Baseline Figure Research Articles

Effects of Aloe Vera Gel on Red Blood Cell-parameters in Phenylhydrazine-induced Anaemic Wistar albino Rats

Background & objective: Anaemia is the most significant disorder of the blood. Many researchers have developed the concept of using medicinal plants as an alternative source of treatment for anaemia with fewer side effects. Aloe vera, being a medicinal plant, is popularly used as a natural drug in haematological disorders. The present study was intended to observe the effects of Aloe vera gel on red blood cell parameters in phenylhydrazine (PHZ)-induced anaemic Wistar albino rats. Methods: This Experimental study was conducted in Dhaka Medical College, Dhaka from July 2021 to June 2022. A total of 24 healthy Wistar albino rats were selected for the study. After procurement, the rats were initially kept in a standard laboratory condition on a 12/12-hour light/dark cycle for 14 days of acclimatization before 21 days of the experiment. All the rats had free access to basal diet and normal saline during the period of acclimatization and experiment. After acclimatization for 14 days, the rats were divided into three groups-Group A (baseline control group, n = 8), Group B (PHZ-treated group, n = 8), and Group C, the Experimental Group (PHZ-induced and Aloe vera gel treated group, n = 8). To induce anaemia, Group B and Group C received intraperitoneal injection of PHZ at a dose of 0.5 ml/100 g body weight on days 1, 3, 5 and day 7. Moreover, the experimental group (Group C) received Aloe vera gel orally at a dose of 0.6 ml/kg body weight from Day 8 to Day 21. On day 22, rats were sacrificed to test their blood samples for haematologic variables (RBC count, Hb conc., and PCV) and haematological indices (MCV, MCH and MCHC). Result: All the haematological parameters and indices were almost similar among the study groups at baseline (on Day 1). On Day 8, rats of groups B and C demonstrated a drastically reduced count of RBC (2.66 ± 0.53 and 2.69 ± 0.52 million/μl respectively) compared to the rats of group A (8.16 ± 0.76 million/μl). On Day 22, the RBC count in rats of Group C staggeringly increased to 7.63 ± 0.64 million/μl; however, the RBC count in rats of Group B remained almost the same as was found on Day 8. A significant decrease in Hb conc. and PCV in PHZ-induced control on Day 8 compared to that on Day 1 was also observed. The mean MCV in all the study groups on Day 1 was around 50 fl, which abnormally increased to 85 and 87 fl in Groups B and C respectively on Day 8. On Day 22, Group B further exhibited an increase in MCV to > 87 fl. Meanwhile, the MCV in Group C (Aloe vera-treated group) favourably decreased to 55 fl. On the 8th Day of intervention, the MCH level significantly decreased in Groups B and C. Although no significant change in MCH was observed in Group B from Day 8 to Day 22, group C demonstrated a significant increase in the mean MCH to nearly 18 pg during the same period. The mean MCHC significantly dropped to < 23% in Groups B and C on Day 8 from the baseline figure of 34%. While no significant change in MCHC was evident in Group B from Day 8 to Day 22, it significantly improved to about 28% in Group C during the same period. Conclusion: From the study, it can be concluded that Aloe vera has significant erythropoietic potentials which result in the improvement of red blood cell parameters (RBC count, Hb conc., PCV, MCV, MCH and MCHC) in PHZ-induced anaemic rats. Ibrahim Card Med J 2023; 13 (1&2): 40-46

The elimination of human African trypanosomiasis: Monitoring progress towards the 2021-2030 WHO road map targets.

Human African trypanosomiasis (HAT) is a neglected tropical disease that usually occurs in rural areas in sub-Saharan Africa. It caused devastating epidemics during the 20th century. Sustained, coordinated efforts by different stakeholders working with national sleeping sickness control programmes (NSSCPs) succeeded in controlling the disease and reducing the number of cases to historically low levels. In 2012, WHO targeted the elimination of the disease as a public health problem by 2020. This goal has been reached and a new ambitious target was stated in the WHO road map for NTDs 2021-2030 and endorsed by the 73rd World Health Assembly: the elimination of gambiense HAT transmission (i.e. reducing the number of reported cases to zero). The interruption of transmission was not considered as an achievable goal for rhodesiense HAT, as it would require vast veterinary interventions rather than actions at the public health level. Data reported to WHO by NSSCPs were harmonized, verified, georeferenced and included in the atlas of HAT. A total of 802 cases were reported in 2021 and 837 in 2022. This is below the target for elimination as a public health problem at the global level (< 2000 HAT cases/year); 94% of the cases were caused by infection with T. b. gambiense. The areas reporting ≥ 1 HAT case/10 000 inhabitants/year in 2018-2022 cover a surface of 73 134 km2, with only 3013 km2 at very high or high risk. This represents a reduction of 90% from the baseline figure for 2000-2004, the target set for the elimination of HAT as a public health problem. For the surveillance of the disease, 4.5 million people were screened for gambiense HAT with serological tests in 2021-2022, 3.6 million through active screening and 0.9 million by passive screening. In 2021 and 2022 the elimination of HAT as a public health problem was validated in Benin, Uganda, Equatorial Guinea and Ghana for gambiense HAT and in Rwanda for rhodesiense HAT. To reach the next goal of elimination of transmission of gambiense HAT, countries have to report zero cases of human infection with T. b. gambiense for a period of at least 5 consecutive years. The criteria and procedures to verify elimination of transmission have been recently published by WHO. HAT elimination as a public health problem has been reached at global level, with seven countries already validated as having reached this goal. This achievement was made possible by the work of NSSCPs, supported by different public and private partners, and coordinated by WHO. The new challenging goal now is to reach zero cases by 2030. To reach this goal is crucial to maintain the engagement and support of donors and stakeholders and to keep the involvement and coordination of all partners. Along with the focus on elimination of transmission of gambiense HAT, it is important not to neglect rhodesiense HAT, which is targeted for elimination as a public health problem in the WHO road map for NTDs 2021-2030.

Abstract MP35: Long-Term Trajectories of Self-Rated Health Are Similar Following Incident Diabetic Foot Disease and Acute Myocardial Infarction Among Adults With Diabetes in the Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Incident diabetic foot disease is associated with significant morbidity and mortality. However, data are lacking on long-term patient-reported outcomes. We aimed to evaluate trajectories of self-rated health among adults with diabetes before and after incident foot disease compared to incident acute myocardial infarction (MI), another major diabetes complication. Methods: We conducted a longitudinal analysis of participants in the ARIC Study with diabetes and incident diabetic foot disease (N=749 hospitalizations, N=73 outpatient encounters) or incident MI (N=703). Diagnosis and procedure codes from active hospitalization surveillance and Medicare claims were used to identify events; only MI events were adjudicated. Self-rated health was collected during annual telephone calls and rated from 1 (poor) to 4 (excellent); a score of 0 was assigned to deaths. We used linear regression to examine changes in self-rated health from 1 year pre-event (baseline). Relative effects of index event type over time were estimated by repeated-measures ANOVA. Results: Self-rated health was similar between groups at baseline ( Figure ). Participants with MI had sharper declines from baseline at 1 year post-event than those with diabetic foot disease (-0.93 vs -0.50 points, P&lt;0.01), largely due to higher mortality (29.4% after MI vs 15.9% after diabetic foot disease). Self-rated health stabilized in the outpatient diabetic foot group after 2 years post-event, whereas it continued to decline over 10 years following both MI and inpatient diabetic foot disease ( Figure ). Conclusions: Our findings suggest outpatient diabetic foot disease is primarily associated with a short-term drop in self-rated health, but inpatient diabetic foot disease is associated with long-term declines in self-rated health similar to those experienced after MI. These results reinforce the importance of early diagnosis and treatment of foot disease and of including patient-reported outcomes to measure sequelae of diabetes complications.

Transcriptional Changes in Patients with CLL Starting Venetoclax Therapy Identifies Inflammatory and Adaptive Stress Responses

Venetoclax is a selective BCL2 inhibitor that was recently approved for CLL treatment. Venetoclax inhibits the pro-survival protein BCL2 and induces deep and durable responses in a significant proportion of CLL patients. Herein, we aimed to study gene expression changes in leukemic cells from CLL patients during the ramp-up period of venetoclax treatment and to assess the transcriptional effect of escalating doses of BCL2 inhibition on tumor biology. We performed RNA sequencing on CD19+ selected tumor cells from 29 patients, ramped-up according to the standard Venetoclax schedule, with weekly increments from 20 mg to 400mg. Four samples were collected per patient, at baseline, and after completing one week on 50mg,100mg, and 400mg. Twelve (41%) patients switched from BTK inhibitor therapy to venetoclax due to disease progression on the BTKi. Those patients discontinued BTKi the day before they started Venetoclax ramp-up. 19 (59%) patients were either treatment-naïve or relapsed with at least months of treatment free-intervals before starting venetoclax. Circulating CD19+ cell counts, typically composed of &amp;gt;95% CLL cells, were enumerated using flow-cytometry. during the ramp-up period, revealed gradual reduction in CLL burden with escalating doses. In the off-BTKi group, median CLL cell counts started to decline on the 100mg dose and were reduced to 98% of baseline at the end of the ramp-up. In the other patients, reductions in median counts were already apparent after one week on 20mg and reached 99% at the end of the ramp-up. Principal component analysis (PCA) of transcriptome data grouped samples by patient, as we have commonly observed in such unsupervised analysis. After batch correcting the patient effect, PCA clearly separated on treatment timepoints from baseline (Figure). Interestingly, patients who recently stopped BTKi had distinct distribution on PCA plots in comparison to the other patients (Others). Indicating distinct transcriptomic changes in patients based on their recent treatment histories. To identify the impact of venetoclax on the CLL transcriptome, we carried out Gene set enrichment analysis using the Hallmark and C3 gene sets from the molecular signature database. Gene sets were identified using a false discovery rate (FDR) of &amp;lt; 0.05, and a normalized enrichment score (NES) of ≥ |1.8|. Gene sets were ranked by NES. In the off-BTKi patient group, 27 gene sets were identified as statistically significantly enriched at 100mg and 400 mg doses. In the “other” patients group, 15 gene sets were found significantly enriched at the same doses. Eight gene sets relating to inflammatory, interferon, and reactive oxygen species responses, cytokine signaling, and fatty acid metabolism. In the off-BTKi we prominently found enriched gene sets regulated by TP53 and related to DNA repair, cell cycle checkpoints, hypoxia and apoptosis. Consistent with an oxidative stress response we identified upregulation of NRF2, NFE2, TCF11, and BACH motif gene sets. The apparent more pronounced transcriptional response to venetoclax in the off-BTKi group prompted us to look more closely at changes in gene. At baseline, expression of BCL2L2 and NOXA was significantly lower in the off-BTKi patients in comparison to the “others” patient group. Surprisingly, on the 50mg dose expression of both the pro-apoptotic and anti-apoptotic BCL2 family members was significantly increased in the off-BTKi group in comparison to the others group; at the 100mg dose only pro-apoptotic genes remained significantly overexpressed in the off-BTKi group. In conclusion, venetoclax induced a distinct and prominent transcriptional response in CLL patients indicating broad impact on tumor biology, even at doses below 400mg. Intriguingly, CLL cells from patients who had progressed on BTKi therapy and switched to venetoclax showed a more extensive stress response that included activation of DNA damage and anti-oxidant pathways. It will be interesting to correlate the identified transcriptional changes with the depth and durability of the venetoclax response.

Estimating the Cost of Wildlife Strikes in Australian Aviation Using Random Forest Modeling

Wildlife strikes in aviation represent a serious economic concern; however, in some jurisdictions, the costs associated with this phenomenon are not collected or shared. This hampers the industry’s ability to quantify the risk and assess the potential benefit from investment in effective wildlife hazard management activities. This research project has applied machine learning to the problem by training a random forest algorithm on wildlife strike cost data collected in the United States and predicting the costs associated with wildlife strikes in Australia. This method estimated a mean annual figure of AUD 7.9 million in repair costs and AUD 4.8 million in other costs from 2008 to 2017. It also provided year-on-year estimates showing variability through the reporting period that was not correlated with strike report numbers. This research provides a baseline figure for the Australian aviation industry to assess and review current and future wildlife hazard management practices. It also provides a technique for other countries, airlines, or airports to estimate the cost of wildlife strikes within their jurisdictions or operational environments.

755-P: A Phase 2 Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Glycemic Control in Adults with Type 2 Diabetes

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a Phase 2 randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 145 adults at over 20 hospital-based sites in China. Eligible participants had T2DM that was inadequately controlled by lifestyle or a single oral hypoglycemic agent. Participants were randomized to receive 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once weekly injections for 20 weeks, including dose escalation. Change in mean HbA1c, body weight, and BMI, as well as safety and tolerability were evaluated. At baseline, participants had mean HbA1c of 8.55 ± 0.707 % and BMI of 26.27 ± 3.308 kg/m2. At the end of treatment, participants receiving ecnoglutide achieved significant HbA1c reductions of 1.81% to 2.39% from baseline (P&amp;lt;0.0001 for all cohorts vs placebo). At end of treatment, up to 67% of participants in the ecnoglutide cohorts achieved HbA1c levels ≤6.5% and up to 33% had body weight reductions ≥5% from baseline (Figure). Ecnoglutide was generally safe and well tolerated. There were no treatment-related ≥Grade 3 AEs and no treatment-related SAEs. The proportion of participants reporting any AE ranged from 72.2 to 78.4% for ecnoglutide and 58.3 % for placebo. The most frequently reported AEs were gastrointestinal, including diarrhea and nausea. Disclosure D.Zhu: None. S.Xu: Employee; Sciwind. M.K.Junaidi: None. H.H.Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q.Zheng: Employee; Sciwind Biosciences. J.Ning: None. Z.Zhu: Employee; Sciwind Biosciences. G.Mengying: None. Y.Bu: Employee; Sciwind Biosciences. C.Jones: Employee; Sciwind Biosciences. M.Fenaux: Employee; Sciwind Biosciences, Stock/Shareholder; Terns Pharmaceuticals. Funding Sciwind Biosciences

CARC12: Surgical Correction of De Novo Aortic Valve Insufficiency after Left Ventricular Assist Device Implantation

Background: Development of significant aortic insufficiency (AI) is a common complication associated with prolonged support with continuous-flow left ventricular assist device (CF-LVAD). The aim of this study is to investigate the clinical outcomes after surgical correction of de novo AI after LVAD implantation. Methods: Between January 2013 and June 2022, 190 patients underwent CF-LVAD implantation. Of them, 24 had trivial or less AI before LVAD implantation and developed moderate or greater de novo AI after LVAD implantation. Those who had undergone aortic valve surgery before or concomitant with LVAD surgery were excluded. Among the 24 patients, surgeries were indicated for medically refractory de novo AI in 11 patients, who were included in the current study. Primary endpoint was post-operative improvement in hemodynamics as assessed with right heart catheter examination, and the secondary endpoint was 3-year survival and freedom from death and/or heart failure readmission rate. Results: Correction of de novo AI were accomplished with aortic valve closure with bovine pericardial patch in 10 patients and prosthetic valve replacement in one patient. After surgery, pulmonary artery wedge pressure (PAWP), and cardiac index (CI), mixed venous blood oxygen saturation (SvO2) significantly improved compared with preoperative baseline (Figure). The mean follow-up after LVAD implantation was 1413days, and the 3-year survival rate was 90.9%. The freedom from postoperative moderate or greater AI rate, and the freedom from heart failure readmission rate were both 90.9% at 3 years. Conclusion: In patients who were indicated for surgical correction of de novo AI after LVAD implantation, postoperative hemodynamic improvement and survival were considered favorable.Figure 1. Hemodynamic change in three states

PO-05-200 GENDER DISPARITIES IN MANAGEMENT AND OUTCOMES OF ATRIAL FIBRILLATION IN A MODERN LOUISIANA COHORT

Female gender is associated with a lower lifetime risk of developing atrial fibrillation (AF) when compared to males. Other gender differences in atrial fibrillation comorbidities, treatments, and outcomes have been described with often conflicting results. We sought to investigate gender differences in comorbidities, treatments, and outcomes of atrial fibrillation patients from a recent Louisiana population. Data on patients aged ≥18 years diagnosed with atrial fibrillation between January 2010 and December 2019 was pulled from the Research Action for Health Network database (REACHnet). The primary outcome was defined as the first occurrence of ischemic stroke, transient ischemic attack (TIA), intracranial bleeding, gastrointestinal bleeding, hospitalization, or death. Chi-squared test was used to study categorical variables. Poisson regression was used to examine the effect of gender on outpatient visits per year, adjusted for comorbidities. 2592 patients were included in this study, 35.1% of whom were females. Female patients were younger (62.2 vs 63.3 years p <0.001), had less coronary artery disease (OR=0.68, p <0.001), and less chronic kidney disease (OR=0.89, p=0.005), but a more frequent stroke history (OR=1.4, p<0.001) at baseline (figure). Females were less likely to receive antiarrhythmic drug therapy (AAD) (OR=0.75, p=0.018). Among those who received AADs, female patients were less likely to receive amiodarone (OR=0.69, p=0.003), and more likely to receive flecainide (OR=3.45, p=0.048). Patients with at least 1 non-gender CHA2DS2-VASc risk factor had similar odds of receiving oral anticoagulation in general, and similar odds for receiving direct oral anticoagulants in particular. Females had one more outpatient visit per year than males did, even after accounting for comorbidity differences (p <0.001). Female patients had higher odds of achieving our primary outcome of stroke, TIA, intracranial bleeding, gastrointestinal bleeding, hospitalization, or death (OR=1.19, p=0.041). Female atrial fibrillation patients have a different comorbidity profile than their male counterparts. We found persistent gender disparities in the management and prognosis of atrial fibrillation in a modern Louisiana population.

Clinicohematologic and Molecular Response of Essential Thrombocythemia Patients Treated with Pegylated Interferon-Alpha: A Multicenter Study on Behalf of the German Study Group-MPN (GSG-MPN)

Cytoreductive treatment with hydroxyurea (HU) or anagrelide (ANA) aims at reducing the risk of vascular complications in essential thrombocythemia (ET), while (pegylated) Interferon-α (pegIFN) may also prevent progression to secondary myelofibrosis (SMF) or acute myeloid leukemia (AML). In contrast to polycythemia vera (PV), the accessibility to pegIFN is limited in ET due to lack of approval. To investigate the clinical benefits of pegIFN in ET, we identified within the German Study Group-Myeloproliferative Neoplasms (GSG-MPN) registry a total of 127 WHO-defined patients (pts) treated at seven University centres. In this study, we analysed clinically relevant parameters before and during pegIFN treatment and assessed the JAK2 V617F variant allele frequency (VAF) in DNA from granulocytes by droplet digital PCR (sensitivity 10-3) in JAK2 mutated pts with available biosamples. Baseline characteristics of the pts were: median age at diagnosis 37.0 years (yrs, range 8.2-77.4), median platelet (PLT) count 780 /nl (124-2,776), median white blood cell (WBC) count 8.2 /nl (3.0-17.3); 67% were female; 53% were JAK2 V617F-, 33% CALR-, and 5% MPL-mutated. According to the International Prognostic Score of thrombosis in ET (IPSET), 37% were low-, 31% intermediate-, and 30% high-risk (2% unknown). Median time from diagnosis to pegIFN start was 1.9 yrs (0.0-37.2); in 59% pegIFN was used as first-line drug, 20% were pre-treated with HU, 9% with ANA, and 11% with both. Main reasons for pegIFN start were high PLT count (39%), prior thrombosis (31%), ET-associated symptoms (9%), age >60 yrs (7%), and pregnancy (7%). Since 31 pts (24%) had ≥2 lines of treatment (LOT) with pegIFN, a total number of 161 LOT was recorded. PegIFN 2a was used in most LOT (54%), followed by pegIFN 2b (35%) and ropegIFN 2b (11%). Median total pegIFN treatment duration per pt was 2.3 yrs (0.1-18.1); 30/127 (24%) and 10/127 (8%) were treated for ≥5 yrs and ≥10 yrs, respectively. At last follow-up, 60% of pts were still on pegIFN. The discontinuation rate was highest in the first yr of treatment (14.3%). Adverse events (16%) and market withdrawal of pegIFN 2b (15%) were the two most frequent reasons for discontinuing a LOT. According to European LeukemiaNET response criteria (Barosi et al. Blood 2009), 89% of pts achieved clinicohematologic response at any time which was complete in 54% and partial in 35%. Median PLT and WBC counts at last follow-up (380 /nl and 5.5 /nl, respectively) were significantly lower compared to baseline (780 /nl and 8.2 /nl) (Figure). Only one pt progressed to SMF during pegIFN treatment, while no pt transformed to secondary AML. Vascular complications were rare with three arterial and five venous events in 469 pegIFN treatment yrs, resulting in an incidence of 0.6% and 1.1% per pt and yr, respectively. Flu-like symptoms were recorded in 41%, abnormal liver tests in 16%, and depression in 14% of LOT (grading and time points unknown). Quantitative assessment of the JAK2 V617F VAF on 70 samples from 14 pts with available DNA before pegIFN start and ≥2x thereafter (each at least one yr apart) revealed a reduction from median 30.5% (7.2-48.1) at baseline to 8.3% and 18.1% after 4 and 8 yrs of pegIFN treatment, respectively (n.s.); 5/14 pts (36%) achieved a ≥50% reduction (partial molecular response) and one pt showed a VAF <1%. In 10/127 pts (8%), pegIFN 2b was stopped due to market withdrawal and not immediately switched to an alternative drug as they had been treated for a median of 9.5 yrs (6-18): 3/10 pts maintained normalized blood cell counts until data cut-off (1.5-4.5 yrs after discontinuation); of these 3, one had 0.1% JAK2 V617F at the time of discontinuation, while the other two were JAK2 V617F negative (baseline VAF not available); 2/3 pts underwent bone marrow biopsy and showed histomorphological remission of ET. Analyses of a large series of ET pts treated with pegIFN confirm a high efficacy of the drugs in achieving clinicohematologic response. Our data, including long-term treated pts with low rates of vascular complications, disease progressions, and adverse events underscore the medical benefit of pegIFN in ET. Although reduction of the JAK2 V617F VAF was not significant, molecular responses <1% and histomorphological remissions were observed in single pts. For treatment discontinuation, molecular thresholds for JAK2 V617F and CALR mutations need to be defined in the future. FS and LLT contributed equally to this study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results from an Open-Label Phase 1/2 Study of Favezelimab (anti-LAG-3) Plus Pembrolizumab in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: PD-1 inhibitors play a key role in the treatment of relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) but improving upon current treatment responses remain of clinical interest. Lymphocyte-activation gene 3 (LAG-3) is involved in T-cell regulation and is commonly coexpressed with PD-1 on anergic T cells. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity leading to US Food and Drug Administration approval for the treatment of patients with unresectable or metastatic melanoma. Favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus pembrolizumab (anti-PD-1) is being investigated in the multicohort phase 1/2 MK-4280-003 efficacy and safety study (NCT03598608) in patients with R/R hematologic malignancies. Initial results from the MK-4280-003 study demonstrated promising antitumor activity and acceptable safety in anti-PD-1-naive patients with R/R cHL (cohort 1) (Johnson NA, et al. J Clin Oncol. 2022;40(16_suppl):7516). Updated results from cohort 1 after additional follow-up are presented. Methods: Part 1 was the safety lead-in phase to determine the recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 1 had R/R cHL after autologous stem cell transplantation (ASCT) or were ineligible for ASCT, and had no prior anti-PD-1 therapy. Part 1 included patients from all cohorts who received escalating doses (per modified toxicity probability index interval design) of pembrolizumab IV 200 mg Q3W and favezelimab IV 200 mg or 800 mg Q3W. In part 2, patients received pembrolizumab plus favezelimab at the established RP2D (800 mg Q3W) for ≤35 cycles (~2 years). CT scans were performed every Q12W and PET scans at Weeks 12 and 24 to assess response by investigator review per the IWG 2007 criteria. Adverse events (AE) were graded per the NCI CTCAE, v4.0. The primary end points were safety and RP2D. Objective response rate (ORR) was a secondary end point. Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Among the 30 patients enrolled in cohort 1, the median age was 40.5 years, 53% had ECOG PS 0, and 80% had ≤3 prior lines of therapy. At database cutoff (May 03, 2022), 6 (20%) patients had completed 2 years of study treatment and 13 (43%) patients had discontinued (9 progressive disease; 4 AEs); 4 (13%) patients discontinued due to treatment-related adverse events [TRAEs]); 11 (37%) patients had treatment ongoing at the time of database cutoff. No deaths were treatment-related. Among the 26 patients (87%) who had TRAEs; the most common (≥10%) were hypothyroidism (27%); infusion-related reaction (23%), fatigue (20%); pruritus and headache (17% each), chills (13%); arthralgia, hyperthyroidism, maculopapular rash, myalgia, nausea and pyrexia (10%, each). Grade 3 or 4 TRAEs occurred in 7 patients (23%); including 1 (3%) event each of thrombocytopenia, enterocolitis, fatigue, autoimmune hepatitis, increased blood creatine phosphokinase, increased amylase, increased lipase, organizing pneumonia, and maculopapular rash. Of 3 patients who received hematopoietic stem cell transplantation after completion of study treatment, 1 had a grade 3 or 4 AE unrelated to study treatment (increased blood bilirubin) that resolved. After a median follow-up of 15.5 months, 22 patients had objective response (ORR, 73% [95% CI, 54-88]; complete response, 9 [30%]; partial response, 13 [43%]). Of 29 patients (97%) who received a postdose scan, 28 had a baseline reduction in target lesions and 23 (79%) had ≥50% reduction from baseline (Figure). Median DOR was not reached (NR; range, 2.6-28.8+ months); 7 patients (56%) had response ≥12 months. Median PFS was 19.4 months (95% CI, 8.5-NR); 12-month PFS rate was 62%. Median OS was NR (95% CI, NR-NR); 12-month OS rate was 96%. Conclusion: After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in anti-PD-1-naive patients with R/R cHL. Further studies comparing the activity of this combination to that of single-agent pembrolizumab would be of clinical benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Treated with Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody: Patient-Reported Outcomes from MonumenTAL-1

Introduction: Studies of multiple myeloma (MM) populations indicate that patients with more advanced and heavily pretreated disease have worse health-related quality of life (HRQoL) than those at earlier stages. In addition, treatment options are limited for triple-class exposed relapsed/refractory MM (RRMM), with little hope of improving HRQoL. Talquetamab is a first-in-class, off-the-shelf, T-cell redirecting bispecific antibody targeting both GPRC5D and CD3 receptors. MonumenTAL-1 is a phase 1/2 trial (NCT03399799/NCT04634552) of talquetamab in patients with RRMM. Patient-reported outcomes (PROs) data on HRQoL, symptoms, and functioning were collected in the phase 2 cohorts of MonumenTAL-1. Here, we report PROs, focusing on global health status (GHS), physical functioning, pain, and fatigue, for the 0.4 mg/kg subcutaneous (SC) weekly (QW) cohort. Data for the 0.8 mg/kg SC every 2 weeks (Q2W) cohort are immature currently. Methods. Patients enrolled in phase 2 must have previously received ≥3 prior lines of therapy, including ≥1 proteosome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 monoclonal antibody (ie, triple-class exposed). After screening, patients received talquetamab step-up doses, requiring hospitalization, before cycle 1. The European Organization for Research and Treatment of Cancer Quality of Life Core 30-item (EORTC QLQ-C30) questionnaire is a cancer-specific PRO instrument administered at screening, cycle 1, and then every other cycle. It includes a subscale to measure HRQoL, 5 functional scales, 3 symptom subscales, and 6 additional single items. Scores range from 0 to 100; higher scores indicate better GHS and functioning, whereas a higher score represents more symptom severity. Compliance with PROs was calculated as the number of completed assessments divided by the number of patients on study treatment at each assessment time point. Treatment effect was assessed with a mixed-effects model with repeated measures. For the analysis of the proportion of patients with meaningful improvement, the threshold for meaningful improvement from baseline was defined as a change of ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: For patients treated with 0.4 mg/kg SC QW (n=122), compliance with completing the EORTC QLQ-C30 was 96% at screening and over 80% at most post-treatment visits. After an immediate decline in overall HRQoL between screening and cycle 1, patients reported meaningful improvements in EORTC QLQ-C30 GHS and a meaningful reduction in pain symptoms compared with baseline (Figure). Least squares [LS] mean change for fatigue symptoms was -8 (95% CI, -13.83, -2.26) at cycle 9 and reached a mean decrease (ie, improvement) of 11.2 points (95% CI, -18.9, -3.53) at cycle 13. Similar results were observed in the physical (LS mean change at cycle 9: 6.5 [95% CI, 2.05, 10.93]) and role (LS mean change at cycle 9: 11.4 [95% CI, 4.55, 18.25]) functioning subscales. With treatment, the proportion of patients with meaningful improvement was high; for example, at cycle 9 for the 0.4 mg/kg cohort, 42% improved in GHS, 34% in physical functioning, 40% in role functioning, 86% in pain symptoms, and 78% in fatigue symptoms. Median time to worsening ranged from 2 (role and social functioning) to 9 months (nausea/vomiting). Overall, changes in PROs were similar in the 0.8 mg/kg SC Q2W cohort in early cycles, but conclusions are limited due to short follow-up and small sample size. The 0.8 mg/kg SC Q2W cohort will be updated with additional follow-up. Conclusions: With talquetamab treatment, patients in the 0.4 mg/kg SC QW cohort reported improvement in overall HRQoL and physical and role functioning and a decrease in pain and fatigue. These findings are consistent with the clinical benefits of talquetamab as demonstrated by the efficacy results from the MonumenTAL-1 study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 11968: Association Between Reduction in Inflammation and Change in Cardiovascular Risk: Results From the Liira Study

Background: Coronary microvascular disease (CMD) is associated with increased cardiovascular (CV) risk in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD, as measured by coronary flow reserve (CFR). However, it is not known whether reducing inflammation results in improvement in CMD or other CV correlates. The objective of this study was to determine the association between reducing inflammation with changes in CV risk. Methods: The Lipids, Inflammation and CV risk in RA (LiiRA) study recruited RA patients age ≥18 yrs with active RA about to initiate a TNFi as part of clinical care. All subjects underwent a stress myocardial perfusion PET scan to quantify CFR at baseline and after 24 weeks. A lower CFR in the absence of obstructive CAD is indicative of CMD, CFR&lt; 2.5 defined CMD. Inflammatory markers and hs-cTnT were performed at baseline and 24 weeks. Primary and secondary outcomes was change in CFR and hs-cTnT, respectively, and tested by Spearman correlations. Results: A total of 66 subjects completed the study, 80% female, mean RA duration 7.7 yrs. Baseline estimated ASCVD risk was 5.6%, yet 47% had evidence of CMD. We observed a significant reduction in all inflammatory markers between baseline and follow-up, along with improvements in RA disease activity; however, no change in the mean CFR or hs-cTnT was observed. A reduction in hsCRP and IL-1beta was associated with a reduction in hs-cTnT. A non-significant trend for correlation of reduced IL-1beta with higher CFR was observed among subjects with CMD at baseline (Figure). Conclusion: There was a high prevalence of CMD at baseline, but CFR did not significantly improve. Reducing inflammation was correlated with improvements in measures of CV risk, mainly in the subset of patients with detectable hs-cTnT, particularly via the IL-1beta pathway. These data suggest that hs-cTnT may be a useful marker when considering targeting inflammation to reduce CV risk in RA.

1416-P: UK First National Health Service (NHS) Endobarrier (EB) Service for Uncontrolled Diabesity: Four-Year Outcomes for All 62 Treated Patients

EB, a 60cm endoscopically inserted proximal intestinal liner, reduces weight and HbA1c over 1 year. In the 1st NHS EB service, we provided EB to patients with sub optimally controlled diabesity and monitored outcomes in a registry. 44/62 (71%) completing 3 years post EB removal (age 51.3±7.8 years, 54% male, diabetes duration 14.56 (8-21) years, BMI 41.7±7.2 kg/m2) attended follow-up. During EB treatment, mean ± SD HbA1c fell by 1.9±1.8 %, from 9.1±1.8 to 7.2±1.0 % (p&amp;lt;0.001) , weight by 17.3±9.0 kg from 122.8 ± 29.8 to 105.4±30.6 kg (&amp;lt;0.001) , systolic BP from 138.8±14.3 to 125.9±14.9 mmHg (&amp;lt;0.001) , serum alanine aminotransferase (liver fat marker) from 30.4±17.2 to 19.1±11.2 U/L (p&amp;lt;0.001) . Median (IQR) total daily insulin dose reduced from 1 (50-171) to 30 (0-63) units (n=29, p&amp;lt;0.001) ; 10/29 (34%) insulin treated patients discontinued insulin. 3-years post EB removal 33/44 (75%) maintained most of the improvement achieved with EB whilst 11/44 (25%) reverted to baseline (figure) . Of those deteriorating, all had depression and/or bereavement and/or major health problems/disability. 10/62 (16%) had early EB removal for adverse events or symptoms; all fully recovered after removal and most derived significant benefit. Our data demonstrates EB as highly effective in patients with refractory diabesity, with maintenance of significant improvement 3 years after removal in 75% Disclosure R.E.J. Ryder: None. P. Sen Gupta: None. M. Yadagiri: None. W. Burbridge: None. S.P. Irwin: None. H. Gandhi: None. M.C. Wyres: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None.

825-P: Composite Glucose and C-Peptide Endpoints Show Early Efficacy in Recent-Onset Type 1 Diabetes (T1D) Clinical Trials

C-peptide area under the curve (AUC) at ≥1 year, a standard endpoint of recent-onset T1D clinical trials, is derived from a 120-minute mixed meal tolerance test (MMTT) . We analyzed whether composite glucose and C-peptide endpoints, useful in post hoc analyses of prevention trials, could detect treatment effects as early as 3 months between the combined treated and placebo groups from 3 TrialNet recent-onset T1D trials that met their primary endpoint. Comparisons were made between treated and placebo groups after adjustments for age, sex, and BMI Z-score using AUC C-peptide (standard measure) , AUC C-peptide/AUC glucose (AUC ratio) , and a new measure, the centroid ratio. Centroids, geometric central points of shapes, were derived from MMTT shapes formed from mean glucose and C-peptide values at 30, 60, 90, and 120 minutes. The centroid ratio is the C-peptide coordinate/glucose coordinate of the centroid. A treatment effect at 3 months was evident for centroid and AUC ratios (p&amp;lt;0.0 and p=0.002, respectively) and not AUC C-peptide (p=0.056) . Similar results were seen when individual trials were compared. The difference between combined groups at 3, 6, and 12 months is demonstrated by vectors that start at baseline (Figure) . In conclusion, composite glucose and C-peptide endpoints appear to identify early treatment efficacy and should be considered in future new-onset pilot studies and trials. Disclosure L.M.Jacobsen: None. A.Pugliese: Advisory Panel; Provention Bio, Inc., Consultant; Quell Tx. P.Gottlieb: Advisory Panel; Janssen Research &amp; Development, LLC, ViaCyte, Inc., Other Relationship; IM Therapeutics, Research Support; Caladrius Biosciences, Inc., Immune Tolerance Network, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Precigen, Inc., Tolerion, Inc. J.Sosenko: None. D.D.Cuthbertson: None. M.J.Haller: Advisory Panel; SAB Biotherapeutics , Consultant; MannKind Corporation, Sanofi. H.M.Ismail: n/a. E.K.Sims: Other Relationship; Medscape, Patent. S.E.Gitelman: Advisory Panel; Abata Therapeutics, Avotres Inc., Biolojic Design, Ltd., Provention Bio, Inc., Rubius, SAB Biotherapeutics, Inc., Tolerion, Inc. D.K.Wherrett: n/a. A.Moran: Advisory Panel; Dompé, Other Relationship; Novo Nordisk, Research Support; Abbott Diabetes, Provention Bio, Inc. M.A.Atkinson: None.

FC055: Effect of Atacicept on Renal Function in SLE Patients

Abstract BACKGROUND AND AIMS Atacicept is a dual BLyS/APRIL inhibitor. APRIL-SLE was a double-blind, placebo-controlled phase 2 study, which randomized moderate-to-severe systemic lupus erythematosus (SLE) patients to atacicept 75 mg, atacicept 150 mg or placebo. The primary endpoint was the proportion of subjects who experienced a new flare during the 52-week treatment period. In total, 111 patients in the placebo group, 112 patients in the atacicept 75 mg group and 62 patients in the atacicept 150 mg group completed 52 weeks of treatment. Patients with severe renal disease were excluded, while patients with proteinuria and mild–moderate chronic kidney disease, as assessed by KDIGO criteria, were eligible. The effect of atacicept on measures of renal function in these patients has not previously been reported. METHOD The study excluded moderate to severe glomerulonephritis, as defined by either of the following: urinary protein/creatinine ratio &amp;gt; 1 mg/mg and/or hematuria or a significant renal impairment as defined by glomerular filtration rate (GFR) &amp;lt; 50 mL/min/1.73 m2. Urine protein/creatinine ratio (UPCR) and GFR were measured at baseline, week 2, and then every 4 weeks until week 52. RESULTS In the APRIL-SLE study, the analysis for GFR and UPCR are of all patients (62–111 per group) with up to 15% of patients having a history of SLE-related renal disease. GFR time course showed stability for the atacicept groups compared to a 4.3% decline in the placebo group at week 52 from baseline (figure and table). Furthermore, reductions in UPCR from baseline at week 52 were observed in the atacicept groups compared to an increase in the placebo group. CONCLUSION In this phase 2 APRIL-SLE study, analysis of renal data suggests potential for improved renal function with atacicept treatment in SLE renal disease.

Dynamic myocardial response to exercise in children with transposition of the great arteries post arterial switch operation

Abstract Funding Acknowledgements Type of funding sources: None. Background The arterial switch operation (ASO) has improved outcomes for patients with transposition of the great arteries (TGA) however the long-term impact on myocardial function and functional reserve during exercise remains poorly described. The aim of this study was to evaluate left (LV), and right ventricular (RV) myocardial response to exercise in children post ASO using semi-supine cycle ergometry stress echocardiography (SSCE). Methods This is a single-center cross-sectional study. Participants prospectively underwent exercise stress echocardiography using a semi-supine bicycle and a stepwise exercise protocol. Systolic (s’) and diastolic (e’) tissue Doppler velocities, as well as myocardial acceleration during isovolumic contraction (IVA) were measured at rest and during exercise at incremental heart rates (HR) in the basal segments of the RV lateral wall, IVS and LV lateral wall. Systolic and diastolic reserve were evaluated by plotting s’ and e’ against HR while contractile reserve was assessed by plotting IVA values against HR which represents the force-frequency relationship (FFR). Results A total of 40 patients with TGA and 29 controls were included. There were no differences between groups in age (14.6 ± 2.9 vs 14.3 ± 3.1 years, p= 0.75), sex (male= 30/40 vs 20/29 p= 0.58), and resting HR (67 ± 12 vs. 71 ± 12 bpm, p = 0.31). Peak HR was lower in the ASO group (142.2 ±12.4 vs 157 ± 12.3 bpm, p&amp;lt; 0.01). At rest, the ASO group showed lower s’ in the RV and IVS (RV s’: 5.7 ± 1.4 vs. 10.2 ± 2.1 cm/s, p &amp;lt;0.001; IVS s’: 4.2 ± 1.3 vs. 6.2 ± 1.8 cm/s, p&amp;lt; 0.001); lower IVA in the IVS and LV (IVS: 1.01 ± 0.37 vs. 1.23 ± 0.4 m/s2, p= 0.03; LV: 0.86 ± 0.32 vs. 1.1 ± 0.4 m/s2, p =0.02), and reduced e’ in all segments. At peak exercise the ASO group showed reduced s’, e’, and IVA in all segments (table1). When plotted against HR, there was blunting of the s’ slope in RV and septal segments while the LV s’ slope was similar between groups. There were no differences in e’ slope when compared to controls (figure 1). The ASO group showed a blunted IVA response to HR in all measured segments compared to controls. Conclusion(s): Our data demonstrate patients post ASO have reduced RV and LV contractile reserve in response to exercise. The etiology and long-term implications of these abnormalities however remains to be described. Abstract Figure. Doppler velocities at baseline and peak Abstract Figure. Dynamic response to exercise

Legal aspects regarding the formation and structure of the share capital of the joint stock company

The share capital of the Joint Stock Company is a baseline figure, contractual (provided in the Articles of association) and accounting (recorded in the liabilities side of the balance sheet) which shows, from a legal point of view, the level of the shareholders’ contribution obligation and, by default, the limit of shareholders’ liability, and the value of the goods of the company’s assets that are subject to the legal rules of the share capital, this being also called nominal capital or figure capital. The share capital of a Joint Stock Company is created by the shares placed by the shareholders and represents the value in kind and in cash, exclusively for certain categories of Joint Stock Companies, paid proportionally to the number and value of the subscribed shares. Analyzing the provisions of the legal acts, as well as the doctrinal opinions, we conclude that the contribution represents the manifestation of will of the shareholders, which consists in undertaking the obligation to contribute to the formation of the share capital of a Joint Stock Company determined by the transfer in ownership or use of a property in the assets of that company, in exchange for any shares, as well as the factual and legal fulfilment of such obligation by the actual transfer of such property to the company. The share capital of the Joint Stock Company includes the value of the cash and in-kind contributions paid at the time of the company’s incorporation or subsequently, by additional subscriptions. The law does not require that the contributions of the shareholders (stockholders) be equal in value or have the same object, and in the event of a single shareholder to be as a unitary object. Because, the property that forms the share capital of the Joint Stock Company ensures its economic activity and free participation in the civil circuit.

P316 Ozanimod is an efficacious oral therapy after, 5-ASA failure in immunomodulator- and biologic-naive patients with ulcerative colitis: post hoc analysis from True North

Abstract Background Oral, 5-aminosalicylates (5-ASA) and corticosteroids (CS) are often the first-line treatment for ulcerative colitis (UC), and patients (pts) who fail these agents typically advance to chronic immunosuppressives. Ozanimod, an oral sphingosine, 1-phosphate receptor modulator, is approved for treating adults with moderately to severely active UC in the US. This post-hoc analysis from the pivotal phase, 3 True North randomised controlled trial evaluated the efficacy of ozanimod at week (wk), 10 (end of induction) in immunomodulator- and biologic-naive pts with moderate to severe UC who failed, 5-ASA with or without concomitant CS. Methods True North consisted of a, 10-wk induction period. Pts in Cohort, 1, stratified by CS use at screening, were randomised to either ozanimod, 0.92 mg (equivalent to ozanimod HCl, 1 mg; n=429) or placebo (n=216) once daily in a double-blind manner; pts in Cohort, 2 (n=367) received open-label daily ozanimod, 0.92 mg. At enrollment, pts were required to be on stable doses of oral, 5-ASA and/or CS for &amp;gt;2 wk and continued on the same dose throughout induction. Pts who received tofacitinib within, 2 wk of screening were excluded. This analysis focused on clinical remission, clinical response, endoscopic improvement, and mucosal healing efficacy outcomes in immunomodulator- and biologic-naive, 5-ASA exposed pts. Results Of, 464 pts treated with, 5-ASA and were immunomodulator- and biologic-naive, with or without CS, 205 were on ozanimod and, 105 were on placebo in Cohort, 1;, 158 received open-label ozanimod in Cohort, 2. Baseline characteristics were similar between groups in Cohort, 1. Compared with placebo at wk, 10, a higher proportion of ozanimod-treated patients achieved clinical remission (23.4% vs, 8.9%), clinical response (53.7% vs, 30.7%), endoscopic improvement (35.6% vs, 14.9%), and mucosal healing (18.0% vs, 5.0%; Figure, 1) in this subgroup. These results are consistent with previously published results of the overall study population,1 which demonstrated significantly greater proportions of patients receiving ozanimod vs placebo achieving clinical remission (18.4% vs, 6.0%), clinical response (47.8% vs, 25.9%), endoscopic improvement (27.3% vs, 11.6%), and mucosal healing (12.6% vs, 3.7%). Additionally, all efficacy endpoints were achieved by a greater proportion of patients on ozanimod vs placebo regardless of CS use at baseline (Figure, 2). Results were similar for open-label ozanimod-treated patients in Cohort 2. Conclusion Ozanimod demonstrated efficacy at wk, 10 in immunomodulator- and biologic-naive patients with UC who had failed, 5-ASA, regardless of CS use at baseline. Reference 1. N Engl J Med, 2021;385:1280.

Effectiveness of a Multifaceted Intervention for Prevention of Obesity in Primary School Children in China

A rapid nutritional transition has caused greater childhood obesity prevalence in many countries, but the repertoire of effective preventive interventions remains limited. To determine the effectiveness of a novel multifaceted intervention for obesity prevention in primary school children. A cluster randomized clinical trial was conducted during a single school year (from September 11, 2018, to June 30, 2019) across 3 socioeconomically distinct regions in China according to a prespecified trial protocol. Twenty-four schools were randomly allocated (1:1) to the intervention or the control group, with 1392 eligible children aged 8 to 10 years participating. Data from the intent-to-treat population were analyzed from October 1 to December 31, 2019. A multifaceted intervention targeted both children (promoting healthy diet and physical activity) and their environment (engaging schools and families to support children's behavioral changes). The intervention was novel in its strengthening of family involvement with the assistance of a smartphone app. The control schools engaged in their usual practices. The primary outcome was the change in body mass index (BMI; calculated as weight in kilograms divided by height in square meters) from baseline to the end of the trial. Secondary outcomes included changes in adiposity outcomes (eg, BMI z score, prevalence of obesity), blood pressure, physical activity and dietary behaviors, obesity-related knowledge, and physical fitness. Generalized linear mixed models were used in the analyses. Among the 1392 participants (mean [SD] age, 9.6 [0.4] years; 717 boys [51.5%]; mean [SD] BMI, 18.6 [3.7]), 1362 (97.8%) with follow-up data were included in the analyses. From baseline to the end of the trial, the mean BMI decreased in the intervention group, whereas it increased in the control group; the mean between-group difference in BMI change was -0.46 (95% CI, -0.67 to -0.25; P < .001), which showed no evidence of difference across different regions, sexes, maternal education levels, and primary caregivers (parents vs nonparents). The prevalence of obesity decreased by 27.0% of the baseline figure (a relative decrease) in the intervention group, compared with 5.6% in the control group. The intervention also improved other adiposity outcomes, dietary, sedentary, and physical activity behaviors, and obesity-related knowledge, but it did not change moderate- to vigorous-intensity physical activity, physical fitness, or blood pressure. No adverse events were observed during the intervention. The multifaceted intervention effectively reduced the mean BMI and obesity prevalence in primary school children across socioeconomically distinct regions in China, suggesting its potential for national scaling. ClinicalTrials.gov Identifier: NCT03665857.

Development of a Predictive Model for Cytokine Release Syndrome to Inform Risk Stratification and CRS Management Following Immunotherapy

Development of a Predictive Model for Cytokine Release Syndrome to Inform Risk Stratification and CRS Management Following Immunotherapy