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Abstract Rational Basal cells (BCs) are bronchial progenitor/stem cells that can regenerate injured airway that, in smokers, may undergo malignant transformation. As a model for early stages of lung carcinogenesis, we set out to characterize cytologically normal BC outgrowths from never-smokers and ever-smokers without cancers (controls), as well as from the normal epithelial “field” of ever-smokers with anatomically remote cancers, including lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) (cases). Methods Primary BCs were cultured and expanded from endobronchial brushings taken remote from the site of clinical or visible lesions/tumors. Donor subgroups were tested for growth, morphology, and underlying molecular features by qRT-PCR, RNAseq, flow cytometry, immunofluorescence, and immunoblot. Results (a) the BC population includes epithelial cell adhesion molecule (EpCAM) positive and negative cell subsets; (b) smoking reduced overall BC proliferation corresponding with a 2.6-fold reduction in the EpCAMpos/ITGA6 pos/CD24pos stem cell fraction; (c) LUSC donor cells demonstrated up to 2.8-fold increase in dysmorphic BCs; and (d) cells procured from LUAD patients displayed increased proliferation and S-phase cell cycle fractions. These differences corresponded with: (i) disparate NOTCH1/NOTCH2 transcript expression and altered expression of potential downstream (ii) E-cadherin (CDH1), tumor protein-63 (TP63), secretoglobin family 1a member 1 (SCGB1A1), and Hairy/enhancer-of-split related with YRPW motif 1 (HEY1); and (iii) reduced EPCAM and increased NK2 homeobox-1 (NKX2-1) mRNA expression in LUAD donor BCs. Conclusions These and other findings demonstrate impacts of donor age, smoking, and lung cancer case-control status on BC phenotypic and molecular traits and may suggest Notch signaling pathway deregulation during early human lung cancer pathogenesis.

Abstract Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh‐EVs). Using our customizable antibody‐purification assay, EV‐CATCHER, we initially determined that exh‐EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh‐EVs harbour lung‐specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh‐EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV‐CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti‐CCSP/SFTPC EV‐CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh‐EV subpopulations from EBC allows non‐invasive sampling of EVs produced by lung tissues.

PurposeDuctal carcinoma in situ (DCIS), is a noninvasive breast cancer, representing 20-25% of breast cancer diagnoses in the USA. Current treatment options for DCIS include mastectomy or breast-conserving surgery (BCS) with or without radiation therapy (RT), but optimal risk-adjusted treatment selection remains a challenge. Findings from past and recent clinical trials have failed to identify a ‘low risk’ group of patients who do not benefit significantly from RT after BCS. To address this unmet need, a DCIS biosignature, DCISionRT (PreludeDx, Laguna Hills, CA), was developed and validated in multiple cohorts. DCISionRT is a molecular assay with an algorithm reporting a recurrence risk score for patients diagnosed with DCIS intended to guide DCIS treatment. In this study, we present results from analytical validity, performance assessment, and clinical performance validation and clinical utility for the DCISionRT test comprised of multianalyte assays with algorithmic analysis.MethodsThe analytical validation of each molecular assay was performed based on the Clinical and Laboratory Standards Institute (CLSI) guidelines Quality Assurance for Design Control and Implementation of Immunohistochemistry Assays and the College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) recommendations for analytic validation of immunohistochemical assays.ResultsThe analytic validation showed that the molecular assays that are part of DCISionRT test have high sensitivity, specificity, and accuracy/reproducibility (≥95%). The analytic precision of the molecular assays under controlled non-standard conditions had a total standard deviation of 6.6 (100-point scale), where the analytic variables (Lot, Machine, Run) each contributed

Purpose: The present study compares the efficacy, safety, and immunogenicity of Lupin's biosimilar ranibizumab with that of Lucentis® in patients with neovascular age-related macular degeneration. Methods: This prospective, double-blind, multi-centric phase-III study was conducted across 19 centers in India. A total of 202 patients with neovascular age-related macular degeneration were randomized (1:1) to receive either Lupin's biosimilar ranibizumab or Lucentis®, 0.5 mg, as an intravitreous injection once every month for 3 months. The primary efficacy endpoint was the proportion of patients who lost fewer than 15 letters from baseline in best-corrected visual acuity. The safety profile included assessment of adverse events, ophthalmic examination, physical and systemic examination, and vital parameters. The immunogenicity assessment was based on evaluation of anti-drug antibodies. Results: Overall, 174 patients (87 [86.14%] in each group) completed the study. The demographics and baseline characteristics were comparable between the treatment groups. The proportion of patients losing fewer than 15 letters from baseline best corrected visual acuity score in the study eye was comparable between two groups. The difference between Lupin's ranibizumab and Lucentis® for the proportion of patients who lost fewer than 15 letters was within the predefined equivalence margin (intention-to-treat population: 1.0%; 95% confidence interval [CI], −3.3% to 5.4% and per protocol population: 1.2%; 95% CI, −3.2% to 6.4%). The incidence of treatment-emergent adverse events was comparable, and 11 (10.89%) patients in Lupin's ranibizumab and 19 (18.81%) patients in Lucentis® group had at least one treatment-emergent adverse event. The immunogenicity incidence as assessed by proportion of patients with positive anti-drug antibodies was numerically lower in Lupin's ranibizumab (4.95%) than Lucentis® (12.87%). Conclusion: Lupin's biosimilar ranibizumab demonstrated therapeutic equivalence, desirable safety, and favorable immunogenicity profile compared to Lucentis®.

Introduction: Pegfilgrastim is indicated in patients receiving myelosuppressive anticancer drugs to reduce the Duration of Severe Neutropenia (DSN) and incidence of Febrile Neutropenia (FN). The efficacy and safety of a proposed Pegfilgrastim biosimilar should be compared with an approved biologic drug to establish therapeutic equivalence. Aim: To compare the efficacy of Lupin’s biosimilar Pegfilgrastim versus Neulastim® (Amgen Inc.) as an adjunct to chemotherapy in patients with non-myeloid malignancies. Materials and Methods: The present prospective, open-label, randomised phase lll clinical study was conducted on a total of 170 patients with histologically or cytologically confirmed non-myeloid malignancies eligible to receive a myelosuppressive chemotherapy regimen. The participants were administered Lupin’s Pegfilgrastim (n=86) or Neulastim® (n=84) 6 mg by subcutaneous injection, once in each chemotherapy cycle for a maximum of three cycles. Patients were chemotherapy naive or had not received myelosuppressive chemotherapy within last 12 months of screening. The primary efficacy endpoint was DSN (number of days on which absolute neutrophil count

ABSTRACT: Purpose: The radiation oncology workforce in the United States is comparatively less diverse than the U.S. population and U.S. medical school graduates. Workforce diversity correlates with higher quality care and outcomes. The purpose of this study was to determine whether student members of the American Society for Radiation Oncology (ASTRO) are any more diverse than resident members-in-training using the recently established medical student membership category. Methods and Materials: Self-reported sex, race and Hispanic ethnicity, medical school, and degree(s) earned for all medical students (n = 268) and members-in-training (n = 713) were collected from the ASTRO membership database. International members were excluded. The χ2 test was used to assess for differences between subgroups. Results: Compared with members-in-training, student members were more likely to be female (40.0% vs 31.5%, P = .032), black or African American (10.7% vs 4.8%, P = .009), candidates for or holders of a DO rather than MD degree (5.2% vs 1.5%, P = .002), and from a U.S. medical school that is not affiliated with a radiation oncology residency program (30.5% vs 20.9%, P = .001). There was no significant difference in self-reported Hispanic ethnicity (7.3% vs 5.4%, P = .356). There were no indigenous members in either category assessed. Conclusions: Medical student members of ASTRO are more diverse in terms of black race, female sex, and osteopathic training, though not in terms of Hispanic ethnicity or nonmultiracial indigenous background, than the members-in-training. Longitudinal engagement with these students and assessment of the factors leading to specialty retention versus attrition may increase diversity, equity, and inclusion in radiation oncology.

Abstract Purpose Study objectives were to examine: (a) biomarker trajectories (change from presurgical baseline values of Lymphedema index (L‐Dex) units and arm volume difference) and symptom cluster scores 24 months after breast cancer surgery and (b) associations of these objective biomarkers and symptom cluster scores. Patient/treatment characteristics influencing trajectories were also evaluated. Methods A secondary analysis of data from the published interim analysis of a randomized parent study was undertaken using trajectory analysis. Five hundred and eight participants included in the prior analysis with 24 months of postsurgical follow‐up were initially measured with bioelectric impedance spectroscopy (BIS) and tape measure (TM) and completed self‐report measures. Patients were reassessed postsurgery for continuing eligibility and then randomized to either BIS or TM groups and measured along with self‐report data at regular and optional* visits 3, 6,12,15*,18, 21*, and 24‐months. Results Three subclinical trajectories were identified for each biomarker (decreasing, stable, increasing) and symptom cluster scores (stable, slight increase/decrease, increasing). Subclinical lymphedema was identified throughout the 24‐month period by each biomarker. An L‐Dex increase at 15 months in the BIS group was noted. The self‐report sets demonstrated contingency coefficients of 0.20 (LSIDS‐A soft tissue, P = .031) and 0.19 (FACTB+4, P = .044) with the L‐Dex unit change trajectories. Conclusions These data support the need for long‐term (24 months) prospective surveillance with frequent assessments (every 3 months) at least 15 months after surgery. Statistically significant convergence of symptom cluster scores with L‐Dex unit change supports BIS as beneficial in the early identification of subclinical lymphedema.

Background: In cancer, platelets may facilitate metastatic spread by a number of mechanisms as well as contribute to thrombotic complications. Ticagrelor, a platelet antagonist- that blocks adenosine diphosphate activation of platelet P2Y12 receptors, is widely used in the treatment of cardiovascular disease, but its efficacy in cancer remains unknown. Objectives: This study sought to evaluate the effect of aspirin and ticagrelor monotherapy, as well as dual antiplatelet therapy, on platelet activation in cancer. Methods: This study consisted of 2 phases: first, an in vitro study of human platelet−tumor cell interaction; and second, a randomized crossover clinical trial of 22 healthy donors and 16 patients with metastatic breast or colorectal cancer. Platelet activation and inhibition were measured by aggregometry and flow cytometry. Results: In vitro, tumor cells induced cellular clusters that were predominantly platelet−platelet aggregates. Ticagrelor significantly inhibited formation of large tumor cell-induced platelet−platelet aggregates: 65.4 ± 4.8% to 50.9 ± 5.9% (p = 0.002) and 62.3 ± 3.1% to 48.3 ± 7.3% (p = 0.014) for MCF-7 and HT-29-induced aggregation, respectively. Supporting this finding, cancer patients on ticagrelor had significantly reduced levels of spontaneous platelet aggregation and activation compared with baseline; 14.8 ± 2.7% at baseline to 7.8 ± 2.3% with ticagrelor (p = 0.012). Conclusions: Our findings suggested that P2Y12 inhibition with ticagrelor might reduce spontaneous platelet aggregation and activation in patients with metastatic cancer and merits further investigation in patients at high risk of cancer-associated thrombosis. (Ticagrelor-Oncology [TICONC] Study; EudraCT: 2014-004049-29)

Abstract Introduction YLB113 is a biosimilar of the reference product (RP), etanercept, under development for treatment of patients with moderate-to-severe rheumatoid arthritis (RA) and other approved indications. A phase 3 study was conducted in Europe, Japan, and India to compare the efficacy, safety, and immunogenicity of YLB113 with the RP over a treatment period of 52 weeks. Methods Overall, 528 patients with moderate-to-severe RA receiving concomitant methotrexate were randomized to receive a once-weekly, subcutaneous dose of 50 mg YLB113 or the RP. The primary endpoint was ACR20 response rate at week 24, with similarity confirmed if the 95% confidence interval (CI) for YLB113 and the RP was within the range of − 15 to 15%. Safety and immunogenicity endpoints were assessed to week 52. Results Based on the European analysis, in the full analysis set, ACR20 response at week 24 was 83.3% and 88.5% for YLB113 and the RP, respectively. Responses were within the predefined clinical equivalence margin. The sensitivity analysis in the per protocol set revealed a similar proportion of subjects exhibiting ACR20 response at week 24 between groups, with a difference of − 5.1% (95% CI − 11.07 to 0.81). The incidence of treatment-emergent adverse events was comparable between groups, and the incidence of antidrug antibody development to week 24 favored YLB113 (0.8 vs. 8.3%). Conclusions This study demonstrated biosimilarity of YLB113 to the RP regarding efficacy, safety, and immunogenicity in patients with moderate-to-severe RA. Based on the same mechanism of action, biosimilarity could be extrapolated to other therapeutic indications approved for etanercept. Trial registration EudraCT Number: 2015-002,809-12.

BackgroundCardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records.Methods and findingsWe built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p < 0.001; Troponin T > 0.05 μg/L versus Troponin T ≤ 0.01 μg/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings.ConclusionsIn this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology.

Background and Aim Interpreting stool form diaries for subtyping patients with the irritable bowel syndrome (IBS) is cumbersome; a picture showing a trend would be easier to interpret. Methods Fifty‐one consecutive adults with IBS (median age 35.5 years; 47 men), diagnosed using the Rome III criteria, were given a picture of the Bristol stool form scale (BSFS) and asked to record their stool frequency and form for 7 days. The numbers were plotted by a technician as dots on a chart. On the y axis, BSFS category 4 was marked as 0, harder stools as +1 to +3, and softer stools as −1 to −3; each bowel movement was represented on the x axis. A line graph was plotted by connecting the dots. Each “fecograph” was then given for visual interpretation to three gastroenterologists (observers). When most readings appeared to be 0, +1, or −1, it was to be reported as normal; most above +1 as IBS‐constipation (IBS‐C); most below −1 as IBS‐diarrhea (IBS‐D); and readings crossing 1 on either side as IBS‐mixed (IBS‐M). If no clear trend was noted, it was IBS‐unclassified (IBS‐U). Each observer reported all graphs in different orders twice, at 1‐month intervals; thus, 306 reports were available. Interclass correlation coefficient (ICC) was calculated. Results Eighteen patients had IBS‐C, 13 IBS‐D, 4 IBS‐M, and 16 IBS‐U. The 51 fecographs were reported in mean 20 min 36 s. ICC for intra‐ and interobserver reliability was 0.62 (0.50–0.73). Conclusion The fecograph is a reliable and easy‐to‐use tool to subtype patients with IBS.

Background: Treatment for locally recurrent breast cancer poses a significant challenge because the benefits in local control must be weighed against the increased risk of side effects of the treatment. Frequently, patients have been heavily pre-treated with radiation and several types of chemotherapy. Moreover, they often present with large volumes of bulky disease, further complicating management. Hyperthermia can be used to improve the efficacy of radiation, particularly in the setting of recurrent disease. Methods: We reviewed our clinical and dosimetric experience of breast cancer patients who received hyperthermia and radiation for recurrent breast cancer from 2011 to 2017. Thirty-six patients were treated with hyperthermia and radiation. Median follow-up was 11 months. Thirty patients (83.3%) received prior radiotherapy. The most commonly used radiation fraction scheme was 32 Gy in 8 fractions. The median radiation dose at the time of recurrence was 35.5 Gy (range 20–64 Gy). Mild temperature hyperthermia was delivered two times per week. Results: The median repeat radiation volume was 574 cc (range 11–3620 cc). Electrons, conventional photons, and IMRT radiation techniques were used. IMRT was used for large and complex treatment volumes and showed acceptable doses to organs at risk. The overall response rate was 61.1%. Complete response was observed in 17 patients (47.2%), partial response in 5 patients (13.9%), stable disease in 11 patients (30.6%), and progressive disease in 3 patients (8.3%). Twenty-six patients experienced acute grade 1 and 2 toxicities, primarily pain and erythema; and 26 experienced long-term grade 1 and 2 toxicities, mainly hyperpigmentation and lymphedema. Three patients developed new ulcerations that healed with conservative management. One patient developed pulmonary fibrosis resulting in mild dyspnea on exertion. Conclusion: Hyperthermia and radiation provide good local control with a favorable side effect profile. Thermoradiotherapy may be offered to patients with recurrent breast cancer, including those with extensive volumes of disease.

Due to the increasing use of the different composite materials in lightweight applications, such as in aerospace, it becomes crucial to understand the different damages occurring within them during life cycle and their possible inspection with different inspection techniques in different life cycle stages. A comprehensive classification of these damage patterns, measuring signals, and analysis methods using a taxonomical approach can help in this direction. In conjunction with the taxonomy, this work addresses damage diagnostics in hybrid and composite materials, such as fibre metal laminates (FMLs). A novel unified taxonomy atlas of damage patterns, measuring signals, and analysis methods is introduced. Analysis methods based on advanced supervised and unsupervised machine learning algorithms, such as autoencoders, self-organising maps, and convolutional neural networks, and a novel z-profiling method, are implemented. Besides formal aspects, an extended use case demonstrating damage identification in FML plates using X-ray computer tomography (X-ray CT) data is used to elaborate different data analysis techniques to amplify or detect damages and to show challenges.

Introduction: Serological surveys estimating the cumulative incidence of the disease are powerful and effective tools for monitoring the epidemic and in determining the immunity status. Objectives: To compare the percentage sero-positivity for IgG antibodies against SARS-CoV2 at two different time period in the same population to understand the pandemic and predict about the immunity status of the population. Methods: As a part of Covid19 pandemic management, two separate population based sero-survey within a gap of 1½ months were carried in Ahmedabad city to scientifically document the progress of the Covid19 pandemic. Various demographic factors and other parameters from both the survey were compared with seropositivity for valid and precise estimation of disease situation as well as immunity status of the population. Results: The study documents an increase in seropositivity by 5.32% (from 17.92% to 23.24%). The seropositivity shows increasing trend with increase in the age group and the seropositivity is significantly higher among females. Overall higher seropositivity against the reported cases in the first sero-survey and the narrow increase in the seropositivity during the subsequent sero-survey inspite of high number of cases may indicate temporary status of the antibodies. This may also be due to the difference in the level of stigma, health care service delivery, service utilization and related field level situation affecting the asymptomatic/unreported case positivity. Conclusion: The result of seropositivity comparison indicates the scopes for further research to confirm and generate greater evidences regarding the factors affecting seropositivity.

PurposeHow modern cardiac sparing techniques and beam delivery systems using advanced x-ray and proton beam therapy (PBT) can reduce incidental radiation exposure doses to cardiac and pulmonary organs individually or in any combination is poorly investigated.MethodsAmong 15 patients with left-sided breast cancer, partial wide tangential 3D-conformal radiotherapy (3DCRT) delivered in conventional fractionation (CF) or hypofractionated (HF) schedules; PBT delivered in a CF schedule; and volumetric modulated arc therapy (VMAT) delivered in an HF schedule, each under continuous positive airway pressure (CPAP) and free-breathing (FB) conditions, were examined. Target volume coverage and doses to organs-at-risk (OARs) were calculated for each technique. Outcomes were compared with one-way analysis of variance and the Bonferroni test, with p-values

Background: Early detection is the key to contain the ongoing pandemic. The current gold standard to detect SARS CoV2 is RT-PCR. However, it has a high false negative rate and long turnaround time. Purpose: In view of the high sensitivity of CT in detection of lower respiratory tract pathologies, a study of 2581 patients comparing RT-PCR status with CT findings was undertaken to see if it augments the diagnostic performance. Materials and Methods: A multi centre prospective study of consecutive cases was conducted. All CT studies suggestive of COVID 19 pneumonia were collated and evaluated independently by three Radiologists to confirm the imaging diagnosis of COVID-19 pneumonia. The RT-PCR values were retrospectively obtained, based on the RT-PCR values, CT studies were categorised into three subgroups, positive, negative and unknown. CT features from all three groups were compared to evaluate any communality or discordance. Results: Out of the 2581 patients with positive CT findings for COVID pneumonia, 825 were females and 1,756 were males in a wide age group of 28-90 years. Predominant CT features observed in all the subgroups were Ground glass densities 94.8%, in mixed distribution (peripheral and central) (59.12%), posterior segments in 92% and multilobar involvement in 70.9%. The CT features across the three subgroups were statistically significant with a P value

The COVID-19 pandemic began in late December in 2019 and has now reached to 216 countries with 1,08,42,028 confirmed cases and 5,21,277 deaths according to the WHO reports and 6,49,666 confirmed cases in india alone with 18,679 deaths (as on 04th july 2020) . RT-PCR has been considered the standard test for diagnosis of COVID 19. However, there has been reported a high false negative rate. This high false negative rate increases the risk of further transmission as well as delays the timely management of suspected cases. We have conducted HRCT chest of various (200 patient case study) proven and suspected cases of COVID-19 infection in the months of April, May and June 2020. Out of 200 scanned patients with clinical complains and suspicion, positive HRCT chest findings were seen in 196 patients, showing clinical-radiological correlation and an accuracy of 98%. The sensitivity of chest CT in suggesting COVID-19 was 98.6% (146/148patients) based on positive RT-PCR results. In patients with negative RT-PCR results and high clinical suspicion, 90% (18/20) had positive chest CT findings. HRCT chest is very sensitive and accurate in picking up lung parenchymal abnormalities in laboratory negative RT-PCR cases with high clinical suspicion of COVID-19 infection and also in all symptomatic patients where RT-PCR was not done. HRCT can also be very sensitive, cost effective and time effective in screening patients with high clinical suspicion. HRCT scores over RT-PCR in giving immediate results, assessing severity of disease and prediction of prognosis. We suggest HRCT chest for detection of early parenchymal abnormalities, assessing severity of disease in all patients with clinical symptoms and suspicion of COVID infection irrespective of laboratory RT-PCR status.

Background The growing awareness of cardiovascular toxicity from cancer therapies has led to the emerging field of cardio‐oncology, which centers on preventing, detecting, and treating patients with cardiac dysfunction before, during, or after cancer treatment. Early detection and prevention of cancer therapy–related cardiac dysfunction (CTRCD) play important roles in precision cardio‐oncology. Methods and Results This retrospective study included 4309 cancer patients between 1997 and 2018 whose laboratory tests and cardiovascular echocardiographic variables were collected from the Cleveland Clinic institutional electronic medical record database (Epic Systems). Among these patients, 1560 (36%) were diagnosed with at least 1 type of CTRCD, and 838 (19%) developed CTRCD after cancer therapy (de novo). We posited that machine learning algorithms can be implemented to predict CTRCDs in cancer patients according to clinically relevant variables. Classification models were trained and evaluated for 6 types of cardiovascular outcomes, including coronary artery disease (area under the receiver operating characteristic curve [AUROC], 0.821; 95% CI, 0.815–0.826), atrial fibrillation (AUROC, 0.787; 95% CI, 0.782–0.792), heart failure (AUROC, 0.882; 95% CI, 0.878–0.887), stroke (AUROC, 0.660; 95% CI, 0.650–0.670), myocardial infarction (AUROC, 0.807; 95% CI, 0.799–0.816), and de novo CTRCD (AUROC, 0.802; 95% CI, 0.797–0.807). Model generalizability was further confirmed using time‐split data. Model inspection revealed several clinically relevant variables significantly associated with CTRCDs, including age, hypertension, glucose levels, left ventricular ejection fraction, creatinine, and aspartate aminotransferase levels. Conclusions This study suggests that machine learning approaches offer powerful tools for cardiac risk stratification in oncology patients by utilizing large‐scale, longitudinal patient data from healthcare systems.

Background: Urethral caruncles are lesions occurring at the urethral orifice, around the posterior lip of the urethra. They are the most common benign growth of the female urethra. They are often asymptomatic and found incidentally on clinical examination. When symptomatic they commonly present with bleeding. Treatment includes vaginal oestrogens or, failing that, surgical excision. We present an unusual finding after excision of a urethral caruncle. Case: A patient with a background of stress urinary incontinence had numerous pelvic surgeries, including colposuspension, tension-free vaginal tape (TVT) and Macroplastique (a urethral bulking agent). She developed bleeding from a 3 cm urethral caruncle, which did not improve with vaginal oestrogens. She proceeded to have a surgical excision of the caruncle. Histology revealed a foreign material with surrounding foreign-body-type multinucleate giant cell reaction. The material was compatible with Macroplastique. Conclusion: This case report describes an unusual and unexpected histological finding. Macroplastique is injected in the urethra, 10–15 mm from the bladder neck. We suspect the caruncle dragged the Macroplastique material out through the urethral meatus. If urethral caruncles are not adequately treated with vaginal oestrogens, surgery should be considered.

Cardiac arrest in an event of acute myocardial infarction most commonly results in life-threatening ventricular tachycardia or ventricular fibrillation (VF). Patients who remain in VF despite optimal epinephrine, amiodarone, and three or more attempts at 200 joules of biphasic current defibrillation are known to be in an electrical storm. Here, we describe a case of defibrillation refractory VF responding to intravenous esmolol resulting in a successful return of spontaneous circulation. Learning objective. This case reinforces the growing body of evidence supporting esmolol as a novel treatment approach for refractory VF before the cessation of resuscitative efforts.

Abstract Cardiac Purkinje cells (PCs) are more susceptible to action potential abnormalities as compared to ventricular myocytes (VMs), which could be associated with their distinct intracellular calcium handling. We developed a detailed biophysical model of a mouse cardiac PC, which importantly reproduces the experimentally observed biphasic cytosolic calcium waves. The model includes a stochastic gating formulation for the opening and closing of ryanodine receptor (RyR) channels, simulated with a Monte Carlo method, to accurately reproduce cytosolic calcium wave propagation and the effects of spontaneous calcium release events. Simulations predict that during an action potential, smaller cytosolic calcium wavelets propagated from the sarcolemma towards the center of the cell and initiated larger magnitude cell‐wide calcium waves via a calcium‐induced‐calcium release mechanism. In the presence of RyR mutations, frequent spontaneous calcium leaks from sarcoplasmic reticulum (SR) initiated calcium waves, which upon reaching the cell periphery produced delayed afterdepolarizations (DADs) via sodium‐calcium exchanger (NCX) and T‐type calcium (ICaT) channel activation. In the presence of isoproterenol‐mediated effects, DADs induced triggered activity by reactivation of fast sodium channels. Based on our model, we found that the activation of either L‐type calcium channels (ICaL), ICaT, sodium‐potassium exchanger (INaK) or NCX is sufficient for occurrence of triggered activity; however, a partial blockade of ICaT or INaK is essential for its successful termination. Our modeling study highlights valuable insights into the mechanisms of DAD‐induced triggered activity mediated via cytosolic calcium waves in cardiac PCs and may elucidate the increased arrhythmogeneity in PCs.

We present the case of a 59-year-old man with atraumatic splenic rupture because of splenic vein thrombosis who was successfully treated with splenic artery embolization.

Accelerated partial breast irradiation (APBI) represents an evolving technique that is a standard of care option in appropriately selected woman following breast conserving surgery. While multiple techniques now exist to deliver APBI, interstitial brachytherapy represents the technique used in several randomized trials (National Institute of Oncology, GEC-ESTRO). More recently, many centers have adopted applicator-based brachytherapy to deliver APBI due to the technical complexities of interstitial brachytherapy. The purpose of this article is to review methods to evaluate and select patients for APBI, as well as to define potential workflow mechanisms that allow for the safe and effective delivery of APBI. Multiple consensus statements have been developed to guide clinicians on determining appropriate candidates for APBI. However, recent studies have demonstrated that these guidelines fail to stratify patients according to the risk of local recurrence, and updated guidelines are expected in the years to come. Critical elements of workflow to ensure safe and effective delivery of APBI include a multidisciplinary approach and evaluation, optimization of target coverage and adherence to normal tissue guideline constraints, and proper quality assurance methods.

PurposeWe evaluated the impact of structured surveillance using bioimpedance spectroscopy (BIS) to reduce the rate of chronic breast cancer-related lymphedema (BCRL) in high-risk patients undergoing axillary lymph node dissection (ALND).MethodsFrom April 2010 through November 2016, 93 patients who underwent ALND were prospectively monitored with BIS using L-Dex. Intervention for an L-Dex increase of >10 consisted of applying an over the counter (OTC) sleeve followed by re-evaluation after 4 weeks. The utilization of complex decongestive physiotherapy (CDP) represented a surrogate for chronic BCRL.ResultsMedian follow-up was 24 months. 55% of patients received taxane-based chemotherapy, 24% received some form of axillary irradiation (includes additional fields or high tangents) and 66% had an elevated body mass index (BMI) with the median number of nodes removed being 19. Overall, 75% of these patients had at least one additional high-risk feature (taxane chemotherapy, axillary radiation, elevated BMI), 48% had at least two, and 6% had all. Thirty-three patients (35.4%) developed an elevated L-Dex score with only 10 (10.8%) requiring CDP (30.3% of those undergoing treatment with sleeve). At last follow-up, only three patients (3%) had unresolved BCRL.ConclusionThe results of this analysis support previous data regarding prospective BCRL surveillance and early intervention using BIS. With this approach, only 3% of patients have chronic BCRL.

IntroductionIntraoperative radiation with Intrabeam™ (IORT) for breast cancer is a newer technology recently implemented into the operating room (OR). This procedure requires time and coordination between the surgeon and radiation oncologist, who both perform their treatments in a single operative setting. We evaluated the surgeons at our center, who perform IORT and their OR times to examine changes in OR times following implementation of this new surgical procedure. We hypothesized that IORT is a technique for which timing could be improved with the increasing number of cases performed.MethodsA prospectively maintained IRB approved database was queried for OR times (incision and close) in patients who underwent breast conserving surgery (BCS), sentinel lymph node biopsy with and without IORT using the Intrabeam™ system at our institution from 2011 to 2015. The total OR times were compared for each surgeon individually and over time. Next, the OR times of each surgeon were compared to each other. Continuous variables were summarized and then a prediction model was created using IORT time, OR time, surgeon, and number of cases performed.ResultsThere were five surgeons performing IORT at our institution during this time period with a total of 96 cases performed. There was a significant difference observed in baseline surgeon-specific OR time for BSC (p = 0.03) as well as for BCS with IORT (p

Purpose. One benefit of intraoperative radiation therapy (IORT) is that it usually requires a single treatment, thus potentially eliminating distance as a barrier to receipt of whole breast irradiation. The aim of this study was to evaluate the distance traveled by IORT patients at our institution. Methods. Our institutional prospective registry was used to identify IORT patients from 10/2011 to 2/2017. Patient’s home zip code was compared to institution zip code to determine travel distance. Characteristics of local (100 miles) patients were compared. Results. 150 were patients included with a median travel distance of 27 miles and mean travel distance of 121 miles. Most were local (68.7%), with the second largest group living faraway (20.0%). Subset analysis of local patients demonstrated 20.4% traveled 1000 miles. The local, regional, and faraway patients did not differ with respect to age, race, tumor characteristics, or whole breast irradiation. Conclusions. Breast cancer patients are traveling for IORT, with 63% traveling >20 miles for care. IORT is an excellent strategy to promote breast conservation in selected patients, particularly those who live remote from a radiation facility.

History of present illness: An 88-year-old female was found lying prone and unresponsive outside of her home with an unknown downtime. She was intubated in the field by medics and brought to the emergency department (ED). In the ED, she had a core temperature of 78 degrees Fahrenheit (°F) with a heart rate of 21 beats per minute. Active rewarming and resuscitation were started and serial electrocardiograms (ECGs) were performed; two hours later, her core temperature had increased to 86°F. Significant findings: The initial ECG shows a junctional rhythm with Osborn waves (or J point elevations/J waves) in the lateral precordial leads, as well as the limb leads (Image 1). The second ECG, 49 minutes later, shows an improving ventricular rate and Osborn wave height decrease of approximately 50% (Image 2). Discussion: Differentiating between mild, moderate and severe hypothermia can help guide resuscitation efforts in these patients. Patients with mild hypothermia have core temperatures between 90-95°F and present with shivering, tachypnea, and tachycardia. Those with moderate hypothermia have core temperatures between 82-90°F and present with muscle rigidity, altered mental status, bradycardia and hypoventilation. Severe hypothermia is defined as a core temperature below 82°F. These patients are often comatose, hypotensive, and apneic.1 Patients with primary hypothermia and cardiac stability who have been treated with active external and minimally invasive rewarming techniques have a rate of neurologically intact survival of approximately 100%.2 For patients with primary hypothermia and cardiac instability or cardiac arrest, extracorporeal membrane oxygenation (ECMO) may be the best treatment option. The rate of neurologically intact survival for patients with cardiac arrest treated with extracorporeal rewarming is approximately 50%. If ECMO or cardiopulmonary bypass is not available and transport to a facility with these capabilities is not possible, circulation should be supported with CPR while the patient is rewarmed with an alternative internal rewarming technique. Topics: EKG, Osborn wave, J wave, ECG, cardiology, environmental, hypothermia, ECMO

History of present illness: A 56-year-old male, with a history of hypertension, diabetes, and dyslipidemia, presented with chest pain, fever, and abdominal pain associated with diarrhea, one day post colonoscopy, for which an electrocardiogram (ECG) was done. On further review of history, the patient reported a syncopal episode 2 monthprior. Additionally, he reports a brother who died of sudden cardiac death (SCD) at the age 50. Significant findings: ECG shows an incomplete right bundle branch block (blue arrow) with coved ST segment elevation and an inverted T wave in V1 (red arrow) and ST segment elevation in V2 (black arrow). Discussion: Brugada syndrome is a rare autosomal dominant disease with mutations in the cardiac sodium channel. It is highly associated with ventricular fibrillation and sudden cardiac death (SCD) in predominately middle-aged males.1 The diagnosis is based on a particular ECG pattern described by the Brugada brothers in 1992.2 There are 3 types of Brugada patterns. Our patient’s ECG was consistent with type 1, which is diagnostic and is characterized by a coved ST segment elevation greater than 2mm followed by a negative T wave in the precordial leads.3 Other types include type 2, which shows a saddle-back ST segment elevation with a J-wave greater than 2mm followed by a positive or biphasic T wave, and type 3, which shows ST elevation less than 2 mm in either coved or saddle-back type T wave.4 Patients with Brugada syndrome often present with syncope, non-sustained ventricular tachycardia, atrial fibrillation, or SCD, with a family history of similar episodes. The presence of fever, alcohol intake, sodium channel blockers, cocaine use, and electrolyte imbalances can significantly increase the incidence of arrhythmia.1 The risk of cardiac events in patients with type 1 Brugada and syncope is 1.9% per year and 7.7% per year in those with aborted SCD.3 An implantable cardiac defibrillator (ICD) is the main treatment for symptomatic patients. Those who are asymptomatic or those with type 2 or 3 morphology should undergo further genetic testing and risk stratification for ICD placement.1 Our patient had a negative cardiac catheterization but with his ECG pattern along with his history of syncope and family history of SCD, he was diagnosed with type 1 Brugada syndrome and received an ICD. Topics: EKG, ECG, cardiology, Brugada, arrhythmia

History of present illness: 70-year-old male with a history ventricular arrhythmia, AICD (automated implantable cardioverter defibrillator), coronary artery disease and cardiac stents presented to the Emergency Department after three AICD discharges with dyspnea but no chest pain. During triage, he was found to have an irregular radial pulse and was placed on a cardiac monitor. Significant findings: The patient was found to be in a polymorphic ventricular tachycardia; he was alert, awake and asymptomatic. A rhythm strip showed a wide complex tachycardia with the QRS complex varying in amplitude around the isoelectric line consistent with Torsades de Pointes. Discussion: Torsades de Pointes (TdP) is a specific type of polymorphic ventricular tachycardia. The arrhythmia’s characteristic morphology consists of the QRS complex “twisting” around the isoelectric line with gradual variation of the amplitude, reflecting its literal translation of “twisting of the points.”1 This arrhythmia occurs in the context of prolonged QT. The most common form of acquired QT prolongation is medication induced. Common causes include antiarrhythmics, antipsychotics, antiemetics, and antibiotics.2 Patient specific risk factors include female sex, bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, hypothermia and heart disease.3 In the setting of prolonged QT, the repolarization phase is extended. TdP is initiated when a PVC (premature ventricular contraction) occurs during this repolarization, known as an ‘R on T’ phenomenon. TdP is often asymptomatic and self-limited. The danger in TdP is its potential to deteriorate into ventricular fibrillation. A mainstay of management of TdP is prevention of risk factors when possible.4 Unstable patients should be treated with synchronized cardioversion. Magnesium sulfate should be administered in all cases of TdP.1 If a patient is not responsive to magnesium, consider isoproterenol, amiodarone, and overdrive pacing. Since this patient was asymptomatic, he was given 2gm of magnesium sulfate and placed on an amiodarone infusion, after which Tdp terminated with a resulting sinus rhythm. AICD interrogation showed multiple episodes of ventricular fibrillation. The patient was admitted for further management and to determine why his AICD was not functioning properly. Topics: EKG, ECG, cardiology, ventricular tachycardia, arrhythmia, Torsades de Pointes

High-risk prostate cancer is an aggressive form of the disease with an increased risk of distant metastasis and subsequent mortality. Multiple randomized trials have established that the combination of radiation therapy and long-term androgen deprivation therapy improves overall survival compared to either treatment alone. Standard of care for men with high-risk prostate cancer in the modern setting is dose-escalated radiotherapy along with 2-3 years of androgen deprivation therapy (ADT). There are research efforts directed towards assessing the efficacy of shorter ADT duration. Current research has been focused on assessing hypofractionated and stereotactic body radiation therapy (SBRT) techniques. Ongoing randomized trials will help assess the utility of pelvic lymph node irradiation. Research is also focused on multimodality therapy with addition of a brachytherapy boost to external beam radiation to help improve outcomes in men with high-risk prostate cancer.

Objectives: To evaluate prospective single centre experience of mid-term safety and efficacy of perventricular device closure of isolated large muscular ventricular septal defect (mVSD) in high-risk infants. Background: Surgical closures of large mVSD in infants represent a challenge with significant morbidity. Methods: Between August 2008–2010, perventricular closure was attempted in 24 infants of 6.01 ± 2.37 months age and 4.27 ± 0.56 kg weight under TEE guidance. Results: The device was successfully deployed in 21/24 infants. Size of mVSD was 8.42 ± 1.46 mm (6.1–12 mm). Mean procedure time was 28.8 ± 11.7 min. The closure rate was 84% immediately and 100% at 6 months. Four patients suffered major complications: 2-died, 1-esophageal perforation, 1-persistent CHB. At 26.23 ± 6.63 months follow-up two patients were symptomatic: 1-required device retrieval, 1-died of severe gastroenteritis. Conclusion: Perventricular device closure of isolated mVSD appears feasible option at mid-term follow-up and may either substitute or complement the conventional surgical technique in selected cases depending on institutional paediatric cardiac surgery performance.

Emerging information media present new challenges to the curators. While archiving objects, and building meaningful collection for long-term preservation and access, have been well-understood practice for centuaries, digital objects present new issues. In the previous article (Shah, 2009) I identified a number of these issues related to digital objects, specifically digital videos of an ephemeral nature. I argued that while preserving such objects, adding contextual information is essential. One of the interesting challenges is to identify what to collect and preserve as contextual information. For ephemeral digital videos, I proposed to harvest four kinds of relevances and five kinds of contexts. In order to implement this proposal, I presented ContextMiner, a framework and a system to support digital video curation. In this article, I will take a closer look at ContextMiner, analyzing it for its functionalities and usability. This is done by usability inspection and content analysis. For the former, we simulated two curatorial tasks, asked our users (curators) to use ContextMiner, and provide us feedback on its usability and functionalities. For the latter, we mined a collection prepared by ContextMiner for its potential usage in preservation. Finally, I have summarized the lessons learned from developing and using our system, providing implications for digital library curators interested in collecting and preserving digital objects of an ephemeral nature.

For centuries the archival community has understood and practiced the art of adding contextual information while preserving an artifact. The question now is how these practices can be transferred to the digital domain. With the growing expansion of production and consumption of digital objects (documents, audio, video, etc.) it has become essential to identify and study issues related to their representation. A cura­tor in the digital realm may be said to have the same responsibilities as one in a traditional archival domain. However, with the mass production and spread of digital objects, it may be difficult to do all the work manually. In the present article this problem is considered in the area of digital video preservation. We show how this problem can be formulated and propose a framework for capturing contextual infor­mation for ephemeral digital video preservation. This proposal is realized in a system called ContextMiner, which allows us to cater to a digital curator's needs with its four components: digital video curation, collection visualization, browsing interfaces, and video harvesting and monitoring. While the issues and systems described here are geared toward digital videos, they can easily be applied to other kinds of digital objects.

Amyloid-β1–42 (Aβ1–42) is crucial to Alzheimer disease (AD) pathogenesis but the conformation of the toxic Aβ species remains uncertain. AD risk is increased by apolipoprotein E4 (apoE4) and decreased by apoE2 compared with the apoE3 isoform, but whether inheritance of apoE4 represents a gain of negative or a loss of protective function is also unresolved. Using hippocampal slices from apoE knockout (apoE-KO) and human apoE2, E3, and E4 targeted replacement (apoE-TR) mice, we found that oligomeric Aβ1–42 inhibited long-term potentiation (LTP) with a hierarchy of susceptibility mirroring clinical AD risk (apoE4-TR > apoE3-TR = apoE-KO > apoE2-TR), and that comparable doses of unaggregated Aβ1–42 did not affect LTP. These data provide a novel link among apoE isoform, Aβ1–42, and a functional cellular model of memory. In this model, apoE4 confers a gain of negative function synergistic with Aβ1–42, apoE2 is protective, and the apoE–Aβ interaction is specific to oligomeric Aβ1–42.

Sex-specific traits that lead to the production of dimorphic gametes, sperm in males and eggs in females, are fundamental for sexual reproduction and accordingly widespread among animals. Yet the sex-biased genes that underlie these sex-specific traits are under strong selective pressure, and as a result of adaptive evolution they often become divergent. Indeed out of hundreds of male or female fertility genes identified in diverse organisms, only a very small number of them are implicated specifically in reproduction in more than one lineage. Few genes have exhibited a sex-biased, reproductive-specific requirement beyond a given phylum, raising the question of whether any sex-specific gametogenesis factors could be conserved and whether gametogenesis might have evolved multiple times. Here we describe a metazoan origin of a conserved human reproductive protein, BOULE, and its prevalence from primitive basal metazoans to chordates. We found that BOULE homologs are present in the genomes of representative species of each of the major lineages of metazoans and exhibit reproductive-specific expression in all species examined, with a preponderance of male-biased expression. Examination of Boule evolution within insect and mammalian lineages revealed little evidence for accelerated evolution, unlike most reproductive genes. Instead, purifying selection was the major force behind Boule evolution. Furthermore, loss of function of mammalian Boule resulted in male-specific infertility and a global arrest of sperm development remarkably similar to the phenotype in an insect boule mutation. This work demonstrates the conservation of a reproductive protein throughout eumetazoa, its predominant testis-biased expression in diverse bilaterian species, and conservation of a male gametogenic requirement in mice. This shows an ancient gametogenesis requirement for Boule among Bilateria and supports a model of a common origin of spermatogenesis.