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Background: Policy evaluation studies that assess how state-level policies affect health-related outcomes are foundational to health and social policy research. The relative ability of newer analytic methods to address confounding, a key source of bias in observational studies, has not been closely examined., Methods: We conducted a simulation study to examine how differing magnitudes of confounding affected the performance of 4 methods used for policy evaluations: (1) the two-way fixed effects difference-in-differences model; (2) a 1-period lagged autoregressive model; (3) augmented synthetic control method; and (4) the doubly robust difference-in-differences approach with multiple time periods from Callaway-Sant'Anna. We simulated our data to have staggered policy adoption and multiple confounding scenarios (i.e., varying the magnitude and nature of confounding relationships)., Results: Bias increased for each method: (1) as confounding magnitude increases; (2) when confounding is generated with respect to prior outcome trends (rather than levels), and (3) when confounding associations are nonlinear (rather than linear). The autoregressive model and augmented synthetic control method had notably lower root mean squared error than the two-way fixed effects and Callaway-Sant'Anna approaches for all scenarios; the exception is nonlinear confounding by prior trends, where Callaway-Sant'Anna excels. Coverage rates were unreasonably high for the augmented synthetic control method (e.g., 100%), reflecting large model-based standard errors and wide confidence intervals in practice., Conclusions: In our simulation study, no single method consistently outperformed the others, but a researcher's toolkit should include all methodologic options. Our simulations and associated R package can help researchers choose the most appropriate approach for their data., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1 -associated macular dystrophy., Methods: Patients in this retrospective, longitudinal case series from a tertiary center had clinical examination and multimodal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time by optical coherence tomography were calculated by two independent graders., Results: Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. The average age was 39 years, and 80% were women. The visual acuity was 20/40 at presentation and 20/57 at last follow-up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (13%), 2) multifocal geographic atrophy (20%), and 3) bull's eye maculopathy (67%). The overall rate of atrophy progression was 0.36 mm 2 /year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm 2 /year for central geographic atrophy, 0.53 mm 2 /year for multifocal geographic atrophy, and 0.23 mm 2 /year for bull's eye maculopathy., Conclusion: Patients with PROM1 -associated macular dystrophy demonstrate distinct phenotypes, with bull's eye maculopathy being the most common. The average rate of atrophy progression may be similar to reported rates for ABCA4 -related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem cell-based therapies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Background: Persons with serious mental illness (SMI) die 10-20 years earlier than the general population; cancer is the second leading cause of death. Differences in cancer screening between SMI and the general population are not well understood., Objectives: To describe receipt of cancer screening among individuals with versus without SMI and to explore clinicians' perceptions around cancer screening for people with SMI., Methods: Mixed-methods study using 2010-2017 MarketScan commercial insurance administrative claims data and semi-structured clinician interviews. In the quantitative analyses, we used multivariate logistic regression analyses to calculate the likelihood of receiving cervical, breast, colorectal, or prostate cancer screening among people with versus without SMI, defined as schizophrenia or bipolar disorder. We conducted semi-structured interviews with 17 primary care physicians and 15 psychiatrists. Interview transcripts were coded using a hybrid deductive/inductive approach., Results: Relative to those without SMI, individuals with SMI were less likely to receive screening for cervical cancer [adjusted odds ratio (aOR): 0.80; 95% confidence interval (CI): 0.80-0.81], breast cancer (aOR: 0.79; 95% CI: 0.78-0.80), colorectal cancer (aOR: 0.90; 95% CI: 0.89-0.91), and prostate cancer (aOR: 0.85; 95% CI: 0.84-0.87). Clinicians identified 5 themes that may help explain the lower rates of cancer screening in persons with SMI: access to care, available support, prioritization of other issues, communication, and patient concerns., Conclusions: People with SMI were less likely to receive 4 common types of cancer screening. Improving cancer screening rates in the SMI population will likely require a multidisciplinary approach to overcome barriers to screening., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Behavioral health home (BHH) models have been developed to integrate physical and mental health care and address medical comorbidities for individuals with serious mental illnesses. Previous studies identified population health management capacity and coordination with primary care providers as key barriers to BHH implementation. This study examines the BHH leaders' perceptions of and organizational capacity to conduct these functions within the community mental health programs implementing BHHs in Maryland., Methods: Interviews and surveys were conducted with 72 implementation leaders and 627 front-line staff from 46 of 48 Maryland BHH programs. In-depth coding of the population health management and primary care coordination themes identified subthemes related to these topics., Results: BHH staff described cultures supportive of evidence-based practices, but limited ability to effectively perform population health management or primary care coordination. Tension between population health management and direct, clinical care, lack of experience, and state regulations for service delivery were identified as key challenges for population health management. Engaging primary care providers was the primary barrier to care coordination. Health information technology and staffing were barriers to both functions., Conclusions: BHHs face a number of barriers to effective implementation of core program elements. To improve programs' ability to conduct effective population health management and care coordination and meaningfully impact health outcomes for individuals with serious mental illness, multiple strategies are needed, including formalized protocols, training for staff, changes to financing mechanisms, and health information technology improvements.

Background: Autosomal dominant radial drusen (ADRD), also termed Malattia Leventinese and Doyne honeycomb retinal dystrophy, causes early-onset vision loss because of mutation in EFEMP1. Drusen in an exceedingly rare ADRD human donor eye was compared with eyes affected with age-related macular degeneration (AMD). This study also elucidated whether variations in high-risk AMD genotypes modify phenotypic severity of ADRD., Methods: Morphologic and histochemical analyses of drusen in one ADRD donor and seven AMD donors. Evaluation of complement factor H (CFH) and ARMS2/HTRA1 alleles in a cohort of 25 subjects with ADRD., Results: Autosomal dominant radial drusen had unique onion skin-like lamination but otherwise shared many compositional features with hard, nodular drusen and/or diffuse soft drusen with basal deposits. Autosomal dominant radial drusen also possessed collagen type IV, an extracellular matrix protein that is absent in age-related drusen. Antibodies directed against the membrane attack complex showed robust labeling of ADRD. Vitronectin and amyloid P were present in drusen of both types. High-risk alleles in the CFH and ARMS2/HTRA1 genes were not associated with increasing ADRD severity., Conclusion: Drusen from ADRD and AMD exhibit overlap of some major constituents, but ADRD exhibit distinct alterations in the extracellular matrix that are absent in AMD.

Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.

Purpose: To demonstrate the value of infrared scanning laser ophthalmoscopy (SLO) for determining structural retinal and choroidal changes in patients with Stargardt disease and its comparison to findings on short-wavelength fundus autofluorescence (SW-AF) imaging, spectral-domain optical coherence tomography, and microperimetry measurements., Methods: Forty-four eyes of 22 patients with Stargardt disease were studied using infrared-SLO, spectral-domain optical coherence tomography, macular microperimetry, SW-AF, electroretinography, and fundus photography., Results: Although SW-AF imaging outlined the regions of retinal pigment epithelial (RPE) atrophy (hypofluorescence) and enhanced the visibility of more funduscopically apparent flecks (hyperfluorescence), infrared-SLO imaging outlined the regions of choroidal, and RPE, atrophic changes. Degenerative changes in photoreceptor and RPE cell layers, evident on spectral-domain optical coherence tomography imaging, were associated with either hyporeflective or hyperreflective images on infrared-SLO imaging, depending on whether both RPE and choroidal atrophy (hyperreflectance) or solely RPE atrophy (hyporeflectance) was present. Threshold elevations on microperimetry testing corresponded to both RPE and choroidal atrophy on infrared-SLO imaging and RPE atrophy on SW-AF., Conclusion: Although SW-AF identifies regions of RPE atrophy, infrared-SLO also identifies the involvement of the choroid that has important implications for the potential improvement in visual function from treatment. Thus, infrared-SLO imaging offers an additional advantage beyond that obtained with SW-AF.

Purpose: To compare vitreous biopsy methods using analysis platforms used in proteomics biomarker discovery., Methods: Vitreous biopsies from 10 eyes were collected sequentially using a 23-gauge needle and a 23-gauge vitreous cutter instrument. Paired specimens were evaluated by UV absorbance spectroscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and liquid chromatography tandem mass spectrometry (LC-MS/MS)., Results: The total protein concentration obtained with a needle and vitrectomy instrument biopsy averaged 1.10 mg/mL (standard error of the mean = 0.35) and 1.13 mg/mL (standard error of the mean = 0.25), respectively. In eight eyes with low or medium viscidity, there was a very high correlation (R = 0.934) between the biopsy methods. When data from 2 eyes with high viscidity vitreous were included, the correlation was reduced (R = 0.704). The molecular weight protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of paired needle and vitreous cutter samples were similar, except for a minority of pairs with single band intensity variance. Using LC-MS/MS, equivalent peptides were identified with similar frequencies (R ≥ 0.90) in paired samples., Conclusion: Proteins and peptides collected from vitreous needle biopsies are nearly equivalent to those obtained from a vitreous cutter instrument. This study suggests both techniques may be used for most proteomic and biomarker discovery studies of vitreoretinal diseases, although a minority of proteins and peptides may differ in concentration.

Human recombinant arginase I cobalt [HuArgI (Co)] coupled with polyethylene glycol 5000 [HuArgI (Co)-PEG5000] has shown potent in-vitro depletion of arginine from tissue culture medium. We now show that HuArgI (Co)-PEG5000 is toxic to almost all cancer cell lines and to some normal primary cells examined. In contrast, HuArgI (Co)-PEG5000 in combination with supplemental L-citrulline is selectively cytotoxic to a fraction of human cancer cell lines in tissue culture, including some melanomas, mesotheliomas, acute myeloid leukemias, hepatocellular carcinomas, pancreas adenocarcinomas, prostate adenocarcinomas, lung adenocarcinomas, osteosarcomas, and small cell lung carcinomas. Unfortunately, a subset of normal human tissues is also sensitive to HuArgI (Co)-PEG5000 with L-citrulline supplementation, including umbilical endothelial cells, bronchial epithelium, neurons, and renal epithelial cells. We further show that cell sensitivity is predicted by the level of cellular argininosuccinate synthetase protein expression measured by immunoblots. By comparing a 3-day and 7-day exposure to HuArgI (Co)-PEG5000 with supplemental L-citrulline, some tumor cells sensitive on short-term assay are resistant in the 7-day assay consistent with the induction of argininosuccinate synthetase expression. On the basis of these results, we hypothesize that HuArgI (Co)-PEG5000 in combination with L-citrulline supplementation may be an attractive therapeutic agent for some argininosuccinate synthetase-deficient tumors. These in-vitro findings stimulate further development of this molecule and may aid in the identification of tissue toxicities and better selection of patients who will potentially respond to this combination therapy.

Purpose: To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease., Methods: Blood samples were obtained from 435 unrelated individuals with a clinical diagnosis of vitelliform macular dystrophy and screened for mutations in the coding sequences of BEST1. Medical records and retinal photographs of selected patients were reviewed., Results: Nine of the 435 probands were found to have 2 plausible disease-causing variations in BEST1, while 198 individuals were found to have heterozygous variations compatible with autosomal dominant inheritance. Inheritance phase was determined in three of the recessive families. Six novel disease-causing mutations were identified among these recessive patients: Arg47Cys, IVS7-2A>G, IVS7+4G>A, Ile205del12ATCCTGCTCCAGAG, Pro274Arg, and Ile366delCAGGTGTGGC. Forty-four novel disease-causing mutations were identified among the patients with presumed autosomal dominant disease. The phenotype of patients with recessive alleles for BEST1 ranged from typical vitelliform lesions to extensive extramacular deposits., Conclusion: The authors provide evidence that two abnormal BEST1 alleles, neither of which causes macular disease alone, can act in concert to cause early-onset vitelliform macular dystrophy.

Purpose: The purpose of this study was to review adverse events and patient preference after bilateral intravitreal injection of antibodies to vascular endothelial growth factor., Methods: A retrospective case-control study. Patients with exudative age-related macular degeneration who received intravitreal antivascular endothelial growth factor agent injections in both eyes (bilateral group) on the same day over a 23-month period were compared with patients who received injections in only 1 eye. The occurrence of endophthalmitis, cerebrovascular accident, myocardial infarction, death, patient discomfort, and patient preference was compared between the two groups., Results: One hundred and two patients received an average of 4.43 bilateral injections (range 1-13). A case-control group of 102 patients received an average of 10.2 unilateral injections, (range 2-28). Bevacizumab was injected 45.5%, ranibizumab 45.5%, and a combination of bevacizumab and ranibizumab 9% of the time for bilateral injections. Bevacizumab was used 50.3% and ranubizumab 49.7% of the time in unilateral injections. The follow-up of both groups averaged 18.4 months (range 4.7-36.5 months). There were no cases of endophthalmitis or cerebrovascular accident in either group. There was a single case of myocardial infarction in each group. There were two deaths in the bilateral group and three deaths in the unilateral group. More than 90% strongly preferred bilateral injections to unilateral injections., Conclusion: Bilateral injections of antivascular endothelial growth factor agents on the same day did not increase the rate of adverse events and was preferred by the majority of patients.

Purpose: To describe the clinical phenotypes associated with various genotypes known to cause Leber congenital amaurosis (LCA)., Methods: One hundred ten LCA patients were screened for various probable disease-causing gene sequence variations. Those patients with a probable disease-causing sequence variation in one of six genotypes were recalled for a follow-up examination. Evaluations included assessment of visual acuity, slit-lamp biomicroscopy, and dilated fundus examination. When possible, Goldmann perimetry was also performed., Results: Of the 37 LCA patients with suspected disease-causing sequence variations, 7 had an AIPL1 variation, 8, a CRB1 variation, 2, a CRX variation, 4, a GUCY2D variation, 11, an RPE65 variation, and 5, an RPGRIP1 variation. Across the 6 genotypes, we observed a wide range of visual acuities from 20/40 to no light perception. The widest range of vision was noted for patients with a CRB1 or RPE65 variation. Younger patients with an AIPL1 or RPGRIP1 variation were found to have severely reduced vision. Drusenlike deposits were more selectively observed in patients with mutations in the AIPL1, CRB1, RPE65, and RPGRIP1 genes, whereas focal regions of peripheral chorioretinal atrophy were observed only in patients with AIPL1 or RPE65 variations. Neurologic, intellectual, or psychomotor developmental delay was noted in 8.1% of our cohort., Conclusions: There was considerable overlap of phenotypic expression in six genetic subtypes in our LCA cohort. However, phenotypic trends were noted in our patients' visual acuities and posterior segment findings within genotypes. These findings have practical value for genetic screening strategies for LCA patients based upon phenotype as well as for counseling patients on their visual prognosis.

Purpose: To characterize the clinical and electroretinogram (ERG) features of our cohort of patients with Stargardt disease (STGD) exhibiting coding sequence variations in the ABCA4 gene., Methods: Review of 76 patients with the clinical diagnosis of Stargardt disease/fundus flavimaculatus (STGD/FF) from the University of Iowa Department of Ophthalmology and Visual Sciences (41 patients) and the Casey Eye Institute (35 patients). Clinical examination, Goldmann perimetry, and electroretinography were performed on all 76 patients. Patients were divided into three groups on the basis of their funduscopic and electroretinographic features: (1) a normal ERG by the standards of the laboratory; (2) minimal rod or cone abnormalities; (3) severe ERG dysfunction. The latter category was further subdivided on the basis of a cone-dominated loss of function (C > R or "cone-rod dystrophy") or diffuse depression of rods and cones (C = R). Mutational analysis of the coding sequence of the ABCA4 gene was performed by single strand conformation polymorphism analysis followed by automated DNA sequencing. Each electroretinographic group was analyzed for the presence of disease causing changes using exact tests of binomial proportions corrected for multiple comparisons by Bonferroni method. Quantitative polymerase chain reaction (QPCR) was performed on patients who were homozygous for disease causing changes in the ABCA4 gene to rule out the possibility of deletions., Results: Overall, 56 of 76 patients (and 77 of 152 alleles) exhibited coding sequence variations that were compatible with high-penetrance disease-causing mutations. The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. However, a significantly greater fraction of patients with normal ERG studies failed to exhibit detectable disease-causing coding sequence variations in the ABCA4 gene identified on either allele (P = 0.0006)., Conclusion: STGD/FF patients in our cohort exhibit a wide range of electroretinographic abnormalities, some of which are more prevalent than previously suspected. No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. The presence of electrophysiologic dysfunction is not uncommon in our cohort of patients with STGD. Thus, the ERG provides clinically important information of retinal function for STGD/FF and, as such, is still indicated as part of the evaluation of these patients.

Purpose: To determine the prognostic significance of widespread flecks, described as fundus flavimaculatus, in patients with Stargardt disease., Design: Historical cohort study., Subjects and Methods: Patients with Stargardt disease were identified by searching preexisting databases at the University of Iowa and Oregon Health Sciences University. The medical records of these patients were evaluated for the validity of the diagnosis, initial and final visual acuity, length of follow-up, and initial and final phenotype. Phenotype was graded as I, II, or III on the basis of the distribution of flecks and the extent of atrophy. The relationship between final visual acuity and final clinical appearance (phenotype I versus II versus III) was evaluated controlling for length of follow-up and age using a Cochran-Mantel-Haenszel test. The clinical progression of visual acuity loss for each phenotype was analyzed using life tables and Kaplan-Meier survival analysis for age and length of follow-up effects., Results: A total of 214 patients were confirmed to have Stargardt disease; 131 patients were seen at multiple visits. Eighty-two patients were identified with phenotype I, 62 with phenotype II, and 70 with phenotype III. The final visual outcome was significantly better for patients whose ophthalmoscopic abnormalities were limited to the macula (phenotype I): 80 of 82 patients with phenotype I (97.6%) maintained 20/200 or better visual acuity in at least one eye as compared to 40/62 (64.5%) patients with phenotype II and 13/70 (18.6%) patients with phenotype III (P < 0.0001). Survival analysis showed a similarly significant difference in the survival probabilities (likelihood of maintaining 20/200 or better vision) for the three phenotypes considered over age and over follow-up length (P < 0.0001), with phenotypes II and III demonstrating significantly more deterioration in vision over time., Conclusions: The presence of midperipheral flecks, especially early in life, carries a poorer visual prognosis for patients with Stargardt disease than when disease is limited to the macula. The development of midperipheral flecks is an indicator of more extensive fundus involvement and thus poorer long-term visual prognosis.

Purpose: To review cases of Best disease associated with subretinal hemorrhage to better understand their long-term visual prognosis., Subject and Methods: Patients were identified through the photographic file database at the University of Iowa. Seventy-eight files of patients with clinical evidence of Best disease were reviewed and 12 patients (14 eyes) were identified with subretinal hemorrhage. The visual acuity and clinical course were reviewed in all of these patients when possible. Three patients demonstrated subretinal hemorrhage on their last follow-up visit. Nine patients (11 eyes) were followed through to resolution of subretinal hemorrhage. Eight patients were screened on the VMD2 gene and all were found to have disease-causing sequence variations., Results: All patients noted visual loss at presentation with subretinal hemorrhage (median 20/100; range 20/30-20/400). The median final visual acuity in the 11 eyes with follow-up was 20/50 (20/16-20/400 range). Ten of 11 eyes demonstrated improvement of vision with 9/11 having a final visual acuity of 20/50 or better., Conclusion: The natural history of patients with Best disease with subretinal hemorrhage and moderate visual loss is relatively good. The presence of subretinal hemorrhage in Best disease may be related to mild, incidental trauma.

We tested the hypothesis that a subset of the Farnsworth-Munsell 100-hue test (FM-100) would be a sensitive, specific, and practical means of monitoring color vision in patients with chronic optic nerve disorders. We retrospectively analyzed the records of 1,113 patients affected with optic neuritis (ON), Graves' ophthalmopathy with suspected optic neuropathy, or idiopathic intracranial hypertension with suspected optic neuropathy (IIH). One hundred six records of patients showed that an FM-100 had been performed (23 ON, 46 Graves', 37 IIH). Forty additional patients were studied prospectively (11 ON, 17 Graves', 12 IIH). The sensitivity and specificity of all possible 21 chip subtests were compared against the same statistics for the entire test. We found that for these three optic nerve disorders, a test consisting of chips 22-42 had nearly the same sensitivity and specificity as the entire test when compared with the clinical diagnosis. At 90% specificity, the ratio of sensitivities of the short version to the original version of the test were IIH, 53%/45%; optic neuritis, 85%/79%; and Graves', 67%/70%. The majority of the clinical value of the test can be achieved in one fourth of the original examination time.