The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center.

Objective: The potential association between diabetic retinopathy (DR) worsening and glucagon-like peptide-1 receptor agonists (GLP-1RA) has affected therapeutic management of diabetic patients but remains controversial. This study compared rates of DR development or progression in patients on GLP-1RA to those on SGLT-2 inhibitors (SGLT-2I). Design: Retrospective cohort study. Subjects: Nine hundred eighty-one patients with diabetes mellitus taking GLP-1RA or SGLT-2I, the latter serving as controls, between 2012 and 2023. Methods: Patients were one-to-one greedy matched by propensity scores on race/ethnicity, age, smoking status, baseline body mass index and hemoglobin A1c %, type of diabetes mellitus, baseline DR status and history of DR procedures, duration of drug use, whether they had taken both drug types, and change in hemoglobin A1c % after 1 year on the drug. Main Outcome Measures: The primary outcome was clinical DR development or progression (termed "worsening") detected by International Classification of Diseases (ICD), 10th edition codes, confirmed by manual review, on GLP-1RA compared with SGLT-2I after propensity score matching. Secondary outcomes included DR worsening indicated by need for procedures due to complications, and time-to-first DR worsening event. Results: The study included 692 GLP-1RA users and 289 SGLT-2I users. The mean follow-up periods for GLP-1RA versus SGLT-2I use were 1.54 (standard deviation [SD] 1.82) years and 1.38 (SD 1.56) years, respectively. The rates of clinical worsening were 2.3% and 2.8%, respectively. After propensity score matching, an association was not identified between GLP1-RA and DR worsening neither clinically by ICD-10 codes (odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.11-1.03) nor by indication for procedures (OR = 0.50, 95% CI 0.13-2.00). Time-to-first DR worsening did not differ between the groups in Kaplan-Meier analysis. The most common type of clinical worsening event for both drug types was vitreous hemorrhage (43.7% and 50% of worsening events in GLP-1RA and SGLT-2I users, respectively). The most common DR procedure indicated was anti-VEGF injections (34% and 35% of GLP-1RA and SGLT-2I events, respectively). Conclusions: Diabetic retinopathy worsening, either clinically or by procedures, was not associated with GLP-1RA compared with SGLT-2I, both before and after propensity score matching on all analyses, including time-to-first worsening event. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

The Impact of Travel Distance on Rhegmatogenous Retinal Detachment Presentation and Outcomes.

BACKGROUND AND OBJECTIVE: Rhegmatogenous retinal detachment (RRD) requires urgent surgical intervention. The effect of travel distance on RRD outcomes is unclear. PATIENTS AND METHODS: This retrospective cohort study included 642 patients who underwent RRD repair at Cole Eye Institute from 2012 to 2020. Google Maps was used to calculate the travel distance in miles from the residential zip code to the presenting and surgery location addresses. Multivariable logistic and bivariate linear regressions were used to compare macula-off status and best-corrected visual acuity (BCVA) in ETDRS letters at presentation and at 6-month follow-up, with patient travel distance divided into < 25 miles, 25 to 50 miles, and > 50 miles. RESULTS: Four hundred sixty-two patients were examined in the final cohort. The retinal reattachment rate was 94.3% for less than 25 miles, 96.3% for 25 to 50 miles, and 95.9% for greater than 50 miles (P = 0.63). In multivariable analysis, distance to presenting location was not associated with macula-off status (P = 0.69) or BCVA at follow-up (P = 0.27). Oneway analysis of distance and time from presentation to surgery in days revealed that distance to surgical site was associated with longer time to surgery (P = 0.003). Subset analysis of patients with income less than $25,520 (n = 18) revealed greater distance to presenting and surgical location was associated with longer time to surgery (P < .0001), but was not associated with BCVA at follow-up (P = 0.53). CONCLUSIONS: This data suggests that patients who live further from the hospital achieve equivalent outcomes from RRD repair, despite delays in surgery. [Ophthalmic Surg Lasers Imaging Retina 2022;53:666-672.].

Intraosseous delivery of platelet-targeted factor VIII lentiviral vector in humanized NBSGW mice.

We previously showed that intraosseous (IO) delivery of factor VIII (FVIII, gene F8) lentiviral vector (LV) driven by the megakaryocyte-specific promoter Gp1bα (G-F8-LV) partially corrected the bleeding phenotype in hemophilia A (HemA) mice for up to 5 months. In this study, we further characterized and confirmed the successful transduction of self-regenerating hematopoietic stem and progenitor cells (HSPCs) in treated mice. In addition, secondary transplant of HSPCs isolated from G-F8-LV-treated mice corrected the bleeding phenotype of the recipient HemA mice, indicating the potential of long-term transgene expression following IO-LV therapy. To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy into human HSPCs. In vitro transduction of human HSPCs by the platelet-targeted G-F8-LV confirmed megakaryocyte-specific gene expression after preferential differentiation of HSPCs to megakaryocyte lineages. Lentiviral integration analysis detected a polyclonal integration pattern in G-F8-LV-transduced human cells, profiling the clinical safety of hemophilia treatment. Most importantly, IO delivery of G-F8-LV to humanized NBSGW mice produced persistent FVIII expression in human platelets after gene therapy, and the megakaryocytes differentiated from human CD34+ HSPCs isolated from LV-treated humanized mice showed up to 10.2% FVIII expression, indicating efficient transduction of self-regenerating human HSPCs. Collectively, these results indicate the long-term safety and efficacy of the IO-LV gene therapy strategy for HemA in a humanized model, adding further evidence to the feasibility of translating this method for clinical applications.

Preincision adjunctive prophylaxis for cesarean deliveries a systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically review the relative effectiveness of preincision cefazolin with or without adjunctive prophylaxis (macrolides or metronidazole) vs cefazolin alone in decreasing the incidence of postcesarean delivery surgical site infections. DATA SOURCES: We performed a systematic search on PubMed, Ovid EMBASE, Google Scholar, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials from October 25, 2020, to November 25, 2020, to identify studies comparing cefazolin with adjunctive macrolides or metronidazole with cefazolin alone. The reference lists were reviewed, and a manual search of articles published after the last database search was performed. STUDY ELIGIBILITY CRITERIA: Overall, 3 randomized controlled trials and 1 prospective observational study of reproductive-age women undergoing cesarean deliveries were included in the study. We excluded studies of women who were immunocompromised (eg, patients who were HIV positive) or women with a diagnosis of chorioamnionitis before cesarean delivery. All patients received first-line cefazolin (either cefazolin 1 g or 2 g). We compared preincision cefazolin alone with preincision cefazolin plus adjunctive therapy (500 mg, oral or intravenous formulations of azithromycin, metronidazole, or clarithromycin). METHODS: A total of 6 review authors independently assessed the risk of bias for each study, using the Cochrane Risk of Bias criteria. Synthesis and further appraisal were done using the Grading of Recommendations, Assessment, Development, and Evaluation levels and the American College of Obstetricians and Gynecologists appraisal guidelines. Disagreements were resolved by discussion. Treatment effects were evaluated using meta-analysis, and pooled relative risks and 95% confidence intervals were generated using random-effects models using the Review Manager 5 software (version 5.4.1). RESULTS: Overall, 3 randomized controlled trials and 1 prospective observational study representing 2613 women met the criteria for inclusion. Significant reductions in surgical site infections (relative risk, 0.46; 95% confidence interval, 0.34-0.63; 3 randomized controlled trials) and the duration of hospital stay (weighted mean difference, -1.46; 95% confidence interval, -2.21 to -0.71; 2 randomized controlled trials) were observed with preincision cefazolin and adjunctive prophylaxis compared with cefazolin alone. No significant difference was observed in maternal febrile morbidity (relative risk, 0.38; 95% confidence interval, 0.11-1.25; 2 randomized controlled trials). CONCLUSION: Our findings have provided evidence for the use of preincision adjunctive extended-spectrum prophylaxis with cefazolin over cefazolin alone. However, future investigations are required to establish the relative efficacies of different adjunctive antibiotic options.