tbuckley/cabot-search huggingface dataset:
Treatment to Target Using Recombinant Interleukin‐1 Receptor Antagonist as First‐Line Monotherapy in New‐Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five‐Year Follow‐Up Study
Authors: Nienke M. ter Haar, E. H. Pieter van Dijkhuizen, Joost F. Swart, Annet van Royen‐Kerkhof, Ayman el Idrissi, Arjen P. Leek, Wilco de Jager, Mark C. H. de Groot, Saskia Haitjema, Dirk Holzinger, Dirk Foell, Jorg van Loosdregt, Nico M. Wulffraat, Sytze de Roock, Sebastiaan J. Vastert
Journal: Arthritis & Rheumatology (2019)

Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage.In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped.Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL-1Ra was equally effective in systemic JIA patients without arthritis at disease onset.Treatment to target, starting with first-line, short-course monotherapy with rIL-1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage in systemic JIA.
The role of IRF1 and IRF2 transcription factors in cancer.
Authors: Patricia Palladinetti, Ailyn Choo, Toby Passioura, Geoff Symonds, Alla Dolnikov
Journal: Cancer Research (2008)

3453  Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. Although of the order of 75-85% of patients will achieve complete remission after induction chemotherapy, long-term survival is still relatively low. Despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathogenomic event to act as a drug target. Interferon regulatory factor 1 (IRF1) is a member of a family of related proteins that act as transcriptional activators or repressors. IRF1 and its functional antagonist IRF2 were originally discovered as transcription factors regulating the interferon-beta (IFN-β) gene, they are involved in the regulation of normal haematopoiesis and leukaemogenesis. IRF1 appears to act as a tumour suppressor gene and IRF2 as an oncogene. Here we show that the interaction of IRF1 with IRF2 plays a critical role in leukaemogenesis and is induced by mutant N-Ras that is mutated in 30-40% of AML cases. Ectopic expression of activated N-Ras in primary human haematopoietic cells and in some leukaemia cell lines leads to inhibition of proliferation that is mediated through the IRF1/p21Waf1 axis. IRF2 acts to repress IRF1 function through the repression of cyclin-dependent kinase (CDK) inhibitor p21Waf1 which is critical for cell growth control. Thus, the tumour suppression function of IRF1 is abolished by IRF2. Down-regulation of IRF2 using siRNA acts to activate IRF1 tumour suppression. In addition, it was recently shown that interaction of IRF1 with IRF2 appears to play an important role in other cancers such as breast, ovarian and esophageal cancers (1-3) Thus, IRF2 may be a viable and specific therapeutic target in human cancer.  1.	Connett, J. M., Badri, L., Giordano, T. J., Connett, W. C. & Doherty, G. M. (2005) Journal of Interferon & Cytokine Research 25, 587-94.  2.	Kim, E. J., Lee, J. M., Namkoong, S. E., Um, S. J. & Park, J. S. (2002) Journal of Cellular Biochemistry 85, 369-80.  3.	Wang, Y., Liu, D.-P., Chen, P.-P., Koeffler, H. P., Tong, X.-J. & Xie, D. (2007) Cancer Res 67, 2535-2543.
Patients’ perspective of quality-of-life issues in a randomized study in open surgery of patients with renal cell carcinoma.
Authors: Britt-Inger Kroger Dahlin, Mascha Thurm, Ola Winso, Borje Ljungberg
Journal: Journal of Clinical Oncology (2019)

642 Background: This randomized study in patients treated with open surgery for renal cell carcinoma (RCC), aimed to evaluate if effective perioperative analgesia can be part of a multimodal approach to minimize morbidity and improve postoperative management [1] . To evaluate the patients’ perspectives, a survey was used before surgery and one month after surgery. Methods: Between 2012 and 2015, 135 patients with RCC, in all stages, were randomized to receive either spinal analgesia with added clonidine, or epidural analgesia in addition to general anesthesia: The patients were stratified according to surgical technique. Inclusion criteria: ASA score ≤ III, age &gt; 18 years, and no chronic pain medication or cognitive disorders. The patient’s survey used was based on the EORTC QLQ-C30 formula. Wilcoxon Signed Rank test and Mann-Whitney-U tests were used for statistical evaluation. Results: Most patients (117 of 135, 86 %) responded to the survey postoperatively. Patients groups treated with partial nephrectomy or radical nephrectomy both had significantly reduced physical and social functioning while emotional functioning improved postoperatively. In both surgical groups the patients reported significant negative financial difficulties. Similar results was achieved for patients treated with either spinal or epidural anesthesia. The epidural group of patients experienced more negative social functioning but had an improved global health. When comparing the surgical procedures there was no significant difference in the quality of life parameters. However when comparing the analgesic groups, spinal anesthesia had significantly better physical and social functioning while the patients in the epidural group reported better global health. Conclusions: In this randomized controlled study on nephrectomy, patients treated with spinal analgesia with clonidine, had better physical and social functioning postoperatively than patients treated with epidural analgesia. Clinical trial information: NCT02030717.
Migalastat: A Review in Fabry Disease
Authors: Emma H. McCafferty, Lesley J. Scott
Journal: Drugs (2019)

Fabry disease is a rare lysosomal disorder characterized by deficient or absent α-galactosidase A activity resulting from mutations in the GLA gene. Migalastat (Galafold™), a pharmacological chaperone, stabilizes and facilitates trafficking of amenable mutant forms of α-galactosidase A enzyme from the endoplasmic reticulum to lysosomes and increases its lysosomal activity. Oral migalastat is the first pharmacological chaperone approved for treating patients [aged ≥ 18 years (USA and Canada) or ≥ 16 years in other countries] with Fabry disease who have a migalastat-amenable GLA mutation. In the FACETS trial in enzyme replacement therapy (ERT)-naive patients with GLA mutations amenable or non-amenable to migalastat, there was no significant difference between the migalastat and placebo groups for the proportion of patients achieving a ≥ 50% reduction in the number of globotriaosylceramide (GL-3) inclusions/kidney interstitial capillary (KIC) at 6 months [primary endpoint; intent-to-treat (ITT) population]. In the modified ITT population (i.e. patients with migalastat-amenable GLA mutations), relative to placebo, migalastat treatment significantly reduced the mean number of GL-3 inclusions/KIC and plasma lyso-globotriaosylsphingosine levels at 6 months. Among evaluable patients, migalastat maintained renal function and reduced cardiac mass after ≤ 24 months' therapy. In the ATTRACT trial in ERT-experienced patients, renal function was maintained during 18 months of migalastat or ERT; however, migalastat significantly reduced cardiac mass compared with ERT. Migalastat was generally well tolerated in both of these trials. Given its convenient oral regimen and the limited therapeutic options available, migalastat is an important treatment option for Fabry disease in patients with migalastat-amenable GLA mutations.
Sipuleucel-T to modify the B7-H3 immune checkpoint in men with castrate resistant prostate cancer.
Authors: Wei Phin Tan, Gregory John Barton, Andrew Chang, Smita Nair, Brant Allen Inman
Journal: Journal of Clinical Oncology (2019)

273 Background: B7-H3 is a T cell costimulatory molecule whose expression correlates with increased prostate cancer stage and mortality. We measured serum B7-H3 (sB7-H3) levels in men undergoing sipuleucel-T (sip-T) immunotherapy for castrate-resistant prostate cancer (CRPC) to determine if sip-T modified B7-H3 levels. Methods: We analyzed 41 banked serum specimens before and after sip-T treatment for CRPC. An ELISA test for sB7-H3 was used to measure serum sB7-H3 levels using a standard curve consisting of B7-H3 fusion protein, and a 4 parameter logistic model fit to back-calculate sB7-H3 levels. Each sample was measured in duplicate and the average of these two measurements used. Generalized additive and segmented regression models were used to model the relationship between sB7-H3 level and time to (and from) sip-T treatment. Results: We found that the sB7-H3 assay had a high degree of reproducibility with a Pearson correlation coefficient of 0.9 between the two measurement occasions. Importantly, sB7-H3 had no correlation with prostate specific antigen (PSA) level, indicating that sB7-H3 was providing incremental biological information not contained in the PSA level. Median PSA before sip-T treatment was 6.2 ng/mL [IQR 3.9-14.7] and median PSA post sip-T treatment was 23.4 ng/mL [IQR 9.8-107.4). Median serum sB7-H3 before sip-T treatment was 24.2 ng/dL [IQR 20.3-27.1] and median serum B7-H3 after sip-T treatment was 23.1 ng/mL [IQR 21.8-26.6]. Using a generalized additive model to measure the level of sB7-H3 from time to sip-T treatment, we found a statistically significant relationship between sB7-H3 levels and sip-T treatment, p=0.038. Using segmented linear regression, we found that sB7-H3 levels increased gradually as CRPC worsened prior to sip-T immunotherapy then, at a mean of 24 days after sip-T initiation, sB7-H3 levels started to fall. Conclusions: We found that sB7-H3 levels increased in men with CRPC and that sip-T treatment reversed this trend. Therefore, sip-T may have a positive immunological effect in CRPC irrespective of PSA change. These results suggest that one potential mechanism of action of sipuleucel-T is the reduction of sB7-H3 production by prostate cancer cells.
Abstract P163: Sex-Based Differences in Cardiac Function, Biomarkers and Exercise Capacity Heart Failure With Preserved Ejection Fraction - Findings From the RELAX Trial
Authors: Ambarish Pandey, Rina Mauricio, Kershaw Patel, Colby Ayers, Jarett Berry, Justin Grodin
Journal: Circulation (2019)

Background: The biological mechanisms underlying the higher burden of Heart failure with preserved ejection fraction (HFpEF) and associated worse clinical outcomes in women vs. men is not well-known. Methods: In a cohort of patients with chronic stable HFpEF that were enrolled in the PDE--5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure trial, sex-based differences in echocardiographic parameters, cardiac biomarkers, and directly measured peak exercise oxygen uptake (peak VO 2 ) were assessed using adjusted linear regression models that accounted for relevant confounders ( Figure ). Results: Among the 214 study participants (49% women), there were no significant differences in measures of cardiac function such as stroke volume (38.1 v. 39.0 ml/m 2 ), diastolic function (E/A: 1.4 v. 1.5), and pulmonary artery systolic pressure (41 v. 43 mm Hg) among women vs. men in unadjusted and adjusted analysis. Women had significantly lower burden of chronic myocardial injury (hs-Troponin-I: 7.3 v. 11.4 ng/l, p &lt; 0.001) and myocardial fibrosis (CTIP: 5.8 v. 6.7 ng/L p = 0.02) and comparable NT-ProBNP levels to men in unadjusted and adjusted comparisons ( Figure ). However, women had significantly lower measures of exercise performance as compared with men including lower peak VO 2 (10.8 vs. 13.3 ml/kg/min, p &lt; 0.01), peak exercise work (60 vs. 83 Watts, p &lt; 0.01), and anaerobic threshold (600 v. 795 ml/min) compared with men. These differences in exercise capacity persisted in adjusted analyses that accounted for demographics, clinical characteristics, measures of cardiac function and biomarkers, and, cardiac biomarkers, and exercise parameters ( Figure ). Conclusion: Among stable patients with HFpEF, despite favorable comparable cardiac structure and function, and lower burden of chronic myocardial injury and fibrosis, women have worse exercise capacity as compared with men. These differences in exercise capacity are not explained by differences in myocardial performance.
Permanent inferior vena cava filters in patients with active malignancy.
Authors: Suneel Deepak Kamath, Elizabeth H. Cull, Robert Lewandowski, Brady Stein, Brandon McMahon
Journal: Journal of Clinical Oncology (2015)

e17655 Background: The use of inferior vena cava (IVC) filters continues to rise in the cancer population. However, data regarding efficacy and complication rates are limited. In this study, we examined the use of permanent IVC filters in cancer patients. Methods: This was a retrospective, single-center study of oncology patients who underwent permanent IVC filter placement from 2009 to 2013. Patients were followed prospectively from time of filter placement. Data collected included demographics, type and stage of malignancy, indication for placement, rate of recurrent venous thromboembolism (VTE) and time from filter placement to death. Only patients with active cancer were included. Results: 175 patients were included. Patient characteristics are shown in table 1. The indications for placement were: bleeding (54%), thrombocytopenia (16%), extensive clot burden (8%), recurrent VTE on anticoagulation (8%), recent or upcoming procedure (7%), cardiopulmonary compromise (3%) and other (4%). 15% of patients had no contraindication to anticoagulation or failure of anticoagulation. 39% were treated with anticoagulation post-filter. Recurrent VTE occurred in 45 patients (26%). A total of 71 recurrent VTEs were observed, including 9 pulmonary emboli. 48% of recurrent VTEs occurred on anticoagulation. 88% of patients had died by study end, largely from progressive cancer. Median time from filter placement to death was 2.14 months (range 0.07-65). Conclusions: Recurrent VTE following permanent IVC filter placement is common in patients with malignancy-associated thrombosis. Time from filter placement to death was short, indicating need for more discriminate utilization in patients with advanced cancer. These results emphasize the need for prospective studies evaluating efficacy and safety of IVC filters in patients with malignancy-associated thrombosis. Patient characteristics. Age, median (range) 65 (21-98) Male sex, N (%) 78 (45%) History of VTE, N (%) 66 (38%) Cancer Stage, N (%) Stage I: 3 (2%) Stage II: 6 (3%) Stage III: 10 (6%) Stage IV: 122 (70%) N/A: 39 (22%) Site of Malignancy, N (%) Gastrointestinal: 57 (33%) Hematologic: 36 (21%) Lung: 31 (18%) Genitourinary: 19 (11%) Brain: 15 (9%) Gynecologic: 14 (8%) Other: 8 (5%)
Abstract MP16: Incremental Diagnostic Yield of 4 Weeks versus 2 Weeks of Ambulatory Heart Rhythm Monitoring for the Detection of Subclinical Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Mary R Rooney, Elsayed Z Soliman, Pamela L Lutsey, Faye L Norby, Laura R Loehr, Thomas Mosley, Michael Zhang, Rebecca Gottesman, Josef Coresh, Aaron R Folsom, Alvaro Alonso, Lin Y Chen
Journal: Circulation (2019)

Introduction: Subclinical atrial fibrillation (AF) has been associated with greater stroke risk; however, subclinical AF can be intermittent, and hence hard to detect. Little is known about the diagnostic yield of extending electrocardiogram (ECG) monitoring beyond 2 weeks on subclinical AF detection, particularly among individuals without a clinical indication. Hypothesis: Extending ECG monitoring from 2 weeks to 4 weeks will increase detection of AF Methods: We included ARIC study participants who attended visit 6 (2016-2017), without a history of AF, and who wore a leadless, ambulatory ECG monitor (Zio® XT Patch by iRhythm Technologies Inc.) twice, each time for up to a maximum of 2 weeks. AF history was based on ARIC ascertainment (hospitalization codes through 2016, ECGs at prior ARIC visits 1-5) or self-reported AF at visit 6. AF on the Zio® XT Patch was defined as an irregularly irregular rhythm with absent P-waves lasting ≥30 seconds. Results: We included 387 ARIC participants (mean ± SD aged 79 ± 4 years, 54% female, 11% non-white race). Mean recording time was 13.3 ± 1.7 days for the first Ziopatch, 13.1 ± 2.0 for the second patch, and 26.4 ± 2.9 for the combined 4 weeks. Based on ≤2 weeks of monitoring, the prevalence of subclinical AF was 2.6% (95% CI: 1.0-4.2%; n=10); this increased to 4.4% (95% CI: 2.4-6.4%; n=17) with ≤4 weeks of monitoring. Thus, the incremental diagnostic yield of 4 weeks versus 2 weeks of monitoring was 70% (95% CI: 41.6-98.4%). The mean time to first AF episode was 10.5 ± 8.0 days with a median of 13.4 days (IQR=2.0-19.7). Cumulative yield of AF detection over the monitoring time is shown in the Figure . Conclusions: Among elderly community-dwelling individuals, extending ECG monitoring from 2 weeks to 4 weeks increased detection of AF. These findings help inform the debate on ECG screening for subclinical AF; however, more research is needed to define the optimal duration of ECG monitoring time.
Effect of organizational approaches on safety-net hospitals’ cancer care quality.
Authors: Nina A. Bickell, Alexandra Moss, Maria Castaldi, Ajay Shah, Alan Sickles, Peter J Pappas, Theophilus Lewis, Margaret Kemeny, Shalini Arora, Lori Schleicher, Anitha Srinivasan, Leslie L. Montgomery, Kezhen Fei, Bonnie Bellacera, Rebeca Franco, Ann Scheck McAlearney
Journal: Journal of Clinical Oncology (2015)

6511 Background: Safety-net hospitals, historically at higher risk for delivering poor-quality care, provide a disproportionate amount of care to vulnerable populations. Some safety-net institutions deliver excellent quality cancer care. We undertook this study to determine the impact of organizational factors on breast cancer care quality. Methods: We abstracted charts of 389 breast cancer patients treated in 2009-12 at 9 inner-city safety-net hospitals with high proportions of minority breast cancer patients to measure underuse of needed adjuvant treatment. We interviewed 90 key informants (n = 59 clinical; n = 16 administrative; n = 12 clerical; n = 3 other) about how care is coordinated and delivered. Using Qualitative Comparative Analysis, we defined “conditions”—handoffs, no-shows, organizational culture—that particularly impact care coordination, categorized hospitals into low ( < 10%), intermediate (10-20%) and high ( > 20%) underuse of needed adjuvant therapies, and calibrated each of the “conditions.” Hierarchical models assess impact of organizational and patient factors on underuse. Results: Underuse ranged from 8% to 29%. Higher quality sites designated individuals to track & follow-up no-shows; shared clinical information during handoffs; had fully integrated EHRs enabling providers and clerks to transfer responsibility across specialties; had strong system support; paid close organizational attention to clinic patients; and allocated adequate resources for the cancer clinics. Organizations with a patient-centered culture focused on making processes easier for patients. Poor quality sites lacked these organizational characteristics. Multivariate modeling found that beyond older patient age (RR = 1.89; 1.14-3.15), hospitals with strong approaches to follow-up affect underuse rates (RR = 0.24; 0.08-0.738). Conclusions: At safety-net hospitals, underuse of needed cancer therapies is affected by older patient age and organizational approaches to track and follow-up treatment. These findings offer strategies to safety-net hospitals to improve cancer care quality.
Marginal Effects—Quantifying the Effect of Changes in Risk Factors in Logistic Regression Models
Authors: Edward C. Norton, Bryan E. Dowd, Matthew L. Maciejewski
Journal: JAMA (2019)

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Point-of-Care Testing Devices for Heart Failure Analyzing Blood and Saliva Samples
Authors: Evanthia E. Tripoliti, Dimitrios I. Fotiadis, Penelope Ioannidou, Petros Toumpaniaris, Aidonis Rammos, Dominique Pacitto, Jean-Christophe Lourme, Yorgos Goletsis, Katerina K. Naka, Abdelhamid Errachid
Journal: IEEE Reviews in Biomedical Engineering (2019)

Heart failure (HF) is the most rapidly growing cardiovascular condition with an estimated prevalence of >37.7 million individuals globally. HF is associated with increased mortality and morbidity and confers a substantial burden, in terms of cost and quality of life, for the individuals and the healthcare systems, highlighting thus the need for early and accurate diagnosis of HF. The accuracy of HF diagnosis, severity estimation, and prediction of adverse events has improved by the utilization of blood tests measuring biomarkers. The contribution of biomarkers for HF management is intensified by the fact that they can be measured in short time at the point-of-care. This is allowed by the development of portable analytical devices, commonly known as point-of-care testing (POCT) devices, which exploit the advancements in the area of microfluidics and nanotechnology. The aim of this review paper is to present a review of POCT devices used for the measurement of biomarkers facilitating decision making when managing HF patients. The devices are either commercially available or in the form of prototypes under development. Both blood and saliva samples are considered. The challenges concerning the implementation of POCT devices and the barriers for their adoption in clinical practice are discussed.