Does Nipple-Ward Positive Margin Contribute to a Higher Rate of Re-Excision Procedures After a Lumpectomy with Pathology-Confirmed Positive Margins? A Retrospective Study.

Background: Positive margins on lumpectomy specimens are associated with a twofold increased risk of local breast tumor recurrence. Prior literature has demonstrated various techniques and modalities for assessing margin status to reduce re-excision rates. However, there is paucity of literature analyzing which margin contributes to the highest re-excision rates. Therefore, the primary aim of the study was to investigate whether the nipple-ward margins resulted in a higher rate of re-excision in our patient population. Methods:  A retrospective chart review was performed on patients who had re-excision surgery. Nipple-ward margin was identified by correlating radiological and pathological reports. A cut-off of more than 25% was used to demonstrate correlation between nipple-ward margin and re-excision rate. Results: A total of 98 patients' data were analyzed, with 41 (41.8%), 14 (14.3%), 5 (5.1%), and 38 (38.8%) diagnosed with DCIS, IDC, ILC, and mixed pathology on their margins, respectively. Overall, 48% (n=47) of the positive margins were nipple-ward, with 44.7% (n=21) reporting DCIS. Upon stratification, 45 (45.9%) cases were single-margin positive, with 26 (57.8%) being nipple-ward. Furthermore, the remaining 53 (54.1%) patients had multiple positive margins, with 21 (39.6.7%) nipple-ward cases. Conclusion: Positive nipple-ward margins significantly contribute to a higher re-excision rate p < 0.001; 48% of re-excision surgeries had positive nipple-ward margins, and 57.8% of positive single-margin cases were nipple-ward. Taking an additional shave during initial lumpectomy decreases re-excision rates. However, planning a lumpectomy procedure with a more elliptical rather than a spherical resection with additional cavity shave (ie, larger volume) in the nipple-ward direction and minimizing the remaining cavity shaves so the total volume resected remains unchanged. Nevertheless, future studies with larger sample sizes are required to bolster our findings.

Purtscher-like retinopathy in a patient with COVID-19-associated coagulopathy / Retinopatia tipo Purtscher em paciente com coagulopatia associada ao COVID-19

ABSTRACT The most frequently reported ophthalmic manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is conjunctivitis. We have described a case of Purtscher-like retinopathy in a patient with severe coronavirus disease 2019 (COVID-19)-associated coagulopathy. A young woman with multiple comorbidities was admitted for COVID-19-related acute respiratory distress syndrome. Her course was complicated by fungemia. Ophthalmic examination revealed bilateral posterior pole, intraretinal lesions and fluconazole was added for presumed fungal retinitis. At 1-week follow-up, widespread peripapillary cotton-wool spots and hemorrhages suggestive of Purtscher-like retinopathy were observed. The levels of D-dimers, fibrinogen, and C-reactive protein were markedly elevated prior to our consultation, indicating preceding prothrombotic and pro-inflammatory states. Subsequent venous duplex revealed deep venous thrombosis in the right subclavian and internal jugular veins. Von Willebrand factor indices were markedly elevated, suggesting severe COVID-19-associated coagulopathy. Purtscher-like retinopathy, a rare occlusive microangiopathy has been described in various pro-inflammatory and prothrombotic conditions. To the best of our knowledge, this is the first report of Purtscher-like retinopathy in COVID-19-associated coagulopathy.

RESUMO A manifestação oftálmica mais frequentemente re­latada da infecção por SARS-CoV-2 é a conjuntivite. Trata-se de estudo de caso de retinopatia tipo Purtscher em uma paciente com coagulopatia grave associada ao COVID-19. Uma jovem com múltiplas comorbidades foi admitida por síndrome do desconforto respiratório agudo relacionado ao COVID-19. Seu quadro foi complicado pela fungemia. O exame oftálmico revelou pólo posterior bilateral, lesões intraretinianas e o fluconazol foi adicionado para tratar a retinite fúngica presumida. No decorrer de uma semana, manchas largas peripapilares de algodão e hemorragias sugestivas de retinopatia tipo Purtscher foram observadas. Os dímeros D, o fibrinogênio e a proteína c-reativa estavam acentuadamente elevados antes da nossa consulta, indicando um estado pró-trombótico e pró-inflamatório precedente. O duplex venoso subsequente revelou trombose venosa profunda nas veias subclávia direita e jugular interna. Os índices de fatores von Willebrand estavam marcadamente elevados, sugerindo coagulopatia grave associada ao COVID-19. A retinopatia tipo Purtscher, uma microangiopatia oclusiva rara foi descrita em várias condições pró-inflamatórias e pró-trombóticas. Para nosso conhecimento, este é o primeiro relatório de retinopatia tipo Purtscher com coagulopatia associada ao COVID-19.

Purtscher-like retinopathy in a patient with COVID-19-associated coagulopathy.

The most frequently reported ophthalmic manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is conjunctivitis. We have described a case of Purtscher-like retinopathy in a patient with severe coronavirus disease 2019 (COVID-19)-associated coagulopathy. A young woman with multiple comorbidities was admitted for COVID-19-related acute respiratory distress syndrome. Her course was complicated by fungemia. Ophthalmic examination revealed bilateral posterior pole, intraretinal lesions and fluconazole was added for presumed fungal retinitis. At 1-week follow-up, widespread peripapillary cotton-wool spots and hemorrhages suggestive of Purtscher-like retinopathy were observed. The levels of D-dimers, fibrinogen, and C-reactive protein were markedly elevated prior to our consultation, indicating preceding prothrombotic and pro-inflammatory states. Subsequent venous duplex revealed deep venous thrombosis in the right subclavian and internal jugular veins. Von Willebrand factor indices were markedly elevated, suggesting severe COVID-19-associated coagulopathy. Purtscher-like retinopathy, a rare occlusive microangiopathy has been described in various pro-inflammatory and prothrombotic conditions. To the best of our knowledge, this is the first report of Purtscher-like retinopathy in COVID-19-associated coagulopathy.

Modeling the relationship between digital nativity and Smartphone usage in learning English as a foreign language contexts.

Introduction: Despite many studies exploring the application of digital devices in foreign language learning, only some have investigated the influencing mechanisms of digital nativity on Smartphone usage in this increasingly seamless learning environment. This research aims to explore the relationships between college students' digital nativity and their use of Smartphones for English learning. Methods: The data were collected from 502 undergraduates in mainland China through self-reported questionnaires, namely the Digital Natives Assessment Scale and the Smartphone Use in Learning Foreign Language Scale. Results and Discussion: The confirmatory factor analysis validated a four-factor measurement model of digital nativity, including "grow up with technology", "comfortable with multitasking", "reliant on graphics for communication" and "thrive on instant gratification and rewards". A second-order measurement construct of favorable Smartphone usage and its first-order adverse effects in foreign language learning were also examined, demonstrating good validity and reliability. Structural equation modeling analysis revealed that students who displayed more attributes of "grow up with technology" and "thrive on instant gratifications and rewards" tended to adopt smartphones positively for English learning. In addition, those who were more familiar with technological assistance might suffer less from the adverse effects of Smartphone usage. However, the preference for immediate responses and feedback could also lead to more adverse effects when using Smartphones for English learning. Besides, "comfortable with multitasking" and "reliant on graphics for communication" didn't have any significant predictive impact on either the favorable functions or the adverse effects of Smartphone usage. Based on the research results, we discuss the theoretical and practical implications.

Coronavirus Disease 2019.

In this article, the authors review manifestations of COVID-19 in older adults, normal physiologic changes and frequent comorbidities of aging that increase pathogenicity, factors contributing to overwhelming viral spread among seniors, negative effects on health and well-being resulting from measures to control the virus, and health-system improvements necessary to protect and care for this vulnerable population.

Abnormal Red Reflex: Etiologies in a Pediatric Ophthalmology Population.

Children who present with an abnormal red reflex (ARR) are often referred to ophthalmology due to concern for retinoblastoma. However, an ARR can indicate a wide variety of pathologies, all of which have the potential to develop amblyopia and irreversible vision loss. In this retrospective cohort study, we demonstrate that children who presented with an ARR had a mean age of 22.0 ± 32.5 months and were more frequently referred by their pediatricians (74.5%). The majority of these patients (61.8%) had a normal examination on further evaluation, followed by refractive error (20.4%). Amblyopia was diagnosed in 83.9% of patients with refractive error, with a mean age of 50.3 ± 49.2 months. Because many ARR-associated pathologies require time-sensitive treatment to prevent vision loss, proper screening is critical for diagnosis. Pediatricians play a key role in screening, so education on more common ARR pathologies can better facilitate referrals and improve outcomes.

Efficacy of quality improvement and patient safety workshops for students: a pilot study.

BACKGROUND: While the Association of American Medical Colleges encourages medical schools to incorporate quality improvement and patient safety (QI/PS) into their curriculum, medical students continue to have limited QI/PS exposure. To prepare medical students for careers that involve QI/PS, the Institute for Healthcare Improvement chapter at an allopathic medical school and school of allied health professions initiated self-directed learning by offering student-led workshops to equip learners with skills to improve the quality and safety of healthcare processes. METHODS: In this prospective cohort study, workshops were hosted for medical students between 2015 and 2018 on five QI/PS topics: Process Mapping, Root-Cause Analysis (RCA), Plan-Do-Study-Act (PDSA) Cycles, Evidence Based Medicine (EBM), and Patient Handoffs. Each workshop included a hands-on component to engage learners in practical applications of QI/PS skills in their careers. Change in knowledge, attitudes, and behaviors was assessed via pre- and post-surveys using 5-point Likert scales, and analyzed using either the McNemar test or non-parametric Wilcoxon signed-rank test. Surveys also gathered qualitative feedback regarding strengths, future areas for improvement, and reasons for attending the workshops. RESULTS: Data was collected from 88.5% of learners (n = 185/209); 19.5% of learners reported prior formal instruction in these topics. Statistically significant improvements in learners' confidence were observed for each workshop. Additionally, after attending workshops, learners felt comfortable teaching the learned QI/PS skill to colleagues (mean pre/post difference 1.96, p < 0.0001, n = 139) and were more likely to pursue QI/PS projects in their careers (mean pre/post difference 0.45, p < 0.0001, n = 139). Lastly, learners demonstrated a statistically significant increase in knowledge in four out of five skills workshop topics. CONCLUSION: Few medical students have formal instruction in QI/PS tools. This pilot study highlights advantages of incorporating an innovative, student-directed modified 'flipped classroom' methodology, with a focus on active experiential learning and minimal didactic instruction.

Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.

Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin ß-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the ß-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin ß-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02-4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1ß and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation.

Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43.

A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-deficient neurons revealed downregulation of ATG7, a critical gene required for macroautophagy/autophagy. Mouse and Drosophila models lacking TARDBP/TBPH in motor neurons exhibiting age-dependent neurodegeneration and motor deficits showed reduction of ATG7 and accumulation of SQSTM1/p62 inclusions. Importantly, genetic upregulation of the autophagy pathway improved motor function and survival in TBPH-deficient flies. Together with our observation that ATG7 is reduced in ALS-FTD brain tissues, these findings identify the autophagy pathway as one key effector of nuclear depletion of TARDBP that contributes to neurodegeneration. We thus suggest that the autophagy pathway is a therapeutic target for ALS-FTD and other disorders exhibiting TARDBP pathology.Abbreviations: ALS: amyotrophic lateral sclerosis; ANOVA: analysis of variance; ChAT: choline acetyltransferase; CTSD: cathepsin D; FTD: frontotemporal dementia; LAMP1: lysosomal associated membrane protein 1; NMJ: neuromuscular junction; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein 43.

A Novel Risk Score to Predict New Onset Atrial Fibrillation in Patients Undergoing Isolated Coronary Artery Bypass Grafting.

BACKGROUND: Atrial fibrillation (AF) is common after cardiac surgery and contributes to increased morbidity and mortality. Our objective was to derive and validate a predictive model for AF after CABG in patients, incorporating novel echocardiographic and laboratory values. METHODS: We retrospectively reviewed patients at our institution without preexisting dysrhythmia who underwent on-pump, isolated CABG from 2011-2015. The primary outcome was new onset AF lasting >1 hour on continuous telemetry or requiring medical treatment. Patients with a preoperative echocardiographic measurement of left atrial diameter were included in a risk model, and were randomly divided into derivation (80%) and validation (20%) cohorts. The predictors of AF after CABG (PAFAC) score was derived from a multivariable logistic regression model by multiplying the adjusted odds ratios of significant risk factors (P < .05) by a factor of 4 to derive an integer point system. RESULTS: 1307 patients underwent isolated CABG, including 762/1307 patients with a preoperative left atrial diameter measurement. 209/762 patients (27%) developed new onset AF including 165/611 (27%) in the derivation cohort. We identified four risk factors independently associated with postoperative AF which comprised the PAFAC score: age > 60 years (5 points), White race (5 points), baseline GFR < 90 mL/min (4 points) and left atrial diameter > 4.5 cm (4 points). Scores ranged from 0-18. The PAFAC score was then applied to the validation cohort and predicted incidence of AF strongly correlated with observed incidence (r = 0.92). CONCLUSION: The PAFAC score is easy to calculate and can be used upon ICU admission to reliably identify patients at high risk of developing AF after isolated CABG.

An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations.

INTRODUCTION: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. METHODS: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. RESULTS: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 ± 10.9% in plasma and -10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. DISCUSSION: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

Profiling Perceptual Learning Styles of Chinese as a Second Language Learners in University Settings.

This study revisited Reid's (1987) perceptual learning style preference questionnaire (PLSPQ) in an attempt to answer whether the PLSPQ fits in the Chinese-as-a-second-language (CSL) context. If not, what are CSL learners' learning styles drawing on the PLSPQ? The PLSPQ was first re-examined through reliability analysis and confirmatory factor analysis (CFA) with 224 CSL learners. The results showed that Reid's six-factor PLSPQ could not satisfactorily explain the CSL learners' learning styles. Exploratory factor analyses were, therefore, performed to explore the dimensionality of the PLSPQ in the CSL context. A four-factor PLSPQ was successfully constructed including auditory/visual, kinaesthetic/tactile, group, and individual styles. Such a measurement model was cross-validated through CFAs with 118 CSL learners. The study not only lends evidence to the literature that Reid's PLSPQ lacks construct validity, but also provides CSL teachers and learners with insightful and practical guidance concerning learning styles. Implications and limitations of the present study are discussed.

Integrated immunochromatographic strip with glucometer readout for rapid quantification of phosphorylated proteins.

A new technology to quantify phospho-p5315 by converting its content to the amount of glucose which is detectable by a glucometer was developed. An immunochromatographic test strip (ITS) was used as a disposable platform, where primary antibody (Ab1)-modified Fe3O4 magnetic nanoparticles (Fe3O4-Ab1) were settled on the test zone to capture both the target phospho-p5315 and the detection antibody (Ab2)-glucose encapsulating liposome (GEL) conjugate. The measurement was based on the release and subsequent detection of glucose from Ab2-GEL using a glucose meter (GM). The amount of glucose is proportional to the phospho-p5315 concentration from 0.1 to 50 ng mL-1, the limit of detection is 50 pg mL-1 (3S/N). The high sensitivity was a result of the huge number of glucose encapsulated in the liposome. Taking the advantage of low cost, widespread availability and portability of the test trip, together with the personal GM, the presented approach can be easily used to detect other disease biomarkers in medical diagnostics and environmental monitoring.

Tdp-43 cryptic exons are highly variable between cell types.

BACKGROUND: TDP-43 proteinopathy is a prominent pathological feature that occurs in a number of human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and inclusion body myositis (IBM). Our recent finding that TDP-43 represses nonconserved cryptic exons led us to ask whether cell type-specific cryptic exons could exist to impact unique molecular pathways in brain or muscle. METHODS: In the present work, we investigated TDP-43's function in various mouse tissues to model disease pathogenesis. We generated mice to conditionally delete TDP-43 in excitatory neurons or skeletal myocytes and identified the cell type-specific cryptic exons associated with TDP-43 loss of function. RESULTS: Comparative analysis of nonconserved cryptic exons in various mouse cell types revealed that only some cryptic exons were common amongst stem cells, neurons, and myocytes; the majority of these nonconserved cryptic exons were cell type-specific. CONCLUSIONS: Our results suggest that in human disease, TDP-43 loss of function may impair cell type-specific pathways.

Management of sickle cell disease in patients undergoing cardiac surgery.

Sickle cell disease is a life-limiting inherited hemoglobinopathy that poses inherent risk for surgical complications following cardiac operations. In this review, we discuss preoperative considerations, intraoperative decision-making, and postoperative strategies to optimize the care of a patient with sickle cell disease undergoing cardiac surgery.

Rodent models of TDP-43: recent advances.

Recently, missense mutations in the gene TARDBP encoding TDP-43 have been linked to familial ALS. The discovery of genes encoding these RNA binding proteins, such as TDP-43 and FUS/TLS, raised the notion that altered RNA metabolism is a major factor underlying the pathogenesis of ALS. To begin to unravel how mutations in TDP-43 cause dysfunction and death of motor neurons, investigators have employed both gain- and loss-of-function studies in rodent model systems. Here, we will summarize major findings from the initial sets of TDP-43 transgenic and knockout rodent models, identify their limitations, and point to future directions toward clarification of disease mechanism(s) and testing of therapeutic strategies that ultimately may lead to novel therapy for this devastating disease. This article is part of a Special Issue entitled RNA-Binding Proteins.

Physiological and pharmacological roles of vascular nucleoside transporters.

Adenosine modulates various vascular functions such as vasodilatation and anti-inflammation. The local concentration of adenosine in the vicinity of adenosine receptors is fine tuned by 2 classes of nucleoside transporters: equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs). In vascular smooth muscle cells, 95% of adenosine transport is mediated by ENT-1 and the rest by ENT-2. In endothelial cells, 60%, 10%, and 30% of adenosine transport are mediated by ENT-1, ENT-2, and CNT-2, respectively. In vitro studies show that glucose per se increases the expression level of ENT-1 via mitogen-activating protein kinase-dependent pathways. Similar results have been demonstrated in diabetic animal models. Hypertension is associated with the increased expression of CNT-2. It has been speculated that the increase in the activities of ENT-1 and CNT-2 may reduce the availability of adenosine to adenosine receptors, thereby weakening the vascular functions of adenosine. This may explain why patients with diabetes and hypertension suffer greater morbidity from ischemia and atherosclerosis. No oral hypoglycemic agents can inhibit ENTs, but an exception is troglitazone (a thiazolidinedione that has been withdrawn from the market). ENTs are also sensitive to dihydropyridine-type calcium-channel blockers, particularly nimodipine, which can inhibit ENT-1 in the nanomolar range. Those calcium-channel blockers are noncompetitive inhibitors of ENTs, probably working through the reversible interactions with allosteric sites. The nonsteroidal anti-inflammatory drug sulindac sulfide is a competitive inhibitor of ENT-1. In addition to their original pharmacological actions, it is believed that the drugs mentioned above may regulate vascular functions through potentiation of the effects of adenosine.