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Background Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases using a precision medicine approach with a companion diagnostic (CDx). This Phase 2 placebo-controlled, multi-center, double-blind study aimed to assess the efficacy and safety of PRA023 for induction treatment in adults with moderately to severely active ulcerative colitis (UC). Methods Key eligibility criteria included a modified Mayo Score of 4-9, a centrally read (with adjudication) endoscopy subscore of ≥ 2, a rectal bleeding subscore of ≥ 1, and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced (approved biologics and JAK inhibitors/S1P modulators) therapies (≤ 4 advanced agents from ≤ 3 classes). Patients were stratified by prior biologic exposure status (yes/no) and CDx status (yes/no) and randomized 1:1 to placebo or intravenous PRA023 (1000mg on Day 1, 500mg at Weeks 2, 6, and 10). The primary endpoint was clinical remission at week 12. Analyses of all ranked secondary endpoints, the first being endoscopic improvement (endoscopy score of ≤ 1), were multiplicity controlled. Results Of the 135 patients in the full analysis data set, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week Induction Period. Baseline characteristics were similar with minor differences in the proportion of patients with baseline endoscopy score of 3 and prior exposure to ≥ 3 advanced therapies (Table 1). A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs. 1.5% placebo, ∆25.0%, p < 0.0001) at Week 12 (Table 2). In addition, substantially more patients who received PRA023 achieved the key secondary endpoint of endoscopic improvement (36.8% PRA023 vs. 6.0% placebo, ∆30.8%, p < 0.0001). All remaining ranked secondary endpoints were met (Table 2). The rates of treatment-emergent adverse events (AEs) were similar between the two arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm (Table 3). There were no safety signals identified from the study. Conclusion PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A Phase 3 study will be conducted to confirm these findings. Recruitment is ongoing for the CDx+ expansion cohort of the study to assess the effectiveness of the CDx, designed to select patients with a higher probability of responding to PRA023.

Background Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases with a precision medicine approach. This Phase 2a multi-center, open-label study aimed to assess the efficacy and safety of PRA023 as induction treatment in adults with moderately to severely active Crohn’s Disease (CD). Methods Key eligibility criteria included Crohn’s disease activity index ≥220 and ≤450 with centrally read [with adjudication] Simple Endoscopic Score (SES)-CD score of ≥6 (≥4 isolated ileal disease) and a history of insufficient/loss of response and/or intolerance to conventional and/or approved biologic therapies (≤4 biologic agents from ≤3 classes). Eligible patients were treated with intravenous PRA023 1000mg on Day 1, 500mg at Weeks 2, 6, and 10. The primary endpoint was endoscopic response (reduction in SES-CD score of ≥50%) at Week 12. Study design utilized historical placebo control rate estimates as a benchmark. Exploratory endpoints include efficacy assessment in a subpopulation identified by a genetics-based companion diagnostic test (CDx). Results Of the 55 patients in the full analysis data set, 53 (96.4%) completed the 12-week Induction Period. The patient population was notable for the high rate of prior biologic exposure (70.9%) and a mean (SD) disease duration of 10.3 (9.3) years (Table 1). A significantly greater proportion of patients receiving PRA023 achieved endoscopic response (26% PRA023 vs. 12% historical placebo estimate, p=0.002) and clinical remission (CDAI < 150 points; 49% PRA023 vs 16% historical placebo estimate, p< 0.001). Efficacy was observed in biologic-exposed patients (33% endoscopic response and 38.5% clinical remission) while concurrent steroid or immunosuppressant use did not impact efficacy. Significant reductions from baseline in C-reactive protein and fecal calprotectin were observed at all timepoints (Figure 1). Although the pre-specified CDx algorithm provided only limited additional benefit in clinical responses, an alternative CD-specific algorithm (not based on clinical trial data) using the same genetic markers demonstrated enhanced performance across both clinical (12/21 [57%] remission) and endoscopic (9/20 [45%] response) outcomes. No serious/severe AEs were deemed as study drug-related. Conclusion This Phase 2a study demonstrated robust proof-of-concept for PRA023’s efficacy in moderately to severely active CD with favorable tolerability. Patient selection using prespecified genetic markers showed promising results. Placebo-controlled clinical trials will be conducted to confirm these findings.

The complex and highly organized structural arrangement of some five billion cardiomyocytes directs the coordinated electrical activity and mechanical contraction of the human heart. The characteristic transmural change in cardiomyocyte orientation underlies base-to-apex shortening, circumferential shortening, and left ventricular torsion during contraction. Individual cardiomyocytes shorten approximately 15% and increase in diameter approximately 8%. Remarkably, however, the left ventricular wall thickens by up to 30-40%. To accommodate this, the myocardium must undergo significant structural rearrangement during contraction. At the mesoscale, collections of cardiomyocytes are organized into sheetlets, and sheetlet shear is the fundamental mechanism of rearrangement that produces wall thickening. Herein we review the histological and physiological studies of myocardial mesostructure that have established the sheetlet shear model of wall thickening. Recent developments in tissue clearing techniques allow for imaging of whole hearts at the cellular scale, while magnetic resonance imaging (MRI) and computed tomography (CT) can image the myocardium at the mesoscale (100µm to 1mm) to resolve cardiomyocyte orientation and organization. Through histology, cardiac diffusion tensor imaging (DTI) and other modalities, mesostructural sheetlets have been confirmed in both animal and human hearts. Recent in vivo cardiac DTI methods have measured reorientation of sheetlets during the cardiac cycle. We also examine the role of pathological cardiac remodeling on sheetlet organization and reorientation, and the impact this has on ventricular function and dysfunction. We also review the unresolved mesostructural questions and challenges that may direct future work in the field.

Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

Purpose Delirium leads to poor outcomes for patients and careers and has negative impacts on staff and service provision. Cancer rates in elderly populations are increasing and frequently, cancer diagnoses are a co-morbidity in the context of frailty. Data relating to the epidemiology of delirium in hospitalised cancer patients are limited. With the overarching purpose of improving delirium detection and reducing the morbidity and mortality of delirium in cancer patients, we reviewed the epidemiological data and approach to delirium detection in hospitalised, adult oncology patients. Methods MEDLINE, EMBASE, CINAHL, PsycINFO, and SCOPUS databases were searched from January 1996 to August 2017. Key concepts were delirium, cancer, inpatient oncology and delirium screening/detection. Results Of 896 unique studies identified; 91 met full-text review criteria. Of 12 eligible studies, four applied recommended case ascertainment methods to all patients, three used delirium screening tools alone or with case ascertainment tools sub-optimally applied, four used tools not recommended for delirium screening or case ascertainment, one used the Confusion Assessment Method with insufficient information to determine if it met case ascertainment status. Two studies presented delirium incidence rates: 7.8%, and 17% respectively. Prevalence rates ranged from 18–33% for general medical or oncology wards; 42–58% for Acute Palliative Care Units (APCU); and for older cancer patients: 22% and 57%. Three studies reported reversibility; 26% and 49% respectively (APCUs) and 30% (older patients with cancer). Six studies had a low risk of bias according to QUADAS-2 criteria; all studies in the APCU setting were rated at higher risk of bias. Tool selection, study flow and recruitment bias reduced study quality. Conclusion The knowledge base for improved interventions and clinical care for adults with cancer and delirium is limited by the low number of studies. A clear distinction between screening tools and diagnostic tools is required to provide an improved understanding of the rates of delirium and its reversibility in this population.

Recent developments in clearing and microscopy enable 3D imaging with cellular resolution up to the whole organ level. These methods have been used extensively in neurobiology, but their uptake in other fields has been much more limited. Application of this approach to the human heart and effective use of the data acquired present challenges of scale and complexity. Four interlinked issues need to be addressed: 1) efficient clearing and labelling of heart tissue, 2) fast microscopic imaging of human-scale samples, 3) handling and processing of multi-terabyte 3D images, and 4) extraction of structural information in computationally tractable structure-based models of cardiac function. Preliminary studies show that each of these requirements can be achieved with the appropriate application and development of existing technologies.

Ablation has recently emerged as a tool for modulating gastric electrical activation and may hold interventional potential for disorders of gastric function. However, previous studies have been limited to the acute intraoperative setting. This study now presents the safety of gastric ablation after postsurgical recovery and healing. Localized electrical conduction blocks created by ablation remained after 2 wk of healing, and no perforation or other complications were observed over the postsurgical period.

Background Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC. Methods Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI). Results In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1). The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent). Conclusion The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications. References: 1. Sandborn WJ, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4. 2. Afif W, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results from The UNIFI Long-term Extension. UEGW 2023. 3. Sandborn WJ, et al. 129 Safety of Ustekinumab In IBD: Pooled Safety Analysis through 5 years in CD and 2 Years in UC. Gastroenterology. 2021;Supplement:S-35-S-36.

Background Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC). Methods In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE. Results The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2). Conclusion In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition. References: 1) Ma C, Hanzel J, Panaccione R, et al. CORE-IBD: A Multidisciplinary International Consensus Initiative to Develop a Core Outcome Set for Randomized Controlled Trials in Inflammatory Bowel Disease. Gastroenterol 2022;4:950-64.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and percutaneous catheter ablation is widely used to treat it. Panoramic mapping with multi-electrode catheters has been used to identify ablation targets in persistent AF but is limited by poor contact and inadequate coverage of the left atrial cavity. In this paper, we investigate the accuracy with which atrial endocardial surface potentials can be reconstructed from electrograms recorded with non-contact catheters. An in-silico approach was employed in which “ground-truth” surface potentials from experimental contact mapping studies and computer models were compared with inverse potential maps constructed by sampling the corresponding intracardiac field using virtual basket catheters. We demonstrate that it is possible to 1) specify the mixed boundary conditions required for mesh-based formulations of the potential inverse problem fully, and 2) reconstruct accurate inverse potential maps from recordings made with appropriately designed catheters. Accuracy improved when catheter dimensions were increased but was relatively stable when the catheter occupied >30% of atrial cavity volume. Independent of this, the capacity of non-contact catheters to resolve the complex atrial potential fields seen in reentrant atrial arrhythmia depended on the spatial distribution of electrodes on the surface bounding the catheter. Finally, we have shown that reliable inverse potential mapping is possible in near real-time with meshless methods that use the Method of Fundamental Solutions.

Enabling efficient injection of light into single-mode fibers (SMFs) is a key requirement in realizing diffraction-limited astronomical spectroscopy on ground-based telescopes. SMF-fed spectrographs, facilitated by the use of adaptive optics (AO), offer distinct advantages over comparable seeing-limited designs, including higher spectral resolution within a compact and stable instrument volume, and a telescope independent spectrograph design. iLocater is an extremely precise radial velocity (EPRV) spectrograph being built for the Large Binocular Telescope (LBT). We have designed and built the front-end fiber injection system, or acquisition camera, for the SX (left) primary mirror of the LBT. The instrument was installed in 2019 and underwent on-sky commissioning and performance assessment. In this paper, we present the instrument requirements, acquisition camera design, as well as results from first-light measurements. Broadband single-mode fiber coupling in excess of 35% (absolute) in the near-infrared (0.97-1.31{\mu}m) was achieved across a range of target magnitudes, spectral types, and observing conditions. Successful demonstration of on-sky performance represents both a major milestone in the development of iLocater and in making efficient ground-based SMF-fed astronomical instruments a reality., Comment: 18 pages, 17 figures. Accepted for publication in MNRAS

Background: Cardiac remodeling underpinning progressive hypertensive heart disease alters the three-dimensional structure of the extracellular matrix, as well as the laminar organization of myocardial sheetlets. The effect of pharmacological intervention on microstructural remodeling is not known. Objective: To examine the changes in myocardial microstructure that occur as a result of hypertensive heart disease, and the effect of pharmacological treatment. Methods: The spontaneously hypertensive rat (SHR) model of hypertensive heart disease was studied, and compared with the normotensive Wistar Kyoto (WKY) rat, and SHRs treated with angiotensin converting enzyme inhibitors (TSHR). Cardiac magnetic resonance was used to assess cardiac function and ventricular geometry. Excised myocardium was stained (picrosirius red) for collagen and extended volume confocal microscopy used to produce high-resolution image stacks. Results: At 24 months, TSHRs had significantly greater ejection fraction (P

Plasticity is a fundamental property of neurons in both the central and peripheral nervous systems, enabling rapid changes in neural network function. The intracardiac nervous system (ICNS) is an extensive network of neurons clustered into ganglionated plexi (GP) on the surface of the heart. GP neurons are the final site of neuronal control of heart rhythm, and pathophysiological remodeling of the ICNS is proposed to feature in multiple cardiovascular diseases, including heart failure and atrial fibrillation. To examine the potential role of GP neuron plasticity in atrial arrhythmia and hypertension, we developed whole cell patch clamp recording techniques from GP neurons in isolated ICNS preparations from aged control (Wistar-Kyoto) and spontaneously hypertensive rats (SHRs). Anesthetized SHRs showed frequent premature ventricular contractions and episodes of atrial arrhythmia following carbachol injection, and isolated SHR atrial preparations were susceptible to pacing induced atrial arrhythmia. Whole cell recordings revealed elevated spontaneous postsynaptic current frequency in SHR GP neurons, as well as remodeled electrophysiology, with significant decreases in action potential amplitude and half-width. SHRs also showed a parallel increase in the number of cholinergic neurons and adrenergic glomus cells in cardiac ganglia, a higher proportion of synaptic α7-subunit but not β2-containing nicotinic receptors, and an elevation in the number of synaptic terminals onto GP neurons. Our data show that significant structural and functional plasticity occurs in the intracardiac nervous system and suggest that enhanced excitability through synaptic plasticity, together with remodeling of cardiac neuron electrophysiology, contributes to the substrate for atrial arrhythmia in hypertensive heart disease.NEW & NOTEWORTHY We have developed intracardiac neuron whole cell recording techniques in atrial preparations from control and spontaneous hypertensive rats. This has enabled the identification of significant synaptic plasticity in the intracardiac nervous system, including enhanced postsynaptic current frequency, increased synaptic terminal density, and altered postsynaptic receptors. This increased synaptic drive together with altered cardiac neuron electrophysiology could increase intracardiac nervous system excitability and contribute to the substrate for atrial arrhythmia in hypertensive heart disease.

Cannabinoids are predominantly produced in the glandular trichomes on cannabis female flowers. There is little known on how cannabinoid biosynthesis is regulated during female flower development. We aim to understand the rate-limiting step(s) in the cannabinoid biosynthetic pathway. We investigated the transcript levels of cannabinoid biosynthetic genes together with cannabinoid contents during 7 weeks of female flower development. We demonstrated that the enzymatic steps for producing cannabigerol (CBG), which involve genes

Introduction: Myocardial collagen structure is a complex three dimensional (3D) hierarchy, organizing cardiomyocytes and providing structural integrity. Changes in collagen organization have a crucial role in cardiac remodeling. However, quantitative methods for the analysis of collagen structures are still lacking. Herein, we apply our collagen shape analysis framework to compare within-sheetlet collagen (both endomysial collagen surrounding myocytes and perimysial cords) against sheetlet-surface collagen (perimysial meshwork collagen deposited between sheetlets) in spontaneously hypertensive rats undergoing quinapril treatment. Hypothesis: The different functional properties of endomysial and perimysial meshwork collagen are linked to their structure and will have markedly different features quantifiable by 3D shape analysis. Methods: Rat myocardium was stained for collagen (picrosirius red), and the left ventricular free wall imaged using extended volume confocal microscopy (0.4 μm 3 voxel size). The 3D image volumes were segmented into within-sheetlet and sheetlet-surface regions. Shape analysis was performed using eigenanalysis of the inertia matrix to derive 3D morphological (elongation and flatness) parameters, characterizing the collagen shape in the two regions. Results: Shape analysis revealed marked differences between within-sheetlet and sheetlet-surface collagen organization. Long-term quinapril treatment resulted in notable differences in within-sheetlet collagen shape in rats at 14 months of age (mo) compared with 24 mo. At 14 mo, the within-sheetlet collagen is a mix of sheet-, ribbon-, and rod-like structures (elongation: 0.43, flatness: 0.05), but by 24 mo this has remodeled to predominately thin rod-like structures (elongation: 0.03, flatness: 0.35). The sheetlet-surface collagen consisted of thick sheet-like structures in both 14 and 24 mo rats (elongation: 0.83 vs 0.79, flatness: 0.13 vs 0.09). Conclusion: Shape analysis in 3D showed marked differences between within-sheetlet and sheetlet-surface collagen structure, as well as differences between early treatment and late treatment of diseased hearts.

Despite the advances of medicine, many illnesses continue to evade cure. Chronic, progressive, incurable illness is a major cause of disability, distress, suffering, and, ultimately, death. This is true for many causes of cancer, AIDS, and other disorders of vital organs. Such progressive, chronic diseases are most common in late adulthood and old age, but they occur at all ages. Disease-modifying treatments and the relief of suffering through symptom management, care planning, and family support are central to care, and these four domains are core goals of palliative care. This chapter offers an overview of how epidemiological studies may be used to clarify the population/s of people who may benefit from palliative care, to assist the planning for how services may meet the needs of people towards the end of life. Symptoms associated with a series of common, progressive, chronic illnesses will be discussed, thereby further facilitating planning for individual patients and for services.

Underlying electrical propagation in the heart and potentially fatal arrhythmia is the cardiac microstructure. Despite the critical role of muscle architecture, a non-destructive approach to examine not only myocyte orientation, but cellular arrangement in to laminar organization is lacking in hearts from translational animal models and humans. X-ray micro computed tomography using contrast enhancing agents achieves three-dimensional images at near-histological resolutions. However, imaging large mammalian hearts presents challenges including X-ray over-attenuation and loss of image contrast. The goal of this study was to rethink tissue pre-treatment to optimize, and benefit from micro computed tomography imaging resolution in large tissues. Whole pig and human hearts were dehydrated and perfused with a tissue reinforcing agent, hexamethyldisilazane, and slowly air-dried. Heart morphology was conserved and temporally stable. This enabled direct air-mounting for micro computed tomography imaging. Moreover, the desiccated tissue density was significantly reduced compared to the initial hydrated state (P=0.04). Three-dimensional image reconstructions of air-dried hearts segmented using a single intensity threshold revealed detailed microstructural architecture of myolaminae. Conversely, one-step segmentation of hearts loaded with contrast agents poorly estimated the gross anatomical morphology of the heart and lacked identification of tissue microarchitecture. Air-drying large mammalian hearts optimizes X-ray imaging of cardiac microstructure.

Background The QUASAR Induction Study 1 (NCT04033445) is a phase 2b randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, as induction therapy in patients with moderately to severely active ulcerative colitis (UC) who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) or advanced therapy (ie, tumor necrosis factor alpha antagonists, vedolizumab, or tofacitinib). Methods Patients included in these analyses had moderately to severely active UC (defined as a modified Mayo score of 5 to 9, inclusive) with a Mayo rectal bleeding subscore ≥ 1 and a Mayo endoscopy subscore ≥ 2 obtained during central review of video endoscopy at baseline. Patients were randomized 1:1:1 to receive IV GUS 200 mg, 400 mg, or placebo at Weeks 0, 4, and 8. The primary endpoint was clinical response at Week 12, and major secondary endpoints included clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization at Week 12. Type 1 error was controlled at the 0.05 significance level for the primary endpoint; no other endpoints were controlled for multiplicity. Safety was assessed through Week 12. Results Three hundred thirteen patients were randomized in the primary analysis population (mean age, 41.6 yrs; male 59.1%, mean UC duration, 7.55 yrs; mean Mayo score, 9.2; endoscopy subscore of 3 indicating severe disease, 70%; baseline oral corticosteroid use, 39.6%). Approximately 50% had a prior inadequate response or intolerance to advanced therapy for UC. The baseline demographics and disease characteristics were generally similar among treatment groups (Table 1). At Week 12, a significantly greater proportion of patients treated with GUS 200 mg and 400 mg achieved clinical response compared with placebo (61.4% and 60.7% vs 27.6%, respectively, both p Conclusion In patients with moderately to severely active UC, GUS induction treatment demonstrated superior efficacy compared with placebo treatment. Overall, safety results through Week 12 were consistent with the known safety profile of GUS in approved indications. The efficacy and safety of GUS 200 mg and 400 mg were comparable.

Background In the UNIFI study of ustekinumab (UST) in ulcerative colitis (UC), patients who achieved histo-endoscopic mucosal healing (HEMH; ie, both histologic and endoscopic improvement of mucosa) after induction had higher clinical remission and corticosteroid-free clinical remission rates through 1 year than those who achieved either histologic or endoscopic improvement alone.1 Here, we report the effect of achieving HEMH after induction on long-term symptomatic outcomes through 3 years. Methods Patients who were in clinical response after 8 wks of IV induction with UST 130mg or ~6mg/kg (wk 8 responders) were randomized to maintenance treatment with SC UST 90mg q12w or q8w on entry into maintenance. Those who were not in clinical response to the initial UST dose at wk8 but achieved response at wk16 after receiving a single SC dose of UST 90mg at wk8 (wk16 responders) entered maintenance receiving SC 90mg q8w. After 44 wks of maintenance treatment, patients were given the option to continue in the long-term extension. HEMH was defined as achieving both endoscopic improvement (Mayo endoscopy subscore ≤1) and histologic improvement (neutrophil infiltration in Results Of the 438 patients who were wk8 or wk16 responders to UST induction and received UST maintenance, 116 (26.5%) achieved HEMH after induction, 30 (6.8%) achieved endoscopic improvement without histologic improvement (EI), and 106 (24.2%) achieved histologic improvement without endoscopic improvement (HI). Patients who achieved HEMH after induction had higher symptomatic remission and corticosteroid-free symptomatic remission rates at wks92 and 152 than those with EI or HI; the differences were statistically significantly greater at wk152, while they were only numerically greater at wk92 (Table). The differences were primarily driven by patients with HEMH after induction being more likely to maintain symptomatic remission between wks92 and 152, than those with EI or HI alone. Symptomatic remission and corticosteroid-free remission rates decreased between wks92 and 152 in patients with EI or HI only. Conclusion Patients with UC who achieved HEMH after induction with UST were more likely to maintain symptomatic remission and corticosteroid-free symptomatic remission between 2 and 3 years of maintenance treatment than those who achieved EI or HI alone. Reference 1. K Li, et al. Poster 1008. Presented at UEGW 2019. October 22, 2019. Barcelona, Spain.

Heart failure (HF) is one of the leading causes of death worldwide. HF is associated with substantial microstructural remodeling, which is linked to changes in left ventricular geometry and impaired cardiac function. The role of myocardial remodeling in altering the mechanics of failing hearts remains unclear. Structurally based constitutive modeling provides an approach to improve understanding of the relationship between biomechanical function and tissue organization in cardiac muscle during HF. In this study, we used cardiac magnetic resonance imaging and extended-volume confocal microscopy to quantify the remodeling of left ventricular geometry and myocardial microstructure of healthy and spontaneously hypertensive rat hearts at the ages of 12 and 24 months. Passive cardiac mechanical function was characterized using left ventricular pressure-volume compliance measurements. We have developed a, to our knowledge, new structurally based biomechanical constitutive equation built on parameters quantified directly from collagen distributions observed in confocal images of the myocardium. Three-dimensional left ventricular finite element models were constructed from subject-specific in vivo magnetic resonance imaging data. The structurally based constitutive equation was integrated into geometrically subject-specific finite element models of the hearts and used to investigate the underlying mechanisms of ventricular dysfunction during HF. Using a single pair of material parameters for all hearts, we were able to produce compliance curves that reproduced all of the experimental compliance measurements. The value of this study is not limited to reproducing the mechanical behavior of healthy and diseased hearts, but it also provides important insights into the structure-function relationship of diseased myocardium that will help pave the way toward more effective treatments for HF.

Background Dispersion and gradients in repolarization have been associated with life‐threatening arrhythmias, but are difficult to quantify precisely from surface electrocardiography. The objective of this study was to evaluate electrocardiographic imaging (ECGI) to noninvasively detect repolarization‐based abnormalities. Methods and Results Ex vivo data were obtained from Langendorff‐perfused pig hearts (n=8) and a human donor heart. Unipolar electrograms were recorded simultaneously during sinus rhythm from an epicardial sock and the torso‐shaped tank within which the heart was suspended. Regional repolarization heterogeneities were introduced through perfusion of dofetilide and pinacidil into separate perfusion beds. In vivo data included torso and epicardial potentials recorded simultaneously in anesthetized, closed‐chest pigs (n=5), during sinus rhythm, and ventricular pacing. For both data sets, ECGI accurately reconstructed T‐wave electrogram morphologies when compared with those recorded by the sock (ex vivo: correlation coefficient, 0.85 [0.52–0.96], in vivo: correlation coefficient, 0.86 [0.52–0.96]) and repolarization time maps (ex‐vivo: correlation coefficient, 0.73 [0.63–0.83], in vivo: correlation coefficient, 0.76 [0.67–0.82]). ECGI‐reconstructed repolarization time distributions were strongly correlated to those measured by the sock (both data sets, R 2 ≥0.92). Although the position of the gradient was slightly shifted by 8.3 (0–13.9) mm, the mean, max, and SD between ECGI and recorded gradient values were highly correlated ( R 2 =0.87, 0.75, and 0.86 respectively). There was no significant difference in ECGI accuracy between ex vivo and in vivo data. Conclusions ECGI reliably and accurately maps potentially critical repolarization abnormalities. This noninvasive approach allows imaging and quantifying individual parameters of abnormal repolarization‐based substrates in patients with arrhythmogenesis, to improve diagnosis and risk stratification.

Background: Delirium is a distressing neuropsychiatric disorder affecting patients in palliative care. Although many delirium screening tools exist, their utility, and validation within palliative care settings has not undergone systematic review. Aim: To systematically review studies that validate delirium screening tools conducted in palliative care settings. Design: Systematic review with narrative synthesis (PROSPERO ID: CRD42019125481). A risk of bias assessment via Quality Assessment Tool for Diagnostic Accuracy Studies-2 was performed. Data sources: Five electronic databases were systematically searched (January 1, 1982–May 3, 2020). Quantitative studies validating a screening tool in adult palliative care patient populations were included. Studies involving alcohol withdrawal, critical or perioperative care were excluded. Results: Dual-reviewer screening of 3749 unique titles and abstracts identified 95 studies for full-text review and of these, 17 studies of 14 screening tools were included ( n = 3496 patients). Data analyses revealed substantial heterogeneity in patient demographics and variability in screening and diagnostic practices that limited generalizability between study populations and care settings. A risk of bias assessment revealed methodological and reporting deficits, with only 3/17 studies at low risk of bias. Conclusions: The processes of selecting a delirium screening tool and determining optimal screening practices in palliative care are complex. One tool is unlikely to fit the needs of the entire palliative care population across all palliative care settings. Further research should be directed at evaluating and/or adapting screening tools and practices to fit the needs of specific palliative care settings and populations.

Cardiomyocytes branch and interconnect with one another, providing important redundancy for propagation of electro-chemical signals. Despite this, cardiomyocyte branching structure remains poorly understood. Herein, myocardium from spontaneously hypertensive rats (SHR) was imaged using extended volume confocal microscopy. Samples from untreated SHRs (\(n = 2\)) were compared with SHRs undergoing ACE inhibitor treatment (\(n = 2\)). From these image-stacks the cardiomyocyte network (center-lines and branches) were manually tracked. The frequency of cardiomyocyte branching was calculated and these branching frequencies were compared according to spatial position within a myocardial sheetlet. ACE inhibitor treatment resulted in significantly reduced total cardiomyocyte branching compared with untreated SHR myocardium at 24 mo (0.49 ± 0.04 vs 1.07 ± 0.15 branches per 100 \(\upmu \)m, \(P = 0.020\)). Cardiomyocytes on the sheetlet-surface branched more frequently within their respective cell-layer (0.59 ± 0.07 branches per 100 \(\upmu \)m) compared with cardiomyocytes in the sheetlet interior (0.29 ± 0.12 branches per 100 \(\upmu \)m). The cardiomyocytes in the sheetlet interior exhibited more frequent between-layer branching (0.56 ± 0.06 branches per 100 \(\upmu \)m) compared to sheetlet-surface cardiomyocytes (0.17 ± 0.03 branches per 100 \(\upmu \)m). The ratio of within-layer to between-layer branching was significantly greater at the surface layer compared with the interior layer (3.93 ± 1.06 vs 0.47 ± 0.16, \(P=0.018\)). This proof-of-concept study demonstrates an approach to measuring branching cardiomyocyte networks and shows the spatial heterogeneity of cardiomyocyte branching.