Sight threatening diabetic retinopathy in patients with macular telangiectasia type 2.

PURPOSE: Although diabetes is highly prevalent in patients with MacTel, progression to severe non-proliferative (NPDR) and proliferative diabetic retinopathy (PDR) is rarely reported. We report multimodal imaging features of sight-threatening diabetic retinopathy (STDR) in eyes with macular telangiectasia type 2 (MacTel). METHODS: Retrospective case series of seven participants of the MacTel Study at the Moorfields Eye Hospital NHS Foundation Trust study site and one patient from the Institute of Retina and Vitreous of Londrina, Brazil. Sight threatening diabetic retinopathy was defined as severe NPDR, PDR or diabetic macular edema. RESULTS: We report imaging features of 16 eyes of eight patients (7/8, 87.5% female) with diagnoses of MacTel and type 2 diabetes mellitus with STDR. Mean (SD) age was 56 (8.3) years. Patients were followed-up for a mean time of 9.1 (4.7) years. A total of 10/16 (62.5%) eyes showed PDR and 2/16 (12.5%) eyes presented a macular epiretinal neovascularization. CONCLUSIONS: People with diabetes mellitus and MacTel may not be protected from STDR as previously reported. Although the two diseases rarely co-exist, regular monitoring for diabetic retinopathy progression is recommended according to baseline retinopathy severity grades in line with established international guidelines. The presence of MacTel may not modify extended screening intervals, but there is no current evidence. The limited case series in the literature support treatment for complications and should follow the standard of care for either condition. Due to dual pathology, reactivation may be difficult to diagnose on standard imaging and multimodal imaging is recommended.

Chondrolipoma of the Breast: A Myofibroblastoma Variant or a Distinct Lesion?

The entity commonly referred to as chondrolipoma is a rare and enigmatic breast lesion with unclear histogenesis and a complete lack of molecular characterization. It is uncertain whether it represents a hamartoma, choristoma, or a distinct neoplasm, including possibly a variant of mammary-type myofibroblastoma. We report two additional chondrolipomatous lesions of the breast. The lesions had varying histologic and immunohistochemical features similar to myofibroblastoma, including the loss of retinoblastoma (Rb) protein expression in one lesion. Molecular analysis by chromosomal microarray analysis performed on a second lesion did not demonstrate a loss of 13q14 or 16q typical of myofibroblastoma. Our findings further support the concept that at least a subset of breast lesions that historically have been classified as chondrolipoma are related to myofibroblastoma. However, the lack of myofibroblastoma-specific molecular alterations in one lesion suggests chondrolipomas may also have varying origins.

Limits of mitochondrial genes in delimiting species within a Carbula species complex (Hemiptera: Pentatomidae).

Molecular data has become a powerful tool for species delimitation, particularly among those that present limited morphological differences; while the mitochondrial genome, with its moderate length, low cost of sequencing and fast lineage sorting, has emerged as a practical data set. Due to the limited morphological differences among the closely related species of Carbula Stål 1865, the species boundaries between Carbula abbreviata (Motschulsky, 1866), Carbula humerigera (Uhler, 1860), and Carbula putoni (Jakovlev, 1876) have remained particularly unclear. In this study, we applied two phylogenetic reconstruction methods to two data sets (mitogenome and COI) to assess the phylogeny of Carbula distributed in Asia, and five species delimitation methods to determine the boundaries between East Asian Carbula species. Our phylogenetic analyses showed Carbula to be paraphyletic; the seven known species distributed within East Asia to form a single monophyletic group, and within this, C. abbreviata, C. humerigera, C. putoni and middle-type to comprise a C. humerigera species complex. Our results show that mitogenome data alone, while effective in the differentiation of more distantly related Carbula species, is not sufficient to accurately delimit the species within this newly described complex.

A novel method to assess copy number variations in melanocytic neoplasms: Droplet digital PCR for precise quantitation of MYC and MYB genes.

INTRODUCTION: While most melanocytic neoplasms can be classified as either benign or malignant by histopathology alone, ancillary molecular diagnostic tests can be necessary to establish the correct diagnosis in challenging cases. Currently, the detection of copy number variations (CNVs) by fluorescence in situ hybridization and chromosomal microarray (CMA) are the most popular methods, but remain expensive and inaccessible. We aim to develop a relatively inexpensive, fast, and accessible molecular assay to detect CNVs relevant to melanoma using droplet digital polymerase chain reaction (ddPCR) technology. METHODS: In this proof-of-concept study, we evaluated CNVs in MYC and MYB genes from 73 cases of benign nevi, borderline melanocytic lesions, and primary and metastatic melanoma at our institution from 2015 to 2022. A multiplexed ddPCR assay and CMA were performed on each sample, and the results were compared. RESULTS: Concordance analysis of ddPCR with CMA for quantification of MYC and MYB CNVs revealed a sensitivity and specificity of 89% and 86% for MYC and 83% and 74% for MYB, respectively. CONCLUSION: We demonstrate the first use of a multiplexed ddPCR assay to identify CNVs in melanocytic neoplasms. With further improvement and validation, ddPCR may represent a low-cost and rapid tool to aid in the diagnosis of histopathologically ambiguous melanocytic tumors.

A case of recurring acute exudative polymorphous vitelliform maculopathy successfully treated with intravitreal Ozurdex injection.

INTRODUCTION: We describe a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) that recurred 9 years after the initial event. To the best of our knowledge, this is the first report of recurrent AEPVM showing recovery of retinal and retinal pigment epithelium (RPE) function and good visual outcome following treatment with intravitreal corticosteroid. CASE DESCRIPTION: A 45-year-old Caucasian woman first presented with AEVPM in 2009. Her condition spontaneously resolved and she remained stable over several years. 9 years later, her condition recurred with bilateral reduction in visual acuity. Fundus examination revealed multiple small yellowish subretinal lesions across the posterior pole in both eyes. Optical coherence tomography (OCT) showed bilateral cystoid macular oedema (CMO). She was referred for electrophysiology and her electrooculogram findings were in keeping with severe generalised RPE dysfunction bilaterally, with a light peak to dark trough ratio (Arden index) of 110%, comparable to her initial presentation 9 years earlier. She was initially treated with oral steroids with some improvement. However, the maculopathy in the left eye recurred on cessation of oral treatment. A sustained-release 700ug dexamethasone intravitreal implant (Ozurdex®) was inserted in the left eye to which she responded remarkably, with improvement in visual acuity and complete resolution of the CMO. A year later, at her most recent clinic visit in March 2021, there was no evidence of any further recurrence. CONCLUSION: Our case demonstrates clinical and imaging findings consistent with recurrence of AEPVM with CMO that has been successfully treated with Ozurdex®.

Learning few-shot imitation as cultural transmission.

Cultural transmission is the domain-general social skill that allows agents to acquire and use information from each other in real-time with high fidelity and recall. It can be thought of as the process that perpetuates fit variants in cultural evolution. In humans, cultural evolution has led to the accumulation and refinement of skills, tools and knowledge across generations. We provide a method for generating cultural transmission in artificially intelligent agents, in the form of few-shot imitation. Our agents succeed at real-time imitation of a human in novel contexts without using any pre-collected human data. We identify a surprisingly simple set of ingredients sufficient for generating cultural transmission and develop an evaluation methodology for rigorously assessing it. This paves the way for cultural evolution to play an algorithmic role in the development of artificial general intelligence.

A Novel Method to Detect Copy Number Variation in Melanoma: Droplet Digital PCR for Quantitation of the CDKN2A Gene, a Proof-of-Concept Study.

ABSTRACT: A definitive diagnosis of nevus or melanoma is not always possible for histologically ambiguous melanocytic neoplasms. In such cases, ancillary molecular testing can support a diagnosis of melanoma if certain chromosomal aberrations are detected. Current technologies for copy number variation (CNV) detection include chromosomal microarray analysis (CMA) and fluorescence in situ hybridization. Although CMA and fluorescence in situ hybridization are effective, their utilization can be limited by cost, turnaround time, and inaccessibility outside of large reference laboratories. Droplet digital polymerase chain reaction (ddPCR) is a rapid, automated, and relatively inexpensive technology for CNV detection. We investigated the ability of ddPCR to quantify CNV in cyclin-dependent kinase inhibitor 2A ( CDKN2A ), the most commonly deleted tumor suppressor gene in melanoma. CMA data were used as the gold standard. We analyzed 57 skin samples from 52 patients diagnosed with benign nevi, borderline lesions, primary melanomas, and metastatic melanomas. In a training cohort comprising 29 randomly selected samples, receiver operator characteristic curve analysis revealed an optimal ddPCR cutoff value of 1.73 for calling CDKN2A loss. In a validation cohort comprising the remaining 28 samples, ddPCR detected CDKN2A loss with a sensitivity and specificity of 94% and 90%, respectively. Significantly, ddPCR could also identify whether CDKN2A losses were monoallelic or biallelic. These pilot data suggest that ddPCR can detect CDKN2A deletions in melanocytic tumors with accuracy comparable with CMA. With further validation, ddPCR could provide an additional CNV assay to aid in the diagnosis of challenging melanocytic neoplasms.

Gain of CCND1 May Occur Too Infrequently in Cutaneous Melanoma, and Too Late in Melanomagenesis, to Be Diagnostically Useful: Genomic Analysis of 88 Cases.

ABSTRACT: Genomic analysis is an important tool in the diagnosis of histologically ambiguous melanocytic neoplasms. Melanomas, in contrast to nevi, are characterized by the presence of multiple copy number alterations. One such alteration is gain of the proto-oncogene CCND1 at 11q13. In melanoma, gain of CCND1 has been reported in approximately one-fifth of cases. Exact frequencies of CCND1 gain vary by melanoma subtype, ranging from 15.8% for lentigo maligna to 25.1% for acral melanoma. We present a cohort of 72 cutaneous melanomas from 2017-2022 in which only 6 (8.3%) showed evidence of CCND1 gain by chromosomal microarray. This CCND1 upregulation frequency falls well below those previously published and is significantly lower than estimated in the literature ( P < 0.05). In addition, all 6 melanomas with CCND1 gain had copy number alterations at other loci (most commonly CDKN2A loss, followed by RREB1 gain), and 5 were either thick or metastatic lesions. This suggests that CCND1 gene amplification may be a later event in melanomagenesis, long after a lesion would be borderline or equivocal by histology. Data from fluorescence in situ hybridization, performed on 16 additional cutaneous melanomas, further corroborate our findings. CCND1 gain may not be a common alteration in melanoma and likely occurs too late in melanomagenesis to be diagnostically useful. We present the largest chromosomal microarray analysis of CCND1 upregulation frequencies in cutaneous melanoma, conjecture 3 hypotheses to explain our novel observation, and discuss implications for the inclusion or exclusion of CCND1 probes in future melanoma gene panels.

Expression unleashed in artificial intelligence.

The problem of generating generally capable agents is an important frontier in artificial intelligence (AI) research. Such agents may demonstrate open-ended, versatile, and diverse modes of expression, similar to humans. We interpret the work of Heintz & Scott-Phillips as a minimal sufficient set of socio-cognitive biases for the emergence of generally expressive AI, separate yet complementary to existing algorithms.

A novel method to assess copy number variation in melanoma: Droplet digital PCR for precise quantitation of the RREB1 gene in formalin-fixed, paraffin-embedded melanocytic neoplasms, a proof-of-concept study.

BACKGROUND: Melanocytic neoplasms can be challenging to diagnose. One well-established diagnostic aid is the detection of copy number variation (CNV) in a few key genetic loci using conventional methods such as fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA). Droplet digital polymerase chain reaction (ddPCR) is a novel, cost-effective, rapid, and automated method to detect CNV. METHODS: We perform the first investigation of ddPCR to assay Ras-responsive element-binding protein-1 (RREB1), the most common CNV in melanoma using formalin-fixed, paraffin-embedded (FFPE) melanocytic lesion samples; CMA data are used as the gold standard. Archival samples from 2013 to 2021 were analyzed, including 153 data points from 39 FFPE samples representing 34 patients. Benign, borderline, malignant, and metastatic melanocytic neoplasms were examined. RESULTS: ddPCR showed a sensitivity and specificity of 93.8% and 95.7% using one reference gene, and 87.5% and 100% using a different reference gene for RREB1 gain detection. CONCLUSIONS: Here we show that ddPCR can provide inexpensive, rapid, and robust data on the commonest copy number alteration in melanoma. Future development and validation could provide a useful ancillary tool in the diagnosis of challenging melanocytic lesions.

Probable IGG4 related ophthalmic disease presenting with uveitis.

We present a case of an uncommon presentation of IgG4-related ophthalmic disease (ROD). A 58-year-old female presented with unilateral acute anterior uveitis of the right eye, which progressed to scleritis with the development of an associated orbital mass despite treatment with oral glucocorticoid. Initial histopathology of an orbital biopsy was non-diagnostic and continued progression of the disease lead to complete loss of vision in the right eye. The development of uveitis in the previously unaffected left eye led to the decision for enucleation of the right globe and further orbital biopsy. Histopathology revealed features supporting IgG4-related ophthalmic disease. Oral glucocorticoid therapy failed to induce remission, and rituximab therapy was initiated, leading to a rapid resolution in her symptoms. Other cases with a similar presentation report a poor visual prognosis, highlighting the need for prompt diagnosis and treatment of uveitis associated with signs of orbital or scleral involvement.

Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment.

The COL9A3 gene encodes one of the three alpha chains of Type IX collagen, with heterozygous variants reported to cause multiple epiphyseal dysplasia, and suggested as contributory in some cases of sensorineural hearing loss. Patients with homozygous variants have midface hypoplasia, myopia, sensorineural hearing loss, epiphyseal changes and carry a diagnosis of Stickler syndrome. Variants in COL9A3 have not previously been reported to cause vitreoretinal degeneration and/or retinal detachments. This report describes two families with autosomal dominant inheritance and predominant features of peripheral vitreoretinal lattice degeneration and retinal detachment. Genomic sequencing revealed a heterozygous splice variant in COL9A3 [NG_016353.1(NM_001853.4):c.1107 + 1G>C, NC_000020.10(NM_001853.4):c.1107 + 1G>C, LRG1253t1] in Family 1, and a heterozygous missense variant [NG_016353.1(NM_001853.4):c.388G>A p.(Gly130Ser)] in Family 2, each segregating with disease. cDNA studies of the splice variant demonstrated an in-frame deletion in the COL2 domain, and the missense variant occurred in the COL3 domain, both indicating the critical role of Type IX collagen in the vitreous base of the eye.

Aerosol generation through pars plana vitrectomy.

PURPOSE: To assess whether pars plana vitrectomy (PPV) is an aerosol-generating procedure (AGP) in an ex vivo experimental model. METHODS: In this ex vivo study on 10 porcine eyes, optical particle counter was used to measure particles ≤10 µm using cumulative mode in the six in-built channels: 0.3 µm, 0.5 µm, 1 µm, 2.5 µm, 5 µm and 10 µm aerosols during PPV. Two parts of the study were as follows: (1) to assess the pre-experimental baseline aerosol count in the theatre environment where there are dynamic changes in temperature and humidity and (2) to measure aerosol generation with 23-gauge and 25-gauge set-up. For each porcine eye, five measurements were taken for each consecutive step in the experiment including pre-PPV, during PPV, fluid-air exchange (FAX) and venting using a flute with 23-gauge set-up and a chimney with 25-gauge set-up. Therefore, a total of 200 measurements were recorded. RESULTS: With 23-gauge and 25-gauge PPV, there was no significant difference in aerosol generation in all six channels comparing pre-PPV versus PPV or pre-PPV versus FAX. Venting using flute with 23-gauge PPV showed significant reduction of aerosol ≤1 µm. Air venting using chimney with 25-gauge set-up showed no significant difference in aerosol of ≤1 µm. For cumulative aerosol counts of all particles measuring ≤5 µm, compared with pre-PPV, PPV or FAX, flute venting in 23-gauge set-up showed significant reduction unlike the same comparison for chimney venting in 25-gauge set-up. CONCLUSION: PPV and its associate steps do not generate aerosols ≤10 µm with 23-gauge and 25-gauge set-ups.

Molecular genetic profiling reveals novel association between FLT3 mutation and survival in glioma.

INTRODUCTION: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). METHODS: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. RESULTS: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). CONCLUSIONS: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.

Effects of Human Electro-Muscular Incapacitation (HEMI) Devices on Cardiovascular Changes in Anesthetized Swine as Measured by Transesophageal Echocardiography (TEE).

The abundance of, and reliance upon, human electro-muscular incapacitation (HEMI) devices, especially in law enforcement, has generated scrutiny and examination of these technologies. The purpose of this study was to examine cardiovascular effects resulting from typical (5 sec) and longer activation (20 sec) HEMI applications studying myocardial function and peripheral vascular system using a combination of invasive cardiovascular catheters and transesophageal echocardiography (TEE). Six healthy swine (Sus scrofa) 3-5 months in age and weighing between 60 and 86 kg were anesthetized and exposed to the TASER Model X26 waveform while transesophageal echocardiography was performed. Stroke volume was shown to statistically decrease during HEMI application indicating an increase in systemic vascular resistance, but HEMI application did not result in myocardial dysfunction ("cardiac stunning").

Atypical presentation of Coats' Syndrome in facioscapulohumeral dystrophy - Reflecting the variation in phenotypic manifestations.

PURPOSE: To report a unique case of atypical Coats' Syndrome in an 80 year old female with facioscapulohumeral dystrophy. OBSERVATIONS: An 80 years old female was diagnosed clinically of retinal telangiectasia with exudation threatening the fovia. She received a successful macular laser photocoagulation with subsequent cessation of leakage. CONCLUSIONS AND IMPORTANCE: This case is in keeping with Coats' syndrome in fascioscapulohumeral dystrophy, which classically affects young male subjects - making this patient an obvious outlier. This once again reflects the variation in phenotypic manifestations of inherited disorders.