Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Education of Patients With Atrial Fibrillation and Evaluation of the Efficacy of a Mobile Virtual Patient Environment: Protocol for a Multicenter Pseudorandomized Controlled Trial.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a leading cause of mortality and morbidity. Patient knowledge about AF and its management is paramount but often limited. Patients need to be appropriately informed about treatment options, medicinal adherence, and potential consequences of nonadherence, while also understanding treatment goals and expectations from it. Mobile health apps have experienced an explosion both in their availability and acceptance as "soft interventions" for patient engagement and education; however, the prolific nature of such solutions revealed a gap in the evidence base regarding their efficacy and impact. Virtual patients (VPs), interactive computer simulations, have been used as learning activities in modern health care education. VPs demonstrably improved cognitive and behavioral skills; hence, they have been effectively implemented across undergraduate and postgraduate curricula. However, their application in patient education has been rather limited so far. OBJECTIVE: This work aims to implement and evaluate the efficacy of a mobile-deployed VP regimen for the education and engagement of patients with AF on crucial topics regarding their condition. A mobile VP app is being developed with the goal of each VP being a simple scenario with a set goal and very specific messages and will be subsequently attempted and evaluated. METHODS: A mobile VP player app is being developed so as to be used for the design of 3 educational scenarios for AF management. A pseudorandomized controlled trial for the efficacy of VPs is planned to be executed at 3 sites in Greece, Ukraine, and Kazakhstan for patients with AF. The Welch t test will be used to demonstrate the performance of patients' evaluation of the VP experience. RESULTS: Our study is at the development stage. A preliminary study regarding the system's development and feasibility was initiated in December 2022. The results of our study are expected to be available in 2024 or when the needed sample size is achieved. CONCLUSIONS: This study aims to evaluate and demonstrate the first significant evidence for the value of VP resources in outreach and training endeavors for empowering and patients with AF and fostering healthy habits among them. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45946.

Diagnostic Accuracy of p16INK4a/Ki-67 Dual Immunostaining for Detection of High-Grade Cervical Intraepithelial Neoplasia in Women Involved in Cervical Cancer Screening in Georgia.

Background: Despite the widespread introduction of primary and secondary preventative measures, death rates for cervical cancer are still significantly high among females, especially in developing countries. Pap cytology and human papillomavirus-based screening often lead to unnecessary additional testing. The aim of this study is to analyze diagnostic accuracy of p16INK4a/Ki-67 dual immunostaining (DS) in cervical smear for identifying high-grade cervical intraepithelial neoplasia (CIN2+). Materials and Methods: We studied the diagnostic performance of p16INK4a/Ki-67 DS in cervical smear of those women, who enrolled in cervical cancer screening due to abnormal previous screening results and compared it with Pap test results in identifying CIN2+. The reference standard was histopathology results. p16INK4a/Ki-67 DS and Pap test results for 162 women and histopathology results for 29 women were available, respectively. Results: In our study, sensitivity, specificity, positive predictive value, and negative predictive value of p16INK4a/Ki-67 DS, irrespective of the morphology of stained cells to detect CIN2+ were 100%, 89%, 85%, and 100% (p < 0.01), respectively. The diagnostic accuracy of p16INK4a/Ki-67 DS is superior to that of existing cervical screening tests in the detection of CIN2+. Conclusion: The findings of cervical cancer screening based on Pap cytology highlight the importance of assessing the cost-effectiveness of integrating p16INK4a/Ki-67 biomarkers in cervical cancer cytology. Furthermore, these findings emphasize the need to enhance support for preventive programs for cervical cancer in Georgia.

Total cardiovascular risk approach to improve efficiency of cardiovascular prevention in resource constrain settings.

OBJECTIVES: To determine the population distribution of cardiovascular risk in eight low- and middle-income countries and compare the cost of drug treatment based on cardiovascular risk (cardiovascular risk thresholds ≥ 30%/≥ 40%) with single risk factor cutoff levels. STUDY DESIGN AND SETTING: Using World Health Organization (WHO) and the International Society of Hypertension risk prediction charts, cardiovascular risk was categorized in a cross-sectional study of 8,625 randomly selected people aged 40-80 years (mean age, 54.6 years) from defined geographic regions of Nigeria, Iran, China, Pakistan, Georgia, Nepal, Cuba, and Sri Lanka. Cost estimates for drug therapy were calculated for three countries. RESULTS: A large fraction (90.0-98.9%) of the study population has a 10-year cardiovascular risk <20%. Only 0.2-4.8% are in the high-risk categories (≥ 30%). Adopting a total risk approach and WHO guidelines recommendations would restrict unnecessary drug treatment and reduce the drug costs significantly. CONCLUSION: Adopting a total cardiovascular risk approach instead of a single risk factor approach reduces health care expenditure by reducing drug costs. Therefore, limited resources can be more efficiently used to target high-risk people who will benefit the most. This strategy needs to be complemented with population-wide measures to shift the cardiovascular risk distribution of the whole population.