Phosphate-Based Dechlorination of Electrorefiner Salt Waste using a Phosphoric Acid Precursor.

Electrochemical processing of spent nuclear fuel in molten chloride salts results in radioactive salt waste. Chlorine removal from the salt has been identified as an effective and efficient first step in the management of high-level waste. In this work, a simple salt was dechlorinated with a phosphoric acid phosphate precursor, resulting in a glassy dechlorinated product. The dechlorination efficacy was evaluated in air and argon environments. This work serves as an initial step to advance the Technological Readiness Level of H3PO4-based dechlorination step toward implementation of iron phosphate waste forms to immobilize electrochemical fuel reprocessing salt waste streams.

Shared and Distinct Genomics of Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Embolism.

RATIONALE: Chronic Thromboembolic Pulmonary Hypertension involves formation and non-resolution of thrombus, dysregulated inflammation, angiogenesis and the development of a small vessel vasculopathy. OBJECTIVES: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. METHODS: We conducted a genome-wide association study on 1907 European cases and 10363 European controls. We co-analysed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism and idiopathic pulmonary arterial hypertension. MEASUREMENTS AND MAIN RESULTS: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our co-analysis we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2 and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. CONCLUSIONS: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations to pulmonary embolism and to deep vein thrombosis.

Mutation detection in saliva from oral cancer patients.

OBJECTIVES: The incidence of head and neck squamous cell carcinoma (HNSCC) continues to increase and although advances have been made in treatment, it still has a poor overall survival with local relapse being common. Conventional imaging methods are not efficient at detecting recurrence at an early stage when still potentially curable. The aim of this study was to test the feasibility of using saliva to detect the presence of oral squamous cell carcinoma (OSCC) and to provide additional evidence for the potential of this approach. MATERIALS AND METHODS: Fresh tumor, whole blood and saliva were collected from patients with OSCC before treatment. Whole exome sequencing (WES) or gene panel sequencing of tumor DNA was performed to identify somatic mutations in tumors and to select genes for performing gene panel sequencing on saliva samples. RESULTS: The most commonly mutated genes identified in primary tumors by DNA sequencing were TP53 and FAT1. Gene panel sequencing of paired saliva samples detected tumor derived mutations in 9 of 11 (82%) patients. The mean variant allele frequency for the mutations detected in saliva was 0.025 (range 0.004 - 0.061). CONCLUSION: Somatic tumor mutations can be detected in saliva with high frequency in OSCC irrespective of site or stage of disease using a limited panel of genes. This work provides additional evidence for the suitability of using saliva as liquid biopsy in OSCC and has the potential to improve early detection of recurrence in OSCC. Trials are currently underway comparing this approach to standard imaging techniques.

Cross-Comparison of Inflammatory Skin Disease Transcriptomics Identifies PTEN as a Pathogenic Disease Classifier in Cutaneous Lupus Erythematosus.

Tissue transcriptomics is used to uncover molecular dysregulations underlying diseases. However, the majority of transcriptomics studies focus on single diseases with limited relevance for understanding the molecular relationship between diseases or for identifying disease-specific markers. In this study, we used a normalization approach to compare gene expression across nine inflammatory skin diseases. The normalized datasets were found to retain differential expression signals that allowed unsupervised disease clustering and identification of disease-specific gene signatures. Using the NS-Forest algorithm, we identified a minimal set of biomarkers and validated their use as diagnostic disease classifier. Among them, PTEN was identified as being a specific marker for cutaneous lupus erythematosus and found to be strongly expressed by lesional keratinocytes in association with pathogenic type I IFNs. In fact, PTEN facilitated the expression of IFN-ß and IFN-κ in keratinocytes by promoting activation and nuclear translocation of IRF3. Thus, cross-comparison of tissue transcriptomics is a valid strategy to establish a molecular disease classification and to identify pathogenic disease biomarkers.

Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria.

BACKGROUND: Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. OBJECTIVE: Our aim was to identify genomic loci at which common genetic variation influences urticaria susceptibility. METHODS: Genome-wide association studies of urticaria (including all subtypes) from 3 European cohorts (UK Biobank, FinnGen, and the Trøndelag Health Study [HUNT]) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified via electronic health care records from primary and/or secondary care. To identify putative causal variants and genes, statistical fine-mapping, colocalization, and interrogation of publicly available single-cell transcriptome sequencing resources were performed. RESULTS: Genome-wide significant associations (P < 5 × 10-8) were identified at 6 independent loci. These included 2 previously reported association signals at 1q44 and the human leucocyte antigen region on chromosome 6. Genes with expected or established roles in mast cell biology were associated with the 4 other genome-wide association signals (GCSAML, FCER1A, TPSAB1, and CBLB). Colocalization of association signals consistent with the presence of shared causal variants was observed between urticaria susceptibility and increased expression of GCSAML (posterior probability of colocalization [PPcoloc] = 0.89) and FCER1A (PPcoloc = 0.91) in skin. CONCLUSION: Common genetic variation influencing the risk of developing urticaria was identified at 6 genomic loci. The relationship between genes with roles in mast cell biology and several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.

Rheumatic Heart Disease in the Developing World.

Despite recent public policy initiatives, rheumatic heart disease (RHD) remains a major source of morbidity worldwide. Rheumatic heart disease occurs as a sequela of Streptococcus pyogenes (group A streptococcal [GAS]) infection in patients with genetic susceptibility. Strategies for prevention of RHD or progression of RHD include prevention of GAS infection with community initiatives, effective treatment of GAS infection, and secondary prophylaxis with intramuscular penicillin. The cardiac surgical community has attempted to improve the availability of surgery in RHD-endemic areas with some success, and operative techniques and outcomes of valve repair continue to improve, potentially offering patients a safer, more durable operation. Innovation offers hope for a more scalable solution with improved biomaterials and transcatheter delivery technology; however, cost remains a barrier.

Systematic review of deep learning image analyses for the diagnosis and monitoring of skin disease.

Skin diseases affect one-third of the global population, posing a major healthcare burden. Deep learning may optimise healthcare workflows through processing skin images via neural networks to make predictions. A focus of deep learning research is skin lesion triage to detect cancer, but this may not translate to the wider scope of >2000 other skin diseases. We searched for studies applying deep learning to skin images, excluding benign/malignant lesions (1/1/2000-23/6/2022, PROSPERO CRD42022309935). The primary outcome was accuracy of deep learning algorithms in disease diagnosis or severity assessment. We modified QUADAS-2 for quality assessment. Of 13,857 references identified, 64 were included. The most studied diseases were acne, psoriasis, eczema, rosacea, vitiligo, urticaria. Deep learning algorithms had high specificity and variable sensitivity in diagnosing these conditions. Accuracy of algorithms in diagnosing acne (median 94%, IQR 86-98; n = 11), rosacea (94%, 90-97; n = 4), eczema (93%, 90-99; n = 9) and psoriasis (89%, 78-92; n = 8) was high. Accuracy for grading severity was highest for psoriasis (range 93-100%, n = 2), eczema (88%, n = 1), and acne (67-86%, n = 4). However, 59 (92%) studies had high risk-of-bias judgements and 62 (97%) had high-level applicability concerns. Only 12 (19%) reported participant ethnicity/skin type. Twenty-four (37.5%) evaluated the algorithm in an independent dataset, clinical setting or prospectively. These data indicate potential of deep learning image analysis in diagnosing and monitoring common skin diseases. Current research has important methodological/reporting limitations. Real-world, prospectively-acquired image datasets with external validation/testing will advance deep learning beyond the current experimental phase towards clinically-useful tools to mitigate rising health and cost impacts of skin disease.

Optical modeling of the entire visual field of the eye.

Vision is rarely evaluated scientifically at very large visual angles, despite being used continuously in everyday life. Furthermore, raytrace calculations indicate that peripheral optical properties are different for a pseudophakic eye, and even though this is rarely noted by patients, it is probably the cause of bothersome "negative dysphotopsia." Simplified paraxial parameters that characterize the basic properties of phakic and pseudophakic eyes are collected together here as a baseline, and then raytracing is used to show that input angles of about 60°, which correspond to obstruction by the nose, eyebrow, and cheek, illuminate a retinal hemisphere. At larger angles in the temporal direction, the image with an intraocular lens (IOL) reaches a limit due to vignetting at about a 90° input angle to the optical axis, in comparison to 105° with the Gullstrand-Emsley eye model, and 109° for the most realistic gradient index crystalline lens model. Scaling the far peripheral vision region more accurately may lead to benefits relating to intraocular lenses, diseases of the peripheral retina, widefield fundus images, and myopia prevention.

Modulating Cortical Hemodynamic Activity in Parkinson's Disease Using Focal Transcranial Direct Current Stimulation: A Pilot Functional Near-infrared Spectroscopy Study.

Reduced thalamocortical facilitation of the motor cortex in PD leads to characteristic motor deficits such as bradykinesia. Recent research has highlighted improved motor function following tDCS, but a lack of neurophysiological evidence limits the progress of tDCS as an adjunctive therapy. Here, we tested the hypothesis that tDCS may modulate M1 hemodynamic activity in PD and healthy using functional near-infrared spectroscopy (fNIRS). In this randomized crossover experiment, fourteen PD and twelve healthy control participants attended three laboratory sessions and performed a regulated (3 Hz) right index finger tapping task before and after receiving tDCS. On each visit, participants received either anodal, cathodal, or sham tDCS applied over M1. Hemodynamic activity of M1 was quantified using fNIRS. Significant task related activity was observed in M1 and the inferior parietal lobe in PD and healthy (p < 0.05). PD additionally recruited the dorsal premotor cortex. During tDCS, while at rest, anodal and cathodal tDCS significantly increased the oxygenated hemoglobin concentration of M1 compared to sham (t62 = 4.09 and t62 = 4.25, respectively). Task related hemodynamic activity was unchanged following any tDCS intervention (p > 0.05). Task related hemodynamic activity of M1 is not modulated by tDCS in PD or healthy. During tDCS, both anodal and cathodal stimulation cause a significant increase of M1 oxygenation, the clinical significance of which remains to be clarified.

Central aortic versus axillary artery cannulation for aortic arch surgery.

Objective: Central aortic cannulation for aortic arch surgery has become more popular over the last decade; however, evidence comparing it with axillary artery cannulation remains equivocal. This study compares outcomes of patients who underwent axillary artery and central aortic cannulation for cardiopulmonary bypass during arch surgery. Methods: A retrospective review of 764 patients who underwent aortic arch surgery at our institution between 2005 and 2020 was performed. The primary outcome was failure to achieve uneventful recovery, defined as having experienced at least 1 of the following: in-hospital mortality, stroke, transient ischemic attack, bleeding requiring reoperation, prolonged ventilation, renal failure, mediastinitis, surgical site infection, and pacemaker or implantable cardiac defibrillator implantation. Propensity score matching was used to account for baseline differences across groups. A subgroup analysis of patients undergoing surgery for aneurysmal disease was performed. Results: Before matching, the aorta group had more urgent or emergency operations (P = .039), fewer root replacements (P < .001), and more aortic valve replacements (P < .001). After successful matching, there was no difference between the axillary and aorta groups in failure to achieve uneventful recovery, 33% versus 35% (P = .766), in-hospital mortality, 5.3% versus 5.3% (P = 1), or stroke, 8.3% versus 5.3% (P = .264). There were more surgical site infections in the axillary group, 4.8% versus 0.4% (P = .008). Similar results were seen in the aneurysm cohort with no differences in postoperative outcomes between groups. Conclusions: Aortic cannulation has a safety profile similar to that of axillary arterial cannulation in aortic arch surgery.

Clinical and electrocardiographic factors associated with adverse cardiovascular events in bupropion exposures.

INTRODUCTION: Bupropion toxicity can cause cardiogenic shock, ventricular dysrhythmias, and death. Clinical and electrocardiographic factors associated with adverse cardiovascular events in bupropion toxicity have not been well-studied. This study aimed to identify factors associated with adverse cardiovascular events in adult patients with isolated bupropion exposures. METHODS: This retrospective cohort study queried the National Poison Data System from 2019 through 2020. We included patients 20 years or older with acute or acute-on-chronic single-agent bupropion exposures evaluated in a healthcare facility. Exclusion criteria were confirmed non-exposure, withdrawal as a reason for exposure, lack of follow-up, documentation that exposure was probably not responsible for the effects, and missing data. The primary outcome was adverse cardiovascular events, defined as the presence of any of the following: vasopressor use, ventricular dysrhythmia, myocardial injury, or cardiac arrest. Independent variables were age, the intentionality of exposure, seizures, tachycardia, QRS widening, and QTc prolongation. Multivariable logistic regression was performed to test for independent associations between independent variables and adverse cardiovascular events. RESULTS: Of 4,640 patients included in the final analysis (56.7% female, 56.5% suspected suicidal intent), 68 (1.47%) experienced an adverse cardiovascular event. Age (odds ratio 1.03; 95% confidence intervals 1.02-1.05), single seizure (odds ratio 9.18; 95% confidence intervals 4.24-19.9) and complicated seizures (odds ratio 38.9; 95% confidence intervals 19.3-78.1), QRS widening (odds ratio 3.01; 95% confidence intervals 1.62-5.59), and QTc prolongation (odds ratio 1.76; 95% confidence intervals 1.00-3.10) were independently associated with adverse cardiovascular events. No patients with unintentional exposure experienced adverse cardiovascular events, prohibiting intentionality from inclusion in the regression model. In the post hoc subgroup analysis of intentional exposures, age, single and complicated seizures, and QRS widening remained independently associated with adverse cardiovascular events. CONCLUSIONS: Increasing age, seizures, QRS widening, and QTc prolongation were associated with adverse cardiovascular events in bupropion exposures. Adverse cardiovascular events did not occur in unintentional exposures. Further research is needed to develop screening tools and treatments for bupropion cardiotoxicity.

Sodium bicarbonate treatment for QRS widening in bupropion overdoses.

INTRODUCTION: Bupropion cardiotoxicity widens QRS complexes by inhibiting cardiac gap junctions. Sodium bicarbonate is the standard treatment for QRS widening from sodium channel blockade, but its effect on QRS widening in bupropion cardiotoxicity is not well-studied. METHODS: This is a retrospective cohort study of bupropion overdoses from 10 hospitals between January 2010 and June 2022. Patients with documented administration of sodium bicarbonate and QRS duration > 100 milliseconds on pre-bicarbonate electrocardiogram were included. Patients with no electrocardiogram within four hours of treatment or with baseline pre-overdose wide QRS and < 10 milliseconds widening from baseline were excluded. The primary outcome was a change in QRS duration between the pre-bicarbonate electrocardiogram and the first electrocardiogram after initial bicarbonate administration. Secondary outcomes included prevalence of post-bicarbonate QRS < 100 milliseconds, change in electrocardiogram intervals after total bicarbonate administration, and change in metabolic parameters and hemodynamics. Wilcoxon signed-rank testing was performed on the primary outcome. Linear regression modeling was performed to test for an association between change in QRS and bicarbonate dosing. RESULTS: Thirteen patients were included for final analysis. The median age was 32 years, and 54% were male. Six patients developed seizures; one developed ventricular tachycardia, and four received vasopressors. The median QRS and QTc pre-bicarbonate were 116 and 495 milliseconds, respectively. The median change in QRS duration was -2.0 milliseconds, which was not statistically significant (P = 0.42). The median bicarbonate dose administered before the first post-bicarbonate electrocardiogram was 100 milliequivalents. We did not identify an association between QRS change and bicarbonate dosing (P = 0.9, R-squared = 0.001). No patient had a QRS duration < 100 milliseconds after the initial bicarbonate dose. There was minimal change in QTc, electrolytes, heart rate, or blood pressure; alkalemia post-bicarbonate was achieved in eight patients. CONCLUSION: Sodium bicarbonate did not significantly decrease QRS duration in this small retrospective cohort of bupropion overdoses.

Focal length, EFL, and the eye.

The focal length is often called the effective focal length, or efl instead, and although this is acceptable for a lens in air, it is not otherwise correct. The eye is used as an example here for an optical system where the object is in air and the image is in fluid. Welford, Aberrations of Optical Systems (1986) has paraxial equations that are consistent with historical use while also clearly defining efl. These are based on power at a surface having to be the same for light traveling in both directions (n '/f '). The focal length f ' is the actual physical distance from the 2nd principal point to the paraxial focus, and the equivalent focal length, or efl, is the focal length divided by the image index (f '/n '). Separately, when the object is in air, the efl is shown to act at the nodal point, with the lens system represented by either an equivalent thin lens at the principal point with a focal length or a different equivalent thin lens in air at the nodal point with an efl. The rationale for using effective instead of equivalent for efl is unclear, but efl is used more as a symbol than as an acronym.

Intensive Care Interventions Among Children With Toxicologic Exposures to Cardiovascular Medications.

OBJECTIVES: Interventions requiring a PICU are rare in toxicologic exposures, but cardiovascular medications are high-risk exposures due to their hemodynamic effects. This study aimed to describe prevalence of and risk factors for PICU interventions among children exposed to cardiovascular medications. DESIGN: Secondary analysis of Toxicology Investigators Consortium Core Registry from January 2010 to March 2022. SETTING: International multicenter research network of 40 sites. PATIENTS: Patients 18 years old or younger with acute or acute-on-chronic toxicologic exposure to cardiovascular medications. Patients were excluded if exposed to noncardiovascular medications or if symptoms were documented as unlikely related to exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,091 patients in the final analysis, 195 (17.9%) received PICU intervention. One hundred fifty-seven (14.4%) received intensive hemodynamic interventions and 602 (55.2%) received intervention in general. Children less than 2 years old were less likely to receive PICU intervention (odds ratio [OR], 0.42; 95% CI, 0.20-0.86). Exposures to alpha-2 agonists (OR, 2.0; 95% CI, 1.11-3.72) and antiarrhythmics (OR, 4.26; 95% CI, 1.41-12.90) were associated with PICU intervention. In the sensitivity analysis removing atropine from the composite outcome PICU intervention, only exposures to calcium channel antagonists (OR, 2.12; 95% CI, 1.09-4.11) and antiarrhythmics (OR, 4.82; 95% CI, 1.57-14.81) were independently associated with PICU intervention. No independent association was identified between PICU intervention and gender, polypharmacy, intentionality or acuity of exposure, or the other medication classes studied. CONCLUSIONS: PICU interventions were uncommon but were associated with exposure to antiarrhythmic medications, calcium channel antagonists, and alpha-2 agonists. As demonstrated via sensitivity analysis, exact associations may depend on institutional definitions of PICU intervention. Children less than 2 years old are less likely to require PICU interventions. In equivocal cases, age and exposure to certain cardiovascular medication classes may be useful to guide appropriate disposition.

Anatomic considerations after commando double valve reconstruction: insights for future valve-in-valve therapies.

OBJECTIVES: The Commando technique for reconstruction of the aortomitral intervalvular fibrous body is effective to facilitate double valve surgery in cases of endocarditis or infiltrative calcification. The length of patch utilized in reconstruction of the intervalvular fibrous body has an important relationship to the geometry of the mitral valve (MV) and aortic valve (AV) and may impact on potential future valve-in-valve (VIV) therapy. Here we report anatomic measurements after Commando reconstruction in a small group of patients and analyse the impact of reconstruction techniques on transcatheter VIV therapies. METHODS: Seven patients from January 2018 to April 2022 who underwent double valve surgery with the Commando technique with postoperative computed tomography (CT) scans were identified. Computed tomographic reconstruction of the AV and MV was performed using 3mensio software and virtual transcatheter valve replacement was performed. Two of these patients who had preoperative imaging was analysed to assess the change in aortomitral geometry resulting from reconstruction. RESULTS: Measurements for each patient post-reconstruction are given in the table. Aortomitral length was grossly inversely proportional to aortomitral angle (AMA). AMA and aortomitral curtain (AMC) length were significantly altered post-Commando in 2 analysed patients with pre- and postoperative computed tomography scan. Transcatheter AV and MV replacements were feasible in all patients post-Commando. The AMA was larger and more favorable for mitral VIV in patients in which the AMC was short. CONCLUSIONS: AMC length, as determined by location of AV annular sutures, may be an important consideration in surgical decision-making for VIV after the Commando procedure.

Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6-36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.