Association of Social Determinants of Health with the Likelihood of Treatment with Laser Trabeculoplasty in a United States Database.

PRECIS: Among 1,861 adults with ocular hypertension or mild or moderate primary open-angle glaucoma, those with Medicaid or no insurance had a statistically significantly lower likelihood of receiving laser trabeculoplasty compared with those with other insurance. PURPOSE: To determine whether social determinants of health are associated with undergoing treatment with laser trabeculoplasty (LTP) among individuals with ocular hypertension (OHT) or mild or moderate primary open angle glaucoma (POAG). METHODS: In this cross-sectional study, we included patients with OHT or mild or moderate POAG from the National Institutes of Health All of Us Research Program, a diverse US nationwide dataset. Logistic regression was performed to study the association between LTP treatment status and seven covariates (diagnosis severity, age, gender, race/ethnicity, income, insurance status, and education). RESULTS: 1,861 subjects were included (median age of 72 y). In univariable logistic regression, diagnosis severity, older age, higher income, and insurance (non-Medicaid) were associated with LTP treatment. On multivariable logistic regression models, those with mild POAG (OR, 3.49; 95% CI [2.12-5.87]) and moderate POAG (OR, 7.15 [4.49-11.8]) were still more likely than OHT patients to have received LTP. Moreover, compared with participants with Medicaid or no insurance, participants with other insurance (e.g. employer provided, Medicare) were still more likely to have received LTP (OR, 2.24 [1.08-5.29]). There was no significant difference in the LTP treatment likelihood based on race/ethnicity. CONCLUSIONS: After controlling for confounders, the likelihood of receiving LTP appears to be driven primarily by insurance rather than income or race/ethnicity. Potential reasons for decreased utilization of LTP among Medicaid patients include higher rates of declining the procedure, or LTP may have been offered less frequently due to Medicaid's lower levels of reimbursement and longer reimbursement delays.

Hypertension Likely Drives Arteriolar Wall Thickening in Preclinical Diabetic Retinopathy While Diabetes Drives Wall Thickness in Clinical Retinopathy.

Purpose: Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the timing and relative impact of hypertension versus diabetes on the WLR in diabetic retinopathy (DR) to address this unresolved question. Methods: This prospective cross-sectional study compared the retinal arteriolar WLR in 17 healthy eyes, 15 with diabetes but no apparent DR (DM no DR), and 8 with diabetic macular edema (DME) and either nonproliferative or proliferative DR. We imaged each arteriole using adaptive optics scanning laser ophthalmoscopy and measured the WLR using ImageJ. Multiple linear regression (MLR) was performed to estimate the effects of hypertension, diabetes, and age on the WLR. Results: Both subjects with DM no DR and subjects with DME had significantly higher WLR than healthy subjects (0.36 ± 0.08 and 0.42 ± 0.08 vs. 0.29 ± 0.07, 1-way ANOVA P = 0.0009). MLR in healthy subjects and subjects with DM no DR showed hypertension had the strongest effect (regression coefficient = 0.08, P = 0.009), whereas age and diabetes were not significantly correlated with WLR. MLR in all three groups together (healthy, DM no DR, and DME) showed diabetes had the strongest effect (regression coefficient = 0.05, P = 0.02), whereas age and hypertension were not significantly correlated with WLR. Conclusions: Hypertension may be an early driver of retinal arteriolar wall thickening in preclinical DR, independent of age or diabetes, whereas changes specific to DR may drive wall thickening in DME and later DR stages. Translational Relevance: We offer a framework for understanding the relative contributions of hypertension and diabetes on the vascular wall, and emphasize the importance of hypertension control early in diabetes even before DR onset.

Imaging the Retinal Vascular Mural Cells In Vivo: Elucidating the Timeline of Their Loss in Diabetic Retinopathy.

BACKGROUND: Vascular mural cells (VMCs) are integral components of the retinal vasculature with critical homeostatic functions such as maintaining the inner blood-retinal barrier and vascular tone, as well as supporting the endothelial cells. Histopathologic donor eye studies have shown widespread loss of pericytes and smooth muscle cells, the 2 main VMC types, suggesting these cells are critical to the pathogenesis of diabetic retinopathy (DR). There remain, however, critical gaps in our knowledge regarding the timeline of VMC demise in human DR. METHODS: In this study, we address this gap using adaptive optics scanning laser ophthalmoscopy to quantify retinal VMC density in eyes with no retinal disease (healthy), subjects with diabetes without diabetic retinopathy, and those with clinical DR and diabetic macular edema. We also used optical coherence tomography angiography to quantify capillary density of the superficial and deep capillary plexuses in these eyes. RESULTS: Our results indicate significant VMC loss in retinal arterioles before the appearance of classic clinical signs of DR (diabetes without diabetic retinopathy versus healthy, 5.0±2.0 versus 6.5±2.0 smooth muscle cells per 100 µm; P<0.05), while a significant reduction in capillary VMC density (5.1±2.3 in diabetic macular edema versus 14.9±6.0 pericytes per 100 µm in diabetes without diabetic retinopathy; P=0.01) and capillary density (superficial capillary plexus vessel density, 37.6±3.8 in diabetic macular edema versus 45.5±2.4 in diabetes without diabetic retinopathy; P<0.0001) is associated with more advanced stages of clinical DR, particularly diabetic macular edema. CONCLUSIONS: Our results offer a new framework for understanding the pathophysiologic course of VMC compromise in DR, which may facilitate the development and monitoring of therapeutic strategies aimed at VMC preservation and potentially the prevention of clinical DR and its associated morbidity. Imaging retinal VMCs provides an unparalleled opportunity to visualize these cells in vivo and may have wider implications in a range of diseases where these cells are disrupted.

Low-range, mid-range and high-range speeding: The association with speeding habits, perceived legitimacy and deterrence.

INTRODUCTION: Speeding is a global road safety concern contributing to an excessive number of fatal crashes and serious debilitating injuries. Research identifying amendable factors associated with speeding to inform interventions is critical. METHOD: This study examined the association of habit, perceived legitimacy of enforcement, and deterrence elements with three levels of speeding behavior; low- (<10 km/hr over the posted speed limit), mid- (10-20 km/hr), and high-range (>20 km/hr) speeding. An online survey of 870 participants aged over 17 years (M = 37 years) was administered. RESULTS: Approximately 80% of participants reported low-range speeding, 40% mid-range speeding, and 20% high-range speeding. Differences were found between speeding on urban and open roads with the proportion of participants greater for mid- and high-range speeding on open roads. Multiple linear regressions were run finding habit and deterrence variables to be significant predictors of all three levels of speeding. Perceived legitimacy of enforcement was a significant predictor of high-range speeding only. PRACTICAL APPLICATIONS: These findings suggest countermeasures that encourage good speed-related habits would be promising. It is also concluded that additional deterrence measures that reduce punishment avoidance experiences (e.g., better detection of speeding behaviors) are needed to further curb speeding behaviors. Nevertheless, the current punishment for all levels of speeding is perceived to be an effective deterrent. These recommendations inform policy, training and education, and campaigns that target engagement in speeding.

A deep population reference panel of tandem repeat variation.

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

A deep population reference panel of tandem repeat variation.

Tandem repeats (TRs) represent one of the largest sources of genetic variation in humans and are implicated in a range of phenotypes. Here we present a deep characterization of TR variation based on high coverage whole genome sequencing from 3,550 diverse individuals from the 1000 Genomes Project and H3Africa cohorts. We develop a method, EnsembleTR, to integrate genotypes from four separate methods resulting in high-quality genotypes at more than 1.7 million TR loci. Our catalog reveals novel sequence features influencing TR heterozygosity, identifies population-specific trinucleotide expansions, and finds hundreds of novel eQTL signals. Finally, we generate a phased haplotype panel which can be used to impute most TRs from nearby single nucleotide polymorphisms (SNPs) with high accuracy. Overall, the TR genotypes and reference haplotype panel generated here will serve as valuable resources for future genome-wide and population-wide studies of TRs and their role in human phenotypes.

Racial Disparities in Barriers to Care for Patients With Diabetic Retinopathy in a Nationwide Cohort.

Purpose: To ascertain specific barriers of care among patients with diabetic retinopathy (DR) from different racial/ethnic groups. Methods: In this cross-sectional study, we included adult participants in the National Institutes of Health All of Us Research Program with DR who answered questions in the Healthcare Access & Utilization survey and Social Determinants of Health (SDoH) survey. Logistic regression was used to study the association between barriers to care and race/ethnicity. Results: Our cohort included 885 DR patients who answered the Healthcare Access & Utilization survey and 385 DR patients who responded to the SDoH survey. After adjusting for confounders, Hispanic individuals were more likely than non-Hispanic White individuals to report delaying getting medical care due to not being able to get child care (odds ratio [OR] = 6.57 [95% confidence interval {CI}, 1.67-27.8]). Furthermore, compared to non-Hispanic White individuals, non-Hispanic Black individuals were significantly more likely to report being treated with less respect (OR = 2.62 [95% CI, 1.15-5.80]), treated with less courtesy (OR = 2.51 [95% CI, 1.01-5.92]), and receive poorer service than other people (OR = 2.85 [95% CI, 1.25-6.34]) when they go to a doctor's office or other healthcare provider. Conclusions: We found that Hispanic and non-Hispanic Black individuals with DR reported greater delays/barriers to care compared to non-Hispanic White individuals even after controlling for individualized socioeconomic factors. Translational Relevance: This study highlights the importance of taking steps to promote health equity, such as increasing access to child care resources and reducing implicit bias among eye care providers, to increase access to care and prevent vision loss from DR.

The Fovea-Protective Impact of Double-Layer Sign in Eyes With Foveal-Sparing Geographic Atrophy and Age-Related Macular Degeneration.

Purpose: The purpose of this study was to investigate the impact of double-layer sign (DLS) on geographic atrophy (GA) progression in eyes with foveal-sparing GA and age-related macular degeneration (AMD). Methods: This is a retrospective, consecutive case series of eyes with foveal-sparing GA secondary to AMD with more than 6 months of follow-up. The size of the foveal-sparing area was measured on the fundus autofluorescence images at the first and last visits. Each eye was evaluated for the presence or absence of DLS inside the foveal-sparing area. We graded eyes based on the presence of DLS within the foveal-sparing area and compared the progression of GA between two groups (DLS (+) versus DLS (-)). Results: We identified 25 eyes with foveal-sparing GA with at least 2 follow-up visits (average interval = 22.7 ± 11.8 months between visits). The mean foveal sparing area was 1.74 ± 0.87 mm2 (range = 0.42-4.14 mm2) at baseline and 1.26 ± 0.75 mm2 (range = 0.25-2.92 mm2) at the last visit. Seventeen eyes (65.3%) were graded as DLS (+) within the foveal-sparing area. Square root progression of GA toward the fovea was significantly faster in the DLS (-) eyes (0.149 ± 0.078 mm/year) compared to the DLS (+) group (0.088 ± 0.052 mm/year; P = 0.04). Conclusions: The DLS (-) group showed significantly faster centripetal GA progression than the DLS (+) group. Our data suggest that the presence of DLS in the spared foveal area could be a protective factor against foveal progression of GA in eyes with AMD.

Micronutrient screening, monitoring, and supplementation in pregnancy after bariatric surgery.

We present the case of a woman with a history of biliopancreatic diversion and duodenal switch procedure who developed severe malnourishment requiring total parenteral nutrition during three pregnancies. The widespread use of bariatric surgery, particularly among those of reproductive age, has led to an increase in the number of women who become pregnant following bariatric surgery. There is a paucity of evidence to guide nutritional recommendations for women during pregnancy post bariatric surgery. We review this literature and summarize key published evidence and provide comprehensive recommendations concerning the common challenges in the management of nutrition status during pregnancy. The focus is on the impact of malabsorptive bariatric surgeries on pregnancy outcomes, nutrient deficiencies, recommendations for micro- and macronutrient monitoring and supplementation, and altered glucose metabolism and implications for diabetes screening. Optimizing pregnancy outcomes for individuals following bariatric surgery requires multidisciplinary team management including obstetrical providers, obstetric medicine specialists, and dietitians.

Hemodynamic Effects of Anti-Vascular Endothelial Growth Factor Injections on Optical Coherence Tomography Angiography in Diabetic Macular Edema Eyes.

Purpose: To evaluate retinal hemodynamic responses to anti-vascular endothelial growth factor (VEGF) injection in eyes with diabetic macular edema using optical coherence tomography angiography (OCTA). We performed a comparison of two different thresholding methods to identify the most accurate for studying the vessel density (VD) in diabetic macular edema eyes. Methods: The study prospectively included 26 eyes of 22 subjects (aged 60.2 ± 13.7 years) who underwent OCTA scan before and after anti-VEGF injection (mean interval between OCTA = 31.1 ± 17.3 days). We analyzed adjusted flow index, VD, and Skeletonized vessel length density in the parafoveal area (3-mm annulus with a 1-mm inner circle), along with full-thickness fovea avascular zone area and central foveal thickness (CFT). Using averaged scans VD as the ground truth, we compared two different algorithms for VD at the different plexuses. Longitudinal changes were assessed using a generalized linear model correcting for central foveal thickness and Q-score. Results: We found significantly decreased adjusted flow index in the DCP layer (P = 0.010) at the follow-up. Furthermore, foveal avascular zone (P < 0.001) and central foveal thickness (P = 0.003) showed significant decrease on follow-up compared with baseline. Comparing the thresholding algorithms showed that vessel length density-based thresholding was more accurate for quantifying the DCP VD. Conclusions: The adjusted flow index decreased significantly in the DCP layer on follow-up OCTA scan, suggesting vascular flow disruption and decreased deep retinal perfusion after anti-VEGF injection. Our results also highlight the fact that the choice of thresholding method is particularly critical for DCP quantification in eyes with diabetic macular edema. Translational Relevance: Findings confirmed impaired deep retinal capillary flow after anti-VEGF injection.

Natural Language Processing in Spine Surgery: A Systematic Review of Applications, Bias, and Reporting Transparency.

BACKGROUND: Natural language processing (NLP) is a discipline of machine learning concerned with the analysis of language and text. Although NLP has been applied to various forms of clinical text, the applications and utility of NLP in spine surgery remain poorly characterized. Here, we systematically reviewed studies that use NLP for spine surgery applications, and analyzed applications, bias, and reporting transparency of the studies. METHODS: We performed a literature search using the PubMed, Scopus, and Embase databases. Data extraction was performed after appropriate screening. The risk of bias and reporting quality were assessed using the PROBAST and TRIPOD tools. RESULTS: A total of 12 full-text articles were included. The most common diseases represented include spondylolisthesis (25%), scoliosis (17%), and lumbar disk herniation (17%). The most common procedures included spinal fusion (42%), imaging (e.g. magnetic resonance, X-ray) (25%), and scoliosis correction (17%). Reported outcomes were diverse and included incidental durotomy, venous thromboembolism, and the tone of social media posts regarding scoliosis surgery. Common sources of bias identified included the use of older methods that do not capture the nuance of a text, and not using a prespecified or standard outcome measure when evaluating NLP methods. CONCLUSIONS: Although the application of NLP to spine surgery is expanding, current studies face limitations and none are indicated as ready for clinical use. Thus, for future studies we recommend an emphasis on transparent reporting and collaboration with NLP experts to incorporate the latest developments to improve models and contribute to further innovation.

A CRISPR screen targeting PI3K effectors identifies RASA3 as a negative regulator of LFA-1-mediated adhesion in T cells.

The integrin lymphocyte function-associated antigen 1 (LFA-1) helps to coordinate the migration, adhesion, and activation of T cells through interactions with intercellular adhesion molecule 1 (ICAM-1) and ICAM-2. LFA-1 is activated during the engagement of chemokine receptors and the T cell receptor (TCR) through inside-out signaling, a process that is partially mediated by phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol 3,4,5-trisphosphate (PIP3). To evaluate potential roles of PI3K in LFA-1 activation, we designed a library of CRISPR/single guide RNAs targeting known and potential PIP3-binding proteins and screened for effects on the ability of primary mouse T cells to bind to ICAM-1. We identified multiple proteins that regulated the binding of LFA-1 to ICAM-1, including the Rap1 and Ras GTPase-activating protein RASA3. We found that RASA3 suppressed LFA-1 activation in T cells, that its expression was rapidly reduced upon T cell activation, and that its activity was inhibited by PI3K. Loss of RASA3 in T cells led to increased Rap1 activation, defective lymph node entry and egress, and impaired responses to T-dependent immunization in mice. Our results reveal a critical role for RASA3 in T cell migration, homeostasis, and function.

Aberrant expansion of spontaneous splenic germinal centers induced by hallmark genetic lesions of aggressive lymphoma.

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B-cell lymphoma (DLBCL). However, the premalignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to 4 hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1, and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivo promoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). As with MCD, these premalignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, displayed a de novo dependence on Tlr9, and were more sensitive to inhibition of Bruton's tyrosine kinase. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all 4 genetic lesions showed a >50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCBs as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.

Cavß1 regulates T cell expansion and apoptosis independently of voltage-gated Ca2+ channel function.

TCR stimulation triggers Ca2+ signals that are critical for T cell function and immunity. Several pore-forming α and auxiliary ß subunits of voltage-gated Ca2+ channels (VGCC) were reported in T cells, but their mechanism of activation remains elusive and their contribution to Ca2+ signaling in T cells is controversial. We here identify CaVß1, encoded by Cacnb1, as a regulator of T cell function. Cacnb1 deletion enhances apoptosis and impairs the clonal expansion of T cells after lymphocytic choriomeningitis virus (LCMV) infection. By contrast, Cacnb1 is dispensable for T cell proliferation, cytokine production and Ca2+ signaling. Using patch clamp electrophysiology and Ca2+ recordings, we are unable to detect voltage-gated Ca2+ currents or Ca2+ influx in human and mouse T cells upon depolarization with or without prior TCR stimulation. mRNAs of several VGCC α1 subunits are detectable in human (CaV3.3, CaV3.2) and mouse (CaV2.1) T cells, but they lack transcription of many 5' exons, likely resulting in N-terminally truncated and non-functional proteins. Our findings demonstrate that although CaVß1 regulates T cell function, these effects are independent of VGCC channel activity.

In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells.

T follicular helper (Tfh) cells provide signals to initiate and maintain the germinal center (GC) reaction and are crucial for the generation of robust, long-lived antibody responses, but how the GC microenvironment affects Tfh cells is not well understood. Here we develop an in vivo T cell-intrinsic CRISPR-knockout screen to evaluate Tfh and Th1 cells in an acute viral infection model to identify regulators of Tfh cells in their physiological setting. Using a screen of druggable-targets, alongside genetic, transcriptomic and cellular analyses, we identify a function of HIF-1α in suppressing mTORC1-mediated and Myc-related pathways, and provide evidence that VHL-mediated degradation of HIF-1α is required for Tfh development; an expanded in vivo CRISPR screen reveals multiple components of these pathways that regulate Tfh versus Th1 cells, including signaling molecules, cell-cycle regulators, nutrient transporters, metabolic enzymes and autophagy mediators. Collectively, our data serve as a resource for studying Tfh versus Th1 decisions, and implicate the VHL-HIF-1α axis in fine-tuning Tfh generation.

Crash proneness? Predictors of repeat crashes in older drivers.

INTRODUCTION: Older drivers are believed to be prone to crashes due to age-related deterioration of their driving abilities. Currently, little is known about the characteristics of repeat crashers and the factors that predict subsequent crashes among these older drivers. METHOD: A dataset containing the records of crash events that occurred between January 2014 and November 2019 was provided by the Department of Transport and Main Roads (DTMR) in Queensland, Australia. This dataset included 16,973 records of older drivers involved in a single crash and 222 cases in multiple crashes, comprising a total of 17,195 cases. Descriptive and inferential analyses were performed to understand the characteristics of repeat crashers. Survival analysis techniques were used to determine risk factors predictive of subsequent crashes. RESULTS: Nearly half (46%) of the repeat crashers were culpable for both of their crashes. Their average age was significantly older than those who were culpable for none or one of their crashes. For older male drivers, riding a motorcycle or driving a heavy vehicle were significant risk factors for having a subsequent crash. The risk for female at-fault drivers being involved in a subsequent crash was 4.53 times greater than those not at-fault. Older female drivers involved in crashes caused by slowing or stopping also presented a higher risk of being involved in subsequent crashes. CONCLUSIONS: This study identified risk factors for older drivers being involved in repeat crashes; distinctive gender differences in the risk for involvement in repeat crashes were found. Practical Applications: To reduce the likelihood of older drivers being involved in subsequent crashes, attention should be directed towards elders living in major cities, male motorcycle riders and heavy vehicle drivers, and at-fault female drivers.

PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8+ T cells at the expense of central memory.

Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cdE1020K/+ mice), we demonstrate that, upon activation, Pik3cdE1020K/+ CD8+ T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cdE1020K/+ CD8+ cells fail to sustain expression of proteins critical for central memory, including TCF1. Strikingly, activated Pik3cdE1020K/+ CD8+ cells exhibit altered transcriptional and epigenetic circuits characterized by pronounced interleukin-2 (IL-2)/STAT5 signatures and heightened IL-2 responses that prevent differentiation to memory-like cells in IL-15. Our data position PI3Kδ as integrating multiple signaling nodes that promote CD8+ T cell effector differentiation, providing insight into phenotypes of patients with APDS.

Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis.

Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.