Trial Phase Research Articles

P0725 The fragility of randomized clinical trials in evaluating novel therapies for Inflammatory Bowel Disease

Abstract Background Numerous randomized clinical trials (RCTs) have evaluated novel therapies for inflammatory bowel disease (IBD). However, these trials often rely solely on P values to determine treatment efficacy, which may not fully capture the robustness of the results. This study aimed to evaluate the fragility of these RCTs and to identify study characteristics that influence result stability. Methods A search for RCTs assessing the efficacy of novel IBD therapies, including biologics, small molecule inhibitors, fecal microbiota transplantation, and stem cell therapies, was conducted in PubMed and Web of Science from January 1, 2014, to November 10, 2024. Included RCTs were required to report at least one statistically significant result (P <0.05) and employ an equal randomization design. The FI and continuous FI (CFI) were computed for binary and continuous outcomes, respectively, as reported in previous studies1, 2. We used Wilcoxon rank-sum and Kruskal-Wallis tests for dichotomous and multi-categorical characteristics, respectively, and Spearman’s rank correlation for continuous characteristics. Multiple linear regression was used to further explore the impact of study characteristics on FI. Results A total of 129 trials from the 53 studies were analyzed. The median FI was 6, and the CFI was 14.8. FI varied significantly by treatment types, trial phases, outcome types, and reported P values. The total sample size (ρ = 0.734) and number of discontinuations (ρ = 0.479) exhibited strong and moderate positive correlations with FI, respectively, while publication year, impact factor, and events percentage showed weak positive correlations. CFI was significantly influenced by outcome types, and moderate and strong correlations were observed with journal impact factor (ρ = 0.426) and sample size (ρ = 0.757), respectively. After adjusting for other characteristics, the association between treatment type (biologics or small molecule drugs vs. fecal microbiota transplantation or stem cell therapy) and the natural logarithm of FI remained statistically significant (B = 0.283). Primary or coprimary outcome showed greater robustness compared to other outcomes in both the FI (B = 0.288) and CFI models (B = 0.459). Sample size was positively associated with both the natural logarithm of FI (B = 0.001) and CFI (B = 0.001), while the per protocol analysis demonstrated a negative association (B = -0.929). Conclusion RCTs evaluating novel IBD therapies show varying levels of robustness, influenced by multiple study characteristics. Fragility should be considered in future research when interpreting the efficacy.

The Determinants of Toxicity in the Treatment of Prostate Cancer with a Focal, Intraprostatic "Microboost".

A single phase III trial has demonstrated that prostate radiotherapy with a focal, intra-prostatic "microboost" can improve disease control without an overall increase in toxicity. It is unclear how these results generalize to other treatment schedules and protocols. A systematic search of PubMed and the Cochrane Review was performed for studies published on or before September 1, 2023. A random-effects meta-analysis was used to pool the cumulative incidence of grade ≥2 (≥G2) acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Heterogeneity was assessed, and the association of trial-level covariates with toxicity were examined via subgroup analyses and meta-regression. Odds ratios (ORs) for dose metrics were reported per Gy EQD2. Thirty-eight patient cohorts were included. The pooled estimate of the cumulative incidence of ≥G2 acute and late GU toxicity was 25.3% (95% confidence interval [CI]: 19.1%-32.8%) and 21.1% (95% CI: 16.7%-26.3%), respectively. Late ≥G2 GI toxicity was less frequent, estimated at 5.6% (95% CI: 3.5%-8.7%) and 6.9% (95% CI: 4.6%-10.1%), respectively. Subgroup factors associated with at least one ≥G2 toxicity category were treatment technique, imaging used for boost volume definition, intrafraction motion management, trial phase, and toxicity grading. Rectal DMax was associated with acute ≥G2 GI toxicity (OR: 1.05 [95% CI: 1.02-1.08], p < 0.001). Additionally, urethral DMax was associated with late ≥G2 GU toxicity (OR: 1.02 [95% CI: 1.01-1.03], p < 0.001), and a stronger relationship was observed with the average plan urethral DMax (OR: 1.05 [95% CI: 1.03-1.07], p < 0.001). No association of toxicity with any bladder dose metric examined was observed. The utilization of a microboost appears tolerable across treatment protocols; however, subgroup factors, including the use of intrafraction motion management and the type of imaging modality utilized, may influence the probability of toxicity. Attention to rectal DMax constraints and urethral DMax dose constraints may help to mitigate GI and GU toxicity, respectively. No association between toxicity and bladder dose constraints was observed.

P0831 Improving efficiency in early phase clinical trials for inflammatory bowel disease through use of external control arms

Abstract Background Although randomised controlled trials (RCTs) are the gold standard for evaluating medical interventions, enrolling enough patients in early-phase trials in inflammatory bowel disease (IBD) to provide sufficient efficacy and safety information prior to confirmatory trials can be difficult.1,2 In a landscape where combination therapies frequently require monotherapy controls and where placebo responses are well-understood, improving trials with external control (EC) data may enhance phase 1-2 trial designs. Methods Current possibilities of using EC data in IBD trials from both methodological and statistical perspectives were explored. Methods of utilising EC data were reviewed, including results of a systematic review of immune-mediated inflammatory disease (IMID) trials that utilised external control arms (ECAs)3, and an example of Bayesian analyses integrating EC data used in an RCT comparing combination treatment to monotherapy benchmarks.4 How EC data fits into the intersection between operational efficiency and good clinical practice was examined. Results Multiple simultaneous ongoing IBD studies, strict objective clinical endpoints (eg, endoscopic remission), and declining enrolment rates have led to increasing difficulty in meeting IBD trial recruitment goals. The prevalence of add-on and combination therapies suggests that trials may need multiple control arms to fully explore efficacy and safety of investigational treatments. Using EC data can increase power and allow for exploratory comparisons across multiple controls in modest-sized trials. Techniques and considerations on how to ethically and effectively use EC data to improve clinical trials, however, are not as thoroughly discussed in the literature. Systematic review of controlled trial databases for IMID studies utilising ECAs resulted in 18 IBD studies that met the search criteria, over three-fourths of which did not control for baseline characteristics between external and trial data (Table 1).1 Furthermore, half of the quality assessment items during evaluation could not be assigned a rating due to insufficient methodology details provided in publications. Conclusion Multiple factors have led to increasing difficulty for IBD trials reaching their recruitment goals. In early phase trials particularly, the use of EC data may allow studies to increase power and decision-making information. More comprehensive reporting, as well as the creation of a validated instrument for appraising ECA methodology, are required to thoroughly understand and evaluate EC data use in studies. References 1Harris MF, Wichary J, Zadnik M, Reinisch W. Competition for clinical trials in inflammatory bowel diseases. Gastroenterology. 2019;157(6):1457-1461. doi:10.1053/j.gastro.2019.08.020 2Ma C, Solitano V, Danese S, Jairath V. The future of clinical trials in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2024;Jul 16:S1542-3565(24)00635-9. doi:10.1016/j.cgh.2024.06.036 3 ayadi A, Edge R, Parker CE, Macdonald JK, Neustifter B, Chang J, et al. Use of external control arms in immune-mediated inflammatory diseases: a systematic review. BMJ Open. 2023;13(12):e076677. doi:10.1136/bmjopen-2023-076677 4Colombel JF, Ungaro RC, Sands BE, Siegel CA, Wolf DC, Valentine JF, et al. Vedolizumab, adalimumab, and methotrexate combination therapy in Crohn’s disease (EXPLORER). Clin Gastroenterol Hepatol. 2024;22(7):1487-1496. doi:10.1016/j.cgh.2023.09.010

A Brief Web-Based Person-Centered Care Group Training Program for the Management of Generalized Anxiety Disorder: Feasibility Randomized Controlled Trial in Spain.

Shared decision-making (SDM) is a crucial aspect of patient-centered care. While several SDM training programs for health care professionals have been developed, evaluation of their effectiveness is scarce, especially in mental health disorders such as generalized anxiety disorder. This study aims to assess the feasibility and impact of a brief training program on the attitudes toward SDM among primary care professionals who attend to patients with generalized anxiety disorder. A feasibility randomized controlled trial was conducted. Health care professionals recruited in primary care centers were randomized to an intervention group (training program) or a control group (waiting list). The intervention consisted of 2 web-based sessions applied by 2 psychologists (VR and YA), based on the integrated elements of the patient-centered care model and including group dynamics and video viewing. The outcome variable was the Leeds Attitudes Towards Concordance scale, second version (LATCon II), assessed at baseline and after the second session (3 months). After the randomized controlled trial phase, the control group also received the intervention and was assessed again. Among 28 randomized participants, 5 withdrew before the baseline assessment. The intervention significantly increased their scores compared with the control group in the total scale (b=0.57; P=.018) and 2 subscales: communication or empathy (b=0.74; P=.036) and shared control (ie, patient participation in decisions: b=0.68; P=.040). The control group also showed significant pre-post changes after receiving the intervention. For a future effectiveness trial, it is necessary to improve the recruitment and retention strategies. The program produced a significant improvement in participants' attitude toward the SDM model, but due to this study's limitations, mainly the small sample size, more research is warranted.

Meta-Analysis of Placebo-Treated Patients: Dropout Rates From Treatment in MASH Randomised Controlled Trials.

Dropout is common and affects the statistical power and randomization balance of randomised controlled trials (RCTs). To estimate the dropout rate in RCTs of metabolic dysfunction-associated steatohepatitis (MASH) and to examine factors associated with dropout in placebo-treated participants. PubMed and Cochrane databases were searched for phase 2-4 MASH RCTs with placebo arms through November 24, 2024. Dropout was defined as the attrition of patients included in the intention-to-treat analysis but did not complete treatment. RCTs were qualitatively reviewed to assess the expected and observed dropouts. Generalised linear mixed model was used to estimate pooled dropout rates. Sixty RCTs with 3230 placebo-treated participants with MASH were analysed. Thirty-three RCTs reported the dropout rate used to estimate the effect size. Of these, 60.6%, 36.4%, and 3.0% had an expected dropout rate that was higher, lower, and similar, respectively, than the observed dropout rate in the placebo arm. Overall, the dropout rate was 11.06% (95% confidence interval [CI] 9.07 to 13.42), with a higher rate in phase 3-4 trials than in phase 2 trials. The corresponding rates due to adverse events, loss to follow-up and patient choice were 2.41% (95% CI 1.67 to 3.48), 1.79% (95% CI 1.06 to 2.99) and 4.06% (95% CI 2.97 to 5.53), respectively. Meta-regression determined that the dropout rate increased with longer treatment duration. Placebo dropout in MASH RCTs is significant, mainly due to patient choice. Factors such as trial phase and treatment duration should be considered when calculating sample size in future clinical trials.

A clinical study of the immunogenicity and protective potency of a live recombinant GamLPV vaccine for intranasal use for the prevention of whooping cough in adult volunteers

Introduction. The increase in incidence rate of pertussis worldwide, short-term insufficient immunity induced by acellular pertussis vaccines (TDaP) and their failure to provide antibacterial protection and to prevent transmission of infection in human population dictate the development of new pertussis vaccines. A new live recombinant pertussis vaccine for intranasal use (GamLPV) has completed preclinical studies in experiments on nonhuman primates and 2 phases of clinical trials involving adult healthy volunteers, in which the safety, immunogenicity and protective activity of the GamLPV were proven. Method and scheme of vaccine administration have been worked out. Aim. Confirmation of the immunogenicity and protective antibacterial potency of GamLPV in a randomized multicenter clinical trial on adult volunteers. Materials and methods. In this multicenter, clinical, randomized, placebo-controlled, double-blind study 260 healthy adults aged 18–65 years were divided into 2 groups: G1 — 210 volunteers (GamLPV) and G2 — 50 volunteers (placebo). 0.25 ml GamLPV delivered to each nostril (5 × 109 CFU) 60 days apart. Levels of Bordetella pertussis-specific IgG, IgA antibodies in blood serum and levels of B. pertussis-specific secretory IgA antibodies in nasopharyngeal aspirates were measured by ELISA method and agglutination test. The dynamics of elimination of attenuated B. pertussis bacteria after the first and second intranasal administration of GamLPV to volunteers was estimated by using qPCR. Results. Significant seroconversion of B. pertussis-specific IgG and IgA antibodies and growth of B. pertussis-specific secretory IgA antibody levels in nasal aspirates of volunteers were demonstrated. The dynamics of changes in the levels of IgG and IgA antibodies indicates a booster effect after second vaccination. Attenuated B. pertussis bacteria persist in the nose/oropharynx of vaccinated volunteers. The period of elimination after second vaccination is more than 2 times shorter than the period after the first one. The number of persistent B. pertussis bacteria after the second vaccination is less than 3% of the values after the first vaccination. Conclusion. High immunogenicity and the formation of antibacterial protection after single and double intranasal vaccination of GamLPV have been proven.

Characterizing Loss of Response Occurring in a Small Number of Patients During 3 Years of Long-Term Maintenance Therapy with Baricitinib 4-mg: Results From BRAVE-AA1 and -AA2 Trials

Introduction: Baricitinib, a approved for adults with severe alopecia areata (AA), demonstrated a high level of sustained efficacy (89.1%) at Week 152 among patients who achieved a Severity of Alopecia Tool (SALT) score ≤20 at Week 52 following one year of treatment with once-daily baricitinib 4 mg in phase 3 trials (BRAVE-AA1, BRAVE-AA2). In this post hoc analysis, we characterize patterns of loss of response during maintenance treatment (Weeks 52–152) among the 10.9% (n=14) of patients who demonstrated loss of response (SALT score &gt;20) at Week 152 and explore differences between patients who lost vs maintained response. Methods: Patient records were reviewed to identify patients who demonstrated loss of response at Week 152. Descriptive statistics were used to summarize baseline characteristics and the timing and extent of loss for these patients. Results: Baseline disease characteristics differed between those losing (10.9%, n=14/129) and those maintaining (89.1%, n=115/129) treatment response. Characteristics that were numerically more common among those losing vs maintaining response were a longer baseline duration of current episode (≥4 years; 50.0% vs 20.9%, respectively) and baseline very severe AA (SALT score 95–100; 64.3% vs 35.7%, respectively). Seven patients who lost response had received a COVID-19 vaccination and/or experienced a COVID-19 infection during the maintenance period; four of these patients had a vaccination or infection ≤6 months before their initial loss of response. Overall, time to loss of response varied: six lost response within the first 4 weeks of maintenance treatment (Weeks 52–56); eight lost response at or after Week 88. The magnitude of change in SALT score also varied: 35.7% (n=5) maintained a SALT score ≤30 throughout Weeks 52–152; 21.4% (n=3) worsened to a SALT score &gt;90 at ≥1 maintenance period visit. The median SALT score at Week 152 among patients demonstrating loss of response was 32.5. Conclusions: A small number of patients demonstrated loss of response at Week 152 during the maintenance phase of the BRAVE trials. A third of those who lost response maintained at least 70% scalp coverage throughout the two-year maintenance period, which followed one year of initial treatment. Future research is needed to confirm what factors potentially trigger loss of response on baricitinib monotherapy and to determine the potential role of adjunctive therapies in mitigating this risk.

Ewing sarcoma – pathomechanisms, standard treatment and new therapeutic perspectives

Introduction: Ewing sarcoma is the second most common bone tumor among children, and due to its high malignancy 5-year survival rate for patients with primary lesions is around 70%. This number drops to merely 30% if metastases are present. Despite combined modality treatment, including radiotherapy, surgery, pre- and post-surgery chemotherapy, the mortality of patients is still too high. This shows a great need to look for new therapeutic options. Methodology: Comprehensive literature review was conducted across databases, including PubMed and Google Scholar for studies published between 2000 and 2023. This review presents factors that play a key role in pathogenesis and are potential points of targeted therapy. The paper discusses, among other things, treatment attempts based on the role of the EWS-FLI1 protein, epigenetics, tyrosine kinase inhibitors, immunotherapies and the use of nanomedicine and viruses, as well as the difficulties associated with their application. Findings: The studies cited vary depending on the phase of the clinical trial they are on, of which teprotumumab, robatumumab, and a combination of cixutumumab/temsyrolimus, ivodesinib, Nivolumab (a PD-1 inhibitor), and Ipilimumab (a CTLA-4 inhibitor) are quite advanced as well as those conducted only on animals and in vitro like YK-4-279 molecule, mithramycin 2'-oxime, NK cells, siRNAs with cationic detonation nanodiamonds (DNDs) and Il-12 by means of lentiviruses. Conclusions: They are new and promising approaches in cases where standard treatments fail, yet they still require further study. Knowledge of the mechanisms of Ewing's sarcoma formation and its metastases, currently accepted treatment standards, critical points in the pathomechanism and current attempts at treating Ewing's sarcoma is essential for choosing the best treatment and effectively reducing its mortality rate.

Neo-adjuvant FOLFOX with and without panitumumab for patients with KRAS-wt locally advanced colon cancer: results following an extended biomarker panel on the FOxTROT Trial embedded phase II population.

The FOxTROT trial has reported advantages of neoadjuvant chemotherapy (NAC) in locally advanced colon cancer (LACC). Here we present results of the embedded randomized phase II trial testing the addition of panitumumab to neoadjuvant FOLFOX compared with FOLFOX alone in RAS and BRAF-wild-type patients and with biomarker hyperselction. Patients had operable, CT-predicted stage T3-4, N0-2, M0 colon adenocarcinoma. KRAS-wt pts allocated to NAC could optionally be sub-randomized 1:1 to FOLFOX ± panitumumab during the pre-operative phase. RAS/BRAF were tested by NGS; EREG/AREG by RNAseq. Primary endpoint is time to recurrence (TTR) in RAS/BRAF-wt patients; secondary endpoints include safety, histological downstaging, disease-free survival (DFS), colon cancer-specific survival (CCSS), overall survival (OS), and impact of primary tumor location and EREG/AREG. In total 269 KRAS-wt patients were enrolled into the embedded phase II trial. Extended RAS/BRAF data were available for 232 (83%) patients; 22/232(9.5%) were RAS-mutant; 41/210(20%) were BRAF-mutant. Median follow up was 42 months. In 169 RAS/BRAF-wt patients there was a trend towards reduced recurrences with FOLFOX plus panitumumab compared with FOLFOX (12% vs 21%, HR=0.51, p=0.09); significant improvements were seen for DFS, CCSS and OS. Within the hyperselected EREG/AREG high group, there was significant reduction in recurrences with panitumumab. Panitumumab was not associated with increased pathological regression of the primary tumor (TRG 1-3 16% vs 22%,p=0.27). FOLFOX plus panitumumab was associated with higher rates of grade 3 diarrhoea (8% vs 3%,) and rash (22% vs 2%). This exploratory analysis from a randomized phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to peri-operative FOLFOX in RAS/BRAF-wt LACC. Hyperselection with EREG/AREG status was associated with increased efficacy. A dedicated prospective trial within a biomarker selected population is under development. ISRCTN87163246.

Sotatercept: A New Era in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative remodeling and obliterative narrowing of the pulmonary vasculature. While outcomes have improved with existing treatments targeting 3 main pathways, there remains a critical need for novel therapies that address different and novel mechanisms of PAH. Sotatercept, recently Food and Drug Administration (FDA) approved, is a groundbreaking fusion protein that binds to activin and growth differentiation factors, rebalancing antiproliferative and pro-proliferative signals to reverse remodeling in both the pulmonary vasculature and the right ventricle. This review highlights current evidence exploring the safety and efficacy of sotatercept in the 2 landmark trials, phase 2 Pulmonary Arterial Hypertension and Sotatercept Trial and Research and phase 3 Sotatercept Treatment in Expansion of Long-term Learning and Assessment in PAH trial, which were instrumental in securing FDA approval for adult PAH patients with WHO functional class II or III symptoms already receiving background pulmonary hypertension therapy. Overall, sotatercept represents a landmark advancement in PAH treatment, offering hope for patients and the potential to delay or avoid lung transplantation. Importantly, this marks the beginning of an era of targeted therapies aimed at reverse remodeling in PAH while improving outcomes.

Evaluation of Safety and Efficacy of a Single Lorecivivint Injection in Patients with Knee Osteoarthritis: A Multicenter, Observational Extension Trial.

Lorecivivint (LOR), a CDC-like kinase/dual-specificity tyrosine kinase (CLK/DYRK) inhibitor thought to modulate inflammatory and Wnt pathways, is being developed as a potential intra-articular knee osteoarthritis (OA) treatment. The objective of this trial was to evaluate long-term safety of LOR within an observational extension of two phase 2 trials. This 60-month, observational extension study (NCT02951026) of a 12-month phase 2a trial (NCT02536833) and 6-month phase 2b trial (NCT03122860) was administratively closed after 36months as data inferences became limited. Participants received a single intra-articular LOR or placebo (PBO) injection at their parent-trial baseline. The primary outcome was the comparative incidence of serious adverse events (SAEs), with AEs and similar safety measures comprising secondary outcomes. A post hoc baseline-adjusted analysis of covariance (ANCOVA) compared changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscores and medial joint space width (JSW) between LOR 0.07mg and PBO groups in a subpopulation of participants with unilateral knee pain and widespread pain low enough to allow participants to differentiate their target knee pain. The safety analysis set for the extension study included 495 LOR-treated and 208 control participants, with 409 (82.6%) and 175 (84.1%) remaining at study close, respectively. There were 68 SAEs reported in 38 (5.4%) patients; none were considered treatment-related by investigators. The incidence of AEs was similar between groups. In the post hoc subgroup efficacy analyses, LOR 0.07mg demonstrated greater mean improvements from baseline compared with PBO in WOMAC pain and function scores out to 12months post-injection. No between-group differences in medial JSW were observed out to 18months. LOR appeared generally safe and well tolerated. Efficacy analyses on the subset of completer patients demonstrated durable symptom improvements in WOMAC pain and function for at least 12months compared to PBO after a single injection of LOR. NCT02951026.

Progress in the study of anti-Alzheimer's disease activity of pyrimidine-containing bioactive molecules.

Pyrimidines are aromatic, heterocyclic organic compounds characterized by a six-membered ring that contains four carbon atoms and two nitrogen atoms. They have been reported to exhibit a variety of biological activities such as antifungal, antiviral, and anti-Parkinsonian effects. Recently, there has been an increased focus on their potential anti-Alzheimer's properties. Several pyrimidine-based drugs and their analogs are currently undergoing various phases of clinical trials, indicating pyrimidine as a promising chemical structure for drug development. Notably, modifications to the pyrimidine structure significantly influence their activity against Alzheimer's disease. For instance, the introduction of heteroatoms into the pyrimidine ring or alternations in the length of the linkage region have been shown to enhance therapeutic efficacy. This review provides a comprehensive overview of pyrimidine derivatives as potential therapeutics for Alzheimer's disease, with a focus on structure-activity relationship (SAR) studies, design strategies, and binding mechanisms. These insights could pave the way for the development of more effective anti-Alzheimer's medications.

Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.

The enhancer of zeste homolog 2 (EZH2) is a catalytic component of Polycomb repressive complex 2 (PRC2) mediating the methylation of histone 3 lysine 27 (H3K27me3) and hence the epigenetic repression of target genes, known as canonical function. Growing evidence indicates that EZH2 has non-canonical roles that are exerted as PRC2-dependent and PRC2-independent methylation of non-histone proteins, and methyltransferase-independent interactions of EZH2 with various proteins contributing to gene expression regulation and alterations in the protein stability. EZH2 is frequently mutated and/or its expression is deregulated in various cancer types. The cancer sensitivity to inhibitors of EZH2 enzymatic activity and state-of-the-art approaches to deplete EZH2 with chemical degraders are discussed. This review also presents the clinical trials in various phases that evaluate the use of EZH2 inhibitors, both as monotherapy and in combination with other agents for the treatment of patients with diverse types of cancers.

Differentiated E-Module Based on Problem-Based Learning: Natural Science Subject

Finding out whether PBL-based differentiated e-modules are feasible, practical, and effective are the three main objectives of this project. This study uses the ADDIE paradigm (Analysis, Design, Develop, Implement, and Evaluate) in conjunction with the Research and Development (R&amp;D) technique. Thirty seventh-grade earth and solar system students served as the study's subjects. In addition to phases of individual trials, small group trials, and field trials, this study included validation tests conducted by professionals in media, instructional design, and materials. The study's findings revealed: In the Very Feasible category, Material Experts scored 85.09, while Learning Design Experts scored 92.87. Extremely feasible Experts in Media Design scored 89.44 in the category of Very Feasible. Field trials scored 87.29 in the Very Feasible category, small group trials scored 87.30, and individual trials scored 87.27 in the Very Feasible category. At a significance threshold of α = 0.05, the computation yielded tcount = 4.256 and ttable = 1.67, indicating that tcount &gt; ttable. These findings indicate that, at a significance level of 5%, there is a substantial difference between the learning outcomes of the students in the experimental and control classes, with H0 being rejected and Ha being accepted. According to the efficacy test's computation, According to the data, students who get instruction using PBL-based differentiated E-modules achieve better learning outcomes than those who receive printed books (81.25% &gt; 73.33%). Therefore, it can be said that the Science on Earth and Solar System class VII PBL-based differentiated E-modules at SMP N 43 Medan are superior to using printed books.

Episode-Based Bundled Payments in Hand Surgery: An Affordable Solution to Overwhelming Health Care Costs.

The purpose of this review is to examine the literature regarding episode-based bundled payment models for hand surgery. Health care and productivity costs associated with the surgical management of hand and wrist pathologies represent a substantial burden on the United States health care system. Traditional fee-for-service models fail to incentivize interdisciplinary collaboration and optimization of resources. More recently, the concept of episode-based bundled payments has evolved as a potential solution to rising health care costs by encouraging care coordination, streamlining billing processes, and linking reimbursement to quality metrics and patient outcomes as opposed to the volume of services rendered. Although episode-based bundled payments have demonstrated the potential to reduce health care costs in various medical specialties, their feasibility in hand surgery remains relatively unexplored. The transition to episode-based bundled payments in hand surgery hinges on the ability to incentivize physicians to work cohesively with other members of the care team to reduce low-value preoperative testing, optimize patients preoperatively, and establish treatment guidelines, especially for patients undergoing high-volume, low-complexity procedures. By fostering collaboration among stakeholders, leveraging data-driven insights, and prioritizing patient-centered care, episode-based bundled payments have the potential to enhance the value and efficiency of hand surgery services while improving patient outcomes. The current literature regarding episode-based bundled payments in hand surgery highlights various avenues for cost savings, including alternative sites of service, surgical approaches, use of anesthesia, and the elimination of low-value tests, and demonstrates that there is sufficient evidence to proceed to a trial phase for episode-based bundled payments in hand surgery.

Analysis of Tour Package Stimulus for Vaccine Recipients in the Pandemic Era Based on Travel Agent’s Perspective

The COVID-19 pandemic has had a significant impact on reducing the number of tourists, resulting in a decline in the performance of the tourism sector, including travel agents. In an effort to accelerate the recovery of the tourism sector, the Indonesian Government has released a stimulus package program for people who receive the complete COVID-19 vaccine which is distributed through travel agents. This stimulus program is a trial phase in tourist destinations in the Riau Islands, Jakarta and its surroundings, Borobudur and its surroundings, and Bali. This research aims to analyze the impact of the tourism package stimulus on vaccine recipient communities from the travel agent's perspective. The research data is primary data from the results of filling out a questionnaire which was analyzed using the conjoint analysis method and Pearson's R and Kendall's Tau analysis tests on travel agents who took part in this stimulus program. The results of research on travel agents show that their guests are willing to buy tourism stimulus packages because of the 4 star hotel facilities, family restaurant, spa body treatment, mini bus, complete destinations (natural, cultural, and man-made), and there is a souvenir shop that sells food. and souvenirs, thus the stimulus impacted these businesses only.

Recent Trends on Plants and Agricultural Products as Nutritional Source in Treating Diabetes

A metabolic disease that requires insulin and is marked by consistently high blood sugar levels is known as diabetes mellitus. Many healthcare systems throughout the world have long relied on medicinal herbs as a means of addressing diabetes and its complications. Traditional medicine derived from plant extracts has several advantages over contemporary pharmaceuticals, including lower costs, greater clinical efficacy, and fewer side effects. Pri-marily, the condition has been managed by a range of synthetic medications that improve the altered glycemic state in individuals with diabetes. Synthetic medications work well, but along with their benefits, they come with noticeable adverse effects. Due to the lack of knowledge regarding their chemical composition, preparation method, active bio-actives, potential side effects, and the optimal way to administer them, medicinal plants have not been fully utilised as acceptable drugs in the treatment of diabetes, despite their long history of use as primary health care. Because of a lack of sufficient data on the parameters described earlier, most medicinal plants that show promise as anti-diabetic agents do not make it to the clinical trial phase. Medicinal plants that have been studied in humans with diabetes and shown promise as a treatment for the disease, either alone or in conjunction with other plants, are summarised in this review. Pharmacologically active phytomolecules with an antidia-betic action that are derived from medicinal plants were the primary topic of this review article. Its goal was to discuss their importance in diabetes management and therapy. These all-natural substances have the potential to be successful and alternative diabetes treatments, as well as a new method of approaching the disease.

The analysis and reporting of multiple outcomes in mental health trials: a methodological systematic review

BackgroundThe choice of a single primary outcome in randomised trials can be difficult, especially in mental health where interventions may be complex and target several outcomes simultaneously. We carried out a systematic review to assess the quality of the analysis and reporting of multiple outcomes in mental health RCTs, comparing approaches with current CONSORT and other regulatory guidance.MethodsThe review included all late-stage mental health trials published between 1st January 2019 to 31st December 2020 in 9 leading medical and mental health journals. Pilot and feasibility trials, non-randomised trials, and early phase trials were excluded. The total number of primary, secondary and other outcomes was recorded, as was any strategy used to incorporate multiple primary outcomes in the primary analysis.ResultsThere were 147 included mental health trials. Most trials (101/147) followed CONSORT guidance by specifying a single primary outcome with other outcomes defined as secondary and analysed in separate statistical analyses, although a minority (10/147) did not specify any outcomes as primary. Where multiple primary outcomes were specified (33/147), most (26/33) did not correct for multiplicity, contradicting regulatory guidance. The median number of clinical outcomes reported across studies was 8 (IQR 5–11 ).ConclusionsMost trials are correctly following CONSORT guidance. However, there was little consideration given to multiplicity or correlation between outcomes even where multiple primary outcomes were stated. Trials should correct for multiplicity when multiple primary outcomes are specified or describe some other strategy to address the multiplicity. Overall, very few mental health trials are taking advantage of multiple outcome strategies in the primary analysis, especially more complex strategies such as multivariate modelling. More work is required to show these exist, aid interpretation, increase efficiency and are easily implemented.RegistrationOur systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 11th January 2023 (CRD42023382274).

Development of a rigorous mathematical thinking-based textbook in the house of worship context to enhance conceptual understanding

Background: This research develops a foundational mathematics textbook for PGMI students based on the Rigorous Mathematical Thinking (RMT) framework, contextualized within houses of worship to foster deeper understanding of mathematical concepts.Aim: The study aims to design and evaluate the feasibility and effectiveness of the textbook while gauging students’ responses and performance improvements.Method: Using a research and development (R&amp;D) model, this study validated the textbook through expert reviews and tested its practicality and effectiveness in small-scale and broader applications. Data were obtained through a combination of observations, interviews, surveys, and tests measuring students' conceptual comprehension. Statistical evaluations, including descriptive analysis and t-tests, were employed.Results: The textbook received validation from subject matter, presentation, and language experts, who confirmed its content and structural accuracy. Trial phases categorized the textbook as highly practical, while broader field testing indicated that students using the textbook demonstrated significantly greater improvement in conceptual understanding compared to those without it.Conclusion: The RMT-based textbook aligns with its intended objectives and provides a contextually appropriate tool for improving mathematical comprehension. These findings highlight its potential as an effective resource for mathematics learning in PGMI contexts.

Geometry Textbook Development Based on Gorontalo Local Wisdom for Elementary School Students

The current use of geometry textbooks in elementary schools still focuses on abstract theories and concepts, adhering to national standards that do not always align with local cultural characteristics. The development of a geometry teaching material based on the local wisdom of Gorontalo was chosen as one of the solutions to this issue. This research and development utilized the ADDIE model, which consists of five stages: Analysis, Design, Development, Implementation, and Evaluation. The subjects of the study were fourth, fifth, and sixth-grade students and teachers at MIT Al-Ishlah and SDN 3 Bulango Ulu. Data were collected through evaluation tests, expert validation questionnaires, and questionnaires for teachers and students. The results of the validation by content experts, language experts, and media experts were 78.4%, 83.33%, and 94.64%, respectively, all categorized as "valid." The responses from teachers and students during the trial phase were 83.33% and 81.71%, respectively, both categorized as "very practical." Thus, the Geometry Textbook Based on Local Wisdom of Gorontalo: Plane Figures and Solid Figures for 4th, 5th, and 6th Grade Students can be declared valid and practical for use in teaching.