients enrolled in the Excellence in Peripheral Artery Disease registry from 2006 to 2019 who were referred for endovascular intervention for IC (n=1983) or CLI (n=1343). The primary outcome was 1-year major adverse limb events, which included death, repeat target limb revascularization, or target limb amputation. Results: Patients with CLI were older and more likely to have diabetes and chronic kidney disease and less likely to receive optimal medical therapy compared with IC. Patients with IC had higher femoropopliteal artery interventions (IC 87% versus CLI 65%; P P P P P P =0.014). Major adverse limb event rates for patients with IC and CLI were 16% and 26%, respectively ( P Conclusions: Patients with IC and CLI have significant anatomic, lesion, and treatment differences with significantly higher mortality and adverse limb outcomes in CLI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01904851. Graphic Abstract: A graphic abstract is available for this article.

Esthesioneuroblastoma (ENB) is a rare malignant neoplasm of the olfactory epithelium with an estimated incidence of 0.4/million. It can directly extend along the cribriform plate in order to metastasize to the central nervous system. However, non-contiguous intracranial involvement without recurrence at the primary site is extremely uncommon. In this report, the authors review the literature and present a case of non-contiguous intracranial metastasis of ENB without recurrence at the primary site. To the best of our knowledge, this case presents the longest disease-free interval reported in the literature.A systematic review of literature was conducted in accordance with the PRISMA guidelines. Additionally, the presentation, surgical management, and post-operative outcomes of an 82-year-old female with non-contiguous intracranial metastasis of ENB after 19 years of remission are described.A total of 137 deduplicated works were identified after the search. Of these, 6 papers satisfied our inclusion criteria for our systematic review. Average age at presentation was 50.8 years (range: 26-66) and 52.6% of patients were female. A majority of cases achieved gross-total resection and received adjuvant radiotherapy for initial treatment. The median interval to intracranial metastasis was 6 years from the time of primary tumor presentation. The median overall survival from ENB recurrence with non-contiguous intracranial metastasis was 11.5 months.ENB is a highly recurrent tumor and harbors the potential to involve the intracranial space even years after remission. Intracranial involvement entails poor overall survival. Lifetime radiographic follow-up should be considered in all patients with ENB.

This study aimed to differentiate isocitrate dehydrogenase (IDH) mutation status with the voxel-wise clustering method of multiparametric magnetic resonance imaging (MRI) and to discover biological underpinnings of the clusters. A total of 69 patients with treatment-naïve diffuse glioma were scanned with pH-sensitive amine chemical exchange saturation transfer MRI, diffusion-weighted imaging, fluid-attenuated inversion recovery, and contrast-enhanced T1-weighted imaging at 3 T. An unsupervised two-level clustering approach was used for feature extraction from acquired images. The logarithmic ratio of the labels in each class within tumor regions was applied to a support vector machine to differentiate IDH status. The highest performance to predict IDH mutation status was found for 10-class clustering, with a mean area under the curve, accuracy, sensitivity, and specificity of 0.94, 0.91, 0.90, and 0.91, respectively. Targeted biopsies revealed that the tissues with labels 7–10 showed high expression levels of hypoxia-inducible factor 1-alpha, glucose transporter 3, and hexokinase 2, which are typical of IDH wild-type glioma, whereas those with labels 1 showed low expression of these proteins. In conclusion, A machine learning model successfully predicted the IDH mutation status of gliomas, and the resulting clusters properly reflected the metabolic status of the tumors.

Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.

Objective To analyze the trends in demographics and outcomes of patients presenting with traumatic brain injury by performing a retrospective database review of the Illinois Department of Public Health (IDPH) Trauma Registry. Methods We utilized the IDPH Trauma Registry to retrieve data on patients treated for traumatic brain injuries at our large, tertiary care hospital from 2004 to 2012, inclusive. From this data, logistic regression models were used to analyze and compare basic demographics such as age, sex, and clinical outcome. Results Three thousand and thirty-nine patients were analyzed with a mean age of 43 (standard deviation, 24) and a median age of 41 (interquartile range, 23 to 60). Over the study period, patients’ age increased steadily from 32 to 49 years. The percentage of female patients increased, from 16.4% to 27.5% over the last 4 years. Overall mortality was greater for males than females (22.1% vs. 17.3%; odds ratio [OR], 1.36; 95% confidence interval [CI], 1.10 to 1.68). Mortality decreased over the period (OR, 0.88; 95% CI, 0.85 to 0.91), with a greater decrease in females (OR, 0.84; 95% CI, 0.78 to 0.90) than in males (OR, 0.90; 95% CI, 0.86 to 0.94). Conclusion Although the age of patients presenting with traumatic brain injury is increasing substantially, the data suggests that overall mortality appears to be decreasing, and this decrease appears to be greater in females than in males. These changes in trends found in the IDPH Trauma Registry supports the importance for further analysis of other reliable public datasets to identify areas of future study.

INTRODUCTION AND OBJECTIVE:Cancer control, minimal complications and preservation of kidney function are all desirable outcomes of any procedure performed in patients with renal mass. Herein we int...

Background Hysterectomy for placenta accreta spectrum may be associated with urologic morbidity, including intentional or unintentional cystostomy, ureteral injury, and bladder fistula. Although previous retrospective studies have shown an association between placenta accreta spectrum and urologic morbidities, there is still a paucity of literature addressing these urologic complications. Objective We sought to report a systematic description of such morbidity and associated factors. Study Design This was a retrospective study of all histology-proven placenta accreta spectrum deliveries in an academic center between 2011 and 2020. Urologic morbidity was defined as the presence of at least one of the following: cystotomy, ureteral injury, or bladder fistula. Variables were reported as median (interquartile range) or number (percentage). Analyses were made using appropriate parametric and nonparametric tests. Multinomial regression analysis was performed to assess the association of adverse urologic events with the depth of placental invasion. Results In this study, 58 of 292 patients (19.9%) experienced urologic morbidity. Patients with urologic morbidity had a higher rate of placenta percreta (compared with placenta accreta and placenta increta) than those without such injuries. Preoperative ureteral stents were placed in 54 patients (93.1%) with and 146 patients (62.4%) without urologic injury (P=.003). After adjusting for confounding variables, multinomial regression analysis revealed that the odds of having adverse urologic events was 6.5 times higher in patients with placenta percreta than in patients with placenta accreta. Conclusion Greater depth of invasion in placenta accreta spectrum was associated with more frequent and severe adverse urologic events. Whether stent placement confers any protective benefit requires further investigation.

Recent advances in robotics promise a future where robots co-exist and collaborate with humans in unstructured environments, which will require frequent physical interactions where accurate tactile information will be crucial for performance and safety. This article describes the design, fabrication, modeling, and experimental validation of a soft-bodied tactile sensor that accurately measures the complete 3-D force vector for both normal and shear loading conditions. Our research considers the detection of changes in the magnetic field vector due to the motion of a miniature magnet in a soft substrate to measure normal and shear forces with high accuracy and bandwidth. The proposed sensor is a pyramid-shaped tactile unit with a tri-axis Hall element and a magnet embedded in a silicone rubber substrate. The non-linear mapping between the 3-D force vector and the Hall effect voltages is characterized by training a neural network. We validate the proposed soft force sensor over static and dynamic loading experiments and obtain a mean absolute error below 11.7 mN or 2.2% of the force range. These results were obtained for a soft force sensor prototype and loading conditions not included in the training process, indicating strong generalization of the model. To demonstrate its utility, the proposed sensor is used in a force-controlled pick-and-place experiment as a proof-of-concept case study.

IMPACT: Our work unveils a novel mechanism of ischemia repurfusion injury driven by pre-existing autoimmunity following lung transplant and a potential therapeutic strategy for blocking complement-dependent injury thereby reducing risk of lung transplant rejection. OBJECTIVES/GOALS: Our goal was to determine if pre-existing autoimmune autoantibodies, such as those resulting from cigarette smoke (CS), contribute to graft rejection in lung transplantation (LTx) and if autoreactive-mediated graft injury is complement-dependent. METHODS/STUDY POPULATION: For in vivo experiments, we utilized our emphysema mouse model. Briefly, eight-week-old C57BL/6J mice are exposed to 3R4F reference cigarette smoke 5 hours per day, 5 days a week for 6 months. Upon completion, cigarette smoked (CS) mice and control (NS) mice received syngeneic orthotopic left-lung transplant from age-matched C57BL/6J donors. To determine if pre-existing autoreactivity mediated graft injury was complement-dependent we treated CS-LTx mice with a novel, bifunctional complement inhibitor. Autoantibody levels were measured by ELISA and lung injury was assessed by blinded histopathological analyses. Complement inhibition was verified by immunofluorescence. RESULTS/ANTICIPATED RESULTS: We found that CS-exposure leads to production of autoreactive antibodies towards extracellular matrix (ECM) components and contributes to graft injury. Interestingly, LTx into CS exposed mice further increased de-novo ECM autoantibody development. Lastly, treatment with our novel, bifunctional complement inhibitor blocked autoantibody spreading and significantly reduced graft rejection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These data demonstrate that smoking induces pre-LTx autoreactivity to ECM proteins that promotes graft injury following LTx. Furthermore, complement inhibition reduces autoantibody production and protects the graft from injury.

Percutaneous left atrial appendage (LAA) occlusion is an emerging treatment option for patients with non-valvular atrial fibrillation who cannot tolerate oral anticoagulation. The Watchman device (Boston Scientific Corporation, Natick, MA, USA) is deployed at the ostium of the LAA, and an appropriately sized device is critical for successful occlusion. However, standardized imaging protocols for device sizing have not been established.We investigated the clinical utility of a standardized imaging protocol, with pre-procedural multi-detector cardiac computed tomography (MDCT), and intra-procedural transesophageal echocardiography (TEE), for Watchman device sizing.Patients who underwent Watchman device implantation between 2010 and 2016 at our center, and who had pre-procedural MDCT and intra-procedural TEE were included. MDCT measurements (CTmax, CTmin, CTmean), and TEE measurement (TEEmax) of the LAA ostium were determined for each case, and correlated with the final size of the Watchman device implanted. Demographic data and clinical outcomes were collected.The study included 80 patients (mean age: 75 ± 9.6 years; male: 68%; mean CHA2DS2-VASc score: 4.5 ± 1.4). CTmax of the LAA ostium correlated strongly with the final deployed Watchman device size (Spearman's rho: 0.81, p 0.001), while TEEmax of the LAA ostium showed only moderate correlation with the final deployed Watchman device size (Spearman's rho: 0.61, p 0.001). Implantation success rate was 100%. At a mean duration of follow-up of 197 days, there were no device-related complications (device embolization, cardiac perforation and pericardial tamponade). At follow-up, the vast majority of patients (76 patients; 95%) had either no or trivial (≤3 mm) residual peri-device leak on TEE.A standardized imaging protocol for assessment of Watchman device implantation incorporating pre-procedural MDCT and intra-procedural TEE, was associated with excellent procedural outcomes at a mean duration of follow-up of 197 days.

(a) Rapamycin nanotherapeutic pre-treatment improves tracheal allograft outcome after transplantation. (b) Nanotherapy reduces aortic allograft vasculopathy. (c) Dose dependency of the nanotherapy in aortic interposition allografts., Hypothermic preservation is the standard of care for storing organs prior to transplantation. Endothelial and epithelial injury associated with hypothermic storage causes downstream graft injury and, as such, the choice of an ideal donor organ preservation solution remains controversial. Cold storage solutions, by design, minimize cellular necrosis and optimize cellular osmotic potential, but do little to assuage immunological cell activation or immune cell priming post transplantation. Thus, here we explore the efficacy of our previously described novel Targeted Rapamycin Micelles (TRaM) as an additive to standard-of-care University of Wisconsin preservation solution as a means to alter the immunological microenvironment post transplantation using in vivo models of tracheal and aortic allograft transplantation. In all models of transplantation, grafts pre-treated with 100 ng mL–1 of TRaM augmented preservation solution ex vivo showed a significant inhibition of chronic rejection post-transplantation, as compared to UW augmented with free rapamycin at a ten-fold higher dose. Here, for the first time, we present a novel method of organ pretreatment using a nanotherapeutic-based cellular targeted delivery system that enables donor administration of rapamycin, at a ten-fold decreased dose during cold storage. Clinically, these pretreatment strategies may positively impact post-transplant outcomes and can be readily translated to clinical scenarios.

Objectives The primary aim of this study was to evaluate the quality of published dental clinical guidelines using the AGREE II instrument. Methods Online searching of a wide range of organisations (national and International) was undertaken to identify dental clinical practice guidelines published between 2000 and 2014. The quality of each included guideline was assessed in relation to the AGREE II instrument by four assessors independently. Inter-rater agreement was assessed. Descriptive statistics and both univariate and multivariate analyses were conducted. Results 162 guidelines were identified. The overall mean quality score was 51.9% (SD 13.3). There was variation in the reporting quality of individual domains with both Applicability (20.4%) and Editorial Independence (34.25%) poorly reported. Variation between the overall quality scores for guidelines produced by different dental specialities was evident. The quality of guidelines improved per publication year (β = 0.76, 95% CI: 0.26, 1.26, p = 0.003). Guidelines based on formal evidence (β = 19.94, 95% CI: 15.25, 24.64, p = 0.001) achieved higher quality scores. Conclusion Overall, the quality of clinical dental practice guidelines is suboptimal. There is variation in the overall quality, reporting of individual items and domains of the AGREE II instrument between different dental speciality clinical practice guidelines. Guidelines based on formal evidence achieved higher quality scores. Clinical significance Clinicians should be aware of the variation in the quality of dental clinical guidelines in particular related to methodological rigour. The use of formal evidence may be a useful indicator of their quality prior to their implementation.

Graphical abstract, Highlights • TEE is an essential imaging modality used in cardiac critical care units. • TEE enables guidance when placing and repositioning bicaval double-lumen catheters. • TEE is widely available, portable, and accurate in preventing CV emergencies.

A novel folic acid conjugated core-shell hybrid iron oxide-zinc oxide nanoparticle was developed for applications as a photosensitier (PS) in photodynamic therapy. Photodegradation studies on methylene blue demonstrated significantly enhanced photophysical properties of the produced nano-PSs, due to the charge recombination via electron trapping by dissolved Fe3+. A time and dose dependant toxicity associated with the nano-PSs was observed upon exposure to human epithelial colorectal adenocarcinoma (Caco-2) cells in the dark. UV irradiation of the synthesised nano-PSs resulted in a significant photo-killing effect with drastic reduction in Caco-2 cell viability to as low as 6%. Reduction in viability upon exposure was due fundamentally to cellular interactions with light irradiated PSs as the influence of radiation alone was subtracted. FA conjugation further enhanced the photo-killing effect.