Contract Research Research Articles

Screen Failures and Causes in Inflammatory Bowel Disease Randomized Controlled Trials: A Study of 16913 Screened Patients.

While recruitment rates in inflammatory bowel disease (IBD) trials are continuously decreasing, the underlying reasons are likely multifactorial but remain poorly defined. Screen failure (SF) proportions and causes have not been extensively explored in IBD. We assessed SF proportions and underlying SF reasons in IBD phase 2 and 3 clinical trials. We analyzed SF-related data from 17 randomized controlled phase 2 or 3 IBD trials. Twelve trials were in ulcerative colitis (UC) and 5 trials were in Crohn's disease (CD) operated by a single contract research organization, IQVIA. Differences between patient groups were tested for significance by Mann-Whitney and Fisher's tests when appropriate. We analyzed a total of 11 161 patients with UC and 5752 patients with CD. The mean SF proportion was 0.43 per trial in UC. The primary reason for SFs in UC was not meeting the overall (modified) Mayo score inclusion threshold and/or the endoscopic subscore of at least 2 (33.8% of all SF). In CD clinical trials, the mean SF proportion was at 0.53. The primary cause for SFs was not meeting the CDAI eligibility criteria (23.1% of all SFs). SF proportions were significantly higher in CD versus UC trials (P = .027). Clostridium difficile or any other intestinal infection and not meeting tuberculosis screening criteria were other major reasons for SFs both in UC and CD. High SF proportion in IBD clinical trials, particularly for CD studies, pose obstacles to patient recruitment. While underlying causes are diverse, arbitrarily defined clinical and/or endoscopic eligibility criteria remain the major limiting factors.

Opportunities of topical drug products in a changing dermatological landscape

Despite the prevalence and the impact on quality of life of dermatological indications, drug products to treat such conditions have rarely been blockbusters. The prevailing perception of a limited commercial potential of dermatological drug products has restricted innovation and encouraged a more conservative development approach. For example, the focus was on repurposing/reformulation of existing active pharmaceutical ingredients (APIs) specifically for the topical delivery route.However, the situation is quite different today catalyzed in part by the blockbuster success of Dupixent (dupilumab), the first monoclonal antibody treatment for atopic dermatitis which has been approved by the US Food and Drug Administration (US FDA) in 2017. Dupixent's success not only encouraged the development of other biologics but also inspired the (re-)development of new dermal drug products that can reap the many benefits of topical administration.We have also witnessed a shift toward outsourcing development efforts (and associated risks) towards small- to mid-size pharmaceutical companies which often require support of contract research and development/manufacturing organizations (CRO and CDMO). Such trends also emphasize the need of greater expertise in topical formulation design, as well as associated commercial and regulatory considerations.Today, we believe that topical drug products remain not only an essential but also commercially viable class of dermatological therapeutics. In this opinion article, we will address the challenges as well as opportunities of coherent development strategies in the current market environment, formulation innovations of topical drug products and technological advances to facilitate rational topical drug formulation development.

Highlights of the 15th Japan Bioanalysis Forum Symposium.

The 15th Japan Bioanalysis Forum (JBF) Symposium was held in Kyoto, Japan, between 5 and 7 February 2024. The conference theme, 'Toward the new world - Science as a universal endeavor' indicated that universal discussion based on science is making a basis of regulatory and analytical sciences, now internationally harmonized. The symposium discussed a wide range of topics, including ICH M10, quantitative PCR, immunogenicity, peptide LC-MS, e-notebooks, artificial intelligence, reliability standards, carrier development, inviting domestic and overseas experts. Approximately 360 attendees from various fields, including pharmaceutical companies, contract research organizations, academia and regulators, gathered in person or online.

Discovery Process Chemistry: An Innovation Hub at the Interface of Academia, the Pharmaceutical Industry, and Contract Research Organizations

AbstractDiscovery Process Chemistry (DPC) is an emerging intersectoral space that is characterized by the development of new chemical reactions or syntheses that enable the efficient elucidation of structure-activity relationships (SARs) and structure-property relationships (SPRs) as well as a rapid transition to process development. Drug discovery and development are accelerated by such efforts and this has led chemists in academia and industry alike to place an increasing importance on these aims. In this Short Review, we explore recent advances in DPC and the impact that it can have on SAR/SPR interrogation and downstream drug development efforts.1 Introduction2 Enabling SAR/SPR Interrogation with Bioisosteres3 Couplings of Diversifiable Reaction Partners4 Late-Stage Functionalization5 Conclusion and Outlook

In India, most principal investigators have run very few trials over the years.

In the past, clinical trials run in India have been the subject of criticism. Among other steps to improve the trial ecosystem, for some time the government limited the number of trials that a Principal Investigator (PI) could run to three at a time. We were interested to know how many trials PIs in India tend to run at a time. We accessed the 52,149 trial records hosted by the Clinical Trials Registry-India in April 2023. Of these, we shortlisted trials that had run in India, were interventional, and involved certain interventions such as drug, biological etc. We used multiple parameters, such as email ID, phone number etc. to determine whether one name always represented the same PI and whether two names corresponded to the same PI. We then determined how many trials each PI had run. We found that 3,916 unique PI names were associated with 6,665 trials. Of these, 2,963 (75.7%) PIs had run a single study. Only 251 (6.4%) had run more than three trials. A mere 14 PIs had run 20 or more trials. The 14 PIs were affiliated with local pharma companies (6), local or global contract research organizations (4), multinational pharma companies (3) and the Central Council for Research in Homeopathy (1). The maximum number of trials run by a single PI was 108. Of these, the largest number run in a single year, 2022, was 53. Each PI name needs to be connected to a unique ID that does not change with time, so that it is easier to track the number of trials that a given PI has run. The number of studies run by a given PI at a given time must not be excessive and needs to be monitored more actively. The government needs to consider whether a cap on the number of trials that a PI runs at a time is required and what infrastructure needs to be in place to facilitate higher numbers of trials. Trial registry records need to be updated more regularly. Other countries may wish to do likewise.

Academic-Industry Engagement: The Role of Machine Learning in Predicting Contract Research Outcomes

Academic-Industry Engagement: The Role of Machine Learning in Predicting Contract Research Outcomes

Improving Access to Patient-Focused, Decentralized Clinical Trials Requires Streamlined Regulatory Requirements: An ASCO Research Statement.

Strategies to bring clinical trials closer to patients gained momentum during the COVID-19 pandemic, enabling more participants to receive treatment and/or testing in their local communities. Incorporation of decentralized trial elements presents both opportunities and challenges, spanning regulatory, technical, and operational aspects. This ASCO research statement includes timely consensus-driven recommendations and a call for engagement of all research stakeholders. ASCO held multistakeholder meetings with leaders in oncology research and concluded that research-related regulatory and administrative requirements and burdens present critical barriers to decentralizing trials. One example is sponsor and contract research organization (CRO) use of US Food and Drug Administration (FDA)'s Statement of Investigator (Form 1572), which was found to exceed FDA's stated intent and used in conservative ways disproportionate to potential risks to participants and scientific integrity. As a result, research sites experience an avalanche of downstream administrative and regulatory activities that consume considerable resources. This statement recommends four key solutions to address such barriers and recalibrate regulatory and administrative expectations for decentralizing trials: (1) FDA should engage the research community in a public-private partnership to modernize standards and enable local access to trials; (2) sponsors and CROs should develop standards and protocols that accommodate flexible approaches, enable local participation, provide clarity around roles and requirements, and promote consistency; (3) research centers, networks, and sites should update policies and procedures to implement decentralized trial elements; and (4) research community should develop a streamlined, uniform mechanism to simplify regulatory data collection and documentation and use it consistently across trials. We can and must prioritize a concerted commitment to simplify and streamline regulatory requirements and practices to broaden access to and participation in cancer clinical trials.

New Russian Trivalent Hepatitis B Vaccine (Bubo®­-Unigep): Reactogenicity, Safety and Immunological Efficacy

Relevance. In Russia, phase III of clinical trials of the domestic trivalent vaccine Bubo®-Unigep, containing protective antigens that provide protection against “wild” forms of the hepatitis B virus subtypes ay and ad, as well as the determinant of serotype ay with the G145R mutation, has been completed. Аim. Evaluation of the effect of the new recombinant polyvaccine against hepatitis B «Bubo-Unigep» on vital functions and laboratory parameters in previously unvaccinated individuals in an adult healthy population. Materials and methods. A randomized multicenter clinical study was conducted to assess the reactogenicity, safety and immunogenicity of Bubo®-Unigep (CJSC NPC «COMBIOTECH») in previously unvaccinated healthy adults (n = 166). The study performed according to the protocol developed by the contract research organization «R&D Pharma» at eight clinical centers located in Russian Federation. Results and discussion. Analysis of the studied parameters throughout the study (frequency and severity of adverse events, physical examination data of volunteers with assessment of vital signs, laboratory test results, etc.) made it possible to establish a high safety profile of Bubo®-Unigep vaccine, which turned out to be virtually areactogenic without causing development of targeted local and systemic post-vaccination adverse events. Conclusion. The wide range of specificity of the immune response, along with the high safety and reactogenicity of the Bubo®-Unigep vaccine, the production of which can be carried out through a full technological cycle without the use of imported substances, will increase the effectiveness of hepatitis B prevention.

Multitask Neural Networks to Predict Antimicrobial Susceptibility Results of Escherichia coli Clinical Isolates

Background: Machine-learning (ML) models, such as neural networks (NNs), have been proposed to predict antimicrobial susceptibility at the patient level while incorporating patient-level information from electronic medical record (EMR) systems. However, NNs often do not perform well in predicting rare outcomes, such as carbapenem resistance. We aimed to apply a novel multitask NN to create personalized antibiograms for individual patients with Escherichia coli clinical isolates to predict antimicrobial resistance (AMR) for four major antimicrobial classes simultaneously with improved accuracy for carbapenem resistance by using shared hidden layers (Figure 1). Methods: We analyzed all E. coli clinical isolates from the US Veterans Health Administration’s network from January 1, 2017, to December 31, 2019, focusing on AMR profiles of aminopenicillins, narrow-spectrum (NS) cephalosporins, extended-spectrum (ES) cephalosporins, and carbapenems. Patient-level clinical data (demographics, antimicrobial exposure history, previous isolates (if any), comorbidities, and recent procedures) were extracted from EMR. Antibiograms for all hospitals were generated using standard methods for the preceding calendar years. We employed logistic regression to evaluate the efficacy of conventional antibiograms in predicting AMR profiles. We adopted the ML approach using conventional NNs and novel multitask NNs on all extracted clinical data and hospital antibiograms. The models were trained with data from 2017 and 2018 and then tested on 2019 data, assessing their performance using the area under the receiver-operating curve (AUC). Results: The study included 257,968 E. coli isolates, split into 171,391 for training and 86,577 for validation. The prevalence of AMR in the test data from 2019 was 49.8% for aminopenicillins, 28.4% for NS cephalosporins, 10.7% for ES cephalosporins, and 0.2% for carbapenems, respectively. Conventional hospital antibiograms showed low prediction accuracy with AUC scores of 0.56 for aminopenicillins, 0.67 for NS cephalosporins, 0.61 for ES cephalosporin, and 0.67 for carbapenem. AUC scores from preliminary models for conventional and multitask NNs were 0.78/0.78 for aminopenicillins, 0.83/0.82 for NS cephalosporins, 0.84/0.85 for ES cephalosporins, 0.68/0.75 for carbapenems. While producing improved accuracy for carbapenem and comparable accuracies for three other classes, multitask NNs took approximately 66% less time for model training than conventional NNs. Conclusions: Integrating EMR data with NNs improved their predictive accuracy, potentially leading to a decision-support tool for better empirical antimicrobial therapy guidance in the window between species identification and confirmed susceptibilities. Multitask NNs can potentially improve the prediction accuracy of uncommon AMRs while maintaining comparable prediction accuracies for common AMRs and optimizing the efficiency of model training.Disclosure: Michi Goto: Contracted Research - Merck

Hospital-Associated Transmission of Candida auris from Adult to Pediatric Patient

Background: Candida auris, an emerging multidrug-resistant fungus, is often difficult to control in hospital outbreaks. We report the hospital investigation and findings of a transmission of C. auris from patients hospitalized in an adult unit to a pediatric unit, the first in Maryland. Methods: Between June and September 2023, C. auris was recovered from two patients admitted to an adult Neuroscience Intensive Care Unit (ICU) and a patient admitted to a pediatric ICU. Infection control initiated an investigation involving staff interviews, observations and chart reviews. Cases were defined as any patient with clinical or surveillance cultures growing C. auris. Point prevalence surveillance was conducted by collecting nares and composite axilla/groin swabs from patients on the affected units. Environmental cultures collected using moistened E-Swabs (Copan, Murrieta, CA) from shared supplies were plated on CHROMagar Candida (BD, Sparks, MD). C. auris isolates from patients hospitalized at the facility between February 2022 and October 2023 were analyzed by WGS for relatedness. WGS was performed using Illumina NextSeq 300 bp paired-end sequencing (Illumina, San Diego, CA). Single nucleotide polymorphism (SNP) analysis was performed by comparing raw reads to the reference C. auris B8441 genome for subsequent clustering analysis (Ares Genetics, Vienna, Austria). Results: WGS demonstrated isolates from two adults and one pediatric patient were less than three SNPs different, suggesting a shared isolate. One additional pediatric case was identified from surveillance cultures collected from 27 patients. Investigation into possible transmission routes revealed healthcare personnel serving both units, specifically clinical teams and continuous electroencephalography (cEEG) technologists. Additionally, cEEG equipment was used on both adult and pediatric patients and twelve equipment surface swabs and three samples each of measuring tape and gel were collected. C. auris was not isolated, however sensitivity of environmental sampling is unclear and suspicion for possible fomite/environmental transmission persisted. Other possible transmission routes included gaps in hand hygiene, isolation, disinfection of shared equipment, and reuse of single-use items. Interventions included improving and monitoring infection prevention practices, educating multi-disciplinary personnel and heightened environmental cleaning. Conclusion: This case highlights the feasibility of transmission of C. auris between patients admitted to a geographically distant unit. Our investigation revealed multiple possible routes of transmission including direct contact (from healthcare personnel or equipment) or indirect environmental sources. Prevention of hospital-associated C. auris transmission likely necessitates meticulous adherence to hand hygiene, contact precautions, and careful cleaning and disinfection of patient environments and equipment used by all disciplines.Disclosure: Patricia Simner: Research Contracts: BD Diagnostics, OpGen Inc., Qiagen Sciences Inc, T2 Diagnostics, Accelerate Diagnostics; Research Collaborators:Ares Genetics, CosmosID, IDbyDNA, Illumina; Consulting: OpGen Inc., BD Diagnostics, Shionogi Inc., GeneCapture, Qiagen Sciences Inc, Entasis, Day Zero Diagnostics, Next Gen Diagnostics

Evaluation of Vulnerabilities for the Spread of Carbapenem Resistant Organisms at Five Hospitals in India

Background: The 2022 WHO global survey on infection prevention and control (IPC) exposes significant gaps in IPC in the WHO Southeast Asia region. A better understanding of IPC vulnerabilities will inform improvement initiatives. We describe an evaluation of IPC practices known to prevent and contain carbapenem-resistant organisms (CROs) at hospitals participating in the United States Centers for Disease Control Global Action in Healthcare Network –Antimicrobial Resistance in India. Prior hospital evaluations suggest resistance to carbapenems among gram-negative isolates is up to 45%. Methods: We conducted a mixed methods evaluation including cross-sectional surveys, semi-structured interviews, and site observations at five hospitals (one government, two private tertiary care, and two private teaching) located in three cities. The number of hospital beds ranged from 362 to 2,011. Hospital and IPC program characteristics, and CRO prevention and containment activities were examined virtually. Site observations focused on hand hygiene, environmental cleaning, personal protective equipment (PPE), CRO containment practices and use of water for patient care. Results: All sites had IPC programs with established policies and qualified IPC staff. The IPC nurse-to-bed ratio ranged from 1:73 to 1:432 (mean, 1:209). Due to the integral role of microbiology staff in IPC at these hospitals, the two departments had strong communication channels associated with CRO identification. Screening for CRO colonization, if done, targeted patients from outside hospitals. Three of the five hospitals routinely implemented contact precautions for patients with identified CROs, displayed isolation signage at the bedside, and provided adequate PPE at point-of-use; however, all sites reported barriers to effective isolation and/or cohorting patients with CROs. Timely communication of CROs to clinical staff varied and no sites effectively relayed CRO status upon patient discharge to another facility. IPC teams identified gaps in environmental cleaning procedures and practices related to medical devices and equipment. All sites used alternatives to tap water for clinical care and sink etiquette was evident. Each IPC team performed audits of patient isolation and hand hygiene practices. Despite the considerable proportion of IPC resources dedicated to daily education and feedback in clinical areas, the IPC teams reported that improvement was often difficult to achieve. Conclusion: Given the high burden of CROs and limited IPC resources, detailed knowledge of IPC opportunities for improvement will help hospitals target novel interventions for CRO prevention and containment. Further investigation of colonization rates and effective performance improvement methods in these settings is needed.Disclosure: Patricia Simner: Research Contracts: BD Diagnostics, OpGen Inc., Qiagen Sciences Inc, T2 Diagnostics, Accelerate Diagnostics; Research Collaborators:Ares Genetics, CosmosID, IDbyDNA, Illumina; Consulting: OpGen Inc., BD Diagnostics, Shionogi Inc., GeneCapture, Qiagen Sciences Inc, Entasis, Day Zero Diagnostics, Next Gen Diagnostics

Prevalence of Candida auris Among High-Risk Patients at a Comprehensive Cancer Center

Background: Candida auris (C. auris) is a multidrug-resistant fungus that is increasingly implicated in outbreaks in healthcare facilities worldwide. The Centers for Disease Control and Prevention (CDC) and the Texas Department of State Health Services recommend healthcare facilities screen patients who are considered high-risk for C. auris, including patients with an overnight stay in a healthcare facility outside the United States (U.S.) in the previous year, or recently stayed in a rehabilitation (rehab) facility, long-term acute care (LTAC), or skilled nursing facility (SNF). Screening patients for C. auris colonization allows for early implementation of infection control measures, preventing transmission to healthcare workers and other patients. According to the CDC, most cases of C. auris result from local spread within and among healthcare facilities in the same city or state. In Texas, 160 clinical cases have been reported during the past 12 months. At present, the necessity of screening high-risk patients at our center for C. auris is not known. We aimed to determine the prevalence of C. auris colonization among our patient population. Method: During a 4-week period, we performed targeted screening of patients meeting the CDC’s high-risk definition for C. auris. Admitted patients were screened by an Infection Preventionist (IP) using the electronic health record to identify patients who were either international or admitted from a rehab or care facility. A composite swab of bilateral axilla and groin creases was collected using an eSwab™ (Becton Dickinson) and sent to a reference lab (Mayo Clinic Laboratories) for polymerase chain reaction (PCR)-based detection of C. auris. Additionally, we reviewed historic cases of C. auris diagnosed at our institution to better define our at-risk patients. Results: Between July 14 – August 8, 2023, we consecutively screened 25 high-risk patients, including 18 (72%) international and 7 (28%) patients from rehabs, LTAC, or SNF. None were positive for C. auris. Since 2019, we identified six patients with C. auris positive cultures, including five clinical cases and one colonization case. Five patients were international and one was local with no history of international travel or stay in a care facility. Interestingly, all six were known to be colonized with extended-spectrum beta-lactamase (ESBL) E. coli. Conclusion: We have a very low prevalence of C. auris among CDC-defined high-risk patients. A review of historic C. auris cases indicated an association with colonization by other multidrug-resistant organisms, specifically ESBL E. coli, which will inform future screening protocols at our institution.Disclosure: Roy Chemaly: Contracted Research paid for my institution: Merck, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, and Eurofins-Viracor; Honorarium/Ad Board/Consultant: ADMA Biologics, Janssen, Merck/MSD, Partner Therapeutics, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Tether, Oxford Immunotec, Karius, Moderna, and Ansun Pharmaceuticals; Stock Options: Xenex

Exploring the Impact of the Psychological Contract on the Well-being of the New Generation of Employees in the Chinese Context

The fulfilment of the psychological contract is an exchange of reciprocity and benefits, making employees feel that their needs and expectations are met, thus enhancing their well-being. As the new generation of employees flourishes and becomes the central human resource of Chinese organisations, the effect of the psychological contract on them is even more worth discussing. This study considered the mediating role of perceived employability and the moderating role of non-traditional work patterns to construct a model of the relationship between psychological contracts and employee well-being. This study collected and analysed data from 300 younger-generation employees from China through an online questionnaire. The study's results indicate that psychological contracts have a significant positive effect on employee well-being. Perceived employability produced a partial mediating effect. Non-traditional work patterns negatively moderated the positive influence relationship between the psychological contract and employee well-being. This study may not be able to track the long-term impact of the psychological contract on the well-being of young employees and is limited to the Chinese context. However, these findings enrich the psychological contract research and provide HR practitioners, employers, and employees with valuable references for management practices.

SIMULATION OF HYDRO-THEORMO-MINERAL AQUIFERS

The paper aims to synthesize the thermo-mineral aquifer simulation methodology elaborated, in the 80s, at the Computing Center of the University of Bucharest, C.C.U.B. Professor Ion Văduva initiate a research contract between C.C.U.B. and the Geological Reserve Coordination Department of the Ministry of Geology, G.R.C.D. The result of this joint contract, carried out over several years, is the methodology presented in this paper. Based on this methodology, a software was written and successfully applied to optimize the exploitation of aquifers in the Oradea area.

Redefining feasibility in clinical trials: Collaborative approaches for improved site selection

BackgroundThis Site Feasibility Task Force convened to assess the complex and burdensome process of site feasibility in clinical trials. The objective was to create mutual understanding of challenges and provide suggestions for improving collaboration among sponsors, contract research organizations (CROs), and sites. MethodsThe task force was composed of representatives from sponsors, CROs and sites (43 % Sites, 20 % Site Networks, 10 % Small/mid-size sponsors, 10 % Small/mid-size CROs, 10 % Large sponsors, 7 % Large CROs). The group collaborated to define the scope of the problem, identify challenges in the current process, and provide suggestions for improving the process. ResultsThe group found there is a need for better differentiation between the three main stages of feasibility, and the four sub-phases of Site Feasibility. The discussion brought to light emerging trends like early initiation of Site Feasibility and premature engagement of sites by CROs. To fully explain these challenges, the group analyzed the current practices and documented their downstream impact on clinical trial execution for all stakeholders. A list of best practices emerged naturally from this analysis. These findings are aggregated into short and actionable best practice guides. ConclusionThe task force suggests practical changes for the feasibility process and raises awareness of emerging trends and their associated risks. This awareness can begin to drive change in the site feasibility process, although industry-wide transformation will require new levels of collaboration, data standardization and automation tools. The potential benefits of evolving this process are significant and meaningful for more efficient and successful clinical trials.

Cytokine Response to Resistance Exercise in Children with Excess Fat and Prader-Willi Syndrome

Background: Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that is secreted from adipose tissue and macrophages; interleukin-6 (IL-6), secreted from adipose tissue, macrophages and skeletal muscle, has both proinflammatory and anti-inflammatory properties. Previous research showed excess adiposity leads to an increased concentration of both cytokines at rest while there is limited research on resistance exercise. Purpose: To compare IL-6 and TNF-α responses to resistance exercise in children with Prader-Willi Syndrome (PWS), a genetic cause for obesity, vs. children with normal fat mass (lean), or excess body fat (obesity) Methods: Nine children with PWS (11.4 ± 3.3 years, 45.6 ± 5.2% body fat), 11 lean children (9.2 ± 1.4 years, 18.6 ± 5.0% bodyfat), and 12 children with obesity (9.6 ± 1.3 years, 40.4 ± 5.4% body fat) participated. Children stepped onto an elevated platform wearing a weighted vest for 6 sets of 10 repetitions per leg (sets separated by 1 min of rest). Children with PWS, stepped to a platform height of 23.0 cm and wore a vest load that was computed as (20% of stature* 50% of lean body mass)/23.0 cm. For the controls, the platform height was 20% of the stature and the vest load was 50% of the lean body mass. Blood samples were obtained before (pre), immediately after (post), and during recovery from exercise (+15 and +60 min). Areas under the curve (AUC) were computed for IL-6 and TNF-α. Results: There was no group by time interaction for IL-6 ( p=0.378) but a group effect ( p=0.011) and a time effect ( p<0.001). Pairwise comparisons showed 60+ (1.065 ± 0.10 pg/mL) was higher than pre (0.660 ± 0.05 pg/mL), post (0.728 ± 0.06 pg/mL), and +15 (0.764 ± 0.066 pg/mL), p<0.001 for all. Children with PWS and children with obesity had higher IL-6 concentrations than lean children (0.943 ± 0.12 pg/mL and 0.951 ± 0.10 pg/mL vs. 0.519 ± 0.11 pg/mL, p≤0.038 for both). For TNF-α, there were no group by time interaction, time or group effects ( p≥0.420 for all). IL-6 AUC ( p=0.013) but not TNF-α AUC ( p=0.404) were different between groups. Children with PWS and children with obesity showed a higher IL-6 AUC than lean children (85.106 ± 41.81 pg/mL, 86.796 ± 33.60 pg/mL vs. 47.611 ± 21.00 pg/mL, p≤ 0.041 for both). Conclusion: There were no differences in IL-6 or TNF-α responses to exercise based on having PWS or having excess body fat in children. However, excess body fat was associated with higher IL-6 concentration and AUC. Peak concentrations for IL-6 were observed at 60 minutes after exercise similar to other studies. Potentially, IL-6 concentrations immediately post-exercise were not elevated because the exercise protocol was not of high intensity or long enough. Study funded by the US Army Medical Research and Material Command Contract W81XWH-08-1-0025 (DAR). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Promoting opioids, a story about how to influence medical science and opinions.

Key origins of the opioid crisis in the US lie in some pharmaceutical companies' substantial efforts to sell prescription painkillers. To legitimize opioids, the companies built up a body of medical science and opinions, and channels with which to communicate. Archival searches found 876 contracts that together provide information on how Mallinckrodt, an opioid manufacturer, attempted the ghost-management of medicine. These records-available because of litigation-involved contract research organizations, medical education and communication companies, publishers, professional societies, researchers, and other people who could be Mallinckrodt's agents. Together, they produced and circulated scientific messages to increase physicians' comfort with prescribing opioids. This article gives an overview of that activity, as seen in the contracts and related documents.

Unravelling psychological contracts in a digital age of work: a systematic literature review

ABSTRACT This study provides a comprehensive overview of psychological contract research in the digital age of work, where digitalization has significantly shaped the nature of work and employment arrangements. It examines the employee-employer relationship through the lens of individual beliefs about reciprocal obligations as reflected in psychological contract research. Through a systematic literature review, the study uncovers four distinct mechanisms of work digitalization (Remote/virtual Cooperation, Online Communication, Algorithm-based Coordination, and Digital Capabilities) encapsulated in the ROAD-framework that impacts psychological contracts, thus laying the conceptual groundwork for future research endeavours on psychological contracts in a digital age of work. The findings of the literature review outline the emergence of novel forms of employment arrangements in the digital age of work that extend dyadic psychological contracts to multiple party arrangements. Additionally, the study reveals the dynamic effects of work digitalization on different phases of psychological contracts. As a result, this enriches the dynamic phase model by considering the impacts of work digitalization through various propositions.

The global patent landscape of emerging infectious disease monkeypox.

Monkeypox is an emerging infectious disease with confirmed cases and deaths in several parts of the world. In light of this crisis, this study aims to analyze the global knowledge pattern of monkeypox-related patents and explore current trends and future technical directions in the medical development of monkeypox to inform research and policy. A comprehensive study of 1,791 monkeypox-related patents worldwide was conducted using the Derwent patent database by descriptive statistics, social network method and linear regression analysis. Since the 21st century, the number of monkeypox-related patents has increased rapidly, accompanied by increases in collaboration between commercial and academic patentees. Enterprises contributed the most in patent quantity, whereas the initial milestone patent was filed by academia. The core developments of technology related to the monkeypox include biological and chemical medicine. The innovations of vaccines and virus testing lack sufficient patent support in portfolios. Monkeypox-related therapeutic innovation is geographically limited with strong international intellectual property right barriers though it has increased rapidly in recent years. The transparent licensing of patent knowledge is driven by the merger and acquisition model, and the venture capital, intellectual property and contract research organization model. Currently, the patent thicket phenomenon in the monkeypox field may slow the progress of efforts to combat monkeypox. Enterprises should pay more attention to the sharing of technical knowledge, make full use of drug repurposing strategies, and promote innovation of monkeypox-related technology in hotspots of antivirals (such as tecovirimat, cidofovir, brincidofovir), vaccines (JYNNEOS, ACAM2000), herbal medicine and gene therapy.

Abstract CT129: A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer

Abstract Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, is designed to overcome the limitations of conventional CAR T-cells in solid tumor malignancies by pairing solid tumor CAR T-cells with CD19-targeting CAR T-cells to amplify the proliferation and activation of the solid tumor CAR T component. GCC19CART targets guanylate cyclase-C (GCC), which is reported to be expressed in the metastatic lesions of 70%-80% of subjects with colorectal cancers and largely restricted to the intestinal tract. A Phase 1 investigator-initiated clinical trial conducted in China showed preliminary efficacy with an overall response rate (ORR) at dose level 1 (1x106 CAR T-cells/kg) of 15.4% ORR (2/13) and 50% ORR (4/8) in dose level 2 (2x106 CAR T-cells/kg). Common side effects included cytokine release syndrome (CRS) and diarrhea/colitis. Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in a smaller proportion of patients. A phase 1 study was initiated in the United States in August 2022 for patients with metastatic colorectal cancer refractory to standard of care chemotherapy. As of a data cutoff on ​November 1, 2023, 4 subjects have been treated in the initial dose level. Methods: Subjects were initially screened for GCC expression; this requirement was later discontinued when immunohistochemistry studies revealed that the frequency of positive GCC expression exceeded 95%. Eligible subjects underwent leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART. Responses were assessed by RECIST v1.1 by site investigator review and an independent third-party imaging contract research organization. Results: 4 subjects have been dosed at level 1 (1x106 cells/kg) and completed the DLT period at the time of data cutoff. The most common adverse events were CRS in 4/4 subjects (Grade 1: 2/4 (50%) or Grade 2: 2/4 (50%)) and diarrhea in 3/4 subjects (Grade 1: 1/4 (25%), Grade 2: 1/4 (25%), or Grade 3: 1/4 (25%)). Three out of four patients had a mild tremor (Grade 1) that resolved with corticosteroids and no other evidence of neurotoxicity. The combined overall response rate (ORR) was 50% (2/4) by independent review. Two subjects demonstrated a partial response (PR) while 1 additional subject had partial metabolic response (PMR) on PET/CT with stable disease (SD) and 1 patient had progressive disease per RECIST 1.1. Per site investigator review, the ORR was 25%, with 1 confirmed PR and 3 SD assessed as best response. The median PFS was 3.8 months in the dose level 1 group. Conclusions: Preliminary results demonstrate that GCC19CART has meaningful clinical activity and an acceptable safety profile in refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented, including from patients treated at dose level 2 (2x106 CAR T-cells/kg). Clinical trial information: NCT05319314. Citation Format: Bridget P. Keenan, Christopher H. Lieu, Marwan Fakih, Dongqi Chen, Lucy Lu, Eric Rowinsky, Victor Lu, Lei Xiao, Alan P. Venook, Benjamin Schlechter. A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT129.