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Few research studies evaluating the impact of dermatologic diseases in the United States (US) have adequately included underrepresented groups. All of Us (AoU) is an ongoing precision medicine-based research initiative by the National Institutes of Health (NIH) that facilitates research in populations traditionally underrepresented in biomedical research by prioritizing them for data collection. Our objective was to evaluate the burden of onychomycosis in underrepresented groups defined by the framework provided by AoU. The AoU Registered Tier dataset version 5 was used which includes data collected between May 30, 2017 and April 1, 2021. We conducted a cross-sectional analysis linking survey and electronic health record (EHR) data to estimate the prevalence of onychomycosis in underrepresented groups defined by race, ethnicity, age (≥75 years), disability, sexual orientation/gender identity (LGBTQIA+), income (annual household income ≤$35 000) and education (less than a high school degree). The latest All of Us data release includes 329,038 participants. Of these, 251,597 (76%) had EHR data and 13,874 had onychomycosis (overall prevalence, 5.5%; 95% CI, 5.4– 5.6). Multivariate analyses adjusted by tinea pedis, diabetes mellitus, immune compromise, nail psoriasis, and insurance status, in addition to the aforementioned variables, revealed that, compared with White participants, Black and Hispanic participants had a higher adjusted odds of onychomycosis (OR, 1.29; 95% CI, 1.23–1.36 and OR, 1.24; 95% CI, 1.17–1.31, respectively). Higher adjusted odds of onychomycosis were also observed in underrepresented groups. Our findings suggest a disproportionately high burden of onychomycosis in underrepresented groups, although further studies are needed to replicate our findings and address this disparity.

Tinea pedis is the most common form of dermatophytosis resulting in interdigital infections. All of Us (AoU) is a National Institute of Health initiative with an emphasis on patient populations traditionally underrepresented in biomedical research.Our objective was to evaluate the burden of tinea pedis in underrepresented groups in the United States, utilising the novel AoU research program.We analysed AoU Registered Tier dataset version 5, which includes data collected between 30 May, 2017, and 1 April, 2021. We conducted a cross-sectional analysis linking survey and electronic health record (EHR) data to estimate the prevalence of tinea pedis in underrepresented groups.All of Us data release includes 329,038 participants. Of these, 251,597 (76.5%) had electronic health record data and 6932 had tinea pedis (overall prevalence, 2.76%; 95% CI, 2.69-2.82). Multivariate analyses revealed that compared with White participants, Black and Hispanic participants had a higher adjusted odds of tinea pedis (OR, 1.29; 95% CI, 1.20-1.38 and OR, 1.38; 95% CI, 1.28-1.48, respectively). Higher adjusted odds of tinea pedis were observed in underrepresented groups defined by: age =75 years (OR, 1.45; 95% CI, 1.33-1.57), LGBTQ status (OR, 1.17; 95% CI, 1.09-1.27), less than a high school education (OR, 1.22; 95% CI, 1.11-1.34), income$35,000 (OR, 1.09; 95% CI, 1.02-1.16) and physical disability (OR, 1.56; 95% CI, 1.08-1.24).Our findings are consistent with overall age, and gender-specific prevalence estimates from prior epidemiologic studies, validating the scientific consistency of the new AoU database. Additionally, there may be an increased burden of tinea pedis among Black and Hispanic individuals.

Sara D Ragi,1 Isabelle Moseley,1 Samantha Ouellette,2 Babar Rao2 1The Warren Alpert Medical School of Brown University, Providence, RI, USA; 2Department of Dermatology, Robert Wood Johnson Medical School, New Brunswick, NJ, USACorrespondence: Sara D Ragi, Email sara_ragi@brown.eduAbstract: The introduction of highly active antiretroviral treatment (HAART) for acquired immunodeficiency syndrome (AIDS) has led to a significant decrease in the incidence of Kaposi’s sarcoma (KS) in recent years. However, a concomitant increase in racial disparities in KS has arisen. Here, we analyze data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program for epidemiology and survival of Kaposi’s sarcoma by race. The highest incidence was observed among Black patients (incidence rate (IR), 1.189; 95% confidence interval (CI), 1.092– 1.189), followed by White patients (IR, 0.486; 95% CI, 0.473– 0.498). Relative survival at 1, 3, and 5 years differed significantly by race, with White patients having the highest survival rates (84.26%, 77.79%, and 74.79% at 1, 3, and 5 years respectively) and Black patients demonstrating the lowest (71.50%, 61.37%, and 57.38%), with intermediate survival rates in Asians/Pacific Islanders (AAPI) (80.62%, 71.19%, and 67.28%) and American Indians/Alaska Natives (AIAN) (80.56%, 61.45%, and 61.45%). We conclude that there are significant racial disparities in the incidence, epidemiology, and survival of KS.Keywords: Kaposi’s sarcoma, racial disparities, race, cancer, soft tissue sarcoma, surveillance, epidemiology, end results program, epidemiology

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient’s case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

The clustered regularly interspaced short palindromic repeats (CRISPR)-Caspase9 (Cas9) system provides a programmable technology that may be used to edit the eukaryotic genome and epigenome. CRISPR/Cas9 includes a guide RNA targeted to a gene of interest which hybridizes to a nucleotide sequence next to a protospacer-adjacent motif (PAM) which guides the Cas9 endonucleases to the target site for cleavage via double-strand breaks. A caveat of the CRISPR/Cas9 system is the creation of off-target double-strand breaks (DSBs) which may result in anomalous insertions, deletions, and translocations. Thus, assays for the sensitive detection and analysis of off-target editing are critical. Here, we describe currently available CRISPR technologies, CRISPR applications, and current analysis platforms to detect off-target effects including genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE-Seq), high-throughput genomic translocation sequencing (HTGTS), breaks labeling, enrichments on streptavidin and next-generation sequencing (BLESS), and in vitro nuclease-digested genome sequencing (Digenome-seq).

Medmont Dark-Adapted Chromatic (DAC) Perimeter enables efficient and quantifiable evaluation of rod-mediated (scotopic) vision. DAC tests rod function at multiple retinal locations, creating a topographical map of rod-mediated vision. These dynamic rod responses can be used as a functional marker to monitor disease progression and functional alterations in inherited retinal dystrophies, such as retinitis pigmentosa, Stargardt disease, cone-rod dystrophy, and choroideremia. In this chapter, we describe a protocol for the operation and analysis of the Medmont DAC in monitoring and assessing various retinal disorders.

Following its implementation in the 1960s, fluorescein angiography (FA) has become a widely used and reliable tool in the diagnosis of retinal and choroidal disorders. FA is an imaging modality utilized to examine the circulation of the retina and choroid. Here, we describe the process of obtaining fundus images with sodium fluorescein dye as a contrast agent. Using this methodology, ophthalmologists may examine the retinal and choroidal vasculature to diagnose a wide scope of retinal and choroidal diseases.

Inherited retinal diseases (IRDs), including retinitis pigmentosa, have devastating consequences for the visual function of affected individuals. Chief among these are a gradual loss of visual field, visual acuity, and night vision (otherwise known as nyctalopia). These changes often occur slowly, over a course of decades. Objective modalities for assessing these many aspects of visual function are crucial, not only to the monitoring of disease progression but, in recent years, also to evaluating the efficacy or lack thereof of new therapeutic interventions in the setting of clinical trials. This chapter will provide descriptions of these valuable assessment modalities, alongside discussions of their advantages and limitations in the context of serving those afflicted by IRDs.

Human retinal organoids derived from induced pluripotent stem cells (iPSCs) serve as a promising preclinical model for testing the safety and efficacy of viral gene therapy. Retinal organoids recapitulate the stratified multilayered epithelium structure of the developing and maturating human retina. As such, retinal organoids are unique tools to model retinal disease and to test therapeutic interventions toward their amelioration. Here, we describe a method for the generation of human iPSC-derived retinal organoids and how they can be utilized for the assessment of recombinant adeno-associated viral (rAAV)-mediated gene delivery.

Ocular gene therapy represents an emerging and promising therapeutic approach for the treatment of several of the inherited retinal diseases. Currently, the focus has been to investigate monogenic inherited retinal disorders. Genetic and cellular therapies can be delivered to the eye by various injection techniques, including those that are intravitreal, subretinal, and suprachoroidal. Each of these three delivery methods are discussed with regard to their historical background, indications, surgical steps, and follow-up.

Indocyanine green (ICG) angiography was first approved by the Food and Drug Administration for human use in the 1956. Prior to its use in chorioretinal angiograms, ICG was used to measure blood flow and track cardiac output. It was only in 1969 when two researchers, Kyuga Kogure and Earl Choromokos from the University of Miami, first used ICG to create more accurate angiograms. In the following years, researchers were able to hone the underlying science of this new form of angiography. As time passed and technology advanced, the application of ICG in clinical practice became widespread. Today ICG is used to diagnose and monitor the progression of retinal and choroidal diseases affecting millions of individuals across the globe. ICG utilizes the injection of indocyanine green dye into a patient's bloodstream to visualize abnormalities of the choroid and retina by evaluating choroidal circulation. ICG angiography is useful in the diagnosis and management of occult choroidal neovascularization in age-related macular degeneration and may be used in other inflammatory conditions with central serous chorioretinopathy. ICG angiography offers advanced imaging for improved monitoring and treatment of a wide variety of choroidal and retinal diseases.

Family pedigrees allow for a more thorough understanding of human genetic disorders. They are used to help establish patterns of inheritance and to identify individuals at risk of disease. Pedigree analysis can be helpful in identifying genetic disorders that demonstrate mechanisms such autosomal dominant or recessive inheritance, X-linked inheritance, and anticipation.

Alopecia areata (AA) is the most common form of immune-mediated hair loss. Studies have begun to establish the most frequent comorbid diseases of AA; however, results have been inconsistent with few prospective studies.A total of 63,692 women in the Nurses' Health Study, 53-80 years, were prospectively followed from 2002 to 2014 to determine whether history of immune-mediated disease was associated with AA risk. Hazard ratios (HRs) and 95% confidence intervals (CIs) for AA in relation to immune-mediated conditions were computed using Cox proportional hazard models, adjusted for AA risk factors.133 AA cases were identified during follow-up. Personal history of any immune-mediated disease was associated with increased AA risk (HR 1.72, 95% CI 1.24-2.37). History of systemic lupus erythematosus (HR 5.43, 95% CI 2.11-13.97), multiple sclerosis (HR 4.10, 95% CI 1.40-11.96), vitiligo (HR 3.13, 95% CI 1.08-9.10), psoriasis (HR 2.01, 95% CI 1.00-4.03), hypothyroidism (HR 1.88, 95% CI 1.30-2.71), and rheumatoid arthritis (HR 1.66, 95% CI 1.09-2.52) were associated with increased AA risk. History of inflammatory bowel disease or Graves' disease/hyperthyroidism was not significantly associated with AA risk.In this prospective study, personal history of immune-mediated diseases either individually or overall was associated with increased AA risk.

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a hereditary degenerative disorder in which mutations in the gene encoding RHO, the light-sensitive G protein-coupled receptor involved in phototransduction in rods, lead to progressive loss of rods and subsequently cones in the retina. Clinical phenotypes are diverse, ranging from mild night blindness to severe visual impairments. There is currently no cure for RHO-adRP. Although there have been significant advances in gene therapy for inherited retinal diseases, treating RHO-adRP presents a unique challenge since it is an autosomal dominant disease caused by more than 150 gain-of-function mutations in the RHO gene, rendering the established gene supplementation strategy inadequate. This review provides an update on RNA therapeutics and therapeutic editing genome surgery strategies and ongoing clinical trials for RHO-adRP, discussing mechanisms of action, preclinical data, current state of development, as well as risk and benefit considerations. Potential outcome measures useful for future clinical trials are also addressed.

Dermatobia hominis, also known as the human botfly, is native to tropical and subtropical Central and South America and seen in travelers from endemic to temperate regions including the United States and Europe. Cutaneous infestation botfly myiasis involves the development of D. hominis larvae in the skin and is common in tropical locations. The distinct appearance of a cutaneous D. hominis infestation facilitates early diagnosis and intervention where cases are common. However, the identification of D. hominis in temperate regions may prove challenging due to its rarity. D. hominis may be misdiagnosed as folliculitis, an epidermal cyst, or an embedded foreign object with secondary impetigo. One should have a heightened suspicion in someone returning from a vacation in an endemic area, such as Belize. Here we describe the presentation, differential diagnosis, and treatment and encourage enhanced preventative measures among tourists when visiting tropical and subtropical regions. Additionally, we propose a novel classification system for assessing the various stages of infestation and suggest that patients reporting travel to Latin America and experiencing pain disproportionate to an insect bite should lead physicians to consider myiasis caused by D. hominis.

Patient safety is a primary priority in the conduction of retinal gene therapy trials. An understanding of risk factors and mitigation strategies for post-procedure complications is crucial for the optimization of gene therapy clinical trial protocols. In this review, we synthesize the literature on ocular delivery methods, vector platforms, and treatment-emergent adverse effects in recent gene therapy clinical trials for inherited retinal diseases.

Racial/ethnic differences in health care are pervasive in the USA, but the literature is limited with regards to racial disparities in the treatment of dermatologic diseases.Data on the management of skin ulcers was analyzed from the National Ambulatory Medical Care Survey (NAMCS) from 2012 to 2018. Data distributions between Blacks and Whites, chi-squared statistics, and Fisher Exact Tests were computed to identify significant differences in demographic factors, patient encounter characteristics, and medication prescribed, as a function of race.Blacks were less likely than Whites to receive: care by a physician (Our data suggests that among outpatient visits for skin ulcers in the USA, racial disparities exist in the probability of seeing a physician, receiving treatment, and follow-up care. Further research must be conducted and interventions implemented in order to combat racial disparities in Black patients' access to dermatologic treatment for skin ulcers.

Background Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic characterization over the past two decades have allowed identification of over 260 causative mutations associated with inherited retinal disorders. Thought to be incurable, gene supplementation therapy offers great promise in treating various forms of these blinding conditions. In gene replacement therapy, a disease-causing gene is replaced with a functional copy of the gene. These therapies are designed to slow disease progression and hopefully restore visual function. Gene therapies are typically delivered to target retinal cells by subretinal (SR) or intravitreal (IVT) injection. The historic Food and Drug Administration (FDA) approval of voretigene neparvovec for RPE65-associated Leber's congenital amaurosis (LCA) spurred tremendous optimism surrounding retinal gene therapy for various other monogenic IRDs. Novel disease-causing mutations continue to be discovered annually, and targeted genetic therapy is now under development in clinical and preclinical models for many IRDs. Numerous clinical trials for other IRDs are ongoing or have recently completed. Disorders being targeted for genetic therapy include retinitis pigmentosa (RP), choroideremia (CHM), achromatopsia (ACHM), Leber's hereditary optic neuropathy, usher syndrome (USH), X-linked retinoschisis, and Stargardt disease. Here, we provide an update of completed, ongoing, and planned clinical trials using gene supplementation strategies for retinal degenerative disorders.

International audience; Cyclic nucleotide-gated channel β1 (CNGB1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.

Background The C677T variant of the MTHFR (5,10‐Methylenetetrahydrofolate reductase) gene is associated with increased susceptibility to homocystinuria (OMIM#236250), neural tube defects (OMIM#601634), schizophrenia (OMIM#181500), thromboembolism (OMIM#188050), and vascular diseases. Protein S deficiency is also associated with an increased risk of thromboembolism from reduced thrombin generation. In this report, we describe the case of a patient who presented with multiple retinal vein occlusions likely caused by an underlying combination of a homozygous MTHFR C677T variant and protein S deficiency. Methods We performed 8 years of continuous ophthalmic follow‐up of one patient diagnosed with central retinal vein occlusion. Peripheral blood was collected for metabolic evaluation and hypercoagulability assessment. Targeted gene sequencing was used for genetic diagnosis. Examination of the retinal vasculature was performed through dilated funduscopic examination, digital color fundus and ultrawide‐field color fundus photography, spectral domain optical coherence tomography, and fluorescein angiography. Results Sequential retinal vein occlusions and a transient ischemic attack were observed during the follow‐up period. Targeted gene sequencing by PCR identified the homozygous MTHFR C677T variant. The metabolic profile indicated low‐protein S activity, high levels of vitamin B6, and LDL cholesterol consistent with her hypercoagulable state. Prescription of low‐dose aspirin and atorvastatin for hypercholesterolemia resulted in no further neovascularization, leakage, or vein occlusion. Conclusion Retinal vein occlusions associated with the MTHFR C677T variant and protein S deficiency may signal impending systemic thromboembolic episodes and warrant aggressive preventative measures., In this report, we describe a case of sequential retinal vein occlusions followed by a transient ischemic attack in a 51‐year old Asian woman secondary to both homozygous MTHFR mutations and protein S deficiency despite controlled plasma homocysteine level. Fluorescein angiography of the right eye at the initial visit demonstrated the presence of a hypofluorescent punctate blocking defects in the superior temporal arcade along with hyperfluorescent window defect at the temporal periphery. With adequate coagulation control, the blocking defects resolved at the follow‐up visit.

The PROM1 (prominin 1) gene encodes an 865-amino acid glycoprotein that is expressed in retinoblastoma cell lines and in the adult retina. The protein is localized to photoreceptor outer segment disc membranes, where it plays a structural role, and in the retinal pigment epithelium (RPE), where it acts as a cytosolic protein that mediates autophagy. Mutations in PROM1 are typically associated with cone-rod dystrophy 12 (OMIM#3612657), autosomal dominant retinal macular dystrophy 2 (OMIM#608051), autosomal recessive retinitis pigmentosa 41 (OMIM#612095), and Stargardt disease 4 (OMIM#603786). Here we describe the first case of PROM1-associated Leber congenital amaurosis (LCA) in a 12-yr-old Asian male, caused by two not previously described deleterious frameshift variants in the compound heterozygous state. Clinical features include the presence of bull's eye maculopathy, pendular horizontal nystagmus, and photodysphoria consistent with the clinical diagnosis of LCA. The patient was evaluated using ophthalmic imaging, electroretinography, and whole-exome sequencing. Electroretinography revealed extinguished retinal activity.