Activation mechanism and novel binding sites of the BKCa channel activator CTIBD.

The large-conductance calcium-activated potassium (BKCa) channel, which is crucial for urinary bladder smooth muscle relaxation, is a potential target for overactive bladder treatment. Our prior work unveiled CTIBD as a promising BKCa channel activator, altering V 1/2 and G max This study investigates CTIBD's activation mechanism, revealing its independence from the Ca2+ and membrane voltage sensing of the BKCa channel. Cryo-electron microscopy disclosed that two CTIBD molecules bind to hydrophobic regions on the extracellular side of the lipid bilayer. Key residues (W22, W203, and F266) are important for CTIBD binding, and their replacement with alanine reduces CTIBD-mediated channel activation. The triple-mutant (W22A/W203A/F266A) channel showed the smallest V 1/2 shift with a minimal impact on activation and deactivation kinetics by CTIBD. At the single-channel level, CTIBD treatment was much less effective at increasing P o in the triple mutant, mainly because of a drastically increased dissociation rate compared with the WT. These findings highlight CTIBD's mechanism, offering crucial insights for developing small-molecule treatments for BKCa-related pathophysiological conditions.

Is the occurrence of extra-articular calcaneal fractures of the joint depression type related to osteoporosis and aging?

PURPOSE: The authors experienced several cases of extra-articular calcaneal fracture accompanied by joint depression involving the entire posterior facet without joint involvement. This type of fracture and its characteristics and treatment outcomes have not been previously reported. The study was performed to analyze the characteristics of extra-articular calcaneal fractures of the joint depression type and their postoperative clinical and radiographic results and complications. METHODS: Between February 2013 and March 2021, 23 extra-articular calcaneal fractures of the joint depression type were consecutively treated by a single surgeon. Relationships between fracture characteristics and patient demographics were assessed. Clinical results were quantified using visual analog scale, American Orthopaedic Foot and Ankle Society ankle-hindfoot scale, and Foot Function Index, radiographic results were evaluated using Böhler's angles, and calcaneal widths were determined using calcaneal axial and lateral radiographs obtained preoperatively and at last follow-up. RESULTS: Twenty (87%) of the 23 cases occurred in women, and the mean age of all patients was 65.8 years (43-90). The three men were older than 65. Five (21.7%) patients had osteopenia, and 12 (52.2%) had osteoporosis. Bone mineral density testing could not be performed in the other six patients. Clinical and radiographic results were significantly improved after surgery. CONCLUSION: Extra-articular calcaneal fractures of the joint depression type are much more common in women and occur at an older age than calcaneal fractures commonly occur. These fractures are also more common in patients with a low bone mineral density. LEVEL OF EVIDENCE: Level IV.

STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

Irisin alleviates CFA-induced inflammatory pain by modulating macrophage polarization and spinal glial cell activation.

Although the potent anti-inflammatory effects of irisin have been documented in various inflammatory disorders, its efficacy against inflammatory pain remains unexplored. Herein, we examined the therapeutic effects of irisin in a mouse model of inflammatory pain induced by complete Freund's adjuvant (CFA). Mice were divided into three groups: normal control, CFA-injected (CFA), and CFA plus irisin-treated (CFA+Irisin). The irisin-treated group exhibited a gradual reduction in mechanical allodynia and thermal hyperalgesia when compared with the CFA group. Moreover, treatment with irisin significantly upregulated the expression of M2 macrophage markers (interleukin [IL]-4 and IL-10) and downregulated M1 macrophage markers (IL-1ß, IL-6, and tumor necrosis factor-α) in the local paw tissue, dorsal root ganglion, and spinal cord tissue. However, there was no significant difference in the total number of F4/80+ macrophages in the paw tissue and dorsal root ganglion, indicating phenotypic exchange. Treatment with irisin also downregulated the expression of the glial cell activation-related markers Iba-1 and GFAP in the spinal cord tissue. To elucidate the underlying mechanisms, we detected the expression of Toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 5 (IRF5) in paw tissues, dorsal root ganglion, and spinal tissues, revealing that irisin could downregulate the expression of these proteins. Irisin alleviated inflammatory pain by modulating local tissue inflammation and peripheral and central neuroinflammation and reducing glial cell activation and M2 macrophage polarization by modulating the TLR4-MyD88-IRF5 signaling pathway. Accordingly, irisin is a promising candidate for treating inflammatory pain in various diseases.

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors.

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

Dual role of transient receptor potential ankyrin 1 in respiratory and gastrointestinal physiology: From molecular mechanisms to therapeutic targets.

The transient receptor potential ankyrin 1 (TRPA1) channel plays a pivotal role in the respiratory and gastrointestinal tracts. Within the respiratory system, TRPA1 exhibits diverse distribution patterns across key cell types, including epithelial cells, sensory nerves, and immune cells. Its activation serves as a frontline sensor for inhaled irritants, triggering immediate protective responses, and influencing airway integrity. Furthermore, TRPA1 has been implicated in airway tissue injury, inflammation, and the transition of fibroblasts, thereby posing challenges in conditions, such as severe asthma and fibrosis. In sensory nerves, TRPA1 contributes to nociception, the cough reflex, and bronchoconstriction, highlighting its role in both immediate defense mechanisms and long-term respiratory reflex arcs. In immune cells, TRPA1 may modulate the release of pro-inflammatory mediators, shaping the overall inflammatory landscape. In the gastrointestinal tract, the dynamic expression of TRPA1 in enteric neurons, epithelial cells, and immune cells underscores its multifaceted involvement. It plays a crucial role in gut motility, visceral pain perception, and mucosal defense mechanisms. Dysregulation of TRPA1 in both tracts is associated with various disorders such as asthma, Chronic Obstructive Pulmonary Disease, Irritable Bowel Syndrome, and Inflammatory Bowel Disease. This review emphasizes the potential of TRPA1 as a therapeutic target and discusses the efficacy of TRPA1 antagonists in preclinical studies and their promise for addressing respiratory and gastrointestinal conditions. Understanding the intricate interactions and cross-talk of TRPA1 across different cell types provides insight into its versatile role in maintaining homeostasis in vital physiological systems, offering a foundation for targeted therapeutic interventions.

Sex Differences in the Association between Prolonged Sitting Time and Anxiety Prevalence among Korean Adults.

Sex differences in the effect of prolonged sitting time on anxiety symptoms have not yet been explored. This study examined the sex-specific association between prolonged sitting time and anxiety prevalence in Korean adults. Community-dwelling adults aged >18 years who underwent a cross-sectional structured study survey of physical activity and mental health tests were enrolled as part of the Kangbuk Samsung Hospital Cohort Study from 2012 to 2019. The prevalence of anxiety was evaluated using the Clinically Useful Anxiety Outcome Scale (CUXOS) questionnaire. The mean daily sitting time was 7.9 ± 3.4 h in men and 6.8 ± 3.6 h in women. After adjustments for possible confounding factors, the adjusted mean CUXOS score was the highest in participants sitting for ≥10 h, followed by 5-9 h, and <5 h, in that order. In the post-hoc Bonferroni analysis, there were significant differences in the adjusted mean CUXOS scores in group comparisons. A multivariate logistic regression analysis was conducted after adjusting for potential confounding factors. A prolonged sitting time was positively associated with an increased prevalence of anxiety in both men and women, with stronger associations in women than in men. It is necessary to prevent anxiety by adjusting or reducing sitting time in adults, especially women.

The effects of medial soft tissue release for varus deformity during medial open wedge supramalleolar osteotomy: a cadaveric study.

This study was performed to investigate the effects of fibular osteotomy and release of medial soft tissues including posterior tibial tendon (PTT), and deep deltoid ligaments, which act as medial stabilizing structures in medial open wedge SMO. Twelve fresh frozen human legs were obtained and disarticulated below the knee. Experiments were conducted in four steps. First, medial open wedge tibial osteotomy was performed. Second, fibular osteotomy was performed in an inferomedial direction at the same level as the tibial osteotomy. Third, the deep deltoid ligament was released from tibial attachments. Forth, total tenotomy of the PTT was performed behind the medial malleolus. After finishing each step, contact area and peak and mean pressures were measured in the tibiotalar and talofibular joints. Fibular osteotomy after medial open wedge SMO significantly decreased mean pressure in the tibiotalar joint, mean and peak pressures in the talofibular joint. Medial soft tissue release resulted in a remarkable lateral shift and decreased tibiotalar joint loading. However, no remarkable change was observed in the tibiotalar joint during releasing medial soft tissues. The overall peak pressure distribution tended to shift more laterally compared to the value of normal alignment. In conclusion, concomitant fibular osteotomy and release of the deltoid ligament and PTT provide a useful means of minimizing tibiotalar joint stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00370-7.

Highly Tough Yet Stiff, Transparent, and Recyclable PMMA Nanocomposites Incorporating TPU Nanofibril Networks with High Thermal Stability and Strong Interfacial Adhesion.

In this paper, we develop high aspect ratio nanofibrils from a polycaprolactone-based thermoplastic polyurethane (TPU) and evaluate their performance as a toughening agent. Poly(methyl methacrylate) (PMMA) was chosen as the matrix material because of its inherent brittleness and low resistance to sudden shocks and impact. We show that the addition of as little as 3 wt % of TPU nanofibrils with an average diameter of ∼98 nm and very high aspect ratio can significantly improve both the tensile toughness (∼212%) and impact strength (∼40%) of the chosen matrix (i.e., PMMA) without compromising its original strength, stiffness, and transparency. We compare the performance of TPU nanofibrils with TPU spherical particles─the form TPU typically manifests into when melt-mixed with an immiscible polymer. Our findings highlight that the structure of TPU plays a crucial role in determining the critical concentration of TPU needed for the brittle-ductile transition of the matrix. We also provide new and valuable insights into the unique interfacial interaction (i.e., formation of fibrillar bridges) observed between the PMMA matrix and TPU. We also show that the inclusion of 3 wt % of TPU nanofibrils can notably enhance resistance to creep deformation, even at temperatures close to the glass transition temperature of the matrix. Finally, we evaluate recyclability and demonstrate that the composite containing 3 wt % of TPU nanofibrils can be mechanically recycled without losing any properties. The proposed TPU nanofibrils can withstand repeated reprocessing at temperatures up to 190 °C due to their very high melting point and thermal stability. This presents the opportunity for them to be utilized not just with amorphous PMMA, but also with a range of other materials that can be processed at or below this temperature to remarkably improve their toughness without sacrificing strength and stiffness.

Mott-Insulator State of FeSe as a Van der Waals 2D Material Is Unveiled.

We undertook a comprehensive investigation of the electronic structure of FeSe, known as a Hund metal, and found that it is not uniquely defined. Through accounting for all two-particle irreducible diagrams constructed from electron Green's function G and screened Coulomb interaction W in a self-consistent manner, a Mott-insulator phase of 2D-FeSe is unveiled. The metal-insulator transition is driven by the strong on-site Coulomb interaction in its paramagnetic phase, accompanied by the weakening of both local and nonlocal screening effects on the Fe-3d orbitals. Our results suggest that Mott physics may play a pivotal role in shaping the electronic, optical, and superconducting properties of monolayer or nanostructured FeSe.

Synergistic Layered Design of Aerogel Nanocomposite of Graphene Nanoribbon/MXene with Tunable Absorption Dominated Electromagnetic Interference Shielding.

Electromagnetic pollution presents growing challenges due to the rapid expansion of portable electronic and communication systems, necessitating lightweight materials with superior shielding capabilities. While prior studies focused on enhancing electromagnetic interference (EMI) shielding effectiveness (SE), less attention is given to absorption-dominant shielding mechanisms, which mitigate secondary pollution. By leveraging material science and engineering design, a layered structure is developed comprising rGOnR/MXene-PDMS nanocomposite and a MXene film, demonstrating exceptional EMI shielding and ultra-high electromagnetic wave absorption. The 3D interconnected network of the nanocomposite, with lower conductivity (10-3-10-2 S/cm), facilitates a tuned impedance matching layer with effective dielectric permittivity, and high attenuation capability through conduction loss, polarization loss at heterogeneous interfaces, and multiple scattering and reflections. Additionally, the higher conductivity MXene layer exhibits superior SE, reflecting passed electromagnetic waves back to the nanocomposite for further attenuation due to a π/2 phase shift between incident and back-surface reflected electromagnetic waves. The synergistic effect of the layered structures markedly enhances total SE to 54.1 dB over the Ku-band at a 2.5 mm thickness. Furthermore, the study investigates the impact of hybridized layered structure on reducing the minimum required thickness to achieve a peak absorption (A) power of 0.88 at a 2.5 mm thickness.

Prognostic Impact of TERT Promoter Mutations in Adult-Type Diffuse Gliomas Based on WHO2021 Criteria.

Mutation in the telomerase reverse transcriptase promoter (TERTp )is commonly observed in various malignancies, such as central nervous system (CNS) tumors, malignant melanoma, bladder cancer, and thyroid carcinoma. These mutations are recognized as significant poor prognostic factors for these tumors. In this investigation, a total of 528 cases of adult-type diffuse gliomas diagnosed at a single institution were reclassified according to the 2021 WHO classifications of CNS tumors, 5th edition (WHO2021). The study analyzed clinicopathological and genetic features, including TERTp mutations in each tumor. The impact of known prognostic factors on patient outcomes was analyzed through Kaplan-Meier survival and Cox regression analysis. TERTp mutations were predominantly identified in 94.1% of oligodendrogliomas (ODG), followed by 66.3% in glioblastoma, IDH-wildtype (GBM-IDHwt), and 9.2% of astrocytomas, IDH-mutant (A-IDHm). When considering A-IDHm and GBM as astrocytic tumors (Group 1) and ODGs (Group 2), TERTp mutations emerged as a significant adverse prognostic factor (p = 0.013) in Group 1. However, within each GBM-IDHwt and A-IDHm, the presence of TERTp mutations did not significantly impact patient prognosis (p = 0.215 and 0.268, respectively). Due to the high frequency of TERTp mutations in Group 2 (ODG) and their consistent prolonged survival, a statistical analysis to evaluate their impact on overall survival was deemed impractical. When considering MGMTp status, the combined TERTp-mutated and MGMTp-unmethylated group exhibited the worst prognosis in OS (p = 0.018) and PFS (p = 0.034) of GBM. This study confirmed that the classification of tumors according to the WHO2021 criteria effectively reflected prognosis. Both uni- and multivariate analyses in GBM, age, MGMTp methylation, and CDKN2A/B homozygous deletion were statistically significant prognostic factors while in univariate analysis in A-IDHm, grade 4, the Ki-67 index and MYCN amplifications were statistically significant prognostic factors. This study suggests that it is important to classify and manage tumors based on their genetic characteristics in adult-type diffuse gliomas.

Routine Stress Testing After PCI in Patients With and Without Acute Coronary Syndrome: A Secondary Analysis of the POST-PCI Randomized Clinical Trial.

Importance: The appropriate follow-up surveillance strategy for patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains unknown. Objective: To assess clinical outcomes in patients with and without ACS who have undergone high-risk PCI according to a follow-up strategy of routine stress testing at 12 months after PCI vs standard care alone. Design, Setting, and Participants: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented vs Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) trial was a randomized clinical trial that compared follow-up strategies of routine functional testing vs standard care alone 12 months after high-risk PCI. Patients were categorized as presenting with or without ACS. Patients were enrolled in the trial from November 2017 through September 2019, and patients were randomized from 11 sites in South Korea; data analysis was performed in 2022. Intervention: Patients categorized as presenting with or without ACS were randomized to either a routine functional testing or standard care alone follow-up strategy 12 months after high-risk PCI. Main Outcomes and Measures: The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years following randomization. Kaplan-Meier event rates through 2 years and Cox model hazard ratios (HRs) were generated, and interactions were tested. Results: Of 1706 included patients, 350 patients (20.5%) were female, and the mean (SD) patient age was 64.7 (10.3) years. In total, 526 patients (30.8%) presented with ACS. Compared with those without ACS, patients with ACS had a 55% greater risk of the primary outcome (HR, 1.55; 95% CI, 1.03-2.33; P = .03) due to higher event rates in the first year. The 2-year incidences of the primary outcome were similar between strategies of routine functional testing or standard care alone in patients with ACS (functional testing: 16 of 251 [6.6%]; standard care: 23 of 275 [8.5%]; HR, 0.76; 95% CI, 0.40-1.44; P = .39) and in patients without ACS (functional testing: 30 of 598 [5.1%]; standard care: 28 of 582 [4.9%]; HR, 1.04; 95% CI, 0.62-1.74; P = .88) (P for interaction for ACS = .45). Although a landmark analysis suggested that the rates of invasive angiography and repeat revascularization were higher after 1 year in the routine functional testing group, the formal interactions between ACS status and either invasive angiography or repeat revascularization were not significant. Conclusion and Relevance: Despite being at higher risk for adverse clinical events in the first year after PCI than patients without ACS, patients with ACS who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing at 12 months compared with standard care alone during follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT03217877.

The Development of an Artificial Intelligence Video Analysis-Based Web Application to Diagnose Oropharyngeal Dysphagia: A Pilot Study.

The gold standard test for diagnosing dysphagia is the videofluoroscopic swallowing study (VFSS). However, the accuracy of this test varies depending on the specialist's skill level. We proposed a VFSS-based artificial intelligence (AI) web application to diagnose dysphagia. Video from the VFSS consists of multiframe data that contain approximately 300 images. To label the data, the server separated them into frames during the upload and stored them as a video for analysis. Then, the separated data were loaded into a labeling tool to perform the labeling. The labeled file was downloaded, and an AI model was developed by training with You Only Look Once (YOLOv7). Using a utility called SplitFolders, the entire dataset was divided according to a ratio of training (70%), test (10%), and validation (20%). When a VFSS video file was uploaded to an application equipped with the developed AI model, it was automatically classified and labeled as oral, pharyngeal, or esophageal. The dysphagia of a person was categorized as either penetration or aspiration, and the final analyzed result was displayed to the viewer. The following labeling datasets were created for the AI learning: oral (n = 2355), pharyngeal (n = 2338), esophageal (n = 1480), penetration (n = 1856), and aspiration (n = 1320); the learning results of the YOLO model, which analyzed dysphagia using the dataset, were predicted with accuracies of 0.90, 0.82, 0.79, 0.92, and 0.96, respectively. This is expected to help clinicians more efficiently suggest the proper dietary options for patients with oropharyngeal dysphagia.

Case report: Dermatophytic pseudomycetoma in a domestic Korean short hair cat treated with intralesional injection of amphotericin B and oral terbinafine administration.

Dermatophytic pseudomycetoma (DPM), which is a deeper dermal and/or subcutaneous infection of dermatophytes, has been rarely reported in Domestic Korean Short Hair Cats. A 3-year-old, spayed female, domestic Korean Short Hair Cat presented with a history of crusts, nodules, and pruritus for 1 year. At the initial presentation, multifocal ulcerative nodules covered with yellowish grains were noted on her ventral thorax, abdomen, flank, and left hindlimb. Cytology of ulcerative nodules revealed degenerative neutrophils, macrophages, multinucleated giant cells, and hyphae. Histological examination of nodules revealed pyogranulomatous dermatitis with fungal plaques, and Microsporum canis and Staphylococcus aureus were identified in the culture. Therefore, the cat was diagnosed with DPM with secondary pyoderma. Oral itraconazole (10 mg/kg, once a day) was administered, but no significant improvement was observed. Therefore, intralesional (IL) injection of amphotericin B (0.6 mg/nodule) and oral administration of terbinafine (30 mg/kg, twice a day) were administered to the cat. With these medications, ulceration and the number and size of nodules decreased significantly, although large dome-shaped nodules remained. Skin lesions were treated with oral terbinafine and itraconazole administration for 5 months. However, after 6 months, recurrence of multifocal ulcerative nodules was observed, and the cat died 10 months after initial presentation. In this case, IL amphotericin B and oral terbinafine administration were partially effective in DPM treatment, suggesting that this may be an option for DPM treatment. Further studies to determine dose and frequency of IL amphotericin B in the management of DPM are warranted.

Loop-mediated isothermal amplification polymerase chain reaction in place of a modified Knott test in screening dogs for heartworm (Dirofilaria immitis) infection combined with antigen detection test.

OBJECTIVE: To improve the current recommendations for the diagnosis of canine heartworm (Dirofilaria immitis) disease. ANIMALS: Blood samples collected from 35 shelter dogs in the Republic of Korea. METHODS: Samples were tested for the presence of microfilaria using the modified Knott (MK) test and D immitis DNA using species-specific loop-mediated isothermal amplification (LAMP) PCR. The blood samples were additionally assessed for the presence of heartworm antigens using the Antigen Rapid Canine Heartworm AG Test Kit 2.0 (Bionote Co). The performance of the MK test and LAMP PCR was assessed through statistical analysis, with a paired McNemar test utilized for comparison. RESULTS: The heartworm antigen was detected in 28.5% of the subjects. Of the 10 positive animals, the MK test detected microfilaria in 4 of 35 (11.4%) animals, and LAMP PCR detected D immitis DNA in 6 of 35 (17.1%). The results of this study indicate that the LAMP PCR showed more positive results in samples compared to the conventional MK test. CLINICAL RELEVANCE: The D immitis-specific LAMP PCR assay has the potential to function as an alternative to current detection methods. It could complement the existing antigen detection tests in diagnosing canine heartworm infections.

GLP-1 and Its Derived Peptides Mediate Pain Relief Through Direct TRPV1 Inhibition Without Affecting Thermoregulation.

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on the transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1 and an antagonist of GLP-1, exendin 9-39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9-39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, the exendin 9-39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund's adjuvant (CFA) and spared nerve injury (SNI) in mice, without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9-39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9-39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among exendin 9-39 fragments, exendin 20-29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, proposing exendin 20-29 as a promising therapeutic candidate.

MRI Scoring Systems for Predicting Isocitrate Dehydrogenase Mutation and Chromosome 1p/19q Codeletion in Adult-type Diffuse Glioma Lacking Contrast Enhancement.

Background According to 2021 World Health Organization criteria, adult-type diffuse gliomas include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and astrocytoma, IDH-mutant, even when contrast enhancement is lacking. Purpose To develop and validate simple scoring systems for predicting IDH and subsequent 1p/19q codeletion status in gliomas without contrast enhancement using standard clinical MRI sequences. Materials and Methods This retrospective study included adult-type diffuse gliomas lacking contrast at contrast-enhanced MRI from two tertiary referral hospitals between January 2012 and April 2022 with diagnoses confirmed at pathology. IDH status was predicted primarily by using T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign, followed by 1p/19q codeletion prediction. A visual rating of MRI features, apparent diffusion coefficient (ADC) ratio, and relative cerebral blood volume was measured. Scoring systems were developed through univariable and multivariable logistic regressions and underwent calibration and discrimination, including internal and external validation. Results For the internal validation cohort, 237 patients were included (mean age, 44.4 years ± 14.4 [SD]; 136 male patients; 193 patients in IDH prediction and 163 patients in 1p/19q prediction). For the external validation cohort, 35 patients were included (46.1 years ± 15.3; 20 male patients; 28 patients in IDH prediction and 24 patients in 1p/19q prediction). The T2-FLAIR mismatch sign demonstrated 100% specificity and 100% positive predictive value for IDH mutation. IDH status prediction scoring system for tumors without mismatch sign included age, ADC ratio, and morphologic characteristics, whereas 1p/19q codeletion prediction for IDH-mutant gliomas included ADC ratio, cortical involvement, and mismatch sign. For IDH status and 1p/19q codeletion prediction, bootstrap-corrected areas under the receiver operating characteristic curve were 0.86 (95% CI: 0.81, 0.90) and 0.73 (95% CI: 0.65, 0.81), respectively, whereas at external validation they were 0.99 (95% CI: 0.98, 1.0) and 0.88 (95% CI: 0.63, 1.0). Conclusion The T2-FLAIR mismatch sign and scoring systems using standard clinical MRI predicted IDH and 1p/19q codeletion status in gliomas lacking contrast enhancement. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Badve and Hodges in this issue.

Exploring the Association between Elevated Anxiety Symptoms and Low Skeletal Muscle Mass among Asymptomatic Adults: A Population-Based Study in Republic of Korea.

Individuals with mental health problems are at higher risk of musculoskeletal diseases. However, the association between low muscle mass (LMM) and anxiety symptoms remains uninvestigated. This cross-sectional study enrolled 174,262 adults (73,833 women, 100,429 men), aged 18 to 89, who completed the anxiety scale and body composition analyses. Using bio-electrical impedance analysis, skeletal muscle mass index (SMI) was calculated based on appendicular skeletal muscle mass (ASM) (kg)/height (m2). LMM was defined as SMI < 7.0 kg/m2 in men and <5.4 kg/m2 in women. Anxiety symptoms were screened using the Clinical Useful Anxiety Outcome Scale (CUXOS) with cut-off scores of 20, 30, and 40. Multivariable logistic regression analyses were performed. LMM prevalence was 20.17% in women, 3.86% in men (p < 0.001). The prevalence of anxiety symptoms in LMM group decreased from mild (CUXOS > 20: women, 32.74%, men, 21.17%) to moderate (CUXOS > 30: 13.34%, 7.32%), to severe anxiety symptoms (CUXOS > 40: 4.00%, 1.73%). In multivariable-adjusted models, LMM was associated with mild (aOR (95% confidence interval)), women, 1.13 (1.08-1.17); men, 1.17 (1.08-1.27)), moderate (1.17 (1.11-1.24); 1.35 (1.19-1.53) and severe anxiety symptoms (1.18 (1.07-1.3), 1.36 (1.06-1.74)), demonstrating an increased risk of ORs with escalating anxiety severity. LMM was independently associated with a higher prevalence of anxiety symptoms.