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Emuella Flood,1 Susan McCutcheon,2 Kathleen Beusterien,3 deMauri S Mackie,3 Stella Mokiou,1 Xavier Guillaume,3 Emily Mulvihill3 1Patient Centered Science, AstraZeneca, Gaithersburg, MD, USA; 2Global Medical Affairs, AstraZeneca, Cambridge, UK; 3Health Division, Cerner Enviza, an Oracle Company, Kansas City, MO, USACorrespondence: Emily Mulvihill, Health Division, Cerner Enviza, an Oracle Company, 2800 Rock Creek Parkway, Kansas, MO, USA, Tel +1 314-724-9386, Email emily.mulvihill@cernerenviza.comPurpose: Patients with early breast cancer (eBC) are increasingly provided with different options, which may involve a sequence of different treatments and treatment modalities, and eligibility for certain adjuvant treatments depending upon pre-surgical and surgical outcomes. This study examined patient preferences around aspects of treatment decision-making in eBC.Patients and Methods: A total of 452 patients with self-reported eBC in Germany (n=151), Italy (n=151), and Japan (n=150) completed an online survey about physician interactions and treatment side effects. The survey included best-worst scaling (BWS) to assess prioritization of 13 statements reflecting aspects of treatment decision-making. In a series of choice tasks, participants chose their most and least preferred options among subsets of 4 statements. Hierarchical Bayesian modeling was used to estimate BWS preference scores for each statement. BWS scores were based on the number of times a statement was chosen as most versus least preferred; scores total 100 for each patient.Results: The most preferred aspects of treatment decision-making were “treatment aggressiveness matches personal risk” (mean BWS score = 13.49), “being told about what is coming” (13.18), deciding based on “own surgical outcome” (11.90), “avoiding unnecessary treatment” (10.35), and “involving in treatment decisions” (9.44). The least preferred aspects were “not being asked about treatment decisions along the way” (3.27) and “receiving the same treatment as other patients” (3.41). Patients in Japan preferred “being told about what is coming”, “deciding based on own surgical outcome”, “avoiding unnecessary treatment”, and being “involved in decisions” more than patients in Italy and Germany. Patients in Germany were more satisfied with their physician interactions and care, although their outcomes were not always better than those in Italy and Japan.Conclusion: Patients value individualized treatment tailored to their risk of recurrence and tolerance of side effects, highlighting the need for focused patient education about options, to encourage their engagement.Plain Language Summary: New treatment pathways based on promising biomarkers are being studied in early breast cancer. This study aimed to understand the importance that patients may place on different features describing how decisions are made along potential treatment pathways for early breast cancer. Participants in Italy, Germany, and Japan were asked to compare various aspects of treatment decision-making and choose those that were most and least important to them. Among the aspects tested, the top 4 were similar across countries: the desire to receive treatment with a level of aggressiveness that matches their individual prognosis, the need to receive adequate and timely information about their upcoming treatment, the need to tailor treatment decisions based on their individual surgery outcomes, and a desire to avoid overtreatment. Not being involved in treatment decisions was the least preferred of the aspects. Patients in Germany and Italy most valued the ability to tailor the aggressiveness of their treatment based on their individual risk of recurrence, whereas patients in Japan prioritized being knowledgeable and prepared for their treatment journey. The results from this study emphasize patients’ desire to be adequately informed about available treatment choices for early breast cancer, to avoid unnecessary treatments, and to be involved in treatment decisions. Keywords: breast cancer, patient perspective, patient priorities, shared decision-making, patient satisfaction

Background: Patients with cancer may progress through multiple treatments with differing adverse effect profiles. Moreover, pathways may be fixed or flexible in allowing for escalation or de-escalation of treatment depending on interim outcomes. We sought to develop a methodology capable of estimating preferences for the entirety of a pathway involving a sequence of different treatments., Methods: Patients with early breast cancer completed an online discrete choice experiment to assess preferences for eight key early breast cancer attributes. Hierarchical Bayesian modeling was used to calculate attribute-level preference weights. Preference weights for hypothetical pathways were estimated by summing the respective weights for efficacy, flexible or fixed pathway, duration, administration regimen, and adverse event risk, the last two of which were time-adjusted by multiplying each weight by the proportion of time spent on a selected treatment., Results: Increases in the risk of a serious adverse event were most influential in treatment pathway preferences, followed by increases in efficacy and decreases in overall pathway duration. Patients preferred a flexible pathway versus a fixed pathway. Pathway preference estimates fluctuated in a logically consistent manner. Switching from a flexible to a fixed pathway yielded a significantly lower pathway preference. For this same pathway, when adjuvant treatment was replaced with a treatment with a more favorable toxicity profile and shorter duration, it offset the negative impact of the more toxic neoadjuvant chemotherapy., Conclusions: This novel methodology accounts for patient preference throughout a sequence of treatments, allowing for comparison of preferences across complex treatment pathways., (© 2024. The Author(s).)

Astrocyte endfeet enwrap brain vasculature, forming a boundary for perivascular glymphatic flow of fluid and solutes along and across the astrocyte endfeet into the brain parenchyma. We evaluated astrocyte sensitivity to shear stress generated by such flow, finding a set point for downstream calcium signaling that is below about 0.1 dyn/cm 2 . This set point is modulated by albumin levels encountered in cerebrospinal fluid (CSF) under normal conditions and following a blood-brain barrier breach or immune response. The astrocyte mechanosome responsible for the detection of shear stress includes sphingosine-1-phosphate (S1P)-mediated sensitization of the mechanosensor Piezo1. Fluid flow through perivascular channels delimited by vessel wall and astrocyte endfeet thus generates sufficient shear stress to activate astrocytes, thereby potentially controlling vasomotion and parenchymal perfusion. Moreover, S1P receptor signaling establishes a set point for Piezo1 activation that is finely tuned to coincide with CSF albumin levels and to the low shear forces resulting from glymphatic flow., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Efforts to prevent human-to-human transmission of variant Creutzfeldt-Jakob disease (vCJD) by contaminated blood would be aided by the development of a sensitive diagnostic test that could be routinely used to screen blood donations. As blood samples from vCJD patients are extremely rare, here we describe the optimisation of real-time quaking-induced conversion (RT-QuIC) for detection of PrPSc (misfolded prion protein, a marker of prion infection) in blood samples from an established large animal model of vCJD, sheep experimentally infected with bovine spongiform encephalopathy (BSE). Comparative endpoint titration experiments with RT-QuIC, miniaturized bead protein misfolding cyclic amplification (mb-PMCA) and intracerebral inoculation of a transgenic mouse line expressing sheep PrP (tgOvARQ), demonstrated highly sensitive detection of PrPSc by RT-QuIC in a reference sheep brain homogenate. Upon addition of a capture step with iron oxide beads, the RT-QuIC assay was able to detect PrPSc in whole blood samples from BSE-infected sheep up to two years before disease onset. Both RT-QuIC and mb-PMCA also demonstrated sensitive detection of PrPSc in a reference vCJD-infected human brain homogenate, suggesting that either assay may be suitable for application to human blood samples. Our results support the further development and evaluation of RT-QuIC as a diagnostic or screening test for vCJD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Thomas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose of Review: The Kidney Research Scientist Core Education and National Training (KRESCENT) is a national Canadian training program for kidney scientists, funded by the Kidney Foundation of Canada (KFOC), the Canadian Institutes of Health Research (CIHR), and the Canadian Society of Nephrology (CSN). We describe our first year of incorporating patient partners into a scientific peer-review committee, the 2017 committee to select senior research trainees and early-career kidney researchers for funding and training, in the hope that it will be helpful to others who wish to integrate the perspective of people with lived experience into the peer-review process., Sources of Information: Other peer-review committees, websites, journal articles, patient partners, Kidney Foundation of Canada Research Council, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Patient Council, participants in the 2017 Kidney Foundation of Canada KRESCENT peer-review panel., Methods: We describe our motivation, rationale, guiding principles, plans, feedback, implementation, and response., Key Findings: We disseminated a "call for patient partners" 8 weeks before the meeting, seeking patients or their care givers to partner with the KRESCENT peer-review panel; we defined these people with lived experience of kidney disease as patient partners. Eight patient partners came forward and all participated as reviewers. Patient partners first participated in a webinar to learn about the function, structure, and processes of a peer-review committee. They practiced reviewing plain language summaries and giving feedback. In a subsequent teleconference, they shared and discussed their reviews. Plain language summaries were scored, overall, on the same 0-5 quality scale used by scientific reviewers. Three patient reviewers participated in some or all of the 6-hour meeting, which was conducted as usual, for this panel, by teleconference (initially audio only; from 2020 onwards by videoconference). In the meeting, the 2 assigned scientific reviewers first gave their scores, followed by the patient reviewers giving their scores, and discussion (mostly scientific, and conducted in usual scientific language). Scientific reviewers then negotiated a consensus score based on their initial scores, the discussion, patient reviewers' scores and statements, and the scientific officer's notes. Patient reviewers, scientific reviewers, and the Kidney Foundation of Canada (KFOC) were generally positive about the process. The increased length of the meeting (estimated at 1 hour) was generally thought to be acceptable. Patient reviewers also provided feedback on the methods used to incorporate patients into the research under review. These comments were concrete, insightful, and helpful. The patients did not uniformly recommend that basic scientists involve patients in their work. We did not detect bias against preclinical science, work that did not involve patients, or rarer diseases. Some patients found participation inspiring and enlightening. All participants appreciated the idea of patient partners as community witnesses to a group process committed to fairness and supportiveness. We discussed assigning formal meaningful weight to patient reviewers' assessments. Most, but not all, patients thought that the scientific reviewers were ultimately the best judges of the allocation of scarce research resources., Limitations: Patient participants tended to be Caucasian, middle class, and well educated. Because of the difficulties of travel for some people living with or supporting those living with kidney disease, our findings may not generalize fully to peer-review meetings that are conducted face to face. This is explicitly a supportive panel, committed to reviewing junior scientists with kindness as well as rigor; our findings may not generalize to panels conducted differently. We did not use formal qualitative methodology., Implications: Inclusion of patient partners as patient reviewers for the KRESCENT program peer-review panel was feasible, added value for scientific and patient reviewers, and for the funding stakeholders (CIHR, KFOC, and CSN). We were glad that we had taken this step and continue to refine the process with each successive competition., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.A.F., K.B., A.C., S.A.D., S.H., G.H., V.J., N.J., S.K., S.L., A.L., A.M., S.M., P.R., S.S., T.T., N.T., and N.V. have no conflict of interests. M.T.J. is the principal investigator of an investigator-initiated research grant from Amgen Canada. J.S. has received research funding from AMGEN Canada Incorporated as matching funds for the CanSOLVE CKD SPOR Research Program. R.T.A. has received consultation fees from Ardylex Inc and Advicienne Inc. C.M.C. has received consultation, advisory board membership, or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer Ingelheim, and Baxter. In 2018, she co-chaired a KDIGO potassium controversies conference sponsored at arm’s length by Fresenius Medical Care, AstraZenec, Vifor Fresenius Medical Care, Relypsa, Bayer HealthCare, and Boehringer Ingelheim., (© The Author(s) 2022.)

Infectious prion diseases have very long incubation periods, and the role that subclinical infections play in transmission, persistence and re-emergence of these diseases is unclear. In this study, we used a well-established model of vCJD (sheep experimentally infected with bovine spongiform encephalopathy, BSE) to determine the prevalence of subclinical infection following exposure by blood transfusion from infected donors. Many recipient sheep survived for years post-transfusion with no clinical signs and no disease-associated PrP (PrP Sc ) found in post mortem tissue samples by conventional tests. Using a sensitive protein misfolding cyclic amplification assay (PMCA), we found that the majority of these sheep had detectable PrP Sc in lymph node samples, at levels approximately 10 5 -10 6 times lower than in equivalent samples from clinically positive sheep. Further testing revealed the presence of PrP Sc in other tissues, including brain, but not in blood samples. The results demonstrate that subclinical infection is a frequent outcome of low dose prion infection by a clinically relevant route for humans (blood transfusion). The long term persistence of low levels of infection has important implications for prion disease control and the risks of re-emergent infections in both humans and animals., (© 2022. The Author(s).)

Glioblastoma multiforme (GBM), classified as World Health Organization grade IV astrocytoma, is the deadliest adult cancer of the central nervous system. An important contributing factor to poor survival rates in GBM is extensive invasion, which decreases the efficacy of resection and subsequent adjuvant therapies. These treatments could be markedly improved with increased resolution of the genetic and molecular initiators and effectors of invasion. Connexin 43 (Cx43) is the principal astrocytic gap junction (GJ) protein. Despite the heterogeneity of GBM, a subpopulation of cells in almost all GBM tumors express Cx43. Functional GJs between GBM cells and astrocytes at the tumor edge are of critical interest for understanding invasion. In this study, we find that both in vitro and in ex vivo slice cultures, GBM is substantially less invasive when placed in a Cx43-deficient astrocyte environment. Furthermore, when Cx43 is deleted in GBM, the invasive phenotype is recovered. These data strongly suggest that there are opposing roles for Cx43 in GBM migration. We find that Cx43 is localized to the tumor edge in our ex vivo model, suggesting that GBM-astrocyte GJ communication at the tumor border is a driving force for invasion. Finally, we find that by a Cx43-dependent mechanism, but likely not direct channel-mediated diffusion, miRNAs associated with cell-matrix adhesion are transferred from GBM to astrocytes and miR-19b promotes invasion, revealing a role for post-transcriptional manipulation of astrocytes in fostering an invasion-permissive peritumoral niche. IMPLICATIONS: Cx43-mediated communication, specifically miRNA transfer, profoundly impacts glioblastoma invasion and may enable further therapeutic insight., (©2021 American Association for Cancer Research.)