Hypomorphic variants in inherited retinal and ocular diseases: A review of the literature with clinical cases.

Hypomorphic variants decrease, but do not eliminate, gene function via a reduction in the amount of mRNA or protein product produced by a gene or by production of a gene product with reduced function. Many hypomorphic variants have been implicated in inherited retinal diseases (IRDs) and other genetic ocular conditions; however, there is heterogeneity in the use of the term "hypomorphic" in the scientific literature. We searched for all hypomorphic variants reported to cause IRDs and ocular disorders. We also discuss the presence of hypomorphic variants in the patient population of our ocular genetics department over the past decade. We propose that standardized criteria should be adopted for use of the term "hypomorphic" to describe gene variants to improve genetic counseling and patient care outcomes.

Identification of the Vibrational Optical Coherence Tomography Corneal Cellular Peak.

Purpose: Our team previously identified the presence of five corneal resonant frequency (RF) peaks in healthy volunteers using vibrational optical coherence tomography (VOCT). Prior studies have suggested that the ≤100 Hz RF peak represents the cellular element of tissue. The aim of this study was to confirm that this peak reflects the human corneal cellular component using VOCT and histological analysis. Methods: Two human research globes were obtained from the same donor, and VOCT measurements were collected from the full-thickness corneas. A microkeratome was then used to create serial-free corneal caps from each cornea, with VOCT performed on the residual stromal bed after each excision. All lamellar sections from both globes were sent for histological analysis to determine cellularity. Cell counts on the specimens were performed by two independent observers. Results: The average of the normalized ≤100 Hz peak values before lamellar sectioning was significantly higher than the average of this peak values after the first, second, and third cuts (P = 0.023), which was 33.9% less than before any cuts. The cell count values in the first slice were significantly higher than the average cell count values of the three deeper slices (P < 0.001), and the cell count dropped 84.4% after the first slice was removed. Conclusions: The findings of this study suggest that the ≤100 Hz corneal peak identified by VOCT corresponds to the cellular component of the cornea. Translational Relevance: This work furthers our understanding of the origin of the corneal ≤100 Hz peak identified using VOCT.

The big warp: Registration of disparate retinal imaging modalities and an example overlay of ultrawide-field photos and en-face OCTA images.

PURPOSE: To develop an algorithm and scripts to combine disparate multimodal imaging modalities and show its use by overlaying en-face optical coherence tomography angiography (OCTA) images and Optos ultra-widefield (UWF) retinal images using the Fiji (ImageJ) plugin BigWarp. METHODS: Optos UWF images and Heidelberg en-face OCTA images were collected from various patients as part of their routine care. En-face OCTA images were generated and ten (10) images at varying retinal depths were exported. The Fiji plugin BigWarp was used to transform the Optos UWF image onto the en-face OCTA image using matching reference points in the retinal vasculature surrounding the macula. The images were then overlayed and stacked to create a series of ten combined Optos UWF and en-face OCTA images of increasing retinal depths. The first algorithm was modified to include two scripts that automatically aligned all the en-face OCTA images. RESULTS: The Optos UWF image could easily be transformed to the en-face OCTA images using BigWarp with common vessel branch point landmarks in the vasculature. The resulting warped Optos image was then successfully superimposed onto the ten Optos UWF images. The scripts more easily allowed for automatic overlay of the images. CONCLUSIONS: Optos UWF images can be successfully superimposed onto en-face OCTA images using freely available software that has been applied to ocular use. This synthesis of multimodal imaging may increase their potential diagnostic value. Script A is publicly available at https://doi.org/10.6084/m9.figshare.16879591.v1 and Script B is available at https://doi.org/10.6084/m9.figshare.17330048.

Signal Peptide Variants in Inherited Retinal Diseases: A Multi-Institutional Case Series.

Signal peptide (SP) mutations are an infrequent cause of inherited retinal diseases (IRDs). We report the genes currently associated with an IRD that possess an SP sequence and assess the prevalence of these variants in a multi-institutional retrospective review of clinical genetic testing records. The online databases, RetNet and UniProt, were used to determine which IRD genes possess a SP. A multicenter retrospective review was performed to retrieve cases of patients with a confirmed diagnosis of an IRD and a concurrent SP variant. In silico evaluations were performed with MutPred, MutationTaster, and the signal peptide prediction tool, SignalP 6.0. SignalP 6.0 was further used to determine the locations of the three SP regions in each gene: the N-terminal region, hydrophobic core, and C-terminal region. Fifty-six (56) genes currently associated with an IRD possess a SP sequence. Based on the records review, a total of 505 variants were present in the 56 SP-possessing genes. Six (1.18%) of these variants were within the SP sequence and likely associated with the patients' disease based on in silico predictions and clinical correlation. These six SP variants were in the CRB1 (early-onset retinal dystrophy), NDP (familial exudative vitreoretinopathy) (FEVR), FZD4 (FEVR), EYS (retinitis pigmentosa), and RS1 (X-linked juvenile retinoschisis) genes. It is important to be aware of SP mutations as an exceedingly rare cause of IRDs. Future studies will help refine our understanding of their role in each disease process and assess therapeutic approaches.

Enucleations, Eviscerations, and Exenterations at a Supratertiary-care Hospital in Puerto Rico: A Retrospective Study.

OBJECTIVE: To provide a descriptive analysis of the indications and the intraoperative and postoperative complications of eye enucleations and eviscerations, and orbital exenterations performed at the only academic institution in Puerto Rico providing supratertiary care. METHODS: A retrospective medical record review of patients who underwent enucleations, eviscerations, and exenterations from January 2015 through June 2020 was conducted. The data were analyzed to generate a descriptive profile of the demographic characteristics of the patients, their clinical indications and surgical complications, and a histopathological diagnosis per type of eye-removal procedure. RESULTS: A total of 118 eyes were removed via enucleation, evisceration, or exenteration over the 66-month study period. The average patient age was 64 (±17.5) years and 63.8% of the patients were male. The most frequently performed eye-removal procedure was enucleation (73.7%), followed by evisceration (18.6%) and exenteration (7.6%). The main clinical indications for enucleations and eviscerations were infectious processes, namely panophthalmitis, endophthalmitis, and/or perforated corneal ulcers, that failed medical management. In our sample, squamous cell carcinoma was the most common diagnosis (both clinically and histopathologically) leading to exenteration. Postoperative complications in our patient cohort were minimal. CONCLUSION: At our institution, enucleations predominate over eviscerations. Retrospective reviews published in recent years indicate that the rate of eviscerations at our institution is comparatively low. The results of this study, the first of its kind at our institution, may encourage a re-evaluation of the indications for evisceration versus enucleation in our patient population.

In Vivo Determination of the Human Corneal Elastic Modulus Using Vibrational Optical Coherence Tomography.

Purpose: To determine the in vivo elastic modulus of the human cornea using vibrational optical coherence tomography (VOCT). Methods: Vibrational analysis coupled with optical coherence tomography (OCT) was used to obtain the resonant frequency (RF) and elastic modulus of corneal structural components. VOCT corneal thickness values were measured using OCT images and correlated with corneal thickness determined with Pentacam (Oculus, Wetzlar, Germany). Moduli were obtained at two locations: central cornea (CC) and inferior cornea (IC). Measurements were obtained with and without anesthetic eye drops to assess their effect on the modulus measurements. Results: VOCT thickness values correlated positively (R2 = 0.97) and linearly (y = 1.039x-16.89) with those of Pentacam. Five RF peaks (1-5) were present, although their presence was variable across eyes. The RF for peaks 1 to 5 in the CC and IC ranged from 73.5 ± 4.9 to 239 ± 3 Hz and 72.1 ± 6.3 to 238 ± 4 Hz, respectively. CC and IC moduli for peaks 1 to 5 ranged from 1.023 ± 0.104 to 6.87 ± 0.33 MPa and 0.98 ± 0.15 to 6.52 ± 0.79 MPa, respectively. Topical anesthesia did not significantly alter the modulus (P > 0.05 for all), except for peak 2 in the CC (P < 0.05). Conclusions: This pilot study demonstrates the utility of VOCT as an in vivo, noninvasive technology to measure the elastic modulus in human corneas. The structural origin of these moduli is hypothesized based on previous reports, and further analyses are necessary for confirmation. Translational Relevance: This work presents VOCT as a novel approach to assess the in vivo elastic modulus of the cornea, an indicator of corneal structural integrity and health.

Syphilitic Outer Retinopathy: A Case Report and Review of the Literature.

Purpose: This work presents a case of syphilitic outer retinopathy with findings similar to those of acute zonal occult outer retinopathy (AZOOR). We also discuss the clinical characteristics, treatment, and prognosis of this entity. Methods: A case report and systematic literature review are presented. Results: A 56-year-old woman presented with acute vision loss, localized photopsia, a central scotoma, and retinal findings that were all consistent with AZOOR. A further workup led to a diagnosis of syphilis. Oral prednisone and intravenous penicillin resulted in the resolution of the posterior uveitis and the restoration of visual acuity. However, the central scotoma remained at the 3-year follow-up visit. Conclusions: Syphilitic outer retinopathy is a distinct entity characterized by the disruption of the ellipsoid zone visible on optical coherence tomography and a corresponding increase in fundus hyperautofluorescence in the affected areas. Although some patients may present with a demarcation line, as is seen with AZOOR, the fundus is oftentimes unremarkable or may show only subtle retinal pigment epithelium changes. Uveitis resolution and visual acuity restoration may be expected following treatment; however, visual field disturbances may persist.

Short-term oral albendazole therapy for diffuse unilateral subacute neuroretinitis: A case report.

PURPOSE: To report on a case of diffuse unilateral subacute neuroretinitis (DUSN) that was successfully treated with a short course of oral albendazole. OBSERVATIONS: A 51-year-old male presented with severe visual loss secondary to DUSN associated with a positive Toxocara serology. Because the parasite could not be detected on fundoscopy, first-line treatment with photocoagulation could not be administered. Treatment with a 6-day course of oral albendazole resulted in the resolution of DUSN as well as the restoration of visual acuity. CONCLUSION AND IMPORTANCE: Although DUSN is characterized by the presence of a parasitic organism in the retina, there are cases in which the parasite is not visible. Albendazole has been used to treat such cases, but a standard treatment regimen has not been determined yet. Our case suggests that the resolution of DUSN can be achieved with short-term albendazole therapy.

Association of tuberculosis with multimorbidity and social networks / Relação da tuberculose com multimorbidade e redes sociais

ABSTRACT The combination of tuberculosis with other diseases can affect tuberculosis treatment within populations. In the present study, social network analysis of data retrieved from the Mexican National Epidemiological Surveillance System was used in order to explore associations between the number of contacts and multimorbidity. The node degree was calculated for each individual with tuberculosis and included information from 242 contacts without tuberculosis. Multimorbidity was identified in 49.89% of individuals. The node degrees were highest for individuals with tuberculosis + HIV infection (p < 0.04) and lowest for those with tuberculosis + pulmonary edema (p < 0.07). Social network analysis should be used as a standard method for monitoring tuberculosis and tuberculosis-related syndemics.

RESUMO A combinação de tuberculose e outras doenças pode afetar o tratamento da tuberculose nas populações. No presente estudo, a análise de redes sociais de dados extraídos do Sistema Nacional de Vigilância Epidemiológica do México foi usada para explorar as relações entre o número de contatos e a multimorbidade. O grau do nó foi calculado para cada indivíduo com tuberculose e incluiu informações a respeito de 242 contatos sem tuberculose. A multimorbidade foi identificada em 49,89% dos indivíduos. Os maiores graus dos nós foram os referentes a indivíduos com tuberculose + infecção pelo HIV (p < 0,04), e os menores foram os referentes a indivíduos com tuberculose + edema pulmonar (p < 0,07). A análise de redes sociais deve ser usada como método-padrão para monitorar a tuberculose e a sindemia relacionada com a tuberculose.

Association of tuberculosis with multimorbidity and social networks.

The combination of tuberculosis with other diseases can affect tuberculosis treatment within populations. In the present study, social network analysis of data retrieved from the Mexican National Epidemiological Surveillance System was used in order to explore associations between the number of contacts and multimorbidity. The node degree was calculated for each individual with tuberculosis and included information from 242 contacts without tuberculosis. Multimorbidity was identified in 49.89% of individuals. The node degrees were highest for individuals with tuberculosis + HIV infection (p < 0.04) and lowest for those with tuberculosis + pulmonary edema (p < 0.07). Social network analysis should be used as a standard method for monitoring tuberculosis and tuberculosis-related syndemics. RESUMO A combinação de tuberculose e outras doenças pode afetar o tratamento da tuberculose nas populações. No presente estudo, a análise de redes sociais de dados extraídos do Sistema Nacional de Vigilância Epidemiológica do México foi usada para explorar as relações entre o número de contatos e a multimorbidade. O grau do nó foi calculado para cada indivíduo com tuberculose e incluiu informações a respeito de 242 contatos sem tuberculose. A multimorbidade foi identificada em 49,89% dos indivíduos. Os maiores graus dos nós foram os referentes a indivíduos com tuberculose + infecção pelo HIV (p < 0,04), e os menores foram os referentes a indivíduos com tuberculose + edema pulmonar (p < 0,07). A análise de redes sociais deve ser usada como método-padrão para monitorar a tuberculose e a sindemia relacionada com a tuberculose.