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Abstract Background Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. Methods This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. Results When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. Conclusions This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central–peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central–peripheral system interaction mechanisms involved in autoimmune diseases.

Abstract Background Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. Methods In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. Results The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. Conclusions The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Profound congenital sensorineural hearing loss (SNHL) prevents children from developing spoken language. Cochlear implantation and auditory brainstem implantation can provide partial hearing sensation, but language development outcomes can vary, particularly for patients with inner ear malformations and/or cochlear nerve deficiency (IEM&CND). Currently, the peripheral auditory structure is evaluated through visual inspection of clinical imaging, but this method is insufficient for surgical planning and prognosis. The central auditory pathway is also challenging to examine in vivo due to its delicate subcortical structures. Previous attempts to locate subcortical auditory nuclei using fMRI responses to sounds are not applicable to patients with profound hearing loss as no auditory brainstem responses can be detected in these individuals, making it impossible to capture corresponding blood oxygen signals in fMRI. In this study, we developed a new pipeline for mapping the auditory pathway using structural and diffusional MRI. We used a fixel-based approach to investigate the structural development of the auditory-language network for profound SNHL children with normal peripheral structure and those with IEM&CND under 6 years old. Our findings indicate that the language pathway is more sensitive to peripheral auditory condition than the central auditory pathway, highlighting the importance of early intervention for profound SNHL children to provide timely speech inputs. We also propose a comprehensive pre-surgical evaluation extending from the cochlea to the auditory-language network, showing significant correlations between age, gender, Cn.VIII median contrast value, and the language network with post-implant qualitative outcomes.

PurposeWe aimed to evaluate the spontaneous neuronal activity and functional connectivity pattern variations using resting-state functional magnetic resonance imaging (rs-fMRI) measures, such as amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), and functional connectivity (FC), in patients with thyroid-associated ophthalmopathy (TAO).MethodA total of 24 active TAO patients, 26 inactive TAO patients, and 27 matched healthy controls (HCs) were included. First, ALFF and fALFF were used to detect local neural activity changes, the MRI data were analyzed, and regions with group differences were taken as seeds. Second, FC analysis was performed to explore the altered connection between seeds and other brain regions. A correlation analysis was performed to assess the relationship between functional brain activity and clinical indices and neuropsychiatric behaviors.ResultsCompared to HCs, both active and inactive TAO patients exhibited significantly lower ALFF values in the right calcarine (Calcarine_R) and left postcentral gyrus (Postcentral_L). Active TAO patients also showed significantly higher ALFF values in the left caudate nucleus (Caudate_L) and increased fALFF values in the superior lobe of the right cerebellum (Cerebelum_Crus1_R). Moreover, both active and inactive TAO patients demonstrated decreased FC within the left postcentral gyrus (Postcentral_L) compared to HCs. Additionally, active TAO patients exhibited lower FC compared to inactive TAO patients. The ALFF values in the Calcarine_R of active TAO patients positively correlated with disease duration (r = 0.5892, p = 0.0049) and the Hamilton Anxiety Rating Scale (HARS; r = 0.5377, p = 0.0119). Furthermore, the ALFF value in the Calcarine_R of inactive TAO patients negatively correlated with visual functioning (r = −0.5449, p = 0.0072), while the ALFF values in the Caudate_L of active TAO patients positively correlated with visual functioning (r = 0.6496, p = 0.0014).ConclusionWe found that the Caudate_L and Cerebelum_Crus1_R related to motor control and coordination in active TAO patients exhibit significant compensatory mechanisms; whereas, the Calcarine_R and Postcentral_L related to visual and somatosensory cortices show varying degrees of impairment. Our findings complement the functional neural mechanism of TAO.

BackgroundThis study aimed to explore whether pre- or postoperative hip structures or surgical changes significantly influence hip range of motion (ROM) symmetry in patients with hip dysplasia during gait after total hip arthroplasty (THA) and provide possible surgical suggestions.MethodsFourteen patients with unilateral hip dysplasia underwent computed tomography before and after surgery to create three-dimensional hip models. Pre- and postoperative acetabular and femoral orientations, hip rotation centers (HRC), and femoral lengths were measured. Bilateral hip ROM during level walking after THA was quantified using dual fluoroscopy. The ROM symmetry in flexion-extension, adduction-abduction, and axial rotation was calculated using the symmetry index (SI). The relationship between SI and the above anatomical parameters and demographic characteristics was tested using Pearson's correlation and linear regression.ResultsThe average SI values for flexion-extension, adduction-abduction, and axial rotation during gait were −0.29, −0.30, and −0.10, respectively. Significant correlations were detected mainly in the postoperative HRC position. A distally placed HRC was associated with increased SI values for adduction-abduction (R = −0.47, p = 0.045), while a medially placed HRC was associated with decreased SI values for axial rotation (R = 0.63, p = 0.007). A regression analysis indicated that horizontal HRC positions significantly determined axial rotational symmetry (R2 = 0.40, p = 0.015). Normal axial rotation SI values were achieved with HRC between 17 mm medially and 16 mm laterally.ConclusionsPostoperative HRC position was significantly correlated with gait symmetry in the frontal and transverse planes in patients with unilateral hip dysplasia after THA. Surgical reconstruction of the HRC to between 17 mm medially and 16 mm laterally may contribute to gait symmetry.

Abstract Objective The aim of this study was to identify genetic etiology in two unrelated Chinese probands with progressive sensorineural hearing loss. Methods Two unrelated Chinese families were recruited. Genetic etiology was identified by targeted next‐generation sequencing (NGS) and verified by Sanger sequencing. Hearing evaluations included pure tone audiometry, auditory brainstem response to clicks, and otoscopic examination. Medical history and computerized tomography scan of temporal bone were also collected. In addition, linear regression was used to summarize all of the reported cases and estimate the progression of hearing loss. Results A 28‐year‐old man with variant c.68delC had progressive, moderately severe hearing loss and a suspicious history of renal impairment. His hearing result was 63.75 dB HL. The other proband was the youngest patient with MPZL2‐related hearing loss reported so far in the literature (genotype: c.220C>T homozygote). Her hearing result by click‐ABR was 25 dB nHL at 3 months of age, and deteriorated to 40 dB nHL at 15 months. Behavioral audiometry identified a hearing loss of 26.25 dB HL. In summarizing all of the reported cases, using linear regression, MPZL2‐related hearing loss may deteriorate by 0.59 dB HL per year, and different MPZL2 variants may lead to different rates of progression. Conclusion In this study, we first identified two unrelated patients with MPZL2‐related hearing loss in Chinese population, and a novel variant c.68delC. Our results expanded the mutation spectrum of deafness genes. Further studies are required to clarify the genotype–phenotype correlation and the progression of MPZL2‐related hearing loss.

Abstract Inflammatory bowel disease (IBD) is an incurable disease of the gastrointestinal tract with a lack of effective therapeutic strategies. The proinflammatory microenvironment plays a significant role in both amplifying and sustaining inflammation during IBD progression. Herein, biocompatible drug-free ceria nanoparticles (CeNP-PEG) with regenerable scavenging activities against multiple reactive oxygen species (ROS) were developed. CeNP-PEG exerted therapeutic effect in dextran sulfate sodium (DSS)-induced colitis murine model, evidenced by corrected the disease activity index, restrained colon length shortening, improved intestinal permeability and restored the colonic epithelium disruption. CeNP-PEG ameliorated the proinflammatory microenvironment by persistently scavenging ROS, down-regulating the levels of multiple proinflammatory cytokines, restraining the proinflammatory profile of macrophages and Th1/Th17 response. The underlying mechanism may involve restraining the co-activation of NF-κB and JAK2/STAT3 pathways. In summary, this work demonstrates an effective strategy for IBD treatment by ameliorating the self-perpetuating proinflammatory microenvironment, which offers a new avenue in the treatment of inflammation-related diseases. Graphical Abstract

Abstract Background POU3F4 is the causative gene for X-linked deafness-2 (DFNX2), characterized by incomplete partition type III (IP-III) malformation of the inner ear. The purpose of this study was to investigate the clinical characteristics and molecular findings in IP-III patients by Sanger or nanopore single-molecule sequencing. Methods Diagnosis of IP-III was mainly based on clinical characteristics including radiological and audiological findings. Sanger sequencing of POU3F4 was carried out for these IP-III patients. For those patients with negative results for POU3F4 Sanger sequencing, nanopore long-read single-molecule sequencing was used to identify the possible pathogenic variants. Hearing intervention outcomes of hearing aids (HAs) fitting and cochlear implantation (CI) were also analyzed. Aided pure tone average (PTA) was further compared between two groups of patients according to their different locations of POU3F4 variants: in the exon region or in the upstream region. Results In total, 18 male patients from 14 unrelated families were diagnosed with IP-III. 10 variants were identified in POU3F4 by Sanger sequencing and 6 of these were reported for the first time (p.Gln181*, p.Val215Gly, p.Arg282Gln, p.Gln316*, c.903_912 delins TGCCA and p.Arg205del). Four different deletions that varied from 80 to 486 kb were identified 876–1503 kb upstream of POU3F4 by nanopore long-read single-molecule sequencing. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutations. Among these 18 patients, 7 had bilateral HAs and 10 patients received unilateral CI. The mean aided PTA for HAs and CI users were 41.1 ± 5.18 and 40.3 ± 7.59 dB HL respectively. The mean PTAs for patients with the variants located in the exon and upstream regions were 39.6 ± 6.31 versus 43.0 ± 7.10 dB HL, which presented no significant difference (p = 0.342). Conclusions Among 14 unrelated IP-III patients, 28.6% (4/14) had no definite mutation in exon region of POU3F4. However, possible pathogenic deletions were identified in upstream region of this gene. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutation. There was no significant difference of hearing intervention outcomes between the IP-III patients with variants located in the exon region and in the upstream region.

Abstract Thyroid‐associated ophthalmopathy (TAO) is a serious, progressive, vision‐threatening and difficult‐to‐treat organ‐specific autoimmune disease. The course, therapeutic effects and prognosis of moderate to severe TAO vary greatly. High‐dose intravenous glucocorticoid (IVGC) therapy is considered a first‐line treatment for active moderate‐to‐severe TAO, but there is still insufficient evidence regarding the treatment duration. Long‐term IVGC therapy can influence the metabolism of glucose, lipids, and bone. This study was designed to compare changes in metabolic and immunological indexes as well as the magnetic resonance imaging apparent diffusion coefficient (ADC) of the extraocular muscles after 4 and 12 weeks of IVGC therapy. Forty‐eight patients with active moderate‐to‐severe TAO were included in this retrospective cohort study. Metabolism and immunological indexes were measured before and after therapy. The ADC and clinical activity score (CAS) were used to evaluate the efficacy of treatment in these patients. We found that the patients in the 12‐week group had increased fasting plasma glucose (p = 0.004), glycated hemoglobin (p = 0.028), total cholesterol (p

Abstract Background This study aimed to establish a deep learning system for detecting the active and inactive phases of thyroid-associated ophthalmopathy (TAO) using magnetic resonance imaging (MRI). This system could provide faster, more accurate, and more objective assessments across populations. Methods A total of 160 MRI images of patients with TAO, who visited the Ophthalmology Clinic of the Ninth People’s Hospital, were retrospectively obtained for this study. Of these, 80% were used for training and validation, and 20% were used for testing. The deep learning system, based on deep convolutional neural network, was established to distinguish patients with active phase from those with inactive phase. The accuracy, precision, sensitivity, specificity, F1 score and area under the receiver operating characteristic curve were analyzed. Besides, visualization method was applied to explain the operation of the networks. Results Network A inherited from Visual Geometry Group network. The accuracy, specificity and sensitivity were 0.863±0.055, 0.896±0.042 and 0.750±0.136 respectively. Due to the recurring phenomenon of vanishing gradient during the training process of network A, we added parts of Residual Neural Network to build network B. After modification, network B improved the sensitivity (0.821±0.021) while maintaining a good accuracy (0.855±0.018) and a good specificity (0.865±0.021). Conclusions The deep convolutional neural network could automatically detect the activity of TAO from MRI images with strong robustness, less subjective judgment, and less measurement error. This system could standardize the diagnostic process and speed up the treatment decision making for TAO.

Background: Total hip arthroplasty (THA) for hip dysplasia patients is sometimes complex and compromises pathomorphological changes in these patients. However, it remains unclear whether it is preoperative deformities or postoperative structures or anatomic changes during THA that have the most remarkable correlation with the hip dynamic function during gait. The purpose of this study was to investigate this relationship and propose insights into the surgical reconstruction strategy in patients with developmental dysplasia of the hip.Methods: A total of 21 unilateral hip dysplasia patients received computed tomography scans for the creation of 3D hip models before surgery and at the last follow-up. Acetabular and femoral orientations, hip center positions, and femoral length were measured before and after THA. Hip kinematics of the operated side during gait was quantified using a dual fluoroscopic imaging technique. Pearson correlation and multiple linear regression were performed to evaluate the relationship between hip maximum range of motion in six directions and demographics characters and above hip anatomic parameters before and after THA and their changes in surgery.Results: Pearson correlation analysis found significant correlations with the gait range of motion mainly in postoperative structures, including postoperative hip center positions and acetabulum and combined anteversion. Further multiple linear regression indicated that a laterally placed hip center was significantly correlated with an increased internal rotation (R2 = 0.25, p = 0.021), which together with increased postoperative acetabulum anteversion explained 45% of external rotation decreasing (p = 0.004). A proximally placed hip center was correlated with more extension (R2 = 0.30, p = 0.010). No significant demographic characters or preoperative deformities or surgical changes were included into other multiple regression models.Conclusion: Strong correlations between postoperative structures, especially hip center positions and gait range of motion in unilateral hip dysplasia patients after THA were found. It indicated that postoperative prosthesis structures, particularly hip center positions had significant impact on the hip gait motion range and should be treated with particular caution in surgery.

Background: As an advanced surgical technique to reduce trauma to the inner ear, robot-assisted electrode array (EA) insertion has been applied in adult cochlear implantation (CI) and was approved as a safe surgical procedure that could result in better outcomes. As the mastoid and temporal bones are generally smaller in children, which would increase the difficulty for robot-assisted manipulation, the clinical application of these systems for CI in children has not been reported. Given that the pediatric candidate is the main population, we aim to investigate the safety and reliability of robot-assisted techniques in pediatric cochlear implantation.Methods: Retrospective cohort study at a referral center in Shanghai including all patients of simultaneous bilateral CI with robotic assistance on one side (RobOtol® system, Collin ORL, Bagneux, France), and manual insertion on the other (same brand of EA and CI in both side), from December 2019 to June 2020. The surgical outcomes, radiological measurements (EA positioning, EA insertion depth, mastoidectomy size), and audiological outcomes (Behavior pure-tone audiometry) were evaluated.Results: Five infants (17.8 ± 13.5 months, ranging from 10 to 42 months) and an adult (39 years old) were enrolled in this study. Both perimodiolar and lateral wall EAs were included. The robot-assisted EA insertion was successfully performed in all cases, although the surgical zone in infants was about half the size in adults, and no difference was observed in mastoidectomy size between robot-assisted and manual insertion sides (p = 0.219). The insertion depths of EA with two techniques were similar (P = 0.583). The robot-assisted technique showed no scalar deviation, but scalar deviation occurred for one manually inserted pre-curved EA (16%). Early auditory performance was similar to both techniques.Conclusion: Robot-assisted technique for EA insertion is approved to be used safely and reliably in children, which is possible and potential for better scalar positioning and might improve long-term auditory outcome. Standard mastoidectomy size was enough for robot-assisted technique. This first study marks the arrival of the era of robotic CI for all ages.

Background: Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease characterized by edema of extraocular muscles (EOMs). Purpose: To characterize the inflammation of EOMs in patients with TAO before and after radiation therapy using apparent diffusion coefficient (ADC) and to analyze the correlation between ADC and clinical activity of TAO. Material and Methods: The ADCs of superior rectus (SR), inferior rectus (IR), medial rectus (MR), and lateral rectus (LR) muscles were measured in 52 eyes of 26 patients with TAO before and three months after orbital radiation therapy. In addition, 38 eyes of 20 healthy volunteers were included. The clinical activity score (CAS) was evaluated. The ADC maps were reconstructed and measured on the coronal diffusion-weighted imaging (DWI) sequence and calculated in mm2/s. Results: The mean ADCs of EOMs before treatment were 1.42 ± 0.23 in SR, 1.37 ± 0.23 in IR, 1.41 ± 0.21 in MR, and 1.28 ± 0.25 in LR. The mean ADCs after treatment were 1.27 ± 0.18, 1.22 ± 0.26, 1.30 ± 0.22, and 1.15 ± 0.21, respectively. The ADCs were significantly decreased after treatment (all P < 0.001). The ADCs of patients with TAO were significantly higher than those of controls. There was a statistically significant correlation between the mean ADCs and the CAS in each patient with TAO both before and after treatment (before: r = 0.520; P < 0.001; after: r = 0.625; P < 0.001). Conclusion: The ADC values of EOMs can be exploited as a quantitative indicator to evaluate the clinical activity and monitor the therapeutic responses of patients with TAO. [ABSTRACT FROM AUTHOR]