Research Agreement Research Articles

Reciprocity and prosocial behavior in democratic dynamic

Prosocial behavior (CP) currently presents some conceptual overlaps with the construct of reciprocity, understood here as a lubricant of democratic dynamics. The proposed study is based on a research agreement between the Universities of Palermo and Malaga, to test the relationship between CP and reciprocity and the multiple dimensions that intervene on the two constructs at the individual, interpersonal and community level. A structural equation model (with the Lisrel method) was used to assess whether the principle of equity, belief in a just world, sense of community and neighborhood norm increase CP and whether this together with worldview and social trust, in turn, increase positive reciprocity and decrease negative reciprocity. The analyses presented are partial and concern the sample of Palermo, consisting of 307 subjects, residing in the eight districts of the city. From the analysis of the data, the parameters of the model are satisfactory even if the effect of the sense of community is not significant.

The anatomy of a data transfer agreement for health research.

In a data-driven era, the exchange and safeguarding of personal information has become paramount. Data transfer agreements (DTAs) serve to guard privacy, defining the rules for sharing and protecting sensitive data. Yet, the complexities surrounding issues such as data privacy, intellectual property, and dispute resolution within these agreements pose challenges that demand careful consideration. Through a scoping review of twenty-four publicly available, English language DTAs relevant to health research, this article undertakes a comprehensive analysis, examining common clauses, their vital components, and charting a course for responsible data sharing through the provision of insights and practical guidance for drafting DTAs. The article underscores the need for attention to detail and an understanding of data protection legislation in order to ensure that DTAs align with the law and maximize legal certainty.

Epidemiology of Homebound Population Among Beneficiaries of a Large National Medicare Advantage Plan.

Interest in home-based care is increasing among Medicare Advantage (MA) plans. The epidemiology of homebound MA beneficiaries is unknown. To determine the prevalence, characteristics, predictors, health service use, and mortality outcomes of homebound beneficiaries of a large national MA plan. Cross-sectional. National MA plan. Humana MA beneficiaries in 2022 (n = 2 435 519). Homebound status was assessed via in-home assessment using previously defined categories: homebound (never or rarely left home in the past month), semihomebound (left home with assistance, had difficulty, or needed help leaving home), and not homebound. Demographic, clinical, health service use, and mortality outcomes were compared by homebound status. In 2022, the overall prevalence of homebound beneficiaries was 22.0% (8.4% of beneficiaries were homebound, and 13.6% were semihomebound). In adjusted models, female sex (odds ratio [OR], 1.36 [95% CI, 1.35 to 1.37), low-income status or dual eligibility for Medicare and Medicaid (OR, 1.56 [CI, 1.55 to 1.57]), dementia (OR, 2.36 [CI, 2.33 to 2.39]), and moderate to severe frailty (OR, 4.32 [CI, 4.19 to 4.45]) were predictive of homebound status. In multivariable logistic regression, homebound status was associated with increased odds of any emergency department visit (OR, 1.14 [ CI, 1.14 to 1.15]), any inpatient hospital admission (OR, 1.44 [CI, 1.42 to 1.46]), any skilled-nursing facility admission (OR, 2.18 [CI, 2.13 to 2.23]), and death (OR, 2.55 [CI, 2.52 to 2.58]). The study period overlapped the tail end of the COVID-19 pandemic, and data were derived from a single national MA plan, which limits generalizability. Overall homebound prevalence in a national MA plan was 22.0% and was independently associated with increased health service use and mortality. Study findings can inform strategic initiatives to identify and manage care for homebound beneficiaries. Humana, under a collaborative research agreement with Johns Hopkins University.

Modeling Bicarbonate Kinetics on Silver Catalysts for CO2 Electrolysis

Low-temperature CO2 electrolyzers transform captured CO2 into more useful chemicals, such as syngas (CO and H2) for systems with silver or gold catalysts and ethylene and other C2+ products for systems with copper catalysts. At low overpotentials, bicarbonate ions act as proton donors and have been shown to have enhanced activity1, leading to nonlinear Tafel slopes for the hydrogen evolution reaction (HER). We have developed a 1D planar electrode model for CO2 electrolysis, similar to the model developed by Gupta et al.,2 including a thin ionomer layer on top of a silver catalyst layer surface. The model includes buffer chemistry and ion transport in the boundary layer as well as the ionomer thin-film layer. Tafel parameters are fit for both bicarbonate and water as proton donors for HER using the model results to account for mass transport in the boundary layer. A comparison against a bare silver electrode shows that the Donnan potential across the ionomer/electrolyte interface has a significant effect on the ion concentrations at the catalyst layer surface, leading to enhanced HER from bicarbonate at low overpotentials. These results are then compared against Butler-Volmer parameters that are derived from a full microkinetic model. The Tafel kinetic parameters were then used in a 1D full-cell membrane electrode assembly (MEA) model, and we found good agreement with experimental data, illustrating that the ionomer in contact with the catalyst layer surface impacts the underlying kinetics both in planar electrodes and industrially-relevant MEA systems.References D. M. Koshy et al., J. Am. Chem. Soc., 143, 14712–14725 (2021) https://doi.org/10.1021/jacs.1c06212.N. Gupta, M. Gattrell, and B. MacDougall, J. Appl. Electrochem., 36, 161–172 (2006). This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344 and was partially supported by a Cooperative Research and Development Agreement (CRADA) between Lawrence Livermore National Laboratory, Stanford University, and TotalEnergies American Services, Inc. (affiliate of TotalEnergies SE) under Agreement No. TC02307 and Laboratory Directed Research and Development (LDRD) funding under project 22-SI-006.LLNL-ABS-857478 Figure 1

National dairy research programs: what is their role in animal health and sustainability research?

The US dairy industry has made great strides in improving animal health over many decades, which has driven substantial improvements in economic, social, and environmental sustainability. As consumer and corporate focus on climate continues to grow, the continued need to research and improve animal health and understand its connection with the environment is integral to the success of the dairy industry. Research to address these areas can be supported by national research programs and collaboration between them. The USDA and Dairy Management Inc established a collaborative research agreement in 2007; to date, this collaboration has not explicitly focused on animal health or its intersection with the environment. It is integral to the success of animal agriculture in an ever-changing sustainability landscape that animal health is addressed as a key piece of socioeconomic and environmental sustainability. An academic-industry stakeholder committee reached a consensus that supported this idea and identified that it is equally important to communicate these research findings with consumers in a way that resonates. The purpose of this Viewpoint article is to highlight that national research programs at the USDA Agricultural Research Service's National Animal Disease Center and Dairy Management Inc can and should play an important role in supporting and facilitating research at the intersection of animal health and sustainability broadly.

Singapore's COVID-19 crisis decision-making through centralization, legitimacy, and agility: an empirical analysis

Decision-making during health crises differs from routine decision-making and is constrained by ambiguity about evolving epidemiological situations, urgency of response, lack of evidence, and fear. Recent analyses of governance and decision-making during COVID-19, focusing on leadership qualities, involvement of specific stakeholders, and effective resource management, do not adequately address a persisting gap in understanding the determinants of decision-making during health crises at the national level. We undertook a study to understand the processes and characteristics of decision-making during the COVID-19 pandemic in Singapore. We used a case study approach and collected empirical evidence about public health decision-making, using a combination of key informant interviews and focus group discussions with stakeholders from government, academia and civil society organizations. We argue that administrative centralization and political legitimacy played important roles in agile governance and decision-making during the pandemic in Singapore. We demonstrate the role of the Singapore government's centralization in creating a unified and coherent governance model for emergency response and the People's Action Party's (PAP) legitimacy in facilitating people's trust in the government. Health system resilience and financial reserves further facilitated an agile response, yet community participation and prioritization of vulnerable migrant populations were insufficient in the governance processes. Our analysis contributes to the theory and practice of crisis decision-making by highlighting the role of political and administrative determinants in agile crisis decision-making. This study is funded by the U.S. Centers for Disease Control and Prevention through a Cooperative Research Agreement (NU2HGH2020000037).

Broadening the Concept of Value in Science and Technology Innovation Policy: Reconsidering Cooperative Research and Development Agreements as an Expression of Public Value Governance

Broadening the Concept of Value in Science and Technology Innovation Policy: Reconsidering Cooperative Research and Development Agreements as an Expression of Public Value Governance

Small-molecule AMPK activation preserves anabolic signaling in a C2C12 myotube cachexia model

AMP-activated protein kinase (AMPK) is a master metabolic regulator that responds to a decline in cellular energy status by promoting processes that generate ATP, while inactivating anabolic processes that consume ATP, thereby restoring the energy charge of the cell. In line with this general function, acute AMPK activation in healthy muscle cells potently inhibits anabolic signaling through the mechanistic target of rapamycin (mTORC1). However, treatment of atrophying muscle (from tumor-bearing mice and cells cultured in tumor cell-conditioned media) with the non-specific AMPK activator AICAR suggests that AMPK has a protective effect on muscle mass and anabolic signaling. We have identified MLX-0867 as a novel AMPK-activating small molecule (EC50 = 32.0 mM in C2C12 myotubes). We hypothesized that similar to AICAR, treatment with MLX-0867 would also preserve muscle mass and anabolic mTORC1 signaling in cultured muscle subjected to hyperinflammatory signaling. To test this, we treated C2C12 myotubes with control media (CM) or CM + 20 ng/mL TNF-ɑ and 100 U/mL interferon-γ (T/I) for 24 hours. Additionally, the cells were concurrently treated with 250 mM AICAR, 40 mM MLX-0867 (a novel AMPK activating small-molecule), or vehicle control during the treatment period. To visualize myotubes, myosin heavy chain (MHC) was detected by immunofluorescence, and average myotube diameter was measured. In a separate experiment, the protein was extracted from treated myotubes to determine the phosphorylation of p-70S6k and ribosomal protein S6 (rpS6) as markers of anabolic signaling through mTORC1. We found that T/I treatment significantly decreased myotube diameter. Neither AICAR nor MLX-0867 attenuated this atrophy. However, while T/I substantially reduced S6k and rpS6 phosphorylation, MLX-0867 (but not AICAR) partially preserved the phosphorylation of rpS6 and tended (p=0.11) to preserve p-70S6k phosphorylation under T/I treatment. In summary, MLX-0867 partially preserved anabolic signaling in T/I treated myotubes. However, this did not preserve muscle mass, at least under the conditions utilized in this experiment. A Brigham Young University Widtsoe Grant and a sponsored research agreement with Biolexis Therapeutics funded this research. 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.

Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. International Clinical Trials Registry Platform No. NTR4746.

FDA experiences with a centralized statistical monitoring tool

ABSTRACT The U.S. Food and Drug Administration (FDA) has broadly supported quality by design initiatives for clinical trials – including monitoring and data validation – by releasing two related guidance documents (FDA 2013 and 2019). Centralized statistical monitoring (CSM) can be a component of a quality by design process. In this article, we describe our experience with a CSM platform as part of a Cooperative Research and Development Agreement between CluePoints and FDA. This agreement’s approach to CSM is based on many statistical tests performed on all relevant subject-level data submitted to identify outlying sites. An overall data inconsistency score is calculated to assess the inconsistency of data from one site compared to data from all sites. Sites are ranked by the data inconsistency score ( − log 10 p , where p is an aggregated p-value). Results from a deidentified trial demonstrate the typical data anomaly findings through Statistical Monitoring Applied to Research Trials analyses. Sensitivity analyses were performed after excluding laboratory data and questionnaire data. Graphics from deidentified subject-level trial data illustrate abnormal data patterns. The analyses were performed by site, country/region, and patient separately. Key risk indicator analyses were conducted for the selected endpoints. Potential data anomalies and their possible causes are discussed. This data-driven approach can be effective and efficient in selecting sites that exhibit data anomalies and provides insights to statistical reviewers for conducting sensitivity analyses, subgroup analyses, and site by treatment effect explorations. Messy data, data failing to conform to standards, and other disruptions (e.g. the COVID-19 pandemic) can pose challenges.

Twin study dissects CXCR3+ memory B cells as non-heritable feature in multiple sclerosis

In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets. In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals. The frequencies of CXCR3+ memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3+ memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their invitro propensity to develop into antibody-secreting cells. Circulating CXCR3+ memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3+ memory B cells mature into antibody-secreting cells to drive MS. This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no.882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478).

Abstract 6022: Investigating the mechanisms behind salivary gland tissue sparing in response to ultra-high dose-rate FLASH proton radiotherapy

Abstract Background: Radiotherapy (RT) is a primary treatment for cancers of the head and neck. However, although highly efficacious in eliminating tumors, incidental damage to underlying tissue remains a major limitation of RT. In the case of head and neck cancer, damage to the otherwise healthy salivary glands is often unavoidable even at low dosages, leaving patients with lifelong xerostomia and other comorbidities. FLASH Proton RT (F-PRT) is a form of ultra-high dose RT and has been reported to spare healthy tissues while retaining its tumor-controlling efficacy. The first system to deliver dosimetrically identical FLASH Proton RT (F-PRT; 60- 110 Gy/sec) or Standard Proton RT (S-PRT; 0.5-1 Gy/sec) using double-scattered protons was designed by our group. Aim: In this study, we aimed to investigate the effect of F-PRT on radiation-induced salivary gland dysfunction and the potential mechanism of this sparing effect by analyzing the effects of FLASH on two distinct salivary gland cell types: acinar and ductal cells. Methods: The head and neck area of C57BL/6 mice were irradiated with a single dose of 16 Gy of F-PRT (128Gy/s) or S-PRT (0.95 Gy/s). Radiation-induced xerostomia was studied by measuring the saliva flow rate of mice at 5, 10, 14, and 28 days post-PRT. Expression of AQP5, SOX9, and Keratin- 18, 19 was studied at 2, 5, 10, 14, and 28 days post irradiation by both immunofluorescence and protein immunoblotting. Results: Following irradiation with a single dose of 16 Gy, saliva flow was reduced by both treatments. However, the F-PRT-treated mice showed a significant improvement in salivary flow at 14 and 28 days post-irradiation, compared to those treated with S-PRT. Expression of AQP5 was significantly downregulated at 2, 5, 10 and 14 days post irradiation with S-PRT while F-PRT-treated mice showed a significant restoration of the AQP5 expression during the same time points. Expression of SOX9 showed no significant differences between S-PRT and F-PRT treated mice at earlier time points (2, 14 days), however, there was a significant difference in expression of SOX9 between the irradiated and unirradiated group. The difference in expression of SOX9 was visible from day 28 post-irradiation, where the F-PRT treated group showed increased expression compared to S-PRT. Conclusion: Our findings demonstrate that F-PRT reduces radiation-induced hyposalivation and reinstates the expression of AQP5 in the acinar cells of the submandibular gland of mice. Furthermore, it demonstrates that on day 28 post-irradiation, F-PRT-treated mice displayed more SOX9-expressing progenitor cells in the submandibular salivary glands compared to S-PRT. Acknowledgements: This work was supported by a Sponsored Research Agreement from IBA to Drs. C. Koumenis and L. Dong. Citation Format: George S. Morcos, Priyanka Chowdhury, Michele M. Kim, Khayrullo Shoniyozov, James Metz, Lei Dong, Constantinos Koumenis. Investigating the mechanisms behind salivary gland tissue sparing in response to ultra-high dose-rate FLASH proton radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6022.

Problems of Systematization of Contracts for Intellectual Products Creation

Systematization of contracts makes it possible to solve the problems of contractual regulation at the legislative level. The problem of contract systematization in civil law in general and in intellectual property law is that in science there is no unified approach regarding the choice of classification criterion that can be used as its basis. Systematization of contracts aimed at creating intellectual products is a «hot button» of the current legislation, the practice of its application and legal science. The paper reasonably points out that the legislative decisions presented in section VII of the Civil Code of the Russian Federation, are ill-conceived and ignore the principle of systematic construction of legislation on contractual obligations aimed at creating intellectual products. An analysis of the rules on contracts aimed at creating works as objects of copyright, and research and development agreements was carried out. The paper proposes amendments to the legislation as to transfer of the rules on the creation of intellectual products to Section IV of the Civil Code of the Russian Federation and changes in the structure and content of Chapter 38 of the Civil Code of the Russian Federation.

A Rural Native American Community Experiences Related to Emotional and Mental Health Well-Being during the COVID19 Pandemic.

This qualitative study was conducted as part of a larger nationwide study, the Aegis Project that investigated the impact of the COVID19 pandemic, infection and reinfection, and the potential long-term immunity to SARS-CoV-2 and will be reported in a future paper. The study is a collaborative effort among The University of Texas at Austin School of Nursing, Indiana University at Bloomington School of Public Health, and a rural-based Tribe located in the Midwest. The qualitative component of the study explored the experiences that impacted the emotional and mental health well-being during the COVID19 pandemic. Data were collected using open-ended interview questions regarding participants' experiences during the pandemic. Results were analyzed using the Consensual Qualitative Research (CQR) method which includes the process of categorizing data into specific themes by means of the research team's discourse, external auditing, and agreement. Four themes emerged related to emotional and mental health well-being experiences that include: 1) loss of connectedness, 2) increase in stress, 3) increase in anxiety, and 4) learning to cope. Understanding the lived experiences of Native Americans during the COVID19 pandemic is needed to help guide the development and testing of culturally based interventions to improve the emotional and mental health well-being of Native American communities during pandemics or other distressful incidences such as natural disasters.

Investigating the Performance of a Degraded Prestressed Concrete Box Girder Half-joint Bridge in the Spirit of the Italian Guidelines

The paper investigates a paired pre-stressed box-girder concrete bridge, according to the framework suggested by the new Italian Guidelines for the risk assessment of existing bridges. The bridges, selected as case study within the research agreement signed by the FABRE Consortium and ANAS S.p.A. for first applications of the Italian Guidelines, present significant age-related degradation phenomena known to the Administrator, who decided for the bridges demolition and reconstruction. Visual inspections confirmed defects in the pre-stressing system, a permanent deflection of the deck, and cracks at half-joints, possibly due to pre-stressing loss and creep effects triggered by the poor quality of concrete. Also, preliminary safety verifications revealed not to meet code requirements in most cross-sections. Consequently, the most degraded bridge was closed. From March 2022, experimental campaigns have been performed by the FABRE Consortium and ANAS for improving their experience on the behaviour of old pre-stressed concrete bridges, as well as to control possible performance loss of the open bridge, sustaining the overall route traffic. The paper summarises these activities and presents some possible future investigations to be carried out before bridge demolition.

The UK and EU competition rules for research and development agreements: falling out of lockstep

Until 2023, the UK and EEA had applied the same rules to govern collaboration and competition in the area of research and development. Post-Brexit, they have now gone their separate ways with each creating their own legislation in the form of so-called ‘block exemptions’, which permit certain restrictions of competition and proscribe others. This article considers the two block exemptions side by side, alongside the statutory guidance which has been drafted by the authorities in each jurisdiction. While both block exemptions are broadly similar, such that the parties can consider their requirements side-by-side when planning their collaboration, the different legislative styles of the UK and EU mean that this cannot readily be done by reading the legislation. This article addresses this issue and also flags the points of difference between the two new regimes which would-be parties to research and development-based collaborations must consider. In particular, this article considers in detail the UK legislation’s new closer scrutiny of so-called ‘competition in innovation’.

CA-125 concentrations are associated with renal function decline but not congestion or prognosis in patients with chronic heart failure: results from EMPEROR-POOLED

Abstract Background Carbohydrate antigen 125 (CA-125, also described as cancer antigen 125), has emerged as a candidate biomarker of congestion in heart failure (HF). Effects of sodium/glucose cotransporter-2 inhibitor therapy on CA-125 and its role as a prognostic measure in HF remains uncertain. Purpose In study participants from the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction (EF) and renal function, we sought to investigate associations between CA-125 and congestion, the effect of empagliflozin on CA-125 concentrations, and the ability of the biomarker to predict cardio-renal outcomes. Methods 1111 patients with HF and available biomarker data were included into this analysis. Serum CA-125 was measured at baseline, 12 and 52 weeks using an Electroluminescence assay. The measurements were performed within a biomarker research agreement of Boehringer Ingelheim, the sponsor of these trials and Roche Diagnostics International Ltd. Congestion signs or symptoms were evaluated across CA-125 tertiles. A mixed model for repeated measurements was used to compare the treatment effects on CA-125. Multivariable analyses adjusted for the prespecified EMPEROR baseline variables plus N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were used to examine the association of CA-125 with HF hospitalization or cardiovascular (CV) death and estimated glomerular filtration rate (eGFR) slope. Results Across CA-125 tertiles at baseline, no significant association was present with HF symptom severity, jugular vein distention, pulmonary rales, S3 gallop or peripheral oedema (all p-values >0.10). Treatment with empagliflozin was associated with 7% greater reduction of CA-125 level versus placebo to week 12 (adjusted geometric mean ratio: 0.93; 95% confidence interval [CI], 0.87-0.99, p = 0.03) but not to week 52 (adjusted geometric mean ratio: 0.97, 95% CI 0.90-1.06; p = 0.50). No significant association was found for tertiles of CA-125 at baseline with the risk of CV death/HF hospitalization; with a hazard ratio (HR) for higher vs lower CA-125 tertiles of 1.34 (95% CI 0.91–1.96). In the same model NT-proBNP and hs-cTnT were strongly prognostic (both p-values <0.0001). Compared to lower tertiles, study participants in the third CA-125 tertile had higher rate of kidney function decline with a more negative eGFR slope (p for trend = 0.03). Conclusion In chronic HF, across a wide range of EF and of renal function, CA-125 levels were not strongly associated with clinical signs or symptoms of congestion. Empagliflozin lowered CA-125 levels more than placebo at week 12 but not at week 52. Among individuals with HF, CA-125 concentrations did not provide additional prognostic information for CV death/HF hospitalization beyond conventional cardiac biomarkers but may predict subsequent kidney function decline.

Prognostic implications of angiopoietin-2 in heart failure and the influence of empagliflozin: the EMPEROR program

Abstract Background Heart failure (HF) development and progression is associated with endothelial dysfunction, oxidative stress, and inflammation. The mechanisms involved in endothelial repair in HF are not fully understood. Emerging evidence suggests that angiopoietin-2 (Angpt2), a vascular destabilizing factor, may be related to outcome in HF. Aim To assess the association between Angpt2 and clinical outcomes in a pooled analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials, and to evaluate if the response to empagliflozin therapy in HF is modulated by Angpt2 levels. Methods and results Angpt2 levels (ng/ml) were measured in serum samples from 1131 EMPEROR study participants by using Roche Cobas Elecsys assay, within biomarker research agreement between Boehringer Ingelheim and Roche Diagnostics International Ltd, at baseline, week 12 and week 52. Patients were divided into tertiles of baseline Angpt2 levels (<2.58 ng/mL; ≥2.58 ng/mL <4.71 ng/mL and ≥4.71 ng/mL). Patients in the highest tertile were more frequently white people, had a higher prevalence of New York Heart Association class III-IV symptoms, HF hospitalization within 12 months, obesity, diabetes, atrial fibrillation, elevated natriuretic peptides, worse renal function, and lower prevalence of coronary disease, compared to the lowest tertile (p<0.05 for all). Higher tertile at baseline was associated with increased risk for adverse HF and kidney events (Table 1). Empagliflozin treatment was associated with reduction of the serum Angpt2 versus placebo at week 12 (adjusted gMean 0.872 [0.828-0.917], p<0.0001) but not at week 52 (adjusted gMean ratio 0.946, [0.879-1.019], p=0.145). Empagliflozin significantly reduced the risk of hospitalization for HF and cardiovascular death particularly for patients with highest baseline Angpt2 levels (lowest tertile HR 1.21 [0.63-2.31]; middle tertile HR 0.65 [0.37-1.16]; highest tertile HR 0.64 [0.42-0.97], P-trend=0.139). Conclusion Higher Angpt2 levels at baseline were associated with more advanced HF and worse prognosis. Treatment with empagliflozin was associated with reduction of Angpt2 level at week 12. The benefit of empagliflozin on major HF events was consistent across baseline Angpt2 levels.Table 1

Abstract 11936: Cardiorenal Prognostic Significance of IGFBP-7 Concentrations in Chronic Heart Failure: Findings From EMPEROR-Pooled

Introduction: Insulin-like growth factor binding protein-7 (IGFBP-7) is a biomarker of tissue senescence with a role in heart failure (HF) pathophysiology. We examined the association of IGFBP-7 with risk of HF hospitalization or cardiovascular (CV) death and progression of renal disease in the EMPEROR-Reduced and EMPEROR-Preserved Trials. Methods: IGFBP-7 was measured in serum samples in the placebo and empaglifozin arms at baseline (N= 561, 564), 12 weeks (N=558, 557) and 52 weeks (N=355, 358). IGFBP-7 was measured using Roche Cobas Elecsys assay within the Biomarker Research Agreement of Boehringer Ingelheim, the sponsor of the EMPEROR trials and Roche Diagnostics International Ltd. Association between IGFBP-7 and risk of HF hospitalization or CV death, estimated glomerular filtration rate (eGFR) slope, and renal composite outcome of sustained eGFR reduction ≥40% or end-stage renal disease were evaluated using multivariable modeling. Results: Study participants with IGFBP-7 levels in the third tertile had a higher risk clinical profile compared to those with lower values. Empagliflozin was not meaningfully associated with change in IGFBP7 at 12 or 52 weeks. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP-7 values above the second tertile predicted a higher risk of HF hospitalization or CV death (HR: 2.00 95% CI 1.28-3.10, p=0.002), higher rate of eGFR decline (β estimate: -2.45, 95% CI: -3.40 - -1.50, p for trend =0.005) and higher risk of renal composite endpoint (HR: 4.66, 95% CI: 1.61-13.53, p=0.005). Empagliflozin reduced risk for CV death/HF hospitalization irrespective of baseline IGFBP-7 (p-trend across IGFBP-7 tertiles=0.26). Concentrations of IGFBP-7 were moderately correlated with other prognostic HF biomarkers of tissue remodeling including fatty acid binding protein-3, growth differentiation factor-15, and angiopoietin-2. Conclusions: IGBP-7 was correlated with worse clinical presentation and associated with adverse cardiovascular outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP-7 levels over time.

A Phase I/II, Intra-Patient Dose-Escalation Study of Bitopertin, a Selective Inhibitor of GlyT1 and Heme Synthesis, for Steroid-Refractory Diamond-Blackfan Anemia

Background: Diamond-Blackfan anemia (DBA) is a heritable bone marrow failure disorder characterized by macrocytic anemia with reticulocytopenia and bone marrow erythroid hypoplasia, usually presenting within the first two years of life. Treatment consists of systemic corticosteroids. Treatment failure or steroid intolerance occurs in approximately half of all cases, necessitating chronic transfusions, which carry the risks of iron overload and infections. Hematopoietic cell transplant remains the sole curative therapy for DBA. In cases where a causative mutation can be identified, with rare exceptions, the affected genes encode ribosomal proteins (RPs), defining DBA as prototypic haploinsufficient ribosomopathy. Erythrocyte hemoglobinization requires balanced heme synthesis and globin translation. Various in vitro and animal models suggest that RP insufficiency results in reduced ribosomal biogenesis, disrupting this balance and leading to excess of heme, resulting in toxicity to developing erythroid cells and premature termination of erythroid differentiation. Bitopertin is an investigational, orally administered, inhibitor of the GlyT1 glycine transporter. Outside the central nervous system (CNS), GlyT1 is expressed almost exclusively on developing erythrocytes. By reducing intracellular glycine, a rate-limiting substrate for heme synthesis, bitopertin slows heme synthesis and thus we hypothesize rebalances hemoglobin synthesis. In preclinical DBA models, bitopertin rescues erythropoiesis. The drug was originally developed for CNS indications, and has been shown to exhibit a favorable safety profile in prior studies with cumulative enrollment of over 4,000 patients and healthy volunteers. It is currently under clinical investigation for the treatment of erythropoietic protoporphyria. Study Design and Methods: This is a phase I/II, intra-patient dose-escalation study of bitopertin for steroid-refractory DBA, conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. Subjects visit the NIH for initial evaluation and eligibility assessment and at the primary endpoint, with interim follow-up conducted via telehealth and local laboratory assessments. Subjects must be 18 years of age or and older, diagnosed with DBA and with clinically significant anemia (hemoglobin < 9/dL and/or requiring 2 units PRBC per 8 weeks). They must have relapsed and/or steroid refractory disease or be intolerant of systemic steroids, and be without significant comorbidities. Ongoing transfusions and chelation therapy are allowed, but other DBA-directed therapy, most notably steroids and growth factors, are not. Each subject will take oral bitopertin daily, escalating the dose monthly (5 mg, 10 mg, 20 mg, 40mg, and 60 mg) until reaching either the study maximum dose of 60 mg, the minimum effective dose (MED), or the maximum tolerated dose (MTD). Subjects will be followed for 8 months (32 weeks), including a minimum of 4 months (16 weeks) at the final dose (MED, MTD or study maximum). Response will be assessed on an ongoing basis and will be defined as an increase in hemoglobin ≥by 1.5 g/dL and/or a reduction in the units of PRBC transfusions by ≥50% from baseline. Furthermore, a robust response will be defined as a hemoglobin ≥10 g/dL and transfusion independence for 8 weeks. Patients with response (robust or non) by the 8-month primary endpoint will be allowed to continue extended therapy for 3 additional years. The primary endpoint is erythroid response. Secondary endpoints include safety as defined by the toxicity profile over 8 months of therapy and on extended therapy, relapse, survival, clonal evolution, health-related quality of life, and ancillary laboratory studies including the impact of bitopertin upon erythroid cell dynamics. The study employs a minmax design. A minimum of 15 patients will be enrolled. If the minimum efficacy threshold is met or surpassed (≥13% response rate), an additional 10 patients will be enrolled. Status: This study has been granted an FDA IND (165778) and is open for enrollment. It is monitored under the NIH Institutional Review Board (001528-H) and is registered with the U.S. National Library of Medicine (NCT05828108). Funding: This study is supported by the NHLBI Division of Intramural Research and in part through a Cooperative Research and Development Agreement (CRADA) with Disc Medicine, Inc. (Watertown, MA).