Prevalence and significance of incidental findings on computed tomography pulmonary angiograms: A retrospective cohort study.

OBJECTIVE: The purpose of this study was to analyze the prevalence and significance of incidental findings on computed tomography pulmonary angiography (CTPA) studies and to assess the diagnostic yield of CTPA in identifying an alternate diagnosis to pulmonary embolism (PE) on PE negative exams. METHODS: All patients who had a CTPA exam for PE evaluation between Jan 2016 and Dec 2018 with a negative PE result were included in the study. A total of 2083 patients were identified. We retrospectively queried the electronic medical record and the radiology report and recorded the following: Age, Sex, BMI, Patient location and Incidental findings. The incidental findings were classified into type 1 (Alternate diagnosis other than PE which could explain the patient's symptoms), type 2 (non-emergent findings which needed further work up) and type 3 findings (non-emergent findings which did not need further work up). Logistic regression analysis was performed to determine what factors affected the probability of finding a type 1 incidental (alternate diagnosis) or a type 2 incidental. RESULTS: 74.5% of the patients in our study had at least one incidental finding. Type 1 incidental findings (alternate diagnosis to PE) were found in 864 patients (41.5%). The most common type 1 finding was pneumonia followed by fluid overload. Male sex, increased age and lower BMI were significantly associated with increased odds of a type 1 incidental(p < 0.05). Similarly, all the patient locations had significantly different odds of finding a type-1 incidental, with ICU having the highest odds, followed by inpatient, ED and outpatient locations (p < 0.05). 563 patients (27%) had at least one type 2 incidental findings and the most common type 2 findings were progressive lung malignancy/ metastatic disease and new pulmonary nodule. Increased age was significantly associated with the probability of a type 2 finding (p < 0.05). CONCLUSIONS: CTPA may suggest an alternative diagnosis to pulmonary embolism in approximately 40% of the patients with a negative study. The probability of finding an alternate diagnosis (type 1 incidental) is higher in elderly patients and in patients referred from ICU and inpatient units.

Pulmonary embolism rule out: positivity and factors affecting the yield of CT angiography.

OBJECTIVE: CT pulmonary angiography (CTPA) is one of the most commonly ordered CT imaging tests. It is often believed to be overutilised with few recent studies showing a yield of less than 2%. This study aimed to determine the overall positivity rate of CTPA examinations and understand the factors that affect the yield of the CTPA examination. METHODS: We retrospectively analysed 2713 patients who received the CTPA exam between 2016 and 2018. Type of study ordered (CTPA chest or CTPA chest with abdomen and pelvis CT), patient location (emergency department (ED), outpatient, inpatient, intensive care unit (ICU)) and patient characteristics-age, sex and body mass index (BMI) were recorded. A logistic regression analysis was performed to determine what factors affect the positivity rate of CT scans for pulmonary embolism (PE). RESULTS: With 296 positive test results, the overall CTPA positivity was 10.9%. Male sex was associated with higher CTPA positivity, gender difference was maximum in 18-year to 35-year age group. Overweight and obese patients had significantly higher positivity as compared with BMI<25 (p<0.05). Higher positivity rate was seen in the BMI 25-40 group (11.9%) as compared with BMI>40 (10.1%) (p<0.05). Significant difference (p<0.001) was also found in CTPA examination yield from ICU (15.3%) versus inpatients (other than ICU) (12.4%) versus ED (9.6%), and outpatients (8.5%). The difference in CTPA yield based on the type of CT order (CTPA chest vs CTPA chest with CT abdomen and pelvis), patient's age and sex was not significant. CONCLUSION: CTPA yield of 10.9% in this study is comparable to acceptable positivity rate for the USA and is higher than recent studies showing positivity of <2%. Patient characteristics like obesity and ICU or inpatient location are associated with higher rate of CT positivity.

Leclercia adecarboxylata in a Patient With Newly Diagnosed Chronic Lymphocytic Leukemia.

Leclercia adecarboxylata is a Gram-negative bacillus commonly seen in immunocompromised individuals and often misdiagnosed as Escherichia coli. L. adecarboxylata is an opportunistic pathogen found in aquatic environments. It is a nonfatal infection that has low virulence and endorses susceptibility to many common antibiotics. We report a case of a 53-year-old immunocompromised male who was managed for L. adecarboxylata bacteremia.

The Association Between Smokeless Tobacco and a Lung Mass in a Healthy Young Male.

Smokeless tobacco is widely used in the United States. Many commonly used forms of smokeless tobacco may contain microorganisms that can change the oral flora of tobacco users. Here we present a case of a previously healthy 21-year-old male who presented with six weeks of worsening cough productive of yellow sputum as well as pleuritic left-sided chest and back pain. Computed tomography (CT) of the chest showed a large 3.9 x 5.5 x 6.3 cm mass-like lesion. He was extensively worked up for potential causes of this mass, including autoimmune, HIV testing, sputum staining for acid-fast bacilli, and fungal serologies. He was empirically treated with antibiotics and antifungals. He ultimately underwent a CT-guided biopsy which was negative for malignancy and tuberculosis. The culture from the biopsy revealed 5,000 colony forming units of Streptococcus intermedius. Based on the sensitivities of the culture, he was switched to intravenous ceftriaxone and discharged to complete a course of intravenous antibiotics.  This case showcases a healthy 21-year-old male with no prior history who had an extensive workup for the possible causes and risk factors predisposing to a lung abscess. This workup was negative, and his only risk factor was the use of smokeless chewing tobacco. Smokeless tobacco may be associated with increased risk of lower respiratory tract infections and can increase the risk of lung abscess in an immunocompetent adult. More research is required to understand this association.

Disparities in Health and Healthcare: Impact of Race on Resource Utilization and Costs Following Transcatheter Edge-to-Edge Repair.

BACKGROUND: This study sought to investigate health and healthcare disparities in the management of severe mitral regurgitation with transcatheter edge-to-edge repair using MitraClip and how racial differences impact resource utilization and costs. METHODS: We retrospectively analyzed the National Inpatient Sample (NIS) for patients who underwent Transcatheter Edge-to-Edge Repair (TEER) using MitraClip between 2016 and 2018. The patients were stratified into four racial cohorts and study outcomes included high resource utilization (HRU), periprocedural complications, and total procedural costs. High resource utilization (HRU) was defined as length of stay (LOS) ≥7 days or a nonhome disposition at discharge. Multivariate logistic regression models were utilized to determine independent predictors of HRU. RESULTS: 17,100 weighted TEER patients were segregated by race: Caucasian (n = 13,270), others (n = 1510), African Americans, AA (n = 1245) and Hispanics (n = 1075). More African Americans and Hispanics had TEER at Urban facilities (P < 0.001), which were teaching hospitals as well (P < 0.001) but were less likely to be covered by public insurance options -Medicare or Medicaid (P < 0.001). More AA (52.2 %) and Hispanics (27.6 %) were likely to be in the lowest median annual income quartile versus Caucasians (19.2 %) (P = 0.003). AA and Hispanics had higher resource utilization (HRU), prolonged length of stay, nonhome disposition at discharge, higher procedural costs and periprocedural complications versus Caucasians. The logistic regression model revealed acute kidney injury (AKI) and actual procedural costs as independent predictors of HRU in both African American and Hispanic groups. CONCLUSION: Significant Health and healthcare disparities do exist among underrepresented, racial minority patients undergoing transcatheter edge-to-edge repair in the US. These disparities were associated with higher resource utilization and actual costs in patients with mitral regurgitation treated with TEER.

SLC38A10 Regulate Glutamate Homeostasis and Modulate the AKT/TSC2/mTOR Pathway in Mouse Primary Cortex Cells.

Glutamate acts as a critical regulator of neurotransmitter balance, recycling, synaptic function and homeostasis in the brain and glutamate transporters control glutamate levels in the brain. SLC38A10 is a member of the SLC38 family and regulates protein synthesis and cellular stress responses. Here, we uncover the role of SLC38A10 as a transceptor involved in glutamate-sensing signaling pathways that control both the glutamate homeostasis and mTOR-signaling. The culture of primary cortex cells from SLC38A10 knockout mice had increased intracellular glutamate. In addition, under nutrient starvation, KO cells had an impaired response in amino acid-dependent mTORC1 signaling. Combined studies from transcriptomics, protein arrays and metabolomics established that SLC38A10 is involved in mTOR signaling and that SLC38A10 deficient primary cortex cells have increased protein synthesis. Metabolomic data showed decreased cholesterol levels, changed fatty acid synthesis, and altered levels of fumaric acid, citrate, 2-oxoglutarate and succinate in the TCA cycle. These data suggests that SLC38A10 may act as a modulator of glutamate homeostasis, and mTOR-sensing and loss of this transceptor result in lower cholesterol, which could have implications in neurodegenerative diseases.

Morphological profiling of environmental chemicals enables efficient and untargeted exploration of combination effects.

Environmental chemicals are commonly studied one at a time, and there is a need to advance our understanding of the effect of exposure to their combinations. Here we apply high-content microscopy imaging of cells stained with multiplexed dyes (Cell Painting) to profile the effects of Cetyltrimethylammonium bromide (CTAB), Bisphenol A (BPA), and Dibutyltin dilaurate (DBTDL) exposure on four human cell lines; both individually and in all combinations. We show that morphological features can be used with multivariate data analysis to discern between exposures from individual compounds, concentrations, and combinations. CTAB and DBTDL induced concentration-dependent morphological changes across the four cell lines, and BPA exacerbated morphological effects when combined with CTAB and DBTDL. Combined exposure to CTAB and BPA induced changes in the ER, Golgi apparatus, nucleoli and cytoplasmic RNA in one of the cell lines. Different responses between cell lines indicate that multiple cell types are needed when assessing combination effects. The rapid and relatively low-cost experiments combined with high information content make Cell Painting an attractive methodology for future studies of combination effects. All data in the study is made publicly available on Figshare.

SLC38A10 Transporter Plays a Role in Cell Survival Under Oxidative Stress and Glutamate Toxicity.

Solute carrier (SLC) transporters regulate amino acids, glucose, ions, and metabolites that flow across cell membranes. In the brain, SLCs are the key regulators of neurotransmission, in particular, the glutamate/GABA-glutamine (GGG) cycle. Genetic mutations in SLCs are associated with various neurodevelopmental and neurodegenerative diseases. In this study, we have investigated the role of SLC38A10 under acute oxidative and glutamate stress in mouse primary cortical cells from SLC38A10 knockout (KO) mice. The ER/golgi localized transporter, SLC38A10, transports glutamate, glutamine, and alanine in brain cells, and the aim of this study was to determine the possible effects of removal of SLC38A10 in primary cortical cells under glutamate and oxidative challenges. Primary cortical neuronal cultures of wild-type (WT) cell and SLC38A10 KO mice were subjected to different concentrations of glutamate and hydrogen peroxide. There was no morphological change observed between KO and WT cortical neurons in culture. Interestingly, KO cells showed significantly lower cell viability and higher cell death compared to WT cells under both glutamate and hydrogen peroxide exposure. Further, we evaluated the possible role of p53 in neuronal cell apoptosis in KO cells. We found decreased intracellular p53 protein levels under glutamate and hydrogen peroxide treatment in KO cortical cells. In contrast, caspase 3/7 activity remains unaltered under all conditions. These results demonstrate an indirect relationship between the expression of SLC38A10 and p53 and a role in the cell defense mechanism against neurotoxicity.

Review of multi-modality imaging update and diagnostic work up of Takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is an acute but reversible non-ischemic heart failure syndrome. It is characterized by a transient form of ventricular dysfunction typically manifesting as basal hyperkinesis with hypokinesia and ballooning of left ventricle mid-cavity and apex. Imaging helps in both diagnosis and follow up. Echocardiogram is the first-line modality to assess the typical contractile dysfunction in suspected patients with catheter angiography showing normal coronary arteries. Cardiac MRI is currently the modality of choice for the non-invasive initial assessment of TC and for follow up imaging. The current review focusses on historical background of TC, its pathophysiology, diagnostic work up and differential diagnosis and provides multimodality imaging work up of TC including role of echocardiogram, invasive catheterization, nuclear imaging, cardiac computed tomography and cardiac MRI including basic and advanced MRI sequences.

Radiomics side experiments and DAFIT approach in identifying pulmonary hypertension using Cardiac MRI derived radiomics based machine learning models.

Side experiments are performed on radiomics models to improve their reproducibility. We measure the impact of myocardial masks, radiomic side experiments and data augmentation for information transfer (DAFIT) approach to differentiate patients with and without pulmonary hypertension (PH) using cardiac MRI (CMRI) derived radiomics. Feature extraction was performed from the left ventricle (LV) and right ventricle (RV) myocardial masks using CMRI in 82 patients (42 PH and 40 controls). Various side study experiments were evaluated: Original data without and with intraclass correlation (ICC) feature-filtering and DAFIT approach (without and with ICC feature-filtering). Multiple machine learning and feature selection strategies were evaluated. Primary analysis included all PH patients with subgroup analysis including PH patients with preserved LVEF (≥ 50%). For both primary and subgroup analysis, DAFIT approach without feature-filtering was the highest performer (AUC 0.957-0.958). ICC approaches showed poor performance compared to DAFIT approach. The performance of combined LV and RV masks was superior to individual masks alone. There was variation in top performing models across all approaches (AUC 0.862-0.958). DAFIT approach with features from combined LV and RV masks provide superior performance with poor performance of feature filtering approaches. Model performance varies based upon the feature selection and model combination.

Radiomics Detection of Pulmonary Hypertension via Texture-Based Assessments of Cardiac MRI: A Machine-Learning Model Comparison-Cardiac MRI Radiomics in Pulmonary Hypertension.

The role of reliable, non-invasive imaging-based recognition of pulmonary hypertension (PH) remains a diagnostic challenge. The aim of the current pilot radiomics study was to assess the diagnostic performance of cardiac MRI (cMRI)-based texture features to accurately predict PH. The study involved IRB-approved retrospective analysis of cMRIs from 72 patients (42 PH and 30 healthy controls) for the primary analysis. A subgroup analysis was performed including patients from the PH group with left ventricle ejection fraction ≥ 50%. Texture features were generated from mid-left ventricle myocardium using balanced steady-state free precession (bSSFP) cine short-axis imaging. Forty-five different combinations of classifier models and feature selection techniques were evaluated. Model performance was assessed using receiver operating characteristic curves. A multilayer perceptron model fitting using full feature sets was the best classifier model for both the primary analysis (AUC 0.862, accuracy 78%) and the subgroup analysis (AUC 0.918, accuracy 80%). Model performance demonstrated considerable variation between the models (AUC 0.523-0.918) based on the chosen model-feature selection combination. Cardiac MRI-based radiomics recognition of PH using texture features is feasible, even with preserved left ventricular ejection fractions.

Factors Affecting Radiation Dose in Computed Tomography Angiograms for Pulmonary Embolism: A Retrospective Cohort Study.

OBJECTIVES: Computed tomography pulmonary angiogram (CTPA) is one of the most commonly ordered and frequently overused tests. The purpose of this study was to evaluate the mean radiation dose to patients getting CTPA and to identify factors that are associated with higher dose. MATERIAL AND METHODS: This institutionally approved retrospective study included all patients who had a CTPA to rule out acute pulmonary embolism between 2016 and 2018 in a tertiary care center. Patient data (age, sex, body mass index [BMI], and patient location), CT scanner type, image reconstruction methodology, and radiation dose parameters (dose-length product [DLP]) were recorded. Effective dose estimates were obtained by multiplying DLP by conversion coefficient (0.014 mSv•mGy-1•cm-1). Multivariate logistic regression analysis was performed to determine the factors affecting the radiation dose. RESULTS: There were 2342 patients (1099 men and 1243 women) with a mean age of 58.1 years (range 0.2-104.4 years) and BMI of 31.3 kg/m2 (range 12-91.5 kg/m2). The mean effective radiation dose was 5.512 mSv (median - 4.27 mSv; range 0.1-43.0 mSv). Patient factors, including BMI >25 kg/m2, male sex, age >18 years, and intensive care unit (ICU) location, were associated with significantly higher dose (P < 0.05). CT scanning using third generation dual-source scanner with model-based iterative reconstruction (IR) had significantly lower dose (mean: 4.90 mSv) versus single-source (64-slice) scanner with filtered back projection (mean: 9.29 mSv, P < 0.001). CONCLUSION: Patients with high BMI and ICU referrals are associated with high CT radiation dose. They are most likely to benefit by scanning on newer generation scanner using advance model-based IR techniques.

CG4928 Is Vital for Renal Function in Fruit Flies and Membrane Potential in Cells: A First In-Depth Characterization of the Putative Solute Carrier UNC93A.

The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK1 channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

Knockdown of SLC38 Transporter Ortholog - CG13743 Reveals a Metabolic Relevance in Drosophila.

Solute Carrier (SLC) is a cluster of families of membrane bound transporters, of which many members lack defined substrate profile, and many more are poorly characterized. Many play a vital role in regulating metabolic systems, protein synthesis, and post translational modifications. SLC38 is one of the families of SLCs, which are also known as sodium-coupled neutral amino acid transporters (SNATs). In mice, it has 11 members (SNAT1-11) but in Drosophila there are two homologs for the SLC38 family; CG13743 and CG30394. Here, we show characteristics of Drosophila CG13743 which closely resembles SLC38A11 in humans. SLC38A11 still remains an orphan member of the SLC38 family which has not been functionally well studied. We used the UAS-GAL4 system to investigate and control gene expression using RNAi lines for ubiquitous knockdown of the CG13743 gene. It was found to be expressed mainly in salivary gland and brain. Knockdown flies had reduced body weight and consumed less sugar compared with controls. The gene knockdown also affected stored energy pools (lipids and glycogen) and influenced feeding pattern and total activity. In all, this shows novel findings for the characterization of CG13743 in Drosophila and a possible role in maintaining general metabolic pathways and behavior of the fly.

Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons.

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells. In this paper, we investigate if bNCSCs may improve survival of MNs harboring a mutant form of human SOD1 (SOD1G93A) in vitro under normal conditions and oxidative stress and in vivo after implantation to the spinal cord. We found that survival of SOD1G93A MNs in vitro was increased in the presence of bNCSCs under normal conditions as well as under oxidative stress. In addition, when SOD1G93A MN precursors were implanted to the spinal cord of adult mice, their survival was increased when they were co-implanted with bNCSCs. These findings show that bNCSCs support survival of SOD1G93A MNs in normal conditions and under oxidative stress in vitro and improve their survival in vivo, suggesting that bNCSCs have a potential for the development of novel stem cell-based therapeutic approaches in ALS models.

Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy.

Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFß1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments.

Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy.

Polyglutamine expansion in androgen receptor (AR) is responsible for spinobulbar muscular atrophy (SBMA) that leads to selective loss of lower motor neurons. Using SBMA as a model, we explored the relationship between protein structure/function and neurodegeneration in polyglutamine diseases. We show here that protein arginine methyltransferase 6 (PRMT6) is a specific co-activator of normal and mutant AR and that the interaction of PRMT6 with AR is significantly enhanced in the AR mutant. AR and PRMT6 interaction occurs through the PRMT6 steroid receptor interaction motif, LXXLL, and the AR activating function 2 surface. AR transactivation requires PRMT6 catalytic activity and involves methylation of arginine residues at Akt consensus site motifs, which is mutually exclusive with serine phosphorylation by Akt. The enhanced interaction of PRMT6 and mutant AR leads to neurodegeneration in cell and fly models of SBMA. These findings demonstrate a direct role of arginine methylation in polyglutamine disease pathogenesis.

Androgens affect muscle, motor neuron, and survival in a mouse model of SOD1-related amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of upper and lower motor neurons and skeletal muscle atrophy. Epidemiologic and experimental evidence suggest the involvement of androgens in ALS pathogenesis, but the mechanism through which androgens modify the ALS phenotype is unknown. Here, we show that androgen ablation by surgical castration extends survival and disease duration of a transgenic mouse model of ALS expressing mutant human SOD1 (hSOD1-G93A). Furthermore, long-term treatment of orchiectomized hSOD1-G93A mice with nandrolone decanoate (ND), an anabolic androgenic steroid, worsened disease manifestations. ND treatment induced muscle fiber hypertrophy but caused motor neuron death. ND negatively affected survival, thereby dissociating skeletal muscle pathology from life span in this ALS mouse model. Interestingly, orchiectomy decreased androgen receptor levels in the spinal cord and muscle, whereas ND treatment had the opposite effect. Notably, stimulation with ND promoted the recruitment of endogenous androgen receptor into biochemical complexes that were insoluble in sodium dodecyl sulfate, a finding consistent with protein aggregation. Overall, our results shed light on the role of androgens as modifiers of ALS pathogenesis via dysregulation of androgen receptor homeostasis.