Rescue of cone and rod photoreceptor function in a CDHR1-model of age-related retinal degeneration.

Age-related macular degeneration (AMD) is the most common cause of untreatable blindness in the developed world. Recently, CDHR1 has been identified as the cause of a subset of AMD that has the appearance of the "dry" form, or geographic atrophy. Biallelic variants in CDHR1-a specialized protocadherin highly expressed in cone and rod photoreceptors-result in blindness from shortened photoreceptor outer segments and progressive photoreceptor cell death. Here we demonstrate long-term morphological, ultrastructural, functional, and behavioral rescue following CDHR1 gene therapy in a relevant murine model, sustained to 23-months after injection. This represents the first demonstration of rescue of a monogenic cadherinopathy in vivo. Moreover, the durability of CDHR1 gene therapy seems to be near complete-with morphological findings of the rescued retina not obviously different from wildtype throughout the lifespan of the mouse model. A follow-on clinical trial in patients with CDHR1-associated retinal degeneration is warranted. Hypomorphic CDHR1 variants may mimic advanced dry AMD. Accurate clinical classification is now critical, as their pathogenesis and treatment are distinct.

Impaired glutamylation of RPGRORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants.

Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGRORF15 isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGRORF15 variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGRORF15 variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGRORF15 variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod-cone dystrophy into a cone dystrophy phenotype.

Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading.

PURPOSE: Deep learning (DL) models have achieved state-of-the-art medical diagnosis classification accuracy. Current models are limited by discrete diagnosis labels, but could yield more information with diagnosis in a continuous scale. We developed a novel continuous severity scaling system for macular telangiectasia (MacTel) type 2 by combining a DL classification model with uniform manifold approximation and projection (UMAP). DESIGN: We used a DL network to learn a feature representation of MacTel severity from discrete severity labels and applied UMAP to embed this feature representation into 2 dimensions, thereby creating a continuous MacTel severity scale. PARTICIPANTS: A total of 2003 OCT volumes were analyzed from 1089 MacTel Project participants. METHODS: We trained a multiview DL classifier using multiple B-scans from OCT volumes to learn a previously published discrete 7-step MacTel severity scale. The classifiers' last feature layer was extracted as input for UMAP, which embedded these features into a continuous 2-dimensional manifold. The DL classifier was assessed in terms of test accuracy. Rank correlation for the continuous UMAP scale against the previously published scale was calculated. Additionally, the UMAP scale was assessed in the κ agreement against 5 clinical experts on 100 pairs of patient volumes. For each pair of patient volumes, clinical experts were asked to select the volume with more severe MacTel disease and to compare them against the UMAP scale. MAIN OUTCOME MEASURES: Classification accuracy for the DL classifier and κ agreement versus clinical experts for UMAP. RESULTS: The multiview DL classifier achieved top 1 accuracy of 63.3% (186/294) on held-out test OCT volumes. The UMAP metric showed a clear continuous gradation of MacTel severity with a Spearman rank correlation of 0.84 with the previously published scale. Furthermore, the continuous UMAP metric achieved κ agreements of 0.56 to 0.63 with 5 clinical experts, which was comparable with interobserver κ values. CONCLUSIONS: Our UMAP embedding generated a continuous MacTel severity scale, without requiring continuous training labels. This technique can be applied to other diseases and may lead to more accurate diagnosis, improved understanding of disease progression, and key imaging features for pathologic characteristics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessing Adequacy: A Meta-Analysis of Rapid Onsite Evaluation of Thyroid Nodules.

INTRODUCTION: Fine-needle aspiration (FNA) is the standard form of preoperative evaluation of thyroid nodule cytological status. A significant number FNAs are classified as inadequate for interpretation, requiring a repeat FNA which is potentially avoidable, costly, and delays treatment. To address these concerns and maximize first-time FNA adequacy, rapid onsite evaluation (ROSE) of FNA specimens was introduced. Our study aims to determine the impact of ROSE on FNA adequacy. METHODS: PubMed, Embase, and Web of Science were searched for primary articles assessing the adequacy of ROSE in thyroid nodules. RESULTS: A total of 17 studies were included for a total of 24,649 thyroid nodes. Thirteen thousand two hundred fifteen (53.6%) thyroid nodules were assessed utilizing ROSE and 11,434 (46.4%) were not. Pooled adequacy increased significantly from 76% without ROSE to 92% with rose (P = 0.001). Use of ROSE increased the odds of adequate FNA by 22% (risk ratio (RR) = 1.22, 95% confidence interval (CI) = 1.12-1.32). At institutions with less than 85% effective diagnostic adequacy without ROSE, the risk for diagnostic adequacy increased by 28% with ROSE implementation (RR = 1.28, 95% CI = 1.20-1.37). In contrast, in studies reported from institutions with an effective diagnostic rate greater than 85% without the use of ROSE, the diagnostic adequacy only increased by 5% with ROSE implementation (RR = 1.05, 95% CI = 1.03-1.06). CONCLUSIONS: The use of ROSE during first-time FNA of thyroid nodules can significantly improve adequacy, especially at institutions with baseline high inadequacy rates. Implementation of ROSE can reduce repeat FNAs and its associated consequences.

Intravitreal Injections: Improving Sustainability by Reducing Clinical Waste. / Intravitreale Injektionen: Nachhaltigkeit durch Reduktion von Klinikabfall.

BACKGROUND: Intravitreal injections are one of the most commonly performed ophthalmic procedures. It is estimated that over 1 million intravitreal injections are performed in Germany annually. The aim of this study was to quantify the waste and carbon footprint associated with single-use injection sets, and to establish a waste reduction strategy. MATERIAL AND METHODS: The clinical waste and associated carbon footprint from standard disposable injection sets used by tertiary referral centres in Germany (n = 6) and the United Kingdom (n = 2) were assessed. The safety of performing intravitreal injections with a minimalistic material-sparing approach was evaluated. RESULTS: The average weight of an injection set (and hence the waste generated from each injection) was 165 g. On average, each injection set comprised 145 g (88%) of plastic, 2.1 g (1.3%) of metal, 4.3 g (2.6%) of paper, and 12.9 g (7.8%) of gauze/swabs. The production of such injection sets was extrapolated to a CO2 equivalent of 752.6 tonnes (t), and the incineration of the resulting waste to a CO2 equivalent of 301.7 t. For 1 million injections, this equates to 145.2 t of plastic, 2.1 t of metal, 4.3 t of paper, and 12.9 t of gauze/swabs. A material-sparing approach can reduce injection set-associated waste by 99% without necessarily compromising patient safety. CONCLUSION: A resource-saving approach to intravitreal injections can minimise the generation of clinical waste and its associated carbon footprint, thereby supporting sustainability.

Cardiovascular Health by Graves' Disease Management Modality - Surgery Versus Radioactive Iodine Versus Antithyroid Medications: A Network Meta-Analysis.

INTRODUCTION: Graves' disease is an autoimmune disorder of the thyroid gland associated with the overproduction of thyroid hormones. Excess secretion of thyroid hormones leads to cardiovascular consequences. Treatment options include antithyroid medications (ATM), radioactive iodine (RAI) ablation, and total thyroidectomy. We examined the cardiovascular outcomes following Graves' disease management modality. METHODS: A systematic search was performed up to September 22nd, 2021, using PubMed, EMBASE, and Web of Science databases. We conducted a network meta-analysis analyzing cardiovascular outcomes of interest, including congestive heart failure (CHF), arrhythmia, atrial fibrillation (AF), and hypertension. RESULTS: Three studies were included in this analysis totaling 6700 patients with Graves' disease, of which 74% were female. The mean age was 44.34 y. When compared to pretreatment, management options lowered the risk of maintaining arrhythmia 81% with surgery (relative risk [RR] = 0.19; 95% confidence interval [CI] = 0.12 to 0.31), 67% with ATM (RR = 0.33; 95% CI = 0.23 to 0.49), and 50% with RAI (RR = 0.50; 95% CI = 0.13 to 1.95). Risk of maintaining CHF was reduced 80% with surgery (RR = 0.20; 95% CI = 0.08 to 0.49), 41% with ATM (RR = 0.59; 95%CI = 0.52 to 0.67), and only 7% with RAI (RR = 0.93; 95%CI = 0.68 to 1.26). Treatment-ranking analysis found all parameters, including CHF, arrhythmia, AF, and hypertension, to be in favor of surgical treatment over medical treatment and RAI ablation. CONCLUSIONS: This is the first network meta-analysis analyzing the cardiovascular outcomes in Graves' disease patients by treatment option. Our study demonstrated that surgery is superior to RAI and medical treatment.

The retinal phenotype in primary hyperoxaluria type 2 and 3.

BACKGROUND: The primary hyperoxalurias (PH1-3) are rare inherited disorders of the glyoxylate metabolism characterized by endogenous overproduction of oxalate. As oxalate cannot be metabolized by humans, oxalate deposits may affect various organs, primarily the kidneys, bones, heart, and eyes. Vision loss induced by severe retinal deposits is commonly seen in infantile PH1; less frequently and milder retinal alterations are found in non-infantile PH1. Retinal disease has not systematically been investigated in patients with PH2 and PH3. METHODS: A comprehensive ophthalmic examination was performed in 19 genetically confirmed PH2 (n = 7) and PH3 (n = 12) patients (median age 11 years, range 3-59). RESULTS: Median best corrected visual acuity was 20/20. In 18 patients, no retinal oxalate deposits were found. A 30-year-old male with PH2 on maintenance hemodialysis with plasma oxalate (Pox) elevation (> 100 µmol/l; normal < 7.4) demonstrated bilateral drusen-like, hyperreflective deposits which were interpreted as crystallized oxalate. Two siblings of consanguineous parents with PH2 presented with retinal degeneration and vision loss; exome-wide analysis identified a second monogenic disease, NR2E3-associated retinal dystrophy. CONCLUSIONS: Retinal disease manifestation in PH2 and PH3 is rare but mild changes can occur at least in PH2-associated kidney failure. Decline in kidney function associated with elevated plasma oxalate levels could increase the risk of systemic oxalosis. Deep phenotyping combined with genomic profiling is vital to differentiate extrarenal disease in multisystem disorders such as PH from independent inherited (retinal) disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

GERD-screening before bariatric surgery: the predictive value of the GERD-HRQL questionnaire score compared with preoperative EGD findings.

BACKGROUND: There is an ongoing debate on how to best identify patients with gastroesophageal reflux disease (GERD) before bariatric surgery. The value of routine preoperative esophagogastroduodenoscopy (EGD) is questioned, and patient reported symptoms are commonly used for screening. The goal of this study is to determine if patient reported symptoms using a validated questionnaire correlate with preoperative EGD findings. METHODOLOGY: A prospective cohort study at a single institution was performed. Patients undergoing bariatric surgery between December 2020 and March 2023 were required to report symptoms of reflux by completing a preoperative GERD. Health-Related Quality of Life (GERD-HRQL) questionnaire and undergo a mandatory preoperative screening EGD. Patients were stratified into two cohorts: (group A) asymptomatic (score = 0) and (group B) symptomatic (score > 0). Statistical analysis was conducted using Pearson's chi-squared test and Wilcoxon rank-sum test in RStudio version 4.2.2. The predictive value of the GERD-HRQL score was analyzed using Areas Under the Curve (AUC; AUC = 0.5 not predictive, 0.5 < AUC ≥ 6 poor prediction & AUC > 0.9 excellent prediction) calculated from Receiver Operating Characteristic (ROC) curves. RESULTS: 200 patients were included; median age was 42.0 years (IQR 36.0 to 49.2). There were 79 patients (39.5%) in Group A and 121 patients (60.5%) in Group B. There was no difference in the frequency esophagitis (27.8% vs 32.2%, p = 0.61) or hiatal hernias (49.4% vs 47.1%, p = 0. 867) between group A and group B, respectively. ROC analysis revealed that the total GERD HRQL scores, heartburn only scores and regurgitation only scores, were poor predictors of esophagitis found on EGD (AUC 0.52, 0.53, 0.52), respectively. In asymptomatic patients, higher BMI was significantly associated with esophagitis (OR 1.15, 95% CI 1.06-1.27, p = 0.002). CONCLUSION: Symptoms, identified through the GERD-HRQL questionnaire, are a poor indicator of esophagitis or its severity in patients undergoing workup for bariatric surgery. Therefore, liberal screening upper endoscopy is recommended for pre-bariatric surgery patients to guide appropriate procedure selection.

Topographic patterns of retinal lesions in multiple evanescent white dot syndrome.

PURPOSE: To demonstrate different topographic distributions of multiple-evanescent white dot syndrome (MEWDS) and secondary MEWDS disease and to describe possible associations. METHODS: Clinical evaluation and multimodal retinal imaging in 27 subjects with MEWDS (29 discrete episodes of MEWDS). Ophthalmic assessment included best-corrected visual acuity testing and multimodal retinal imaging with OCT, blue-light autofluorescence, fluorescein and indocyanine green angiography, fundus photography, and widefield pseudocolor and autofluorescence fundus imaging. RESULTS: The topographic distribution of MEWDS lesions was centered on or around the optic disc (n = 17, 59%), centered on the macula (n = 7, 24%), sectoral (n = 2, 7%), or was indeterminate (n = 3, 10%). The MEWDS episodes either occurred in the absence ('primary MEWDS'; n = 14, 48%) or presence of concurrent chorioretinal pathology ('secondary MEWDS'; n = 15, 52%). In patients with the latter, MEWDS lesions were often centered around a coexisting chorioretinal lesion. The majority of patients in both groups experienced resolution of their symptoms and retinal changes on multimodal imaging by 3 months. CONCLUSIONS: Distinct distributions of MEWDS lesions were identified. MEWDS may occur in tandem with other chorioretinal pathology, which may impact the topography of MEWDS lesions.

PHOTORECEPTOR DAMAGE IN TERSON SYNDROME.

PURPOSE: To describe photoreceptor damage in patients with Terson syndrome as a potential cause for inconsistent clinical outcomes. METHODS: Clinical evaluation and retinal imaging in six patients. RESULTS: Four patients were women and two men, with an average age of 46.8 years (SD 8.9). Four patients suffered aneurysmal subarachnoid hemorrhage, one vertebral artery dissection, and one superior sagittal sinus thrombosis. In 11 eyes, a consistent pattern of outer retinal changes within the central retina affecting the ellipsoid zone and the outer nuclear layer was observed, indicating photoreceptor damage. Areas of photoreceptor damage showed poor spatial correlation with intraocular hemorrhage, particularly subinternal limiting membrane hemorrhage. The observed retinal abnormalities demonstrated incomplete recovery over long-term follow-up 3.5 to 8 years posthemorrhage, irrespective of surgical or conservative treatment strategy, and had variable impact on the patients' visual function. CONCLUSION: The observations suggest that photoreceptor damage in Terson syndrome likely represents a distinct manifestation of this condition, which could be caused by transient ischemia of the outer retina secondary to acute rise in intracranial pressure.

Current Management of Patients with RPE65 Mutation Associated Inherited Retinal Degenerations in Europe: Results of a 2-Year Follow-Up Multinational Survey.

INTRODUCTION: The aim of this study was to evaluate the current management of RPE65 biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of voretigene neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-EYE) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. METHODS: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. RESULTS: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1-19/center, median 6) and 43 planned for treatment (range 0-10/center, median 6). The overall age range was 3-52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2-60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full-field stimulus test improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. CONCLUSION: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-EYE HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of 2 class 4 or 5 mutations on both alleles or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers.

Current Management of Inherited Retinal Degeneration Patients in Europe: Results of a 2-Year Follow-Up Multinational Survey by the European Vision Institute Clinical Research Network - EVICR.net.

INTRODUCTION: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the EVICR.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey. METHODS: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R. RESULTS: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500-999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to EVICR.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40-80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2-4 weeks to 24 months (2019 survey >4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter. DISCUSSION: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors.

Recommend with caution: A meta-analysis investigating papillary thyroid carcinoma tumor progression under active surveillance.

BACKGROUND: Papillary thyroid carcinoma (PTC) is an indolent disease with favorable outcomes. The non-surgical treatment approach known as active surveillance (AS) has been introduced as an alternative treatment instead of the traditional thyroidectomy. However, 10-15 % of PTC tend to progress. We sought to determine factors predicting the progression of PTC under AS. METHODS: A systematic search was performed in January 2022 using PubMed, Embase, Google Scholar, Web of Science, and ScienceDirect. PRISMA guidelines were used by multiple reviewers to extract study characteristics (author name, publication date, journal name, country, institution, and study design), as well as main outcomes and measures. A combination of utilization of thyroid replacement therapy, baseline tumor size and volume, follow-up tumor size and volume, and the presence of lymph node metastasis and its distribution, as well as surveillance duration, were the main measures of this study. RESULTS: Nine studies with 4166 patients were included, of which 354 showed tumor progression during AS (15 %; 95%CI = 7 % - 23 %). The average follow-up period was 41.58 months. The mean tumor maximum diameter was 8.54 mm (95%CI = 7.04-10.03). Tumor progression was most commonly secondary to an increase in volume by ≥50 % (75 %; 95%CI = 68 % - 80 %), then increase in diameter by ≥3 mm (41 %; 95%CI = 13 % - 76 %), and finally the development of lymph node metastasis (13 %; 95%CI = 9 % - 19 %). Approximately only 2 % of all patients thus developed new lymph node metastasis. Patient age, sex, and tumor size were not associated with higher risks of tumor progression. 12 % of AS patients eventually underwent surgery, though only 40 % (95%CI = 27 % - 53 %) of these patients displayed tumor progression. CONCLUSIONS: Our meta-analysis determined a tumor progression rate of 15 % in patients who underwent AS management, 13 % of which (2 % of all patients) developed lymph node metastasis. We found no protective or risk factors for tumor progression, and that almost half of all patients who underwent delayed surgery did so for reasons other than tumor progression. While not biopsying small (<1 cm) or very low suspicious nodules is already recommended, AS may be an appropriate treatment option in patients appropriately counseled, considering the low risk of advanced tumor progression but also the considerable patient population who fail to adhere to treatment. Alternatively, in aim of preventing overtreatment in patients who would rather take proactive measures against their low-risk carcinoma, minimally-invasive ablation techniques may be an attractive option.

Efficacy and Safety of Radiofrequency Ablation of Thyroid Nodules: A Multi-institutional Prospective Cohort Study.

BACKGROUND: Radiofrequency ablation (RFA) has been recently adopted into the practice of thyroidology in the United States, although its use as an alternative to traditional thyroid surgery in Asia and Europe came near the turn of the 21st century. In the United States, only a few studies with small sample sizes have been published to date. We examined outcomes of benign thyroid nodules treated with RFA from 2 North American institutions. METHODS: We performed a prospective, multi-institutional cohort study of thyroid nodules treated with RFA between July 2019 and January 2022. Demographics, sonographic characteristics of thyroid nodules, thyroid function profiles, procedural details, complications, and nodule volume measurements at 1, 3, 6, and 12 months follow-up were evaluated. Adjusted multivariate logistic regression analysis was performed to identify sonographic features associated with treatment failure. RESULTS: A total of 233 nodules were included. The median and interquartile range of volume reduction rate (VRR) at 1, 3, 6, and 12 months were 54% [interquartile range (IQR): 36%-73%], 58% (IQR: 37%-80%), 73% (IQR: 51%-90%), and 76% (IQR: 52%-90%), respectively ( P <0.001). Four patients presented with toxic adenomas. All patients were confirmed euthyroid at 3-month postprocedure follow-up. Two patients developed temporary hoarseness of voice, but no hematoma or nodular rupture occurred postprocedure. Elastography was significantly associated with VRR. Compared with soft nodules, stiff nodules were more likely to have a lower VRR (odds ratio: 11.64, 95% confidence interval: 3.81-35.53, P <0.05), and mixed elasticity was also more likely to have a lower VRR (odds ratio: 4.9; 95% confidence interval: 1.62-14.85, P <0.05). CONCLUSIONS: This is the largest multi-institutional North American study examining thyroid nodule treatment response to RFA. RFA is a safe and effective treatment option that allows preservation of thyroid function with minimal risk of procedural complications.

Choriocapillaris Flow Signal Impairment in Sorsby Fundus Dystrophy.

PURPOSE: The aim of the study was to quantify choriocapillaris (CC) flow alterations in early Sorsby fundus dystrophy (SFD) and to investigate the relationship of the CC flow deficits with the choroidal and outer retinal microstructure. METHODS: In this prospective case-control study, 18 eyes of 11 patients with early SFD and 31 eyes of 31 controls without ocular pathology underwent multimodal imaging, including spectral-domain optical coherence tomography (OCT), followed by deep-learning-based layer segmentation. OCT angiography (OCTA) was performed to quantify CC flow signal deficits (FDs). Differences in CC FD density between SFD patients and controls were determined, and the relationships with choroidal thickness, retinal pigment epithelium-drusen complex (RPEDC) thickness and outer retinal layer thicknesses were analyzed using mixed-model analysis. RESULTS: SFD patients exhibited a significantly greater CC FD density than controls (estimate [95% CI]: +20.0%FD [13.3; 26.7], p < 0.001 for SFD patients), even when adjusted for age. Square-root transformed choroidal thickness was a structural OCT surrogate of the CC FD density (-2.1%FD per √µm, p < 0.001), whereas RPEDC thickness was not informative regarding CC FD (p = 0.061). The CC FD density was associated with an altered microstructure of the overlying photoreceptors (outer segments, inner segments, and outer nuclear layer thinning of -0.19 µm, -0.08 µm and -0.30 µm per %FD, respectively, all p < 0.001). CONCLUSIONS: Patients with early SFD exhibit pronounced abnormalities of CC flow signal on OCTA, which are not limited to areas of sub-RPE deposits seen on OCT imaging. Thus, analysis of the CC flow may enable clinical trials at earlier disease stages in SFD.

Structural Abnormalities of the Central Retina in Neurofibromatosis Type 2.

INTRODUCTION: This case-control study seeks to systematically characterize the central retinal findings in a large cohort of patients with neurofibromatosis type 2 (NF2) using spectral domain optical coherence tomography (SD-OCT) as well as the examination of the potential use of this technique as a diagnostic tool in NF2. METHODS: Fifty-four patients with an NF2 diagnosis seen in a quaternary national service were age- and gender-matched to 55 controls from the normal population. Two masked assessors categorized SD-OCT images using predefined abnormalities: retinal tufts, epiretinal membrane (ERM) appearance, retinal hamartoma, and foveal contour. Specificity, sensitivity, and positive and negative predictive values were calculated for each retinal abnormality. Trends of retinal abnormalities with NF2 genetic severity groups (1. tissue mosaic; 2A. mild classic; 2B. moderate classic; and 3. severe) were investigated. RESULTS: We found retinal abnormalities in 26 patients with NF2 (48%) and 2 control patients (4%); retinal tufts were the most common abnormality therein (43%) and were not seen in controls. The specificity and sensitivity of the graded abnormalities on OCT scans in NF2 were 96% and 48%, respectively, with a positive predictive value of 93%. In our cohort, retinal tufts had a specificity of 100%, a sensitivity of 43%, and a positive predictive value of 100%. Retinal hamartomas were seen only in NF2 patients (35% sensitivity and 100% specificity). ERMs had 96% specificity and 13% sensitivity. The proportion of patients with retinal abnormalities increased statistically significantly with NF2 genetic severity; all patients within the 3. severe genetic severity had an abnormal SD-OCT. DISCUSSION/CONCLUSION: We present a systematic study of central retinal abnormalities in an NF2 population as seen on SD-OCT imaging. Our results show a high frequency of retinal abnormalities that are readily detected by SD-OCT imaging. The presence of retinal tufts may be a novel marker of NF2 with both high specificity and a positive predictive value for NF2, compared to other well-known ocular features of NF2, and may have a place in the NF2 diagnostic criteria.

The Diagnostic Performance of Ultrasonography in the Evaluation of Extrathyroidal Extension in Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

Extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) is an indication of disease progression and can influence treatment aggressiveness. This meta-analysis assesses the diagnostic accuracy of ultrasonography (US) in detecting ETE. A systematic review and meta-analysis were performed by searching PubMed, Embase, and Cochrane for studies published up to April 2022. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. The areas under the curve (AUC) for summary receiver operating curves were compared. A total of 11 studies analyzed ETE in 3795 patients with PTC. The sensitivity of ETE detection was 76% (95%CI = 74-78%). The specificity of ETE detection was 51% (95%CI = 49-54%). The DOR of detecting ETE by US was 5.32 (95%CI = 2.54-11.14). The AUC of ETE detection was determined to be 0.6874 ± 0.0841. We report an up-to-date analysis elucidating the diagnostic accuracy of ETE detection by US. Our work suggests the diagnostic accuracy of US in detecting ETE is adequate. Considering the importance of ETE detection on preoperative assessment, ancillary studies such as adjunct imaging studies and genetic testing should be considered.

Radiofrequency Ablation of Indeterminate Thyroid Nodules: The First North American Comparative Analysis.

Thyroid nodules can be classified as benign, malignant, or indeterminate, the latter of which make up 10-30% of nodules. Radiofrequency ablation (RFA) has become an attractive and promising therapy for the treatment of benign thyroid nodules. However, few studies have investigated the safety and efficacy of RFA for the management of indeterminate thyroid nodules. In this study, 178 patients with thyroid nodules diagnosed as benign (Bethesda II) or indeterminate (Bethesda III/IV) by preoperative cytopathological analysis were included. Patients in the benign and indeterminate cohorts had similar thyroid nodule volume reduction rates at 65.60% and 64.20%, respectively (p = 0.68). The two groups had similar nodular regrowth rates, at 11.2% for benign nodules and 9.40% for indeterminate nodules (p = 0.72). A total of three cases of transient dysphonia were reported. RFA of indeterminate thyroid nodules was comparable to that of benign thyroid nodules in all parameters of interest, including volume reduction rate. To our best knowledge, our work is the first North American analysis comparing benign and indeterminate thyroid nodules and suggests RFA to be a promising modality for the management of indeterminate thyroid nodules.

Association of BRAFV600E Mutation with the Aggressive Behavior of Papillary Thyroid Microcarcinoma: A Meta-Analysis of 33 Studies.

An association between the BRAFV600E mutation and the clinicopathological progression of papillary thyroid microcarcinoma (PTMC) has been suggested. We aimed to summarize the relevant literature and determine the predictive value of BRAFV600E mutation in predicting clinical outcomes and risk stratification in patients with PTMC. A systematic search using PubMed, Cochrane, and Embase up to February 2020 was performed. A total of 33 studies met the inclusion criteria, resulting in a pool of 8838 patients, of whom 5043 (57.1%) patients were positive for BRAFV600E mutation. Tumors with positive BRAFV600E mutation had a higher tendency for multifocality (RR = 1.09, 95%CI = 1.03-1.16), extrathyroidal extension (RR = 1.79, 95%CI = 1.37-2.32), and lymph node metastasis (RR = 1.43, 95%CI = 1.19-1.71). Patients with BRAFV600E mutation were at increased risk of disease recurrence (RR = 1.90, 95%CI = 1.43-2.53). PTMC in patients positive for the BRAFV600E mutation is more aggressive than wild-type BRAF PTMC. Since BRAF-mutated PTMC is generally more resistant to radioiodine treatment, patients with BRAFV600E-mutated PTMC may require earlier management, such as a minimally invasive ablative intervention. Conservative management by active surveillance may be suitable for patients with wild-type BRAFV600E PTMC.

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy.

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 µg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.