Intravitreal Aflibercept vs Laser Therapy for Retinopathy of Prematurity: Two-Year Efficacy and Safety Outcomes in the Nonrandomized Controlled Trial FIREFLEYE next.

Importance: Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. Objective: To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). Design, Setting, and Participants: This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Interventions: Complications of ROP treated at investigator discretion (no study treatment). Main Outcomes and Measures: Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Results: Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. Conclusions and Relevance: In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. Trial Registration: ClinicalTrials.gov Identifier: NCT04015180.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial.

BACKGROUND: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO. METHODS: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503). FINDINGS: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]). INTERPRETATION: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO. FUNDING: Regeneron Pharmaceuticals and Bayer.

The ethics of clinical research in the era of COVID-19.

There is an urgent need for increased understanding of COVID-19 and strategies for its prevention, treatment, and mitigation. All participants in the research enterprise, including institutional review boards, have an ethical duty to protect participants and ensure that the benefits gained from such research do not conflict with the core principles that guided researchers prior to the pandemic. In this review, we discuss the ethical issues surrounding initiation and conduct of clinical trials, focusing on novel COVID-19 therapeutic, vaccine, or biospecimen research, using the principles of autonomy, beneficence, and justice. We discuss strategies to manage the practical challenges associated with the conduct of clinical trials, with an emphasis on maintaining the rights and welfare of research participants.

Characteristics of Veterans Experiencing Homelessness using Telehealth for Primary Care Before and After COVID-19 Pandemic Onset.

BACKGROUND: The COVID-19 pandemic expanded telehealth use across healthcare systems, including the Veterans Health Administration (VA). Little is known about how large-scale telehealth rollout affected access to primary care for patients experiencing homelessness. OBJECTIVE: To examine the extent to which homeless-experienced veterans used telehealth services in primary care and to characterize users before and after the onset of the COVID-19 pandemic. DESIGN: Retrospective cohort study, 3/16/2019-3/15/2022. PARTICIPANTS: 394,731 veterans with homelessness diagnoses nationally using 4,068,109 primary care visits. MAIN MEASURES: The outcomes were use of 1 + telehealth visits (video, phone, secure messaging) for primary care during each year. Through multivariable regression models, we examined associations between telehealth use, patient characteristics (e.g., age, sex, race-ethnicity, comorbidity), and VA homeless services use (e.g., homeless-tailored primary care (HPACT), permanent supportive housing). KEY RESULTS: Compared to pre-pandemic, telehealth in primary care among homeless-experienced veterans increased substantially 2 years post-pandemic (video: 1.37% versus 20.56%, phone: 60.74% versus 76.58%). Secure messaging was low over time (1.57-2.63%). In adjusted models, video users were more likely to be young (65 + years: OR = 0.43, CI: 0.42-0.44), women (OR = 1.74, CI: 1.70-1.78), Black (OR = 1.14, CI: 1.12-1.16), Hispanic (OR = 1.34, CI: 1.30-1.38), and with more comorbidities (2 + on the Charlson Comorbidity Index; OR = 1.16, CI: 1.14-1.19), compared to video non-users. HPACT patients were less likely to use video (OR = 0.68, CI: 0.66-0.71) than other primary care patients. This was not observed among users of other VA homeless services. CONCLUSIONS: Despite decreased access to health information technology and low pre-pandemic telehealth use, veterans experiencing homelessness still sustained high use of telehealth in primary care post-pandemic. Women and racial-ethnic minorities had higher video uptake proportionately, suggesting that telehealth may address access disparities among these homeless-experienced patient groups. Identifying and targeting organizational characteristics (e.g., HPACT users) that predict telehealth use for improvement may be key to increasing adoption among VA primary care patients experiencing homelessness.

Disparities in Video-Based Primary Care Use Among Veterans with Cardiovascular Disease.

BACKGROUND: Cardiovascular disease (CVD) is prevalent among Veterans, and video care enhances access to CVD care. However, it is unknown which patients with CVD conditions receive video care in primary care clinics, where a large proportion of CVD services is delivered. OBJECTIVE: Characterize use of VA video primary care for Veterans with two common CVDs, heart failure and hypertension. DESIGN: Retrospective cohort study. PATIENTS: Veterans seen in VA primary care with diagnoses of heart failure and/or hypertension in the year prior to the COVID-19 pandemic and for the first two pandemic-years. MAIN MEASURES: The primary outcome was use of any video-based primary care visits. Using multilevel regressions, we examined the association between video care use and patient sociodemographic and clinical characteristics, controlling for time and adjusting for patient- and site-level clustering. KEY RESULTS: Of 3.8M Veterans with 51.9M primary care visits, 456,901 Veterans had heart failure and hypertension, 50,753 had heart failure only, and 3,300,166 had hypertension only. Veterans with heart failure and hypertension had an average age of 71.6 years. 2.9% were female, and 34.8% lived in rural settings. Patients who were male, aged 75 or older, or rural-dwelling had lower odds of using video care than female patients, 18-44-year-olds, and urban-dwellers, respectively (male patients' adjusted odds ratio [AOR] 0.73, 95% confidence interval [CI] 0.72-0.74; 75 years or older, AOR 0.38, 95% CI 0.37-0.38; rural-dwellers, AOR 0.71, 95% CI 0.70-0.71). Veterans with heart failure had higher odds of video care use than those with hypertension only (AOR 1.05, 95% CI 1.04-1.06). CONCLUSIONS: Given lower odds of video primary care use among some patient groups, continued expansion of video care could make CVD services increasingly inequitable. These insights can inform equitable triage of patients, for example by identifying patients who may benefit from additional support to use virtual care.

SON is an essential m6A target for hematopoietic stem cell fate.

Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. m6A RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential m6A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m6A identified that m6A mRNA methylation of Son increases during HSC commitment. Upon m6A depletion, Son mRNA increases, but its protein is depleted. Reintroduction of SON rescues defects in HSC symmetric commitment divisions and engraftment. Conversely, Son deletion results in a loss of HSC fitness, while overexpression of SON improves mouse and human HSC engraftment potential by increasing quiescence. Mechanistically, we found that SON rescues MYC and suppresses the METTL3-HSC inflammatory gene expression program, including CCL5, through transcriptional regulation. Thus, our findings define a m6A-SON-CCL5 axis that controls inflammation and HSC fate.

Depression care quality among patients with solid tumor cancers detected to have depression in Veterans Health Administration primary care clinics.

Patients with cancer, especially advanced cancer, experience depression at high rates. We aimed to evaluate the quality of depression care received by patients with solid tumor cancer and advanced solid tumor cancer in Veterans Affairs (VA) primary care clinics. This is a retrospective cohort study of patients seen in 82 VA primary care clinics who newly screened positive for depression on the Patient Health Questionnaire (PHQ-2). Outcomes included timely follow-up within 84 or 180 days (3+ mental health specialty, 3+ psychotherapy, or 3+ primary care visits with depression diagnosis codes) and minimum treatment within 1 year (60+ days antidepressants prescribed, 4+ mental health specialty visits, or 3+ psychotherapy visits). 608,042 individuals were seen in VA primary care clinics during this period; 49,839 patients (8.2%) had solid tumor cancer and 9,278 (1.5%) had advanced or poor-prognosis solid tumor cancer. For 686 observations of patients with cancer and new depression, rates of appropriate follow-up were 22.3% within 84 days and 38.2% within 180 days. For 73 observations of patients with advanced or poor-prognosis cancer and new depression, rates of appropriate follow-up were 21.9% within 84 days and 34.3% within 180 days. Rates of minimum treatment within 1 year were 68.4% and 64.4% for patients with cancer and patients with advanced or poor-prognosis cancer, respectively. Quality of timely depression management is low in patients with solid tumor cancers. Even in health systems with well-integrated mental health services, care gaps remain for patients with cancer and depression. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial.

Importance: Aflibercept, 8 mg, may have greater therapeutic benefits compared with aflibercept, 2 mg, in patients with neovascular age-related macular degeneration (nAMD), including potentially improved outcomes and decreased treatment burden. Objective: To assess safety and efficacy of aflibercept, 8 mg, in patients with nAMD. Design, Setting, and Participants: The CANDELA trial was a phase 2, randomized, single-masked, open-label, 44-week clinical trial conducted in the US. Treatment-naive patients with active subfoveal choroidal neovascularization secondary to nAMD and a best-corrected visual acuity score of 78 to 24 letters (approximately 20/32 to 20/320) in the study eye were enrolled between November 2019 and November 2021. Interventions: Eligible participants were randomized 1:1 to receive 3 monthly doses of 8 mg (70 µL) or 2 mg (50 µL) of aflibercept followed by doses at weeks 20 and 32. Main Outcomes and Measures: Coprimary end points were the proportion of eyes without fluid (absence of intraretinal and subretinal fluid) in the central subfield at week 16 and safety. Results: All 106 eligible eyes were randomized to receive aflibercept, 8 mg (n = 53), or aflibercept, 2 mg (n = 53). Overall, 66 participants (62.3%) were female. The proportion of eyes without fluid in the central subfield with 8-mg vs 2-mg aflibercept was 50.9% (n = 27) vs 34.0% (n = 18) (difference, 17.0 [95% CI, -1.6 to 35.5] percentage points; P = .08) at week 16 and 39.6% (n = 21) vs 28.3% (n = 15) (difference, 11.3 [95% CI, -6.6 to 29.2] percentage points; nominal P = .22) at week 44. At week 44, mean (SE) change in central retinal thickness was -159.4 (16.4) vs -137.2 (22.8) µm with 8 mg vs 2 mg of aflibercept, respectively (least squares mean difference, -9.5 [95% CI, -51.4 to 32.4]; nominal P = .65) and mean (SE) change in best-corrected visual acuity score was +7.9 (1.5) vs +5.1 (1.5) letters (least squares mean difference, +2.8 [95% CI, -1.4 to +7.0]; nominal P = .20). No differences in safety profiles between the groups were observed. Conclusions and Relevance: Although aflibercept, 8 mg, did not achieve the primary efficacy end point at week 16 at the 2-sided significance level of 5%, the observed trends in anatomic and visual improvements over 44 weeks with aflibercept, 8 mg, indicate potential additional therapeutic benefit over aflibercept, 2 mg. No new safety signals were observed over 44 weeks. These findings support further evaluation of aflibercept, 8 mg, in pivotal trials of exudative retinal diseases including nAMD and diabetic macular edema. Trial Registration: ClinicalTrials.gov Identifier: NCT04126317.

Accuracy of Artificial Intelligence in Estimating Best-Corrected Visual Acuity From Fundus Photographs in Eyes With Diabetic Macular Edema.

Importance: Best-corrected visual acuity (BCVA) is a measure used to manage diabetic macular edema (DME), sometimes suggesting development of DME or consideration of initiating, repeating, withholding, or resuming treatment with anti-vascular endothelial growth factor. Using artificial intelligence (AI) to estimate BCVA from fundus images could help clinicians manage DME by reducing the personnel needed for refraction, the time presently required for assessing BCVA, or even the number of office visits if imaged remotely. Objective: To evaluate the potential application of AI techniques for estimating BCVA from fundus photographs with and without ancillary information. Design, Setting, and Participants: Deidentified color fundus images taken after dilation were used post hoc to train AI systems to perform regression from image to BCVA and to evaluate resultant estimation errors. Participants were patients enrolled in the VISTA randomized clinical trial through 148 weeks wherein the study eye was treated with aflibercept or laser. The data from study participants included macular images, clinical information, and BCVA scores by trained examiners following protocol refraction and VA measurement on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. Main Outcomes: Primary outcome was regression evaluated by mean absolute error (MAE); the secondary outcome included percentage of predictions within 10 letters, computed over the entire cohort as well as over subsets categorized by baseline BCVA, determined from baseline through the 148-week visit. Results: Analysis included 7185 macular color fundus images of the study and fellow eyes from 459 participants. Overall, the mean (SD) age was 62.2 (9.8) years, and 250 (54.5%) were male. The baseline BCVA score for the study eyes ranged from 73 to 24 letters (approximate Snellen equivalent 20/40 to 20/320). Using ResNet50 architecture, the MAE for the testing set (n = 641 images) was 9.66 (95% CI, 9.05-10.28); 33% of the values (95% CI, 30%-37%) were within 0 to 5 letters and 28% (95% CI, 25%-32%) within 6 to 10 letters. For BCVA of 100 letters or less but more than 80 letters (20/10 to 20/25, n = 161) and 80 letters or less but more than 55 letters (20/32 to 20/80, n = 309), the MAE was 8.84 letters (95% CI, 7.88-9.81) and 7.91 letters (95% CI, 7.28-8.53), respectively. Conclusions and Relevance: This investigation suggests AI can estimate BCVA directly from fundus photographs in patients with DME, without refraction or subjective visual acuity measurements, often within 1 to 2 lines on an ETDRS chart, supporting this AI concept if additional improvements in estimates can be achieved.

Intravitreal Nesvacumab (Anti-Angiopoietin-2) Plus Aflibercept in Neovascular AMD: Phase 2 ONYX Randomized Trial.

Purpose: To compare intravitreal nesvacumab (anti-angiopoietin-2) + aflibercept vs intravitreal aflibercept injection (IAI) in neovascular age-related macular degeneration (nAMD). Methods: Eyes were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, week 4, and week 8. The LD combo was continued every 8 weeks (q8w). At week 12, the HD combo was re-randomized to q8w or every 12 weeks (q12w) and IAI was re-randomized to q8w, q12w, or HD combo q8w through week 32. Results: The study comprised 365 eyes. At week 12, the mean best-corrected visual acuity (BCVA) gains from baseline were similar in the LD combo group, HD combo group, and IAI group (5.2 letters, 5.6 letters, and 5.4 letters, respectively); the mean central subfield thickness (CST) reductions were similar (182.2 µm, 200.0 µm, and 178.6 µm, respectively). The mean changes in BCVA and CST through week 36 were similar across groups. At week 12, complete retinal fluid resolution was observed in 49.1% (LD combo), 50.8% (HD combo), and 43.6% (IAI) of eyes; the proportions with a CST of 300 µm or less were similar across groups. Numerical trends at week 32 toward complete retinal fluid resolution with combination treatment were not maintained at week 36. Serious ocular adverse events were infrequent and comparable across groups. Conclusions: In nAMD, nesvacumab + aflibercept showed no additional BCVA or CST benefit over IAI monotherapy.

RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

Rates of Primary Care and Integrated Mental Health Telemedicine Visits Between Rural and Urban Veterans Affairs Beneficiaries Before and After the Onset of the COVID-19 Pandemic.

Importance: Telemedicine can increase access to care, but uptake has been low among people living in rural areas. The Veterans Health Administration initially encouraged telemedicine uptake in rural areas, but telemedicine expansion efforts have broadened since the COVID-19 pandemic. Objective: To examine changes over time in rural-urban differences in telemedicine use for primary care and for mental health integration services among Veterans Affairs (VA) beneficiaries. Design, Setting, and Participants: This cohort study examined 63.5 million primary care and 3.6 million mental health integration visits across 138 VA health care systems nationally from March 16, 2019, to December 15, 2021. Statistical analysis took place from December 2021 to January 2023. Exposures: Health care systems with most clinic locations designated as rural. Main Outcomes and Measures: For every system, monthly visit counts for primary care and mental health integration specialties were aggregated from 12 months before to 21 months after pandemic onset. Visits were categorized as in person or telemedicine, including video. A difference-in-difference approach was used to examine associations in visit modality by health care system rurality and pandemic onset. Regression models also adjusted for health care system size as well as relevant patient characteristics (eg, demographic characteristics, comorbidities, broadband internet access, and tablet access). Results: The study included 63 541 577 primary care visits (6 313 349 unique patients) and 3 621 653 mental health integration visits (972 578 unique patients) (6 329 124 unique patients among the cohort; mean [SD] age, 61.4 [17.1] years; 5 730 747 men [90.5%]; 1 091 241 non-Hispanic Black patients [17.2%]; and 4 198 777 non-Hispanic White patients [66.3%]). In fully adjusted models for primary care services before the pandemic, rural VA health care systems had higher proportions of telemedicine use than urban ones (34% [95% CI, 30%-38%] vs 29% [95% CI, 27%-32%]) but lower proportions of telemedicine use than urban health care systems after pandemic onset (55% [95% CI, 50%-59%] vs 60% [95% CI, 58%-62%]), signifying a 36% reduction in the odds of telemedicine use (odds ratio [OR], 0.64; 95% CI, 0.54-0.76). The rural-urban telemedicine gap was even larger for mental health integration (OR, 0.49; 95% CI, 0.35-0.67) than for primary care services. Few video visits occurred across rural and urban health care systems (unadjusted percentages: before the pandemic, 2% vs 1%; after the pandemic, 4% vs 8%). Nonetheless, there were rural-urban divides for video visits in both primary care (OR, 0.28; 95% CI, 0.19-0.40) and mental health integration services (OR, 0.34; 95% CI, 0.21-0.56). Conclusions and Relevance: This study suggests that, despite initial telemedicine gains at rural VA health care sites, the pandemic was associated with an increase in the rural-urban telemedicine divide across the VA health care system. To ensure equitable access to care, the VA health care system's coordinated telemedicine response may benefit from addressing rural disparities in structural capacity (eg, internet bandwidth) and from tailoring technology to encourage adoption among rural users.

Longitudinal Quantitative Ultrawide-field Fluorescein Angiography Dynamics in the RUBY Diabetic Macular Edema Study.

OBJECTIVE: The purpose of this study was to evaluate the longitudinal change in quantitative ultrawide-field angiographic (UWFA) parameters and correlate them with functional outcomes and spectral domain-OCT metrics. DESIGN: This study is a post hoc analysis of the phase II RUBY study: a prospective, randomized trial of patients with diabetic macular edema (DME) treated with either intravitreal aflibercept injection (IAI) or combined IAI/nesvacumab (antiangiopoietin 2 mAb). SUBJECTS: Subjects with DME that underwent UWFA across all treatment groups (n = 44). METHODS: A machine learning-enabled feature extraction system generated panretinal quantitative UWFA metrics, including leakage, ischemia, and microaneurysm (MA) burden. Zonal assessments were performed corresponding to the macula, midperiphery, and far periphery. MAIN OUTCOME MEASURES: Changes in ischemic area and index (proportion of nonperfusion in analyzable retina), leakage area and index (proportion of leakage in analyzable retina), and MA count at baseline, week 12, week 24, and week 36 were analyzed. Spectral-domain-OCT quantitative metrics, such as central subfield thickness, ellipsoid zone (EZ) integrity parameters, intraretinal fluid (IRF) volume, and subretinal fluid (SRF) volume were extracted via a machine learning-enhanced OCT feature extraction platform and analyzed. Additionally, the effect of these changes on best-corrected visual acuity (BCVA) was evaluated. RESULTS: Mean panretinal leakage index, zonal leakage area, and panretinal MA count improved significantly between baseline and week 36. Panretinal ischemic index decreased between baseline and week 36, with some aspects showing significant improvement. Mean BCVA significantly improved from baseline to week 36. There was a significant inverse correlation between change in BCVA and change in macular leakage area. A direct correlation was observed between both baseline macular leakage area and panretinal leakage index with IRF volume, SRF volume, and EZ disruption on OCT. CONCLUSIONS: Assessment of UWFA parameters demonstrates a significant improvement in panretinal leakage index, leakage area, and MA burden in eyes treated with IAI with or without nesvacumab. A numeric reduction in panretinal ischemic index and area was noted. The analysis also shows the critical association of leakage with visual and OCT features. This highlights the potential role of UWFA in disease burden assessment, with leakage parameters serving as a primary end point. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Quality of Depression Care for Veterans Affairs Primary Care Patients with Experiences of Homelessness.

BACKGROUND: Persons who experience homelessness (PEH) have high rates of depression and incur challenges accessing high-quality health care. Some Veterans Affairs (VA) facilities offer homeless-tailored primary care clinics, although such tailoring is not required, within or outside VA. Whether services tailoring enhances care for depression is unstudied. OBJECTIVE: To determine whether PEH in homeless-tailored primary care settings receive higher quality of depression care, compared to PEH in usual VA primary care. DESIGN: Retrospective cohort study of depression treatment among a regional cohort of VA primary care patients (2016-2019). PARTICIPANTS: PEH diagnosed or treated for a depressive disorder. MAIN MEASURES: The quality measures were timely follow-up care (3 + completed visits with a primary care or mental health specialist provider, or 3 + psychotherapy sessions) within 84 days of a positive PHQ-2 screen result, timely follow-up care within 180 days, and minimally appropriate treatment (4 + mental health visits, 3 + psychotherapy visits, 60 + days antidepressant) within 365 days. We applied multivariable mixed-effect logistic regressions to model differences in care quality for PEH in homeless-tailored versus usual primary care settings. KEY RESULTS: Thirteen percent of PEH with depressive disorders received homeless-tailored primary care (n = 374), compared to usual VA primary care (n = 2469). Tailored clinics served more PEH who were Black, who were non-married, and who had low income, serious mental illness, and substance use disorders. Among all PEH, 48% received timely follow-up care within 84 days of depression screening, 67% within 180 days, and 83% received minimally appropriate treatment. Quality metric attainment was higher for PEH in homeless-tailored clinics, compared to PEH in usual VA primary care: follow-up within 84 days (63% versus 46%; adjusted odds ratio [AOR] = 1.61, p = .001), follow-up within 180 days (78% versus 66%; AOR = 1.51, p = .003), and minimally appropriate treatment (89% versus 82%; AOR = 1.58, p = .004). CONCLUSIONS: Homeless-tailored primary care approaches may improve depression care for PEH.

Impact of HLA Polymorphism on the Immune Response to Bacillus Anthracis Protective Antigen in Vaccination versus Natural Infection.

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma.

To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.

Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial.

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04004208.

Examining telehealth use among primary care patients, providers, and clinics during the COVID-19 pandemic.

BACKGROUND: At the onset of COVID-19, there was a rapid expansion of telehealth (video/telephone) visits to maintain delivery of primary care (PC) services at the Veterans Health Administration (VA). This study examines patient, provider, and site-level characteristics of any virtual and video-based care in PC. METHODS: Interrupted time series (ITS) design was conducted using VA administrative/clinical, electronic healthcare data, 12-months before and 12-months after COVID-19 onset (set at March 2020) at the VA Greater Los Angeles Healthcare System (GLA), between 2019 and 2021. Patients with at least one visit to a VA PC clinic at GLA (n = 547,730 visits) were included in the analysis. The two main outcomes for this study were 1) any telehealth (versus in-person), as well as 2) video-based care (versus telephone). For the ITS analysis, segmented logistic regression on repeated monthly observations of any telehealth and video-based care was used. RESULTS: Percent telehealth and video use increased from 13.9 to 63.1%, and 0.3 to 11.3%, respectively, before to after COVID-19 onset. According to adjusted percentages, GLA community-based clinics (37.7%, versus 29.8% in hospital-based clinics, p < .001), social workers/pharmacists/dietitians (53.7%, versus 34.0% for PC clinicians, p < .001), and minority groups, non-Hispanic African Americans (36.3%) and Hispanics (34.4%, versus 35.3% for Whites, p < .001) were more likely to use telephone than video. Conversely, mental health providers (43.3%) compared to PC clinicians (15.3%), and women (for all age groups, except 75+) compared to men, were more likely to use video than telephone (all p's < .001). CONCLUSIONS: Since telehealth care provision is likely to continue after COVID-19, additional research is needed to identify which PC outpatient services are better suited for telephone (e.g., case management) versus video-based care (e.g., integrated mental health visits). Additionally, it is important to understand how all clinics can systematically increase access to both telephone- and video-based PC services, while ensuring equitable care for all patient populations.