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The IQ Consortium Uniformity Testing Working Group reviewed the current BU and CU testing practices among ten member companies. All ten companies presented their current approach to BU and CU testing at the three stages of Product Lifecycle Management: the Process Design Stage, the Process Qualification Stage, and the Continuous Verification Stage. With this information on hand, the Uniformity Testing Working Group members developed a risk-based approach to BU and CU testing, and proposed innovative methods to reduce or eliminate blend sampling based on risk to Uniformity of Dosage Unit (UDU) testing. This approach uses prior knowledge, mechanistic understanding, and structured risk assessment tools to classify formulations as low-risk or high-risk, thus guiding the testing strategy. A decision tree was outlined on this basis for low-risk and high-risk formulations. The Working Group aims to influence health authorities on the matter, enabling streamlined testing expectations., Competing Interests: Declarations. Conflict of Interest: The authors declare having no personal or financial conflicts of interest pertaining to the topics discussed herein., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Syngenta responded to significant agricultural losses caused by plant-parasitic nematodes by initiating a next-generation nematicide discovery program. This effort led to the development of TYMIRIUM® technology, a nematicide and fungicide solution containing Cyclobutrifluram as its active ingredient. In 2022, this innovative solution received its first registration. Cyclobutrifluram, a chiral phenyl-cyclobutyl-pyridineamide, demonstrates wide-ranging effectiveness against all economically important plant parasitic nematodes and several soil-borne diseases, particularly those caused by Fusarium species. The discovery of this molecule involved hit the identification, lead exploration, and optimization stages, which made use of various methods such as phenotypic nematicide screening platforms, targeted screening libraries, rapid target identification through biochemical and genetic approaches, in vitro assays for structure-activity relationship (SAR) analysis, and homology models for structure-based design. This multi-disciplinary approach led to the successful identification of Cyclobutrifluram as the key component in TYMIRIUM® technology. © 2025 Society of Chemical Industry., (© 2025 Society of Chemical Industry.)

Background: Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced in abnormal amounts by mutants of the γ-secretase subunit presenilin-1 (PS1), which represent the primary cause of familial AD (FAD). Lowering these peptides by γ-secretase modulators (GSMs) is increasingly considered a safe strategy to treat AD since these compounds do not affect the overall cleavage of γ-secretase substrates. GSMs were shown to modulate not only wild-type (WT) γ-secretase but also FAD mutants, expanding their potential use also to the familial form of the disease. Unlike most other FAD mutants, the very aggressive PS1 L166P mutant is largely resistant to GSMs. However, these data were mostly obtained from overexpression models, which mimic more the less relevant homozygous state rather than the heterozygous patient situation., Methods: Mouse embryonic fibroblast and induced pluripotent stem cell-derived neuronal PS1 L166P knock-in (KI) cell models were treated with various GSMs and Aβ responses were assessed by immunoassays and/or gel-based analysis., Results: We identified GSMs that lower Aβ42 and/or Aβ43 when PS1 L166P is heterozygous, as it is the case in affected patients, and could reduce the amount of pathogenic Aβ species towards WT levels. RO7019009 was the most potent of these compounds, reducing both pathogenic species and concomitantly increasing the short Aβ37 and Aβ38, of which the latter has been associated with delayed AD progression. Another effective compound, the structurally novel indole-type GSM RO5254601 specifically acts on the Aβ42 product line leading to a selective increase of the beneficial Aβ38. Interestingly, we further found that this class of GSMs can bind not only one, but both presenilin fragments suggesting that it targets γ-secretase at an unusual binding site., Conclusion: Our data show that even highly refractory presenilin FAD mutants are in principle tractable with GSMs extending the possibilities for potential clinical studies in FAD with suitable GSM molecules., Competing Interests: Declarations. Ethics approval and consent to participate: All experiments were performed in accordance with all relevant guidelines and regulations. Female iPSC line A18944 was purchased from ThermoFisher (A18945). No human subjects were involved in this study; confirmation of consent was not necessary. Consent for publication: Not applicable. Competing interests: H.S. has received research funding from Roche. D.P. is a scientific advisor of ISAR Bioscience. R.M.R.S., K.B., and L.L. are full-time employees of F. Hoffmann-La Roche AG, are inventors of patents in the name of F. Hoffmann-La Roche AG, and might own stocks / stock options of F. Hoffmann-La Roche AG. All other authors declare that they have no conflict of interest., (© 2025. The Author(s).)

Stargardt disease type 1 (STGD1) is a genetic disorder that leads to progressive vision loss, with no approved treatments currently available. The development of effective therapies faces the challenge of identifying appropriate outcome measures that accurately reflect treatment benefits. Optical Coherence Tomography (OCT) provides high-resolution retinal images, serving as a valuable tool for deriving potential outcome measures, such as retinal thickness. However, automated segmentation of OCT images, particularly in regions disrupted by degeneration, remains complex. In this study, we propose a deep learning-based approach that incorporates a pathology-aware loss function to segment retinal sublayers in OCT images from patients with STGD1. This method targets relatively unaffected regions for sublayer segmentation, ensuring accurate boundary delineation in areas with minimal disruption. In severely affected regions, identified by a box detection model, the total retina is segmented as a single layer to avoid errors. Our model significantly outperforms standard models, achieving an average Dice coefficient of [Formula: see text] for total retina and [Formula: see text] for retinal sublayers. The most substantial improvement was in the segmentation of the photoreceptor inner segment, with Dice coefficient increasing by [Formula: see text]. This approach provides a balance between granularity and reliability, making it suitable for clinical application in tracking disease progression and evaluating therapeutic efficacy., Competing Interests: Declarations. Competing interests: The authors declare the following competing interests: Dr. Scholl is chief medical officer of Belite Bio and director of Bioptima AG. He is member of the Scientific Advisory Board of: Boehringer Ingelheim Pharma GmbH & Co, Janssen Research & Development, LLC (J&J Innovative Medicine), Kerna Ventures, Okuvision GmbH, and Tenpoint Therapeutics. Dr. Scholl is member of the Investment Advisory Board of Droia NV. Dr. Scholl is a member of the Data Monitoring and Safety Board/Committee of ViGeneron (NCT06291935) and adviser of the Steering Committee of Novo Nordisk (FOCUS trial; NCT03811561). The other authors declare no competing interests., (© 2025. The Author(s).)

Purpose: Faricimab, the first bispecific antibody designed for intraocular use, is approved for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Here, we report the usability of a novel faricimab 6 mg pre-filled syringe (PFS) configuration that has been designed specifically for intravitreal use., Patients and Methods: A simulated-use human factors validation study enrolling 15 retina specialists and 15 ophthalmic assistants was conducted in a market research facility configured to represent an ophthalmology clinic. Participants' ability to complete tasks related to package handling, dose preparation, and injection of a faricimab 6 mg dose into a polymer eye using the PFS was assessed. In a second Phase 3b, single-arm, actual-use study, the ability of seven retina specialists and six ophthalmic assistants to prepare and administer the PFS in accordance with the instructions for use was assessed. Injections were performed into single eyes of 35 patients with nAMD or DME in three US clinics and patients were followed for 7 days for safety reporting (ClinicalTrials.gov identifier: NCT05569148)., Results: In the simulated-use study, most retina specialists and ophthalmic assistants completed all tasks deemed essential for PFS preparation and administration correctly and without error. Of the 22 tasks, the pass rate was 86.7-100%; 16 tasks had a pass rate of 100%. No use errors were observed during the actual-use study. One patient experienced one mild adverse event of eye irritation that resolved the same day and was deemed unrelated to the study drug., Conclusion: Participants were able to safely and correctly prepare and administer a faricimab 6 mg dose using the PFS in accordance with the instructions for use, under realistic conditions representing the real world. The faricimab 6 mg PFS may therefore offer a more convenient, safe-handling alternative to vial administration., Competing Interests: MRB has received personal fees from AbbVie Inc., Alcon, Allegro, Allergan, Alimera, Apellis, Arctic Vision, Astellas, Bausch & Lomb, Biocryst, Biogen, Boehringer Ingelheim, Coherus BioSciences, CalciMedica, Celltrion, Cencora, EyeBio, Harrow, Janssen, Kanghong/Vanotech, Neurotech, Ocular Therapeutix, Outlook Therapeutics, Oxurion, Perfuse, RegenxBio, RevOpsis Therapeutics, Stealth Biotherapeutics, Palatin Technologies, Regeneron, Roche; grants and personal fees from Adverum Biotechnologies, Clearside Biomedical, EyePoint Pharmaceuticals, Graybug, Genentech, Kodiak Sciences, Opthea, Novartis, and RegenxBio; other from NeuBase and RevOpsis Therapeutics; grants and other from Oxurion; and grants from Annexon Biosciences, Gemini Therapeutics, Gyroscope Therapeutics, Oculis, Oxular, ReNeuron, Ribomic, Stealth Biotherapeutics, and Unity Biotechnology. HMKJr has received consulting/speaking fees from Dutch Ophthalmic Research Centre International and Ocular Therapeutix; and research grants/support from Acelyrin, Adverum, Alexion, Alimera, Alkeus, Amydis, Apellis, Aviceda, Boehringer Ingelheim Pharmaceuticals, Clearside, Eyepoint, F. Hoffmann-La Roche AG, Gemini, Genentech, Inc., Henlius, Ionis, Janssen, Nanoscope, Ocugen, Ocular Therapeutix, Ocuterra, Opthea, Rezolute, Smilebiotek Zhuhai, Stealth BioTherapeutics, and Xolaris. GM is an employee of F. Hoffmann-La Roche AG and reports patents (015065385, 29/950674 and 29/950679) pending to F. Hoffmann-La Roche AG. LPP and YT are employees of Genentech, Inc. PS and OEO are employees of F. Hoffmann-La Roche AG and hold stock/stock options. PS reports a patent (P39400-US) pending to F. Hoffmann-La Roche AG. JMG has received personal fees from Alimera, Apellis, Hi-Health, IvericBio, Ocular Therapeutix, Regeneron, RegenxBio, and Roche; grants and research support from Kyowa Kirin, Ocular Therapeutix, Regeneron, RegenxBio, and Roche. The authors report no other conflicts of interest in this work., (© 2025 Barakat et al.)

In this study, we employed a novel fluorescent probe, RO7304924-which selectively targets cannabinoid 2 receptor (CB2R)-to assess the lateral mobility of CB2R within the plasma membrane of Chinese hamster ovary cells stably expressing a functional, untagged receptor variant. Utilizing confocal fluorescence recovery after photobleaching (FRAP), we quantified the diffusion coefficient and mobile fraction of CB2R, thereby demonstrating the efficacy of RO7304924 as an innovative tool for elucidating the dynamics of this major endocannabinoid-binding G protein-coupled receptor. Our present findings highlight the potential of combining advanced ligand-based fluorescent probes with FRAP for future investigations into the biochemical details of CB2R mobility in living cells, and its impact on receptor-dependent cellular processes., (© 2025 Wiley‐VCH GmbH.)

Objectives: Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management., Methods: The Society for Immunotherapy of Cancer convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the quantitative image analysis of mIHC/IF output and data management considerations., Results: Best-practice approaches for image acquisition, color deconvolution and spectral unmixing, tissue and cell segmentation, phenotyping, and algorithm verification are reviewed. Additional quality control (QC) measures such as batch-to-batch correction and QC for assembled images are also discussed. Recommendations for sharing raw outputs, processed results, key analysis programs and source code, and representative photomicrographs from mIHC/IF assays are included. Lastly, multi-institutional harmonization efforts are described., Conclusions: mIHC/IF technologies are maturing and are routinely included in research studies and moving towards clinical use. Guidelines for how to perform and standardize image analysis on mIHC/IF-stained slides will likely contribute to more comparable results across laboratories and pave the way for clinical implementation. A checklist encompassing these two-part guidelines for the generation of robust data from quantitative mIHC/IF assays will be provided in a third publication from this task force. While the current effort is mainly focused on best practices for characterizing the tumor microenvironment, these principles are broadly applicable to any mIHC/IF assay and associated image analysis., Competing Interests: Competing interests: JT—Contracted research: Bristol Myers Squibb, Akoya Biosciences; Consulting fees: Bristol Myers Squibb, Roche/Genentech, Merck, AstraZeneca, Regeneron, Lunaphore, Akoya Biosciences, Compugen; Stock holdings: Akoya Biosciences; JCS—Contracted research: Palleon Pharmaceuticals; MA—Consulting fees: Ionpath; Royalties: Ionpath; GA—Salary and employment: Merck; LLE—Royalties: Akoya Biosciences; CSF—Salary and employment: Roche; Stock ownership: Roche; BG—Consulting fees: Rome Therapeutics, PMV Pharma, Merck; Contracted research: Bristol Myers Squibb; IP rights: Rome Therapeutics; SGn—Contracted research: Regeneron, Boehringer Ingelheim, Janssen R&D, Genentech, Takeda, Bristol Myers Squibb, Celgene; Patents: Named coinventor on an issued patent for multiplex immunohistochemistry to characterize tumors and treatment responses, filed through Icahn School of Medicine at Mount Sinai (ISMMS) and currently unlicensed; CVH—Consulting fees: PathAI; TJH—Salary and employment (current): Bristol Myers Squibb; KK—Salary and employment: F. Hoffman-La Roche AG; AL—Salary and employment: Bristol Myers Squibb; Stock holdings; Bristol Myers Squibb; ERP—Consulting fees: Nucleai, iTeos Belgium SA; MCR—Salary and employment: AstraZeneca; DLR—Consulting fees: AstraZeneca, Cell Signaling Technology, Cepheid, Danaher, Daiichi Sankyo, NextCure, Paige.AI, Regeneron, Sanofi; Royalties: RareCyte; SJR—Consulting fees: Immunitas Therapeutics; Contracted research: Bristol Myers Squibb, Kite/Gilead; JR-C—Salary and employment: Daiichi Sankyo; KAS—Consulting fees: Shattuck Labs, EMD Serono, Clinica Alemana de Santiago, Genmab, Takeda, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Agenus, Repertoire; Fees for non-CE services: Bristol Myers Squibb, Fluidigm Corporation, Genmab, Merck, Takeda; Contracted research: Navigate BioPharma, Tesaro/GSK, Moderna, Pierre Fabre, Takeda, Surface Oncology, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Akoya Biosciences, Boehringer Ingelheim, Eli Lilly; ES—Salary and employment: AstraZeneca; KES—Salary, employment, and ownership: SR Pathology LLC; MJS—Salary and employment: AstraZeneca; Stock holdings: AstraZeneca; IIW—Consulting fees: Genentech/Roche, Bayer, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, Guardant Health, Flame, Novartis, Sanofi, Daiichi Sankyo, Amgen, Jansen, Merus, AbbVie, Catalyst Therapeutics, Regeneron, Oncocyte; Contracted research; Genentech, Merck, Bristol Myers Squibb, MedImmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, Akoya; JHY—Salary and employment: Merck; CBB—Ownership: PrimeVax; Consulting fees: Sanofi, Agilent, Roche, Incendia, PrimeVax, BioAI, Lunaphore; Contracted research: Illumina; ME, SGr, NFG, DJ-S, JSR, MTT, ASS—Nothing to disclose; SITC Staff: BL, HS—Nothing to disclose., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An interactive tool has been developed to help design oral solid dosage form formulations. The tool enables quantitative explorations and comparisons of physical, bulk, and mechanical properties, and takes into account functional characteristics as well. In this manner, comparisons and clustering of both excipients and APIs can be carried out. These comparisons enable the generation of alternatives as well as surrogate identification, so as to spare resources and material. Multiple data sources were merged to create a "joint" data table with all relevant properties. Four main workflow activities are supported: Explore Materials, Search Similar APIs, Search Similar Excipients and Search Material Clusters. Multi-dimensional filtering can be superimposed to each functionality. Suggested visualizations are made particularly accessible by providing them as "standard plots". The underlying philosophy is to empower formulation scientists to explore options, rather than prescribe decisions on exclusively mathematical grounds. The tool described here is the first step towards a holistic optimization incorporating predictions of mixture properties. Methodology of use is illustrated through three material selection application examples., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Some or all co-authors may own F. Hoffmann-La Roche stock. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Caregivers can play an important role in supporting and caring for people with progressive, life-threatening, or debilitating conditions. However, this supportive role can expose caregivers to various detrimental financial, physical, and psychosocial issues. When evaluating medical technologies for reimbursement decisions, health technology assessment (HTA) agencies typically focus on the treatment's impact on patients and ignore or downplay the impact on caregivers. Including caregiver impacts within a wider societal perspective may better enable health systems to maximize health benefits from available resources. However, the lack of clear guidance or methodological recommendations from decision makers on the inclusion of caregiver impacts limits the number of HTA submissions that consider these effects. We outline a conceptual framework based on intensity and duration of caregiving to guide researchers, industry, and decision makers when developing policies for the inclusion of caregiver outcomes and justify their inclusion based on expected caregiver burden in identified circumstances.

Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&D., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This publication was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Many countries around the world use health technology assessment (HTA) to inform reimbursement and pricing decisions. HTA is often split into two steps, called assessment and appraisal. While the term HTA itself has been defined by international consortia, there is heterogeneity in the way different stakeholders use the terms assessment and appraisal. This creates ambiguity regarding which activities are included in technology assessment. With the new EU HTA Regulation, the HTA community should urgently seek to clarify the distinction between assessment and appraisal, as the regulation aims to centralize the clinical part of technology assessment at the European level. Failure to clarify this terminology will put the ambition of the regulation such as increased efficiency and reduction in duplication at risk. In this article, we argue that the distinction between assessment and appraisal should be seen as a science/value dichotomy. We discuss the transition from centralized assessment activities to country-level appraisal, which should culminate in a categorization of the overall added benefit in a local context. Finally, we touch on the important dimension of uncertainty always present in medical decision making., Competing Interests: Conflicts of InterestSandro Gsteiger is an employee of F. Hoffmann-La Roche AG and holds shares of F. Hoffmann-La Roche AG, Novartis AG, and Sandoz Group AG. James Ryan is an employee of Astra Zeneca. Jörg Ruof holds shares of Hoffmann-La Roche AG., (© 2024 by the authors.)

Background: T cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy., Methods: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types., Results: The screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells., Conclusions: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer., Competing Interests: Competing interests: ARom and OG reports personal fees from Hoffmann-La Roche during the conduct of the study and personal fees from Hoffmann-La Roche outside the submitted work. AZ received consulting/advisor fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics, Engimmune, and maintains further non-commercial research agreements with Hoffmann–La Roche, T3 Pharma, Bright Peak Therapeutics, AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Acquiring and exploiting memories of rewarding experiences is critical for survival. The spatial environment in which a rewarding stimulus is encountered regulates memory retrieval. The ventral hippocampus (vH) has been implicated in contextual memories involving rewarding stimuli such as food, social cues or drugs. Yet, the neuronal representations and circuits underlying contextual memories of socially rewarding stimuli are poorly understood. Here, using in vivo electrophysiological recordings, in vivo one-photon calcium imaging, and optogenetics during a social reward contextual conditioning paradigm in male mice, we show that vH neurons discriminate between contexts with neutral or acquired social reward value. The formation of context-discriminating vH neurons following learning was contingent upon the presence of unconditioned stimuli. Moreover, vH neurons showed distinct contextual representations during the retrieval of social reward compared to fear contextual memories. Finally, optogenetic inhibition of locus coeruleus (LC) projections in the vH selectively disrupted social reward contextual memory by impairing vH contextual representations. Collectively, our findings reveal that the vH integrates contextual and social reward information, with memory encoding of these representations supported by input from the LC., (© 2024. The Author(s).)

Increased adoption of personalized medicine has brought comprehensive genomic profiling (CGP) to the forefront. However, differences in assay, bioinformatics, and reporting systems and lack of understanding of their complex interplay are a challenge for implementation and achieving uniformity in CGP testing. Two commercially available, tissue-based, in-house CGP assays were compared, in combination with a tertiary analysis solution in a research use only (RUO) context: the AVENIO Tumor Tissue CGP RUO Kit paired with navify Mutation Profiler (RUO) software and the TruSight Oncology 500 RUO assay paired with PierianDx Clinical Genomics Workspace software. Agreements and differences between the assays were assessed for short variants, copy number alterations, rearrangements, tumor mutational burden, and microsatellite instability, including variant categorization and clinical trial-matching (CTM) recommendations. Results showed good overall agreement for short variant, known gene fusion, and microsatellite instability detection. Important differences were obtained in tumor mutational burden scoring, copy number alteration detection, and CTM. Differences in variant and biomarker detection could be explained by bioinformatic approaches to variant calling, filtering, tiering, and normalization; differences in CTM, by underlying reported variants and conceptual differences in system parameters. Thus, distinctions between different approaches may lead to inconsistent results. Complexities in calling, filtering, and interpreting variants illustrate key considerations for implementation of any high-quality CGP in the laboratory and bringing uniformity to genomic insight results., Competing Interests: Disclosure Statement H.-P.A., F.F., and U.S. are employees of Signature Diagnostics GmbH (H.-P.A. at the time of the analysis, but now retired). M.C.H., J.O., and J.M.A. are employees of Foundation Medicine, Inc. (J.O. at the time of the analysis, but is no longer an employee), and M.C., S.O., and T.W. are employees of Foundation Medicine GmbH; all hold stock in F. Hoffmann-La Roche Ltd. K.H. is an employee of Helios MVZ Pathologie Erfurt GmbH. M.T. is an employee of F. Hoffmann-La Roche AG and holds stock in F. Hoffmann-La Roche Ltd. D.G. holds stock in Univ8 Genomics Ltd.; has received honoraria (institution) from Roche, Illumina, Novartis, AstraZeneca, Eli Lilly, Amgen, and Janssen; has participated in a consulting or advisory role (institution) for AstraZeneca and Novartis; has participated in a speakers' bureau (institution) for AstraZeneca; and has received travel, accommodations, and expenses (institution) from Roche, AstraZeneca, and Illumina. E.P. received compensation for speaking engagements and advisory roles, with payments made directly to his affiliated university, from Roche, AstraZeneca, Novartis, and MSD. H.S. and M.D.V. are employees of Roche Diagnostics Solutions, Inc., and M.D.V. holds stock in F. Hoffmann-La Roche Ltd. E.S. reports lectures for Bio-Rad, Seracare, Novartis, Roche, Biocartis, Illumina, Eli Lilly, Janssen-Cilag, Pfizer, AstraZeneca, and Agena Bioscience; he is consultant in advisory boards for MSD/Merck, GSK, AstraZeneca, Astellas Pharma, Sysmex, Roche, Pfizer, Novartis, Bayer, Bristol Myers Squibb, Eli Lilly, Amgen, Biocartis, Illumina, Agena Bioscience, Janssen-Cilag (Johnson & Johnson), Sinnovisionlab, Diaceutics, and CC Diagnostics; and received research grants from Pfizer, Biocartis, Invitae-ArcherDX, AstraZeneca, Agena Bio-science, Bristol Myers Squibb, Bio-Rad, Roche, Boehringer Ingelheim, CC Diagnostics, and Abbott (all paid to University Medical Center Groningen account); and travel reimbursements from Bio-Rad, Abbott, Illumina, Agena Bioscience, and Roche. All authors received support in the form of third-party writing assistance for this manuscript, furnished by Nucleus Global, an Inizio company, and provided by F. Hoffmann-La Roche Ltd./Roche Diagnostics Solutions, Inc., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The "Paediatric Excipient Risk Assessment (PERA)" framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products. This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool's usefulness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The pharmaceutical industry is increasingly embracing laboratory automation to enhance experimental efficiency and operational resilience, particularly through the integration of automated liquid handlers (ALHs). This paper explores the integration of the low-cost Opentrons OT-2 liquid handling robot with F. Hoffmann-La Roche AG's in-house workflow orchestration software, AutoLab, to overcome barriers to lab automation. By leveraging the OT-2's development-oriented interfaces and AutoLab's modular architecture, we achieved a user-friendly, cost-efficient, and flexible automation solution that aligns with FAIR (findable, accessible, interoperable, reusable) data principles. We demonstrate an advanced workflow development methodology, utilizing the software architecture, that facilitates the creation of two flexible pipetting protocols and medium complexity assays. This deep integration approach diminishes the learning curve for novice users while simultaneously enhancing the overall efficiency and reliability of the experimental workflow. Our findings suggest that such integrations can significantly mitigate the challenges associated with lab automation, including cost, complexity, and adaptability, paving the way for more accessible and robust automated systems in pharmaceutical research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees or contractors at F. Hoffmann-La Roche AG If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Excipients are often the major component of the formulation that critically affect the dosage form, manufacturing process, product performance, stability and safety. They exert different roles and functions in a dosage form. Selecting excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. The suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, and clinical risk-benefit of the disease, active and excipient. Scientists are encouraged to apply the principle of risk-benefit to assess the suitability of excipients to the specific paediatric population. Indicative list of parameters that should be taken into consideration and hierarchy of information sources when assessing the excipients risks is provided by regulatory agencies. However, the approach to be taken and details of how the risk evaluation should be undertaken are lacking. There is a need for a systematic approach to selection of excipients and assessment of the risk of excipient exposure. The Paediatric Excipients Risk Assessment (PERA) framework developed and proposed in this paper provides a structured, systematic decision-making framework via customizable tools and processes that can help to improve the transparency and communications on the selection and justification of use of excipients in a paediatric formulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In a unique collaboration between Simulations Plus and several industrial partners, we were able to develop a new version 11.0 of the previously published in silico pK a model, S+pKa, with considerably improved prediction accuracy. The model's training set was vastly expanded by large amounts of experimental data obtained from F. Hoffmann-La Roche AG, Genentech Inc., and the Crop Science division of Bayer AG. The previous v7.0 of S+pKa was trained on data from public sources and the Pharmaceutical division of Bayer AG. The model has shown dramatic improvements in predictive accuracy when externally validated on three new contributor compound sets. Less expected was v11.0's improvement in prediction on new compounds developed at Bayer Pharma after v7.0 was released (2013-2023), even without contributing additional data to v11.0. We illustrate chemical space coverage by chemistries encountered in the five domains, public and industrial, outline model construction, and discuss factors contributing to model's success., (© 2024 The Author(s). Molecular Informatics published by Wiley-VCH GmbH.)

Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by central nervous system demyelination and axonal degeneration. Fatigue affects a major portion of MS patients, significantly impairing their daily activities and quality of life. Despite its prevalence, the mechanisms underlying fatigue in MS are poorly understood, and measuring fatigue remains a challenging task. This study evaluates the efficacy of automated speech analysis in detecting fatigue in MS patients. MS patients underwent a detailed clinical assessment and performed a comprehensive speech protocol. Using features from three different free speech tasks and a proprietary cognition score, our support vector machine model achieved an AUC on the ROC of 0.74 in detecting fatigue. Using only free speech features evoked from a picture description task we obtained an AUC of 0.68. This indicates that specific free speech patterns can be useful in detecting fatigue. Moreover, cognitive fatigue was significantly associated with lower speech ratio in free speech ( ρ  = -0.283, p  = 0.001), suggesting that it may represent a specific marker of fatigue in MS patients. Together, our results show that automated speech analysis, of a single narrative free speech task, offers an objective, ecologically valid and low-burden method for fatigue assessment. Speech analysis tools offer promising potential applications in clinical practice for improving disease monitoring and management., Competing Interests: AD received personal compensation and travel grants from Biogen, Celgene/Bristol-Myers Squibb, Roche, Janssen-Cilag and Sanofi for speaker activity. TZ reports personal fees for lecturing and consulting from Biogen, BMS, F. Hoffmann-La Roche Ltd, Merck, Novartis, Sanofi, Teva and Almirall; and grants or research support from Biogen, F. Hoffmann-La Roche Ltd, Teva, Sanofi and Novartis. MD, FD, SS, NL, JT, LS and AK are employees of ki:elements GmbH. Nicklas Linz and JT are shareholders of ki:elements. BT, HH-K and JO are employees of F.Hoffmann LaRoche AG, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dias, Dörr, Garthof, Schäfer, Elmers, Schwed, Linz, Overell, Hayward-Koennecke, Tröger, König, Dillenseger, Tackenberg and Ziemssen.)

Introduction: This study sought to evaluate the cost-effectiveness of baloxavir marboxil compared with oseltamivir or no antiviral treatment from a US payer perspective using data from a real-world US administrative claims study. Given baloxavir's ability to rapidly stop viral shedding, the potential health economic implications of a baloxavir-induced population-level reduction in viral transmission was also explored., Methods: A decision tree cost-effectiveness model was developed for seasonal influenza (2018-2020) using a lifetime time horizon with 3.0% discounting for costs and quality-adjusted life-years (QALYs). Patients aged ≥ 12 years could receive baloxavir, oseltamivir or no antiviral treatment. Patient characteristics, complications, and costs were derived from the Merative™ MarketScan ® Research Databases including US commercial claims and Medicare and Medicaid Supplemental databases. A scenario analysis explored the impact of reduced viral transmission with baloxavir., Results: In the base case analysis, baloxavir was cost-effective within a willingness-to-pay threshold of US$100,000/QALY compared with oseltamivir [incremental cost-effectiveness ratio (ICER), $6813/QALY gained] or no antiviral treatment (ICER, $669/QALY gained). The net monetary benefit (NMB) of baloxavir was $1180 and $6208 compared with oseltamivir and no treatment, respectively. The NMB of baloxavir increased linearly with reductions in viral transmission, where a 5% transmission reduction yielded an NMB of $2592 versus oseltamivir and $7621 versus no treatment. Baloxavir became dominant (more effective and less costly, with ICERs < 0) starting with a 12.0% reduction in viral transmission versus oseltamivir and 6.0% versus no antiviral treatment., Conclusion: Baloxavir was cost-effective compared with oseltamivir or no antiviral treatment. The potential of baloxavir to reduce viral transmission offers a substantial economic benefit from a US payer perspective., (© 2024. The Author(s).)

Over the last decade, a new paradigm for cancer therapies has emerged which leverages the immune system to act against the tumor. The novel mechanism of action of these immunotherapies has also introduced new challenges to drug development. Biomarkers play a key role in several areas of early clinical development of immunotherapies including the demonstration of mechanism of action, dose finding and dose optimization, mitigation and prevention of adverse reactions, and patient enrichment and indication prioritization. We discuss statistical principles and methods for establishing the prognostic, predictive aspect of a (set of) biomarker and for linking the change in biomarkers to clinical efficacy in the context of early development studies. The methods discussed are meant to avoid bias and produce robust and reproducible conclusions. This review is targeted to drug developers and data scientists interested in the strategic usage and analysis of biomarkers in the context of immunotherapies., Competing Interests: All authors were employed by company F.Hoffmann-La Roche AG., (Copyright © 2024 Dejardin, Kraxner, Schindler, Städler and Wolbers.)

Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Subretinal fibrosis is associated with worse visual outcomes in patients with neovascular age-related macular degeneration. As there is a lack of optimal biomarkers and no method that directly detects collagen in the back of the eye, novel tools that monitor fibrosis-related changes in neovascular age-related macular degeneration are needed. Here, using two mouse models (the laser-induced choroidal neovascularization model, and the JR5558 mouse presenting with spontaneous subretinal neovascularization with fibrosis), we imaged active fibrotic lesions using fluorescently labeled collagen hybridizing peptides (CHPs), short peptides that bind to single α-chain collagen structures during collagen remodeling. JR5558 retinal pigment epithelium/choroid flat mounts showed CHP co-staining with fibrosis and epithelial mesenchymal transition-related markers; additionally, CHP histopathology staining correlated with in vivo CHP imaging. After laser-induced choroidal neovascularization, in vivo CHP binding correlated with laser intensity, histopathology CHP and fibronectin staining. Laser-induced choroidal neovascularization showed decreased CHP intensity over time in healing/regressing versus active scars in vivo, whereas increased CHP binding correlated with elevated fibrosis in JR5558 mouse eyes with age. In bispecific angiopoietin 2/vascular endothelial growth factor antibody-treated JR5558 mice, CHPs detected significantly decreased collagen remodeling versus immunoglobulin G control. These results demonstrate the first use of CHPs to directly image remodeling collagen in the eye and as a potential clinical optical biomarker of active subretinal fibrosis associated with ocular neovascularization., (© 2024. The Author(s).)

Nonadditivity (NA) in Structure-Activity and Structure-Property Relationship (SAR) data is a rare but very information rich phenomenon. It can indicate conformational flexibility, structural rearrangements, and errors in assay results and structural assignment. While purely ligand-based conformational causes of NA are rather well understood and mundane, other factors are less so and cause surprising NA that has a huge influence on SAR analysis and ML model performance. We here report a systematic analysis across a wide range of properties (20 on-target biological activities and 4 physicochemical ADME-related properties) to understand the frequency of various different phenomena that may lead to NA. A set of novel descriptors were developed to characterize double transformation cycles and identify trends in NA. Double transformation cycles were classified into "surprising" and "mundane" categories, with the majority being classed as mundane. We also examined commonalities among surprising cycles, finding LogP differences to have the most significant impact on NA. A distinct behavior of NA for on-target sets compared to ADME sets was observed. Finally, we show that machine learning models struggle with highly nonadditive data, indicating that a better understanding of NA is an important future research direction., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Prostate-specific antigen (PSA) levels are widely used to screen for prostate cancer, yet the test has poor sensitivity, specificity and predictive value, which leads to overdiagnosis and overtreatment. Alterations in the glycosylation status of PSA, including fucosylation, may offer scope for an improved biomarker. We sought to generate a monoclonal antibody (mAb) targeting α-1,6-fucosylated PSA (fuc-PSA) and to develop a tissue-based immunological assay for fuc-PSA detection. Immunogens representing fuc-PSA were used for immunisation and resultant mAbs were extensively characterised. The mAbs reacted specifically with fuc-PSA-specific glycopeptide, but not with aglycosylated PSA or glycan without the PSA peptide. Reactivity was confirmed using high-throughput surface plasmon resonance spectroscopy. X-ray crystallography investigations showed that the mAbs bound to an α-helical form of the peptide, whereas the native PSA epitope is linear. Protein unfolding was required for detection of fuc-PSA in patient samples. Peptide inhibition of fuc-PSA mAbs was observed with positive screening reagents, and target epitope specificity was observed in formalin-fixed, paraffin-embedded tissue samples. This research introduces a well-characterised, first-in-class antibody targeting fuc-PSA and presents the first crystal structure of an antibody demonstrating glycosylation-specific binding to a peptide., (© 2024. The Author(s).)

Accurate and timely reporting of adverse events (AEs) in clinical trials is crucial to ensuring data integrity and patient safety. However, AE under-reporting remains a challenge, often highlighted in Good Clinical Practice (GCP) audits and inspections. Traditional detection methods, such as on-site investigator audits via manual source data verification (SDV), have limitations. Addressing this, the open-source R package {simaerep} was developed to facilitate rapid, comprehensive, and near-real-time detection of AE under-reporting at each clinical trial site. This package leverages patient-level AE and visit data for its analyses. To validate its efficacy, three member companies from the Inter coMPany quALity Analytics (IMPALA) consortium independently assessed the package. Results showed that {simaerep} consistently and effectively identified AE under-reporting across all three companies, particularly when there were significant differences in AE rates between compliant and non-compliant sites. Furthermore, {simaerep}'s detection rates surpassed heuristic methods, and it identified 50% of all detectable sites as early as 25% into the designated study duration. The open-source package can be embedded into audits to enable fast, holistic, and repeatable quality oversight of clinical trials., (© 2024. The Author(s).)

Background: This work aimed to determine the role and action points for the involvement of medical societies in the European Health Technology Assessment (EU HTA) Methods: An online pre-convention survey was developed addressing four areas related to the EU HTA: (i) medical societies' role; (ii) role of clinical guidelines; (iii) interface with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS); and (iv) approaching 'best-available evidence' (BAE). A descriptive analysis of questionnaire outcomes was conducted to inform the European Access Academy (EAA) Fall Convention 2023. Within the working groups (WGs), action points were identified and prioritised., Results: A total of 57 experts from 15 countries responded to the survey. The WGs were attended by (i) 11, (ii) 10, (iii) 12, and (iv) 12 experts, respectively, representing a variety of national backgrounds and stakeholder profiles. The most relevant action points identified were as follows: (i) incorporation of clinical context into population, intervention, comparator, outcomes (PICO) schemes, (ii) timely provision of up-to-date therapeutic guidelines, (iii) ensuring the inclusion of MCBS insights into the EU HTA process, and (iv) considering randomized controlled trials (RCTs) as the gold standard and leveraging regulatory insights if development programs only include single-arm trials., Conclusions: The involvement of medical societies is a critical success factor for the EU HTA. The identified key action points foster the involvement of patient associations and medical societies., Competing Interests: Conflicts of InterestJR and EJ received an unrestricted grant from Abbvie, AstraZeneca, Bayer, Novartis, Roche, Sanofi, and Seagen that partially funded this research. The authors have no further financial or non-financial interests to disclose. BPV has received personal honoraria for advisory boards from Pfizer, Astellas Pharma, Bristol Myers Squibb, Ipsen, EUSA Pharma, MSD, EUSA Pharma, Novartis, AAA, Bayer, and Merck; has been an invited speaker for Astellas Pharma, Janssen, Roche, Pfizer, Bristol Myers Squibb, Roche, Bayer, EUSA Pharma, MSD, AstraZeneca, and Merck; and has received travel support from Merck/Pfizer and Bristol Myers Squibb., (© 2024 by the authors.)

In this paper, we report two Accelerated Stability Assessment Program (ASAP) studies for a pediatric drug product. Whereas the first study using a generic design failed to establish a predictive model, the second one was successful after troubleshooting the first study and customizing the study conditions. This work highlighted important lessons learned from designing an ASAP study for formulations containing excipients that could undergo phase change at high humidity levels. The stability predictions by the second ASAP model were consistent with available long-term stability data of the drug product under various storage conditions in two different packaging configurations. The ASAP model was part of the justifications accepted by the health authority to submit a stability package with reduced long-term stability data from the primary stability batches for a Supplemental New Drug Application (sNDA)., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The earliest phases of drug discovery require diverse scientific disciplines to work hand in hand to address many unknowns. Good decision making is crucial for success in this context and, yet, the topic of sound planning has rarely been addressed for the earliest stages of drug discovery. We propose a tailored, qualitative 'decision quality' process that can serve as a guide toward generating project plans optimized to address a given project situation. Furthermore, we propose a visual flow-chart format for the selected plan that includes key decisions and activities, together forming a decision roadmap of the plan. We illustrate each step of the process by means of a real-life example and provide recommendations for its implementation., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent.

The cell surface molecule CD40 is a member of the tumor necrosis factor receptor superfamily and is broadly expressed by immune cells including B cells, dendritic cells, and monocytes, as well as other normal cells and some malignant cells. CD40 is constitutively expressed on antigen-presenting cells, and ligation promotes functional maturation, leading to an increase in antigen presentation and cytokine production, and a subsequent increase in the activation of antigen-specific T cells. It is postulated that CD40 agonists can mediate both T cell-dependent and T cell-independent immune mechanisms of tumor regression in mice and patients. In addition, it is believed that CD40 activation also promotes apoptotic death of tumor cells and that the presence of the molecule on the surface of cancer cells is an important factor in the generation of tumor-specific T cell responses that contribute to tumor cell elimination. Notably, CD40 agonistic therapies were evaluated in patients with solid tumors and hematologic malignancies with reported success as a single agent. Preclinical studies have shown that subcutaneous administration of CD40 agonistic antibodies reduces systemic toxicity and elicits a stronger and localized pharmacodynamic response. Two independent studies in cynomolgus macaque (Macaca fascicularis) were performed to further evaluate potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response., Competing Interests: Conflict of interests: G.B., C.S., A.B.-B., and J.C. are employees and stockholders at Roche., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Genetic data are widely considered inherently identifiable. However, genetic data sets come in many shapes and sizes, and the feasibility of privacy attacks depends on their specific content. Assessing the reidentification risk of genetic data is complex, yet there is a lack of guidelines or recommendations that support data processors in performing such an evaluation., Objective: This study aims to gain a comprehensive understanding of the privacy vulnerabilities of genetic data and create a summary that can guide data processors in assessing the privacy risk of genetic data sets., Methods: We conducted a 2-step search, in which we first identified 21 reviews published between 2017 and 2023 on the topic of genomic privacy and then analyzed all references cited in the reviews (n=1645) to identify 42 unique original research studies that demonstrate a privacy attack on genetic data. We then evaluated the type and components of genetic data exploited for these attacks as well as the effort and resources needed for their implementation and their probability of success., Results: From our literature review, we derived 9 nonmutually exclusive features of genetic data that are both inherent to any genetic data set and informative about privacy risk: biological modality, experimental assay, data format or level of processing, germline versus somatic variation content, content of single nucleotide polymorphisms, short tandem repeats, aggregated sample measures, structural variants, and rare single nucleotide variants., Conclusions: On the basis of our literature review, the evaluation of these 9 features covers the great majority of privacy-critical aspects of genetic data and thus provides a foundation and guidance for assessing genetic data risk., (©Mara Thomas, Nuria Mackes, Asad Preuss-Dodhy, Thomas Wieland, Markus Bundschus. Originally published in JMIR Bioinformatics and Biotechnology (https://bioinform.jmir.org), 27.05.2024.)

Lay Abstract: Autistic individuals are more likely than non-autistic individuals to experience a mental health condition in their lifetime, and this includes externalising and internalising symptoms. We know very little about how different environments and family conditions impact these symptoms for autistic individuals. Improving our understanding of these relationships is important so that we can identify individuals who may be in greater need of support. In this article, we seek to improve our understanding of how environmental and family conditions impact externalising and internalising symptoms in autistic and non-autistic people. To do this, we conducted analyses with two cohorts in very different settings - in Europe and South Africa - to ensure our findings are globally representative. We used advanced statistical methods to establish environmental and family conditions that were similar to each other, and which could be combined into specific 'factors'. We found that four similar 'factors' could be identified in the two cohorts. These were distinguished by personal characteristics and environmental conditions of individuals, and were named Person Characteristics, Family System, Parental and Material Resources. Interestingly, just 'Family System' was associated with internalising and externalising symptoms, and this was the same in both cohorts. We also found that having high traits of autism impacted this relationship between Family System and mental health conditions with opposite directions in the two settings. These results show that characteristics in the Family System are associated with internalising and externalising symptoms, and autistic persons are particularly impacted, reinforcing the notion that family stressors are important to consider when implementing policy and practice related to improving the mental health of autistic people., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.T. has acted as a paid consultant and is a current employee of F. Hoffmann-La Roche AG. T.C. has acted as a paid consultant of F. Hoffmann-La Roche Ltd and Servier and receives royalties for the publication of textbooks for Guilford Press and Sage Publications. J.B. has been in the past 3 years a consultant to/member of advisory boards of/and/or speaker for Janssen Cilag BV, Eli Lilly, Lundbeck, Shire, Roche, Novartis, Medice, and Servier. S.B. receives royalties for the German and Swedish KONTAKT manuals and adaptations of the ADI-R, ADOS, and S.R.S. from Hogrefe Publishers, and has in the past 3 years acted as an author, consultant or lecturer for Medice and Roche. T.B. has served in an advisory or consultancy role for eye level, Infectopharm, Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Roche and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalties from Hogrefe, Kohlhammer, CIP Medien and Oxford University Press; the present work is unrelated to these relationships. A.S.J.C. has acted as a paid consultant for F. Hoffman-La Roche and Servier, and has been actively involved in clinical trials managed by both companies. All other authors report no biomedical financial interests or potential conflicts of interest.