Implementation of a Stereoscopic Camera System for Clinical Electron Simulation and Treatment Planning.

PURPOSE: A 3-dimensinal (3D) stereoscopic camera system developed by .decimal was commissioned and implemented into the clinic to improve the efficiency of clinical electron simulations. Capabilities of the camera allowed simulations to be moved from the treatment vault into any room with a flat surface that could accommodate patient positioning devices, eliminating the need for clinical patient setup timeslots on the treatment machine. This work describes the process used for these simulations and compares the treatment parameters determined by the system to those used in delivery. METHODS AND MATERIALS: The Decimal3D scanner workflow consisted of: scanning the patient surface; contouring the treatment area; determining gantry, couch, collimator, and source-to-surface distance (SSD) parameters for en face entry of the beam with sufficient clearance at the machine; and ordering custom electron cutouts when needed. Transparencies showing the projection of in-house library cutouts at various clinical SSDs were created to assist in choosing an appropriate library cutout. Data from 73 treatment sites were analyzed to evaluate the accuracy of the scanner-determined beam parameters for each treatment delivery. RESULTS: Clinical electron simulations for 73 treatment sites, predominately keloids, were transitioned out of the linear accelerator (LINAC) vault using the new workflow. For all patients, gantry, collimator, and couch parameters, along with SSD and cone size, were determined using the Decimal3D scanner with 57% of simulations using library cutouts. Tolerance tables for patient setup were updated to allow differences of 10, 20, and 5° for gantry, collimator, and couch, respectively. Approximately 7% of fractions (N = 181 total fractions) were set up outside of the tolerance table based on physician direction during treatment. This reflects physician preference to adjust the LINAC rather than patient position during treatment setup. No scanner-derived plan was untreatable because of cutout shape inaccuracy or clearance issues. CONCLUSIONS: Clinical electron simulations were successfully transitioned out of the LINAC vault using the Decimal3D scanner without loss of setup accuracy, as measured through machine parameter determination and electron cutout shape.

The Role of Radiation Therapy in Adult and Pediatric Keloid Management: A National Survey of Radiation Oncologists.

INTRODUCTION: Radiation therapy is a promising modality for treating keloids after surgical excision. However, it is currently not standard practice among physicians because of concern surrounding the risk of radiation-induced secondary cancers, especially among pediatric patients. There is minimal research assessing the complications for radiation therapy in keloid management. AIM: The goal of this study was to determine radiation oncologists' perspectives about the utility and appropriateness of radiation therapy for keloid management in both adult and pediatric patients. This study also aimed to characterize radiation modality, dose, fractionation, and secondary complications observed by providers. METHODS: An electronic survey was delivered to 3102 members of the American Society for Radiation Oncology. The survey subjects were radiation oncologists who are currently practicing in the United States. Rates of responses were analyzed. RESULTS: A total of 114 responses from practicing radiation oncologists were received. Of these, 113 providers (99.1%) supported radiation therapy for keloid management in adults, whereas only 54.9% supported radiation therapy for pediatric patients. Of 101 providers that treated adults in the past year, the majority used external beam: electrons (84.2%), applied 3 fraction regimens (54.4%), and delivered radiation within 24 hours postexcision (45.5%). In pediatric patients, only 42 providers reported treating at least 1 patient. The majority used electron beam radiation (76.2%), applied 3 faction regimens (65%), and delivered radiation on the same day of keloid excision (50.0%) The main concern when treating pediatric patients were risk of secondary malignancy (92.1%). CONCLUSION: Although radiation therapy appears to be a widely accepted adjuvant treatment option for adults with keloids, the use of radiation therapy for pediatric patients is less widely accepted because of concerns regarding secondary malignancy. The findings suggest additional studies need to be carried out to assess the risk of those complications.

COVID vaccine-associated myocarditis in an 8-year-old patient.

COVID vaccine-associated myocarditis was first identified in March 2021. There have been numerous case reports that detail the clinical course of paediatric patients older than age 12 with COVID vaccine-associated myocarditis. There are still very few reports of children between the ages of 5 and 11 with COVID vaccine-associated myocarditis. We present an 8 year- old with COVID vaccine-associated myocarditis after his second vaccination against SARS-CoV-2.

Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature.

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

Radiation therapy modalities for keloid management: A critical review.

OBJECTIVE: To provide a critical overview of current radiation modalities for keloid management. BACKGROUND: Despite multimodal therapies, keloids that can develop following injury are poorly controlled. A number of studies have suggested that post-excisional radiation therapy can reduce rates of keloid recurrence. However, existing reports span multiple radiation modalities, including brachytherapy, electron beam radiation, and photon radiation. In this review, we describe the advantages and disadvantages of commonly used radiation techniques and highlight their efficacy in keloid management. RESULTS: Electron beam radiation and high-dose rate brachytherapy are the two most commonly used modalities for adjuvant radiotherapeutic management of keloids and can provide effective keloid control but may be suited for different kinds of keloid growth patterns. Increasing biologically equivalent dose (BED) likely improves rates of control, though the clinical significance of this finding remains to be elucidated. Though radiation treatments are associated with acute and chronic side effects, the risk of developing a secondary malignancy is minimal. CONCLUSIONS: While radiation therapy is a promising modality for treating keloids, more studies of a prospective, randomized nature are needed to standardize its utility.

Chronic anal pain: A review of causes, diagnosis, and treatment.

Chronic anal pain is difficult to diagnose and treat, especially with no obvious anorectal cause apparent on clinical examination. This review identifies 3 main diagnostic categories for chronic anal pain: local causes, functional anorectal pain, and neuropathic pain syndromes. Conditions covered within these categories include proctalgia fugax, levator ani syndrome, pudendal neuralgia, and coccygodynia. The signs, symptoms, relevant diagnostic tests, and main treatments for each condition are reviewed.

Substitution of the SERCA2 Cys674 reactive thiol accelerates atherosclerosis by inducing endoplasmic reticulum stress and inflammation.

BACKGROUND AND PURPOSE: The cysteine674 (C674) thiol of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 is easily and irreversibly oxidized under atherosclerotic conditions. However, the contribution of the C674 thiol redox status in the development of atherosclerosis remains unclear. Our goal was to elucidate the possible mechanism involved. EXPERIMENTAL APPROACH: Heterozygous SERCA2 C674S knock-in mice in which half of the C674 was substituted by serine (S674) were used to mimic the removal of the reactive C674 thiol, which occurs under pathological conditions. Bone marrow-derived macrophages (BMDMs) and cardiac endothelial cells (ECs) were used for intracellular Ca2+ , macrophage adhesion, and protein expression analysis. The whole aorta and aortic root were isolated for histological analysis. KEY RESULTS: Cell culture studies suggest the partial substitution of SERCA2 C674 increased intracellular Ca2+ levels and induced ER stress in both BMDMs and ECs. The release of proinflammatory factors and macrophage adhesion increased in SKI BMDMs. In ECs, overexpression of S674 induced endothelial inflammation and promoted macrophage recruitment. SKI mice developed more severe atherosclerotic plaque and macrophage accumulation. Additionally, 4-phenyl butyric acid, an ER stress inhibitor, suppressed ER stress and inflammatory responses in BMDMs and ECs, and alleviated atherosclerosis in SKI mice. CONCLUSIONS AND IMPLICATIONS: The substitution of SERCA2 C674 thiol accelerates the development of atherosclerosis by inducing ER stress and inflammation. Our findings highlight the importance of SERCA2 C674 redox state in the context of atherosclerosis and open up a novel therapeutic strategy to combat atherosclerosis.

The role of microvesicles as biomarkers in the screening of colorectal neoplasm.

BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer death worldwide. The role of circulating microvesicles as a screening tool is a novel, yet effective approach that warrants prioritised research. METHODS: In a two-gate diagnostic accuracy study, 35 patients with benign colorectal polyps (BCRP) (n = 16) and colorectal cancer (CRC) (n = 19) were compared to 17 age-matched healthy controls. Total annexin-V positive microvesicles and sub-populations positive for selected biomarkers relevant to bowel neoplasm were evaluated in patients' plasma using flow cytometry. Statistical methods including factor analysis utilising two component factors were performed to obtain optimal diagnostic accuracy of microvesicles in identifying patients with colorectal neoplasms. RESULTS: Total plasma microvesicles, and sub-populations positive for CD31, CD42a, CD31+/CD42a-, EPHB2, ICAM and LGR5 (component factor-1) were able to identify patients with BCRP and CRC with a receiver operator curve (AUC) accuracy of a 100% (95% CI: 100%-100%) and 95% (95% CI: 88%-100%), respectively. To identify patients with BCRP, a cut-off point value of component factor-1761 microvesicles/µl demonstrated a 100% sensitivity, specificity and negative predictive value (NPV) and a 93% positive predictive value (PPV). To identify patients with CRC, a cut-off value of component factor-1 3 439 microvesicles/µl demonstrated a 100% sensitivity, specificity and NPV and a 65% PPV. CEA+ microvesicles sub-population were significantly (p < 0.02) higher in CRC in comparison to BCRP. CONCLUSIONS: Microvesicles as biomarkers for the early and accurate detection of CRC is a simple and effective tool that yields a potential breakthrough in clinical management.

Radiofrequency ablation using a novel insulated-tip ablation catheter can create uniform lesions comparable in size to conventional irrigated ablation catheters while using a fraction of the energy and irrigation.

INTRODUCTION: During radiofrequency ablation (RFA) using conventional RFA catheters (RFC), ~90% of the energy dissipates into the bloodstream/surrounding tissue. We hypothesized that a novel insulated-tip ablation catheter (SMT) capable of blocking the radiofrequency path may focus most of the energy into the targeted tissue while utilizing reduced power and irrigation. METHODS: This study evaluated the outcomes of RFA using SMT versus an RFC in silico, ex vivo, and in vivo. Radiofrequency applications were delivered over porcine myocardium (ex vivo) and porcine thigh muscle preparations superfused with heparinized blood (in vivo). Altogether, 274 radiofrequency applications were delivered using SMT (4-15 W, 2 or 20 ml/min) and 74 applications using RFC (30 W, 30 ml/min). RESULTS: RFA using SMT proved capable of directing 66.8% of the radiofrequency energy into the targeted tissue. Accordingly, low power-low irrigation RFA using SMT (8-12 W, 2 ml/min) yielded lesion sizes comparable with RFC, whereas high power-high irrigation (15 W, 20 ml/min) RFA with SMT yielded lesions larger than RFC (p < .05). Although SMT was associated with greater impedance drops ex vivo and in vivo, ablation using RFC was associated with increased charring/steam pop/tissue cavitation (p < .05). Lastly, lesions created with SMT were more homogeneous than RFC (p < .001). CONCLUSION: Low power-low irrigation (8-12 W, 2 ml/min) RFA using the novel SMT ablation catheter can create more uniform, but comparable-sized lesions as RFC with reduced charring/steam pop/tissue cavitation. High power-high irrigation (15 W, 20 ml/min) RFA with SMT yields lesions larger than RFC.

Recommendations for the application and follow-up of quality controls in medical laboratories.

This is a translation of the paper "Recommendations for the application and follow-up of quality controls in medical biology laboratories" published in French in the journal Annales de Biologie Clinique (Recommandations pour la mise en place et le suivi des contrôles de qualité dans les laboratoires de biologie médicale. Ann Biol Clin (Paris). 2019;77:577-97.). The recommendations proposed in this document are the result of work conducted jointly by the Network of Accredited Medical Laboratories (LABAC), the French Society of Medical Biology (SFBC) and the Federation of Associations for External Quality Assessment (FAEEQ). The different steps of the implementation of quality controls, based on a risk analysis, are described. The changes of reagent or internal quality control (IQC) materials batches, the action to be taken in case of non-conform IQC results, the choice of external quality assessment (EQA) scheme and interpretation of their results as well as the new issue of analyses performed on several automatic systems available in the same laboratory are discussed. Finally, the concept of measurement uncertainty, the robustness of the methods as well as the specificities of near-patient testing and rapid tests are described. These recommendations cannot apply for all cases we can find in medical laboratories. The implementation of an objective alternative strategy, supported with documented evidence, might be equally considered.

BCL11B Regulates Arterial Stiffness and Related Target Organ Damage.

[Figure: see text].

Use of the inverse solution guidance algorithm method for RF ablation catheter guidance.

INTRODUCTION: We previously introduced the inverse solution guidance algorithm (ISGA) methodology using a Single Equivalent Moving Dipole model of cardiac electrical activity to localize both the exit site of a re-entrant circuit and the tip of a radiofrequency (RF) ablation catheter. The purpose of this study was to investigate the use of ISGA for ablation catheter guidance in an animal model. METHODS: Ventricular tachycardia (VT) was simulated by rapid ventricular pacing at a target site in eleven Yorkshire swine. The ablation target was established using three different techniques: a pacing lead placed into the ventricular wall at the mid-myocardial level (Type-1), an intracardiac mapping catheter (Type-2), and an RF ablation catheter placed at a random position on the endocardial surface (Type-3). In each experiment, one operator placed the catheter/pacing lead at the target location, while another used the ISGA system to manipulate the RF ablation catheter starting from a random ventricular location to locate the target. RESULTS: The average localization error of the RF ablation catheter tip was 0.31 ± 0.08 cm. After analyzing approximately 35 cardiac cycles of simulated VT, the ISGA system's accuracy in locating the target was 0.4 cm after four catheter movements in the Type-1 experiment, 0.48 cm after six movements in the Type-2 experiment, and 0.67 cm after seven movements in the Type-3 experiment. CONCLUSION: We demonstrated the feasibility of using the ISGA method to guide an ablation catheter to the origin of a VT focus by analyzing a few beats of body surface potentials without electro-anatomic mapping.

Inflammation and fibrosis in Crohn's disease: location-matched histological correlation of small bowel ultrasound features.

PURPOSE: To evaluate the utility of mural and extramural sonographic features of Crohn's Disease as potential imaging biomarkers of inflammation and fibrosis against whole-mount histological sections. METHODS: Twelve Crohn's disease patients (Mean age 35(25-69), 7 males) underwent small bowel ultrasound prior to small bowel resection. Two radiologists in consensus graded multiple parameters including mural, mucosal and submucosal thickness, submucosal/mesenteric echogenicity and clarity and mural Doppler signal in 50 selected bowel cross-sections. Matching with histological sampling sites was facilitated via scanning of the resected specimen. A histopathologist scored acute and chronic inflammation, and fibrosis (using histological scoring systems) following analysis of whole mount block sections. The association between sonographic observations and histopathological scores was examined via univariable and multivariable analysis. RESULTS: In univariate analyses, bowel wall thickness (regression co-efficient and 95% CI 0.8 (0.3, 1.3) p = 0.001), mesenteric fat echogenicity (8.7(3.0, 14.5) p = 0.005), submucosal layer thickness (7.4(1.2, 13.5) p = 0.02), submucosal layer clarity (4.4(0.6, 8.2) p = 0.02) and mucosal layer thickness (4.6(1.8, 7.4) p = 0.001) were all significantly associated with acute inflammation. Mesenteric fat echogenicity (674(8.67, 52404) p = 0.009), submucosal layer thickness (79.9(2.16, 2951) p = 0.02) and mucosal layer thickness (13.6(1.54, 121) p = 0.02) were significantly associated with chronic inflammation. Submucosal layer echogenicity (p = 0.03), clarity (25.0(1.76, 356) p = 0.02) and mucosal layer thickness (53.8(3.19, 908) p = 0.006) were significantly associated with fibrosis. In multivariate analyses, wall and mucosal thickness remained significantly associated with acute inflammation (p = 0.02), mesenteric fat echogenicity with chronic inflammation (p = 0.009) and mucosal thickness (p = 0.006) with fibrosis. CONCLUSION: Multiple sonographic parameters are associated with histological phenotypes in Crohn's disease although there is overlap between ultrasonic stigmata of acute inflammation, chronic inflammation and fibrosis.

Redox-Resistant SERCA [Sarco(endo)plasmic Reticulum Calcium ATPase] Attenuates Oxidant-Stimulated Mitochondrial Calcium and Apoptosis in Cardiac Myocytes and Pressure Overload-Induced Myocardial Failure in Mice.

BACKGROUND: SERCA [sarco(endo)plasmic reticulum calcium ATPase] is regulated by oxidative posttranslational modifications at cysteine 674 (C674). Because sarcoplasmic reticulum (SR) calcium has been shown to play a critical role in mediating mitochondrial dysfunction in response to reactive oxygen species, we hypothesized that SERCA oxidation at C674 would modulate the effects of reactive oxygen species on mitochondrial calcium and mitochondria-dependent apoptosis in cardiac myocytes. METHODS: Adult rat ventricular myocytes expressing wild-type SERCA2b or a redox-insensitive mutant in which C674 is replaced by serine (C674S) were exposed to H2O2 (100 µmol/Lµ). Free mitochondrial calcium concentration was measured in adult rat ventricular myocytes with a genetically targeted fluorescent probe, and SR calcium content was assessed by measuring caffeine-stimulated release. Mice with heterozygous knock-in of the SERCA C674S mutation were subjected to chronic ascending aortic constriction. RESULTS: In adult rat ventricular myocytes expressing wild-type SERCA, H2O2 caused a 25% increase in mitochondrial calcium concentration that was associated with a 50% decrease in SR calcium content, both of which were prevented by the ryanodine receptor inhibitor tetracaine. In cells expressing the C674S mutant, basal SR calcium content was decreased by 31% and the H2O2-stimulated rise in mitochondrial calcium concentration was attenuated by 40%. In wild-type cells, H2O2 caused cytochrome c release and apoptosis, both of which were prevented in C674S-expressing cells. In myocytes from SERCA knock-in mice, basal SERCA activity and SR calcium content were decreased. To test the effect of C674 oxidation on apoptosis in vivo, SERCA knock-in mice were subjected to chronic ascending aortic constriction. In wild-type mice, ascending aortic constriction caused myocyte apoptosis, LV dilation, and systolic failure, all of which were inhibited in SERCA knock-in mice. CONCLUSIONS: Redox activation of SERCA C674 regulates basal SR calcium content, thereby mediating the pathologic reactive oxygen species-stimulated rise in mitochondrial calcium required for myocyte apoptosis and myocardial failure.

Comparison of cardiovascular parameter estimation methods using swine data.

In this study, new and existing methods of estimating stroke volume, cardiac output and total peripheral resistance from analysis of the arterial blood pressure waveform were tested over a wide range of conditions. These pulse contour analysis methods (PCMs) were applied to data obtained in six swine during infusion of volume, phenylephrine, dobutamine, isoproterenol, esmolol and nitroglycerine as well as during progressive hemorrhage. Performance of PCMs was compared using true end-ejection pressures as well as estimated end-ejection pressures. There was considerable overlap in the accuracies of the PCMs when using true end-ejection measures. However, for perhaps the most clinically relevant condition, where radial artery pressure is the input, only Wesseling's Corrected Impedance method and the Kouchoukos Correction method achieved statistically superior results. We introduced a method of estimating end-ejection by determining when the systolic pressure dropped to a value equal to the sum of the end-diastolic pressure plus a fraction of the pulse pressure. The most accurate estimation of end-ejection was obtained when that fraction was set to 60% for the central arterial pressure and to 50% for the femoral and radial arterial pressures. When the estimated end-ejection measures were used for the PCMs that depend on end-ejection measures and when radial artery pressure was used as the input, only Wesseling's Corrected Impedance method and the modified Herd's method achieved statistically superior results. This study provides a systematic comparison of multiple PCMs' ability to estimate stroke volume, cardiac output, and total peripheral resistance and introduces a new method of estimating end-systole.

Accuracy of cardiac ablation catheter guidance by means of a single equivalent moving dipole inverse algorithm to identify sites of origin of cardiac electrical activation.

We have developed a system that could potentially be used to identify the site of origin of ventricular tachycardia (VT) and to guide a catheter to that site to deliver radio-frequency ablation therapy. This system employs the Inverse Solution Guidance Algorithm based upon Single Equivalent Moving Dipole (SEMD) localization method. The system was evaluated in in vivo swine experiments. Arrays consisting of 9 or 16 bipolar epicardial electrodes and an additional mid-myocardial pacing lead were sutured to each ventricle. Focal tachycardia was simulated by applying pacing pulses to each epicardial electrode at multiple pacing rates during breath hold at the end-expiration phase. Surface potentials were recorded from 64 surface electrodes and then analyzed using the SEMD method to localize the position of the pacing electrodes. We found a close correlation between the locations of the pacing electrodes as measured in computational and real spaces. The reproducibility error of the SEMD estimation of electrode location was 0.21 ± 0.07 cm. The vectors between every pair of bipolar electrodes were computed in computational and real spaces. At 120 bpm, the lengths of the vectors in the computational and real space had a 95% correlation. Computational space vectors were used in catheter guidance simulations which showed that this method could reduce the distance between the real space locations of the emulated catheter tip and the emulated arrhythmia origin site by approximately 72% with each movement. We have demonstrated the feasibility of using our system to guide a catheter to the site of the emulated VT origin.

Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice.

Glutaredoxin-1 (Glrx) is a small cytosolic enzyme that removes S-glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription. Although Glrx up-regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell-specific Glrx overexpression remained unknown. Here, we examined the role of EC-specific Glrx up-regulation in distinct models of angiogenesis; namely, hind limb ischemia and tumor angiogenesis. EC-specific Glrx transgenic (EC-Glrx TG) overexpression in mice significantly impaired EC migration in Matrigel implants and hind limb revascularization after femoral artery ligation. Additionally, ECs migrated less into subcutaneously implanted B16F0 melanoma tumors as assessed by decreased staining of EC markers. Despite reduced angiogenesis, EC-Glrx TG mice unexpectedly developed larger tumors compared with control mice. EC-Glrx TG mice showed higher levels of VEGF-A in the tumors, indicating hypoxia, which may stimulate tumor cells to form vascular channels without EC, referred to as vasculogenic mimicry. These data suggest that impaired ischemic vascularization does not necessarily associate with suppression of tumor growth, and that antiangiogenic therapies may be ineffective for melanoma tumors because of their ability to implement vasculogenic mimicry during hypoxia.-Yura, Y., Chong, B. S. H., Johnson, R. D., Watanabe, Y., Tsukahara, Y., Ferran, B., Murdoch, C. E., Behring, J. B., McComb, M. E., Costello, C. E., Janssen-Heininger, Y. M. W., Cohen, R. A., Bachschmid, M. M., Matsui, R. Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice.