tbuckley/cabot-search huggingface dataset:
Projected Estimates of Opioid Mortality After Community-Level Interventions
Authors: Benjamin P. Linas, Alexandra Savinkina, R. W. M. A. Madushani, Jianing Wang, Golnaz Eftekhari Yazdi, Avik Chatterjee, Alexander Y. Walley, Jake R. Morgan, Rachel L. Epstein, Sabrina A. Assoumou, Sean M. Murphy, Bruce R. Schackman, Stavroula A. Chrysanthopoulou, Laura F. White, Joshua A. Barocas
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The United States is experiencing a crisis of opioid overdose. In response, the US Department of Health and Human Services has defined a goal to reduce overdose mortality by 40% by 2022. <h3>Objective</h3> To identify specific combinations of 3 interventions (initiating more people to medications for opioid use disorder [MOUD], increasing 6-month retention with MOUD, and increasing naloxone distribution) associated with at least a 40% reduction in opioid overdose in simulated populations. <h3>Design, Setting, and Participants</h3> This decision analytical model used a dynamic population-level state-transition model to project outcomes over a 2-year horizon. Each intervention scenario was compared with the counterfactual of no intervention in simulated urban and rural communities in Massachusetts. Simulation modeling was used to determine the associations of community-level interventions with opioid overdose rates. The 3 examined interventions were initiation of more people to MOUD, increasing individuals' retention with MOUD, and increasing distribution of naloxone. Data were analyzed from July to November 2020. <h3>Main Outcomes and Measures</h3> Reduction in overdose mortality, medication treatment capacity needs, and naloxone needs. <h3>Results</h3> No single intervention was associated with a 40% reduction in overdose mortality in the simulated communities. Reaching this goal required use of MOUD and naloxone. Achieving a 40% reduction required that 10% to 15% of the estimated OUD population not already receiving MOUD initiate MOUD every month, with 45% to 60%% retention for at least 6 months, and increased naloxone distribution. In all feasible settings and scenarios, attaining a 40% reduction in overdose mortality required that in every month, at least 10% of the population with OUD who were not currently receiving treatment initiate an MOUD. <h3>Conclusions and Relevance</h3> In this modeling study, only communities with increased capacity for treating with MOUD and increased MOUD retention experienced a 40% decrease in overdose mortality. These findings could provide a framework for developing community-level interventions to reduce opioid overdose death.
Caution Against Overinterpreting Time-Restricted Eating Results—Reply
Authors: Ethan J. Weiss, Dylan A. Lowe, Eric Vittinghoff
Journal: JAMA Internal Medicine (2021)

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Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome–caspase-1-mediated trafficking of hematopoietic stem/progenitor cells
Authors: Arjun Thapa, Mateusz Adamiak, Kamila Bujko, Janina Ratajczak, Ahmed K. Abdel-Latif, Magda Kucia, Mariusz Z. Ratajczak
Journal: Leukemia (2021)

Abstract Like their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome–caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.
Abstract 11665: Early Aspirin Use, Rejection, and the Development of Cardiac Allograft Vasculopathy Following Orthotopic Heart Transplantation
Authors: Brian A Bergmark, Thomas A Zelniker, Miae Kim, Mandeep R Mehra, Garrick C Stewart, Deborah Page, Erica Woodcome, Michael Givertz
Journal: Circulation (2019)

Background: We previously observed early aspirin (ASA) use after orthotopic heart transplantation (OHT) to be associated with lower rates of moderate to severe cardiac allograft vasculopathy (CAV)....
An Intravenous 100-mL Lipid Emulsion Infusion Dramatically Improves Myocardial Glucose Metabolism Extinction in Cardiac FDG PET Clinical Practice
Authors: Matthieu Dietz, Benoît Paulmier, Frédéric Berthier, Filippo Civaia, François Mocquot, Benjamin Serrano, Valérie Nataf, Florent Hugonnet, Marc Faraggi
Journal: Clinical Nuclear Medicine (2021)

Purpose Physiological myocardial accumulation of FDG impairs the diagnosis of inflammatory/infectious or tumoral myocardial detection by FDG PET/CT. We prospectively evaluated the addition, 3 hours before imaging, of an intravenous 100-mL lipid emulsion infusion (Intralipid) to a high-fat, low-carbohydrate diet (HFLCD) for at least 2 meals followed by a fast of at least 6 to 12 hours in patients referred for the diagnosis of myocardial inflammation, endocarditis, cardiac or paracardiac masses, intracardiac device, or prosthetic valve infections. Methods Data of 58 patients consecutively included (28 Intralipid patients, 30 controls with HFLCD alone) were compared. FDG uptake in normal myocardium was scored from 0 (complete myocardial suppression) to 3 (high diffuse uptake). Myocardial maximal, peak, and mean SUV and the rate of interpretable images according to the clinical indication were measured. Results Compared with controls, Intralipid infusion significantly improved the rate of score 0 (89% vs 63%, P = 0.021), of interpretable images according to the clinical indication (100% vs 72%, P = 0.0047) and decreased all myocardial SUV values (eg, SUVmax median, 1.9 [interquartile range, 1.7–2.5] vs 3.1 [interquartile range, 2.3–4.1]; P &lt; 0.001). Conclusions A lipid emulsion infusion in addition to HFLCD better suppresses cardiac glucose metabolism than HFLCD alone.
MicroRNA Biophysically Modulates Cardiac Action Potential by Direct Binding to Ion Channel
Authors: Dandan Yang, Xiaoping Wan, Adrienne T. Dennis, Emre Bektik, Zhihua Wang, Mauricio G.S. Costa, Charline Fagnen, Catherine Vénien-Bryan, Xianyao Xu, Daniel H. Gratz, Thomas J. Hund, Peter J. Mohler, Kenneth R. Laurita, Isabelle Deschênes, Ji-Dong Fu
Journal: Circulation (2021)

Background: MicroRNAs (miRs) play critical roles in regulation of numerous biological events, including cardiac electrophysiology and arrhythmia, through a canonical RNA interference mechanism. It remains unknown whether endogenous miRs modulate physiologic homeostasis of the heart through noncanonical mechanisms. Methods: We focused on the predominant miR of the heart (miR1) and investigated whether miR1 could physically bind with ion channels in cardiomyocytes by electrophoretic mobility shift assay, in situ proximity ligation assay, RNA pull down, and RNA immunoprecipitation assays. The functional modulations of cellular electrophysiology were evaluated by inside-out and whole-cell patch clamp. Mutagenesis of miR1 and the ion channel was used to understand the underlying mechanism. The effect on the heart ex vivo was demonstrated through investigating arrhythmia-associated human single nucleotide polymorphisms with miR1-deficient mice. Results: We found that endogenous miR1 could physically bind with cardiac membrane proteins, including an inward-rectifier potassium channel Kir2.1. The miR1–Kir2.1 physical interaction was observed in mouse, guinea pig, canine, and human cardiomyocytes. miR1 quickly and significantly suppressed I K1 at sub–pmol/L concentration, which is close to endogenous miR expression level. Acute presence of miR1 depolarized resting membrane potential and prolonged final repolarization of the action potential in cardiomyocytes. We identified 3 miR1-binding residues on the C-terminus of Kir2.1. Mechanistically, miR1 binds to the pore-facing G-loop of Kir2.1 through the core sequence AAGAAG, which is outside its RNA interference seed region. This biophysical modulation is involved in the dysregulation of gain-of-function Kir2.1–M301K mutation in short QT or atrial fibrillation. We found that an arrhythmia-associated human single nucleotide polymorphism of miR1 (hSNP14A/G) specifically disrupts the biophysical modulation while retaining the RNA interference function. It is remarkable that miR1 but not hSNP14A/G relieved the hyperpolarized resting membrane potential in miR1-deficient cardiomyocytes, improved the conduction velocity, and eliminated the high inducibility of arrhythmia in miR1-deficient hearts ex vivo. Conclusions: Our study reveals a novel evolutionarily conserved biophysical action of endogenous miRs in modulating cardiac electrophysiology. Our discovery of miRs’ biophysical modulation provides a more comprehensive understanding of ion channel dysregulation and may provide new insights into the pathogenesis of cardiac arrhythmias.
Abstract PS1-54: Risk factors for lymph node metastasis and the role of SLNB in microinvasive breast cancer
Authors: Pill Sun Paik, Min Kyung Cho, Juneyoung Ahn, Chang Ik Yoon, Tae-Kyung Yoo, Woo-Chan Park
Journal: Cancer Research (2021)

Abstract Introduction Incidence of microinvasive Breast cancer (DCISM) along with ductal carcinoma in situ is increasing due to mammographic screening. However, DCISM is not a common pathologic entity and surgical management of the axilla, overall treatment, and prognosis of this entity still remains unclear. Our study aims to determine whether sentinel lymph node biopsy (SLNB) is necessary for all DCISM patients and analyze the characteristics of lymph node-positive patients among DCISM patients to identify risk factors associated with lymph node metastasis. Materials and MethodsA total of 184,007 Breast cancer patients treated were registered in the Korean Breast Cancer Society Registry between 1978 to 2020. A retrospective review of the database was performed and the analysis includes diagnostic and clinic-pathologic characteristics such as positive lymph node and immunohistochemistry. A univariate analysis was carried out to determine associations between lymph node positivity and the clinical variables via Fisher’s exact test.ResultsOf the 184,007 patients, 2,556 (1.4%) breast cancer patients were classified as DCISM and 134 (5.2%) had at least one lymph node (node-positive), while 2,422 were node-negative patients. We found statistically significant results with hormone receptor status between node-positive and node-negative patients. Estrogen receptor (ER) and progesterone receptor (PR)-negative cases were associated with lower ORs (ER: OR=0.63, 95CI=0.43-0.92, P=0.016; PR: 0.67, 0.46-0.96, 0.026, respectively). A particularly interesting finding is that human epidermal growth factor receptor 2 (HER2)-negative cases were associated with higher OR (HER2: 2.03, 1.36-3.06, 0.001), suggesting hormone receptor status could be useful to identify potential lymph node metastases.ConclusionOur study suggests that we could omit axillary staging in DCISM patients, and consider optional SLNB in patients with ER, PR, and HER2 status with other overrepresented clinical entities such as palpable mass, BMI, and histologic grade.KeywordsMicroinvasive ductal carcinoma, Sentinel lymph node biopsy, lymph node metastasis Citation Format: Pill Sun Paik, Min Kyung Cho, Juneyoung Ahn, Chang Ik Yoon, Tae-Kyung Yoo, Woo-Chan Park. Risk factors for lymph node metastasis and the role of SLNB in microinvasive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-54.
Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy
Authors: Karen Sliwa, Peter van der Meer, Mark C. Petrie, Alexandra Frogoudaki, Mark R. Johnson, Denise Hilfiker‐Kleiner, Righab Hamdan, Alice M. Jackson, Bassem Ibrahim, Amam Mbakwem, Carsten Tschöpe, Vera Regitz‐Zagrosek, Elmir Omerovic, Jolien Roos‐Hesselink, Michael Gatzoulis, Oktay Tutarel, Susanna Price, Stephane Heymans, Andrew J.S. Coats, Christian Müller, Ovidiu Chioncel, Thomas Thum, Rudolf A. de Boer, Ewa Jankowska, Piotr Ponikowski, Alexander R. Lyon, Giuseppe Rosano, Petar M. Seferovic, Johann Bauersachs
Journal: European Journal of Heart Failure (2021)

Abstract This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with ( de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non‐classified cardiomyopathies, left ventricular non‐compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo‐/radiotherapy for cancer or haematological malignancies need specific pre‐, during and post‐pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
A Tuft Cell–Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer Histotypes
Authors: Yosuke Yamada, Katja Simon-Keller, Djeda Belharazem-Vitacolonnna, Hanibal Bohnenberger, Mark Kriegsmann, Katharina Kriegsmann, Gerhard Hamilton, Thomas Graeter, Gerhard Preissler, German Ott, Eric Dominic Roessner, Ilona Dahmen, Roman K. Thomas, Philipp Ströbel, Alexander Marx
Journal: Journal of Thoracic Oncology (2021)

In-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell-like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell-like features was described.We interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for expression of tuft cell genes and KIT. Expression of KIT and of POU2F3 protein, the master regulator of tuft cells, was analyzed in cancer tissue (N = 344) by immunohistochemistry.Normal human thymic tuft cells and most TCs coexpressed KIT and known tuft cell genes, particularly POU2F3 and GFI1B. Unexpectedly, small subsets of tuft cell-like tumors coexpressing POU2F3, GFI1B, and KIT were also identified among pulmonary squamous cell carcinomas, adenocarcinomas, and large cell neuroendocrine carcinoma and clustered together in each histologic cohort. In addition to the tuft cell-like signature, both thymic and lung tuft cell-like carcinomas had distinct genetic, pathologic, and clinical features in each cohort.We suggest that the tuft cell-like phenotype defines novel subsets of thymic and pulmonary carcinoma. Its high prevalence in thymic squamous cell carcinomas that have no known toxic or viral etiologies suggests a new mechanism of carcinogenesis that may lead to specific drug susceptibilities.
Prostatic Artery Embolisation Versus Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia: 2-yr Outcomes of a Randomised, Open-label, Single-centre Trial
Authors: Dominik Abt, Gautier Müllhaupt, Lukas Hechelhammer, Stefan Markart, Sabine Güsewell, Hans-Peter Schmid, Livio Mordasini, Daniel S. Engeler
Journal: European Urology (2021)

Prostatic artery embolisation (PAE) for the treatment of lower urinary tract symptoms secondary to benign prostatic obstruction (LUTS/BPO) still remains under investigation. To compare the efficacy and safety of PAE and transurethral resection of the prostate (TURP) in the treatment of LUTS/BPO at 2 yr of follow-up. A randomised, open-label trial was conducted. There were 103 participants aged ≥40 yr with refractory LUTS/BPO. PAE versus TURP. International Prostate Symptoms Score (IPSS) and other questionnaires, functional measures, prostate volume, and adverse events were evaluated. Changes from baseline to 2 yr were tested for differences between the two interventions with standard two-sided tests. The mean reduction in IPSS after 2 yr was 9.21 points after PAE and 12.09 points after TURP (difference of 2.88 [95% confidence interval 0.04–5.72]; p = 0.047). Superiority of TURP was also found for most other patient-reported outcomes except for erectile function. PAE was less effective than TURP regarding the improvement of maximum urinary flow rate (3.9 vs 10.23 ml/s, difference of –6.33 [–10.12 to –2.54]; p < 0.001), reduction of postvoid residual urine (62.1 vs 204.0 ml; 141.91 [43.31–240.51]; p = 0.005), and reduction of prostate volume (10.66 vs 30.20 ml; 19.54 [7.70–31.38]; p = 0.005). Adverse events were less frequent after PAE than after TURP (total occurrence n = 43 vs 78, p = 0.005), but the distribution among severity classes was similar. Ten patients (21%) who initially underwent PAE required TURP within 2 yr due to unsatisfying clinical outcomes, which prevented further assessment of their outcomes and, therefore, represents a limitation of the study. Inferior improvements in LUTS/BPO and a relevant re-treatment rate are found 2 yr after PAE compared with TURP. PAE is associated with fewer complications than TURP. The disadvantages of PAE regarding functional outcomes should be considered for patient selection and counselling. Prostatic artery embolisation is safe and effective. However, compared with transurethral resection of the prostate, its disadvantages regarding subjective and objective outcomes should be considered for individual treatment choices.
Abstract PS8-38: Development of random forest classifier method to predict breast cancer mortality among early stage breast cancer patients
Authors: Arwen Chandler
Journal: Cancer Research (2021)

Abstract Background: Among women diagnosed with early stage breast cancer, breast cancer mortality was conditional on the onset of distant recurrence. Gene expression profiling (GEP) tests (e.g., Oncotype Dx) have been commonly used to determine the risk level of distant recurrence, but its predictive ability is often questioned. The objective of this study aims to explore the potential of random forest machine learning to predict the risk of breast cancer mortality.Method: 63,104 patients with node-negative early stage breast cancer in the SEER-GHI dataset were randomly sampled into two groups, for the purpose of training and testing the model where each group consisted of 67% and 33% of all patients, respectively. The patient characteristics and tumor features in the study included age, tumor size, grade, chemotherapy use, Oncotype DX test recurrence score, and more. Further feature selection in the construction of the predictive model was conducted via the Boruta algorithm. As the dataset is highly imbalanced with only a very small percentage of samples being fatal, Synthetic Minority Over-Sampling Technique (SMOTE) was employed to address this issue. A cross-validated grid search finds the best combination of hyper-parameters to improve the model’s performance.Results: The mean and standard deviation of follow-up duration in the cohort of patients were 32.4 and 14.3 months, respectively. Of 37,043 patients, there were 158 breast cancer deaths. Within up to a 59-month follow-up period, the breast cancer specific mortality rate was 0.43%. Based on the limited available data, the outcome of the random forest classifier method in predicting breast cancer mortality shows sensitivity 0.712, specificity 0.773, overall accuracy 0.773, and AUC (area under ROC curve) 0.742. Conclusion: The use of the random forest ML algorithm to predict breast cancer mortality is promising when the hyper-parameters are fine-tuned. However, the model's positive predictive value is highly associated with sufficient data sources. Citation Format: Arwen Chandler. Development of random forest classifier method to predict breast cancer mortality among early stage breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-38.