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Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses., (© 2024. The Author(s).)

Background and Aims: Artificial intelligence-powered digital pathology offers the potential to quantify histological findings in a reproducible way. This analysis compares the evaluation of histological features of NASH between pathologists and a machine-learning (ML) pathology model., Approach and Results: This post hoc analysis included data from a subset of patients (n=251) with biopsy-confirmed NASH and fibrosis stage F1-F3 from a 72-week randomized placebo-controlled trial of once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg (NCT02970942). Biopsies at baseline and week 72 were read by 2 pathologists. Digitized biopsy slides were evaluated by PathAI's NASH ML models to quantify changes in fibrosis, steatosis, inflammation, and hepatocyte ballooning using categorical assessments and continuous scores. Pathologist and ML-derived categorical assessments detected a significantly greater percentage of patients achieving the primary endpoint of NASH resolution without worsening of fibrosis with semaglutide 0.4 mg versus placebo (pathologist 58.5% vs. 22.0%, p < 0.0001; ML 36.9% vs. 11.9%; p =0.0015). Both methods detected a higher but nonsignificant percentage of patients on semaglutide 0.4 mg versus placebo achieving the secondary endpoint of liver fibrosis improvement without NASH worsening. ML continuous scores detected significant treatment-induced responses in histological features, including a quantitative reduction in fibrosis with semaglutide 0.4 mg versus placebo ( p =0.0099) that could not be detected using pathologist or ML categorical assessment., Conclusions: ML categorical assessments reproduced pathologists' results of histological improvement with semaglutide for steatosis and disease activity. ML-based continuous scores demonstrated an antifibrotic effect not measured by conventional histopathology., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD., Aims: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments., Methods: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic., Results: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies., Conclusions: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD., (© 2024 John Wiley & Sons Ltd.)

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need., Aim: To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH., Methods: This proof-of-concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21-75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability., Results: Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2-point improvement in NAFLD activity score with ≥1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was -64.7% (95% CI: -71.7, -57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths., Conclusions: Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH., Clinicaltrials: gov: NCT04048135., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Sensorineural hearing loss (SNHL), which typically arises from the inner ear, is the most common sensory deficit worldwide. The traditional method for studying pathophysiology underlying human SNHL involves histological processing of the inner ear from temporal bones collected during autopsy. Histopathological analysis is destructive and limits future use of a given specimen. Non-destructive strategies for the study of the inner ear are urgently needed to fully leverage the utility of each specimen because access to human temporal bones is increasingly difficult and these precious specimens are required to uncover disease mechanisms and to enable development of new devices. We highlight the potential of reversible iodine staining for micro-computed tomography imaging of the human inner ear. This approach provides reversible, high-resolution visualization of intracochlear structures and is becoming more rapid and accessible., Competing Interests: The 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., (© 2022 Bommakanti, Iyer, Sagi, Brown, Ma, Gonzales and Stankovic.)

Sensorineural hearing loss (SNHL) is one of the most profound public health concerns of the modern era, affecting 466 million people today, and projected to affect 900 million by the year 2050. Advances in both diagnostics and therapeutics for SNHL have been impeded by the human cochlea's inaccessibility for in vivo imaging, resulting from its extremely small size, convoluted coiled configuration, fragility, and deep encasement in dense bone. Here, we develop and demonstrate the ability of a sub-millimeter-diameter, flexible endoscopic probe interfaced with a micro-optical coherence tomography (μOCT) imaging system to enable micron-scale imaging of the inner ear's sensory epithelium in cadaveric human inner ears., (© 2021. The Author(s).)

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide, and it typically originates from the cochlea. Methods to visualize intracochlear cells in living people are currently lacking, limiting not only diagnostics but also therapies for SNHL. Two-photon fluorescence microscopy (TPFM) is a high-resolution optical imaging technique. Here we demonstrate that TPFM enables visualization of sensory cells and auditory nerve fibers in an unstained, non-decalcified adult human cochlea., Competing Interests: The 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., (Copyright © 2021 Iyer, Seist, Moon and Stankovic.)

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in vivo in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects., (Copyright © 2020 Katsumi, Sahin, Lewis, Iyer, Landegger and Stankovic.)

Sensorineural hearing loss (SNHL) is an extraordinarily common disability, affecting 466 million people across the globe. Half of these incidents are attributed to genetic mutations that disrupt the structure and function of the cochlea. The human cochlea's interior cannot be imaged or biopsied without damaging hearing; thus, everything known about the morphologic correlates of hereditary human deafness comes from histopathologic studies conducted in either cadaveric human temporal bone specimens or animal models of genetic deafness. The purpose of the present review is to a) summarize the findings from all published histopathologic studies conducted in human temporal bones with known SNHL-causing genetic mutations, and b) compare the reported phenotypes of human vs. mouse SNHL caused by the same genetic mutation. The fact that human temporal bone histopathologic analysis has been reported for only 22 of the nearly 200 identified deafness-causing genes suggests a great need for alternative and improved techniques for studying human hereditary deafness; in light of this, the present review concludes with a summary of promising future directions, specifically in the fields of high resolution cochlear imaging, intracochlear fluid biopsy, and gene therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The present study deals co-pyrolysis of neem seeds (NM) and waste nitrile gloves (WNG) in a semi-batch reactor with and without catalysts. Results confirmed that the yield of pyrolytic liquid was higher (43.52 wt% at NM: WNG ratio of 3:1) during thermal co-pyrolysis compared to that of catalytic co-pyrolysis (40.42 wt% and 37.14 wt% respectively with CaO and Al 2 O 3 as catalysts). The use of catalysts increased the carbon content, acidity, and heating value and reduced the oxygen content, viscosity, and density of the pyrolytic oil. FTIR analysis suggested the presence of useful functional groups while 1 H NMR analysis confirmed high amounts of paraffin and aromatic compounds in the pyrolytic oil. GC-MS analysis of pyrolytic oil confirmed that blending of NM + WNG and use of catalysts reduced the oxygenated compounds and increased the alcohol and aldehyde thereby enhancing the fuel properties., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The gold standard method for visualizing the pathologies underlying human sensorineural hearing loss has remained post-mortem histology for over 125 years, despite awareness that histological preparation induces severe artifacts in biological tissue. Historically, the transition from post-mortem assessment to non-invasive clinical biomedical imaging in living humans has revolutionized diagnosis and treatment of disease; however, innovation in non-invasive techniques for cellular-level intracochlear imaging in humans has been difficult due to the cochlea's small size, complex 3D configuration, fragility, and deep encasement within bone. Here we investigate the ability of synchrotron radiation-facilitated X-ray absorption and phase contrast imaging to enable visualization of sensory cells and nerve fibers in the cochlea's sensory epithelium in situ in 3D intact, non-decalcified, unstained human temporal bones. Our findings show that this imaging technique resolves the bone-encased sensory epithelium's cytoarchitecture with unprecedented levels of cellular detail for an intact, unstained specimen, and is capable of distinguishing between healthy and damaged epithelium. All analyses were performed using commercially available software that quickly reconstructs and facilitates 3D manipulation of massive data sets. Results suggest that synchrotron radiation phase contrast imaging has the future potential to replace histology as a gold standard for evaluating intracochlear structural integrity in human specimens, and motivate further optimization for translation to the clinic., Competing Interests: The authors declare that there are no conflicts of interest associated with this work.

The mammalian cochlea has historically resisted attempts at high-resolution, non-invasive imaging due to its small size, complex three-dimensional structure, and embedded location within the temporal bone. As a result, little is known about the relationship between an individual's cochlear pathology and hearing function, and otologists must rely on physiological testing and imaging methods that offer limited resolution to obtain information about the inner ear prior to performing surgery. Micro-optical coherence tomography (μOCT) is a non-invasive, low-coherence interferometric imaging technique capable of resolving cellular-level anatomic structures. To determine whether μOCT is capable of resolving mammalian intracochlear anatomy, fixed guinea pig inner ears were imaged as whole temporal bones with cochlea in situ. Anatomical structures such as the tunnel of Corti, space of Nuel, modiolus, scalae, and cell groupings were visualized, in addition to individual cell types such as neuronal fibers, hair cells, and supporting cells. Visualization of these structures, via volumetrically-reconstructed image stacks and endoscopic perspective videos, represents an improvement over previous efforts using conventional OCT. These are the first μOCT images of mammalian cochlear anatomy, and they demonstrate μOCT's potential utility as an imaging tool in otology research.

Basaloid squamous cell carcinoma (BSCC) is a distinctive aggressive variant of squamous cell carcinoma. We present a case of a 60-year-old man with tender swelling in the right cheek region for 6 months and continuous unilateral nasal discharge for 2 months. Extraoral examination revealed an ovoid, well-defined swelling from the right infraorbital rim to the angle of the mouth superoinferiorly and the right lateral wall of the nose to preauricular region anteroposteriorly. Intraorally, an ulceroproliferative growth from right upper gingivobuccal sulcus to mid palatine raphe with bicortical expansion was evident. CT revealed a hypodense mass obliterating the right maxillary sinus. Histopathology showed closely packed basaloid cells, with hyperchromatic palisading nuclei, arranged in a solid pattern with a lobular configuration. Prominent areas of comedo necrosis and keratin pearl formation were seen. These features suggested BSCC. The patient underwent surgical excision with adjuvant radiation but was lost to follow-up after 6 months of radiation therapy., (2015 BMJ Publishing Group Ltd.)