Exploratory Trials Research Articles

The BET inhibitor Apabetalone protects against heart failure with preserved ejection fraction by suppressing myocardial inflammation

Abstract Background Posttranslational histone modifications, play a major role in cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. Purpose We sought to investigate whether APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF). Methods Mice were subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Histology, mouse echocardiography (Vevo3100) and Treadmill exhaustion test were performed. Unbiased gene expression profiling by PCR array and proteomics analysis (Olink) was employed in left ventricular (LV) myocardial specimens from HFpEF mice and control animals. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) were used as an in vitro model of metabolic stress. cHFpEF mice were chronically treated with the BET inhibitor APA (150mg/kg/day) or vehicle (DMSO). In order to translate our findings to the human setting, passive stiffness of skinned CMs collected from cHFpEF patients was assessed before and after APA treatment. Results HFpEF mice displayed LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion and impaired exercise tolerance as compared to controls. Interestingly, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) - and lung congestion were significantly reduced in HFpEF mice treated with APA, while exercise tolerance was improved. Transcriptomic analysis in PA-treated CMs and LV mouse specimens from cHFpEF mice showed a profound deregulation of genes controlling inflammation, namely IL-6, TNF-alpha, and IL-1beta. ChIP assays showed BRD4 occupancy on the promoter of several inflammatory genes, including IL6. Treatment with APA suppressed most of inflammatory genes, with a pronounced effect on IL6 expression. Moreover, APA reduced circulating levels of several inflammatory chemokines. The beneficial effects of APA were explained by modulation of IL-6/CaMKII/STAT3 pathway both in cHFpEF hearts and PA-treated CMs. In skinned CMs from cHFpEF patients, both APA and IL6 blockade were able to attenuate passive stiffness. Conclusions Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.

Psychedelic research at a crossroads

There is an urgent need to develop better treatments for mental health conditions that affect one in every eight people in the world. To combat this concern, psychedelic drugs have been combined with psychotherapy and studied in clinical trials in the United States and Europe. Psychedelics are hallucinogenic drugs that alter brain activity and facilitate altered states of consciousness. The proposed benefits of psychedelic-assisted therapy (PAT) include relatively short treatment times and stronger effects compared to other treatments. Although results of trials using MDMA for trauma or psilocybin for depression are promising, PAT is controversial because many questions about its safety and effectiveness are unanswered. This is evident in the recent ruling by the US Food and Drug Administration against the approval of MDMA therapy for post-traumatic stress disorder and the retraction of several papers about MDMA trials owing to unethical conduct by study therapists and data integrity, among other concerns. This field is at a crossroads, and the research community must address several obstacles to transition from exploratory trials to established, evidence-based treatments while avoiding pitfalls that can hinder advancement.

Open-label, phase 2 study of adebrelimab combined with fuzuloparib in the treatment of patients with HRD-positive, recurrent platinum-resistant ovarian cancer.

TPS5634 Background: Adebrelimab, a humanized anti-PD-L1 monoclonal antibody, selectively targets PD-L1 molecules to inhibit the PD-1/PD-L1 pathway, reversing tumor-induced immune tolerance and revitalizing the immune system's capacity to combat tumors. Fuzuloparib, a novel PARP inhibitor, impedes the activity of poly (ADP-ribose) polymerase, halting the DNA repair mechanism for single-stranded breaks, resulting in DNA damage accumulation and consequent cancer cell apoptosis. Emerging evidence strongly supports that PARP inhibitors significantly extend progression-free survival in homologous recombination-deficient (HRD)-positive ovarian cancer. The TOPACIO study demonstrated that the combination of niraparib and pembrolizumab for platinum-resistant ovarian cancer achieved an objective response rate (ORR) of 18%, with durable responses in patients. This underscores the potential of integrating PARP inhibitors with immune checkpoint inhibitors in clinical protocols. For platinum-resistant recurrent ovarian cancer, known for its challenging prognosis, we propose conducting exploratory clinical trials on the combination of adebrelimab and fuzuloparib, aiming to establish robust evidence for future clinical applications. Methods: This open-label, single-arm, Phase 2 study aims to evaluate the anti-tumor activity and safety of adebrelimab in combination with fuzuloparib in approximately 37 patients with HRD-positive, recurrent platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer (hereinafter referred to as ovarian cancer). The primary endpoint is to determine the objective response rate of the combined treatment regimen, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints encompass disease control rate, progression-free survival overall survival, along with the assessment of safety and tolerability. Patients must be aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed ovarian cancer with HRD-positive tumor. Patients must have progressed within less than 6 months after the last treatment with platinum-containing chemotherapy. HRD status confirmed by testing BRCA gene, loss of heterozygosity, telomeric allelic imbalance and large-scale transition. Adebrelimab (20 mg/kg) is administered intravenously every 3 weeks and fuzuloparib (100mg) is administered orally twice daily as until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. This clinical trial is in progress and 7 patients have been enrolled. Clinical trial information: NCT05753826 .

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials.

CT041 is a chimeric antigen receptor (CAR)-modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC). These two multicenter, open-label phase I/Ib trials (CT041-CG4006, CT041-ST-01) have a similar target population and evaluation schedule. The primary objective was to assess the safety and tolerability of CT041, whereas secondary objectives included efficacy, pharmacokinetics, and immunogenicity. The combined cohort comprised 24 patients with advanced PC. Among them, five patients (20.8%) had previously received one line of therapy, whereas 19 (79.2%) received ≥2 lines of therapy. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) and GI disorders were most reported grade 1 or 2 adverse events. The overall response rate and disease control rate were 16.7% and 70.8%. The median progression-free survival (mPFS) after infusion was 3.3 months (95% CI, 1.8 to 6.2), and the median overall survival (mOS) was 10.0 months (95% CI, 5.5 to 17.6). The median duration of response (mDoR)was 9.5 months (95% CI, 2.6 to Not reached), with a DoR rate at 12 months of 50% (95% CI, 5.8 to 84.5). The mPFS (6.0 v 1.0 months, P < .001) and mOS (17.6 v 4.0 months, P < .001) were prolonged in patients achieving partial response/stable disease than the progressive disease group. CA19-9 levels had reduced by at least 30% in 17 (70.8%) patients. In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.

Cutaneous Warts Treated with Individualised Homoeopathic Medicine: A Case Series

AbstractCutaneous warts are visible growths on the skin caused by infection of keratinocytes caused by the human papilloma virus. They appear in various forms on different locations on the skin and mucous membranes, the most common being hands, feet, face and neck. Despite the availability of various treatments, its persistent and recurring nature remains a matter of frustration among the medical fraternity. This case series includes eight cutaneous warts cases treated with an individualistic approach. Each case was prescribed a single medicine as per the cardinal principles of homoeopathy. The cases were assessed through Modified Naranjo Criteria for Homeopathy inventory to attribute the causal relationship of homoeopathic treatment provided for inferring the clinical outcome of cases. In every case, a single dose of the most appropriate homoeopathic remedy in centesimal potency was prescribed, followed by placebo. All cases were followed up for approximately 04-month duration after medication. No recurrence of warts or relapses of symptoms was noticed during the follow-ups. All cases showed marked improvement and the warts were completely resolved. Individualised homoeopathic medicines prescribed for cases were Lachesis mutus, Causticum, Natrum muriaticum, Antimonium crudum, Nitricum acidum, Thuja occidentalis, Sulphur and Dulcamara. Through this case series, we encourage more homoeopathic research on warts including exploratory observational trials and randomised controlled trials.

The effective combination therapies with irinotecan for colorectal cancer.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

Current status of optoacoustic breast imaging and future trends in clinical application: is it ready for prime time?

Optoacoustic imaging (OAI) is an emerging field with increasing applications in patients and exploratory clinical trials for breast cancer. Optoacoustic imaging (or photoacoustic imaging) employs non-ionizing, laser light to create thermoelastic expansion in tissues and detect the resulting ultrasonic emission. By combining high optical contrast capabilities with the high spatial resolution and anatomic detail of grayscale ultrasound, OAI offers unique opportunities for visualizing biological function of tissues in vivo. Over the past decade, human breast applications of OAI, including benign/malignant mass differentiation, distinguishing cancer molecular subtype, and predicting metastatic potential, have significantly increased. We discuss the current state of optoacoustic breast imaging, as well as future opportunities and clinical application trends. CLINICAL RELEVANCE STATEMENT: Optoacoustic imaging is a novel breast imaging technique that enables the assessment of breast cancer lesions and tumor biology without the risk of ionizing radiation exposure, intravenous contrast, or radionuclide injection. KEY POINTS: • Optoacoustic imaging (OAI) is a safe, non-invasive imaging technique with thriving research and high potential clinical impact. • OAI has been considered a complementary tool to current standard breast imaging techniques. • OAI combines parametric maps of molecules that absorb light and scatter acoustic waves (like hemoglobin, melanin, lipids, and water) with anatomical images, facilitating scalable and real-time molecular evaluation of tissues.

The rational dose for MaXingShiGan decoction is crucial for its clinical effectiveness in treating bronchial pneumonia: three randomized, double-blind, dose-parallel controlled clinical studies

The rational dose for MaXingShiGan decoction is crucial for its clinical effectiveness in treating bronchial pneumonia: three randomized, double-blind, dose-parallel controlled clinical studies

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis

Abstract Introduction AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) by using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. Material and methods We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. Results FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3,258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2&amp;gt;50%) between the trials for any of the analyzed outcomes. Conclusions Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD without benefit on CVD. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.Summary

Chinese Clinical Trial Registry 13-year data collection and analysis: geographic distribution, financial support, research phase, duration, and disease categories.

To evaluate the current status of trial registration on the Chinese Clinical Trial Registry (ChiCTR). In this descriptive study, a multi-dimensional grouping analysis was conducted to estimate trends in the annual trial registration, geographical distribution, sources of funding, targeted diseases, and trial subtypes. We have analyzed all clinical trial records (over 30,000) registered on the Chinese Clinical Trial Registry (ChiCTR) from 2007 to 2020 executed in China. The main outcome was the baseline characteristics of registered trials. These trials were categorized and analyzed based on geographical distribution, year of implementation, disease type, resource and funding type, trial duration, trial phase, and the type of experimental approach. From 2008 to 2017, a consistent upward trend in clinical trial registrations was observed, showing an average annual growth rate of 29.2%. The most significant year-on-year (yoy%) growth in registrations occurred in 2014 (62%) and 2018 (68.5%). Public funding represented the predominant source of funding in the Chinese healthcare system. The top five ChiCTR registration sites for all disease types were highly populated urban regions of China, including Shanghai (5,658 trials, 18%), Beijing (5,127 trials, 16%), Guangdong (3,612 trials, 11%), Sichuan (2,448 trials, 8%), and Jiangsu (2,196 trials, 7%). Trials targeting neoplastic diseases accounted for the largest portion of registrations, followed by cardio/cerebrovascular disease (CCVD) and orthopedic diseases-related trials. The largest proportions of registration trial duration were 1-2 years, less than 1 year, and 2-3 years (at 27.36, 26.71, and 22.46%). In the case of the research phase, the top three types of all the registered trials are exploratory research, post-marketing drugs, and clinical trials of new therapeutic technology. Oncological and cardiovascular diseases receive the highest share of national public funding for medical clinical trial-based research in China. Publicly funded trials represent a major segment of the ChiCTR registry, indicating the dominating role of public governance in this health research sector. Furthermore, the growing number of analyzed records reflect the escalation of clinical research activities in China. The tendency to distribute funding resources toward exceedingly populated areas with the highest incidence of oncological and cardiovascular diseases reveals an aim to reduce the dominating disease burden in the urban conglomerates in China.

Understanding of Economic Student on the Relationship between Green Supply Chain Management and Sustainability

Purpose: This research collects primary data on how well economic students at colleges in Can Tho, Vietnam comprehend how green supply chain management (GSCM) affects sustainability performance. Methodology: This research examines five GSCM factors—internal environmental management, green procurement, green manufacturing, green distribution, and environmental education—and three sustainability performance characteristics (economic, environmental, and social performance). Exploratory trials and a literature review on GSCM and sustainability performance lead to this model. Using a questionnaire, 534 participants provided primary data. Based on a structural equation model, SPSS and AMOS 22.0 analysed the data quantitatively and descriptively (SEM). Findings: GSCM affects sustainability performance differently. Green procurement affects economic, environmental, and social performance. Internal environmental management impacts environmental and social performance. Environmental education affects solely social performance. Green production and distribution do not affect sustainability. The results showed that universities must prioritise five areas—internal environmental management, green procurement, green production, green distribution, and environmental education—for the long-term development of the economy, environment, and society. Originality/Value: GSCM's impact on sustainability performance has been studied, however economic scholars don't know how it affects a company's sustainability. Economics majors will become entrepreneurs who grasp their role in company and economic progress. Economic students must understand the value of corporate social responsibility, community involvement, and environmentally responsible production to help firms, communities, and ecosystems succeed. Keywords: Economic student, green supply chain management, sustainability.

Mechanisms of desensitization with oral immunotherapy and epicutaneous immunotherapy.

Oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) are emerging therapies for food allergy. With several recently published exploratory trials and randomized controlled clinical trials that support these procedures, there is a clear progress and interest toward making these treatment options available for allergist/immunologists and patients with food allergies entrusted to their care. However, there still remain many questions and concerns to be addressed before these procedures can be fully understood. The purpose of the present report is to trace some of the important historical milestones in the development of OIT and EPIT that have contributed to their evolving clinical application to the treatment of food allergy, to describe some of the current understandings of the immunologic mechanisms by which these procedures elicit desensitization, and to provide some areas for future inquiry and research. An extensive research was conducted in the medical literature data bases by applying terms such as food allergy, desensitization, tolerance, unresponsiveness, Treg cells, allergen immunotherapy (AIT), oral immunotherapy (OIT), and epicutaneous immunotherapy (EPIT). OIT and EPIT take their origins from AIT (also called desensitization), a procedure first reported for the treatment of hay fever over a 100 years ago in which slowly increasing doses of a specifically relevant allergen were administered until a maintenance dosage was achieved when the patient was free of symptoms. OIT and EPIT differ from AIT in certain aspects including the route of administration of the allergen as well as their relative shorter period of sustained unresponsiveness. The origins and important historical landmarks that have been made in the field of food allergy immunotherapy are presented in the context of the immunologic mechanisms that contribute to the pathogenesis of these disorders. Although considerable progress has been made in recent years toward making these treatment options available for allergist/immunologists and patients with food allergies, there still remain many questions and concerns to be addressed before these procedures can be fully understood, which can be illuminated by future research.

Robust time selection for interim analysis in the Bayesian phase 2 exploratory clinical trial

ABSTRACT In phase 2 clinical trials, we expect to make a right Go or No-Go decision during the interim analysis (IA) and make this decision at the right time. The optimal time for IA is usually determined based on a utility function. In most previous research, utility functions aim to minimize the expected sample size or total cost in confirmatory trials. However, the selected time can vary depending on different alternative hypotheses. This paper proposes a new utility function for Bayesian phase 2 exploratory clinical trials. It evaluates the predictability and robustness of the Go and No-Go decision made during the IA. We can make a robust time selection for the IA based on the function regardless of the treatment effect assumptions.

Learning to Act Safely With Limited Exposure and Almost Sure Certainty

This paper puts forward the concept that learning to take safe actions in unknown environments, even with probability one guarantees, can be achieved without the need for an unbounded number of exploratory trials. This is indeed possible, provided that one is willing to navigate trade-offs between optimality, level of exposure to unsafe events, and the maximum detection time of unsafe actions. We illustrate this concept in two complementary settings. We first focus on the canonical multi-armed bandit problem and study the intrinsic trade-offs of learning safety in the presence of uncertainty. Under mild assumptions on sufficient exploration, we provide an algorithm that provably detects all unsafe machines in an (expected) finite number of rounds. The analysis also unveils a trade-off between the number of rounds needed to secure the environment and the probability of discarding safe machines. We then consider the problem of finding optimal policies for a Markov Decision Process (MDP) with almost sure constraints. We show that the action-value function satisfies a barrier-based decomposition which allows for the identification of feasible policies independently of the reward process. Using this decomposition, we develop a Barrier-learning algorithm, that identifies such unsafe state-action pairs in a finite expected number of steps. Our analysis further highlights a trade-off between the time lag for the underlying MDP necessary to detect unsafe actions, and the level of exposure to unsafe events. Simulations corroborate our theoretical findings, further illustrating the aforementioned trade-offs, and suggesting that safety constraints can speed up the learning process.

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis

IntroductionAFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses.Material and methodsWe meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF.ResultsFCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69–0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71–1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66–0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71–1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71–1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57–1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88–1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes.ConclusionsUse of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.Graphical

A win ratio-based framework to combine multiple clinical endpoints in exploratory basket trials

ABSTRACT In contemporary exploratory phase of oncology drug development, there has been an increasing interest in evaluating investigational drug or drug combination in multiple tumor indications in a single basket trial to expedite drug development. There has been extensive research on more efficiently borrowing information across tumor indications in early phase drug development including Bayesian hierarchical modeling and the pruning-and-pooling methods. Despite the fact that the Go/No-Go decision for subsequent Phase 2 or Phase 3 trial initiation is almost always a multi-facet consideration, the statistical literature of basket trial design and analysis has largely been limited to a single binary endpoint. In this paper we explore the application of considering clinical priorities of multiple endpoints based on matched win ratio to the basket trial design and analysis. The control arm data will be simulated for each tumor indication based on the corresponding null assumptions that could be heterogeneous across tumor indications. The matched win ratio matching on the tumor indication can be performed for individual tumor indication, pooled data, or the pooled data after pruning depending on whether an individual evaluation or a simple pooling or a pruning-and-pooling method is used. We conduct the simulation studies to evaluate the performance of proposed win ratio-based framework and the results suggest the proposed framework could provide desirable operating characteristics.

2022 Canadian Surgery Forum Sept. 15–17, 202201. Operative classification of ventral abdominal hernias: new and practical classification02. Watchful waiting for large primary splenic cysts03. Transversus abdominis plane (TAP) blocks with and without dexamethasone in colorectal surgery04. What factors determine publication of resident research day projects?05. Characterization of near-infrared imaging and indocyanine green use amongst general surgeons06. Variation in opioid prescribing

# 01. Operative classification of ventral abdominal hernias: new and practical classification {#article-title-2} Ventral hernias of the abdomen are defined as a noninguinal, nonhiatal defect in the fascia of the abdominal wall. Unfortunately, there is not currently a universal classification system

Credulity of exploratory trials for cerebral cavernous malformations

Cerebral cavernous malformations are vascular lesions that affect approximately 0·3% of the population and can cause haemorrhage, seizures, and neurological deficits. Familial cases with autosomal dominant disease, cases of symptomatic cerebral cavernous malformation, and cases with recent haemorrhage meet rare disease criteria according to regulatory agencies in the USA and EU. To date, the only treatment for people with cerebral cavernous malformations is resection of a symptomatic lesion or radiosurgery, but there is scant evidence of the effectiveness of these approaches, which can be associated with substantial morbidity.

In silico thrombectomy trials for acute ischemic stroke

Background and objective: In silico trials aim to speed up the introduction of new devices in clinical practice by testing device design and performance in different patient scenarios and improving patient stratification for optimizing clinical trials. In this paper, we demonstrate an in silico trial framework for thrombectomy treatment of acute ischemic stroke and apply this framework to compare treatment outcomes in different subpopulations and with different thrombectomy stent-retriever devices. We employ a novel surrogate thrombectomy model to evaluate the thrombectomy success in the in silico trial.Methods:The surrogate thrombectomy model, built using data from a fine-grained finite-element model, is a device-specific binary classifier (logistic regression), to estimate the probability of successful recanalization, the outcome of interest. We incorporate this surrogate model within our previously developed in silico trial framework and demonstrate its use with three examples of in silico clinical trials. The first trial is a validation trial for the surrogate thrombectomy model. We then present two exploratory trials: one evaluating the performance of a commercially available device based on the fibrin composition in the occluding thrombus and one comparing the performance of two commercially available stent retrievers.Results: The Validation Trial showed the surrogate thrombectomy model was able to reproduce a similar recanalization rate as the real-life MR CLEAN trial (p=0.6). Results from the first exploratory trial showed that the chance of successful thrombectomy increases with higher blood cell concentrations in the thrombi, which is in line with observations from clinical data. The second exploratory trial showed improved recanalization success with a newer stent retriever device; however, these results require further investigation as the surrogate model for the newer stent retriever device has not yet been validated.Conclusions: In this novel study, we have shown that in silico trials have the potential to help inform medical device developers on the performance of a new device and may also be used to select populations of interest for a clinical trial. This would reduce the time and costs involved in device development and traditional clinical trials.

Effectiveness of a standardized skin care regimen to prevent atopic dermatitis in infants at risk for atopy: a randomized, pragmatic, parallel-group study.

It has been proposed that regular emollient application in early life could enhance skin barrier function and prevent atopic dermatitis (AD) especially in predisposed infants. This hypothesis was supported by evidence from exploratory and pilot trials showing protective effects in terms of reduced cumulative atopic dermatitis incidence with the use of daily emollient therapy starting immediately after birth. To investigate the effectiveness of a standardized skin care regimen for infants on the development of AD compared to not structured skin care regimen in infants with atopic predisposition. Prospective, parallel group, randomized, pragmatic, investigator-blinded intervention trial including 160 infants with 52 weeks intervention and 52 weeks follow up phase up to the age of two years. Infants were randomly assigned to receive a standardized skin care regimen including once daily leave-on product application (lipid content 21%) or skin care as preferred by the parents. Using the intention to treat approach, the cumulative AD incidence was 10.6% after one year, and 19.5% after two years in the total sample. There were no statistical significant differences between intervention and control groups. Skin barrier parameters between the intervention and control groups were comparable. AD severity was higher and quality of life was more affected in the control group. Regular emollient application during the first year of life does not prevent the development of atopic dermatitis. A standardized skin care regimen does not delay skin barrier development or causes side effects.