Diabetic retinopathy: Screening, prevention, and treatment.

Internists are integral in the multidisciplinary approach to diabetic retinopathy, contributing significantly to the management of diabetes and diabetes-related complications. Effective screening processes, timely referrals, and strategic diabetes management are imperative to prevent and mitigate the consequences of diabetic retinopathy. The evolution of treatments for diabetic retinopathy has markedly improved vision outcomes and reduced the burden on patients. Despite these advances, a collaborative approach to care is essential to prevent the progression of vision impairment and manage associated complications.

Predictive Accuracy of Infant Clinical Sign Algorithms for Mortality in Young Infants Aged 0 to 59 Days: A Systematic Review.

CONTEXT: Clinical sign algorithms are a key strategy to identify young infants at risk of mortality. OBJECTIVE: Synthesize the evidence on the accuracy of clinical sign algorithms to predict all-cause mortality in young infants 0-59 days. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Registry of Trials. STUDY SELECTION: Studies evaluating the accuracy of infant clinical sign algorithms to predict mortality. DATA EXTRACTION: We used Cochrane methods for study screening, data extraction, and risk of bias assessment. We determined certainty of evidence using Grading of Recommendations Assessment Development and Evaluation. RESULTS: We included 11 studies examining 26 algorithms. Three studies from non-hospital/community settings examined sign-based checklists (n = 13). Eight hospital-based studies validated regression models (n = 13), which were administered as weighted scores (n = 8), regression formulas (n = 4), and a nomogram (n = 1). One checklist from India had a sensitivity of 98% (95% CI: 88%-100%) and specificity of 94% (93%-95%) for predicting sepsis-related deaths. However, external validation in Bangladesh showed very low sensitivity of 3% (0%-10%) with specificity of 99% (99%-99%) for all-cause mortality (ages 0-9 days). For hospital-based prediction models, area under the curve (AUC) ranged from 0.76-0.93 (n = 13). The Score for Essential Neonatal Symptoms and Signs had an AUC of 0.89 (0.84-0.93) in the derivation cohort for mortality, and external validation showed an AUC of 0.83 (0.83-0.84). LIMITATIONS: Heterogeneity of algorithms and lack of external validation limited the evidence. CONCLUSIONS: Clinical sign algorithms may help identify at-risk young infants, particularly in hospital settings; however, overall certainty of evidence is low with limited external validation.

Diagnostic Accuracy of Clinical Sign Algorithms to Identify Sepsis in Young Infants Aged 0 to 59 Days: A Systematic Review and Meta-analysis.

CONTEXT: Accurate identification of possible sepsis in young infants is needed to effectively manage and reduce sepsis-related morbidity and mortality. OBJECTIVE: Synthesize evidence on the diagnostic accuracy of clinical sign algorithms to identify young infants (aged 0-59 days) with suspected sepsis. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Registry of Trials. STUDY SELECTION: Studies reporting diagnostic accuracy measures of algorithms including infant clinical signs to identify young infants with suspected sepsis. DATA EXTRACTION: We used Cochrane methods for study screening, data extraction, risk of bias assessment, and determining certainty of evidence using Grading of Recommendations Assessment Development and Evaluation. RESULTS: We included 19 studies (12 Integrated Management of Childhood Illness [IMCI] and 7 non-IMCI studies). The current World Health Organization (WHO) 7-sign IMCI algorithm had a sensitivity of 79% (95% CI 77%-82%) and specificity of 77% (95% CI 76%-78%) for identifying sick infants aged 0-59 days requiring hospitalization/antibiotics (1 study, N = 8889). Any IMCI algorithm had a pooled sensitivity of 84% (95% CI 75%-90%) and specificity of 80% (95% CI 64%-90%) for identifying suspected sepsis (11 studies, N = 15523). When restricting the reference standard to laboratory-supported sepsis, any IMCI algorithm had a pooled sensitivity of 86% (95% CI 82%-90%) and lower specificity of 61% (95% CI 49%-72%) (6 studies, N = 14278). LIMITATIONS: Heterogeneity of algorithms and reference standards limited the evidence. CONCLUSIONS: IMCI algorithms had acceptable sensitivity for identifying young infants with suspected sepsis. Specificity was lower using a reference standard of laboratory-supported sepsis diagnosis.

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.

Real-world first-line treatment patterns and outcomes in recurrent/advanced endometrial cancer patients in Europe.

Background: The treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer in Europe are not well known. Materials & methods: Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter, retrospective chart review study conducted in the UK, Germany, Italy, France and Spain. Patients diagnosed with recurrent/advanced endometrial cancer who initiated first-line systemic therapy between 1 July 2016 and 31 March 2020 were eligible. Results: Among 242 patients, median age was 69 years and 82.2% had stage IIIB-IV disease. In first-line, most patients received platinum-based chemotherapy (78.9%); others received endocrine therapy (6.2%), taxane monotherapy (5.8%) and nonplatinum or taxane-based chemotherapy (4.1%). Median real-world progression-free survival since first-line initiation was 10.8 months and median overall survival was 20.7 months. Conclusion: Poor prognosis with platinum-based first-line chemotherapy suggests significant unmet medical need.

Treatment patterns & survival for recurrent/advanced endometrial cancer patients in Europe who received their first treatmentThe treatments and survival for recurrent/advanced endometrial (uterus lining) cancer patients in real-life European settings are not well known. Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter study that was conducted in the UK, Germany, Italy, France and Spain and used de-identified information from existing patient medical records. Patients diagnosed with recurrent/advanced endometrial cancer who initiated a first treatment between 1 July 2016 and 31 March 2020 were included. Among 242 included patients, the average age was 69 years and 82.2% had stage IIIB-IV disease (indicating the size and extent of their cancer). As their first treatment, most patients received platinum-based chemotherapy (78.9%), which is a type of drug that kills cancer cells. Overall, patients lived for an average of 20.7 months since their first treatment. The average length of time patients lived without their disease getting worse was 10.8 months since their first treatment. We found that patients who received platinum-based chemotherapy as their first treatment had poor survival, which suggests significant unmet medical need.

Long-term visual outcomes and fluid compartment changes in limited-early versus early response to anti-VEGF treatment for diabetic macular edema.

OBJECTIVE: This study assessed best visual acuity (BVA) and central subfield thickness (CST) outcomes for LER (limited early responder) and ER (early responder) patients at 24 and 36 months. DESIGN: Retrospective chart review PARTICIPANTS: One-hundred and twelve patients characterized at 3 months after their first anti-VEGF injections as either LER if they met the anatomic criteria (aLER = CST reductions ≤ 10%), visual criteria (vLER = ETDRS letter gains < 5 letter), or both (cLER). All other patients were classified as ER (aER/vER/cER). METHODS: Variables collected include CST and ETDRS letters at baseline, 3, 24, and 36 months following injections, comorbidities, smoking status, demographics, baseline systemic factors, and the type and quantity of anti-VEGF injections. Analyses were performed using Welch's t-test, multivariable linear and multivariable logistic regression. RESULTS: BVA changes from 3 months were significant between cLER versus cER and vLER versus vER groups (p < 0.05). There was a greater decrease in mean BVA from 3 months to 36 months in the cER group compared to the cLER group. Alternatively, mean BVA decreased in the vER cohort, while the vLER cohort slightly increased. CST changes from 3 months were statistically significant (p < 0.01) between all LER and ER groups with LER groups showing greater reductions compared to ER counterparts. BVA and CST changes from baseline to 24 and 36 months were not significant after controlling for baseline differences between LER and ER groups. CONCLUSION: Results highlight the value of long-term anti-VEGF treatment and the need to further explore options that may lead to continued BVA improvements beyond 3 months.

Drug-Induced Intracranial Hypertension: The Adverse Effects of Acne Medications and Topical Retinoids.

BACKGROUND: Tetracyclines and vitamin A derivatives, major components in acne care and antiaging products, have been associated with the development of drug-induced intracranial hypertension (DIIH). Treatment practices and longitudinal visual outcomes have been highly understudied in DIIH. The purpose of this study was to provide management guidelines for DIIH and report visual outcomes of patients with DIIH. METHODS: This was a single institute ophthalmology center case-control study where patients were seen between June 1, 2012, and September 1, 2023, in the United States. Patients with an International Classification of Disease (ICD) code for IIH and meeting the IIH diagnostic criteria who were taking a tetracycline or a vitamin A derivative during their diagnosis were included in this study. Patients were stratified into the following 3 categories: tetracyclines only, vitamin A derivatives only, or both, and compared with Kruskal-Wallis rank-sum tests. Poor visual outcomes were evaluated for and defined as a visual field mean deviation (peripheral visual measure) of -7 dB or greater. Individuals were followed for up to 1.5 years after diagnosis. RESULTS: Among patients with IIH (n = 839), DIIH occurred in 8.10% of them (n = 68) with 83% taking the medication for acne. 88% of cases were female, and patients had a mean age of 24.96 years. DIIH medications were taken for an average length of 25.79 weeks before diagnosis of IIH. 20.5% of patients with DIIH were not treated with any IIH medication and were discontinued from the inducing drug. 3 patients had a poor visual outcome on follow-up with all of them taking a vitamin A derivative (P < 0.05). Patients identified as having a poor visual outcome did not report discontinuing the DIIH drug (P < 0.05). CONCLUSIONS: We propose treatment guidelines highlighting that patients taking a DIIH medication who develop headaches or visual changes should be immediately referred to ophthalmology, removal of the offending agent, and close monitoring by ophthalmology for vision loss. Importantly, vitamin A DIIH may have more severe visual outcomes, but further research is needed to corroborate this finding.

American Society of Retina Specialists Artificial Intelligence Task Force Report.

Since the Artificial Intelligence Committee of the American Society of Retina Specialists developed the initial task force report in 2020, the artificial intelligence (AI) field has seen further adoption of US Food and Drug Administration-approved AI platforms and significant development of AI for various retinal conditions. With expansion of this technology comes further areas of challenges, including the data sources used in AI, the democracy of AI, commercialization, bias, and the need for provider education on the technology of AI. The overall focus of this committee report is to explore these recent issues as they relate to the continued development of AI and its integration into ophthalmology and retinal practice.

Evidence for the Hepato-Retinal Axis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Liver health has been reported to be associated with retinal pathology in various ways. These include deposition of retino-toxins, neovascular drive, and disruption of the blood-retina barrier. Extrahepatic synthesis of implicated molecules and hemodynamic changes in liver dysfunction are also considered. The objective was to review the current evidence for and against a hepato-retinal axis that may guide further areas of preclinical and clinical investigation. METHODS: This was a systematic review. PubMed and Cochrane were queried for English language studies examining the connection between hepatic dysfunction and retinal pathology. RESULTS: Fourteen studies were included and examined out of 604 candidate publications. The studies selected include preclinical studies as well as clinical case series and studies. CONCLUSIONS: Several liver pathologies may be linked to retinal pathology as mediated by hepatically synthesized molecules. The hepato-retinal axis may be present and further, targeted studies of the axis are warranted. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Serum from patients with cirrhosis undergoing liver transplantation induces permeability in human pulmonary microvascular endothelial cells ex vivo.

Introduction: Patients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells ex vivo. Methods: Adults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture was assessed by transendothelial resistance measured using the ECIS ZΘ system. Confluent cells from two different endothelial cell donors were stimulated with human serum from liver transplant patients. Pooled serum from healthy men and purified inflammatory agonists served as controls. The permeability response to serum was quantified as the area under the normalized resistance curve. Responses were compared between time points and analyzed for associations with clinical characteristics of liver transplant patients and their grafts. Results: Liver transplant sera from all time points during surgery-induced permeability in both endothelial cell lines. The magnitude of permeability change was heterogeneous between patients, and there were differences in the effects of sera on the two endothelial cell lines. In one of the cell lines, the severity of liver disease was associated with greater permeability at the start of surgery. In the same cell line, serum collected 15 min after liver reperfusion induced significantly more permeability as compared to that collected at the start of surgery. Early postreperfusion sera from patients undergoing living donor transplants induced more permeability than sera from deceased donor transplants. Sera from two exemplary cases of patients on preoperative dialysis, and one patient with an unexpectedly long warm ischemia time of the liver graft, induced exaggerated and prolonged endothelial permeability. Discussion: Serum from patients with cirrhosis undergoing liver transplantation induces permeability of cultured human pulmonary microvascular endothelial cells. Increased endothelial permeability during liver transplantation may contribute to organ injury and present a target for future therapeutics.

Retrospective Cohort Study of Sickle Cell Disease and Large Vessel Retinal Vascular Occlusion Risk in a National US Database.

OBJECTIVE: To determine if differences exist in the risk of developing large vessel retinal vascular occlusions in patients with sickle cell states. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with sickle cell disease or trait evaluated by an ophthalmologist were compared to matched controls without sickle cell disease or trait also evaluated by an ophthalmologist. METHODS: This study used deidentified data from a national database (2006-2024), using International Classification of Diseases 10 codes to select for retinal vascular occlusions. Propensity score matching was performed with respect to age, sex, race, ethnicity, smoking, hypertension, diabetes, dyslipidemias, and obesity, resulting in HbSS, HbSC, and sickle cell trait (SCT) cohorts and matched control cohorts. MAIN OUTCOME MEASURES: Risk ratios and 95% confidence intervals (CI) of retinal vascular occlusion diagnosis, including central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), central retinal venous occlusion (CRVO), branch retinal venous occlusion (BRVO), and corneal dystrophy as a negative control, given sickle cell disease or trait. RESULTS: After propensity score matching, HbSS (n=10,802, mean ± standard deviation age of 38.6 ± 20.6 years), HbSC (n=4,296, 34.3 ± 17.8 years), and SCT (n=15,249, 39.8 ± 23.7 years) cohorts were compared to control cohorts (n=10,802, 38.7 ± 20.7 years; n=4,296, 34.6 ± 18.0 years; n=15,249, 39.9 ± 23.8 years, respectively). Patients with sickle cell disease (HbSS) had higher risk of developing any retinal vascular occlusion (RR 2.33; 95% CI 1.82-3.00), CRAO (RR 2.71; 95% CI 1.65-4.47) and BRAO (RR 4.90; 95% CI 2.48-9.67) than matched controls. Patients with HbSC disease had higher risk (RR 3.14; 95% CI 1.95-5.06) of developing any retinal vascular occlusion than matched controls without sickle cell disease. Patients with sickle cell trait did not have higher risk of developing retinal vascular occlusions (RR 1.01; 95% CI 0.81-1.26) than matched controls. CONCLUSIONS: In a retrospective cohort study, patients with HbSS sickle cell disease have an increased risk of developing retinal vascular occlusions, and more specifically CRAO and BRAO compared to patients without sickle cell disease.

Characterization and prevalence of ocular comorbidities and risk of legal blindness across the United States.

BACKGROUND/OBJECTIVES: Vision loss is a top disability in the United States (US). Patients commonly present with multiple ocular diseases, but the extent to which this places them at risk for vision loss, and if sex and race impacts this, is poorly understood. This exploratory analysis evaluated which ocular comorbidities and demographics are at highest risk for visual impairment. SUBJECTS/METHODS: A retrospective cross-sectional study was conducted through the TriNetX Analytics Network, an aggregated network encompassing over 90 million insured and uninsured patients across 50 healthcare organizations from all regions in the US. Patients with diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), glaucoma, and uveitis were included in this study. Ocular diseases and visual impairment were determined through ICD-10 codes. Prevalence and odds ratios were calculated while stratifying by sex and racial demographics. Statistical analyses were completed using RStudio and Excel with 95% confidence intervals calculated. RESULTS: The comorbid conditions with the highest prevalence of visual impairment were uveitis and RVO (39.94%), uveitis and neovascular AMD (37.61%), and uveitis and glaucoma (33.23%). The comorbidity with the highest odds for visual impairment was uveitis and RVO (POR 4.86; 95% CI 4.49, 5.26). Compared to white males, Black and Hispanic males were disproportionately affected by visual impairment across ocular comorbidities. CONCLUSION: This study quantified the prevalence and odds of visual impairment for unilateral and comorbid ocular disease, with the addition of uveitis causing the greatest increase. Black and Hispanic males were disproportionately affected by visual impairment across comorbid conditions.

Etiology of hospital mortality in children living in low- and middle-income countries: a systematic review and meta-analysis.

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.

Characterisation and Visual Outcomes of Fulminant Idiopathic Intracranial Hypertension: A Narrative Review.

Fulminant idiopathic intracranial hypertension (IIH) is a rapid vision-degrading presentation of IIH with limited published studies. This study composed a narrative review of fulminant IIH with the aim of better characterising fulminant IIH presentation and visual outcomes. SCOPUS and PubMed were searched for papers referencing IIH, benign intracranial hypertension, or pseudotumour cerebri. Abstracts were screened for rapid degradation in vision. All studies were required to meet both the modified Dandy and fulminant IIH criteria. Thirty-six studies met the inclusion criteria. Demographics, treatments, and visual outcome data were collected. Case studies made up 69% of the studies and 31% were case series. In total, 72 patients with fulminant IIH were reported, of which 23.6% were paediatric and 96% were female. Surgical intervention occurred in 85% of patients. Anaemia was present in 11% of patients and 85.7% of paediatric patients had a sixth cranial nerve palsy. In conclusion, we propose the following practice guidelines to assist in diagnosing and treating fulminant IIH patients: 1) patients who present with optic disc oedema require urgent visual field testing to evaluate for vision loss; 2) a paediatric patient presenting with a sixth cranial nerve palsy should have a comprehensive eye examination; 3) fulminant IIH can occur in patients with a normal body mass index; and 4) anaemia should be tested for in the setting of fulminant IIH. As little is known about the optimal treatment mechanisms for this presentation, multi-institutional and international collaborations will be a critical step for future research.

Evaluating the Implementation of the Pediatric Acute Care Education (PACE) Program in Northwestern Tanzania: A Mixed-Methods Study Guided by Normalization Process Theory.

Background: In low- and -middle-income countries (LMICs) like Tanzania, the competency of healthcare providers critically influences the quality of pediatric care. To address this, we introduced PACE (Pediatric Acute Care Education), an adaptive e-learning program tailored to enhance provider competency in line with Tanzania's national guidelines for managing seriously ill children. Adaptive e-learning presents a promising alternative to traditional in-service education, yet optimal strategies for its implementation in LMIC settings remain to be fully elucidated. Objectives: This study aimed to (1) evaluate the initial implementation of PACE in Mwanza, Tanzania, using the constructs of Normalization Process Theory (NPT), and (2) provide insights into its feasibility, acceptability, and scalability potential. Methods: A mixed-methods approach was employed across three healthcare settings in Mwanza: a zonal hospital and two health centers. NPT was utilized to navigate the complexities of implementing PACE. Data collection involved a customized NoMAD survey, focus groups and in-depth interviews with healthcare providers. Results: The study engaged 82 healthcare providers through the NoMAD survey and 79 in focus groups and interviews. Findings indicated high levels of coherence and cognitive participation, demonstrating that PACE is well-understood and resonates with existing healthcare goals. Providers expressed a willingness to integrate PACE into their practice, distinguishing it from existing educational methods. However, challenges related to resources and infrastructure, particularly affecting collective action, were noted. The short duration of the study limited the assessment of reflexive monitoring, though early indicators point towards the potential for PACE's long-term sustainability. Conclusion: This study offers vital insights into the feasibility and acceptability of implementing PACE in a Tanzanian context. While PACE aligns well with healthcare objectives, addressing resource and infrastructure challenges is crucial for its successful and sustainable implementation. Furthermore, the study underscores the value of NPT as a framework in guiding implementation processes, with broader implications for implementation science and pediatric acute care in LMICs.

Melatonin and Risk of Age-Related Macular Degeneration.

Importance: Melatonin has been shown to oppose several processes that are known to mediate age-related macular degeneration (AMD), but whether melatonin can confer benefits against AMD remains unclear. Objective: To examine the association between melatonin supplementation and the risk of the development or progression of AMD. Design, Setting, and Participants: This retrospective cohort study accessed data from TriNetX, a national database of deidentified electronic medical records from both inpatient and outpatient health care organizations across the US, between December 4, 2023, and March 19, 2024. Patients aged 50 years or older, 60 years or older, and 70 years or older with no history of AMD (AMD-naive group) and with a history of nonexudative AMD (nonexudative AMD group) were queried for instances of melatonin medication codes between November 14, 2008, and November 14, 2023. Patients were then classified into either a melatonin group or a control group based on the presence of medication codes for melatonin. Propensity score matching (PSM) was performed to match the cohorts based on demographic variables, comorbidities, and nonmelatonin hypnotic medication use. Exposure: The presence of at least 4 instances of melatonin records that each occurred at least 3 months apart. Main Outcomes and Measures: After PSM, the melatonin and the control cohorts were compared to evaluate the risk ratios (RRs) and the 95% CIs of having an outcome. For the AMD-naive group, the outcome was defined as a new diagnosis of any AMD, whereas for the nonexudative AMD group, the outcome was progression to exudative AMD. Results: Among 121 523 patients in the melatonin-naive group aged 50 years or older (4848 in the melatonin cohort [4580 after PSM; mean (SD) age, 68.24 (11.47) years; 2588 female (56.5%)] and 116 675 in the control cohort [4580 after PSM; mean (SD) age, 68.17 (10.63) years; 2681 female (58.5%)]), melatonin use was associated with a reduced risk of developing AMD (RR, 0.42; 95% CI, 0.28-0.62). Among 66 253 patients aged 50 years or older in the nonexudative AMD group (4350 in the melatonin cohort [4064 after PSM; mean (SD) age, 80.21 (8.78) years; 2482 female (61.1%)] and 61 903 in the control cohort [4064 patients after PSM; mean (SD) age, 80.31 (8.03) years; 2531 female (62.3%)]), melatonin was associated with a reduced risk of AMD progression to exudative AMD (RR, 0.44; 95% CI, 0.34-0.56). The results were consistent among subsets of individuals aged 60 years or older (AMD-naive cohort: RR, 0.36 [95% CI, 0.25-0.54]; nonexudative AMD cohort: RR, 0.38 [95% CI, 0.30-0.49]) and 70 years or older (AMD-naive cohort: RR, 0.35 [95% CI, 0.23-0.53]; nonexudative AMD cohort: RR, 0.40 [95% CI, 0.31-0.51]). Conclusions and Relevance: Melatonin use was associated with a decreased risk of development and progression of AMD. Although lifestyle factors may have influenced this association, these findings provide a rationale for further research on the efficacy of using melatonin as a preventive therapy against AMD.

Longitudinal Trends and Disparities in Diabetic Retinopathy Within an Aggregate Health Care Network.

Importance: Diabetic retinopathy (DR) is a leading cause of blindness in the US, warranting updates on its prevalence and incidence in the setting of advancements in diabetic care over recent years. Objective: To determine recent trends in DR prevalence stratified by baseline demographics to identify those populations at greater risk. Design, Setting, and Participants: This was a cross-sectional epidemiologic evaluation conducted using deidentified data from the large federated TriNetX Analytics health research network composed of 56 health care organizations in the US. Patients from 2015 to 2022 who had an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of type 1 DR (T1DR) or type 2 DR (T2DR) were included in this analysis. Patients were further stratified by age cohorts (20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, and 70 years or older), race and ethnicity, and sex. Main Outcomes and Measures: Prevalence per 100 000 patients and prevalence odds ratios (ORs) were calculated in Microsoft Excel and Posit (formerly RStudio). Results: A total of 359 126 patients with T1DR or T2DR (mean [SD] age, 67 [14] years; 52% female) were included in this study between January 1, 2015, and December 21, 2022. T1DR increased in prevalence from 2015 to 2022, with T1DR increasing 1.15-fold affecting 70.4 patients per 100 000 in 2022. T2DR increased 1.07-fold affecting 461.7 patients per 100 000 in 2022. For T1DR, the cohort aged 20 to 39 years had the most substantial increase at 4.7 and 1.96 fold. Overall, White males had the largest prevalence ORs of T1DR at 1.41 (95% CI, 1.36-1.47) compared with White females (reference group). In T2DR, patients aged 20 to 39 years again had a 2.5- and 1.6-fold prevalence increase from 2015 to 2022. Regardless of age group, Hispanic males demonstrated larger prevalence OR at 4.08 (95% CI, 3.97-4.19) compared with White females followed by Hispanic females at 2.49 (95% CI, 2.42-2.56), Black males at 2.23 (95% CI, 2.17-2.29), and Black females at 2.00 (95% CI, 1.95-2.05). Conclusion and Relevance: The prevalence of both T1DR and T2DR increased in this network from 2015 to 2022, with individuals aged 20 to 39 years showing large increases. Additionally, T2DR was associated with greater increases in both Hispanic and Black communities. These findings support DR screening in young adults and for T2DR interventions specifically designed for racial and ethnic minoritized patients most affected by disease. Future investigations are warranted to further investigate these trends among young adults.

Long-term Treatment Patterns for Diabetic Macular Edema: Up to 6-Year Follow-up in the IRIS® Registry.

OBJECTIVE: To characterize anti-VEGF intravitreal therapy (IVT) patterns and long-term visual outcomes among patients with diabetic macular edema (DME) in routine clinical practice in the United States. DESIGN: Retrospective analysis of the American Academy of Ophthalmology's IRIS® (Intelligent Research in Sight) Registry. PARTICIPANTS: Treatment-naïve patients with DME (no previous IVT in the past 12 months) initiating anti-VEGF IVT from January 1, 2015, to March 31, 2021. METHODS: Baseline characteristics, treatment patterns, and long-term visual acuity (VA) outcomes were reported for up to 6 years of follow-up. MAIN OUTCOME MEASURES: Outcomes included the annualized number of injections, change in VA, and anti-VEGF agents. RESULTS: A total of 190 345 eyes met the inclusion criteria. After 1 year of anti-VEGF IVT initiation, eyes received a mean of 3.9 (±2.8) injections and gained +3.2 (±16.4) letters of vision. Of the 1236 eyes with year 6 data, eyes received a mean of 2.9 (±2.1) injections in year 6 and gained +0.5 (±19.7) letters from baseline. The number of injections decreased, and injection intervals increased year over year up to 6 years regardless of baseline VA initiation. The average injection interval was 10 weeks in year 1 and increased to 13.2 weeks in year 2 before plateauing in years 3 to 6 (12.6, 12.3, 12.2, and 12.3 weeks, respectively). Improvements in VA from baseline were greatest in eyes that received 5 or more injections each year. At the end of follow-up, eyes with good baseline vision (>20/25) lost vision, whereas those with worse baseline vision (<20/25) gained vision. Although 51.7% of patients with DME discontinued IVT after a mean of 6 months, 32.8% reinitiated anti-VEGF IVT. Worse VA outcomes were associated with patients of Hispanic ethnicity (-1.08; 95% confidence interval: -1.34, -0.83] compared with non-Hispanic), Medicaid insurance (-1.15; 95% confidence interval: -1.48, -0.81 compared with commercial), and older age (-0.06; 95% confidence interval: -0.07, -0.05] each additional year). CONCLUSIONS: Patients with DME in routine clinical settings receive fewer injections than those in clinical trials and fewer than recommended per the label of US Food and Drug Administration-approved anti-VEGF IVT. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references in the Footnotes and Disclosures at the end of this article.

Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.