tbuckley/cabot-search huggingface dataset:
Exosomal Interferon‐Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti–Hepatitis B Virus Efficacy of Exogenous Interferon Alpha
Authors: Ying Shi, Lingyao Du, Duoduo Lv, Hong Li, Jin Shang, Jiajie Lu, Lingyun Zhou, Lang Bai, Hong Tang
Journal: Hepatology (2019)

The negative regulators in the interferon (IFN) signaling pathway inhibit intrahepatic immune response, resulting in suboptimal therapeutic response to IFNα treatment in chronic hepatitis B (CHB) patients. Identifying the key negative factors and elucidating the regulating mechanism are essential for improving anti‐HBV (hepatitis B virus) efficacy of IFNα. From the Gene Expression Omnibus (GEO) database, we downloaded and analyzed gene expression profiles of CHB patients with different responses to IFNα (GSE54747), and found that innate immune status was associated with the IFNα‐based therapeutic response in CHB patients. Through PCR array, we found higher baseline level of IFN‐induced transmembrane protein 2 (IFITM2) mRNA and lower baseline level of IFNα mRNA in peripheral blood mononuclear cells (PBMCs) of CHB patients with suboptimal response to IFNα treatment. Increased IFITM2 protein was also found in the serum of IFNα nonresponsive patients. With further experiments, we found that overexpressing IFITM2 in Huh7 cells suppressed endogenous IFNα synthesis by inhibiting phosphorylation of extracellular signal–regulated kinase (ERK), TANK‐binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3); knocking out IFITM2 enhanced activation of the endogenous IFNα synthesis pathway, exhibiting better inhibition on HBV replication. We also found that IFITM2 protein was shuttled by exosomes to dendritic cells (DCs), the main source of endogenous IFNα. Exosome‐mediated transport of IFITM2 inhibited synthesis of endogenous IFNα in DCs whereas the inhibitory effect was abolished when IFITM2 was knocked out. Furthermore, we demonstrated that both palmitoylation inhibitor and mutation on 70/71 sites of IFITM2 protein influenced its incorporation into exosomes. Mutated IFITM2 protein increased the effect of IFNα against HBV. Conclusion: Exosome‐mediated transport of IFITM2 to DCs inhibits IFNα pathway activation and blocks anti‐HBV efficacy of exogenous IFNα. The findings provide an explanation to the suboptimal response of CHB patients to IFNα treatment.
Primary results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) as neoadjuvant chemotherapy for locally advanced gastric cancer.
Authors: Takaki Yoshikawa, Kentaro Sakamaki, Kazuhiro Nishikawa, Kazumasa Fujitani, Kazuaki Tanabe, Yuichi Ito, Takanori Matsui, Akira Miki, Hiroshi Nemoto, Tetsu Fukunaga, Yutaka Kimura, Naoki Hirabayashi, Tsutomu Hayashi
Journal: Journal of Clinical Oncology (2019)

93 Background: Neoadjuvant chemotherapy is promising to improve the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both active for metastatic gastric cancer. Methods: We conducted a randomized phase II trial to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and docetaxel/cisplatin/S-1 (DCS) using a two-by-two factorial design for locally resectable advanced gastric cancer. Patients with M0 and either T4 or T3 in case of junctional cancer or schirrhous type received two or four courses of cisplatin (60 mg/m 2 at day 8)/S-1 (80 mg/m 2 for 21 days with 1 week rest) or docetaxel (40 mg/m 2 at day 1)/cisplatin (60 mg/m 2 at day 1)/S-1 (80 mg/m 2 for 14 days with 2 weeks rest) as neoadjuvant chemotherapy. Then, patients underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was 3-year overall survival. The planned sample size was 120 eligible patients in total so that the treatment group with the superior observed 3-year OS rate by more than 60% as compared with 50% of the control group was to be selected with a probability of 85% or higher. Results: Between October 2011 and September 2014, 132 patients were assigned to CS (n = 66; 33 in 2-courses and 33 in 4-courses) and DCS (n = 66; 33 in 2-courses and 33 in 4-courses). The 3-year OS was 58.1% (95% CI, 45.8-70.3%) in CS and 60.0% (95% CI, 48.0-71.9%) in DCS with hazard ratio of 0796 (95% CI, 0.475-1.335), while that was 53.1% (95% CI, 40.9-65.4%) in the two courses and 65.0% (95% CI, 53.2-76.8%) in the four courses with hazard ratio of 0.722 (95% CI, 0.429-1.216). In the survival analysis by duration in each regimen, the 3-year OS was 58.1% (95% CI, 45.8-70.3%) both for two and four courses in CS, while that was 48.5% (95% CI, 31.4-65.5%) for two courses of DCS and was 71.9% (95% CI, 56.3-87.5%) for four courses of DCS. Conclusions: Considering high 3-year OS, four courses DCS has a value to be tested in a future phase III study to confirm superiority of neoadjuvant chemotherapy for locally advanced gastric cancer. Clinical trial information: UMIN000006378.
Stratum corneum in early life
Authors: M.A. McAleer, I. Jakasa, N. Raj, C.P.F. O'Donnell, M.E. Lane, A.V. Rawlings, R. Voegeli, W.H.I. McLean, S. Kezic, A.D. Irvine
Journal: British Journal of Dermatology (2018)
Abstract B062: Proteomic characterization of the secretome from prostate cancer and bone progenitor cell coculture
Authors: Nicolás Anselmino, Alejandra Páez, Sofía Lage Vickers, Javier Cotignola, Pía Valacco, Geraldine Gueron, Elba Vázquez
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is one of the most frequent sites of primary tumor development in human beings. PCa tumor cells tend to disseminate to and form metastatic lesions in the bone. Given the evident prevalence and clinical significance of bone metastases, unraveling the mechanisms exploited by cancer to form these destructive lesions is of critical interest. This is partly due to the fact that the metastatic cascade encompasses many rate-limiting steps demanding tumor cells to employ new mechanisms at each stage. Our work aimed at evaluating which soluble factors could mediate the chemical crosstalk between PCa cells and bone progenitor cells. For this purpose, we used coculture transwell systems of PC3 (human PCa cells) with the preosteoclastic Raw264.7 or preosteoblastic MC3T3 cell lines (murine cells), where cells shared the culture media (CMs) without physical contact for 24h. We employed mass spectrometry—nanoLC-MS/MS(Orbitrap) —for the secretome analysis of the CMs. The obtained spectra were analyzed with the Proteome Discover Software and compared with both human and murine protein databases. Results highlight a differential secretome profile released to the CM when tumor cells are grown in coculture compared to controls. These results could potentially explain the altered mRNA expression levels assessed by RTqPCR in PCa cells growing in coculture, displaying significant upregulation for HO-1 ANXA2, ANXA2R, OPG, and PTHrP (p&amp;lt;0.05). Of note, coculture secretomes showcase highly bone-associated proteins released by tumoral cells such as periostin, cartilage oligomeric matrix protein, OPN, BMP and ILGF-II, IL-7, FGF, Mx-1—involved in prostate carcinogenesis—compared to controls, evidencing a misregulated microenvironment. These results may offer a better understanding of the molecular affinity between PCa cells and the bone microenvironment, allowing the improvement of PCa patient prognosis Citation Format: Nicolás Anselmino, Alejandra Páez, Sofía Lage Vickers, Javier Cotignola, Pía Valacco, Geraldine Gueron, Elba Vázquez. Proteomic characterization of the secretome from prostate cancer and bone progenitor cell coculture [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B062.
Exhaled Breath Temperature Measurement in Allergic Respiratory Disease
Authors: Rosalaura Villarreal Gonzalez, Sandra N. Gonzalez-Diaz, Alfredo Arias-Cruz, Alejandra Macias-Weinmann, Barbara Elizondo-Villarreal, Cindy Elizabeth de Lira-Quezada, Rosa Ivett Guzman-Avilan
Journal: Journal of Allergy and Clinical Immunology (2019)
Does weight loss reduce the severity and incidence of psoriasis or psoriatic arthritis? A Critically Appraised Topic
Authors: S.K. Mahil, S.M. McSweeney, E. Kloczko, B. McGowan, J.N. Barker, C.H. Smith
Journal: British Journal of Dermatology (2019)

Does weight loss reduce the severity and incidence of psoriasis or psoriatic arthritis (PsA) in obese individuals? Obesity presents a rising public health challenge and is more prevalent among individuals with psoriasis or PsA than in the general population. Longitudinal population‐based studies suggest a causal role for obesity in psoriasis and PsA onset and that obesity drives greater disease severity. We systematically reviewed evidence within the MEDLINE, Embase and CENTRAL databases and clinical trials registries examining lifestyle, pharmacological and surgical weight loss interventions in the treatment and prevention of psoriasis and PsA in obese individuals. Meta‐analysis was conducted using random‐effects models, followed by sensitivity analyses. Of 176 full‐text articles reviewed, 14 met the inclusion criteria. Meta‐analysis of six randomized control trials (RCTs) confirmed that weight loss following lifestyle interventions (diet or physical activity) improves psoriasis compared with control [mean change in Psoriasis Area and Severity Index −2·59, 95% confidence interval (CI) −4·09 to −1·09; P < 0·001]. One RCT demonstrated a greater likelihood of achieving minimal PsA activity following diet‐induced weight loss (odds ratio 4·20, 95% CI 1·82–9·66; P < 0·001). Three studies of pharmacological treatments reported conflicting results, and no RCTs of bariatric surgery were identified. Two cohort studies suggested that bariatric surgery, particularly gastric bypass, reduces the risk of developing psoriasis (hazard ratio 0·52, 95% CI 0·33–0·81; P < 0·01). These limited data indicate that weight loss can improve pre‐existing psoriasis and PsA, and prevent the onset of psoriasis in obese individuals. Together with the National Institute for Health and Care Excellence obesity guidance, this informed a local obesity screening and management pathway, providing multidisciplinary weight loss interventions alongside conventional skin‐focused care for patients with psoriasis.
Pharmacogenomic Prediction of Bleomycin-Induced Pneumonitis in South East Asian Hodgkin Lymphoma Patients
Authors: Joanne Shu Xian Lee, Li Mei Poon, Xin Liu, Yi Ching Yuen, Nagavalli Somasundaram, Suk Teng Chin, Chia Meng Teoh, Benedict Yan, Hian Li Esther Hian Li Chan, Yen-Lin Chee, Tiffany Tang, Noorul Farzana, Caroline Hui Ting Aw, Chiea Chuen Khor, Joanne Yuen Yie Ngeow, Choon Kiat Ong, E Shyong Tai, Wee Joo Chng, Boon Cher Goh, Soo Chin Lee, Folefac Aminkeng
Journal: Blood (2018)
Outcome analysis of chemotherapy duration for resected stage I-II and unresected stage III pancreatic cancer.
Authors: Sung Jun Ma, Austin J Iovoli, Kavitha M Prezzano, Gregory Hermann, Lucas M Serra, Anurag K Singh
Journal: Journal of Clinical Oncology (2019)

375 Background: For resected early-stage pancreatic cancer, RTOG 9704 has evaluated the outcome of 3 weeks of adjuvant chemotherapy (C) followed by chemoradiation (CRT) and post-CRT C. For locally advanced pancreatic cancer, a recent literature review showed that the typical duration for induction C is between 1 and 6 months prior to CRT. The ideal duration of C prior to CRT remains unclear. This National Cancer Database (NCDB) study was performed to identify the optimal duration of C prior to CRT in patients with pancreatic cancer. Methods: The NCDB was queried for primary stage I-II, cT1-3N0-1M0, resected and stage III, cT4N0-1M0, unresected pancreatic adenocarcinoma treated with C+CRT (2004-2015). Cohorts I-II and III included stage I-II and stage III cases, respectively. In each cohort, the patients were stratified by the short (short C) and long duration (long C) of chemotherapy based on their median durations (70 and 90 days between the onset of chemotherapy and radiation for cohorts I-II and III, respectively). Baseline patient, tumor, and treatment characteristics were examined. The primary endpoint was overall survival (OS). Kaplan-Meier analysis, multivariable Cox proportional hazards method, and propensity score matching were used. Results: Among 1,577 patients, cohort I-II had 839 patients (n = 409 with short C, n = 430 with long C) and cohort III had 738 patients (n = 360 with short C, n = 378 with long C). Median follow-up was 39.5 months and 24.3 months for cohorts I-II and III, respectively. The long C group showed improved OS in the multivariable analysis in both cohort I-II (HR 0.72, p &lt; 0.001) and cohort III (HR 0.83, p = 0.025). Using 1:1 propensity score matching, a total of 610 patients for cohort I-II and 542 patients for cohort III were matched. After matching, long C remained statistically significant for improved OS compared with short C in both cohort I-II (median OS 26.1 vs 21.9 months, p = 0.003) and cohort III (median OS 16.7 vs 14.2 months, p = 0.021). Conclusions: Our NCDB study using propensity score matched analysis showed a survival benefit in the use of longer duration chemotherapy compared to shorter duration chemotherapy for both resected stage I-II and unresected stage III pancreatic cancer.
Serum Soluble Interleukin-2 Receptor As a Surrogate Biomarker of Metabolic Tumor Volume Measured By 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma
Authors: Hajime Senjo, Minoru Kanaya, Koh Izumiyama, Koichiro Minauchi, Kenji Hirata, Akio Mori, Makoto Saito, Masanori Tanaka, Hiroaki Iijima, Eriko Tsukamoto, Kazuo Itoh, Shuichi Ota, Masanobu Morioka, Daigo Hashimoto, Takanori Teshima
Journal: Blood (2018)
Pklr Intron Splicing-Associated Mutations and Alternate Diagnoses Are Common in Pyruvate Kinase Deficient Patients with Single or No Pklr Coding Mutations
Authors: Kimberly Lezon-Geyda, Melissa J. Rose, Melissa A. McNaull, Christine M. Knoll, Hassan M. Yaish, Yves D. Pastore, Elisa Fermi, Bertil Glader, Paola Bianchi, Rachael F. Grace, Patrick G. Gallagher
Journal: Blood (2018)
Prognostic Implication of Early Molecular Response at 3 Months in Chronic Myeloid Leukemia Patients: A Comparison of Imatinib and Second Generation Tyrosine Kinase Inhibitors
Authors: Dong-Wook Kim, Sung-Eun Lee, Soo Young Choi, Dae Young Zang, Won-Sik Lee, Yeung-Chul Mun, Young Rok Do, Sukjoong Oh
Journal: Blood (2018)
Impact of Degree of Left Ventricular Remodeling on Clinical Outcomes From Cardiac Resynchronization Therapy
Authors: Fadi Shamoun, Teresa De Marco, David DeMets, Chaoqun Mei, JoAnn Lindenfeld, Leslie A. Saxon, John P. Boehmer, Jill Leigh, Patrick Yong, Arthur M. Feldman, Michael R. Bristow
Journal: JACC Heart Failure (2019)
Preprocedural prediction of non-curative endoscopic submucosal dissection for early gastric cancer.
Authors: Cheol Woong Choi, Dae Hwan Kang, Su Jin Kim
Journal: Journal of Clinical Oncology (2019)

74 Background: Endoscopic submucosal dissection (ESD) has been accepted as the treatment of choice for early gastric cancer (EGC) without lymph node metastasis. However, additional surgical gastrectomy should be considered after non-curative endoscopic resection. We aimed to evaluate the predictive factors associated with non-curative endoscopic resection. Methods: Between November 2008 and June 2015, a retrospective study was conducted in a single, tertiary, referral hospital. A total of 596 EGC lesions resected by ESD were analyzed. Non-curative endoscopic resection was defined as the occurrence of lesions associated with piecemeal resection, positive resection margins, lymphovascular invasion, or lesions that did not meet the expanded indications for ESD. Results: The rate of non-curative endoscopic resection was 16.1%. The mean follow-up period was 35.3 ± 25.0 months. Associated predictive factors for non-curative endoscopic resection were female sex (OR, 2.470; p = 0.004), lesion size ≥ 20 mm (OR 3.714; p &lt; 0.001), longer procedure time (OR 2.449, p = 0.002), ulceration (OR 3.538, p = 0.002), nodularity (OR 2.967, p &lt; 0.001), depression (OR 1.806, p = 0.038), undifferentiated carcinoma (OR 2.825, p = 0.031) and lesion located in the mid or upper third of stomach (OR 7.135 and OR 4.155, p &lt; 0.001, respectively). As the number of risk factors increased, the risk of non-curative ESD also increased. Conclusions: Prior to selection of ESD, the risks associated with non-curative ESD should be considered so that appropriate treatment modalities may be selected.
Trazodone use and risk of dementia: A population-based cohort study
Authors: Ruth Brauer, Wallis C. Y. Lau, Joseph F. Hayes, Kenneth K. C. Man, David P. J. Osborn, Robert Howard, Joseph Kim, Ian C. K. Wong
Journal: PLoS Medicine (2019)

In vitro and animal studies have suggested that trazodone, a licensed antidepressant, may protect against dementia. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice.The Health Improvement Network (THIN), an archive of anonymised medical and prescribing records from primary care practices in the United Kingdom, contains records of over 15 million patients. We assessed patients from THIN aged ≥50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017. We compared the risk of dementia among patients who were prescribed trazodone to that of patients with similar baseline characteristics prescribed other antidepressants, using a Cox regression model with 1:5 propensity score matching. Patients prescribed trazodone who met the inclusion criteria (n = 4,716; 59.2% female) were older (mean age 70.9 ± 13.1 versus 65.6 ± 11.4 years) and were more likely than those prescribed other antidepressants (n = 420,280; 59.7% female) to have cerebrovascular disease and use anxiolytic or antipsychotic drugs. After propensity score matching, 4,596 users of trazadone and 22,980 users of other antidepressants were analysed. The median time to dementia diagnosis for people prescribed trazodone was 1.8 years (interquartile range [IQR] = 0.5-5.0 years). Incidence of dementia among patients taking trazodone was higher than in matched users of other antidepressants (1.8 versus 1.1 per 100 person-years), with a hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.56-2.09; p < 0.001). However, our results do not suggest a causal association. When we restricted the control group to users of mirtazapine only in a sensitivity analysis, the findings were very similar to the results of the main analysis. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Due to the observational nature of this study, we cannot rule out residual confounding.In this study of UK population-based electronic health records, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.
A 54-Year-Old Man With Pancytopenia
Authors: Kapil Saxena, Khoan Vu, Heather E. Nye
Journal: JAMA (2019)

A 54-year-old man presented for evaluation of new-onset pancytopenia.He had a distant history of viral myocarditis and was taking lisinopril, carvedilol, furosemide, aspirin, and a multivitamin.No new medications had been started in the past year.Twelve years prior, he underwent uncomplicated Roux-en-Y gastric bypass (RYGB) surgery.Review of systems was notable for fatigue and negative for fever, night sweats, weight loss, dyspnea, or abnormal bleeding.Examination revealed temperature of 36.7°C;heart rate, 91/min; blood pressure, 120/70 mm Hg; and body mass index, 20.1 (calculated as weight in kilograms divided by height in meters squared).He was well-appearing with conjunctival pallor but no petechiae, no hepatosplenomegaly, and a normal neurologic examination.Laboratory evaluation showed a white blood cell count of 1.7 × 10 3 /μL with an absolute neutrophil count of 0.17 × 10 3 /μL; hemoglobin level, 7 g/dL with mean corpuscular volume of 103 fL (reticulocyte index, 0.94); and platelet count, 116 × 10 3 /μL.Results of a complete blood cell count from 8 months prior were normal.Results of serum protein electrophoresis were normal, as were levels of lactate dehydrogenase, ferritin, folate, vitamin B 12 , and thyroid-stimulating hormone.A computed tomography (CT) scan of the abdomen showed no lymphadenopathy, masses, or hepatosplenomegaly.Peripheral blood smear showed occasional pseudo Pelger-Huet cells and rare teardrop cells.Histopathologic examination of bone marrow aspirate revealed a normocellular marrow and dyserythropoiesis with vacuolized and dysplastic erythroid precursors (Figure , panel A), leftshifted granulocytic maturation with vacuolized granulocytic precursors, ring sideroblasts (Figure, panel B), and no increase in blasts.Cytogenetic studies from the bone marrow did not reveal any abnormalities.
Disease-Associated KIF3A Genetic Variants Alter Gene Methylation And Expression Resulting In Skin Barrier Dysfunction And Increased Risk For Atopic Dermatitis
Authors: Mariana L. Stevens, Zhonghua Zhang, Elisabet Johansson, Amrita Jagpal, Brandy P. Ruff, Hua He, Lisa J. Martin, Hong Ji, Kathryn A. Wikenheiser-Brokamp, Jocelyn M. Biagini Myers, Gurjit K. Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2019)
Mixed cellular inflammation is increased in adult asthma with severe chronic rhinosinusitis
Authors: Tomoko Nishio, Keiko Wakahara, Yoshihiro Suzuki, Suguru Majima, Naoki Nishio, Masaaki Teranishi, Michihiko Sone, Yoshinori Hasegawa
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 16801: A Dissimilar Time Course of Neointimal Formation After Deployment of Metallic and Polymeric Stents in Rats
Authors: Ilia Fishbein, Tre R Welch, Surendranath R Veeram Reddy, David T Guerrero, Ivan S Alferiev, Michael Chorny, Robert J Levy
Journal: Circulation (2017)

Introduction: Both non-degradable metallic and biodegradable polymeric stents are in clinical use. Very few prior experimental studies have directly compared the extent and time course of neointima...
Single-Agent Ibrutinib Versus Real-World Treatments for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia: Adjusted Comparison of Resonate-2™ with Real-World Databases
Authors: Gilles Salles, Lukas Smolej, Emmanuel Bachy, Lucile Baseggio, Hervé Besson, Ruben Hermans, Nollaig Healy, Jamie Garside, Wafae Iraqi, Joris Diels, Finlay MacDougall, Corinna Pick-Lauer, Martin Spacek, Renata Urbanova, Daniel Lysak, Evelyne Callet-Bauchu, Michael Doubek
Journal: Blood (2017)
Efficacy of RPC4046, an Anti-Interleukin-13 Monoclonal Antibody, in Patients With Active Eosinophilic Esophagitis: Analysis of the Steroid-Refractory Subgroup From the HEROES Study
Authors: Ikuo Hirano, Evan S. Dellon, Margaret H. Collins, Yehudith Assouline-Dayan, Larry Evans, Sandeep Gupta, Alain Schoepfer, Alex Straumann, Ekaterina Safroneeva, Amy Woo, Gregory J. Opiteck, Allan Olson, Richard Aranda, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 16598: Simulation of Impact on Cardiovascular Events With Lipid-lowering Treatment Intensification in Patients With Atherosclerotic Cardiovascular Disease in the US
Authors: Irfan Khan, Christopher P Cannon, Alexa Klimchak, Matthew R Reynolds, Robert J Sanchez, William J Sasiela
Journal: Circulation (2016)

Introduction: Recent developments in lipid-lowering therapies (LLT) include the approval of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and reductions in cardiovascular (CV) e...