Northeast Ohio Medical University

The ongoing spread of antimicrobial resistance has generated an urgent need for new antibiotics, especially against multidrug-resistant (MDR) gram-negative pathogens. Taniborbactam (previously VNRX-5133) is a novel bicyclic boronate β-lactamase inhibitor with potent, selective, and direct inhibitory activity against Ambler class A, B, C, and D enzymes, including serine and metallo-β-lactamases. Taniborbactam has a broader spectrum of inhibition than any other current β-lactamase inhibitor. The combination of cefepime with taniborbactam is in advanced clinical development. Investigators are studying the activity of cefepime-taniborbactam against gram-negative pathogens, including Enterobacterales species like carbapenem-resistant Klebsiella pneumoniae and MDR Pseudomonas aeruginosa with characterized carbapenem resistance mechanisms. In this review, we discuss the advances in medicinal chemistry that led to the development of cefepime-taniborbactam, the pharmacokinetics and pharmacodynamics, the antimicrobial spectrum of activity, potential uses in the clinic, and mechanisms of resistance. We propose future clinical scenarios to better explore the precise niche of this novel inhibitor combination.

“My first contact with Rod Feldmann was his voicemail message: ‘An incredible set of circumstances makes it impossible for me to come to the phone right now. Please leave a message and I will get back to you as soon as possible.’ I was considering coming to Kent for graduate school and I thought, ‘Wow, this guy is either really important or really arrogant.’ I was right and wrong. He was never arrogant, but always important, and eventually of utmost importance to me.

Background Intestinal mucosal injury may arise from various factors. While many drugs target the causative factors, none directly stimulate mucosal wound healing. We found that the specific focal adhesion kinase (FAK) activator, M64HCl, promotes intestinal mucosal healing in mice. This study aims to further validate the therapeutic impact of M64HCl on intestinal mucosal repair in rats as a second species. Methods Wistar rats were assigned to one of four groups: normal control, 1-day injury + vehicle, 4-day injury + vehicle, or 4-day injury + M64HCl. Intestinal injury was induced by serosally applying 75% acetic acid. Immediately after injury, rats received either a continuous infusion of M64HCl (25 mg/kg/day) or its vehicle (saline). Four days post-injury, blood was drawn to measure M64HCl levels and assess liver and kidney function. The intestines were removed and opened, ulcer areas were photographed for size quantification, and tissues were fixed for histological and immunohistochemical analysis. Results M64HCl substantially reduced ulcer area on gross examination, while histological analysis showed alleviation of pathological changes with M64HCl treatment. Immunohistochemical analysis confirmed increased immunoreactivity for phosphorylated FAK in the epithelium adjacent to the injury in M64HCl-treated rats. However, there was no change in the percentage of Ki67-positive cells in each crypt at the edge of the ulcer area. Serum creatinine, ALT, and AST levels did not differ between the 4-day injury groups with or without M64HCl treatment. Conclusions M64HCl, a water-soluble FAK activator, promotes acetic acid-induced ulcer healing in rats and may be useful in treating gastrointestinal mucosal injury.

The tongue, as a muscular hydrostat, performs several dynamic behaviors and functions, including feeding, vocalizing and respiration. As such, this hydrostat must be capable of performing complex movements, which are powered via a set of muscles typically defined as ‘extrinsic’ (originating outside of the tongue) and ‘intrinsic’ (contained wholly in the tongue). These muscles are typically classified based on their gross anatomical positions and also are often ascribed functions based on these positions, with the extrinsic muscles being assigned the role of positioning the tongue, and the intrinsic muscles thought to function to shape it. For example, genioglossus is typically described as a tongue protruder, whereas hyoglossus is often described as a tongue retractor. However, the neural control of these muscles involves relatively small motor units, and defining the function of tongue muscles based on anatomy, when they occupy overlapping space and exhibit refined control may oversimplify their function. Yet, distinguishing between gross anatomical structures and refined neural control can be challenging due to the complexity of functions the tongue performs. Here, we used an infant animal model (pigs) to evaluate how the neural control of the tongue is modulated in anatomical space given a relatively simplified behavior (suckling). We tested for variation in control along the anteroposterior and dorsoventral axis of the tongue using high speed videofluoroscopy coupled with electromyography (EMG). We found variation in EMG firing timing along both axes, which correspond to differences in behaviors. Furthermore, this variation in activity is likely reflected by regional variation in function within a muscle. These data suggest that defining muscles by their anatomical structure over-simplifies their functional roles and that studies investigating the three-dimensional structure and function of the tongue should evaluate it based on regional variation in control, in the context of the behavior of interest.

Several bat species live >20–40 years, suggesting that they possess efficient anti-aging and anti-cancer defenses. Here we investigate the requirements for malignant transformation in primary fibroblasts from four bat species Myotis lucifugus, Eptesicus fuscus, Eonycteris spelaea, and Artibeus jamaicensis – spanning the bat evolutionary tree and including the longest-lived genera. We show that bat fibroblasts do not undergo replicative senescence, express active telomerase, and show attenuated SIPs with dampened secretory phenotype. Unexpectedly, unlike other long-lived mammals, bat fibroblasts are readily transformed by two oncogenic “hits”: inactivation of p53 or pRb and activation of HRASG12V. Bat fibroblasts exhibit increased TP53 and MDM2 transcripts and elevated p53-dependent apoptosis. M. lucifugus shows a genomic duplication of TP53. We hypothesize that some bat species have evolved enhanced p53 activity as an additional anti-cancer strategy, similar to elephants. Further, the absence of unique cell-autonomous tumor suppressive mechanisms may suggest that in vivo bats may rely on enhanced immunosurveillance.

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Artificial intelligence (AI) is revolutionizing cancer imaging, enhancing screening, diagnosis, and treatment options for clinicians. AI-driven applications, particularly deep learning and machine learning, excel in risk assessment, tumor detection, classification, and predictive treatment prognosis. Machine learning algorithms, especially deep learning frameworks, improve lesion characterization and automated segmentation, leading to enhanced radiomic feature extraction and delineation. Radiomics, which quantifies imaging features, offers personalized treatment response predictions across various imaging modalities. AI models also facilitate technological improvements in non-diagnostic tasks, such as image optimization and automated medical reporting. Despite advancements, challenges persist in integrating AI into healthcare, tracking accurate data, and ensuring patient privacy. Validation through clinician input and multi-institutional studies is essential for patient safety and model generalizability. This requires support from radiologists worldwide and consideration of complex regulatory processes. Future directions include elaborating on existing optimizations, integrating advanced AI techniques, improving patient-centric medicine, and expanding healthcare accessibility. AI can enhance cancer imaging, optimizing precision medicine and improving patient outcomes. Ongoing multidisciplinary collaboration between radiologists, oncologists, software developers, and regulatory bodies is crucial for AI’s growing role in clinical oncology. This review aims to provide an overview of the applications of AI in oncologic imaging while also discussing their limitations.

Principal neurons (PNs) of the lateral superior olive (LSO) are a critical component of brain circuits that compare information between the two ears to extract sound source-location-related cues. LSO PNs are not a homogenous group but differ in their transmitter type, intrinsic membrane properties, and projection pattern to higher processing centers in the inferior colliculus. Glycinergic inhibitory LSO PNs have higher input resistance than glutamatergic excitatory LSO PNs (∼double). This suggests that the inhibitory cell type has a lower minimum input or signal intensity required to produce an output (activation threshold) which may impact how they integrate binaural inputs. However, cell-type-specific differences in the strength of synaptic drive could offset or accentuate such differences in intrinsic excitability and have not been assessed. To evaluate this possibility, we used a knock-in mouse model to examine spontaneous and electrically stimulated (evoked) synaptic events in LSO PN types using voltage-clamp technique. Both excitatory and inhibitory spontaneous postsynaptic currents were larger in inhibitory LSO PNs, but evoked events were not. Additionally, we found that LSO PN types had inputs with similar short-term plasticity and number of independent fibers. An important contrast was that inhibitory LSO PNs received inhibitory inputs with slower decay kinetics which could impact integrative functions. These data suggest that synaptic inputs onto LSO PNs are unlikely to offset excitability differences. Differences in activation threshold along with transmitter type and projection laterality may allow for distinct roles for LSO PN types in inferior colliculus information processing.

Concussion commonly occurs in sports and military venues and is difficult to diagnose and manage. A medical device is needed to perform an assessment for concussion and identify functional deficits. This report presents the developmental methodology, including user experience and human factors results, for a new virtual reality (VR)-based technology. Data collection occurred between 2020 and 2024, amassing 1008 participants between the ages of 18 and 40 years. The initial software was modified, informed by human factors and user experience data, including symptom report and need for examiner assistance. The second version resulted in less necessity for examiner intervention to ensure participant understanding of the VR tests. Symptom provocation during the VR tests demonstrated that less than 5% of participants had a > 2-point increase in headache, nausea, and mental fogginess across the tests; 9.2% had > 2-point increase in dizziness. This is in line with reports from similar clinical tests, demonstrating that the VR environment does not pose an additional risk. Our work demonstrates that clinical tests of functional neurology (i.e., oculomotor, vestibular, reaction) were translated into a virtual environment and multidimensional sensor-based data was able to be collected on a sample of participants, who did not experience unexpected symptom provocation during test completion. The approach described here regarding the translation of real-world clinical tests into the VR environment, towards the development of a medical device, may be useful to many other healthcare disciplines and fields. Pending results of the machine learning classification, this device may prove useful in decision support for concussion diagnostics and determination of recovery.

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors.

Background: Clinical adoption of ultrasound attenuation coefficient (AC) measurements has been hindered by lack of uniform measurement protocol and a range of factors that may cause variability. Objective: To evaluate associations of ROI depth, ROI size, and confidence map threshold with interobserver agreement and diagnostic performance of ultrasound AC measurements in detecting and grading hepatic steatosis using MRI proton-density fat fraction (PDFF) as the reference standard. Methods: This prospective study enrolled adults with known steatosis or at risk for steatosis from October 2023 to August 2024. One of two operators obtained videos of AC acquisitions using a single ultrasound unit. Both operators independently reviewed all videos and placed circular ROIs to obtain AC measurements for all 24 possible combinations of four ROI depths (2.0, 2.5, 3.0, and 4.0 cm from liver capsule to ROI outer edge), three ROI sizes (3.0, 3.5, and 4.0 cm), and two confidence map thresholds (20% and 40%). Participants underwent MRI PDFF measurement as reference. Results: The analysis included 101 participants (mean age, 54.5±12.1 years; 62 female, 39 male). Interoperator agreement was excellent for all combinations (intraclass correlation coefficient: 0.92-0.98). AC measurements showed strongest correlations (Spearman rho, 0.81 and 0.80 for operators 1 and 2, respectively) with MRI PDFF at a ROI depth of 4.0 cm. The optimal combination considering correlations with MRI PDFF and AUC across steatosis grades included a depth of 4.0 cm, size of 4.0 cm, and threshold of 40%. This combination had AUC for detecting steatosis with grade >0, >1, and >2 for operator 1 of 0.93, 0.88, and 0.81, respectively, and operator 2 of 0.92, 0.86, and 0.81, respectively. However, accuracy for detecting steatosis (grade >0) was highest for the combination of depth of 3.0 cm, size of 4.0 cm, and threshold of 40% (operator 1, 90.1%; operator 2, 82.2%). Conclusion: AC measurements showed excellent interoperator agreement across parameter combinations. Correlations with MRI PDFF were strongest at a depth of 4.0 cm. Combinations yielding highest diagnostic performance were identified. Clinical Impact: These results will help determine a standardized optimal protocol for ultrasound AC measurements, facilitating clinical adoption for liver fat quantification.

Essential thrombocythemia (ET) is a rare myeloproliferative neoplasm characterized by excessive platelet production and a predisposition to thrombotic or hemorrhagic complications. We report a case of a 62-year-old male with no conventional cardiovascular risk factors who presented with a non-ST-segment elevation myocardial infarction (NSTEMI). Initial coronary angiography showed isolated proximal LAD stenosis. Laboratory tests revealed marked thrombocytosis (>1,000,000/μL) and a CALR mutation, confirming a diagnosis of ET. The patient was treated with percutaneous coronary intervention (PCI), dual antiplatelet therapy, and cytoreductive therapy with hydroxyurea, leading to a favorable outcome. This case illustrates how ET, particularly CALR-mutated subtypes, can manifest as acute coronary syndrome in the absence of atherosclerosis and underscores the need to consider hematologic malignancies in atypical presentations of myocardial infarction.

Purpose: Infantile nystagmus syndrome (INS), the most prevalent form of nystagmus in children, often indicates underlying ocular and neurological conditions. Genetic assessment plays a crucial role in clinical management, genetic counseling, and access to emerging gene-based therapies. This study aims to characterize the clinical and genetic landscape of inherited ocular diseases (IODs) in children with INS. Methods: We retrospectively analyzed clinical and genetic data from 205 unrelated pediatric patients with INS enrolled in an IRB-approved nystagmus registry (2010-2024). All underwent next-generation sequencing (NGS) with targeted gene panels to detect pathogenic variants. Results: The cohort comprised 117 males and 88 females (mean [SD] age, 8.85 [10.37] years). The most common INS-associated IODs included albinism (32%), Leber congenital amaurosis (LCA) (14%), and achromatopsia (14%). Genetic testing achieved a definitive diagnosis in 85 of 205 patients, yielding a molecular diagnostic rate of 41.5%. A total of 83 pathogenic and likely pathogenic variants were identified across 30 genes. The seven most frequently disease-causing genes-TYR, CNGB3, RPGR, GPR143, ABCA4, OCA2 and FRMD7-accounted for 65% of the genetically solved cases. Additionally, eight genes associated with LCA (AIPL1, CABP4, GUCY2D, IMPDH1, NMNAT1, RDH12, PRPH2, and RPGRIP1) contributed to 15% of these cases. Conclusions: This study underscores the utility of NGS in diagnosing INS-associated IODs, providing essential insights for targeted interventions and identifying patients as candidates potentially eligible for ongoing gene-based therapy clinical trials.