Geographic and socioeconomic access disparities to Phase 3 clinical trials in ophthalmology in the United States.

BACKGROUND/OBJECTIVE: To identify geographic and socioeconomic variables associated with residential proximity to Phase 3 ophthalmology clinical trial sites. METHODS: The geographic location of clinical trial sites for Phase 3 clinical trials in ophthalmology was identified using ClinicalTrials.gov. Driving time from each United States (US) census tract centroid to nearest clinical trial site was calculated using real traffic patterns. Travel data were crosslinked to census-tract level public datasets from United States Census Bureau American Community Survey (ACS). Cross-sectional multivariable regression was used to identify associations between census-tract sociodemographic factors and driving time (>60 min) from each census tract centroid to the nearest clinical trial site. RESULTS: There were 2330 unique clinical trial sites and 71,897 census tracts. Shortest median time was to retina sites [33.7 min (18.7, 70.1 min)]. Longest median time was to neuro-ophthalmology sites [119.8 min (48.7, 240.4 min)]. Driving >60 min was associated with rural tracts [adjusted odds ratio (aOR) 7.60; 95% CI (5.66-10.20), p < 0.0001]; Midwest [aOR 1.84(1.15-2.96), p = 0.01], South [aOR 2.57 (1.38-4.79), p < 0.01], and West [aOR 2.52 (1.52-4.17), p < 0.001] v. Northeast; and tracts with higher visual impairment [aOR 1.07 (1.03-1.10), p < 0.001)]; higher poverty levels [4th v.1st Quartile of population below poverty, aOR 2.26 (1.72-2.98), p < 0.0001]; and lower education levels [high school v. Bachelor's degree or higher aOR 1.02 (1.00-1.03), p = 0.0072]. CONCLUSIONS: There are significant geographic and socioeconomic disparities in access to ophthalmology clinical trial sites for rural, non-Northeastern, poorer, and lower education level census tracts, and for census tracts with higher levels of self-reported visual impairment.

Predictors of Vision Loss after Surgery for Macula-Sparing Rhegmatogenous Retinal Detachment.

PURPOSE: To determine factors associated with loss of good vision (defined as Snellen visual acuity [VA] < 20/40) after surgery among eyes presenting with macula-on primary rhegmatogenous retinal detachment (RRD) with initial VA ≥20/40. METHODS: Multicenter, retrospective, cohort study of eyes undergoing scleral buckle (SB), pars plana vitrectomy (PPV), or combined pars plana vitrectomy/scleral buckle (PPV/SB) for non-complex macula-on RRD with initial VA ≥20/40. RESULTS: Among 646 eyes with macula-on RRDs with initial VA ≥20/40, 106 (16.4%) had VA <20/40 (i.e. lost good vision) at final follow-up. Eyes losing good vision had slightly worse pre-operative logMAR VA (mean 0.15 ± 0.10 [20/28]) compared to eyes that preserved good vision (mean 0.11 ± 0.10 [20/26]) (p = 0.004). RRDs extending greater than 6 clock-hours were more likely to lose good vision than smaller detachments (multivariate OR 4.57 [95% CI 1.44-14.51]; p = 0.0099). Compared to eyes repaired with SB alone, eyes undergoing PPV (multivariate OR 7.22 [95% CI 2.10-24.90]; p = 0.0017) or PPV/SB (multivariate OR 10.74 [95% CI 3.20-36.11]; p = 0.0001) were each more likely to lose good vision. Eyes requiring further RRD-related (multivariate OR 8.64 [95% CI 1.47-50.66]; p < 0.017) and non-RRD related vitreoretinal surgery (multivariate OR 14.35 [95% CI 5.39-38.21]; p < 0.0001) were more likely to lose good vision. CONCLUSION: Among macula-on RRDs, loss of good vision was associated with worse vision on presentation, vitrectomy-based procedures, greater extent of detachment, and lack of single surgery success. Understanding predictors of visual outcome in macula-on RRD repair may guide pre-operative counseling regarding visual prognosis.

Unilateral Retinal Arteritis and Macroaneurysm in Sarcoidosis.

BACKGROUND: Sarcoidosis, an idiopathic systemic disorder characterized by noncaseating granulomas, is often associated with granulomatous uveitis. Anterior segment involvement can present with mutton-fat keratic precipitates, anterior chamber cell, and iris nodules. Sarcoid associated posterior uveitis may present with vitritis, retinal vasculitis, and choroidal lesions. CASE SUMMARY: Sarcoid-associated retinal vasculitis is classically thought of as predominantly involving veins, but in this case report we describe a 76-year-old Caucasian woman presenting with bilateral posterior uveitis, unilateral optic nerve head granuloma, and retinal arteritis as the first manifestation of ocular involvement in systemic sarcoidosis. CONCLUSION: This case describes the uncommon first manifestation of ocular involvement in systemic sarcoidosis presenting with unilateral retinal arteritis, macroaneurysms and optic nerve head granuloma.

Geographic Access Disparities of Clinical Trials in Neovascular Age-Related Macular Degeneration in the United States.

To identify geographic and socioeconomic variables predictive of residential proximity to neovascular age-related macular degeneration (nAMD) clinical trial locations. DESIGN: Retrospective, cross-sectional study. METHODS: Census tract-level data from public datasets and trial-level data from ClinicalTrials.gov were analyzed. We calculated the driving distance (>60 miles) and time (>60 minutes) from the population-weighted US census tract centroid to the nearest clinical trial site. RESULTS: We identified 42 trials studying nAMD across 829 unique clinical trial sites in the United States. In a multivariable model, driving distance >60 miles had a significant association with rural location (adjusted odds ratio [aOR] 5.54; 95% confidence interval [CI] 3.86-7.96, P < .0001) and with Midwest (aOR 2.30; 95% CI 1.21-4.38, P = .01) and South (aOR 2.43; 95% CI 1.21-4.91, P = .01) as compared to the Northeast region, and with some college or an associate's degree, as compared to a bachelor's degree (aOR 1.02; 95% CI 1.01-1.04, P = .0007, and aOR 1.05; 95% CI 1.00-1.10, P = .04, respectively). Lower odds of traveling >60 miles to the nearest nAMD trial site were associated with census tracts with a higher percentage of blacks (aOR 0.98; 95% CI 0.97-0.99, P < .0001), Hispanics (aOR 0.97; 95% CI 0.95-0.99, P = .002), and Asians (aOR 0.90; 95% CI 0.88-0.93, P < .0001), as compared to whites, and with a lower percentage of the population <200% of the federal poverty level. Similar predictors were found in time traveled >60 minutes. CONCLUSIONS: There are geographic access disparities of clinical trial sites for nAMD in the United States.

Geographic Access Disparities to Clinical Trials in Diabetic Eye Disease in the United States.

PURPOSE: To identify geographic and socioeconomic variables predictive of residential proximity to diabetic eye disease clinical trial locations. DESIGN: Cross-sectional, retrospective study. PARTICIPANTS: De-identified census tract-level data from public datasets and trial-level data from ClinicalTrials.gov. METHODS: Using public data from ClinicalTrials.gov, we identified all active interventional clinical trials in diabetic eye disease since 2017. After geolocating every trial site, we used an origin-destination cost-matrix to calculate the driving distance and travel time from the population-weighted United States census tract centroid to the nearest site. We then used public databases to identify census tract-level socioeconomic factors predictive of driving distance and time. MAIN OUTCOME MEASURES: Driving distance > 60 miles and time traveled > 60 minutes to the nearest clinical trial site. RESULTS: In a multivariate model, driving distance of more than 60 miles had a significant association with rural versus urban location (adjusted odds ratio, 5.22; 95% confidence interval [CI], 3.75-7.26; P < 0.001), percentage of population at less than 200% of federal poverty level compared with the fourth quartile (first quartile: adjusted odds ratio, 0.40 [95% CI, 0.29-0.55]; second quartile: adjusted odds ratio, 0.60 [95% CI, 0.47-0.77]; third quartile: adjusted odds ratio, 0.76 [95% CI, 0.63-0.91]; P < 0.001) and the Midwest (adjusted odds ratio, 2.15; 95% CI, 1.13-4.07; P = 0.02), South (adjusted odds ratio, 2.71; 95% CI, 1.23-5.99; P = 0.01), and West (adjusted odds ratio, 3.01; 95% CI, 1.21-7.54; P = 0.02) regions as compared with the Northeast. Driving distance was associated with county-level prevalence of diabetes in the univariate model (odds ratio, 1.12; 95% CI, 1.06-1.19; P < 0.001), although it was nonsignificant in the multivariate model. Similar predictors were found for time traveled in minutes. CONCLUSIONS: Geographic maldistributions of clinical trial sites exist for diabetic eye disease in the United States. Those with higher travel burden are more likely to reside in a census tract that is rural, low income, and from areas outside the Northeast.

Adherence to the International Committee of Medical Journal Editors' (ICMJE) prospective registration policy and implications for outcome integrity: a cross-sectional analysis of trials published in high-impact specialty society journals.

BACKGROUND: Registration of clinical trials is critical for promoting transparency and integrity in medical research; however, trials must be registered in a prospective fashion to deter unaccounted protocol modifications or selection of alternate outcomes that may enhance favorability of reported findings. We assessed adherence to the International Committee of Medical Journal Editors' (ICMJE) prospective registration policy and identified the frequency of registrations occurring after potential observation of primary outcome data among trials published in the highest-impact journals associated with US professional medical societies. Additionally, we examined whether trials that are unregistered or registered after potential observation of primary outcome data were more likely to report favorable findings. METHODS: We conducted a retrospective, cross-sectional analysis of the 50 most recently published clinical trials that reported primary results in each of the ten highest-impact US medical specialty society journals between 1 January 2010 and 31 December 2015. We used descriptive statistics to characterize the proportions of trials that were: registered; registered retrospectively; registered retrospectively potentially after initial ascertainment of primary outcomes; and reporting favorable findings, overall and stratified by journal and trial characteristics. Chi-squared analyses were performed to assess differences in registration by journal and trial characteristics. RESULTS: We reviewed 6869 original research reports published between 1 January 2010 and 31 December 2015 to identify a total of 486 trials across 472 publications. Of these 486 trials, 47 (10%) were unregistered. Among 439 registered trials, 340 (77%) were registered prospectively and 99 (23%) retrospectively. Sixty-seven (68%) of these 99 retrospectively registered trials, or 15% of all 439 registered trials, were registered after potential observation of primary outcome data ascertained among participants enrolled at inception. Industry-funded trials, those with enrollment sites in the US, as well as those assessing FDA-regulated interventions each had lower rates of retrospective registration. Unregistered trials were more likely to report favorable findings than were registered trials (89% vs. 64%; relative risk (RR) = 1.38, 95% confidence interval (CI) = 1.20-1.58; p = 0.004), irrespective of registration timing. CONCLUSIONS: Adherence to the ICMJE's prospective registration policy remains sub-standard, even in the highest-impact journals associated with US professional medical societies. These journals frequently published unregistered trials and trials registered after potential observation of primary outcome data.

Biomedical journal speed and efficiency: a cross-sectional pilot survey of author experiences.

BACKGROUND: Although the peer review process is believed to ensure scientific rigor, enhance research quality, and improve manuscript clarity, many investigators are concerned that the process is too slow, too expensive, too unreliable, and too static. In this feasibility study, we sought to survey corresponding authors of recently published clinical research studies on the speed and efficiency of the publication process. METHODS: Web-based survey of corresponding authors of a 20% random sample of clinical research studies in MEDLINE-indexed journals with Ovid MEDLINE entry dates between December 1 and 15, 2016. Survey addressed perceived manuscript importance before first submission, approximate first submission and final acceptance dates, and total number of journal submissions, external peer reviews, external peer reviewers, and revisions requested, as well as whether authors would have considered publicly sharing their manuscript on an online platform instead of submitting to a peer-reviewed journal. RESULTS: Of 1780 surveys distributed, 27 corresponding authors opted out or requested that we stop emailing them and 149 emails failed (e.g., emails that bounced n = 64, returned with an away from office message n = 70, or were changed/incorrect n = 15), leaving 1604 respondents, of which 337 completed the survey (21.0%). Respondents and non-respondents were similar with respect to study type and publication journals' impact factor, although non-respondent authors had more publications (p = 0.03). Among respondents, the median impact factor of the publications' journal was 2.7 (interquartile range (IQR), 2.0-3.6) and corresponding authors' median h-index and number of publications was 9 (IQR, 3-20) and 27 (IQR, 10-77), respectively. The median time from first submission to journal acceptance and publication was 5 months (IQR, 3-8) and 7 months (IQR, 5-12), respectively. Most respondents (62.0%, n = 209) rated the importance of their research as a 4 or 5 (5-point scale) prior to submission. Median number of journal submissions was 1 (IQR, 1-2), external peer reviews was 1 (IQR, 1-2), external peer reviewers was 3 (IQR, 2-4), and revisions requested was 1 (IQR, 1-1). Sharing manuscripts to a public online platform, instead of submitting to a peer-reviewed journal, would have been considered by 55.2% (n = 186) of respondents. CONCLUSION: Corresponding authors have high perceptions of their research and reported requiring few manuscript submissions prior to journal acceptance, most commonly by lower impact factor journals.

Incremental Revisions across the Life Span of Ophthalmic Devices after Initial Food and Drug Administration Premarket Approval, 1979-2015.

PURPOSE: To characterize the frequency, nature, and regulatory mechanisms by which ophthalmic devices are iteratively modified after initial Food and Drug Administration (FDA) Premarket Approval (PMA). DESIGN: Retrospective cross-sectional analysis using publicly available FDA data. PARTICIPANTS: Ophthalmic devices initially approved via the FDA's PMA pathway between January 1, 1979 and December 31, 2015. METHODS: We used the FDA's PMA Database to identify and characterize initial approvals and subsequent postmarket modifications to Class III ophthalmic devices. The FDA Recalls Database was used to identify associated safety events. MAIN OUTCOME MEASURES: Median iterated life span (timespan across which modifications occurred after initial PMA) and median number of supplements approved per device, by device type, and overall, stratified by regulatory pathway and modification type. RESULTS: Between 1979 and 2015, the FDA approved 168 original ophthalmic devices via the PMA pathway and 2813 subsequent modifications. More than one third (n = 64; 38%) of original approvals were intraocular lenses. Overall, devices underwent a median of 11 postmarket modifications (interquartile range [IQR], 3-24.8) across a median 10.0-year iterated life span (IQR, 4.1-16.7). The majority of devices (n = 144; 86%) underwent more than 1 postapproval modification, including more than 1 design modification (n = 84; 50%). The median number of changes altering device design or labeling was 3.5 (IQR, 1-9). Although manufacturing alterations (n = 834 of 2813; 30%) were the most frequent type of revision, changes involving device design (n = 667; 24%) and labeling (n = 417; 15%) were common. Recalled devices underwent more frequent postapproval modifications per year (median, 1.4; IQR, 0.7-2.3; mean, 1.5; 95% confidence interval, 1.1-1.9) in the period preceding recall than did nonrecalled devices (median, 0.5; IQR, 0.2-1.1; mean, 0.8; 95% confidence interval, 0.7-1.0) across their market approval period (P < 0.001). CONCLUSIONS: Most ophthalmic devices approved via the FDA's PMA pathway have undergone extensive revisions, including serial design and labeling changes, since their initial approvals, often without supporting clinical data. Ophthalmologists should take into consideration that cumulative revisions may render the clinical evidence that supported an original FDA approval less relevant to newer device models.

An unusual cause of left ventricular outflow tract obstruction.

Left ventricular outflow tract obstruction (LVOTO) has been reported with bio-prosthetic and mechanical mitral valves (MV), though it is more common with the former. The obstruction can be dynamic or fixed. We hereby report a case of fixed LVOTO following bio-prosthetic MV replacement (MVR).

Outcomes and statistical power in adult critical care randomized trials.

RATIONALE: Intensive care unit (ICU)-based randomized clinical trials (RCTs) among adult critically ill patients commonly fail to detect treatment benefits. OBJECTIVES: Appraise the rates of success, outcomes used, statistical power, and design characteristics of published trials. METHODS: One hundred forty-six ICU-based RCTs of diagnostic, therapeutic, or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied. MEASUREMENT AND MAIN RESULTS: Of 146 RCTs, 54 (37%) were positive (i.e., the a priori hypothesis was found to be statistically significant). The most common primary outcomes were mortality (n = 40 trials), infection-related outcomes (n = 33), and ventilation-related outcomes (n = 30), with positive results found in 10, 58, and 43%, respectively. Statistical power was discussed in 135 RCTs (92%); 92 cited a rationale for their power parameters. Twenty trials failed to achieve at least 95% of their reported target sample size, including 11 that were stopped early due to insufficient accrual/logistical issues. Of 34 superiority RCTs comparing mortality between treatment arms, 13 (38%) accrued a sample size large enough to find an absolute mortality reduction of 10% or less. In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5%. CONCLUSIONS: ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects, particularly when using mortality as the primary outcome. Additional concerns include a lack of standardized methods for assessing common outcomes, unclear justifications for statistical power calculations, insufficient patient accrual, and incorrect predictions of baseline event rates.

Isoniazid Toxicity among an Older Veteran Population: A Retrospective Cohort Study.

BACKGROUND: our objective was to determine the incidence of toxicity among veterans initiating isoniazid therapy for latent tuberculosis infection (LTBI) and determine whether advancing age was a risk factor for toxicity. METHODS: we performed a retrospective cohort study among all adults initiating isoniazid treatment for LTBI at a Veterans Medical Center from 1999 to 2005. We collected data on patient demographics, co-morbidities, site of initiation, and treatment outcome. RESULTS: 219 patients initiated isoniazid therapy for LTBI during the period of observation, and the completion of therapy was confirmed in 100 patients (46%). Among 18/219 patients (8%) that discontinued therapy due to a documented suspected toxicity, the median time to onset was 3 months (IQR 1-5 months). In an adjusted Cox regression model, there was no association between discontinuation due to suspected toxicity and advancing age (HR 1.03, 95% CI 0.99, 1.07). In contrast, hepatitis C infection was a significant predictor of cessation due to toxicity in the adjusted analysis (HR 3.03, 95% CI 1.08, 8.52). CONCLUSIONS: cessation of isoniazid therapy due to suspected toxicity was infrequently observed among a veteran population and was not associated with advancing age. Alternative LTBI treatment approaches should be further examined in the veteran population.

Resonance Raman spectroscopic investigation of the light-harvesting chromophore in escherichia coli photolyase and Vibrio cholerae cryptochrome-1.

Photolyases and cryptochromes are flavoproteins that belong to the class of blue-light photoreceptors. They usually bind two chromophores: flavin adenine dinucleotide (FAD), which forms the active site, and a light-harvesting pigment, which is a 5,10-methenyltetrahydrofolate polyglutamate (MTHF) in most cases. In Escherichia coli photolyase (EcPhr), the MTHF cofactor is present in substoichiometric amounts after purification, while in Vibrio cholerae cryptochrome-1 (VcCry1) the MTHF cofactor is bound more strongly and is present at stoichiometric levels after purification. In this paper, we have used resonance Raman spectroscopy to monitor the effect of loss of MTHF on the protein-FAD interactions in EcPhr and to probe the protein-MTHF interactions in both EcPhr and VcCry1. We find that removal of MTHF does not perturb protein-FAD interactions, suggesting that it may not affect the physicochemical properties of FAD in EcPhr. Our data demonstrate that the pteridine ring of MTHF in EcPhr has different interactions with the protein matrix than that of MTHF in VcCry1. Comparison to solution resonance Raman spectra of MTHF suggests that the carbonyl of its pteridine ring in EcPhr experiences stronger hydrogen bonding and a more polar environment than in VcCry1, but that hydrogen bonding to the pteridine ring amine hydrogens is stronger in VcCry-1. These differences in hydrogen bonding may account for the higher binding affinity of MTHF in VcCry1 compared to EcPhr.