Search

Abstract Age-related macular degeneration (AMD) is a leading cause of blindness. It is associated with peripheral drusen which has not been categorized. We investigated peripheral drusen to validate an image grading system and to understand possible associations between peripheral drusen and AMD. We collated clinical data, ultra-widefield (UWF) pseudocolor fundus images and Spectral-Domain Optical Coherence Tomography (SD-OCT) scans from consecutive retinal patients. SD-OCT scans were used to determine AMD stage. A masked retinal specialist recorded the types of peripheral drusen observed in UWF images. Eyes whose UWF images did not pass quality screening and those without AMD and peripheral drusen were excluded from the study. Statistical tests were utilized to determine the validity of our grading system and associations of peripheral drusen with AMD. A total of 481 eyes (283 subjects) were included in the study (mean age 73.1 ± 1.2years, 64.3% female). Interobserver and test–retest statistical analyses to evaluate the UWF image grading system resulted in Cohen’s Kappa 0.649 (p

In this study, an automated, targeted next-generation sequencing (tNGS) assay to detect and serotype Salmonella from sample enrichments was evaluated. The assay generates millions of reads to detect multiple Salmonella-specific genes and serotype-specific alleles, detecting all Salmonella spp. tested to date, and serotyping 62 common Salmonella serotypes. Accuracy was tested on 291 pure reference cultures (251 Salmonella, 40 non-Salmonella), 21 artificially contaminated poultry carcass rinse samples, and 363 naturally contaminated poultry environmental samples. Among the 291 pure reference cultures, the automated tNGS assay resulted in 100% detection accuracy, 100% serotyping accuracy for the claimed serotypes, and 0% false positives. The limit of detection was estimated at 5 × 104 CFU/mL by testing enumerated cultures of strains representative of six serotypes. In cocontamination studies with mixtures of two serotypes (Enteritidis, Typhimurium, Kentucky, Infantis, and Newport) at a 1:1 ratio, tNGS detected both serotypes with 100% accuracy. The assay demonstrated 100% accuracy in artificially contaminated poultry carcass rinse sample enrichments. Targeted NGS was highly effective in detecting Salmonella in samples collected from poultry production facilities. Results demonstrated that tNGS could detect Salmonella and provide accurate serotyping information consistent with conventional serology. These findings highlight the reliable and efficient performance of a fully automated tNGS Salmonella assay in detecting and identifying Salmonella strains in complex matrices, reducing the time to results from 4 to 5 days required by the traditional isolation and serotyping to 10–12 h for tNGS after primary enrichment.

Abstract Ultra-widefield retinal imaging is increasingly used in ophthalmology and optometry practices to image patients identifying peripheral abnormalities. However, the clinical relevance of these peripheral retinal abnormalities is unclear. This cross-sectional study aims to firstly validate a new grading system, secondly, assess the prevalence of peripheral retinal abnormalities in retinal patients, and finally understand how peripheral findings may associate with retinal disease. Ultra-widefield pseudocolor fundus images were taken from the eyes of clinic patients. Demographic data and clinical diagnosis for each patient was noted. The grading system was validated using masked retinal specialists. Logistic regression identified associations between retinal disease and peripheral retinal findings. Using the grading system, inter-observer agreement was 76.1% with Cohen’s Kappa coefficient 0.542 (p

Abstract To evaluate if Indigenous Australians have higher coronary inflammation demonstrated non-invasively using pericoronary adipose tissue attenuation on coronary computed tomography angiography (CCTA). We retrospectively obtained a cohort 54 Indigenous patients age- and sex-matched to 54 non-Indigenous controls (age: 46.5 ± 13.1 years; male: n = 66) undergoing CCTA at the Royal Darwin Hospital and Monash Medical Centre. Patient groups were defined to investigate the interaction of ethnicity and sex: Indigenous + male, Indigenous + female, control + male, control + female. Semi-automated software was used to assess pericoronary adipose tissue attenuation (PCAT-a) and volume (PCAT-v). Males had significantly higher PCAT-a (– 86.7 ± 7.8 HU vs. − 91.3 ± 7.1 HU, p = 0.003) than females. Indigenous patients had significantly higher PCAT-v (1.5 ± 0.5cm3 vs. 1.3 ± 0.4cm3, p = 0.032), but only numerically higher PCAT-a (p = 0.133) than controls. There was a significant difference in PCAT-a and PCAT-v across groups defined by Indigenous status and sex (p = 0.010 and p = 0.030, respectively). Among patients with matching CCTA contrast density, multivariable linear regression analysis showed an independent association between Indigenous status and PCAT-a. Indigenous men have increased PCAT-a in an age- and sex-matched cohort. Male sex is strongly associated with increased PCAT-a. Coronary inflammation may contribute to adverse cardiovascular outcomes in Indigenous Australians, but larger studies are required to validate these findings.

Isatuximab is an IgG1κ-derived monoclonal antibody against CD38 approved for the treatment of adult patients with multiple myeloma. Here we describe the successful treatment of a therapy-refractory pure red cell aplasia case following ABO-mismatched allogeneic stem cell transplantation with isatuximab. Our patient was a 75-year-old female with acute myeloid leukemia who received an HLA-B antigen mismatched, unrelated peripheral blood stem cell transplant with a major ABO incompatibility (blood group A+ in the donor and blood group O+ in the recipient). The patient developed persistent red cell aplasia and anti-A antibodies for more than 500 days from transplant. She received therapy with rituximab, bortezomib, prednisone, and darbepoetin alfa with partial to no response. After repeated insurance denials for daratumumab, isatuximab was obtained from the manufacturer through their CareASSIST program. Following the completion of 2 cycles of isatuximab (8 doses), significant and sustained red cell recovery was observed.

Abstract The atherogenic index of plasma (AIP) is a novel biomarker of atherogenic dyslipidaemia (AD), but its relationship with cardiac adipose tissue depots is unknown. We aimed to assess the association of AD with cardiac adipose tissue parameters on coronary computed tomography angiography (CCTA). We studied 161 patients who underwent CCTA between 2008 and 2011 (age 59.0 ± 14.0 years). AD was defined as triglyceride (TG) > 1.7 mmol/L and HDL

Trichloroethylene (TCE) is a prominent groundwater pollutant due to its stability, widespread contamination, and negative health effects upon human exposure; thus, an immense need exists for enhanced environmental remediation techniques. Temperature-responsive domains and catalyst incorporation in membrane domains bring significant advantages for toxic organic decontamination. In this study, hollow fiber membranes (HFMs) were functionalized with stimuli-responsive poly-N-isopropylacrylamide (PNIPAm), poly-methyl methacrylate (PMMA), and catalytic zero-valent iron/palladium (Fe/Pd) for heightened reductive degradation of such pollutants, utilizing methyl orange (MO) as a model compound. By utilizing PNIPAm’s transition from hydrophilic to hydrophobic expression above the LCST of 32 °C, increased pollutant diffusion and adsorption to the catalyst active sites were achieved. PNIPAm-PMMA hydrogels exhibited 11.5× and 10.8× higher equilibrium adsorption values for MO and TCE, respectively, when transitioning from 23 °C to 40 °C. With dip-coated PNIPAm-PMMA-functionalized HFMs (weight gain: ~15%) containing Fe/Pd nanoparticles (dp~34.8 nm), surface area-normalized rate constants for batch degradation were determined, resulting in a 30% and 420% increase in degradation efficiency above 32 °C for MO and TCE, respectively, due to enhanced sorption on the hydrophobic PNIPAm domain. Overall, with functionalized membranes containing superior surface area-to-volume ratios and enhanced sorption sites, efficient treatment of high-volume contaminated water can be achieved.

Abstract Background We sought to evaluate the association of metabolic syndrome (MetS) and computed tomography (CT)-derived cardiometabolic biomarkers (non-alcoholic fatty liver disease [NAFLD] and epicardial adipose tissue [EAT] measures) with long-term risk of major adverse cardiovascular events (MACE) in asymptomatic individuals. Methods This was a post-hoc analysis of the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study of participants who underwent baseline coronary artery calcium (CAC) scoring CT and 14-year follow-up for MACE (myocardial infarction, late revascularization, or cardiac death). EAT volume (cm3) and attenuation (Hounsfield units [HU]) were quantified from CT using fully automated deep learning software (

Summary: Background: Atherosclerotic plaque quantification from coronary CT angiography (CCTA) enables accurate assessment of coronary artery disease burden and prognosis. We sought to develop and validate a deep learning system for CCTA-derived measures of plaque volume and stenosis severity. Methods: This international, multicentre study included nine cohorts of patients undergoing CCTA at 11 sites, who were assigned into training and test sets. Data were retrospectively collected on patients with a wide range of clinical presentations of coronary artery disease who underwent CCTA between Nov 18, 2010, and Jan 25, 2019. A novel deep learning convolutional neural network was trained to segment coronary plaque in 921 patients (5045 lesions). The deep learning network was then applied to an independent test set, which included an external validation cohort of 175 patients (1081 lesions) and 50 patients (84 lesions) assessed by intravascular ultrasound within 1 month of CCTA. We evaluated the prognostic value of deep learning-based plaque measurements for fatal or non-fatal myocardial infarction (our primary outcome) in 1611 patients from the prospective SCOT-HEART trial, assessed as dichotomous variables using multivariable Cox regression analysis, with adjustment for the ASSIGN clinical risk score. Findings: In the overall test set, there was excellent or good agreement, respectively, between deep learning and expert reader measurements of total plaque volume (intraclass correlation coefficient [ICC] 0·964) and percent diameter stenosis (ICC 0·879; both p

Abstract Background Membranous nephropathy (MN) has been recognized to occur in patients with human immunodeficiency virus (HIV) infection since the beginning of the HIV epidemic. The prevalence of phospholipase A2 receptor (PLA2R)-associated MN in this group has not been well studied. Methods We conducted a retrospective review of electronic pathology databases at three institutions to identify patients with MN and known HIV at the time of renal biopsy. Patients with comorbidities and coinfections known to be independently associated with MN were excluded. Results We identified 11 HIV-positive patients with biopsy-confirmed MN meeting inclusion and exclusion criteria. Patient ages ranged from 39 to 66 years old, and 10 of 11 patients (91%) were male. The majority of patients presented with nephrotic-range proteinuria, were on anti-retroviral therapy at the time of biopsy and had low or undetectable HIV viral loads. Biopsies from 5 of 10 (50%) patients demonstrated capillary wall staining for PLA2R. Measurement of serum anti-PLA2R antibodies was performed in three patients, one of whom had positive anti-PLA2R antibody titers. Follow-up data was available on 10 of 11 patients (median length of follow-up: 44 months; range: 4–145 months). All patients were maintained on anti-retroviral therapy (ARV) and 5 patients (52%) received concomitant immunosuppressive regimens. Three patients developed end-stage renal disease (ESRD) during the follow-up period. Conclusions MN in the setting of HIV is often identified in the setting of an undetectable viral loads, and similar to other chronic viral infection-associated MNs, ~ 50% of cases demonstrate tissue reactivity with PLA2R antigen, which may be seen without corresponding anti-PLA2R serum antibodies.

Abstract Objectives Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. Methods In vitro human PDAC cell lines MiaPaca2 and S2‐013 were treated with 5μm 3‐Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 μm 5‐Azacytidine (5‐AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti‐PD‐L1 combined with DZNep and 5‐AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5‐AZA). qRT‐PCR and microarray assays were performed for the evaluation of Th1‐attracting chemokines and cancer‐associated antigen induction. Results Drug treatments induced significant upregulation of gene expressions of Th1‐attracting chemokines, CXCL9 and CXCL10, and the cancer–testis antigens, NY‐ESO‐1, LAGE and SSX‐4 (P

Zebrafish is a popular high-throughput vertebrate model to study human cardiac electrophysiology, arrhythmias, and myopathies. One reason for this popularity is the purported striking similarities between zebrafish and human electrocardiograms (ECGs). However, zebrafish electrical heart axes were unknown. It is impossible to define heart axis based on single-lead ECG because determination of an electrical heart axis in the frontal plane requires the use of the hexaxial reference system (or Cabrera system) derived from Einthoven’s triangle. Construction of Einthoven’s triangle requires simultaneous ECG recording from at least two Einthoven bipolar leads. Therefore, we systematically constructed the first zebrafish Einthoven’s triangle by simultaneous bipolar dual-lead ECG recording to determine for the first time the three frontal electrical heart axes using the Cabrera system. Comparing zebrafish with human Einthoven’s triangle reveals that their normal frontal electrical axes were reflections of each other across 0° in the Cabrera system. The responsible mechanisms involve zebrafish vs. human cardiac activation propagating in the same direction along the heart horizontal axis but in opposite directions along the heart longitudinal axis. The same observations are true for zebrafish vs. human cardiac repolarization. This study marks a technical breakthrough in the first bipolar dual-lead ECG recording in live adult zebrafish to construct for the first time zebrafish Einthoven’s triangle. This first systematic analysis of the actual differences and similarities between normal adult zebrafish and human Einthoven’s triangles unmasked differences and similarities in the underlying cardiac axis mechanisms. Insights of the live adult zebrafish main heart axis and its three frontal electrical heart axes provide critical contextual framework to interpret the clinical relevance of the adult zebrafish heart as model for human cardiac electrophysiology.

Life-threatening ventricular arrhythmias, typically arising from interfaces between fibrosis and surviving cardiomyocytes, are feared sequelae of structurally remodeled hearts under oxidative stress. Incomplete understanding of the proarrhythmic electrical remodeling by fibrosis limits the development of novel antiarrhythmic strategies. To define the mechanistic determinants of the proarrhythmia in electrical crosstalk between cardiomyocytes and noncardiomyocytes, we developed a novel in vitro model of interface between neonatal rat ventricular cardiomyocytes (NRVMs) and controls [NRVMs or connexin43 (Cx43)-deficient HeLa cells] vs. Cx43+ noncardiomyocytes [aged rat ventricular myofibroblasts (ARVFs) or HeLaCx43 cells]. We performed high-speed voltage-sensitive optical imaging at baseline and following acute H2O2 exposure. In NRVM-NRVM and NRVM-HeLa controls, no arrhythmias occurred under either experimental condition. In the NRVM-ARVF and NRVM-HeLaCx43 groups, Cx43+ noncardiomyocytes enabled passive decremental propagation of electrical impulses and impaired NRVM activation and repolarization, thereby slowing conduction and prolonging action potential duration. Following H2O2 exposure, arrhythmia triggers, automaticity, and non-reentrant and reentrant arrhythmias emerged. This study reveals that myofibroblasts (which generate cardiac fibrosis) and other noncardiomyocytes can induce not only structural remodeling but also electrical remodeling and that electrical remodeling by noncardiomyocytes can be particularly arrhythmogenic in the presence of an oxidative burst. Synergistic electrical remodeling between H2O2 and noncardiomyocytes may account for the clinical arrhythmogenicity of myofibroblasts at fibrotic interfaces with cardiomyocytes in ischemic/non-ischemic cardiomyopathies. Understanding the enhanced arrhythmogenicity of synergistic electrical remodeling by H2O2 and noncardiomyocytes may guide novel safe-by-design antiarrhythmic strategies for next-generation iatrogenic interfaces between surviving native cardiomyocytes and exogenous stem cells or engineered tissues in cardiac regenerative therapies.

Since the clinical use of digitalis as the first pharmacological therapy for atrial fibrillation (AF) 235 years ago in 1785, antiarrhythmic drug therapy has advanced considerably and become a cornerstone of AF clinical management. Yet, a preventive or curative panacea for sustained AF does not exist despite the rise of AF global prevalence to epidemiological proportions. While multiple elevated risk factors for AF have been established, the natural history and etiology of AF remain incompletely understood. In the present article, the first section selectively highlights some disappointing shortcomings and current efforts in antiarrhythmic drug therapy to uncover reasons why AF is such a clinical challenge. The second section discusses some modern takes on the natural history of AF as a relentless, progressive fibro-inflammatory “atriomyopathy.” The final section emphasizes the need to redefine therapeutic strategies on par with new insights of AF pathophysiology.

EGFR is frequently mutated in non-small-cell lung carcinomas (NSCLCs). Clinically available tyrosine kinase inhibitors (TKIs) are effective in treating EGFR-mutant NSCLC. In this case series, we present five patients with TKI-treated EGFR-mutated NSCLC who developed leptomeningeal disease (LMD) lacking characteristic imaging findings. All five patients received TKIs prior to development of cytology-confirmed LMD. Clinical signs of LMD preceded radiographic evidence by 2–12 months. T790M, the most common resistance mutation to first-generation EGFR inhibitors, was identified in four cases. These cases illustrate that in patients with EGFR-mutant NSCLC, TKIs may effectively control LMD, creating a lag between onset of symptoms and observation of radiographic findings.

Background: High-risk plaques (HRP) detected on coronary computed tomography angiography (CTA) confer an increased risk of acute coronary syndrome (ACS). Pericoronary adipose tissue attenuation (PCAT) is a novel biomarker of coronary inflammation. This study aimed to evaluate the association of PCAT with HRP and subsequent ACS development in patients with stable coronary artery disease (CAD). Methods: Patients with stable CAD who underwent coronary CTA from 2011 to 2016 and had available outcome data were included. We studied 41 patients with HRP propensity matched to 41 controls without HRP (60 ± 10 years, 67% males). PCAT was assessed using semi-automated software on a per-patient basis in the proximal right coronary artery (PCATRCA) and a per-lesion basis (PCATLesion) around HRP in cases and the highest-grade stenosis lesions in controls. Results: PCATRCA and PCATLesion were higher in HRP patients than controls (PCATRCA: −80.7 ± 6.50 HU vs. −84.2 ± 8.09 HU, p = 0.03; PCATLesion: −79.6 ± 7.86 HU vs. −84.2 ± 10.3 HU, p = 0.04), and were also higher in men (PCATRCA: −80.5 ± 7.03 HU vs. −86.1 ± 7.08 HU, p < 0.001; PCATLesion: −79.6 ± 9.06 HU vs. −85.2 ± 7.96 HU, p = 0.02). Median time to ACS was 1.9 years, within a median follow-up of 5.3 years. PCATRCA alone was higher in HRP patients who subsequently presented with ACS (−76.8 ± 5.69 HU vs. −82.0 ± 6.32 HU, p = 0.03). In time-dependent analysis, ACS was associated with HRP and PCATRCA. Conclusions: PCAT attenuation is increased in stable CAD patients with HRP and is associated with subsequent ACS development. Further investigation is required to determine the clinical implications of these findings.

A large body of evidence arising from recent randomized clinical trials demonstrate the association of vascular inflammatory mediators with coronary artery disease (CAD). Vascular inflammation localized in the coronary arteries leads to an increased risk of CAD-related events, and produces unique biological alterations to local cardiac adipose tissue depots. Coronary computed tomography angiography (CTA) provides a means of mapping inflammatory changes to both epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) as independent markers of coronary risk. Radiodensity or attenuation of PCAT on coronary CTA, notably, provides indirect quantification of coronary inflammation and is emerging as a promising non-invasive imaging implement. An increasing number of observational studies have shown robust associations between PCAT attenuation and major coronary events, including acute coronary syndrome, and ‘vulnerable’ atherosclerotic plaque phenotypes that are associated with an increased risk of the said events. This review outlines the biological characteristics of both EAT and PCAT and provides an overview of the current literature on PCAT attenuation as a surrogate marker of coronary inflammation.

Radiomics, via the extraction of quantitative information from conventional radiologic images, can identify imperceptible imaging biomarkers that can advance the characterization of coronary plaques and the surrounding adipose tissue. Such an approach can unravel the underlying pathophysiology of atherosclerosis which has the potential to aid diagnostic, prognostic and, therapeutic decision making. Several studies have demonstrated that radiomic analysis can characterize coronary atherosclerotic plaques with a level of accuracy comparable, if not superior, to current conventional qualitative and quantitative image analysis. While there are many milestones still to be reached before radiomics can be integrated into current clinical practice, such techniques hold great promise for improving the imaging phenotyping of coronary artery disease.