GlaxoSmithKline (Netherlands)

Abstract Background Patients with complicated urinary tract infections (cUTIs) caused by multidrug-resistant (MDR) uropathogens often require hospitalization and intravenous (IV) antibiotic treatment. This real-world cohort study aimed to describe clinical complications in patients with cUTI. Methods Adults (≥ 18 years) who received IV-carbapenem (IVC) treatment within 7 days of a primary or admitting UTI diagnosis between January 1, 2018 and September 30, 2023 were identified using Optum’s de-identified Electronic Health Record dataset. These patients had cUTI infection (pyelonephritis, complicated cystitis or urosepsis), with the index date defined as the date of IVC treatment initiation. IV complications were evaluated from index to the earlier of 30 days following index or death. Complications related to extended length of stay (LOS) were evaluated from hospital admission to the earlier of discharge or death among a subgroup of hospitalized patients admitted for cUTI. Clinical complications were assessed overall and by LOS (1–3 vs 4+ days). Results In total, 16,144 patients treated with IVC for UTI were included: median age 71.0 years, 63.8% female, 41.9% obese, 30.5% uncontrolled and complicated diabetes, 42.2% severe renal dysfunction, and median (interquartile range [IQR]) Quan-Charlson comorbidity index of 2.0 (0.0, 4.0; Table). The incidence of any IV-related complication was 23.0% (n=3708), with a median (IQR) time to event of 3.0 days (1.0, 11.0; Figure 1). Among the subgroup of hospitalized patients (n=10,090), median (IQR) LOS was 6.0 days (4.0, 8.0). The incidence of any non-IV-related complications related to hospital LOS was 51.1% (n=5153); the incidence of any complication among patients with a LOS of 1–3 and 4+ days was 30.8% and 55.0%, respectively. The most common complication related to extended LOS was falls (overall, 30.7%; 1–3 days, 16.9%; 4+ days, 33.3%; Figure 2). Conclusion Over half of cUTI patients treated with IV carbapenems experienced at least one complication, with higher incidence among patients with extended LOS. These findings highlight the clinical burden of patients treated with IVC and the potential value of new oral treatment options in cUTI. Funding: GSK study 221138. Disclosures Myriam Drysdale, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Rose Chang, ScD, Analysis Group: Employee|GSK: Grant/Research Support Louise Yu, MS, Analysis Group: Employee|GSK: Grant/Research Support Maral DerSarkissian, PhD, Analysis Group: Employee|GSK: Grant/Research Support Megan Pinaire, MPH, Analysis Group: Employee|GSK: Grant/Research Support Zhuo Chen, MPH, Analysis Group: Employee|GSK: Grant/Research Support Mei Sheng Duh, MPH, ScD, Analysis Group: Employee|GSK: Grant/Research Support Alanna Farrell-Foster, GSK: Employee|GSK: Stocks/Bonds (Public Company) Fanny S. Mitrani-Gold, MPH, GSK: Employee|GSK: Stocks/Bonds (Public Company)

Abstract Tropical forests are rich in biodiversity but face the rapid loss of their wildlife due to increasing anthropogenic pressure, underscoring the urgent need for effective monitoring. Remote‐sensing tools such as camera traps offer faster, less invasive alternatives to human observations. These technologies can provide complementary insights into elusive species, especially in habitats that are difficult to access through direct observation. However, analysing the large volumes of data they produce is labour‐intensive, often leaving datasets underutilised due to limited human resources. Deep learning algorithms can automate aspects of data analysis, but their value to research and conservation efforts depends on their ability to reliably identify target species and be easily deployed in field conditions. To improve wildlife monitoring in African forests using camera trap data, we develop DeepForestVision, the first deep learning algorithm tailored to these challenging habitats that can be used in the field to process both photographs and videos. DeepForestVision was trained on an unprecedented dataset of 2,775,671 photographs and 221,982 videos gathered from camera traps from more than 63 research sites across 11 African countries. It identifies 33 non‐human vertebrate taxa, including 31 mammal taxa, from the most common to the most threatened ones observed on ground‐level camera traps, as well as humans, vehicles and blank photographs or videos. Classification tests demonstrate that DeepForestVision achieves an accuracy of 87.7% on the video test set with 23 taxa. It outperforms the three existing species identification algorithms applicable to these environments: Zamba by 13.1%, Mbaza by 45.0% and SpeciesNet by 37.7%. We provide the model weights for researchers and developers and offer DeepForestVision through a free offline interface. The interface is designed to function in the field in a low‐resource setting and requires no programming expertise. Solution : DeepForestVision is a reliable field tool for monitoring species observed on camera trap photos and videos in African tropical forests. Used by research, conservation, private or political actors, it can guide conservation strategies inside and outside of protected areas, and thus contribute to reducing the loss of biodiversity in African tropical forests.

Shigellosis is a global public health challenge that mostly affects low- and middle-income countries and causes considerable morbidity and mortality among children under 5 y of age. Multi- and extensively drug-resistant Shigella sonnei strains associated with recent outbreaks in high-income countries exacerbate the problem and have prompted the World Health Organization to include Shigella spp. among the high-risk pathogens for which novel prophylactic and therapeutic tools are urgently needed. Among the most promising and cutting-edge solutions, monoclonal antibodies are gaining considerable attention in the infectious diseases field. Here, we report the discovery of human monoclonal antibodies against S. sonnei, a species whose prevalence is constantly increasing worldwide and is associated with frequent drug-resistant infections. We isolated antibodies generated in response to an experimental S. sonnei vaccine followed by a controlled human infection and screened them by using a panel of high-throughput assays. We identified a molecule which exhibited potent bactericidal activity in vitro, inhibition of invasion of epithelial cells and conferred full protection from S. sonnei infection in vivo. Overall, our study provides a candidate antibody that can rapidly progress to industrial development for application as a prophylactic, therapeutic, and diagnostic tool against shigellosis.

Summary B cells play a pivotal role in shaping the tumor microenvironment (TME) and tertiary lymphoid structures (TLS), but the functions of specific B cell subsets in cancer pathogenesis remain unclear. Using a novel tissue-centric single cell RNA-sequencing (scRNA-seq) bioinformatic workflow aimed at unraveling cancer-specific clusters, combined with flow cytometry and high-plex spatial imaging, we identify a renal cell carcinoma (RCC)-specific enrichment of CD27-IgD-CD21+CD11c- double negative 1 (DN1) B cells associated with worse prognosis and regulatory function. Spatial profiling localizes DN1 Bregs within immature TLSs, in close proximity to IL-10⁺ and TGFβ⁺CD8⁺T cells. RCC-resident DN1 B cells are enriched for endosomal Toll-like receptor (TLR) signaling pathways and stimulation of tumor-infiltrating lymphocytes (TILs) with TLR agonists induces the differentiation of IL-10+ and TGFβ+DN Bregs suppressing CD8+T cell cytotoxicity, partially via IL-10 and TGFβ. These findings identify a pro-tumorigenic B cell population with potential diagnostic and therapeutic relevance in RCC.

The assessment and control of potential mutagenic impurities (PMIs) within pharmaceutical products are managed in accordance with the ICH M7 guideline “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”. This guidance highlights four control options that can be used to give assurance of control of PMIs to below a level of toxicological concern for the intended use. These control options range from testing to confirm that impurity levels within the active pharmaceutical ingredient or product are below an acceptable limit (ICH M7 Option 1 Control) to a control strategy that relies on process controls and scientific principles (e.g., purging) to demonstrate impurity presence to below a level of concern in lieu of analytical testing (option 4). While ICH M7 control option 4 is an established approach to justify that levels of a potential mutagenic impurity are below an acceptable limit, there have been health authority challenges that the use of ICH M7 control option 4 rationales is not appropriate for N-nitrosamines without included confirmatory analytical testing data to confirm absence. The reasons behind this lack of acceptance for ICH M7 control option 4 alone may include (i) a higher perceived potency for nitrosamines over other mutagenic impurities as they alert as part of the cohort of concern and (ii) inappropriate application of purge rationales such that, in some instances, confirmatory testing data highlighted higher levels for the impurity than had been predicted to be present. Through the inclusion of industry relevant case studies, this publication outlines that, while some nitrosamines may require control to lower levels than the ICH M7 threshold of toxicological concern, the concept of the ICH M7 option 4 control is scientifically justified when the properties for the nitrosamine are considered and an appropriate conservative purge rationale is applied.

Context: In severe asthma (SA), a history of exacerbations is associated with a poorer prognosis. Mepolizumab reduces clinically significant asthma exacerbations (CSEs) and maintenance oral corticosteroid (mOCS) use in SA.

Abstract Patients with metastatic, Estrogen Receptor (ER) positive, HER2-negative, breast cancer, before initiating CDK4/6 inhibitors, receive either single agent endocrine- or chemotherapy based on their clinical risk. In this first-ever trial-based economic evaluation of Circulating Tumor Cells (CTCs), the cost-effectiveness of standardizing the prescription of endocrine- or chemotherapy using a CTC count threshold (with >5 CTCs/7.5mL indicative of unfavorable disease outcomes) was compared to current clinical practice. N=755 ER+ HER2-patients, enrolled in 17 French centres, were randomized to CTC guided or standard of care and were treated according to either through the CTC score or clinical examination. Health state utilities were calculated by mapping the QLQ-C30 to EQ-5D utilities and used to calculate Quality-Adjusted Life Years (QALY) over a 2-year time horizon. Bootstrapping and additional sensitivity analyses were performed to quantify the impact of uncertainty. Health outcomes in both arms were similar, but costs were higher in the CTC guided arm (€19,403) compared to the usual care (€18,254), resulting in an ICER of €104,078/QALY in favor of usual care. However, when the analysis was performed for the clinically high- and low-risk groups separately, CTC enumeration could be a dominant strategy (cost saving) if treatment is de-escalated in clinically high-risk patients as indicated by CTC scores. However, the current analysis was based on the PFS and OS data reported in 2021 and long-term Overall Survival data is collected since then (JCO, 2023 in press). A further analysis of the health economic impact of CTC enumeration in clinically low and high-risk groups is therefore indicated.

Biotherapeutic masses are a means of verifying identity and structural integrity. Mass spectrometry (MS) of intact proteins or protein subunits provides an easy analytical tool for different stages of biopharmaceutical development. The protein's identity is confirmed when the experimental mass from MS is within a pre-defined mass error range of the theoretical mass. While several computational tools exist for the calculation of protein and peptide molecular weights, they either were not designed for direct application to biotherapeutic entities, have access limitations due to paid licenses, or require uploading protein sequences to host servers. We have developed a modular mass calculation routine that enables the easy determination of the average or monoisotopic masses and elemental compositions of therapeutic glycoproteins, including monoclonal antibodies (mAb), bispecific antibodies (bsAb), and antibody-drug conjugates (ADC). The modular nature of this Python-based calculation framework will allow the extension of this platform to other modalities such as vaccines, fusion proteins, and oligonucleotides in the future, and this framework could also be useful for the interrogation of top-down mass spectrometry data. By creating an open-source standalone desktop application with a graphical user interface (GUI), we hope to overcome the restrictions around use in environments where proprietary information cannot be uploaded to web-based tools. This article describes the algorithms and application of this tool, mAbScale, to different antibody-based therapeutic modalities.

Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [116, 27]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [9, 54, 64] and FFA4 receptors [45, 52, 94], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [10, 66, 90] and FFA3 [10, 66] receptors. The crystal structure for agonist bound FFA1 has been described [113].