Digital Commons Network^™

Growth Dynamics In Naturally Progressing Chronic Lymphocytic Leukaemia, M. Gruber, I. Bozic, I. Leshchiner, D. Livitz, K. Stevenson, L. Rassenti, D. Rosebrock, A. Taylor-Weiner, K. R. Rai, C. J. Wu, +17 Additional Authors

Journal Articles

No abstract provided.

Structural Variation Of Centromeric Endogenous Retroviruses In Human Populations And Their Impact On Cutaneous T-Cell Lymphoma, Sézary Syndrome, And Hiv Infection, M. H. Kaplan, M. Kaminski, J. M. Estes, S. D. Gitlin, J. Zahn, J. T. Elder, T. Tejasvi, E. Gensterblum, J. P. Mcgowan, R. Contreras-Galindo, +7 Additional Authors

Journal Articles

© 2019 The Author(s). Background: Human Endogenous Retroviruses type K HML-2 (HK2) are integrated into 117 or more areas of human chromosomal arms while two newly discovered HK2 proviruses, K111 and K222, spread extensively in pericentromeric regions, are the first retroviruses discovered in these areas of our genome. Methods: We use PCR and sequencing analysis to characterize pericentromeric K111 proviruses in DNA from individuals of diverse ethnicities and patients with different diseases. Results: We found that the 5′ LTR-gag region of K111 proviruses is missing in certain individuals, creating pericentromeric instability. K111 deletion (-/- K111) is seen in about 15% …

Phase Iii, Multicentre, Randomised, Double-Blind, Placebo-Controlled, 104-Week Study Of Subcutaneous Belimumab Administered In Combination With Rituximab In Adults With Systemic Lupus Erythematosus (Sle): Bliss-Believe Study Protocol, Y. K. Onno Teng, I. N. Bruce, B. Diamond, R. A. Furie, R. F. Van Vollenhoven, D. Gordon, J. Groark, R. B. Henderson, M. Oldham, P. P. Tak

Journal Articles

© 2019 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Introduction Belimumab, an anti-B-lymphocyte-stimulator antibody, is approved for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Rituximab, a B cell-depleting anti-CD20 antibody, remains in the SLE treatment armamentarium despite failed trials in lupus nephritis and extrarenal lupus. These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE. This study aims to evaluate …

Older-Patient-Specific Cancer Trials: A Pooled Analysis Of 2,277 Patients (A151715)., D. Dao, T. Zemla, A. Jatoi, R. A. Freedman, A. Hurria, H. Muss, H. J. Cohen, M. Citron, D. Budman, J. G. Le-Rademacher, +6 Additional Authors

Journal Articles

BACKGROUND: Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older-patient-specific trials, defined as those designed for older patients with cancer, with those enrolled in age-unspecified trials.

MATERIALS AND METHODS: We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985-2012.

RESULTS: Among 2,277 patients, 1,014 had been enrolled to older-patient-specific and 1,263 to age-unspecified trials. The median age (range) in the older-patient-specific trials was 72 (65-89) years compared with 68 (65-84) …

Tubular Cell And Keratinocyte Single-Cell Transcriptomics Applied To Lupus Nephritis Reveal Type I Ifn And Fibrosis Relevant Pathways, E. Der, H. Suryawanshi, P. Morozov, M. Kustagi, Goilav, Ranabathou, P. Izmirly, A. Davidson, R. Furie, F. Zhang, +57 Additional Authors

Journal Articles

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to …

Effect Of Vitamin D On Serum Markers Of Bone Turnover In Sle In A Randomised Controlled Trial, S. K. Tedeschi, C. Aranow, D. L. Kamen, M. Leboff, Diamond, H. Costenbader

Journal Articles

© 2019 Author(s). Objective Bone health in SLE is adversely affected by vitamin D deficiency, inflammatory cytokines and glucocorticoid use. We hypothesised that vitamin D supplementation would increase markers of bone formation and decrease markers of bone resorption in SLE subjects. Methods We studied 43 vitamin D-deficient SLE subjects who participated in a 12-week randomised controlled trial of 2000-4000 IU/day vitamin D supplementation versus placebo. Subjects had inactive SLE (SLE Disease Activity Index ≤4) and were taking D, N-terminal propeptide of type 1 collagen (P1NP) and C-telopeptide (CTX). We tested the effect of vitamin D versus placebo on change (δ) …

Mus Musculus Deficient For Secretory Antibodies Show Delayed Growth With An Altered Urinary Metabolome, K. R. Simpfendorfer, N. Wang, D. L. Tull, D. P. De Souza, A. Nahid, A. Mu, D. M. Hocking, J. S. Pedersen, O. L. Wijburg, R. A. Strugnell, +1 Additional Author

Journal Articles

© 2019 The Author(s). Background: The polymeric immunoglobulin receptor (pIgR) maintains the integrity of epithelial barriers by transporting polymeric antibodies and antigens through the epithelial mucosa into the lumen. In this study, we examined the role of pIgR in maintaining gut barrier integrity, which is important for the normal development in mice. Methods: Cohorts of pIgR -/- mice and their wildtype controls were housed under Specific Pathogen Free (SPF) conditions and monitored for weight gain as an indicator of development over time. The general physiology of the gastrointestinal tract was analysed using immunohistochemistry in young (8-12 weeks of age) and …

Focused Hla Analysis In Caucasians With Myositis Identifies Significant Associations With Autoantibody Subgroups., S. Rothwell, H. Chinoy, J. A. Lamb, F. W. Miller, L. G. Rider, L. R. Wedderburn, N. J. Mchugh, A. T. Lee, P. K. Gregersen, I. E. Lundberg, +23 Additional Authors

Journal Articles

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies.

METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested …

Tele-Monitored Tdcs Rehabilitation: Feasibility, Challenges And Future Perspectives In Parkinson's Disease, A. Cucca, K. Sharma, S. Agarwal, A. S. Feigin, M. C. Biagioni

Journal Articles

© 2019 The Author(s). Transcranial direct current stimulation (tDCS) is a modality of non-invasive brain stimulation involving the application of low amplitude direct current via surface electrodes on the scalp. tDCS has been studied in healthy populations and in multiple brain disorders and has the potential to be a treatment for several neuropsychiatric conditions by virtue of its capability of influencing cognitive, motor and behavioral processes. tDCS is a generally safe technique when performed within standardized protocols in research or clinical settings. Furthermore, tDCS portability, high acceptability and user-friendly interface makes it highly appealing for telemedicine practices. The term "telemedicine" …

Novel Bioactive And Therapeutic Dental Polymeric Materials To Inhibit Periodontal Pathogens And Biofilms, M. Chi, M. Qi, A. Lan, P. Wang, M. D. Weir, M. A. Melo, X. Sun, B. Dong, C. Li, H. H. Xu, +2 Additional Authors

Journal Articles

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Periodontitis is a common infectious disease characterized by loss of tooth-supporting structures, which eventually leads to tooth loss. The heavy burden of periodontal disease and its negative consequence on the patient’s quality of life indicate a strong need for developing effective therapies. According to the World Health Organization, 10–15% of the global population suffers from severe periodontitis. Advances in understanding the etiology, epidemiology and microbiology of periodontal pocket flora have called for antibacterial therapeutic strategies for periodontitis treatment. Currently, antimicrobial strategies combining with polymer science have attracted tremendous interest in the …

Incins-Igf2 Promotes Cell Proliferation And Migration By Promoting G1/S Transition In Lung Cancer, S. Gao, Z. Lin, C. Li, Y. Wang, L. Yang, B. Zou, J. Chen, J. Li, D. Feng, G. Liu, +1 Additional Author

Journal Articles

© The Author(s) 2019. Long noncoding RNAs are capable of regulating gene expression at multiple levels. These RNA molecules are also involved in a variety of physiological and pathological processes. Emerging data demonstrate that a series of differentially expressed long noncoding RNAs are implicated in tumorigenesis. In the present study, we used microarray analysis to identify long noncoding RNAs that are dysregulated in non-small-cell lung cancer when compared to normal lung tissues. Accordingly, we performed quantitative real-time polymerase chain reaction to analyze the levels of long noncoding RNA and the cis target gene. We further found the oncogene property of …

Septin 9 Isoforms Promote Tumorigenesis In Mammary Epithelial Cells By Increasing Migration And Ecm Degradation Through Metalloproteinase Secretion At Focal Adhesions, J. Marcus, M. Bejerano-Sagie, N. Patterson, S. Bagchi, V. V. Verkhusha, D. Connolly, G. L. Goldberg, A. Golden, V. P. Sharma, C. Montagna, +1 Additional Author

Journal Articles

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. The cytoskeletal interacting protein Septin 9 (SEPT9), a member of the septin gene family, has been proposed to have oncogenic functions. It is a known hot spot of retroviral tagging insertion and a fusion partner of both de novo and therapy-induced mixed lineage leukemia (MLL). Of all septins, SEPT9 holds the strongest link to cancer, especially breast cancer. Murine models of breast cancer frequently exhibit SEPT9 amplification in the form of double minute chromosomes, and about 20% of human breast cancer display genomic amplification and protein over expression at …

Molecular Study Of Thyroid Cancer In World Trade Center Responders, M. A. Van Gerwen, S. Tuminello, G. J. Riggins, T. B. Mendes, M. Donovan, E. K. Benn, E. Genden, J. M. Cerutti, E. Taioli

Journal Articles

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Thyroid cancer incidence is higher in World Trade Center (WTC) responders compared with the general population. It is unclear whether this excess in thyroid cancer is associated with WTC-related exposures or if instead there is an over-diagnosis of malignant thyroid cancer among WTC first responders due to enhanced surveillance and physician bias. To maximize diagnostic yield and determine the false positive rate for malignancy, the histological diagnoses of thyroid cancer tumors from WTC responders and age, gender, and histology matched non-WTC thyroid cancer cases were evaluated using biomarkers of malignancy. Using …

The Fate And Prognostic Implications Of Hyperreflective Crystalline Deposits In Nonneovascular Age-Related Macular Degeneration, S. Fragiotta, P. Fernáandez-Avellaneda, M. P. Breazzano, C. A. Curcio, B. C. Leong, K. Kato, L. A. Yannuzzi, K. B. Freund

Journal Articles

© 2019 The Authors. All rights reserved. PURPOSE. To explore patterns of disease progression in nonneovascular age-related macular degeneration (AMD) associated with hyperreflective crystalline deposits (HCDs) in the subretinal pigment epithelium–basal laminar space. METHODS. Retrospective review of medical records, multimodal imaging, and longitudinal eyetracked near-infrared reflectance (NIR) and optical coherence tomography (OCT) spanning years. NIR/OCT images were analyzed with ImageJ software to identify HCD morphology and location. Associated macular complications were reviewed from the time of HCD detection to the most recent follow-up, using NIR/OCT. RESULTS. Thirty-three eyes with HCDs from 33 patients (mean age: 72 ± 7.5 years) had …

Differentiating Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features From Classic Papillary Thyroid Carcinoma: Analysis Of Cytomorphologic Descriptions Using A Novel Machine-Learning Approach., S. Maleki, A. Zandvakili, S. Gera, S. D. Khutti, A. Gersten, S. N. Khader

Journal Articles

Background:Recent studies show various cytomorphologic features that can assist in the differentiation of classic papillary thyroid carcinoma (cPTC) from noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Differentiating these two entities changes the clinical management significantly. We evaluated the performance of support vector machine (SVM), a machine learning algorithm, in differentiating cases of NIFTP and encapsulated follicular variant of papillary thyroid carcinoma with no capsular or lymphovascular invasion (EFVPTC) from cases of cPTC with the use of microscopic descriptions. SVM is a supervised learning algorithm used in classification problems. It assigns the input data to one of two categories …

A Prospective Investigation Of Interleukin-8 Levels In Pediatric Acute Respiratory Failure And Acute Respiratory Distress Syndrome, H. Flori, A. Sapru, M. W. Quasney, G. Gildengorin, M. A. Curley, M. A. Matthay, M. K. Dahmer, S. T. Bateman, J. B. Schneider, D. Wypij, +20 Additional Authors

Journal Articles

© 2019 The Author(s). Background: The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure. Methods: This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 …

Plasma Zonulin Levels In Childhood Nephrotic Syndrome, H. Trachtman, D. S. Gipson, K. V. Lemley, J. P. Troost, C. Faul, D. J. Morrison, S. M. Vento, D. H. Ahn, C. Sethna, C. Avila-Casado, +90 Additional Authors

Journal Articles

© 2019 Trachtman, Gipson, Lemley, Troost, Faul, Morrison, Vento, Ahn and Goldberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome …

Serum S100a8/A9 And S100a12 Levels In Children With Polyarticular Forms Of Juvenile Idiopathic Arthritis: Relationship To Maintenance Of Clinically Inactive Disease During Anti–Tumor Necrosis Factor Therapy And Occurrence Of Disease Flare After Discontinuation Of Therapy, C. H. Hinze, D. Foell, A. L. Johnson, S. J. Spalding, B. S. Gottlieb, P. W. Morris, Y. Kimura, K. Onel, S. C. Li, D. J. Lovell, +33 Additional Authors

Journal Articles

© 2018, American College of Rheumatology Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti–tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, …

Demographics And Anthropometrics Impact Benefits Of Health Intervention: Data From The Reduce Obesity And Diabetes Project., L. Ostrowski, P. W. Speiser, S. Accacha, L. Altshuler, I. Fennoy, B. Lowell, R. Rapaport, W. Rosenfeld, S. P. Shelov, Road Group, +2 Additional Authors

Journal Articles

Objective:To determine the efficacy of a 4-month school-based health, nutrition and exercise intervention on body fatness and examine possible effects of demographic and anthropometric covariates. Methods:Height, weight, waist circumference and body composition were measured in a diverse population of 644 NYC middle school students (mean ± SD age 12.7 ± 0.9 years; 46% male; 38% Hispanic, 17% East Asian, 15% South Asian, 13.5% African American, 8.5% Caucasian, 8% other) during the fall and spring semesters. Year 1 participants (n = 322) were controls. Experimental participants (year 2, n = 469) received a 12-session classroom-based health and nutrition educational programme with …

Proceeding Report Of The Second Symposium On Hidradenitis Suppurativa Advances (Shsa) 2017, E. Shavit, A. Alavi, F. G. Bechara, R. G. Bennett, M. Bourcier, R. Cibotti, S. Daveluy, J. W. Frew, A. Garg, M. A. Lowes, +20 Additional Authors

Journal Articles

No abstract provided.

Examination Of Fluconazole-Induced Alopecia In An Animal Model And Human Cohort, G. R. Thompson, C. R. Krois, V. K. Affolter, A. D. Everett, E. K. Varjonen, V. R. Sharon, A. Singapuri, M. Dennis, I. Mchardy, S. D. White, +6 Additional Authors

Journal Articles

No abstract provided.

Social And Functional Outcomes With Two Doses Of Aripiprazole Lauroxil Vs Placebo In Patients With Schizophrenia: A Post-Hoc Analysis Of A 12-Week Phase 3 Efficacy Study, C. U. Correll, A. D. Stanford, A. Claxton, Y. Du, P. J. Weiden

Journal Articles

No abstract provided.

A Nomogram For Predicting Survival Of Patients With Locally Advanced Pancreatic Cancer Treated With Chemoradiotherapy: An Editorial Comment, J. Wong

Journal Articles

No abstract provided.

How Many Lymph Nodes Are Enough? Assessing The Adequacy Of Lymph Node Yield For Staging In Favorable Histology Wilms Tumor, A. F. Saltzman, D. E. Smith, D. Gao, D. Ghosh, A. Amini, J. H. Aldrink, R. Dasgupta, K. W. Gow, R. D. Glick, N. G. Cost, +1 Additional Author

Journal Articles

© 2019 Elsevier Inc. Purpose: Current investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. Materials & methods: The National Cancer Database was queried for patients with unilateral …

Anti-Human Interleukin(Il)-4 Clone 8d4-8 Cross-Reacts With Myosin-9 Associated With Apoptotic Cells And Should Not Be Used For Flow Cytometry Applications Querying Il-4 Expression, Robert Z. Harms, Kiana Borengasser, Vikas Kumar, Nora Sarvetnick

Journal Articles: Surgery

Interleukin(IL)-4 is produced by T cells and other leukocytes and is a critical mediator of monocyte and B cell responses. During routine flow cytometry panel validation for the investigation of intracellular cytokines, we observed unique IL-4 expression patterns associated with the widely available monoclonal antibody 8D4-8. Namely, IL-4 (8D4-8) expression was observed in the absence of cellular activation and enhanced following staurosporine exposure. Mass spectrometry analysis of immunoprecipitates from peripheral blood lymphocytes (PBL) revealed that 8D4-8 cross-reacts with the ubiquitous cytoskeletal protein myosin-9. We confirmed these results by western blotting immunoprecipitates, using immunofluorescence among staurosporine-treated Caco-2 cells, and by surface-labeling …

Ca2+ Sensor Synaptotagmin-1 Mediates Exocytosis In Mammalian Photoreceptors, Justin J. Grassmeyer, Asia L. Cahill, Cassandra L. Hays, Cody Barta, Rolen M. Quadros, Channabasavaiah B. Gurumurthy, Wallace B. Thoreson

Journal Articles: Pharmacology & Experimental Neuroscience

To encode light-dependent changes in membrane potential, rod and cone photoreceptors utilize synaptic ribbons to sustain continuous exocytosis while making rapid, fine adjustments to release rate. Release kinetics are shaped by vesicle delivery down ribbons and by properties of exocytotic Ca²⁺ sensors. We tested the role for synaptotagmin-1 (Syt1) in photoreceptor exocytosis by using novel mouse lines in which Syt1 was conditionally removed from rods or cones. Photoreceptors lacking Syt1 exhibited marked reductions in exocytosis as measured by electroretinography and single-cell recordings. Syt1 mediated all evoked release in cones, whereas rods appeared capable of some slow Syt1-independent release. Spontaneous …

Data-Informed Duties In Ai Development, Frank A. Pasquale

Faculty Scholarship

Law should help direct—and not merely constrain—the development of artificial intelligence (AI). One path to influence is the development of standards of care both supplemented and informed by rigorous regulatory guidance. Such standards are particularly important given the potential for inaccurate and inappropriate data to contaminate machine learning. Firms relying on faulty data can be required to compensate those harmed by that data use—and should be subject to punitive damages when such use is repeated or willful. Regulatory standards for data collection, analysis, use, and stewardship can inform and complement generalist judges. Such regulation will not only provide guidance to …

Emerging Medical Therapies For Congenital Adrenal Hyperplasia, P. W. Speiser

Journal Articles

© 2019 Speiser PW. Congenital adrenal hyperplasia has traditionally been treated with daily oral doses of glucocorticoids and mineralocorticoid supplements. Such therapy does not precisely replicate the adrenal cortex's circadian pattern. As a consequence, patients are intermittently overtreated or undertreated leading to growth suppression in children, excess weight gain and altered metabolism. Several new treatments are on the horizon. This article will summarize some new potential therapies as adjuncts to, or replacement for, standard therapy.

Sr-B1 Drives Endothelial Cell Ldl Transcytosis Via Dock4 To Promote Atherosclerosis, L. Huang, K. L. Chambliss, X. Gao, I. S. Yuhanna, E. Behling-Kelly, S. Bergaya, M. Ahmed, P. Michaely, K. Luby-Phelps, P. W. Shaul, +5 Additional Authors

Journal Articles

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Atherosclerosis, which underlies life-threatening cardiovascular disorders such as myocardial infarction and stroke1, is initiated by passage of low-density lipoprotein (LDL) cholesterol into the artery wall and its engulfment by macrophages, which leads to foam cell formation and lesion development2,3. It is unclear how circulating LDL enters the artery wall to instigate atherosclerosis. Here we show in mice that scavenger receptor class B type 1 (SR-B1) in endothelial cells mediates the delivery of LDL into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized …

Evaluation Of The Prognostic Utility Of The Combination Of Platelet Count With Mean Platelet Volume As A Prognostic Indicator In Head And Neck Cancer., T. Tham, E. Leung, C. Olson, M. Wotman, J. Khaymovich, J. Coury, S. Teegala, P. Costantino

Journal Articles

The combination of platelet count to mean platelet volume (COP-MPV) has been recently reported as a prognostic indicator of oral cavity cancer and other cancer sites. The aim of the present study was to validate the utility of the COP-MPV as a prognostic indicator in all head and neck cancer (HNC) sites. The clinicopathological characteristics of the COP-MPV with HNC were also investigated. This is a retrospective cohort study that recruited consecutively treated patients at a tertiary level academic hospital. Clinicopathological characteristics were recorded, including the COP-MPV scores. Survival was analyzed using Kaplan-Meier analysis, as well as multivariate Cox Proportional …