Results Of Trial Research Articles

Abstract 4115832: Statin Intolerance due to Muscle Symptoms Affects Management of Patients: Insights from the CLEAR Outcomes Trial

Background: In CLEAR Outcomes the non-statin bempedoic acid (BA) 180 mg daily reduced MACE-4 (nonfatal MI, nonfatal stroke, coronary revascularization, or CV death) by 13% in 13970 patients at high CV risk with statin intolerance (SI) over a median of 40.6 months. This is the largest prospective database of patients with SI. Aims: To assess whether there were differences in SI symptom history and whether this influenced the clinical course during CLEAR Outcomes. Methods: SI symptoms and impact on activities of daily living (ADL) were recorded prior to randomization. Patients were grouped post hoc as reporting only statin associated muscle symptoms (SAMS), only non-muscle adverse effects (NonSAMS), or BOTH. Results: At baseline 6887 (49.3%) patients reported SAMS, 2485 (18%) NonSAMS, and 4587 (33%) BOTH. SI symptoms had a moderate/severe impact on ADL in 62% SAMS, 48% NonSAMS, and 69% BOTH. Use of any lipid modifying treatment at baseline was 43% SAMS, 36% NonSAMS, and 42% BOTH. Compared to placebo, BA reduced LDL-C at 6 months by 21% in SAMS, 22% in NonSAMS, and 21% in BOTH. There was no difference in the effect on MACE-4 by SI group. New use of moderate/high intensity statin during the study was relatively infrequent (3.2-8.0%) but higher in PBO than BA in all SI groups and was not generally maintained at study end (Table 1). Muscle adverse events (AE) were more frequent and resulted in higher rates of treatment DC in SAMS/BOTH vs NonSAMS (Table 2). There was no difference between BA and PBO in the rate of muscle related AE. Conclusion: SAMS are the predominant cause of SI in patients in CLEAR Outcomes. Patients with a history of SAMS had higher rates of muscle AE and study drug DC due to muscle AE versus NonSAMS. Muscle AE rates and study drug DC were balanced between BA and PBO within each SI symptom subgroup. CLEAR Outcomes exhibits the challenges of treating patients with SI. These data also demonstrate that BA can be useful in reducing CV risk in this patient population.

Abstract 4120229: Shift in body mass index category and associated cardiometabolic risk factors: a post hoc analysis from the SURMOUNT-4 trial

Background: In SURMOUNT-4, participants with obesity demonstrated a mean weight reduction of 21% during the 36-week lead-in with the maximum tolerated dose (MTD) of tirzepatide (TZP). During the 52-week double-blind period, participants who switched to placebo (PBO) experienced a 14% weight regain, while those who continued TZP achieved an additional 6% weight reduction. This post hoc analysis assessed whether participants who shifted to a lower BMI category had improved cardiometabolic factors. Methods: Shift in BMI category (<25 kg/m 2 , 25 to <30 kg/m 2 , 30 to <35 kg/m 2 , 35 to <40 kg/m 2 , and ≥40 kg/m 2 ) from baseline (week 0) during the lead-in period (week 36) and at the primary endpoint (week 88) and from week 36 to week 88 was assessed in participants from SURMOUNT-4 randomized to TZP MTD (N=332) or PBO (N=329). BMI shifts were grouped into “improved” (shift to ≥1 lower category) or “not improved” (stable/attenuated [no change/shift to a higher category]). Changes from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, vitals and lipid profile were assessed. Results: From weeks 0 to 36, 296 (89%) participants improved in BMI category with TZP, and none had attenuated (Table). From weeks 36 to 88, 130 (39%) participants improved in BMI category with TZP, while the majority (99%) randomized to PBO did not. Overall, from weeks 0 to 88, 304 (92%) vs 189 (57%) participants improved in BMI category with TZP vs PBO, respectively, where the improvements observed in the PBO group originated from the 36-week lead-in period. In general, participants who improved in BMI category at week 88 were noted to have greater improvements in cardiometabolic parameters with TZP vs PBO, including decreases from baseline in waist circumference, fasting insulin, fasting glucose, HbA1c, blood pressure, triglycerides, and cholesterol (total, non-HDL-c, LDL-c, and VLDL-c). Conclusions: In this post hoc analysis of SURMOUNT-4, the majority of TZP-treated participants shifted to lower “improved” BMI categories. Shift to an improved BMI category was accompanied by improved cardiometabolic risk factors, suggesting that TZP treatment may lower further cardiovascular outcomes. Relevant outcomes trials are ongoing.

Abstract 4136724: Early Adoption of Sodium-Glucose Cotransporter-2 Inhibitor Among Patients Hospitalized with Heart Failure and Preserved Ejection Fraction in the United States

Introduction: In August 2021, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) found that empagliflozin reduced rates of cardiovascular death and hospitalization by 21% in patients with heart failure with mildly reduced ejection fraction of 41-49% (HFmrEF) and with preserved ejection fraction of > 50% (HFpEF). National trends in Sodium-Glucose Cotransporter-2 Inhibitors ( SGLT2i) use among patients with HFmrEF and HFpEF following this trial are unknown. Methods: We identified patients hospitalized for HFmrEF and HFpEF in the AHA Get With The Guidelines-Heart Failure registry between July 2021 and September 2023. We examined temporal trends in SGLT2i prescriptions at discharge after the publication of the EMPEROR-Preserved trial using the Cochran-Armitage trend test. Results: Among 158,849 hospitalizations with an EF > 40% across 557 hospitals, 27,712 (17.4%) had HFmrEF, and 131,137 (82.6%) had HFpEF. Overall, 22,126 (13.9%) patients were discharged with a prescription for SGLT2i, with higher rates among those with HFmrEF (18.5% vs. 13.0% in those with HFpEF). Patients prescribed SGLT2i were more likely to be younger, male, of Black race, have type II diabetes, have Medicaid insurance, and be discharged from large hospitals. After publication of the EMPEROR-Preserved trial during Q3 2021, rates of SGLT2i prescription at hospital discharge increased from 4.2% in Q3 2021 to 23.5% in Q3 2023, with a 29% relative increase in the rate of SGLT2i prescription for each quarter (adjusted OR, 1.29 [95% CI: 1.28, 1.29]; P<.001). Prescription rates increased from 6.1% in Q3 2021 to 31.6% in Q3 2023 among patients with HFmrEF and from 3.8% to 21.9% for patients with HFpEF (Figure). Conclusion: In the U.S., the use of SGLT2i at discharge has increased for patients hospitalized with HFmrEF and HFpEF following the publication of the EMPEROR-Preserved trial. However, the majority of eligible patients hospitalized for decompensated HF remain untreated with SGLT2i, indicating the need for further efforts to apply the scientific findings into clinical practice.

Abstract 4140115: Comparison of Lipoprotein(a) and Other Apo B Containing Lipoproteins as Predictors of Major Adverse Cardiovascular Events in ODYSSEY OUTCOMES

Background: Lipoprotein(a) [Lp(a)] and other atherogenic lipoproteins each contain one molecule of apolipoprotein B (apoB) per particle. Recent studies have suggested that on a per particle basis, Lp(a) is more strongly associated with major adverse cardiovascular events (MACE) than low density lipoprotein. Hypothesis: In statin-treated patients with recent acute coronary syndrome (ACS), we tested the hypothesis that, on a per particle basis, Lp(a) and its change on treatment with alirocumab (ALI) are more strongly associated with MACE than other [non-Lp(a)] apoB-containing particles. Methods: Molar apolipoprotein(a) [corresponding to Lp(a)] and apo B were measured by mass spectrometry at baseline and month 4 (M4) in a subgroup of 11,957 patients who provided consent for use of stored samples in the ODYSSEY OUTCOMES trial. Non-Lp(a) apoB in nmol/L was calculated as total apo B – Lp(a). Lp(a) and non-Lp(a) apo B at baseline in the placebo group, and absolute changes in their levels on ALI, were related to risk of MACE using proportional hazards models. The latter analysis was adjusted for baseline Lp(a) and non-Lp(a) apo B and stratified by baseline Lp(a) (<125 nmol/L and ≥125 nmol/L). Results: Baseline levels of Lp(a) and non-Lp(a) apoB are shown in the Table . In the placebo group, both baseline Lp(a) and non-Lp(a) apo B independently predicted MACE. At M4 in the ALI group, median Lp(a) change from baseline was -40.9 and -7.0 in those with baseline levels ≥ or <125 nmol/L, respectively. Corresponding median changes in non-Lp(a) apoB were -739 and -776 nmol/L (all P<0.001). In the ALI group with baseline Lp(a)>125 nmol/L, the decrease from baseline in Lp(a), but not the decrease in non-Lp(a) apo B, was significantly related to risk of MACE. Among those with baseline Lp(a)≤125 nmol/L, the decrease from baseline in non-Lp(a) apo B, but not in Lp(a), with ALI was significantly related to risk of MACE. Conclusions: On a per particle basis, baseline Lp(a) and non-Lp(a) apo B both predicted MACE. Among those with high baseline Lp(a), reduction in MACE with ALI was predominantly associated with reduction of Lp(a); among those with lower baseline Lp(a) reduction in MACE with ALI was predominantly associated with reduction in non-Lp(a) apo-B. Lp(a) may be an important target of treatment with ALI in those with elevated levels after ACS.

Abstract 4134364: Predicted Low-Density Lipoprotein Cholesterol and Cardiovascular Outcomes Lowering With Inclisiran in Patients With or Without stroke: Insights from SIRIUS in silico trial.

Introduction: Inclisiran, an siRNA, targeting PCSK9 mRNA, reduces LDL-c levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower cardiovascular (CV) events in virtual patients with atherosclerotic cardiovascular disease (ASCVD). Research question: This analysis predicted the potential efficacy of inclisiran on CV outcomes in virtual patients with or without prior ischemic stroke (IS). Methods: The SIRIUS trial was conducted using a calibrated and validated knowledge-based mechanistic computational model of ASCVD applied to a virtual population with LDL-C ≥ 70 mg/dL. Each virtual patient was its own control. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statin with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal IS over 5 years in patients with or without prior IS. Occurrence of fatal and non-fatal (IS) was also individually assessed in time-to-first-event analyses. Results: Among 204,691 virtual SIRIUS ASCVD patients, 39 371 (19%) had prior IS. At 5 years, the predicted mean percentage reduction in LDL-C with inclisiran as compared to placebo was –49.17% and –49.88% in patients with or without prior IS respectively. Patients with prior IS were at higher risk of 3P-MACE than patients without IS both with placebo and inclisiran (17.01% vs 14.41% with placebo and 13.44% vs 10.83% with inclisiran). However, the predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm for both prior IS and no prior IS (HR 0.78 medium uncertainty and 0.74 low uncertainty respectively). Compared to placebo, inclisiran was also predicted to consistently reduce fatal and non-fatal IS in patients with or without prior IS (5.45% vs 7.22%; HR: 0.75 medium uncertainty and 1.87% vs 2.54%; HR: 0.73 medium uncertainty respectively). Conclusion: SIRIUS provides insights into the potential efficacy of inclisiran on CV events suggesting a substantial 3P-MACE and fatal and non-fatal IS reduction in ASCVD patients including those with prior IS, several years before the availability of results from ongoing outcomes trials (ORION-4, VICTORION-2P).

Abstract 4137516: Disparities in Participation: Analyzing Age, Sex, Race, and Ethnicity in Atrial Fibrillation Clinical Trials in the United States

Introduction: Atrial fibrillation (AF) is a prevalent cardiovascular disease that significantly impacts public health in the United States. Although numerous clinical trials aim to optimize AF management, concerns about demographic disparities in trial participation persist. This study assesses the representation of age, sex, race, and ethnicity among participants in AF trials conducted in the US, highlighting potential biases that could affect the generalizability of trial outcomes. Methods: An extensive review of clinical trials registered on ClinicalTrials.gov involving patients with AF up to April 2024 was performed. The search was filtered to include all completed interventional trials across phases 2 to 4 without restrictions on the initiation or completion dates. Data were extracted concerning mean age, age distribution, sex, and the racial and ethnic composition of the trial participants. Results: From the 173 trials analyzed, a total of 1,355,239 participants were included, with an average age of 64.7 years. The demographic breakdown revealed a participant pool consisting predominantly of older adults (>65 years: 70.8%), with a significant underrepresentation of the younger age group (18-65 years: 29.2%). Males constituted 65.2% of the trial population, highlighting a gender imbalance. Racially, 74.1% of participants were White, while African Americans (7.7%) and Asians (5.9%) and other racial groups were notably underrepresented. Ethnic disparities were also evident, with Hispanic participants making up only 11.5% of the study population. Conclusion: The findings demonstrate significant disparities in the age, sex, race, and ethnic backgrounds of AF clinical trial participants in the US. These imbalances could potentially limit the applicability of trial results across the broader, diverse population. Efforts to enhance the diversity of clinical trial cohorts are essential to ensure more equitable health outcomes and the universal applicability of clinical research findings. Future strategies should focus on targeted recruitment and inclusive study designs to address these disparities.

Transformative Assessment Review

The rapid advancement of generative artificial intelligence (AI) in education and the workforce necessitates that students acquire critical competencies, including digital literacy, data integrity, and ethical AI use, to navigate an increasingly AI-driven world. Equally, academic staff must be upskilled to effectively guide students in the ethical and practical applications of AI. This project examines how a private higher education (HE) institute has modified its Quality Assessment Framework (QAF) to incorporate an AI competence dimension, improve HE assessment and foster students’ competencies. This new dimension complements the existing QAF elements—Intellectual Quality, Significance, and Student Support to ensure a holistic approach in preparing students for AI-integrated academic and professional environments. This project’s framework and innovative tools, such as the enhanced QAF and an AI-driven Generative Pre-trained Transformer (GPT) assessment review tool, support educators in adapting curriculum and assessment design, and empower them to integrate AI competencies seamlessly into the curriculum. The development of these tools drew upon established frameworks, particularly the QAF (Gore et al., 2009) and the AI Assessment Scale (AIAS) by Perkins et al. (2024), which categorises AI usage across five levels, guides assessment reviews and ensures consistent standards for AI integration in student work. A trial, conducted across selected disciplines at the institute, involved academic staff as assessment reviewers and utilised the GPT tool to streamline the assessment review process by aiding in feedback provision, coding, and suggestions for improvement. Evaluation of the tool includes qualitative and quantitative methodologies, gathering academic feedback on usability, clarity, and effectiveness, as well as comparative studies to assess review time and quality before and after GPT integration. Usability testing evaluates workflow compatibility, while academic performance data provide insights into the tool’s impact on student outcomes. Initial results on the tool’s success in enhancing assessment alignment with institutional goals and fostering a comprehensive understanding of AI competence were also examined. Developing and implementing these tools has presented challenges, including the complexity of aligning them with diverse curriculum needs across disciplines, the time investment required for staff training, and the necessity of continuous updates to keep pace with AI technology. Addressing these challenges has been crucial to ensuring the effectiveness and sustainability of these solutions. This digital poster provides insights into the project, covering its development process, trial outcomes, challenges encountered, and future directions for integrating AI competence in higher education assessments.

Pharma in The Digital Era: The Role of Artificial Intelligence in Drug Development

The integration of Artificial Intelligence (AI) in the pharmaceutical sector marks a transformative era, where technology reshapes traditional drug development processes. This paper delves into the pivotal role AI plays in enhancing efficiency and precision in drug discovery, testing, and approval. Existing methods in drug development often suffer from high costs, extended timelines, and high attrition rates in clinical trials, posing significant barriers to timely patient care. To address these issues, we propose the Drug Development based on Artificial Intelligence (DD-AI) framework, leveraging AI-driven algorithms and machine learning models. The DD-AI framework enhances the identification and optimization of drug candidates, predicts clinical trial outcomes, and personalizes patient treatment plans. AI algorithms analyze vast datasets to discover potential drug molecules, simulate their interactions, and streamline the clinical trial process by identifying the most promising candidates. Implementing the DD-AI framework has demonstrated substantial improvements in reducing drug development costs and timelines while increasing the accuracy of trial outcomes. AI's predictive capabilities also personalize treatments, optimizing efficacy and minimizing adverse effects for patients. The DD-AI framework offers a robust solution to existing challenges in drug development, fostering a more efficient, cost-effective, and patient-centered approach. The findings underscore AI's transformative potential in revolutionizing pharmaceutical practices, ultimately benefiting patients with faster and more precise medical solutions.

DDDR-37. OHSV AND RADIATION THERAPIES SENSITIZE GLIOBLASTOMA TO IGF1R-TARGETED THERAPY AND SYNERGIZE IN TRIPLE COMBINATION THERAPY

Abstract Glioblastoma (GBM) continues to have a dismal prognosis despite remarkable advances in the field due to both tumor-intrinsic factors (i.e., IDH1 or EGFRvIII mutations) and extrinsic factors (i.e., relating to the tumor microenvironment (TME)), necessitating therapeutic innovation. Oncolytic herpes simplex virus-1 (oHSV) is an FDA-approved therapy that has shown promising results in clinical trials; however, therapeutic efficacy is limited to a small subset of patients. Thus, elucidating both the tumor-TME interplay and feedback/feedforward tumor-cell signaling in the context of viro-immunotherapy is essential in augmenting therapeutic outcomes. We recently discovered a novel mechanism of resistance to oHSVs, in which infection increases secretion of Insulin-like growth factor 2 (IGF2), activating the Insulin-like Growth Factor-1 Receptor (IGF1R). Upregulation of the IGF1R signaling pathway in GBM is correlated with poor prognosis and has been implicated in resistance to conventional therapies including radiotherapy (RTx). Herein, we further elucidate the impact of oHSVs on IGF1R activation, demonstrating a dose-dependent enhancement of downstream signaling. While IGF1R targeting therapies (e.g., OSI-966, Picropodophyllin (PPP)) have displayed limited efficacy in clinical trials, they significantly increased oHSV-induced cytotoxicity in all tested primary GBM cells compared to either agent alone in vitro and in vivo, resulting in a dose-dependent increase in PARP and caspase 3 activity by western blot and immunohistochemistry. We further found that RTx-induced IGF1 secretion and subsequent IGF1R activation were enhanced when combined with oHSV treatment. Triple combination therapy with oHSV, IGF1R inhibition, and RTx significantly increased tumor cell killing in vitro and improved survival of orthotopic GBM tumor-bearing mice. Collectively, our study provides preclinical evidence of enhanced therapeutic efficacy of oHSVs and RTx in combination with IGF1R blockade, supporting future use of IGF1R inhibitors in combination with the standard of care and FDA-approved oHSV therapies in patients with GBM.

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

PATH-12. CLINICAL AND NEUROPATHOLOGICAL MARKERS FOR DISTINGUISHING BETWEEN IDH-MUTANT ASTROCYTOMAS OF WHO GRADE 2 AND 3

Abstract BACKGROUND The neuropathological criteria of anaplasia to distinguish between IDH-mutant astrocytomas of WHO grade 2 and 3 are ill-defined by the WHO 2021 classification. Following the positive phase III trial results and the expected approval of Vorasidenib for grade 2 astrocytomas, identifying prognostic markers distinguishing grade 2 and 3 tumors remains crucial. METHODS We retrospectively searched our institutional database for patients meeting the diagnostic criteria for IDH-mutant astrocytomas per the WHO 2021 classification. Clinical, neuropathological, and molecular data were collected, and outcomes compared using log-rank analysis. Centralized slide review is ongoing to exclude inter-rater variability due to the study’s retrospective nature. RESULTS We identified 99 patients with IDH-mutant astrocytomas in which detailed neuropathological and clinical information were available for review, including 63 tumors (63.6%) which were assigned to WHO grade 2 and 36 tumors (36.4%) assigned to WHO grade 3. At a median follow-up of 7.5 years, median progression-free survival was 5.7 years for WHO grade 2 tumors and 4.4 years for WHO grade 3 tumors. Median overall survival for WHO grade 2 and WHO grade 3 tumors was not reached. On univariate analysis, higher WHO grade, an increased number of mitoses, elevated Ki67 indices and the presence of contrast-enhancement on pre-operative imaging were associated with less favourable outcome. However, only the presence of contrast-enhancement retained its prognostic significance when forwarded into a multivariate model (p = 0.034 for overall survival, p = 0.012 for progression-free survival). The findings on the association between contrast-enhancement and outcome were confirmed in treatment-based subgroups, including individuals treated with a watch-and-scan approach (n = 30), radiotherapy (n = 25), or chemotherapy (n = 33). CONCLUSION While our findings await confirmation in larger prospective cohorts, neuropathological criteria for anaplasia might need to be accompanied by clinical information including contrast enhancement to prognostically distinguish grade 2 from grade 3 tumors particularly in patients undergoing biopsy given the risk for undersampling.

Pengembangan Media Pembelajaran Go Puzzle Pada Mata Pelajaran Pendidikan Pancasila dan Kewarganegaraan untuk Siswa Sekolah Menengah Pertama

This study aims to develop and test the validity, attractiveness, effectiveness, and applicability of Go Puzzle learning media in the subjects of Pancasila and Civic Education. The procedure used is research and development based on the steps proposed by Borg and Gall. The products produced in this development study are Go Puzzle learning media material for the Formulation and Determination of Pancasila as a State Basis that is valid, interesting, effective, and can be applied in learning. The product validity test is based on the results of material expert validation of 92.78 percent, media expert validation of 91.42 percent, expert validation of learning implementation plans of 95.63 percent, and field learning expert validation of 98.21 percent. The product attractiveness test is based on the results of small group trials of 90.36 percent and the results of large group trials of 93.46 percent. The product effectiveness test is based on the results of large group trials which resulted in an average completeness of students’ scores when pretest was 20.89 percent and post test was 86.89. This shows that there is an increase in the percentage of completeness of scores obtained by students, which is 66 percent. The product applicability test is based on the educator response questionnaire, which is 96.88% which shows that the product developed can be applied in learning. Abstrak: Kajian ini bertujuan untuk mengembangk

Sheffield Adaptive Patterned Electrical Stimulation (SHAPES) Therapy for Post Stroke Arm spasticity: study protocol for a 3-arm, a partially blinded, randomised controlled trial

IntroductionPost stroke elbow spasticity (PSES) affects over a third of individuals following stroke and negatively impacts on functional recovery, comfort and quality of life. Drug therapies have limited efficacy and unwanted side effects, botulinum toxin, although effective, is costly, and conventional electrical stimulation therapies are limited long term by habituation. We aim to investigate the efficacy of Sheffield Adaptive Patterned Electrical Stimulation (SHAPES), that delivers temporally and spatially varying pattern of electrical stimulation, against transcutaneous electrical stimulation (TENS) and standard care at reducing PSES.Methods and designOverall, 297 people with PSES will be randomised (1:1:1) to one of 3 arms: Standard care (no electrical stimulation), TENS (conventional patterned electrical stimulation) or SHAPES (adaptive patterned electrical stimulation). Both SHAPES and TENS are delivered using a specially designed electrical stimulation sleeve used for 60 min each day for 6-weeks. Outcome measures are completed at baseline, end of treatment (EOT 6 weeks) and then 6-weeks, 12-weeks and 24-weeks after the end of treatment. Efficacy will be determined based on the proportion of participants experiencing meaningful improvement (18%) in the 7-day Numerical Rating Scale (NRS-S) for PSES, compared between both intervention arms and standard care, and between the two intervention groups. Measures of arm motor function (Action Research Arm Test, MRC scale), and quality of life (SQoL-6D, EQ-5D) will also be measured along with a parallel health economic evaluation.DiscussionThe results of the SHAPES trial will inform management of elbow spasticity after stroke. The SHAPES intervention is a low cost, self-administered intervention for the management of spasticity that can be used repeatedly, and if found to be more effective than TENS or control has the potential to be widely implemented in the UK NHS healthcare setting. Furthermore, despite the wide use of TENS in the management of spasticity, this study will provide critically required evidence regarding its efficacy. The trial has been registered with the ISRCTN registry (ISRCTN26060261).

Effect of Supplementation of Spirulina (Spirulina platensis) on Growth Performance of Broiler in Konkan Region, India

The experimental trial of six weeks was conducted on 200 broiler chicks. They were randomly distributed into five experimental treatment groups. Each treatment group was replicated into four with 10 birds per replication. The control (T1) group was fed standard ration and T2, T3, T4 and T5 group were provided same standard ration supplemented with 1.00 g, 2.00 g, 3.00 g and 4.00 g spirulina powder, respectively. The result of experimental trial showed that supplementation of spirulina powder was significantly highest live body weight in treatment T5 (1944.50 g/bird) as well as average live body weight gain (277.79 g/bird). It is concluded that, 4.00 g of spirulina powder significantly improved growth performance of broiler chicks than other treatments groups.

Cardiovascular, Metabolic, and Safety Outcomes with Semaglutide by Baseline Age: Post Hoc Analysis of SUSTAIN6 and PIONEER6.

The high risk of cardiovascular events in people with type2 diabetes increases with age. The cardiovascular effects of once-weekly subcutaneous and once-daily oral semaglutide versus placebo in people with type2 diabetes at high cardiovascular risk were investigated in the SUSTAIN6 and PIONEER6 cardiovascular outcomes trials, respectively. It is unknown whether the effects of semaglutide are age dependent. This post hoc analysis evaluated cardiovascular, metabolic, and safety outcomes with semaglutide versus placebo in age subgroups (≤ 60; > 60 to ≤ 65; > 65 to ≤ 70; and > 70years) pooled from SUSTAIN6 and PIONEER6. Major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), changes from baseline in glycated hemoglobinA1c (HbA1c) and body weight, and adverse events were analyzed. Semaglutide reduced major adverse cardiovascular events and its components versus placebo across age subgroups (most hazard ratios < 1.0; pinteraction > 0.05). The treatment difference in HbA1c reduction was greater in those aged ≤ 60years than in older subgroups (pinteraction = 0.01). Reductions in body weight with semaglutide versus placebo were consistent across agesubgroups (pinteraction = 0.124). Serious adverse events or severe hypoglycemic episodes did not differ between semaglutide and placebo across age subgroups. Semaglutide consistently reduced major adverse cardiovascular events and body weight versus placebo across age subgroups; its safety profile did not differ with age. These results suggest that relaxing HbA1c targets based solely on age may not always be required for people with type2 diabetes. SUSTAIN6 (NCT01720446) and PIONEER6 (NCT02692716) are registered at ClinicalTrials.gov.

Centrally adjudicated vs. investigator-reported outcomes in randomized heart failure trials.

Heart failure endpoints in cardiovascular outcome trials are commonly identified through centralized adjudication of investigator-reported events. It remains unclear whether central adjudication improves the accuracy of treatment effect estimates in terms of log[hazard ratios (HR)]. Data from seven cardiovascular outcome trials with >1000 patients that included centrally adjudicated heart failure outcomes were utilized to assess (i) the concordance between investigator-reported and centrally adjudicated heart failure and cardiovascular death events; (ii) rates of subsequent all-cause mortality following positively vs. negatively adjudicated heart failure events; and (iii) the correlation of log(HR) based on centrally adjudicated vs. investigator-reported events. Positive adjudication rates for investigator-reported events varied widely across trials, but were generally higher for cardiovascular death (range: 87.9%-99.2%) than for heart failure hospitalization (range: 61.6%-88.0%). The risk for subsequent all-cause death was similar for positively and negatively adjudicated heart failure hospitalizations. Log(HR) correlated well for cardiovascular death [R2 = .80, 95% credible interval (CrI): 0.53-0.93] and the composite of cardiovascular death or heart failure hospitalization (R2 = .79, 95% CrI: 0.46-0.93), but less for heart failure hospitalization (R2 = .57, 95% CrI: 0.10-0.83). Positive adjudication rates were lower for heart failure events than cardiovascular death, but even negatively adjudicated heart failure events are prognostically important. Central adjudication of events did not alter the results (precision or estimated log(HR)), though some variation was observed, depending on the indication. The results suggest that the decision to pursue centralized adjudication of heart failure events in a specific trial may need to be individualized.

Symptoms Burden as a Clinical Outcomes Assessment in HeartFailure Patients With Atrial Fibrillation.

Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period. The authors sought to develop and validate a method of measuring symptom burden of AF in a HF population. The authors constructed a patient-reported outcome instrument (Atrial Fibrillation Symptoms Questionnaire [AFSQ]) to function in the setting of AF/HF, and used it to measure symptoms throughout long-term follow-up. The AFSQ queries the presence of 10 new or worsening symptoms, equally divided between those associated with AF or HF. In a 267 patient AF/HF trial comparing 2 AF prevention treatments, the AFSQ was linked to electrocardiography documented AF to form a 2-component clinical outcome assessment (SxBAF) that was subjected to psychometric testing, anchor validation, and endpoint efficiency comparison to TTFSE. SxBAF exhibited greater efficiency than time to first symptomatic event for treatment difference detection, resulting in smaller projected clinical trial sample sizes. SxBAF correlated well with device-detected AF burden (Spearman's ρ=0.74; P< 0.0001), while permitting gradation in symptom severity. SxBAF also identified treatment group differences in cardiovascular serious adverse events and AF interventions and in recent-onset AF provided specificity for AF- or worsening HF-associated symptoms (P< 0.001 for each). Measurement of symptoms burden throughout clinical trial follow-up is feasible in AF/HF and should be useful for evaluating patient-centered outcomes in AF prevention trials. (Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With HeartFailure [GENETIC-AF]; NCT01970501).

IMMUNE DYSREGULATION IN AUTOIMMUNE HEPATITIS: THE ROLE OF AUTOANTIBODIES, T-REG CELLS, AND NOVEL THERAPEUTIC APPROACHES

Introduction. The liver is a crucial immunological tolerogenic organ with a unique ability to generate effective immune responses against hepatotropic pathogens while maintaining both local and systemic immune tolerance to self and foreign antigens. Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease caused by the loss of tolerance to liver-specific antigens, leading to autoimmune liver damage.Aim – to summarize current knowledge on the immunopathogenesis of AIH based on information from open sources.Material and methods. The selection of publications was conducted using databases such as PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection, and Google Scholar, which covered information on the immunopathogenesis of AIH. Literature search was performed using keywords: autoimmune diseases, autoimmune hepatitis, Kupffer cells, autoantibodies to liver microsomal antibodies, and mesenchymal stem cells.Research results. Liver immune regulation is mediated by unique cell populations, including T-reg cells, Kupffer cells, and NK cells, which interact to maintain immune tolerance and regulate inflammation. Deficiency or dysfunction of T-reg cells, along with the activation of Th17 cells, contribute to the development of inflammatory processes and autoimmune liver damage. The quantitative and qualitative composition of immune cells in the liver differs significantly from that in secondary lymphoid organs, such as lymph nodes, spleen, or peripheral blood. The CD8+/CD4+ ratio (3.5:1) of liver T cells contrasts with the 1:2 ratio observed in peripheral blood, lymph nodes, and spleen.Conclusions. AIH is a complex disease with a multifaceted immunopathogenesis. T-reg and MSC-based therapies show promising results in clinical trials; however, further research is needed to optimize these methods and ensure their safe and effective application.

Special Section on Patient-Reported Outcomes and Informatics: Collection of Patient-Reported Outcome Measures in Rural and Underserved Populations.

The NIH Pragmatic Trials Collaboratory supports the design and conduct of 31 embedded pragmatic clinical trials, and many of these trials use patient-reported outcome measures (PROMs) to provide valuable information about their patients' health and wellness. Often these trials enroll medically underserved patients, including people with incomes below the federal poverty threshold, racial or ethnically minoritized groups, or rural or frontier communities. In this series of trial case reports, we provide lessons learned about collecting PROMs in these populations. The unbiased collection of PROM data is critical to increase the generalizability of trial outcomes and to address health inequities. Use of electronic health records (EHRs) and other digital modes of PROM administration have gained traction. However, engagement with these modes is often low among disparities prone populations due to lessened digital proficiency, device access, and uptake of EHR portals and web interfaces. To maximize the completeness and representativeness of their trial outcome data, study teams tested a range of strategies to improve PROM response rates with emphasis on disparities prone and underserved patient groups. This manuscript describes the approaches, their implementation, and the targeted populations. Optimized PROM collection required hybrid approaches with multiple outreach modes, high-touch methods, creativity in promoting digital uptake, multi-modal participant engagement, and text messaging.

Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial

IntroductionGenetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside...