tbuckley/cabot-search huggingface dataset:
Association Between Patient Activation and Health Care Utilization After Thoracic and Abdominal Surgery
Authors: Teodora Dumitra, Olivia Ganescu, Richard Hu, Julio F. Fiore, Pepa Kaneva, Nancy Mayo, Lawrence Lee, A. Sender Liberman, Prosanto Chaudhury, Lorenzo Ferri, Liane S. Feldman
Journal: JAMA Surgery (2020)

<h3>Importance</h3> Increased patient activation (PA) (ie, knowledge, skills, motivation, confidence to participate in care) may result in improved outcomes, especially in surgical settings. <h3>Objective</h3> To estimate the extent to which PA is associated with 30-day postdischarge unplanned health care utilization after major thoracic or abdominal surgery. <h3>Design, Setting, and Participants</h3> This cohort study was performed at 2 centers of a tertiary care hospital network between October 2017 and January 2019. Adult patients undergoing thoracic or abdominal surgery were included. Of 880 patients assessed for eligibility, 692 were deemed eligible, of whom 34 declined to participate, 1 withdrew consent, and 4 were excluded after consent. <h3>Exposures</h3> Patient activation was measured immediately after surgery during the initial admission using the Patient Activation Measure (score range, 0-100). Patients were dichotomized into low and high PA groups using previously described thresholds (Patient Activation Measure score, ≤55.1). <h3>Main Outcomes and Measures</h3> The primary outcome was unplanned 30-day postdischarge health care utilization (composite including emergency department and outpatient clinic visits and/or hospital readmission). Secondary outcomes were length of stay, 30-day emergency department visits, 30-day readmissions, and postoperative complications. <h3>Results</h3> A total of 653 patients admitted for thoracic, general, colorectal, and gynecologic surgery were included in the study (mean [SD] age, 58 [15] years; 369 women [56%]; 366 [56%] had minimally invasive surgery; 52 [8%] had emergency surgery), of which 152 (23%) had a low level of PA. Baseline characteristics were similar between patients with low- and high-level PA. Low PA was associated with unplanned health care utilization (odds ratio [OR], 3.15; 95% CI, 2.05-4.86;<i>P</i> &lt; .001), emergency department visits (OR, 1.64; 95% CI, 1.02-2.64;<i>P</i> = .04), complications (OR, 1.63; 95% CI, 1.11-2.41;<i>P</i> = .01), and length of stay (adjusted mean difference, 1.19 days; 95% CI, 0.06-2.33;<i>P</i> = .04). Low PA was not associated with a higher risk of readmission (adjusted OR, 1.04; 95% CI, 0.56-1.93;<i>P</i> = .90). <h3>Conclusions and Relevance</h3> In this study, low level of PA was associated with postdischarge unplanned health care use, hospital stay, and complications after major surgery. Identification of patients with low activation may allow the implementation of interventions to improve health care knowledge and support self-management postdischarge.
A Phase 1 Study of Tasquinimod in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Dan T. Vogl, Yulia Nefedova, E. Paul Wileyto, Harjeet Sembhi, Inna Strakovsky, Chau Nguyen, Rimzim Taneja, Eva Bondesson, Helena Eriksson, Helen Tuvesson
Journal: Blood (2020)
Trends in Abortion Policies in Low- and Middle-Income Countries
Authors: Pascale Allotey, T.K. Sundari Ravindran, Vithiya Sathivelu
Journal: Annual Review of Public Health (2020)

The decision to terminate a pregnancy is not one that is taken lightly. The need for an abortion reflects limited sexual autonomy, ineffective or lack of access to contraceptive options, or a health indication. Abortion is protected under human rights law. That notwithstanding, access to abortions continues to be contested in many parts of the world, with vested interests from politically and religiously conservative states, patriarchal societies, and cultural mores, not just within local contexts but also within a broader geopolitical context. Criminalization of a women's choice not to carry a pregnancy is a significant driver of unsafe procedures, and even where abortions are provided legally, the policies remain constrained by the practice or by a lack of coherence. This review outlines the trends in abortion policy in low- and middle-income countries and highlights priority areas to ensure that women are safe and able to exercise their reproductive rights.
Abstract MP121: Deleting the 2-oxoglutarate- and Iron-dependent Prolyl Hydroxylase Ogfod1 Alters Purine Nucleotide Regulation and is Cardioprotective
Authors: Leslie Kennedy, Junhui Sun, Michael Harris, Matthew Cockman, Peter Ratcliffe, Elizabeth Murphy
Journal: Circulation Research (2020)

Prolyl hydroxylation is a post-translational modification that regulates protein stability, turnover, and activity. The proteins that catalyze prolyl hydroxylation belong to the 2-oxoglutarate- and iron-dependent oxygenase family of enzymes. A newly-described member of this family is 2-oxoglutarate- and iron-dependent oxygenase domain containing protein 1 (Ogfod1), which catalyzes prolyl hydroxylation of the ribosomal protein s23 (Rps23). To investigate the cardiovascular function of Ogfod1, we isolated hearts from 5 Ogfod1 -WT and 5 Ogfod1 -KO mice and used Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) to identify proteomic changes. Ingenuity Pathway Analysis (IPA) identified “Purine Nucleotides Degradation II (Aerobic)” ( P = 0.00017) to be one of the most significantly-enriched pathways. We then did metabolomics and found that Inosine 5’-monophosphate (IMP) was 3.5x higher in Ogfod1 -KO hearts ( P = 0.011), further supporting a role for Ogfod1 in regulating purine nucleotide metabolism. Recent evidence has shown that altering purine nucleotide degradation protects against diet-induced obesity and insulin resistance, so we tested this hypothesis in Ogfod1 -KO mice by feeding them high-fat diets. Ogfod1 ablation protects against high-fat diet-induced obesity and insulin resistance. Altering purine nucleotide degradation has also been shown to be protective against cardiac injury, so we tested the hypothesis that Ogfod1 loss protects the heart from ischemia-reperfusion (I/R) injury by subjecting perfused hearts from 6 Ogfod1 -WT and 6 Ogfod1 -KO mice to ischemia and reperfusion and assessed tissue death. We found a 37% decrease in infarct size in Ogfod1 -KO hearts (56% in Ogfod1 -WT and 35% in Ogfod1 -KO, P = 0.0003). In a separate set of experiments, we treated Ogofd1 -KO mice with isoproterenol to induce hypertrophy, and Ogfod1 -KO hearts showed protection against hypertrophic remodeling. Interestingly, OGFOD1 transcripts were up-regulated in human heart failure, indicating a potential role for OGFOD1 in the human failing heart. Altogether, these data show that Ogfod1 deletion alters the myocardial proteome and myocardial metabolism and protects against obesity, insulin sensitivity, I/R injury, and hypertrophy.
Machine Learning-Based Flow Cytometry Diagnostics in Myelodysplastic Syndromes: Validation in the HOVON89 Clinical Trial (EudraCT 2008-002195-10)
Authors: Carolien Duetz, Sofie Van Gassen, Theresia M. Westers, Florentien in t Hout, Eline Cremers, Canan Alhan, Costa Bachas, Margot F. Van Spronsen, Heleen Visser-Wisselaar, Dana Chitu, Aniek O. De Graaf, Joop Jansen, Yvan Saeys, Arjan van de Loosdrecht
Journal: Blood (2020)
Acute Myeloid Leukaemia in Elderly: Expression Analysis of DNA Damage Response (DDR) and Anti-Apoptosis Genes Identify Novel Targets for Potential "Synergistic Lethality"
Authors: Hassan Rizwan, Hamza Kamran, Ariz Akhter, Ghaleb Elyamany, Meer-Taher Shahbani-Rad, Adnan Mansoor
Journal: Blood (2020)
Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations
Authors: V. Subbiah, T. Shen, S.S. Terzyan, X. Liu, X. Hu, K.P. Patel, M. Hu, M. Cabanillas, A. Behrang, F. Meric-Bernstam, P.T.T. Vo, B.H.M. Mooers, J. Wu
Journal: Annals of Oncology (2020)
A Phase I Study of FT819, a First-of-Kind, Off-the-Shelf, iPSC-Derived TCR-Less CD19 CAR T Cell Therapy for the Treatment of Relapsed/Refractory B-Cell Malignancies
Authors: Jae H. Park, Nitin Jain, Andy Chen, Joseph P. McGuirk, Monica Diaz, Bahram Valamehr, Yu-Waye Chu, Januario E. Castro
Journal: Blood (2020)
Sequential Intravenous to Oral Proteasome Inhibitor Based Regimens for the Treatment of Newly Diagnosed Multiple Myeloma Patients: A Real-World Study
Authors: Aijun Liu, Rong Fu, Zunmin Zhu, Li Bao, Huizheng Bao, Da Gao, Yanping Ma, Chen Wenming, Hong Yu
Journal: Blood (2020)
Quality of life, treatment goals, preferences and satisfaction in older adults with psoriasis: a patient survey comparing age groups
Authors: M.E.C. Winden, E.L.M. Haar, J.M.M. Groenewoud, P.C.M. Kerkhof, E.M.G.J. Jong, S.F.K. Lubeek
Journal: British Journal of Dermatology (2020)

protocol no.H-15004238) and the Danish Data Protection Agency (GEH-2015-071 I-Suite no.03641).Contrary to expectations, tonsillar carriage of S. pyogenes was similar among cases and genetically disposed and undisposed controls (0%, 1Á8% and 3Á3%, respectively; Table 1).Likewise, no significant differences in tonsillar or perineal carriage of S. agalactiae or S. dysgalactiae were detected, although carriage of these strains was more prevalent among cases.In contrast to analyses of data from microbiological cultures, self-reported tonsillectomy and frequent tonsillitis were more frequently reported among adolescents with psoriasis (11%) than among undisposed controls (2Á4%) (Table 1).Our results suggest that adolescents with psoriasis are not more likely to be carriers of S. pyogenes than their peers.Nonetheless, they are more likely to report recurrent tonsillitis, which is in line with our previous findings, but may be due to information bias. 5Interestingly, the proportion of genetically disposed controls with recurrent tonsillitis was intermediate to that of cases and undisposed controls.The HLA-Cw*0602 allele may increase the risk of both psoriasis and streptococcal tonsillitis, which may explain this observation. 8ack of streptococcal carriers of S. pyogenes among cases of psoriasis runs contrary to our own expectations, and certain explanations may be plausible.The most obvious of these is that casesas our data suggestare more likely to undergo a tonsillectomy, thereby reducing the risk of future streptococcal colonization.In this context, a tonsillectomy may be a result of recurrent tonsillitis and may serve as a disease severity modifier.Lastly, S. pyogenes is known to create biofilms, leading to negative cultures even in the presence of colonization.Carefully taken samples and microbiome analyses may provide a clearer picture in future studies.Differences between our study and that of Mallbris et al. 8 deserve attention, but are likely explained by differences in time from disease onset.
Australian and New Zealand Registry of Anticoagulation in the Obese: Prescribing Patterns, Drug Levels and Patient Outcomes
Authors: Georgia J McCaughan, Helen Jane Crowther, Vivien Chen, Sanjeev D Chunilal, Eileen Merriman, Hadley Bortz, Laura Young, Huyen A Tran, Hiu Lam Agnes Yuen, Jennifer Curnow
Journal: Blood (2020)
Post-Transplant Lymphoproliferative Disorder after Liver Transplant in the Pediatric Population: A Systematic Review
Authors: Mobeen Zaka Haider, Zarlakhta Zamani, Muhammad Taqi, Hasan Mahmood Mirza, Yousra Khalid, Hafsa Shahid, Aneeza Irfan, Khadija Noor Sami, Deepak Kumar, Fnu Kiran, Ahmed Ali Aziz, Faiz Anwer
Journal: Blood (2020)
Association Between African American Race and Clinical Outcomes in Men Treated for Low-Risk Prostate Cancer With Active Surveillance
Authors: Rishi Deka, P. Travis Courtney, J. Kellogg Parsons, Tyler J. Nelson, Vinit Nalawade, Elaine Luterstein, Daniel R. Cherry, Daniel R. Simpson, Arno J. Mundt, James D. Murphy, Anthony V. D’Amico, Christopher J. Kane, Maria Elena Martinez, Brent S. Rose
Journal: JAMA (2020)

<h3>Importance</h3> There is concern that African American men with low-risk prostate cancer may harbor more aggressive disease than non-Hispanic White men. Therefore, it is unclear whether active surveillance is a safe option for African American men. <h3>Objective</h3> To compare clinical outcomes of African American and non-Hispanic White men with low-risk prostate cancer managed with active surveillance. <h3>Design, Setting, and Participants</h3> Retrospective cohort study in the US Veterans Health Administration Health Care System of African American and non-Hispanic White men diagnosed with low-risk prostate cancer between January 1, 2001, and December 31, 2015, and managed with active surveillance. The date of final follow-up was March 31, 2020. <h3>Exposures</h3> Active surveillance was defined as no definitive treatment within the first year of diagnosis and at least 1 additional surveillance biopsy. <h3>Main Outcomes and Measures</h3> Progression to at least intermediate-risk, definitive treatment, metastasis, prostate cancer–specific mortality, and all-cause mortality. <h3>Results</h3> The cohort included 8726 men, including 2280 African American men (26.1%) (median age, 63.2 years) and 6446 non-Hispanic White men (73.9%) (median age, 65.5 years), and the median follow-up was 7.6 years (interquartile range, 5.7-9.9; range, 0.2-19.2). Among African American men and non-Hispanic White men, respectively, the 10-year cumulative incidence of disease progression was 59.9% vs 48.3% (difference, 11.6% [95% CI, 9.2% to 13.9%);<i>P</i> &lt; .001); of receipt of definitive treatment, 54.8% vs 41.4% (difference, 13.4% [95% CI, 11.0% to 15.7%];<i>P</i> &lt; .001); of metastasis, 1.5% vs 1.4% (difference, 0.1% [95% CI, –0.4% to 0.6%];<i>P</i> = .49); of prostate cancer–specific mortality, 1.1% vs 1.0% (difference, 0.1% [95% CI, –0.4% to 0.6%];<i>P</i> = .82); and of all-cause mortality, 22.4% vs 23.5% (difference, 1.1% [95% CI, –0.9% to 3.1%];<i>P</i> = 0.09). <h3>Conclusions and Relevance</h3> In this retrospective cohort study of men with low-risk prostate cancer followed up for a median of 7.6 years, African American men, compared with non-Hispanic White men, had a statistically significant increased 10-year cumulative incidence of disease progression and definitive treatment, but not metastasis or prostate cancer–specific mortality. Longer-term follow-up is needed to better assess the mortality risk.
High-Density Domain-Focused CRISPR Screens Reveal Epigenetic Regulators of <i>Hox/Meis</i> Gene Expression in Acute Myeloid Leukemia
Authors: Karina Barbosa, Anagha Deshpande, Ping Xiang, Bo-Rui Chen, Adam Brown, Neil Robertson, Younguk Sun, John Doench, Peter D Adams, R. Keith Humphries, Prashant Mali, Aniruddha J. Deshpande
Journal: Blood (2020)
Association Between Aspirin and Cholangiocarcinoma in a Large Asian Cohort
Authors: Min-Hyung Kim, Sang Min Park, Jooyoung Chang, In Cheol Hwang
Journal: JAMA Oncology (2020)

unmethylated, suggesting that untested glioblastomas comprise a mix of methylation statuses whose management could be improved by appropriate testing.Notable limitations included the database's limited details about test types and timing.The results of this study indicate that substantial socioeconomic and care setting disparities exist in the testing of this important biomarker for patients with glioblastoma.With MGMT status increasingly becoming a critical trial eligibility criterion, failure to test in a timely manner will compound existing barriers to patients' access to clinical trials. 5,6 Future studies are needed to define how these disparities in MGMT promoter methylation testing arise and to help develop strategies to ensure equitable access to quality oncologic care for patients with glioblastoma.
KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancer
Authors: Camillo Porta, Aristotelis Bamias, Farhad R. Danesh, Alicja Dębska-Ślizień, Maurizio Gallieni, Morie A. Gertz, Jan T. Kielstein, Petra Tesarova, Germaine Wong, Michael Cheung, David C. Wheeler, Wolfgang C. Winkelmayer, Jolanta Małyszko, Ali K. Abu-Alfa, Hatem Amer, Gernot Beutel, Jeremy Chapman, Xiaohong Chen, Jerzy Chudek, Laura Cosmai, Romano Danesi, Filippo De Stefano, Kunitoshi Iseki, Edgar A. Jaimes, Kenar D. Jhaveri, Artur Jurczyszyn, Rümeyza Kazancioğlu, Abhijat Kitchlu, Christian Kollmannsberger, Amit Lahoti, Yang Li, Manuel Macía, Takeshi Matsubara, Dionysios Mitropoulos, Eisei Noiri, Mark A. Perazella, Pierre Ronco, Mitchell H. Rosner, Maria Jose Soler Romeo, Ben Sprangers, Walter M. Stadler, Paul E. Stevens, None ladimír Tesař, Verônica Torres da Costa e Silva, David H. Vesole, Anitha Vijayan, Ondřej Viklický, Biruh T. Workeneh, Motoko Yanagita, Elena Zakharova
Journal: Kidney International (2020)

The association between kidney disease and cancer is multifaceted and complex. Persons with chronic kidney disease (CKD) have an increased incidence of cancer, and both cancer and cancer treatments can cause impaired kidney function. Renal issues in the setting of malignancy can worsen patient outcomes and diminish the adequacy of anticancer treatments. In addition, the oncology treatment landscape is changing rapidly, and data on tolerability of novel therapies in patients with CKD are often lacking. Caring for oncology patients has become more specialized and interdisciplinary, currently requiring collaboration among specialists in nephrology, medical oncology, critical care, clinical pharmacology/pharmacy, and palliative care, in addition to surgeons and urologists. To identify key management issues in nephrology relevant to patients with malignancy, KDIGO (Kidney Disease: Improving Global Outcomes) assembled a global panel of multidisciplinary clinical and scientific expertise for a controversies conference on onco-nephrology in December 2018. This report covers issues related to kidney impairment and solid organ malignancies as well as management and treatment of kidney cancer. Knowledge gaps, areas of controversy, and research priorities are described.
Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) - Updated Data from the Phase 2 ACE-536-MF-001 Study
Authors: Aaron T. Gerds, Alessandro M. Vannucchi, Francesco Passamonti, Marina Kremyanskaya, Jason Gotlib, Jeanne M. Palmer, Kelly McCaul, Vincent Ribrag, Adam J. Mead, Claire Harrison, Ruben Mesa, Jean-Jacques Kiladjian, Giovanni Barosi, Torsten G. Gerike, Jeevan K. Shetty, Joseph Pariseau, Gabriel Miranda, Martin Schwickart, Ana Carolina Giuseppi, Jennie Zhang, Jay T. Backstrom, Srdan Verstovsek
Journal: Blood (2020)
Bleeding and Thrombosis Are Associated with Endothelial Dysfunction in CAR-T Cell Therapy and Are Increased in Patients Experiencing Neurologic Toxicity
Authors: Andrew Johnsrud, Juliana Craig, John H. Baird, Jay Y. Spiegel, Lori S. Muffly, James Zehnder, Robert S. Negrin, Laura J. Johnston, Sally Arai, Judith A Shizuru, Robert Lowsky, Everett H Meyer, Wen-Kai Weng, Parveen Shiraz, Andrew R. Rezvani, Theresa Latchford, Crystal L. Mackall, David B. Miklos, Matthew J. Frank, Surbhi Sidana
Journal: Blood (2020)
Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants
Authors: Everett H Meyer, Rasmus Hoeg, Anna Moroz, Bryan Xei, Hsin-Hsu Wu, Rahul Pawar, Kartoosh Heydari, David B. Miklos, Parveen Shiraz, Lori S. Muffly, Sally Arai, Laura J. Johnston, Robert Lowsky, Andrew R. Rezvani, Judith A Shizuru, Wen-Kai Weng, Nathaniel Fernhoff, Gerhard Bauer, Arpita Gandhi, Amy Putnam, J. Scott Scott McClellan, Bronwen E. Shaw, Joseph P. McGuirk, Mehrdad Abedi, Robert S. Negrin
Journal: Blood (2020)
Axial involvement in patients with early peripheral spondyloarthritis: a prospective MRI study of sacroiliac joints and spine
Authors: Thomas Renson, Philippe Carron, Ann-Sophie De Craemer, Liselotte Deroo, Manouk de Hooge, Simon Krabbe, Lennart Jans, Min Chen, Mikkel Østergaard, Filip E Van den Bosch, Dirk Elewaut
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To assess axial involvement on MRI in early peripheral spondyloarthritis (pSpA) and to evaluate whether axial inflammation predicts relapse on treatment withdrawal. Methods Fifty-six patients with early, active, newly diagnosed pSpA underwent MRI of the sacroiliac joints (SIJs) and spine prior to golimumab initiation. At sustained clinical remission of pSpA, treatment was withdrawn and a second MRI was performed. Bone marrow oedema (BME) was scored by three readers according to the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Scores were compared with an axial spondyloarthritis cohort (Belgian Arthritis and Spondylitis cohort). Structural lesions were assessed using a similar method. Furthermore, fulfilment of the Assessment of Spondyloarthritis International Society (ASAS) definition of a positive MRI for sacroiliitis was assessed. Spinal images were evaluated for BME and structural lesions using the Canada-Denmark MRI spine scoring system by two readers. Results Thirty-six per cent showed SIJ BME at baseline, all fulfilling the ASAS definition of sacroiliitis. No association with back pain was found. Twenty-one per cent displayed SIJ structural lesions. Spinal BME was limited: the median inflammation scores were low and no patients had ≥5 inflammatory corner lesions. On clinical remission, a significant decrease in SIJ SPARCC scores was detected. On clinical remission, no significant differences in SIJ SPARCC scores were noted between patients relapsing and those maintaining remission after treatment discontinuation. Conclusion In patients with early pSpA, a surprisingly high prevalence of sacroiliitis on MRI was observed; SPARCC scores decreased significantly on tumour necrosis factor inhibition. Residual inflammation on MRI was not predictive of relapse of peripheral manifestations. No relevant inflammatory spinal involvement was detected. Collectively, our findings suggest a higher inflammatory burden in patients with early pSpA than anticipated.
Polyphenol-cisplatin complexation forming core-shell nanoparticles with improved tumor accumulation and dual-responsive drug release for enhanced cancer chemotherapy
Authors: Jiajia Xiang, Yinwen Li, Yifan Zhang, Guowei Wang, Hongxia Xu, Zhuxian Zhou, Jianbin Tang, Youqing Shen
Journal: Journal of Controlled Release (2020)
Impact of late administration of corticosteroids in COVID-19 ARDS
Authors: Nicolas Mongardon, Michael Piagnerelli, David Grimaldi, Bastien Perrot, Jean-Baptiste Lascarrou
Journal: Intensive Care Medicine (2020)

Dear Editor,Acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19) is challenging.As pro-inflammatory patterns and cytokine storm are among the hallmarks of severe COVID-19 pneumonia, early low dose of corticosteroids (CTC) has been proved to be effective in the RECOVERY trial [1] and subsequent meta-analysis [2].However, a large proportion of patients remained dependent of mechanical ventilation at the end of the CTC therapy, and questions about late administration and possibly high doses of CTC to prevent or treat lung fibrosis in persistent ARDS [3] are unresolved.We, therefore, aimed to evaluate the impact of late CTC for COVID-19 ARDS patients versus the absence of CTC administration.We performed a post hoc analysis from the COVADIS project, a multicenter observational study gathering 21 French and Belgian intensive care units (ICUs) [4].All consecutive patients (from 10/03 to 15/04/2020) with moderate to severe ARDS according to Berlin definition under invasive ventilation and positive SARS-CoV-2 RT-PCR were included.We studied patients who did not receive (no CTC group) or received CTC later than 13 days after symptoms onset (75% percentile of patients included in the RECOV-ERY trial [1]) (CTC group).We analyzed the effect of CTC administration on ICU 90-day survival with a Cox model by specifying the delay between intubation and administration of CTC as a time-dependent covariate.