Genetic Testing of Patients with Inherited Retinal Diseases in the European Countries. An International Survey by the European Vision Institute.

INTRODUCTION: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80% and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialised centres, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. CONCLUSION: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.

Long-Term Stability of Benign Lobular Inner Nuclear Layer Proliferations.

This case report describes an asymptomatic 55-year-old woman with unilateral benign lobular inner nuclear layer proliferations and hyperreflective lesions causing distortion of adjacent retinal layers.

Back pain in adolescent idiopathic scoliosis: frequency and risk factors.

PURPOSE: Although back pain is commonly reported in patients with adolescent idiopathic scoliosis (AIS), factors that influence the presence and severity of back pain in AIS, including curve-specific variables, have not been well studied. This study aims to describe the prevalence and severity of back pain in AIS patients and determine the extent to which patient characteristics, including curve-specific factors, are associated with a higher risk of back pain in AIS. METHODS: The study was a retrospective medical records review of adolescents (aged 10-17 years) diagnosed with AIS between 01/01/2018 and 12/31/2021 at an academic tertiary children's hospital. Patients with previous spine surgery were excluded. Variables collected included demographics (age, sex, race, insurance), Lenke classification, major coronal curve, back pain-related information, Risser stage, vitamin D levels, post-diagnosis brace utilization, physical therapy or chiropractic treatment, and surgery. RESULTS: A total of 891 AIS patients were included in the analysis. The sample was predominantly female (73.3%) and insured by Medicaid (57.8) with a mean age of 12.8 years. The mean major coronal curve was 26.3 degrees. Most patients had Lenke type 1 (47%) and type 5 (41%) curves. Nearly half of patients reported back pain (48.5%) with average pain severity in the low-to-moderate range (4.7) on FACES pain scale (0-10). Among those who reported back pain, 63.2% specified a location with the majority reporting pain in the lumbar region (56%) and, less commonly, in the thoracic (39%) and scapular (8%) regions. Lumbar pain was associated with significantly higher pain intensity (p = 0.033). Additionally, the location of pain reported was associated with location of major coronal curve (p < 0.0001). No association was observed between pain presence and vitamin D deficiency (p = 0.571, n = 175), major coronal curve magnitude (p = 0.999), Lenke curve type (p = 0.577), and sex (p = 0.069). Older patients, those insured by Medicaid, and those with higher Risser scores were more likely to report pain scores (p = 0.001 for all). CONCLUSION: Nearly half (48%) of newly diagnosed AIS patients experience back pain which is higher than the prevalence of 33% seen in the general adolescent population. Pain was more prevalent among patients over the age of 13, with heavier body weight, and those insured by Medicaid. Pain was most commonly reported in the lumbar region, especially among patients with lumbar curves. This information can be helpful in counseling AIS patients, though further investigations are needed, especially to determine the underlying causes of back pain in AIS and to elucidate the discrepancy in pain between patients with Medicaid and commercial insurance. LEVEL OF EVIDENCE: Prognostic Study Level II.

Greener intravitreal injections: a narrative review.

Healthcare services are significant contributors to climate change. Ophthalmology, by virtue of the volume of appointments and procedures it generates, is thought to play a major role in this regard. Intravitreal injections (IVI) are a commonly performed ophthalmological procedure to treat patients with conditions such as macular neovascularisation secondary to neovascular age-related macular disease or myopia, diabetic macular oedema, and retinal vein occlusions. As IVIs become more ubiquitous, addressing their environmental impact and sustainability will become increasingly important. Strategies to tackle carbon emissions from IVIs may target the following areas which align with the Greenhouse Gas Protocol scopes: building energy; water consumption; travel to appointments; manufacture and procurement of the drug and other necessary materials; and waste disposal. We propose a path towards a more sustainable approach for IVIs, and discuss its potential safety as well as the patient experience.

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.

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.

Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules.

RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype. See also the graphical abstract(Fig. 1).

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.

Radiofrequency ablation as a treatment modality for primary hyperparathyroidism: a systematic literature review.

Background: Primary hyperparathyroidism (pHPT) is an endocrine disorder typically characterized by elevated serum calcium and elevated parathyroid hormone (PTH). While parathyroidectomy is the standard treatment, non-operative intervention such as radiofrequency ablation (RFA) has been adopted as an alternative for the management of pHPT, as it has been utilized in other endocrine glands such as thyroid and adrenal. In this literature review, we aim to evaluate the current practice of RFA for pHPT. Methods: A systematic literature search using PubMed, Web of Science, and Embase through June 2022 was conducted. Studies included in the review consisted of patient cohorts who had an unequivocal diagnosis of pHPT and underwent the treatment of pHPT with RFA. When more than one study was published from a similar cohort of patients, only the study with the most number of patients was considered. Studies included were assessed for bias using the critical appraisal instruments from the Joanna Briggs Institute (JBI) System. Results: A total of 14 studies describing 167 parathyroid glands treated in 163 patients were reviewed. The overall cure rate was 91.2%, with 5 patients undergoing more than one ablation. The most common adverse effect encountered was temporary dysphonia. Incomplete ablation and missed multiglandular disease were the most common reasons for RFA treatment failure. Conclusions: RFA may be an effective and safe alternative to parathyroidectomy in select patients with a well-localized, well-located parathyroid adenoma. Additional long-term data are needed to refine its role in the pHPT treatment algorithm.

A clinical practice review of percutaneous ethanol injection for thyroid nodules: state of the art for benign, cystic lesions.

Percutaneous ethanol injection (PEI) is a widely used treatment option for cystic and predominantly cystic thyroid nodules. It has several advantages over other treatment modalities. Compared to surgery, PEI is less painful, can be performed in the outpatient setting, and carries less risk of transient or permanent side effects. Compared to other minimally invasive techniques such as radiofrequency ablation (RFA), PEI is less expensive and does not require specialized equipment. PEI performs well in the context of cystic nodules. PEI does not perform as well as other techniques in solid nodules, so its use as a primary treatment is limited to cystic and predominantly cystic thyroid nodules. However, PEI is also being explored as an adjunct treatment to improve ablation of solid nodules with other techniques. Here, we provide a clinical review discussing the genesis, mechanism of action, and patient selection with respect to ethanol ablation, as well as the procedure itself. Predictors of operative success, failure, and common adverse events are also summarized. Altogether, PEI allows impressive volume reduction rates with minimal complications. Several recent studies have also evaluated the long-term impact of PEI up to 10 years after treatment and revealed maintenance of robust treatment efficacy with no undesirable long-term sequelae. Thus, PEI remains the treatment of choice for benign but symptomatic cystic and predominantly cystic thyroid nodules.

Radiofrequency ablation of thyroid nodules: a clinical review of treatment complications.

Radiofrequency ablation (RFA) is a minimally invasive ablative modality for the treatment of thyroid nodules. Reports of RFA use have demonstrated an impressive safety profile and excellent volume reduction rates between 60-90%. Given its increased popularity in the United States as well as globally, numerous recent works have been published and a discussant of relevant complications incorporating recent insight may assist practitioners in minimizing complications and optimizing patient outcomes. Herein, we provide a comprehensive and updated review of the reported complications and side effects following RFA, summarizing their frequency and clinical presentation. We also describe a means of minimizing such complications and/or side effects. Overall, the safety profile of RFA is impressive and superior to that of thyroid surgery. The overall risk of complication is reportedly 2-3%. The risk of permanent complication or severe injury is very unlikely, below 1%. Complications are infrequent, but may be nerve-related, endocrine-related, or iatrogenic-related, and consequences of localized heat delivery. The vast majority of complications related to RFA can be managed conservatively, without need for invasive measures. This review will assist surgeons and clinicians in recognizing and treating the various complications and side effects in clinical practice.

Clinical outcomes and tumor microenvironment response to radiofrequency ablation therapy: a systematic review and meta-analysis.

Background: Radiofrequency ablation (RFA) utilizes minimally invasive high-energy current to precisely ablate tumor cells. It has been utilized in many cancer types including thyroid, lung, and liver cancer. It has been shown to provide adequate ablative margins with minimal complications; however, incomplete RFA may lead to recurrence of tumor. The underlying cellular mechanism and behavior of ablated cancer tissue is poorly understood. Methods: A systematic review was performed, searching EMBASE, Web of Science, PubMed, and Scopus for studies published up to March 2022 and reported following PRISMA guidelines. Collection was performed by two groups of investigators to avoid risk of bias. The Cochrane Collaboration's tool was used for assessing risk of bias. We identified human, in vivo, and in vitro research studies utilizing RFA for tumor tissues. We required that the studies included at least one of the following: complications, recurrence, or survival, and took interest to studies identifying cellular signaling pathway patterns after RFA. Descriptive statistical analysis was performed in 'R' software including mean and confidence interval. Results: The most frequent cancers studied were liver and lung cancers accounting for 57.4% (N=995) and 15.4% (N=267), followed by esophageal (N=190) and breast cancer (N=134). The most common reported complications were bleeding (19%) and post-operative pain (14%). In our literature search, four independent studies showed upregulation and activation of the VEGF pathway following RFA, four showed upregulation and activation of the AKT pathway following RFA, three studies demonstrated involvement of matrix metalloproteinases, and four showed upregulation of c-Met protein following RFA. Conclusions: In our review and meta-analysis, we identify several proteins and pathways of interest of which are important in wound healing, angiogenesis, and cellular growth and survival. These proteins and pathways of interest may implicate areas of research towards RFA resistance and cancer recurrence.

Risk Factors for Postoperative Infections Following Appendectomy of Complicated Appendicitis: A Meta-analysis and Retrospective Single-institutional Study.

Patients with complicated appendicitis have an increased risk for postoperative infections. Potential risk factors for postoperative infections through a meta-analysis and retrospective chart review are discussed. A meta-analysis consisting of 35 studies analyzing complicated appendicitis treated with an appendectomy noting at least 1 postoperative infection was performed. A retrospective review was then conducted in patients diagnosed with complicated appendicitis after appendectomy. Of 5326 patients in total, 15.4% developed postoperative infections. Laparoscopic surgery and perioperative hyperoxygenation were found to be protective factors for the development of infection. Retrospectively, 53.2% of patients presented with complicated appendicitis. Patients with complicated appendicitis were more likely to be older in age and have an increased length of stay. Patient demographics, operative time, and comorbid status had no effect on postoperative infection or readmission rate. Physicians should strongly consider minimally invasive techniques to treat all cases of complicated appendicitis irrespective of comorbidities, age, sex, or body mass index.

Hypomorphic CDHR1 variants may result in retinitis pigmentosa with relative preservation of cone function.

PURPOSE: Retinitis pigmentosa (RP) associated with biallelic variants in CDHR1 has rarely been reported, and detailed phenotyping data are not available. RP implies relative preservation of foveal cones, when compared to cone-rod dystrophy associated with biallelic null variants in CDHR1. We hypothesize that RP may occur in association with one or more hypomorphic CDHR1 alleles. MATERIALS AND METHODS: Retrospective report of a 48-year-old patient with CDHR1-associated RP with a hypomorphic missense variant c.562 G>A, p. (Gly188Ser) and a novel, unreported variant affecting a canonical splice acceptor site (c.784-1 G>C). Clinical examination, multimodal retinal imaging, electroretinography, visual field testing, and mesopic microperimetry were undertaken 8 years apart. Scotopic microperimetry was also performed. The DNA sequence context of the variants was examined to identify theoretical CRISPR-Cas9 base-editing strategies. RESULTS: The patient presented at 35 years with a 12-year history of nyctalopia. His best corrected visual acuity was 20/20. Clinical presentation, multimodal retinal imaging studies, electroretinography, and mesopic microperimetry were typical of a progressive rod-cone dystrophy (i.e. classic RP). There were no scotomas within the central field as would be expected at this age in CDHR1-associated cone-rod dystrophy. Scotopic microperimetry suggested some preservation of macular cone over rod function, although both were severely impaired. A suitable CRISPR adenine base editor was identified that could theoretically correct the missense variant c.562 G>A, p. (Gly188Ser). CONCLUSIONS: CDHR1-associated RP shows a relative preservation of cone function in the presence of a presumed hypomorphic allele and may be considered a hypomorphic disease phenotype. Further work is required to identify modifying factors that determine disease phenotype since macular dystrophy, with relative sparing of rods, may also occur with hypomorphic CDHR1 alleles.

IMPG2-Related Maculopathy.

PURPOSE: To investigate the phenotype, variability, and penetrance of IMPG2-related maculopathy. DESIGN: Retrospective observational case series. METHODS: Clinical evaluation, multimodal retinal imaging, genetic testing, and molecular modeling. RESULTS: A total of 25 individuals with a mono-allelic IMPG2 variant were included, 5 of whom were relatives of patients with IMPG2-associated retinitis pigmentosa. A distinct maculopathy was present in 17 individuals (median age, 52 years; range, 20-72 years), and included foveal elevation with or without subretinal vitelliform material or focal atrophy of the retinal pigment epithelium. Best-corrected visual acuity (BCVA) was ≥20/50 in the better eye (n = 15), and 5 patients were asymptomatic. Longitudinal observation (n = 8, up to 19 years) demonstrated stable maculopathy (n = 3), partial/complete resorption (n = 4) or increase (n = 1) of the subretinal material, with overall stable vision (n = 6). No manifest maculopathy was observed in 8 individuals (median age, 58 years; range, 43-83 years; BCVA ≥20/25), all were identified through segregation analysis. All 8 individuals were asymptomatic, with minimal foveal changes observed on optical coherence tomography in 3 cases. A total of 18 different variants were detected, 11 of them truncating. Molecular modeling of 5 missense variants [c.727G>C, c.1124C>A, c.2816T>A, c.3047T>C, and c.3193G>A] supported the hypothesis that these have a loss-of-function effect. CONCLUSIONS: Mono-allelic IMPG2 variants may result in haploinsufficiency manifesting as a maculopathy with variable penetrance and expressivity. Family members of patients with IMPG2-related retinitis pigmentosa may present with vitelliform lesions. The maculopathy often remains limited to the fovea and is usually associated with moderate visual impairment.