Migraine is a prevalent neurological disorder frequently accompanied by auditory symptoms such as tinnitus and hyperacusis. While their associations suggest shared neural mechanisms, objective evidence regarding the specific involvement of brainstem-mediated auditory efferent pathways in migraine remains limited. The medial olivocochlear reflex (MOCR) and the middle ear muscle reflex (MEMR) are two key auditory protective mechanisms, yet their integrity in migraine patients remains to be investigated. This study aimed to evaluate the functional integrity of the MOCR and MEMR pathways in migraine patients with and without comorbid tinnitus. In this cross-sectional study, 143 participants were classified into four groups based on strict diagnostic criteria: healthy controls (HC, n = 44), tinnitus-only (T, n = 49), migraine-only (M, n = 25), and migraine with tinnitus (TM, n = 25). Groups were matched for age, sex, and hearing thresholds. All participants underwent comprehensive audiological assessments, including pure-tone audiometry, ipsilateral and contralateral acoustic reflex threshold (ART) testing to assess MEMR function, and distortion-product otoacoustic emissions (DPOAE) with contralateral suppression evaluation to assess MOCR function. The migraine group (M) demonstrated significantly elevated contralateral ART (indicating MEMR impairment) at 500 Hz and 1000 Hz (p < 0.001) and globally reduced DPOAE suppression (reflecting MOCR dysfunction) (p < 0.001) compared to healthy controls. The TM group exhibited a similar pattern of MOCR and MEMR dysfunction to the M group, with no significant additive effect from tinnitus comorbidity. A clear gradient of contralateral ART impairment was observed across groups: HC < T < (M ≈ TM). Ipsilateral ART results showed less consistent abnormalities. Migraine may be associated with specific dysfunction of brainstem auditory efferent pathways, particularly affecting both MOCR and MEMR systems, independent of peripheral hearing status. The convergent abnormalities in migraine patients with and without tinnitus indicate that auditory efferent disruption may be an intrinsic component of migraine pathophysiology. These findings support the potential of contralateral ART as an objective biomarker of migraine-related auditory pathway involvement, highlighting the clinical value of auditory assessment in migraine management and providing insights for the development of targeted therapeutic strategies.
To evaluate factors associated with inpatient swallowing management changes following supraglottoplasty in infants and to assess postoperative swallowing trajectories using IDDSI levels. Retrospective cohort study. Single tertiary pediatric center. Infants (<12 months) undergoing supraglottoplasty between 2017 and 2024. Neuro/syndromic diagnosis, prematurity, airway findings, and perioperative factors. Primary outcome was SLP-recommended change in feeding/swallowing management (e.g., IDDSI level modification, thickening, pacing, or NPO status). Secondary outcomes included IDDSI level transitions over time. Of 132 patients, 68 (52%) received inpatient SLP evaluation; 15/68 (22%) required feeding plan modification. Neuro/syndromic diagnosis was associated with increased odds of inpatient feeding modification (OR 5.94, 95% CI 1.38-25.33; p = 0.039). Most patients demonstrated stable or improved IDDSI levels over time. Inpatient SLP evaluation frequently alters feeding management in high-risk infants following supraglottoplasty. These findings support a risk-stratified rather than universal consultation strategy.
To investigate the role of Notch2-expressing regulatory T cells (Notch2+ Tregs) in modulating the function of dendritic cells (DCs) and their impact on the development of allergic rhinitis (AR). Peripheral blood mononuclear cells (PBMC) from patients with allergic rhinitis (AR) and Control groups were analyzed by flow cytometry to quantify Notch2+ Tregs. Murine T cells were isolated and transduced with a lentiviral vector overexpressing Notch2 to assess changes in the immunosuppressive function of Tregs. Scanning electron microscopy (SEM) was performed to visualize the morphological interactions between Tregs and Bone marrow-derived dendritic cells (BMDCs). BMDCs were cocultured with Notch2-overexpressing or control Tregs in direct-contact and Transwell coculture systems to evaluate changes in surface MHC class II (MHC II) expression. In vivo, Notch2-overexpressing Tregs were adoptively transferred into a conventional AR mouse model, after which the Treg and DC frequencies, surface MHC II expression, and allergic inflammatory responses were assessed. Patients with AR had a significantly lower frequency of peripheral Notch2+ Tregs than controls (P < 0.01), and Notch2+ Treg frequency was negatively correlated with allergen-specific IgE levels and TNSS (P < 0.01). In vitro, Notch2 enhanced the immunosuppressive function of Tregs, increased MHC II expression on Tregs, and decreased MHC II expression on DCs. In vivo, adoptive transfer of Notch2-overexpressing Tregs significantly alleviated allergic inflammation in AR mice by reducing MHC II expression on DCs (P < 0.05). Notch2 attenuates allergic inflammation in AR by enhancing Treg immunosuppressive function and downregulating MHC II expression on DCs. Notch2 in Tregs may represent a novel therapeutic target for allergic airway diseases.
The use of monopolar cautery is regarded as a contraindication in cochlear implant (CI) recipients, despite a large amount of contradicting data. The objectives are as follows: (1) Evaluate the effects of high-powered electrocautery on CI devices. (2) Record any high-powered electrocautery induced temperature changes. After IACUC approval, 12 manufacturer-donated CIs were implanted in two anesthetized pigs. All devices underwent pre-study integrity checks; six had onsite impedance testing, while six received post-cautery analysis. Fifty watts coagulation was applied for 20 min at sites 1-15 cm from the CI. Bluetooth thermometers monitored three sites of temperatures. Devices were explanted for analysis. Stata 17.0 was used for statistical analysis. A p-value < 0.05 was considered statistically significant. Outcome measurements were as follows: (1) Changes in the temperature. (2) Changes to the implanted CIs during electrocautery. (3) CI integrity analysis following electrocautery. The mean temperatures at the three sites (a*, b*, c*) was 32.9°C-38.8°C. Maximum absolute temperature changes averaged 4.1°C (95% CI: 1.4-6.8) for scalp measurements and 2.9°C (95% CI: 1.0-4.9) for round window measurements. Neither time (p = 0.09) nor distance (p = 0.64) generated significant scalp temperature changes. Devices were stratified by proximity. Mean maximum temperature changes showed a gradient by distance. Differences in device proximity were not statistically significant. Postimplantation device analysis was performed on six devices, and all passed the manufacturer in-depth device analysis. This controlled experimental evidence, demonstrating 100% device integrity across all tested conditions, challenges current manufacturer contraindications and supports evidence-based guideline revision. N/A.
In Parkinson disease (PD), enhanced beta frequency band activity in cortico-basal ganglia networks has been proposed as a possible biomarker for adaptive deep brain stimulation (DBS). Previous studies demonstrated enhanced beta frequency peaks both in the acute Haloperidol (HALO) and the chronic 6-hydroxydopamine (6-OHDA) rat models of parkinsonism. Beta peaks decreased after apomorphine (APO) injection or with DBS of the subthalamic nucleus (STN). We investigate changes in motor cortical oscillatory activity using fractal dimension (FD) in the HALO and the 6-OHDA rat models of PD. Additionally, we test a support vector machine (SVM) model to predict neuronal dynamics in the 6-OHDA PD model which has been used earlier in an acute rat model of PD. In the HALO model, electrocorticogram (ECoG) was recorded from the motor cortex (MCtx) (1) during basal activity, (2) after injection of HALO (0.5 mg/kg), and (3) after subsequent APO injection (1 mg/kg). For the chronic 6-OHDA model, MCtx-ECoG recordings were obtained (1) during basal activity, and (2) during STN DBS. Higuchi's FD algorithm and SVM-based classification were utilized for analysis. Average FD values in the MCtx were higher in both PD models compared to controls (P < 0.001). APO injection (P < 0.001) and STN DBS (P < 0.05) reduced average FD values in both models. The SVM model achieved 80% classification accuracy and an AUC of 0.86 in the 6-OHDA rat model. The non-linear analysis of FD reveals changes in cortical oscillatory patterns in rodent models of PD. SVM-based predictions demonstrate potential for classifying altered neural activity, which may offer future strategies for adaptive DBS.
To elucidate the association between olfactory dysfunction (OD) and metabolic syndrome components. PubMed (National Library of Medicine-National Institutes of Health), Scopus (Elsevier), CINAHL Complete (EBSCOhost), and the Cochrane Library (Wiley) databases were searched from inception through March 23rd, 2026. Eligible studies were stratified by olfactory dysfunction or different metabolic parameters. Extracted variables included metabolic measures (BMI, waist circumference, cholesterol levels, blood pressure, fasting glucose, HbA1c), olfactory scores, and comorbidities. Data were summarized as means, proportions (%), and corresponding differences (Δ) with 95% confidence intervals (CI). Risk of bias was evaluated using the Joanna Briggs Institute (JBI) tool. A total of 4045 studies were screened using Covidence, with 47 studies included for data analysis. Participants with OD demonstrated greater odds of smoking (OR = 1.2, p = 0.002), antihypertensive medication use (OR = 1.2, p = 0.03), atrial fibrillation (OR = 1.7, p < 0.00001), heart failure (OR = 1.6, p = 0.008), and diabetes (OR = 1.2, p < 0.0001). Additionally, adults with OD had higher fasting glucose (MD +0.8 mg/dL; p < 0.00001), lower total cholesterol (MD -6.0 mg/dL; p = 0.04), and lower HDL levels (MD -1.8 mg/dL; p < 0.00001). Individuals with diabetes and elevated BMI had significantly lower TDI composite scores (MD -5.6; p < 0.00001 and MD -2.8; p < 0.00001, respectively). Patients with OD showed increased rates of conditions that comprise and contribute to metabolic syndrome. Conversely, individuals with metabolic disorders exhibited lower mean scores on olfactory testing, indicating a bidirectional relationship between olfactory impairment and metabolic dysregulation.
Osteoporosis and fragility fractures are major causes of disability and loss of independence in older adults. Prospective evidence on the associations between allergic diseases and these outcomes in older populations remains limited, particularly regarding coexistence patterns and allergic disease burden. This study therefore evaluated these associations in a large prospective cohort of older adults. UK Biobank participants aged 60 years or older and free of the corresponding outcome at baseline were included. Baseline allergic rhinitis, atopic dermatitis, and asthma were identified from inpatient records and self-report and were further summarised as coexistence patterns and allergic disease burden. Associations with incident major osteoporotic fracture and hospital-recorded osteoporosis, ascertained from linked inpatient hospital records, were evaluated using multivariable Cox proportional hazards models adjusted for sociodemographic, lifestyle, psychosocial, and comorbidity factors. Robustness was assessed through multiple prespecified sensitivity analyses. Over a median follow-up of 13.8 years, 11,442 major osteoporotic fracture events and 12,096 cases of hospital-recorded osteoporosis occurred among 190,594 and 191,881 participants, respectively. In fully adjusted models, asthma was associated with major osteoporotic fracture (hazard ratio 1.20, 95% confidence interval 1.14-1.27) and hospital-recorded osteoporosis (1.45, 1.38-1.52). The coexistence of allergic rhinitis and asthma was also associated with both outcomes (major osteoporotic fracture: 1.36, 1.16-1.59; hospital-recorded osteoporosis: 1.46, 1.26-1.69). In addition, allergic disease burden showed a graded association with both outcomes. Findings were broadly consistent across sensitivity analyses. In older adults, asthma, particularly when coexisting with allergic rhinitis, and greater allergic disease burden were associated with incident hospital-recorded osteoporosis and major osteoporotic fracture. These observational findings should be interpreted cautiously and require confirmation in further studies.
With global population ageing, frailty poses a major threat to healthy independence in the elderly. However, whether metabolic syndrome (MetS) increases the risk of frailty is still unclear. This study investigated this association in two prospective cohorts. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS) and the English Longitudinal Study of Ageing (ELSA). Logistic and linear regression were utilized in cross-sectional analyses to assess associations between MetS and frailty and the frailty index (FI), respectively. Cox models were employed in longitudinal analyses to evaluate whether baseline MetS predicted the development of frailty during follow-up among participants who were non-frail at study entry. Additionally, Kaplan-Meier (KM) survival analysis was performed to assess cumulative frailty incidence across different MetS status groups. A total of 14,604 participants were included at baseline (CHARLS: 8425; ELSA: 6179), with 10,763 followed longitudinally (CHARLS: 5647; ELSA: 5116). After multivariable adjustment, MetS was significantly associated with increased frailty prevalence (CHARLS: OR = 1.45, 95%CI 1.26-1.66; ELSA: OR = 1.49, 1.27-1.75) and higher FI (CHARLS: β = 0.020, 0.015-0.024; ELSA: β = 0.026, 0.019-0.033). Longitudinally, MetS predicted elevated frailty risk (CHARLS: HR = 1.28, 1.16-1.42; ELSA: HR = 1.20, 1.06-1.36). KM survival analysis revealed that participants with MetS had a significantly higher cumulative incidence of frailty in both cohorts. Our findings suggest that MetS may play a significant role in the development and progression of frailty. Accordingly, targeting MetS could be a viable approach for preventing or delaying the onset of frailty in older adults.
The optimal treatment for oropharyngeal squamous cell carcinoma (OPSCC) remains undetermined. The choice between primary surgery with risk-adapted adjuvant (chemo)radiotherapy and primary (chemo)radiotherapy is left to therapeutic teams and patients. We compared survival outcomes between these approaches in large cohort stratified by p16 status. Nonmetastatic OPSCC patients diagnosed between 2007 and 2021, with determined p16 status and treated with curative primary surgery or primary (chemo)radiotherapy, were retrospectively reviewed. Univariate, multivariate, and propensity score matching analyses were performed to compare progression-free survival (PFS) and overall survival (OS). Of 696 identified patients, 642 met the inclusion criteria: 329 patients (51.3 %) underwent primary surgery and 313 (48.7 %) received primary (chemo)radiotherapy. p16 positivity was confirmed in 34 % and 38 % of patients, respectively. In the unmatched cohort, upfront surgery was associated with superior PFS and OS in the p16-negative group, but not in the p16-positive group. After propensity score matching, no survival advantage was observed for either treatment scenario in the p16-negative group (surgery vs. non-surgery, 5-year PFS: 52 vs. 43 %, p = 0.259; OS: 54 vs. 47 %, p = 0.396) or the p16-positive group (5-year PFS: 84 vs. 84 %, p = 0.988; OS: 86 vs. 87 %, p = 0.868). When prognostic factors are adequately balanced, primary surgery with risk-adapted adjuvant therapy and primary (chemo)radiotherapy provide similar survival outcomes in both p16-positive and p16-negative OPSCC. Treatment decisions should be based on shared decision-making, considering patient preferences, expected oncological and functional outcomes, and institutional experience.
Neoplasms of the mandibular ascending ramus and condyle cause facial asymmetry, trismus, malocclusion, swelling in the temporomandibular joint area, and pain. Conventional surgeries require an external incision, with a risk of facial nerve injury and leaving a scar. This study aimed to establish a minimally invasive approach for mandibular ramus-condyle tumour resection, using intraoperative navigation and endoscopes. The safety and feasibility were assessed by cadaveric dissection. Nine patients with osteomas or osteochondromas occurring from the mandibular ascending ramus and condyle were included in this study. All patients underwent navigation-assisted transoral endoscopic resection of the tumours. Cadaveric dissection demonstrated how the transoral endoscopic approach to the mandibular ramus-condyle unit was established and enabled analysis of the anatomical structures. Mandibular tumours were successfully resected in all the patients, with a low incidence of postoperative complications, and the morphologies and functions of the mandible were satisfactorily preserved. The results indicate that navigation-assisted transoral endoscopic surgeries for the mandibular ramus-condyle tumours are feasible and effective in a preliminary clinical setting. Studies with larger sample sizes and further assessment of the navigation system are required to confirm the accuracy of the surgeries.
The mammalian vestibular system has two types of sensory receptors (hair cells), type I and type II. Understanding the roles of type I and II hair cells in the vestibular system's control of motor behaviors is difficult because most primary vestibular neurons receive inputs from both hair cell types. To test if type I hair cells are required for motor behaviors, we ablated them from peripheral zones of vestibular epithelia in young adult (3-6 months) Fbxo2CreERT2::Rosa26DTA (experimental) mice of both sexes, then examined motor behaviors and brainstem neuronal responses. Over 90% of peripheral type I hair cells were ablated from vestibular organs by one week post-tamoxifen, while central type I and all type II hair cell numbers did not change significantly out to 8 weeks post-tamoxifen. Right after ablation, mice displayed no obvious locomotor abnormalities. However, they could only balance on a rotarod or beam for a few seconds, and gains of the horizontal vestibulo-ocular reflex were reduced by 50%. Deficits persisted to 8 weeks post-tamoxifen, with one exception: 3-6 month old mice showed partial recovery of rotarod performance after 4 weeks post-tamoxifen, likely due to adaptive motor strategies. Remarkably, 16 month-old mice with type I hair cell ablation failed to recover rotarod function. Motion-induced CFOS expression in vestibular brainstem neurons was nearly eliminated after hair cell ablation, suggesting inputs from vestibular organs had changed significantly. This study demonstrates that peripheral type I hair cells are essential for a vestibular reflex and for some tasks requiring balance and motor coordination.Significance Statement This study demonstrates that a specific subpopulation of vestibular sensory receptor cells (peripherally located type I hair cells) is required in adult mice to maintain normal vestibular function, including the vestibulo-ocular reflex, balance and motor coordination, and neuronal responses to a motion stimulus. These findings have implications for the underlying pathology in some types of balance disorders and may inform new strategies to restore vestibular function after hair cell damage or degeneration.
The objective of this study was to evaluate the effectiveness and adverse effect profile of prophylactic levetiracetam in preventing epilepsy after traumatic brain injury (TBI). This retrospective cohort study used the TriNetX Research Network, encompassing >150 million patients. Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded were included. Patients with pre-existing epilepsy, seizures on the day of injury, or prior levetiracetam exposure were excluded. The cohort (n = 51,263) was stratified into mild (GCS 13-15; n = 33,625) and severe (GCS 3-8; n = 10,805) TBI. The risk of early (<7 days) and late (<1 year) epilepsy was assessed using Cox proportional hazards models adjusted for known predictors. Adverse events were evaluated for up to 5 years. Levetiracetam was administered to 14,630 patients (30%). After adjustment, levetiracetam reduced early epilepsy in severe TBI (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.31-0.97, p = 0.04) but not in mild TBI (HR = 0.85, 95% CI = 0.45-1.61, p = 0.61). Levetiracetam did not reduce late epilepsy in either mild (HR = 1.00, 95% CI = 0.79-1.15, p = 0.997) or severe (HR = 0.90, 95% CI = 0.68-1.19, p = 0.45) TBI. Older age, cerebral edema, and subdural hemorrhage were consistent risk factors. Adverse outcomes included impaired memory and awareness, metabolic disorders, and psychiatric symptoms. Levetiracetam prophylaxis reduced early epilepsy only in severe TBI and conferred no long-term protection. Given its adverse effect burden, routine prophylaxis should be limited to severe TBI or high-risk patients. These findings support re-evaluation of current seizure prophylaxis guidelines, which are based on older antiseizure medications and predate large-scale real-world data. ANN NEUROL 2026.
Patient-specific 3D-printed temporal-bone (PS-TB) models may improve rehearsal, planning and navigation in temporal-bone surgery, yet their optimal use-cases, required fidelity, and desirable enhancements remain undefined from the surgeon's perspective. The purpose is to investigate surgeons' preferred use-cases, physical resemblance requirements, and valuable enhancements for PS-TB models. Otosurgeons from national and international societies were surveyed in the period December 2024-April 2025. Respondents were stratified into either high-volume (HV) surgeons defined as performing ≥50 mastoidectomies per year or low-volume (LV) surgeons. The survey consisted of 88 questions comprising Likert-scale rating (1-5) and free-text responses. Group means were compared with Welch t-tests. Of the 87 participating surgeons, 69 completed the questionnaire (79% response rate; 55 LV/32 HV). PS-TB models were perceived most clinically relevant for pre-operative rehearsal in cases of anatomical malformation (4.14 LV vs 3.62 HV) and least relevant in tympanoplasty and stapes surgical cases. Overall mean perceived pre-operative relevance across procedures was higher for LV than HV surgeons (2.80 vs 2.36; p < 0.01). The same was found for intraoperative use (2.67 vs 2.30; p < 0.05). Critical anatomical landmark structures should have sub-millimeter precision, in particular the facial nerve and lateral semicircular canal (≥4.3). Model enhancements that support visualization of critical structures are rated likely to add clinical value. Otosurgeons perceive PS-TB models as a relevant tool for cases of malformed anatomy or otherwise complex surgery, especially among LV surgeons. However, models need to replicate critical landmarks with sub-millimeter accuracy. These requirements define a trajectory towards improving model value for clinicians.
Achieving negative surgical margins remains a critical determinant of local recurrence and survival in head and neck cancer (HNC) surgery. Current intraoperative margin assessment techniques, including frozen section analysis, suffer from sampling errors and procedural delays. Tumor-targeted fluorescence imaging offers real-time tumor visualization but lacks standardized quantitative approaches for clinical decision-making. We developed a Tumor Probability Mapping (TPM) framework using panitumumab-IRDye800 fluorescence imaging in 16 HNC patients. Ex vivo specimens and gross tissue sections were imaged using near-infrared fluorescence systems. A total of 5,442 regions of interest (ROIs) were manually distributed across fluorescence images of gross specimen sections validated by histopathology. Signal-to-background ratios (SBR) were calculated and used to train the following predictive models: generalized linear model fit standard logistic regression (MATLAB, glmfit), standard logistic regression (R, LOG), mixed-effects logistic regression (GLMER), and Bayesian mixed-effects regression (BRMS). Model performance was evaluated using receiver operating characteristic and area under the curve (ROC-AUC) analysis, sensitivity, specificity, along with beta-calibration and model fit. All models demonstrated excellent (> 90%) discriminative ability between tumor and normal tissue. The glmfit model, selected for clinical implementation, achieved 95.8% accuracy, 90.8% sensitivity, 98.8% specificity, and an AUC of 0.989 on test data. The final TPM algorithm provides real-time probability assessment of tumor presence based on fluorescence intensity quantified by histopathology validated historical data. TPM represents a significant advancement in fluorescence-guided surgery by converting qualitative fluorescence signals into quantitative probability assessments validated against histopathology. This approach provides surgeons with standardized, real-time tumor probability information that extends beyond qualitative assessments and/or binary threshold determinations, potentially improving surgical outcomes by enhancing margin assessment and reducing local recurrence rates.
Subperiosteal implants were historically conceived as fixation-based devices rather than osseointegrated implants and were progressively abandoned due to unfavorable long-term outcomes. Recent advances in digital planning and additive manufacturing have led to the reintroduction of custom-made titanium subperiosteal implants; however, direct clinical evidence of osteointegration in humans has not been reported. This case series presents three patients rehabilitated with additively manufactured titanium subperiosteal implants who underwent surgical re-entry for the removal of loosened osteosynthesis screws associated with recurrent, non-infective inflammatory episodes. In all cases, intraoperative exploration revealed partial to complete bone coverage of the subperiosteal implant framework and the associated titanium fixation screws. Two patients showed complete bone coverage of the implant arms anchored to basal bone structures, while early bone apposition was observed in the third case. Removal of the loosened screws resulted in complete resolution of clinical symptoms in all patients. These findings provide direct clinical evidence of bone apposition and ossification and suggest the possibility of osseointegration in modern subperiosteal implants. Further clinical studies with larger cohorts and long-term follow-up are required to determine the impact of bone coverage and potential osteointegration on the long-term survival of contemporary subperiosteal rehabilitations.
The aggressive and immunotherapy-resistant characteristics of anaplastic thyroid carcinoma (ATC) are driven by an immunosuppressive tumor microenvironment and intercellular crosstalk; however, its regulatory mechanisms remain poorly understood. Here, we identified Glucose-6-Phosphate Isomerase (GPI) as a pivotal metabolic immune checkpoint that orchestrates myeloid cells-driven immunosuppression in ATC. We demonstrated that GPI enhances the hexosamine biosynthesis pathway to promote O-GlcNAcylation of thrombospondin-1 (THBS1) at serine-1068. This site-specific modification competes with ubiquitination to stabilize THBS1 and augment its secretion. Released THBS1 engages macrophages to trigger a CEBPB-dependent transcriptional program that drives the expression of the chemokine CCL2. Macrophage-derived CCL2 then acts on tumor-associated neutrophils, promoting their STAT3-dependent differentiation into polymorphonuclear myeloid-derived suppressor cells, which ultimately suppresses CD8+ T cell function. Genetic deletion of either GPI or THBS1 robustly inhibited tumor growth and reversed immunosuppression in vivo. To intervene this axis, we repurposed the multi-kinase inhibitor Regorafenib as a novel GPI inhibitor. We confirmed that Regorafenib disrupts this entire axis and, in combination with anti-PD-1 therapy in ATC, overcomes immunosuppression to elicit potent anti-tumor immunity. Our studies revealed the GPI/O-GlcNAcylation/THBS1 signal as a master regulator of myeloid cell crosstalk and established a novel therapeutic strategy for targeting this metabolic checkpoint to potentiate ATC immunotherapy.
Synaptopathy is a common cochlear pathology involving damage, dysfunction, and loss of auditory-nerve synapses with sensory hair cells. Cochlear synaptopathy can occur following sound overexposure due to glutamate excitotoxicity. Synaptopathy is undetectable with the clinical audiogram and is widely hypothesized to cause "hidden hearing loss," i.e., impaired perception of speech and other complex sounds under challenging listening conditions. However, evidence that cochlear synaptopathy causes hidden hearing loss is mixed, and the specific aspects of auditory perception impacted by synaptopathy remain unknown. We quantified the effects of excitotoxic cochlear synaptopathy/deafferentation on behavioral tone-in-noise detection in trained budgerigars (Melopsittacus undulatus). The budgerigar is a parakeet species with the capacity to mimic speech and highly developed complex-sound discrimination abilities. Synaptopathy was induced through excitotoxicity with intracochlear kainic-acid infusions. Tone signals varied in duration and onset time relative to the start of the noise. Animals with cochlear synaptopathy showed normal detection of 200-ms tones regardless of whether tones were delayed by 100 ms relative to the start of the noise or had the same onset time as the noise. In contrast, detection of shorter 20-ms tones was normal for delayed tones but significantly impaired for tones sharing the same onset time as the noise. These results provide the first evidence to our knowledge that synaptopathy selectively impairs perception of acoustic onset cues. In humans, impaired perception of onset cues by cochlear synaptopathy would represent a major challenge to real-world communication due to the extensive information carried by acoustic onset cues in speech.
Otologic surgery provides safe and effective treatment for a variety of ear and skull base pathologies. However, even routine procedures are not without risk of serious surgical complications. Ear surgery requires sub-millimeter tolerances near a variety of critical structures in a complex anatomic region. As such, preoperative computed tomography (CT) can be helpful to surgeons and radiologists for identifying anatomic variants that can influence surgical technique, and which may predispose patients to surgical complications. However, the analysis and reporting of temporal bone CT is not always detailed, consistent, or comprehensive. The purpose of this narrative review is to illustrate important landmarks and anatomic variants on the preoperative temporal bone CT, with special attention towards features important in otologic surgery and that may impact surgical risk. These critical landmarks and variants can be recalled using the mnemonic "Making Miracles Involves Focused Vision," which provides an educational framework for the major regions that should be systematically reviewed in the imaging report: mastoid, middle ear, inner ear, facial nerve, and vascular anatomy.
Older adults bear a substantial and increasing share of the cancer burden in Asia, yet its temporal trends, geographical heterogeneity, and inequalities remain insufficiently characterised. Using estimates from the Global Burden of Disease Study 2023, we assessed cancer incidence, mortality, and disability-adjusted life-years (DALYs) among adults aged 65 years and older across 34 Asian countries from 1990 to 2023, and examined demographic and epidemiological drivers, variations by location, sociodemographic index, age, and sex, with projections to 2050. In 2023, this population experienced 4.59 million new cancer cases, 3.27 million deaths, and 57.49 million DALYs. East Asia had the highest burden, whereas South Asia had the lowest rates but the fastest increases in incidence and mortality. Lung cancer remained the leading cancer, and digestive system cancers accounted for the greatest system-level burden. Population growth and population aging were the main contributors to rising cases and deaths, while favourable epidemiological changes were observed only in East and Southeast Asia. By 2050, the age-standardised incidence rate is projected to reach 1146.25 per 100,000 in females and 1518.97 in males. These findings call for more equitable and age-responsive cancer prevention and care strategies across Asia.
The middle meningeal artery (MMA) often traverses a bony canal, rendering it vulnerable during craniotomy. In moyamoya disease (MMD), it serves as a collateral pathway for cerebral perfusion, making vessel preservation essential during bypass surgery. This study examined the anatomy of MMA bony canals in dry skulls and compared findings in patients with MMD and atherosclerotic cerebrovascular disease (ACVD). A total of 175 adult and pediatric dry skulls and cranial CT scans of MMD (n = 100) and ACVD (n = 100) patients were analyzed retrospectively. The relationship of bony canals to the convergence of the coronal, sphenofrontal, and sphenoparietal sutures, serving as an anatomical landmark, was assessed. Bony canals containing the frontal MMA branch were present in 91.2% of adult skulls (≥ 18 years). Before fontanelle closure (< 2 years), the incidence was 1.8%, increasing to 47.7% in skulls ≥ 2 years (p < 0.0001). The mean canal length was 12.0 ± 5.9 mm in adult skulls, 10.1 ± 4.5 mm in skulls ≥ 2 years, and 7.5 ± 3.5 mm in skulls < 2 years (p = 0.212). In adult skulls, the mean distances of the canal entry and exit points posterior to the landmark were 11.6 ± 4.8 mm and 13.8 ± 6.4 mm, respectively. Parietal branch canals were rare (≤ 12.9%) and typically located below the squamous suture. Clinically, MMD patients were younger than ACVD patients (41.6 ± 12.2 vs 55.0 ± 11.6 years, p < 0.0001) and had a similar prevalence of frontal branch canals (80.0% vs 84.0%, p = 0.36). Bony canals were longer (15.9 ± 9.7 mm vs 13.3 ± 6.2 mm, p = 0.02) and wider (1.6 ± 0.4 mm vs 1.3 ± 0.5 mm, p < 0.0001) in MMD patients. After fontanelle closure, the likelihood of the MMA traversing a bony canal located within one thumb's width posterior to the pterion increases with age. Comprehensive knowledge of MMA anatomy is crucial for its preservation during bypass surgery.