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Judith J Stephenson,1 Jonathon Colby Gable,2 Rebekah Zincavage,1 Gregory L Price,2 Collin Churchill,2 Emily Zhu,2 Keri Stenger,2 Mukul Singhal,1 Bal Nepal,1 Michael Grabner,1 Michael J Fisch,3 David Debono,4 Amy R Geschwender,5 Gebra Cuyun Carter2 1HealthCore, Inc., Wilmington, DE, USA; 2Eli Lilly and Company, Indianapolis, IN, USA; 3AIM Specialty Health, Chicago, IL, USA; 4Anthem, Inc., Indianapolis, IN, USA; 5SWOG Cancer Research Network, San Antonio, TX, USACorrespondence: Judith J Stephenson Tel +1 302-547-5770Email JStephenson@healthcore.comPurpose: To describe patients’ perspectives on the use of and potential challenges and barriers with adherence/persistence to cyclin-dependent kinase 4 and 6 inhibitors (CDK4& 6i’s) to treat metastatic breast cancer (MBC).Methods: This qualitative study consisted of 60-minute semi-structured telephone interviews with patients with MBC in the US who were either current or recent CDK4& 6i users, identified from administrative claims of survey-eligible commercial and Medicare Advantage patients in the HealthCore Integrated Research Database between November 1, 2018 and November 1, 2019. Patients were recruited by email and/or mailed letter. The 60-minute telephone interviews were conducted by a trained facilitator using a study-developed interview discussion guide that included topics impacting treatment choice and adherence/persistence. Interviews were audio-recorded, transcribed, and thematically analyzed.Results: All 462 eligible patients were sent a recruitment email and/or letter to which 36 patients responded, consented to participate, and met study inclusion criteria; 25 patients scheduled interviews, and 24 completed them. Study participants were predominately white, non-Hispanic (96%) with a mean age of 59.5 years. Participants reported a largely positive experience and mentioned very few adherence/persistence issues. They further reported appreciating the ease and convenience of oral oncolytics, coped with side effects, had strong medical and social support, and experienced few cost issues.Conclusion: The few adherence/persistence issues reported by participants contrasts with other findings of suboptimal oral oncolytic use. Interview themes indicated several factors that likely contributed to the lack of adherence/persistence issues: trusted relationship with oncologist, belief in importance of medication, positive medication views, strong medical and social support, and minimal personal drug cost. Future research should focus on whether and how much these factors impact adherence/persistence in more diverse populations. If adherence/persistence issues are identified in these populations, then it would be appropriate to study the development of interventions that target factors associated with better adherence/persistence.Keywords: oral oncolytics, patient perspective, semi-structured interviews, adherence, persistence, CDK4& 6i users

Purpose: The Functional Assessment of Cancer Therapy item (FACT-GP5) has the potential to provide an understanding of global treatment tolerability from the patient perspective. Longitudinal evaluations of the FACT-GP5 and challenges posed by data missing-not-at-random (MNAR) have not been explored. Robustness of the FACT-GP5 to missing data assumptions and the responsiveness of the FACT-GP5 to key side-effects are evaluated., Methods: In a randomized, double-blind study (NCT00065325), postmenopausal women (n = 618) with hormone receptor-positive (HR+), advanced breast cancer received either fulvestrant or exemestane and completed FACT measures monthly for seven months. Cumulative link mixed models (CLMM) were fit to evaluate: (1) the trajectory of the FACT-GP5 and (2) the responsiveness of the FACT-GP5 to CTCAE grade, Eastern Cooperative Oncology Group (ECOG) Performance Status scale, and key side-effects from the FACT. Sensitivity analyses of the missing-at-random (MAR) assumption were conducted., Results: Odds of reporting worse side-effect bother increased over time. There were positive within-person relationships between level of side-effect bother (FACT-GP5) and severity of other FACT items, as well as ECOG performance status and Common Terminology Criteria for Adverse Events (CTCAE) grade. The number of missing FACT-GP5 assessments impacted the trajectory of the FACT-GP5 but did not impact the relationships between the FACT-GP5 and other items (except for nausea [FACT-GP2])., Conclusions: Results support the responsiveness of the FACT-GP5. Generally speaking, the responsiveness of the FACT-GP5 is robust to missing assessments. Missingness should be considered, however, when evaluating change over time of the FACT-GP5., Trial Registration: NCT00065325., Trial Registration Year: 2003., (© 2024. The Author(s).)

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions., Competing Interests: KG is a former employee of and owns stock in Invitae Laboratories. EJ is a paid consultant for both RTI International and the ASF. AW has received funding from the ASF, Foundation for Angelman Syndrome Therapeutics (FAST), Ovid Therapeutics, Ionis Pharmaceuticals, and F. Hoffmann-La Roche. The remaining authors declare that they have no relevant competing interests., (© The Author(s), 2024.)

Significance: The development of genetically encoded fluorescent indicators of neural activity with millisecond dynamics has generated demand for ever faster two-photon (2P) imaging systems, but acoustic and mechanical beam scanning technologies are approaching fundamental limits. We demonstrate that potassium tantalate niobate (KTN) electro-optical deflectors (EODs), which are not subject to the same fundamental limits, are capable of ultrafast two-dimensional (2D) 2P imaging in vivo ., Aim: To determine if KTN-EODs are suitable for 2P imaging, compatible with 2D scanning, and capable of ultrafast in vivo imaging of genetically encoded indicators with millisecond dynamics., Approach: The performance of a commercially available KTN-EOD was characterized across a range of drive frequencies and laser parameters relevant to in vivo 2P microscopy. A second KTN-EOD was incorporated into a dual-axis scan module, and the system was validated by imaging signals in vivo from ASAP3, a genetically encoded voltage indicator., Results: Optimal KTN-EOD deflection of laser light with a central wavelength of 960 nm was obtained up to the highest average powers and pulse intensities tested (power: 350 mW; pulse duration: 118 fs). Up to 32 resolvable spots per line at a 560 kHz line scan rate could be obtained with single-axis deflection. The complete dual-axis EO 2P microscope was capable of imaging a 13    μ m by 13    μ m field-of-view at over 10 kHz frame rate with ∼ 0.5    μ m lateral resolution. We demonstrate in vivo imaging of neurons expressing ASAP3 with high temporal resolution., Conclusions: We demonstrate the suitability of KTN-EODs for ultrafast 2P cellular imaging in vivo , providing a foundation for future high-performance microscopes to incorporate emerging advances in KTN-based scanning technology., (© 2024 The Authors.)

While nitro and amino alkenes are common in pharmaceuticals, pesticides, and munitions, their environmental fates are not well known. Ozone is a ubiquitous atmospheric oxidant for alkenes, but the synergistic effects of nitrogen-containing groups on the reactions have not been measured. The kinetics and products of ozonolysis of a series of model compounds with different combinations of these functional groups have been measured in the condensed phase using stopped-flow and mass spectrometry methods. Rate constants span about six orders of magnitude with activation energies ranging from 4.3 to 28.2 kJ mol -1 . Vinyl nitro groups substantially decrease the reactivity, while amino groups have the opposite effect. The site of the initial ozone attack is highly structure dependent, consistent with local ionization energy calculations. The reaction of the neonicotinoid pesticide nitenpyram, which forms toxic N -nitroso compounds, was consistent with model compounds, confirming the utility of model compounds for assessing environmental fates of these emerging contaminants.

Sickle cell disease (SCD) is the most common inherited disease. Pain is a key morbidity of SCD and opioids are the main treatment but their side effects emphasize the need for new analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of pain. Homozygous (HbSS) Berkley mice express >99% human sickle hemoglobin and several features of clinical SCD including hyperalgesia. Previously, we reported that the endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator prostaglandin E2-glyceryl ester (PGE2-G) which contributes to hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in hyperalgesia in sickle mice. Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of PGE2 and PGE2-G, pronociceptive derivatives of 2-AG. A single intravenous injection of 2-AG produced hyperalgesia in non-hyperalgesic HbSS mice, but not in control (HbAA) mice expressing normal human HbA. JZL184, an inhibitor of 2-AG hydrolysis, also produced hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat hyperalgesia in HbSS mice. The decrease in hyperalgesia was accompanied by reductions in 2-AG, PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat pain in SCD.

Background: The importance of dignity in health care is well described, yet limited interventions exist to improve dignity, particularly patient-driven interventions. Objectives: To test the hypothesis that patient-selected photographs at the bedside would impact patients' sense of dignity and clinicians' sense of meaningful work, stimulate conversation between patients and clinicians, and serve as a visual and patient-driven complement to the Patient Dignity Question (PDQ). Methods: Patients admitted to three units at an academic medical center displayed photographs above their head of bed and were interviewed for this study. We used thematic content analysis to compare themes extracted from patient interviews, the PDQ, and clinician surveys. Results: Eight themes emerged from patient interviews ( n  = 19): conveying goals, joy, capturing the patient's spirit, faith and spirituality, sense of belonging, physical appearance and health, stimulating conversation and meaningful connections, and humanizing the patient. The same themes emerged from the PDQ, with the exception of physical appearance and health. Notably, analysis of the clinician surveys ( n  = 40) yielded six similar themes: conveying goals, joy, stimulating conversation and meaningful connections, humanizing the patient, meaningful work, and compassion and empathy. Conclusions: Patient-selected photographs at the bedside impact both patients and clinicians by stimulating conversation and meaningful connections, humanizing patients, and fostering meaning and joy in work. Photographs and the PDQ provide a similar window into personhood, thereby supporting the use of a photograph as a visual and patient-driven complement to the PDQ.

Background: Historically, high hepatocellular carcinoma (HCC)-related mortality has been, in part, due to lack of effective therapies; however, several systemic therapies have been recently approved for HCC treatment, including regorafenib and ramucirumab. These two treatments utilize different routes of administration (four daily tablets and biweekly intravenous infusions, respectively) and have different risks of adverse events (AEs). However, we lack data on patient preferences in balancing the route of administration and risk of AEs in patients with HCC. We aimed to determine patient preferences and trade-offs for second-line treatment in patients with HCC.  METHODS: Patients with advanced or metastatic HCC were recruited through their physicians for this study. Patient preferences were assessed by using a modified threshold technique (TT) design in which respondents were asked two direct-elicitation questions before (assuming same safety and efficacy and only varying mode of administration) and after (incorporating the safety profiles of ramucirumab and regorafenib) the TT series on seven risks of clinically relevant AEs., Results: In total, of the 157 patients recruited by their physicians, 150 were eligible and consented to participate. In the first elicitation question (assuming risk and efficacy were equivalent), 61.3% of patients preferred daily tablets. However, 76.7% of patients preferred the biweekly infusion when the safety profiles of the two available second-line therapies were included. The TT analysis confirmed that preferences for oral administration were not strong enough to balance out the risk of AEs that differentiate the two therapies., Discussion: We found that when patients were asked to choose between a daily, oral medication and a biweekly IV medication for HCC, they were more likely to choose a daily, oral medication if efficacy and safety profiles were the same. However, when risks of AEs representing the safety profiles of two currently available second-line treatments were introduced in a second direct-elicitation question, respondents often selected an IV administration with a safety profile similar to ramucirumab, rather than oral tablets with a safety profile similar to regorafenib. Our findings indicate that the risk profile of a second-line treatment for HCC may be more important than the mode of administration to patients., (© 2023. Eli Lilly & Company.)

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient K p as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios ( K p,uu ) to cure a CNS disease such as HAT.

Artificial intelligence (AI) is becoming established in drug discovery. For example, many in the industry are applying machine learning approaches to target discovery or to optimize compound synthesis. While our organization is certainly applying these sorts of approaches, we propose an additional approach: using AI to augment human intelligence. We have been working on a series of recommendation systems that take advantage of our existing laboratory processes, both wet and computational, in order to provide inspiration to our chemists, suggest next steps in their work, and automate existing workflows. We will describe five such systems in various stages of deployment within the Novartis Institutes for BioMedical Research. While each of these systems addresses different stages of the discovery pipeline, all of them share three common features: a trigger that initiates the recommendation, an analysis that leverages our existing systems with AI, and the delivery of a recommendation. The goal of all of these systems is to inspire and accelerate the drug discovery process.