The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Analysis of Factors Influencing Financial Cost and Morbidity in Nonfatal Firearm Injuries.

Representing 68% of firearm-related injuries, nonfatal firearm injuries cause substantial morbidity and are associated with high costs to patients and the health care system. A retrospective analysis was performed to evaluate 359 adults in the Southeastern United States from 2019 to 2021. IBM SPSS was used for descriptive and parametric statistical analysis. The mean total cost of stay (TCOS) was $36,639.12, length of stay (LOS) was 8.61 days, number of times to the operating room was 1.88, and number of follow-ups was 3.21. Vascular and traumatic brain injuries were associated with higher TCOS and LOS. Vascular injuries were associated with more operating room visits. Bony injuries and non-TBI neurological injuries were associated with more follow-up appointments. In this brief report, we aim to understand the effect injury types have on these factors to help inform trauma protocol development with the goal of decreasing financial burdens.

Diagnosis and management of intraoperative thyroid storm in a child with undiagnosed Graves' disease: a case report.

BACKGROUND: Thyroid storm is a life-threatening manifestation of thyrotoxicosis and presents with fever, diaphoresis, tachycardia, hypertension, and widened pulse pressure. CASE PRESENTATION: We present a case of intraoperative thyroid storm in a 12-year-old female undergoing posterior spinal fusion. Despite adequate depth of anesthesia and analgesia, the patient was persistently tachycardic and hypertensive. The surgical procedure was uneventful. A thyroid panel drawn immediately after surgery showed undetectable thyroid stimulating hormone (TSH) and high free thyroxine (T4) consistent with thyroid storm. CONCLUSIONS: Intraoperative thyroid storm in a pediatric patient is extremely rare with nonspecific clinical symptoms. Low to undetectable TSH and elevated free T4 is diagnostic.

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma-pheochromocytoma syndrome.

PURPOSE: Minimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma-pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. METHODS: A multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. RESULTS: Two hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n = 188/263, 72%), followed by SDHD (n = 35/263, 13%) and SDHC (n = 28/263, 11%). SDHx-related tumors were found in 17% (n = 45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n = 39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n = 14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n = 12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n = 75/491) of imaging screens. CONCLUSION: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

Improved Sensitivity and Reader Confidence in CT Colonography Using Dual-Layer Spectral CT: A Phantom Study.

Background Limited cathartic preparations for CT colonography with fecal tagging can improve patient comfort but may result in nondiagnostic examinations from poorly tagged stool. Dual-energy CT may overcome this limitation by improving the conspicuity of the contrast agent, but more data are needed. Purpose To investigate whether dual-energy CT improves polyp detection in CT colonography compared with conventional CT at different fecal tagging levels in vitro. Materials and Methods In this HIPAA-compliant study, between December 2017 and August 2019, a colon phantom 30 cm in diameter containing 60 polyps of different shapes (spherical, ellipsoid, flat) and size groups (5-9 mm, 11-15 mm) was constructed and serially filled with simulated feces tagged with four different iodine concentrations (1.26, 2.45, 4.88, and 21.00 mg of iodine per milliliter), then it was scanned with dual-energy CT with and without an outer fat ring to simulate large body size (total diameter, 42 cm). Two readers independently reviewed conventional 120-kVp CT and 40-keV monoenergetic dual-energy CT images to record the presence of polyps and confidence (three-point scale.) Generalized estimating equations were used for sensitivity comparisons between conventional CT and dual-energy CT, and a Wilcoxon signed-rank test was used for reader confidence. Results Dual-energy CT had higher overall sensitivity for polyp detection than conventional CT (58.8%; 95% confidence interval [CI]: 49.7%, 67.3%; 564 of 960 polyps vs 42.1%; 95% CI: 32.1%, 52.8%; 404 of 960 polyps; P < .001), including with the fat ring (48% and 31%, P < .001). Reader confidence improved with dual-energy CT compared with conventional images on all tagging levels (P < .001). Interrater agreement was substantial (κ = 0.74; 95% CI: 0.70, 0.77). Conclusion Compared with conventional 120-kVp CT, dual-energy CT improved polyp detection and reader confidence in a dedicated dual-energy CT colonography phantom, especially with suboptimal fecal tagging. © RSNA, 2020.

Use of Antimetastatic SOD3-Mimetic Albumin as a Primer in Triple Negative Breast Cancer.

Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer. Here, we characterize the antimetastatic therapeutic mechanisms of a macromolecular extracellular SOD3-mimetic polynitroxyl albumin (PNA, also known as VACNO). PNA is macromolecular human serum albumin conjugated with multiple nitroxide groups and acts as an SOD-mimetic. Here we show that PNA works as a SOD3-mimetic in a highly metastatic 4T1 mouse model of triple negative breast cancer (TNBC). In vitro, PNA dose dependently inhibited 4T1 proliferation, colony formation, and reactive oxygen species (ROS) formation. In vivo, PNA enhanced reperfusion time in the hypoxic cores of 4T1 tumors as measured by ultrasound imaging. Furthermore, PNA enhanced ultrasound signal intensity within the cores of the 4T1 tumors, indicating PNA can increase blood flow and blood volume within the hypoxic cores of tumors. Lung metastasis from 4T1 flank tumor was inhibited by PNA in the presence or absence of doxorubicin, a chemotherapy agent that produces superoxide and promotes metastasis. In a separate study, PNA increased the survival of mice with 4T1 flank tumors when used in conjunction with three standard chemotherapy drugs (paclitaxel, doxorubicin, and cyclophosphamide), as compared to treatment with chemotherapy alone. In this study, PNA-increased survival was also correlated with reduction of lung metastasis. These results support the hypothesis that PNA works through the inhibition of extracellular superoxide/ROS production leading to the conversion of 4T1 cells from a metastatic tumorigenic state to a cytostatic state. These findings support future clinical trials of PNA as an antimetastatic SOD3-mimetic drug to increase overall survival in TNBC patients.

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas.

Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/- mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766-77. ©2017 AACR.

Can dual-energy computed tomography improve visualization of hypoenhancing liver lesions in portal venous phase? Assessment of advanced image-based virtual monoenergetic images.

PURPOSE: The purpose was to assess image quality of portal-venous phase dual-energy computed tomography (DECT) for liver lesions. METHODS: We performed 120-kVp-equivalent linear-blended (LB) and monoenergetic reconstructions from 40 to 190 keV by standard (VMI) and advanced virtual monoenergetic (VMI+) methods. Diagnostic performance, and quantitative and qualitative image analyses were assessed and compared. RESULTS: Liver contrast to noise ratio peaked at 40 keV_VMI+, while image quality and reader preference peaked at 50 keV_VMI+. 50 keV_VMI+ scored overall higher diagnostic performance: lesion sensitivity 95.4% vs. 83.3% for both 75 keV_VMI and LB. CONCLUSIONS: DECT improves assessment of hypoenhancing liver lesions on portal venous phase. 50 keV_VMI+ demonstrated the highest image quality and diagnostic performance over VMI and LB.

Cesarean-Section Scar Endometrioma: A Case Report and Review of the Literature.

Endometriomas can occur after any surgery where there is endometrial manipulation, and there are a number of reports of endometriomas developing in the abdominal wall at the site of the Pfannenstiel incision following Cesarean-section. Although this is ultimately a histopathologically-confirmed diagnosis, preoperative imaging including ultrasound, computed tomography, and magnetic resonance imaging may be helpful in the diagnosis and assessment. We report a pathology-confirmed case of Cesarean-section endometrioma with a classic, clinical presentation and imaging findings on computed tomography. A comprehensive literature review and discussion of the multi-modality imaging appearance of Cesarean-section endometrioma is also provided.

Optimization of window settings for virtual monoenergetic imaging in dual-energy CT of the liver: A multi-reader evaluation of standard monoenergetic and advanced imaged-based monoenergetic datasets.

OBJECTIVES: To evaluate optimal window settings for display of virtual monoenergetic reconstructions in third-generation dual-source, dual-energy computed tomography (DECT) of the liver. METHODS: Twenty-nine subjects were prospectively evaluated with DECT in arterial (AP) and portal venous (PVP) phases. Three reconstructed datasets were calculated: standard linearly-blended (LB120), 70-keV standard virtual monoenergetic (M70), and 50-keV advanced image-based virtual monoenergetic (M50+). Two readers assessed optimal window settings (width and level, W/L), establishing a mean for each reconstruction which was used for a blinded assessment of liver lesions. RESULTS: The optimal W/L for M50+ were significantly higher for both AP (W=429.3 ± 44.6 HU, L=129.4 ± 9.7 HU) and PVP (W=376.1 ± 14.2HU, L=146.6 ± 7.0 HU) than for LB120 (AP, W=215.9 ± 16.9 HU, L=82.3 ± 9.4 HU) (PVP, W=173.4 ± 8.9 HU, L=69.3 ± 6.0 HU) and M70 (AP, W=247.1 ± 22.2 HU, L=72.9 ± 6.8 HU) (PVP, W=232.0 ± 27.9 HU, L=91.6 ± 14.4 HU). Use of the optimal window setting for M50+ vs. LB120 resulted in higher sensitivity (AP, 100% vs. 86%; PVP, 96% vs. 63%). CONCLUSIONS: Application of dedicated window settings results in improved liver lesion detection rates in advanced image-based virtual monoenergetic DECT when customized for arterial and portal venous phases.

Detection and Clinical Significance of Sternal Lesions on Breast MRI.

The purpose of this study is to characterize sternal lesions detected on breast magnetic resonance imaging (MRI), compare MRI detection of sternal lesions with other imaging modalities (bone scan, positron emission tomography/computed tomography (PET/CT) and chest CT), and ascertain how often patient management is altered by discovery of sternal lesions. Retrospective review of 1143 breast MRIs between 2007 and 2012 identified 17 patients with sternal lesions including 15 patients with newly diagnosed breast cancer and two patients with remote history of breast cancer. Tumor size, histopathology, receptor status, nodal and distant metastasis, and images of breast MRI, and other modalities were reviewed. Sternal lesions in 9 of the 17 patients were determined to be malignant (metastasis) either by biopsy or presence of widespread metastases. Sternal lesions in 8 of the 17 were benign, confirmed by biopsy or presumed benign as not detected by other modalities. The malignant group had statistically significant larger breast cancer size (malignant: 6.4 cm; benign: 2.3 cm), a higher percentage of diffuse sternal lesions (malignant: 56%; benign: 0%), and more frequently showed rapid initial enhancing (malignant: 100%; benign: 63%) and delayed washout curves (malignant: 67%; benign: 13%). Although not statistically significant, the malignant group had a higher frequency of invasive lobular carcinoma (malignant: 44%; benign: 13%) and more lymph node involvement (malignant: 78%; benign: 50%). Breast MRI detected more sternal lesions than did bone scan, PET/CT and chest CT. Four of the 17 (24%) patients were upgraded to stage 4 due to unsuspected metastatic sternal lesions on breast MRI. In conclusion, breast MRI is more sensitive than other modalities in detecting sternal lesions. Sternal metastases occur more frequently in aggressive breast cancer and exhibit malignant-type dynamics on breast MRI. Detection of unsuspected sternal metastasis alters staging and improves patient management with more appropriate treatment.