Search

Abstract Bats are increasingly recognized as reservoirs of emerging zoonotic pathogens. Egyptian rousette bats (ERBs) are the known reservoir of Marburg virus (MARV), a filovirus that causes deadly Marburg virus disease (MVD) in humans. However, ERBs harbor MARV asymptomatically, likely due to a coadapted and specific host immunity-pathogen relationship. Recently, we measured transcriptional responses in MARV-infected ERB whole tissues, showing that these bats possess a disease tolerant strategy that limits pro-inflammatory gene induction, presumably averting MVD-linked immunopathology. However, the host resistant strategy by which ERBs actively limit MARV burden remains elusive, which we hypothesize requires localized inflammatory responses unresolvable at bulk-tissue scale. Here, we use dexamethasone to attenuate ERB pro-inflammatory responses and assess MARV replication, shedding and disease. We show that MARV-infected ERBs naturally mount coordinated pro-inflammatory responses at liver foci of infection, comprised of recruited mononuclear phagocytes and T cells, the latter of which proliferate with likely MARV-specificity. When pro-inflammatory responses are diminished, ERBs display heightened MARV replication, oral/rectal shedding and severe MVD-like liver pathology, demonstrating that ERBs balance immunoprotective tolerance with discreet MARV-resistant pro-inflammatory responses. These data further suggest that natural ERB immunomodulatory stressors like food scarcity and habitat disruption may potentiate viral shedding, transmission and therefore outbreak risk.

Abstract In northern Australia, a region with limited access to healthcare and a substantial population living remotely, antibiotic resistance adds to the complexity of treating infections. Focussing on Escherichia coli urinary tract infections (UTIs) and Staphylococcus aureus skin & soft tissue infections (SSTIs) captured by a northern Australian antibiotic resistance surveillance system, we used logistic regression to investigate predictors of a subsequent resistant isolate during the same infection episode. We also investigated predictors of recurrent infection. Our analysis included 98,651 E. coli isolates and 121,755 S. aureus isolates from 70,851 patients between January 2007 and June 2020. Following an initially susceptible E. coli UTI, subsequent recovery of a cefazolin (8%) or ampicillin (13%) -resistant isolate during the same infection episode was more common than a ceftriaxone-resistant isolate (2%). For an initially susceptible S. aureus SSTI, subsequent recovery of a methicillin-resistant isolate (8%) was more common than a trimethoprim-sulfamethoxazole-resistant isolate (2%). For UTIs and SSTIs, prior infection with a resistant pathogen was a strong predictor of both recurrent infection and resistance in future infection episodes. This multi-centre study demonstrates an association between antibiotic resistance and an increased likelihood of recurrent infection. Particularly in remote areas, a patient’s past antibiograms should guide current treatment choices since recurrent infection will most likely be at least as resistant as previous infection episodes. Using population-level surveillance data in this way can also help clinicians decide if they should switch antibiotics for patients with ongoing symptoms, while waiting for diagnostic results.

Abstract The natural reservoir of Ebola virus (EBOV), agent of a zoonosis burdening several African countries, remains unidentified, albeit evidence points towards bats. In contrast, the ecology of the related Marburg virus is much better understood; with experimental infections of bats being instrumental for understanding reservoir-pathogen interactions. Experiments have focused on elucidating reservoir competence, infection kinetics and specifically horizontal transmission, although, vertical transmission plays a key role in many viral enzootic cycles. Herein, we investigate the permissiveness of Angolan free-tailed bats (AFBs), known to harbour Bombali virus, to other filoviruses: Ebola, Marburg, Taï Forest and Reston viruses. We demonstrate that only the bats inoculated with EBOV show high and disseminated viral replication and infectious virus shedding, without clinical disease, while the other filoviruses fail to establish productive infections. Notably, we evidence placental-specific tissue tropism and a unique ability of EBOV to traverse the placenta, infect and persist in foetal tissues of AFBs, which results in distinct genetic signatures of adaptive evolution. These findings not only demonstrate plausible routes of horizontal and vertical transmission in these bats, which are expectant of reservoir hosts, but may also reveal an ancillary transmission mechanism, potentially required for the maintenance of EBOV in small reservoir populations.

Purpose: Despite advances in immunotherapy, unresectable recurrent/metastatic head and neck cancer (HNC) carries a poor prognosis, and effective treatments are needed. As nectin-4 is widely expressed in HNC, enfortumab vedotin (EV), a nectin-4-directed antibody-drug conjugate, was explored in HNC in EV-202 (ClinicalTrials.gov identifier: NCT04225117)., Methods: This open-label, multicohort, phase II study evaluated intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle. In the HNC cohort, eligible patients had recurrent/metastatic HNC and had received platinum-based therapy for locally advanced/metastatic disease and a PD-1/PD-L1 inhibitor. The primary end point was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary end points were investigator-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); overall survival (OS); and safety., Results: The primary analysis included 46 patients; all received EV (median follow-up, 9.3 months). Most patients (52.2%) had ≥3 previous lines of systemic therapy in the metastatic setting. Confirmed ORR was 23.9%, DCR was 56.5%, and median DOR was not reached (median DOR was 9.4 months at a later data cutoff [median follow-up, 11.3 months]). Median PFS and OS were 3.9 and 6.0 months, respectively. Treatment-related adverse events (TRAEs) occurring in >20% of patients were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Sixteen patients (34.8%) experienced grade ≥3 TRAEs; anemia and decreased neutrophil count occurred in ≥1 patient (both n = 2; 4.3%)., Conclusion: EV demonstrated antitumor activity in heavily pretreated HNC. Safety was consistent with the known safety profile of EV; no new safety signals were identified. These data support further evaluation of EV for advanced HNC not amenable to definitive local therapy.

Background: Multiparametric MRI markers of liver health corrected T1 (cT1) and proton density fat fraction (PDFF) have shown utility in the management of various chronic liver diseases. We assessed the normal population reference range of both cT1 and PDFF in healthy child and adult volunteers without any known liver disease., Methods: A retrospective multi-centre pooled analysis of 102 child and young adult (9.1 years (6-18)) volunteers from three centres: Children's Memorial Health Institute (N = 21), University Hospital Southampton (N = 28) and Hospital Infantil de Mexico (N = 53). Sex and ethnic differences were investigated for both cT1 and PDFF. Age effects were investigated with comparison to a pooled adult cohort from the UK Biobank (N = 500) and CoverScan (N = 71), covering an age range of 21 to 81 years., Results: cT1 values were normally distributed with a median of 748 ms (IQR: 725-768 ms; 2.5-97.5 percentiles: 683-820 ms). PDFF values followed a normal distribution with a median of 1.7% (IQR: 1.3-1.9%; 2.5-97.5 percentiles: 1-4.4%). There were no significant age and sex differences in cT1 and PDFF between children and young adults. No differences in cT1 and PDFF were found between ethnicities. Age comparisons showed statistically significant, but clinically negligible, cT1 (748 ms vs. 732 ms) and PDFF (2.4% vs. 1.9%) differences between paediatric and adult groups, respectively., Conclusions: Median healthy cT1 and PDFF reference ranges in children and young adults fall within the reported limits for normal of 800 ms and 5%, respectively.

Vein graft disease is the process by which saphenous vein grafts, utilised for revascularisation during coronary artery bypass graft surgery, undergo an inflammation-driven intimal hyperplasia and accelerated atherosclerosis process in subsequent years after implantation. The role of the arterial circulation, particularly the haemodynamic properties' impact on graft patency, have been investigated but have not to date been explored in depth at the transcriptomic level. We have undertaken the first-in-man spatial transcriptomic analysis of the long saphenous vein in response to ex vivo acute arterial haemodynamic stimulation, utilising a combination of a custom 3D-printed perfusion bioreactor and the 10X Genomics Visium Spatial Gene Expression technology. We identify a total of 413 significant genes (372 upregulated and 41 downregulated) differentially expressed in response to arterial haemodynamic conditions. These genes were associated with pathways including NFkB , TNF , MAPK , and PI3K/Akt , among others. These are established pathways involved in the initiation of an early pro-inflammatory response, leukocyte activation and adhesion signalling, tissue remodelling, and cellular differentiation. Utilising unsupervised clustering analysis, we have been able to classify subsets of the expression based on cell type and with spatial resolution. These findings allow for further characterisation of the early saphenous vein graft transcriptional landscape during the earliest stage of implantation that contributes to vein graft disease, in particular validation of pathways and druggable targets that could contribute towards the therapeutic inhibition of processes underpinning vein graft disease.

HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT. There are no significant differences between genotypes for clinical efficacy endpoints. Enzalutamide significantly improves radiographic progression-free survival and overall survival vs. placebo irrespective of HSD3B1 status. Men with the AP genotype have higher post-progression mortality and treatment-emergent adverse events, including hypertension, cardiovascular events, and gynecomastia, but a lower fracture rate. Overall, enzalutamide is beneficial in men with mHSPC independent of the HSD3B1 genotype. Inherited polymorphisms of HSD3B1 may account for differential toxicities., Competing Interests: Declaration of interests N.S. reports consulting for Celgene and Roivant, research funding from Astellas, and a filed patent application by Cleveland Clinic for a method of steroid-dependent disease treatment based on HSD3B1. A.A.A. reports honoraria from Aculeus Therapeutics, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, Merck Serono, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; consulting for Aculeus Therapeutics, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, Merck Serono, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; speakers’ bureau for Amgen, Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, and Novartis; grants from Aptevo (institutional), Astellas (institutional), Astellas (investigator), AstraZeneca (institutional), AstraZeneca (investigator), Bionomics (institutional), Bristol Myers Squibb (institutional), Exelixis (institutional), Gilead Sciences (institutional), GlaxoSmithKline (institutional), Hinova (institutional), Ipsen (institutional), Janssen (institutional), Lilly (institutional), MedImmune (institutional), Merck Serono (institutional), Merck Serono (investigator), Merck Sharpe & Dohme (institutional), Novartis (institutional), Pfizer (institutional), Sanofi Aventis (institutional), and Synthorx (institutional); travel/accommodation reimbursement from Amgen, Astellas, Bayer, Janssen, Merck Serono, Pfizer, Sanofi, and Tolmar; participation on an advisory board for Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, Merck Serono, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; and participation as the chair of the Urologic Oncology Group for the Clinical Oncology Society of Australia and as a chair of the Translational Research Subcommittee and member of the Scientific Advisory Committee for the ANZUP Cancer Trials Group. J.W.D.H. reports consulting for Astellas. M.W. is an employee of Astellas and reports ownership of stock of ADMA Biologics, CASI, Merck, and Seelos. F.Z. is an employee of Pfizer and reports ownership of stock of Pfizer and AlloVir and patents with AlloVir. J.S. is an employee of Astellas and reports ownership of stock of AstraZeneca. G.P.H. is an employee of Astellas. A.S. reports consulting for Alere, Astellas, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Roche, Steba Biotech, and Synergo; research funding from Amgen, Astellas, AstraZeneca, Bayer, Cepheid, GenomeDx, Immatics, Janssen, Johnson & Johnson, Karl Storz, Medivation, Novartis, and Roche; patents for A290/99 implantable incontinence device, AT00/0001:C-Trap implantable device to treat urinary incontinence, and 2018/6579 gene-expression signature for subtype and prognostic prediction of renal cell carcinoma; expert testimony for GBA Pharma; and travel support from Amgen, Astellas, AstraZeneca, CureVac, Ferring, Ipsen, Janssen, and Sanofi/Aventis. A.J.A. reports research support (institutional) to Duke from the NIH/NCI, PCF/Movember, DOD, Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen, and Novartis and personal compensation from consulting or advising relationships with Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis, Dendreon, Epic Sciences, Exact Sciences, Exelixis, Forma, GoodRx, Janssen, Merck, Myovant, Novartis, Pfizer, and Point., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pork is the most widely consumed meat on the planet, placing swine health as a critical factor for both the world economy and the food industry. Infectious diseases in pigs not only threaten these sectors but also raise zoonotic concerns, as pigs can act as "mixing vessels" for several animals and human viruses and can lead to the emergence of new viruses that are capable of infecting humans. Several efforts are ongoing to develop pig vaccines, albeit with limited success. This has been largely attributed to the complex nature of pig infections and incomplete understanding of the pig immune responses. Additionally, pig has been suggested to be a good experimental model to study viral infections (e.g., human influenza). Despite the significant importance of studying pig immunology for developing infection models, zoonosis, and the crucial need to develop better swine vaccines, there is still very limited information on the response of the swine adaptive immune system to several emerging pathogens. Particularly, very little is known about the pig B cell repertoire upon infection. Understanding the B cell repertoire is especially crucial towards designing better vaccines, predicting zoonosis and can provide insights into developing new diagnostic agents. Here, we developed methods for performing parallel single pig B cell (up to 10,000 B cells) global and immunoglobulin transcriptome sequencing. We then adapted a computational pipeline previously built for human/mouse sequences, to now analyze pig sequences. This allowed us to comprehensively map the B cell repertoire and get paired antibody sequences from pigs in a single parallel sequencing experiment. We believe that these approaches will have significant implications for swine diseases, particularly in the context of swine mediated zoonosis and swine and human vaccine development., (© 2024. The Author(s).)

Heart sound analysis plays an important role in early detecting heart disease. However, manual detection requires doctors with extensive clinical experience, which increases uncertainty for the task, especially in medically underdeveloped areas. This paper proposes a robust neural network structure with an improved attention module for automatic classification of heart sound wave. In the preprocessing stage, noise removal with Butterworth bandpass filter is first adopted, and then heart sound recordings are converted into time-frequency spectrum by short-time Fourier transform (STFT). The model is driven by STFT spectrum. It automatically extracts features through four down sample blocks with different filters. Subsequently, an improved attention module based on Squeeze-and-Excitation module and coordinate attention module is developed for feature fusion. Finally, the neural network will give a category for heart sound waves based on the learned features. The global average pooling layer is adopted for reducing the model's weight and avoiding overfitting, while focal loss is further introduced as the loss function to minimize the data imbalance problem. Validation experiments have been conducted on two publicly available datasets, and the results well demonstrate the effectiveness and advantages of our method.

Background: Chronic liver disease diagnoses depend on liver biopsy histopathological assessment. However, due to the limitations associated with biopsy, there is growing interest in the use of quantitative digital pathology to support pathologists. We evaluated the performance of computational algorithms in the assessment of hepatic inflammation in an autoimmune hepatitis in which inflammation is a major component., Methods: Whole-slide digital image analysis was used to quantitatively characterize the area of tissue covered by inflammation [Inflammation Density (ID)] and number of inflammatory foci per unit area [Focal Density (FD)] on tissue obtained from 50 patients with autoimmune hepatitis undergoing routine liver biopsy. Correlations between digital pathology outputs and traditional categorical histology scores, biochemical, and imaging markers were assessed. The ability of ID and FD to stratify between low-moderate (both portal and lobular inflammation ≤1) and moderate-severe disease activity was estimated using the area under the receiver operating characteristic curve (AUC)., Results: ID and FD scores increased significantly and linearly with both portal and lobular inflammation grading. Both ID and FD correlated moderately-to-strongly and significantly with histology (portal and lobular inflammation; 0.36≤R≤0.69) and biochemical markers (ALT, AST, GGT, IgG, and gamma globulins; 0.43≤R≤0.57). ID (AUC: 0.85) and FD (AUC: 0.79) had good performance for stratifying between low-moderate and moderate-severe inflammation., Conclusion: Quantitative assessment of liver biopsy using quantitative digital pathology metrics correlates well with traditional pathology scores and key biochemical markers. Whole-slide quantification of disease can support stratification and identification of patients with more advanced inflammatory disease activity., Competing Interests: The members and employees of The Children's Memorial Health Institute declare no conflict of interest with this study. Perspectum Ltd is a privately funded commercial enterprise that develops medical devices to address unmet clinical needs, including LiverMultiScan. Perspectum is the sponsor of this study. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elizabeth Shumbayawonda reports financial support was provided by Perspectum Ltd. Abhishek Roy reports financial support was provided by Perspectum Ltd. Caitlin Langford reports financial support was provided by Perspectum Ltd. Paul Aljabar reports financial support was provided by Perspectum Ltd. Rajarshi Banerjee reports financial support was provided by Perspectum Ltd. Ken Fleming reports financial support was provided by Perspectum Ltd. Elizabeth Shumbayawonda reports a relationship with Perspectum Ltd. that includes: employment and equity or stocks. Abhishek Roy reports a relationship with Perspectum Ltd that includes: employment. Caitlin Langford reports a relationship with Perspectum Ltd that includes: employment. Paul Aljabar reports a relationship with Perspectum Ltd that includes: employment and equity or stocks. Rajarshi Banerjee reports a relationship with Perspectum Ltd that includes: employment and equity or stocks. Ken Fleming reports a relationship with Perspectum Ltd that includes: consulting or advisory., (© 2024 The Authors.)

Purpose: In cochlear implantation with flexible lateral wall electrode arrays, a cochlear coverage (CC) range between 70% and 80% is considered ideal for optimal speech perception. To achieve this CC, the cochlear implant (CI) electrode array has to be chosen according to the individual cochlear duct length (CDL). Here, we mathematically analyzed the suitability of different flexible lateral wall electrode array lengths covering between 70% and 80% of the CDL., Methods: In a retrospective cross-sectional study preoperative high-resolution computed tomography (HRCT) from patients undergoing cochlear implantation was investigated. The CDL was estimated using an otosurgical planning software and the CI electrode array lengths covering 70-80% of the CDL was calculated using (i) linear and (ii) non-linear models., Results: The analysis of 120 HRCT data sets showed significantly different model-dependent CDL. Significant differences between the CC of 70% assessed from linear and non-linear models (mean difference: 2.5 mm, p < 0.001) and the CC of 80% assessed from linear and non-linear models (mean difference: 1.5 mm, p < 0.001) were found. In up to 25% of the patients none of the existing flexible lateral wall electrode arrays fit into this range. In 59 cases (49,2%) the models did not agree on the suitable electrode arrays., Conclusions: The CC varies depending on the underlying CDL approximation, which critically influences electrode array choice. Based on the literature, we hypothesize that the non-linear method systematically overestimates the CC and may lead to rather too short electrode array choices. Future studies need to assess the accuracy of the individual mathematical models., (© 2023. The Author(s).)

The receptor for advanced glycation end-products (RAGE or AGER) is a transmembrane, immunoglobulin-like receptor that, due to its multiple isoform structures, binds to a diverse range of endo- and exogenous ligands. RAGE activation caused by the ligand binding initiates a cascade of complex pathways associated with producing free radicals, such as reactive nitric oxide and oxygen species, cell proliferation, and immunoinflammatory processes. The involvement of RAGE in the pathogenesis of disorders such as diabetes, inflammation, tumor progression, and endothelial dysfunction is dictated by the accumulation of advanced glycation end-products (AGEs) at pathologic states leading to sustained RAGE upregulation. The involvement of RAGE and its ligands in numerous pathologies and diseases makes RAGE an interesting target for therapy focused on the modulation of both RAGE expression or activation and the production or exogenous administration of AGEs. Despite the known role that the RAGE/AGE axis plays in multiple disease states, there remains an urgent need to develop noninvasive, molecular imaging approaches that can accurately quantify RAGE levels in vivo that will aid in the validation of RAGE and its ligands as biomarkers and therapeutic targets. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Diagnostic Tools > Biosensing., (© 2023 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)