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Abstract Background AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. Methods During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP])

Abstract Introduction One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. Methods The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. Primary endpoint: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). Results Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. Conclusions The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. Trial Registration ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB)

Introduction Current animal models of brain aneurysms used for testing neuro‐interventional devices have highly simplistic vascular anatomy in comparison with human aneurysm‐parent vessel complexes. Poly(vinyl alcohol) (PVA) is a leading biomaterial for manufacture of artificial vascular grafts because of its biocompatibility, hemocompatibility, availability, low cost, moldability/castability, and tunable mechanical properties to match arterial compliance [1,2]. However, PVA is non‐cell adhesive and requires modification with additives to promote endothelialization of the luminal surface to maintain long‐term graft patency [1,3]. We have previously studied the biocompatibility of resorcinol bis(diphenyl phosphate) (RDP) coated clays blended with polymers and have found excellent cell adhesion and proliferation with human dermal fibroblasts as well as dental pulp stem cells [4]. Our overall goal is to develop a new in vivo model of brain aneurysms by manufacturing patient‐specific aneurysm anatomies with a blend of PVA and RDP clay and grafting them into animals. Here, we evaluate the casting of PVA in the shape of patient‐specific aneurysms. Methods 10% PVA (w/w) (99% hydrolyzed, 85–124K molecular weight, Sigma Aldrich) was dissolved in deionized water, to which 1% RDP clay (ICL Industrial Products, Be’er Sheva, Israel) was added. The PVA was crosslinked using 15% (w/w) of sodium trimetaphosphate and 30% (w/w) of sodium hydroxide, after which rheological studies (stress sweeps using a Bohlin Gemini rheometer) were conducted. In the casting procedure, negative molds of both simple tubes and complex aneurysm geometries were designed using Rhinoceros 3D software (Robert McNeel & Associates, Seattle, WA) and 3D printed in ABS plastic. The negative mold was then filled with beeswax, resulting in a positive wax mold that was dip‐coated 8 times in PVA solution, and spun on a two‐axis spinner in between each dip to ensure even coverage. After overnight drying in a fume hood, the model was placed in heated water, allowing the wax to melt out and leaving behind the luminal PVA cast. Results Rheology on the crosslinked polymers showed that the PVA/RDP blend exhibited over twice the elastic modulus of unblended PVA (Figure A). Such enhanced mechanical properties are consistent with previous studies [5]. Both simple tubular geometries and patient‐specific anatomies were able to be successfully cast using the methodology developed here (Figure B). Conclusions This proposed casting methodology demonstrates a realistic, efficient way to replicate complex aneurysm geometries with comparatively inexpensive materials and short time frame. Future endeavors will include further exploration of the PVA/RDP biocompatibility as well as completing the casting procedure with a PVA/RDP blend.

Objective The goal of this article is to present the analysis of anti‐abatacept antibody data from children with polyarticular‐course juvenile idiopathic arthritis (pJIA), treated with abatacept. The data are from 395 participants with pJIA from two abatacept registrational trials. Methods We analyzed immunogenicity data according to age groups, administration route (intravenous [IV] or subcutaneous [SC]), drug treatment interruption, and co‐medications (with or without methotrexate [MTX]) to assess impact on the incidence of anti‐abatacept antibodies. Results The overall immunogenicity incidences observed in both JIA trials ranged between 4.7% and 23.3%. There was a slightly higher immunogenicity incidence in the 2–5‐year‐old participants (15.2%) compared with 6–17‐year‐old participants (4.7%). In the study with SC dosing, the overall incidence on treatment was 2.3% (3% if co‐dosed with MTX), similar to the incidence for Period A of the IV study (similar duration of treatment as the SC study), which was 2.1% (1.4% if co‐dosed with MTX). In the IV study, the period following a 6‐month interruption in treatment had comparable immunogenicity incidences (22.9% with interruption vs. 18.2% without interruption, both co‐dosed with MTX and 0% for both not co‐dosed with MTX). In most cases, participants co‐dosed with MTX had higher immunogenicity incidences than those on abatacept alone. Conclusion Although some trends were noted in terms of incidence according to age and MTX co‐dosing, none where conclusive owing to differences in population size. Drug holiday had no impact on immunogenicity incidence once treatment was resumed, and incidences across SC and IV dosing were comparable. There was no impact of immunogenicity on pharmacokinetics, safety, and efficacy.

Objective To investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA).Methods Assessing Very Early Rheumatoid arthritis Treatment-2 (AVERT-2; NCT02504268) included disease-modifying antirheumatic drug-naive, anti-citrullinated protein antibody (ACPA)-positive patients randomised to weekly subcutaneous abatacept+methotrexate (MTX) or abatacept placebo+MTX for 56 weeks. This post hoc exploratory subanalysis assessed the association between baseline disease activity and eight biomarkers (Spearman’s correlation coefficient), and whether baseline biomarkers (continuous or categorical variables) could predict treatment response at weeks 24 and 52 (logistic regression).Results Patient characteristics were similar between overall (n=752) and biomarker subgroup (n=535) populations and across treatments. At baseline, neoepitopes of matrix metalloproteinase-mediated degradation products of types III and IV collagen and of C reactive protein (CRP) showed the greatest correlations with disease activity; cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) showed weak correlation. Only CTX-I predicted treatment response; baseline CTX-I levels were significantly associated with achieving Simplified Disease Activity Index remission and Disease Activity Score in 28 joints (DAS28 (CRP))

Abstract Background Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA. Findings This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2–5 years, with ≥2 continuous months of weekly weight-tiered (10– 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6–12 and 2–

The Internet of Vehicles (IoV) is an emerging research framework, with network and graph theories as two of the major fields. Researchers in these topics use a variety of tools and approaches to simulate and perform experimentation on their proposed methodologies. A comprehensive study to facilitate the selection of such simulation tools is lacking from the literature. In this work, we provide a systematic review of the different simulation platforms. More precisely, the contributions of this paper are fourfold: firstly, we propose a two-tier hierarchical taxonomy based on the trends in the literature; secondly, we investigate the strengths and limitations of different simulation platforms; and thirdly, we take a network theoretic approach to identify the patterns in IoV research. To this end, we create a network of the publications and populate the edges among them. Community detection is performed using Louvian and Clauset-Newman-Moore algorithms. To the best of our knowledge, this is a novel approach to reviewing the literature which provides a more in-depth analysis of the trends in the literature. Finally, we review the common datasets for IoV experimentation.

Blind intersections have high accident rates due to the poor visibility of oncoming traffic, high traffic speeds, and lack of infrastructure (e.g., stoplights). These intersections are more commonplace in rural areas, where traffic infrastructure is less developed. The Internet of Vehicles (IoV) aims to address such safety concerns through a network of connected and autonomous vehicles (CAVs) that intercommunicate. This paper proposes a Road-Side Unit-based Virtual Intersection Management (RSU-VIM) over 802.11p system consisting of a Field-Programmable Gate Array (FPGA) lightweight RSU that is solar power-based and tailored to rural areas. The RSU utilizes the proposed RSU-VIM algorithm adapted from existing virtual traffic light methodologies to communicate with vehicles over IEEE 802.11p and facilitate intersection traffic, minimizing visibility issues. The implementation of the proposed system has a simulated cloud delay of 0.0841 s and an overall system delay of 0.4067 s with 98.611% reliability.

Extremely low birth weight (ELBW) infants weighing less than 1 kilogram are at a high-risk for delayed patent ductus arteriosus (PDA) closure. Percutaneous PDA closure offers a less invasive approach when compared with surgical PDA closure, which may provide faster recovery times and less transfusion requirements. However, this procedure involves transporting tenuous, unstable patients from the neonatal intensive care unit (NICU) to the catheterization laboratory which introduces many potential risks for the neonate. Performing percutaneous PDA closure at the bedside offers a successful alternative to performing the procedure in the catheterization laboratory and avoiding risk associated with transporting ELBW neonates.

BackgroundAlcoholic hepatitis (AH) is a unique syndrome characterized by high short-term mortality. The impact of the academic status of a hospital (urban and teaching) on outcomes in AH is unknown.MethodsNational Inpatient Sample dataset (2006–2014) on AH admissions stratified to academic center (AC) or non-academic center (NAC) and analyzed for in-hospital mortality (IHM), hospital resource use, length of stay in days (d), and total charges (TC) in United States dollars (USD). Admission year was stratified to 2006–2008 (TMI), 2009–2011 (TM2), and 2012–2014 (TM3).ResultsOf 62,136 AH admissions, the proportion at AC increased from 46% in TM1 to 57% in TM3, Armitage trend, p < 0.001. On logistic regression, TM3, younger age, black race, Medicaid and private insurance, and development of acute on chronic liver failure (ACLF) were associated with admission to an AC. Of 53,264 admissions propensity score matched for demographics, pay status, and disease severity, admissions to AC vs. NAC (26,622 each) were more likely to have liver disease complications (esophageal varices, ascites, and hepatic encephalopathy) and hospital-acquired infections (HAI), especially Clostridioides difficile and ventilator-associated pneumonia. Admissions to AC were more likely transfers from outside hospital (1.6% vs. 1.3%) and seen by palliative care (4.8% vs. 3.3%), p < 0.001. Use of endoscopy, dialysis, and mechanical ventilation were similar. With similar IHM comparing AC vs. NAC (7.7% vs. 7.8%, p = 0.93), average LOS and number of procedures were higher at AC (7.7 vs. 7.1 d and 2.3 vs. 1.9, respectively, p < 0.001) without difference on total charges ($52,821 vs. $52,067 USD, p = 0.28). On multivariable logistic regression model after controlling for demographics, ACLF grade, and calendar year, IHM was similar irrespective of academic status of the hospital, HR (95% CI): 1.01 (0.93–1.08, p = 0.70). IHM decreased over time, with ACLF as strongest predictor. A total of 63 and 22% were discharged to home and skilled nursing facility, respectively, without differences on academic status of the hospital.ConclusionAdmissions with AH to AC compared to NAC have higher frequency of liver disease complications and HAI, with longer duration of hospitalization. Prospective studies are needed to reduce HAI among hospitalized patients with AH.

Objective The range of normal serum alkaline phosphatase is not well defined. We used data from the National Health and Nutrition Examination Survey from 2009 to 2016 to generate normal ranges for a racially diverse sample of healthy adults.Methods Respondents 18 years or older were included. Conditions known to elevate alkaline phosphatase were cause for exclusion. Alkaline phosphatase was measured using a colorimetric method based on standardised National Health and Nutrition Examination Survey protocols. Because alkaline phosphatase values were not normally distributed, log transformation was used. We calculated upper limits of normal (97.5 percentile), stratified by sex and race/ethnicity, and 90% CIs for the upper limits of normal.Results 1199 respondents (673 female, 526 male) had body mass index from 18.5 to less than 25. Upper limits of normal were highest among Hispanics (123.2 IU/L (90% CI 110.2 to 136.7) for females; 123.8 IU/L (90% CI 112.0 to 135.1) for males), followed by African Americans (109.9 IU/L (90% CI 97.3 to 122.4) for females; 116.3 IU/L (90% CI 105.0 to 126.1) for males) and whites (97.1 IU/L (90% CI 91.0 to 103.4) for females; 109.6 IU/L (90% CI 102.1 to 116.3) for males). Asian American/Pacific Islander respondents had the lowest results: 93.8 IU/L (90% CI 88.2 to 99.5) for females and 95.3 IU/L (90% CI 88.1 to 102.1) for males.Conclusions The upper limit of normal alkaline phosphatase varies by race/ethnicity in a large US sample with body mass index of 18.5