Medical Certification of Pilots Through the Insulin-Treated Diabetes Mellitus Protocol at the FAA.

INTRODUCTION: In 2019, the Federal Aviation Administration (FAA) announced a protocol to evaluate pilots with insulin treated diabetes mellitus (ITDM) for special issuance (SI) medical certification for first-/second-class pilots. The protocol's aim is improved assessment of ITDM control/hypoglycemia risk and relies on continuous glucose monitoring (CGM) data. This study compares the characteristics of first-/second-class pilots with ITDM and certification outcome.METHODS: Data was collected retrospectively from the FAA Document Imaging Workflow System (DIWS) for pilots considered for a first-/second-class SI under the ITDM program between November 2019 and October 2021. Inclusion criteria required submission of information required for certification decision (SI vs. denial). We extracted data on demographics and CGM parameters including mean glucose, standard deviation, coefficient of variance, time in range (%), time > 250 mg · dl-1 (%), and time < 70-80 mg · dl-1 (%). We compared these parameters between pilots issued an SI vs. denial with Mann-Whitney U-tests and Fisher exact tests using R.RESULTS: Of 200 pilots with ITDM identified, 77 met inclusion criteria. Of those, 55 received SIs and 22 were denied. Pilots issued SI were statistically significantly older (46 vs. 27 yr), had a lower hemoglobin A1c (6.50% vs. 7.10%), lower average glucose (139 mg · dl-1 vs. 156 mg · dl-1), and spent less time with low glucose levels (0.95% vs. 2.0%).DISCUSSION: The FAA program has successfully medically certificated pilots with ITDM for first-/second-class. Pilots granted an ITDM SI reflect significantly better diabetes control, including less potential for hypoglycemia. As this program continues, it will potentially allow previously disqualified pilots to fly safely.Stanwyck LK, DeVoll JR, Pastore J, Gamble Z, Poe A, Gui GV. Medical certification of pilots through the insulin-treated diabetes mellitus protocol at the FAA. Aerosp Med Hum Perform. 2022; 93(8):627-632.

Correlation of Immunological Markers with Disease and Clinical Outcome Measures in Patients with Autoimmune Retinopathy.

Purpose: To determine if immunological markers (1) are significantly different between autoimmune retinopathy (AIR) patients and controls and (2) correlate with disease progression in AIR patients. Methods: We enrolled patients with a possible AIR diagnosis, as well as control participants without eye disease, autoimmunity, or cancer. Immunological markers were tested in all participants. In addition, AIR patients had up to three blood draws for testing over their disease course. For AIR patients, clinical measures, including visual acuity (VA) and Goldmann visual field (GVF) area, were recorded at each draw. We used the Mann-Whitney U test to compare the immunological markers between AIR patients and controls. We used multilevel mixed-effect regression to investigate the correlation between markers and clinical parameters over time in AIR patients. Results: Seventeen patients with AIR and 14 controls were included. AIR patients had a higher percent of monocytes (Z = 3.076, P = 0.002). An increase in immunoglobulin G against recoverin was correlated with a VA decrease (ß = 0.0044, P < 0.0001). An increase in monocyte proportion was correlated with a decrease in GVF area (ß = -7.27, P = 0.0021). Several markers of B-cell depletion were correlated with GVF improvement. Conclusions: Monocytes may play a role in AIR pathophysiology and be a disease activity marker. B-cell depletion markers correlated with clinical parameter improvement, particularly GVF. Translational Relevance: This work elucidates immunologic markers that may improve the accuracy of diagnosis and treatment of AIR.

Predictive value of genetic testing for inherited retinal diseases in patients with suspected atypical autoimmune retinopathy.

PURPOSE: The clinical features of autoimmune retinopathy (AIR) can resemble and be difficult to differentiate from inherited retinal degenerations (IRDs). Misdiagnosis of an IRD as AIR causes unnecessary treatment with immunosuppressive agents. The purpose of this study is to calculate the predictive value of genetic testing for IRDs in patients with suspected AIR and provide clinical examples where genetic testing has been useful. METHODS: We identified patients seen at MEEI between April 2013 and January 2017 for whom the differentiation of AIR vs. IRDs was difficult based on clinical assessment alone. All patients had some atypical features for AIR, but tested positive for anti-retinal antibodies. Within this group, we identified six patients who had genetic testing for IRDs with the Genetic Eye Disease panel for retinal genes (GEDi-R). We calculated the positive predictive value (PPV) and negative predictive value (NPV) of genetic testing in a population with approximately equal numbers of IRD and AIR patients. RESULTS: Six patients had clinical features that made distinguishing between IRDs and AIR on a clinical basis difficult and were sent for genetic testing: four women and two men with a mean age of 59.5 years. In two of these six patients, genetic diagnoses were made based upon the identification of known pathogenic variants in the common IRD genes USH2A and RHO. Two patients had variants of unknown significance within genes associated with IRDs, and the other two had no relevant genetic findings. Given the 60% sensitivity and 3% false positive rate for GEDi-R testing and assuming a 50% pre-test probability of having an IRD, the PPV for GEDi-R for detecting IRD is 95.2% and the NPV is 70.8%. CONCLUSIONS AND IMPORTANCE: In patients for whom the differential diagnosis of AIR and IRDs is unclear based on clinical information, genetic testing can be a valuable tool when it identifies an IRD, sparing the patient unnecessary immunosuppressive treatment. However, the test has a low NPV so a negative genetic testing result does not confidently exclude IRD as the true diagnosis.

Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis.

Purpose: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. Methods: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. Results: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36-2.72, p = 2.32 × 10-4]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94-0.97, p = 9.87 × 10-6; scleritis: OR = 0.96, 95% CI = 0.93-0.99, p = 0.009). Conclusion: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study.

Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value <1 × 10-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

Association of Hypovitaminosis D With Increased Risk of Uveitis in a Large Health Care Claims Database.

Importance: Understanding the role of vitamin D-which regulates inflammatory responses-in noninfectious uveitis (an inflammatory disease) may provide insight into treatment and prevention of this disease. Objective: To investigate whether there is an association between hypovitaminosis D and incident noninfectious uveitis. Design, Setting, and Participants: In a retrospective case-control study, data from a health care claims database containing deidentified medical claims from a large private insurer were used to identify 558 adults enrolled from January 1, 2000, to December 31, 2016, who received a diagnosis of noninfectious uveitis from an eye care clinician (with receipt of a confirmatory diagnosis within 120 days of the initial diagnosis) and who had a vitamin D level measured within 1 year before the first diagnosis. Exclusion criteria included having systemic disease or receiving medication known to lower vitamin D levels, having undergone intraocular surgery, and having infectious uveitis. Each case patient was matched with 5 controls on the basis of age, sex, race/ethnicity, and index date (2790 controls). The controls had vitamin D level determined either within 1 year before or within 6 months after receiving an eye examination with normal findings. Multiple logistic regression models were used to examine the association between hypovitaminosis D and noninfectious uveitis. Main Outcomes and Measures: The primary, prespecified analysis assessed the association of noninfectious uveitis with hypovitaminosis D (vitamin D level ≤20 ng/mL). Results: The 558 cases and 2790 controls were matched on age, and each group had a mean (SD) age of 58.9 (14.7) years. Among the cohort of 3348 patients, 2526 (75.4%) were female, and the racial/ethnic distribution in the matched samples was 2022 (60.4%) white, 552 (16.5%) black, 402 (12.0%) Hispanic, 162 (4.8%) Asian, and 210 (6.3%) unknown. Patients with normal vitamin D levels had 21% lower odds of having noninfectious uveitis than patients with low vitamin D levels (odds ratio [OR], 0.79; 95% CI, 0.62-0.99; P = .04). In a race-stratified analysis, an association between vitamin D and uveitis was found in black patients (OR, 0.49; 95% CI, 0.30-0.80; P = .004) and was qualitatively similar but nonsignificant in white patients (OR, 0.87; 95% CI, 0.62-1.21; P = .40) and Hispanic patients (OR, 0.60; 95% CI, 0.33-1.10; P = .10). Conclusions and Relevance: This and other reports have found an association between hypovitaminosis D and noninfectious uveitis. However, these studies cannot establish a causal relationship. Prospective studies are warranted to evaluate whether hypovitaminosis D causes increased risk of uveitis and the role of vitamin D supplementation in prevention and treatment of uveitis.

Association of genetic variants in RAB23 and ANXA11 with uveitis in sarcoidosis.

Purpose: Uveitis occurs in a subset of patients with sarcoidosis. The purpose of this study was to determine whether genetic variants that have been associated previously with overall sarcoidosis are associated with increased risk of developing uveitis. Methods: Seventy-seven subjects were enrolled, including 45 patients diagnosed with sarcoidosis-related uveitis as cases and 32 patients with systemic sarcoidosis without ocular involvement as controls. Thirty-eight single nucleotide polymorphisms (SNPs) previously associated with sarcoidosis, sarcoidosis severity, or other organ-specific sarcoidosis involvement were identified. Allele frequencies in ocular sarcoidosis cases versus controls were compared using the chi-square test, and p values were corrected for multiple hypotheses testing using permutation. All analyses were conducted with PLINK. Results: SNPs rs1040461 and rs61860052, in ras-related protein RAS23 (RAB23) and annexin A11 (ANXA11) genes, respectively, were associated with sarcoidosis-associated uveitis. The T allele of rs1040461 and the A allele of rs61860052 were found to be more prevalent in ocular sarcoidosis cases. These associations remained after correction for the multiple hypotheses tested (p=0.01 and p=0.02). In a subanalysis of Caucasian Americans only, two additional variants within the major histocompatibility complex (MHC) genes on chromosome 6, in HLA-DRB5 and HLA-DRB1, were associated with uveitis as well (p=0.009 and p=0.04). Conclusions: Genetic variants in RAB23 and ANXA11 genes were associated with an increased risk of sarcoidosis-associated uveitis. These loci have previously been associated with overall sarcoidosis risk.

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.