Retinopathy of prematurity (ROP) is a neurovascular retinal disease affecting extremely preterm infants (<28 weeks' gestational age), and links between early lipid metabolism and ROP are unclear. We investigated whether the lipid mediator sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (ApoM) are associated with ROP and parenteral nutrition in preterm infants. In this multicenter cohort, extremely preterm infants were grouped by ROP outcome: no ROP (n = 72) or any ROP (n = 105). Serum was collected at birth and longitudinally to postnatal day 100. S1P was quantified by LC-MS/MS and ApoM by proximity extension assay. Associations between first month mean parenteral fluid intake, S1P, ApoM, and ROP were analyzed using logistic regression; log-normal linear regression was applied to continuous outcomes, adjusting for gestational age and LCPUFA supplementation. Results showed that serum S1P and ApoM were positively correlated (r = 0.53, 95% confidence interval [CI] = 0.50-0.56). Higher first-month parenteral fluid intake was associated with lower S1P and ApoM (per 50 ml/kg/day increase, geometric mean ratio = 0.84, 95% CI = 0.79-0.88 for S1P; 0.97, 95% CI = 0.96-0.98 for ApoM; both P < 0.001). Higher mean S1P in the first month was associated with reduced odds of any ROP (per 0.1 μmol/l increase, adjusted odds ratio = 0.84; 95% CI = 0.71-0.99; P = 0.037). Mean ApoM was associated with ROP only in unadjusted analyses. In conclusion, low S1P and ApoM levels were linked to high parenteral fluid exposure and ROP development, suggesting that infants with high parenteral nutrition requirements may be particularly vulnerable to S1P-ApoM depletion, supporting this pathway as a potential therapeutic target.

OBJECTIVE:Investigate whether enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA), from birth to term-equivalent age (TEA), promotes brain maturation as a prespecified secondary outcome of a multicentre randomised controlled trial. PARTICIPANTS:206 infants born at 22-28 weeks gestational age (GA) were randomised into intervention or control groups from three university hospitals in Sweden. INTERVENTION:The intervention group received an oil with AA (100 mg/kg/d) and DHA (50 mg/kg/d) starting at birth until 40 weeks postmenstrual age (PMA) in addition to standard nutrition. Standard-of-care infants received standard nutrition according to national guidelines. MAIN OUTCOME AND MEASURES:MRI volumetrics were defined a priori as a secondary outcome of the trial and included total brain, white and cortical grey matter, central structures and cerebellum. Univariable and multivariable linear regression models were used for comparisons. RESULTS:MRI data in 117 infants had sufficient quality for inclusion (n=58 intervention). Birth weight, GA at birth, sex distribution, and PMA at MRI were similar in the groups. Infants receiving intervention had significantly larger white-matter volume at TEA, as compared with standard of care, in models adjusted for GA at birth, sex, study centre and PMA at MRI (β=6.8 cm3, 95% CI 0.7 to 12.9, p=0.028). The contribution of the intervention to white-matter volume corresponded to 10 days of prolonged gestation. CONCLUSION AND RELEVANCE:Our findings in this hypothesis-generating study suggest that AA+DHA promotes white matter growth, which may protect the developing brain in this vulnerable population. TRIAL REGISTRATION NUMBER:NCT03201588.

Importance:Identifying early proteomic profiles in infants who develop severe retinopathy of prematurity (ROP) may reveal targets for preventive interventions to reduce retinal vessel loss and the subsequent risk of severe ROP. Objective:To assess early longitudinal profiles of blood protein levels in preterm infants with or without severe ROP and the effect of arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation. Design, Setting, and Participants:This was an exploratory, post hoc analysis of serum proteome profiles in preterm infants in the double-masked Mega Donna Mega (MDM) randomized clinical trial using targeted Olink Proximity Extension Assay proteomics covering 538 analytes. The setting was 3 university hospitals in Sweden and included extremely preterm infants born before 28 weeks of gestational age (GA), from 2016 to 2019. Data were analyzed from January to March 2025. Exposures:All infants received standard nutrition; additionally, half received enteral lipid supplementation with AA/DHA (100/50 mg/kg per day) from birth to term equivalent age. Main Outcomes and Measures:Longitudinal protein profiles during the first month of life were examined using mixed models for repeated measures, adjusted for GA, study center, and AA/DHA supplementation, and tested for the interaction between severe ROP (stage ≥3 and/or treated) and postnatal age. Results:A total of 177 extremely preterm infants (mean [SD] GA, 25.6 [1.4] weeks; 100 male [56.5%]) were included, of whom 50 (28.2%) developed severe ROP. Of 538 longitudinal analyzed proteins, 109 protein profiles in the first month of life associated with severe ROP, proteins related to immune response, apoptotic processes, blood coagulation, and lipid metabolism. The most pronounced association with severe ROP was a fast rise in fibroblast growth factor 21 (FGF-21; β = 0.68; 95% CI, 0.39-0.97; Q =.002) and tissue plasminogen activator (tPA; β = 0.21; 95% CI, 0.13-0.29; Q <.001) during the first postnatal days. The increase in serum FGF-21 level in the first week of life was associated with lower GA, lower birth weight, low enteral energy intake, and more days receiving mechanical ventilation. No association was observed between AA/DHA supplementation and the proteome. Conclusions and Relevance:In this post hoc exploratory analysis of data from the MDM randomized clinical trial, a fast rise in FGF-21 levels, a metabolic stress-induced hormone, during the first postnatal days was strongly associated with the development of severe ROP in extremely preterm infants. These findings suggest that early interventions improving bioenergetic status may help prevent severe ROP. Trial Registration:ClinicalTrials.gov Identifier: NCT03201588.

Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.

This secondary analysis of a randomized clinical trial examines what risk factors for retinopathy of prematurity are influenced by supplementation with arachidonic acid and docosahexaenoic acid and their interactions with severe retinopathy of prematurity.

Importance:Current treatment for type 1 retinopathy of prematurity (ROP), including laser photocoagulation and intravitreal anti-vascular endothelial growth factor therapy, is invasive but necessary to prevent blindness. Experimental evidence and limited clinical experience suggest that topical steroids may reduce disease progression and the need for invasive treatment. Objective:To evaluate whether dexamethasone eye drops reduce the proportion of preterm infants with prethreshold ROP progressing to treatment-requiring type 1 ROP. Design, Setting, and Participants:The DROPROP trial was a double-masked randomized clinical trial at 6 university hospitals and 8 county hospitals in Sweden. It evaluated infants born before 30 weeks' gestational age (GA), from 2022 to 2025, with severe ROP. Data analysis was performed from November 2025 to January 2026. Exposures:Infants were randomized to receive dexamethasone eye drops (1 mg/mL) or placebo (saline). One eye drop was administered every day or every other day for up to 12 weeks. Main Outcomes and Measures:The primary outcome was progression to type 1 ROP requiring invasive treatment. Logistic regression adjusted for GA and site was used for the primary analysis. Intention-to-treat analysis was performed. Adverse events were monitored as safety outcomes. Results:Among 100 infants, the mean (SD) GA at birth was 25.1 (1.4) weeks, 42 (42.0%) were female, and the mean (SD) birth weight was 712.9 (202.1) g. In the intention-to-treat population, type 1 ROP occurred in 10 of 50 infants (20.0%) in the dexamethasone group and 19 of 50 infants (38.0%) in the placebo group (adjusted odds ratio, 0.44; 95% CI, 0.17-1.12; P = .08), corresponding to a relative risk reduction of 47%. In the per-protocol population, type 1 ROP occurred in 9 of 48 infants (18.8%) in the dexamethasone group vs 19 of 49 infants (38.8%) in the placebo group (adjusted odds ratio, 0.40; 95% CI 0.15-1.05). No clinically significant differences in adverse events were observed between groups. Conclusions and Relevance:Timely administration of topical dexamethasone numerically reduced the risk of prethreshold ROP progressing to treatment-requiring type 1 ROP. Although the analysis did not reach statistical significance, these findings suggest that topical dexamethasone may be a safe, noninvasive strategy to reduce the need for invasive treatment. Trial Registration:euclinicaltrials.eu Identifier: 2023-505318-97-00.

Importance Current treatment for type 1 retinopathy of prematurity (ROP), including laser photocoagulation and intravitreal anti–vascular endothelial growth factor therapy, is invasive but necessary to prevent blindness. Experimental evidence and limited clinical experience suggest that topical steroids may reduce disease progression and the need for invasive treatment. Objective To evaluate whether dexamethasone eye drops reduce the proportion of preterm infants with prethreshold ROP progressing to treatment-requiring type 1 ROP. Design, Setting, and Participants The DROPROP trial was a double-masked randomized clinical trial at 6 university hospitals and 8 county hospitals in Sweden. It evaluated infants born before 30 weeks’ gestational age (GA), from 2022 to 2025, with severe ROP. Data analysis was performed from November 2025 to January 2026. Exposures Infants were randomized to receive dexamethasone eye drops (1 mg/mL) or placebo (saline). One eye drop was administered every day or every other day for up to 12 weeks. Main Outcomes and Measures The primary outcome was progression to type 1 ROP requiring invasive treatment. Logistic regression adjusted for GA and site was used for the primary analysis. Intention-to-treat analysis was performed. Adverse events were monitored as safety outcomes. Results Among 100 infants, the mean (SD) GA at birth was 25.1 (1.4) weeks, 42 (42.0%) were female, and the mean (SD) birth weight was 712.9 (202.1) g. In the intention-to-treat population, type 1 ROP occurred in 10 of 50 infants (20.0%) in the dexamethasone group and 19 of 50 infants (38.0%) in the placebo group (adjusted odds ratio, 0.44; 95% CI, 0.17-1.12; P = .08), corresponding to a relative risk reduction of 47%. In the per-protocol population, type 1 ROP occurred in 9 of 48 infants (18.8%) in the dexamethasone group vs 19 of 49 infants (38.8%) in the placebo group (adjusted odds ratio, 0.40; 95% CI 0.15-1.05). No clinically significant differences in adverse events were observed between groups. Conclusions and Relevance Timely administration of topical dexamethasone numerically reduced the risk of prethreshold ROP progressing to treatment-requiring type 1 ROP. Although the analysis did not reach statistical significance, these findings suggest that topical dexamethasone may be a safe, noninvasive strategy to reduce the need for invasive treatment. Trial Registration euclinicaltrials.eu Identifier: 2023-505318-97-00

Oxidative stress is proposed to be a driver of age-related diseases. Age-related macular degeneration (AMD) is one such disease, where the retinal pigment epithelium (RPE) is affected early in the disease. Vasculature damage also occurs, sometimes preceding RPE damage. To model some aspects of dry AMD, we used the NaIO3 mouse model of oxidative damage. Disruption of the deep retinal vascular plexus, disorganization and death of capillaries within the choriocapillaris, and marked electroretinographic decline were observed. Adeno-associated virus (AAV) overexpressing the transcription factor, NRF2, which induces antioxidation enzymes and represses inflammation, was tested for protection of damage. The BEST1 promoter limited expression to the RPE. The RPE, photoreceptors, and vascular architecture in both retinal and choroidal compartments were protected. Conditioned medium from RPE-choroid explants, infected by AAV8/BEST1-NRF2, was sufficient to transfer partial protection in vivo, suggesting that NRF2 induces a protective secreted factor(s). Analysis of RNA-seq data nominated growth differentiation factor 15 (GDF15) as a candidate secreted mediator. Injection of recombinant GDF15 reproduced key protective phenotypes in vivo, whereas Gdf15 deficiency attenuated NRF2-mediated rescue. Pharmacologic inhibition of TGF-β receptor signaling diminished NRF2-induced protection, supporting involvement of this signaling pathway. In a laser-induced choroidal neovascularization model, intravitreal GDF15 injection reduced fluorescein leakage and lesion size. These findings support a model in which NRF2 activation in the RPE induces expression of GDF15, which is capable of protecting the RPE, photoreceptors, and the retinal and choroidal vasculature. NRF2 and GDF15 have therapeutic potential for ocular diseases, as well as for other diseases with vascular pathology.

As the survival rate of preterm infants continues to rise worldwide, more infants are at risk of developing sight-threatening retinopathy of prematurity (ROP). Destructive retinal laser treatment and intravitreal injections of anti-vascular endothelial growth factor (VEGF), factor, which have potential systemic side effects, are necessary to prevent blindness in severe cases of ROP. Off-label use in clinical settings suggests that dexamethasone eye drops, 1 mg/ml, may prevent the progression of ROP to severe disease (Type 1 ROP) requiring treatment. Our current study aims to assess the efficacy and safety of timely administered dexamethasone eye drops to reduce the need for laser or anti-VEGF ROP treatment in preterm infants. In a randomized prospective interventional, multi-centre, double-blinded trial, we plan to include 100 infants with severe ROP born before gestational age 30 weeks in Sweden. Infants will be randomized to intervention with dexamethasone eye drops (1 mg/ml) (n = 50) or placebo, saline (n = 50) until either ROP is resolved or severe ROP (Type 1 ROP) development occurs, fulfilling ROP treatment criteria. Eye drops will be administered one drop per day or every other day, depending on the severity of ROP, with a maximum duration of 12 weeks. The primary objective is to evaluate whether dexamethasone intervention reduces the proportion of infants developing Type 1 ROP compared to infants receiving a placebo. Adverse events and potential side effects will be recorded, such as high intraocular pressure and growth restriction. Levels of cortisol in saliva and glucose in urine will be measured repeatedly. Secondary outcomes will include the timing of ROP progression, the recurrence rate after ROP treatment and retinal morphology. An ophthalmological follow-up will be initiated at 2 and 5.5 years of age, evaluating visual acuity, refractive errors, strabismus, retinal morphology and ophthalmological complications. All outcomes in the study will be compared between the infants receiving dexamethasone intervention and those receiving placebo. Timely administration of dexamethasone eye drops may prevent severe ROP from progressing to Type 1 ROP, which requires treatment. This study aims to assess the efficacy and safety of dexamethasone intervention to support its clinical use and national guidelines. EudraCT, 2020–004933-19, registered in January 2021 and CTIS, 2023–505318-97–00, registered in August 2023. Not applicable.

Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration, a leading cause of irreversible vision loss in the elderly. While immune dysregulation and myeloid cell activation have been implicated in CNV pathogenesis, the molecular mechanisms by which myeloid subsets influence NV remain incompletely understood. Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor enriched in microglia and tissue macrophages, known to play protective roles in retinal and neurodegenerative diseases. However, its function in CNV has not been fully characterized. In this study, we investigated the role of TREM2 in CNV using transcriptomic, genetic, and functional approaches. Single-cell RNA sequencing revealed selective upregulation of Trem2 in activated microglia and macrophages following laser-induced CNV. These findings were validated at the protein level using immunostaining, which confirmed robust TREM2 expression in lesion-associated IBA1+ myeloid cells. Functionally, Trem2 haploinsufficiency exacerbated CNV lesion size and vascular leakage, indicating a protective role in disease modulation. Transcriptomic profiling demonstrated that Trem2-expressing myeloid cells exhibit distinct angiogenic and inflammasome-related gene signatures, suggesting that TREM2 regulates angiogenesis through modulation of inflammatory pathways. We further examined the functional interaction between TREM2 and suppressor of cytokine signaling 3 (SOCS3), another anti-inflammatory mediator upregulated during CNV. Using compound mutant mice, we showed that Trem2 and SOCS3 function through overlapping but independent anti-angiogenic programs, and their combined deficiency leads to additive worsening of CNV pathology. These findings establish TREM2 as a key regulator of myeloid cell function and angiogenesis in the diseased retina.

BACKGROUND:Mononuclear phagocytes contribute to pathological angiogenesis in age-related macular degeneration, a leading worldwide cause of visual impairment. However, the mechanisms that orchestrate the functions of mononuclear phagocytes remain poorly understood. TREM2 (triggering receptor on myeloid cells 2) has been shown to be crucial for the activation of mononuclear phagocytes in atherosclerosis, fatty liver disease, and Alzheimer disease. The objective of this study was to investigate the role of TREM2 in pathological angiogenesis in age-related macular degeneration. METHODS:C57BL/6J and Trem2 knockout mice were subjected to laser-induced choroidal neovascularization, a model of choroidal neovascular age-related macular degeneration. Purified bovine sulfatide and agonist anti-TREM2 antibody was used to activate TREM2 signaling. The expression of TREM2 or downstream signals were assessed with immunohistochemistry or real-time quantitative PCR. In vitro murine macrophage RAW264.7 cells were used to investigate the direct impact of sulfatide on inflammatory and phagocytic responses. RESULTS:We found that pharmacological activation of TREM2 suppressed laser-induced choroidal neovessel formation. The activation of TREM2 in mononuclear phagocytes suppressed TNF (tumor necrosis factor) and subsequently promoted phagocytosis. CONCLUSIONS:These findings demonstrate that activation of TREM2 in mononuclear phagocytes suppresses the proinflammatory response, promotes phagocytosis, and impedes choroidal neovessel formation. Our study provides insight into the critical role of TREM2 in pathological angiogenesis.

Neovascular age-related macular degeneration (nAMD) is a major cause of vision loss worldwide. Current standard of care is repetitive intraocular injections of vascular endothelial growth factor (VEGF) inhibitors, although responses may be partial and non-durable. We report that circulating sphingosine 1-phosphate (S1P) carried by apolipoprotein M (ApoM) acts through the endothelial S1P receptor 1 (S1PR1) to suppress choroidal neovascularization (CNV) in mouse laser-induced CNV, modeling nAMD. In humans, low plasma ApoM levels were associated with increased choroidal and retinal pathology. Additionally, endothelial S1pr1 knockout and overexpressing transgenic mice showed increased and reduced CNV lesion size, respectively. Systemic administration of ApoM-Fc, an engineered S1P chaperone protein, not only attenuated CNV to an equivalent degree as anti-VEGF antibody treatment but also suppressed pathological vascular leakage. We suggest that modulating circulating ApoM-bound S1P action on endothelial S1PR1 provides a novel therapeutic strategy to treat nAMD.

Retinopathy of prematurity (ROP) with early vessel loss (Phase I) followed by uncontrolled vessel growth (Phase II) causes visual impairment in premature infants. Although supplementation with omega-3 (n-3) docosahexaenoic acid (DHA) alone shows mixed results in preventing ROP, supplementation with both n-3 DHA and n-6 arachidonic acid (ARA) in early postnatal life reduces severe ROP by 50 % (Mega Donna Mega study). In the Mega Donna Mega study, 146 (72.6 %) of 201 included infants had at least one hyperglycemic episode during the first 14 days of life, which is a strong ROP risk factor. We therefore evaluated the protective effects and mechanisms of combined dietary n-3 DHA and n-6 ARA in a neonatal mouse model of hyperglycemia-induced suppression of retinal vascular development (Phase I ROP). At postnatal day (P) 10, retinal vessel growth was improved in pups from mothers on diets enriched with 1 % DHA + 2 % ARA vs. 3 % DHA. Lipid changes in pup plasma and RPE complex (retinal pigment epithelium with choroid and sclera) were in accordance with maternal diets' DHA and ARA levels, indicating that milk lipids reflected maternal diets. Proteomic retinal analysis revealed increased abundances of proteins related to mitochondrial respiration and glucose metabolism with the combined diet. Inhibition of mitochondrial ATP synthase negated the protective effects of the combined diet. In conclusion, combined DHA+ARA oral maternal supplementation protects against hyperglycemia-induced retinopathy in mouse neonates (Phase I ROP model) through enhanced retinal metabolism, suggesting the potential of balanced lipid supplementation for ROP prevention.

Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological neovessels to a physiological phenotype, hastening vascular regeneration of the ischemic retina and improving vision. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.

PURPOSE:To describe the refractive outcomes and best-corrected visual acuity (BCVA) for pediatric patients with Marfan syndrome. METHODS:The medical records of patients with Marfan syndrome seen at a pediatric tertiary care center between 2015 and 2023 were reviewed retrospectively. Patients >21 years of age at presentation or with follow-up <6 months were excluded. Eyes were grouped based on lens and refractive status at last follow-up: (A) no subluxation, (B) subluxation with phakic refraction, (C) subluxation with aphakic refraction or aphakia following lensectomy, and (D) pseudophakia. RESULTS:A total of 210 eyes of 105 patients were included: group A, 59 (28.1%); group B, 77 (36.7%); group C, 43 (20.5%); and group D, 31 (14.7%). Fifty-five patients were male (52.4%). Mean age at initial visit was 5.4 ± 4.5 years, and mean follow-up was 9.0 ± 5.5 years. Groups differed in the proportion of eyes with BCVA worse than 20/40 (A, 1 [1.7%]; B, 7 [9.6%]; C, 9 [20.9%]; D, 1 [3.2%]; P = 0.005) and in mean spherical equivalent (A, -2.1 ± 3.0 D; B, -6.1 ± 6.5 D; C, +10.0 ± 4.1 D; D, -0.7 ± 1.8 D; P < 0.001) at final examination. The most common cause for vision worse than 20/40 was amblyopia. Major postoperative complications included retinal detachment in 3 (1.4%) eyes and glaucoma in 3 (1.4%) eyes. CONCLUSIONS:Lens subluxation requires precise refraction measurements and some patients may benefit from aphakic correction. Pseudophakic eyes often demonstrate low residual refractive error and BCVA comparable to phakic eyes without lens subluxation.

ABSTRACT Introduction Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness. We investigated the association of early postnatal low-dose intravenous hydrocortisone used for the prevention of bronchopulmonary dysplasia (BPD) with ROP-outcome among extremely preterm infants in a Swedish cohort. Methods This retrospective cohort study included extremely preterm infants born before 28 weeks of gestational age (GA). Infants born September 2020 - August 2022, treated with low-dose intravenous hydrocortisone for prevention of BPD, were compared to untreated controls born September 2016 - August 2020. Hydrocortisone was administered postnatally with a dose of 0.5 mg/kg twice daily for seven days, followed by 0.5 mg/kg per day for three days. Logistic regression, adjusted for GA, birth weight (BW), sex, and parenteral nutrition, was used in the primary analysis. For robustness we performed 1:1 propensity score (PS) matching followed by logistic regression. Results Of 245 preterm infants included, 65 were treated with low-dose hydrocortisone and 180 were untreated controls. Incidence of ROP treatment was reduced in the hydrocortisone group 18.5% (12/65) versus controls 32.2% (58 /180), p=0.038. One-to-one PS-matching (n= 62+62) confirmed the reduced incidence of ROP treatment in the hydrocortisone-treated infants (OR 0.38, 95% CI 0.16 - 0.88, p=0.025). After adjusting for GA, BW, sex, and parenteral nutrition ≥14 days the reduced risk of ROP treatment after early hydrocortisone treatment persisted (OR 0.31, 95% CI 0.16 - 0.60, p=0.0005). Conclusion Early postnatal low-dose intravenous hydrocortisone used to prevent BPD may reduce the risk of ROP treatment among extremely preterm infants.

Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.

Background & aim: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on in flammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and in flammation-related proteins during the neonatal period in extremely preterm infants. Methods: A retrospective exploratory study of infants (n 1 / 4 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center. Results: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identi fied 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to in flammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to upand down-regulation of the preterm neonate in flammatory proteome. Primary examples of this were the in flammation-modulating cytokines IL -6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period. Conclusions: This study supports postnatal non -antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population. Clinical registration number: ClinicalTrials.gov (NCT03201588). (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Aim: To investigate the association between retinopathy of prematurity and autism spectrum disorder in extremely preterm children. Methods: Data in children born extremely preterm at <28 weeks' gestational age in the Region Vastra Gotaland, 2013-2017, were analysed for association between retinopathy of prematurity and neurodevelopmental disorders. We focussed on autism spectrum disorder and excluded children with perinatal brain injuries or genetic disorders. Results: Of 266 children with neurodevelopmental evaluation, 143 had no documented brain injury or genetic disorders. Of these 143, autism spectrum disorder was diagnosed in 18%, attention deficit hyperactivity disorder in 15% and intellectual disability in 7%. Of the 72/143 children with a history of no or mild retinopathy of prematurity (stage <1), 10% were diagnosed with autism spectrum disorder compared to 27% of 71/143 with prior moderate-to-severe retinopathy of prematurity (stages >= 2), (p = 0.008). A history of retinopathy of prematurity stages >= 2 was associated with a threefold increased likelihood of later autism spectrum disorder even when adjusting for gestational age and sex (p = 0.011). Conclusion: Moderate-to-severe retinopathy of prematurity associated with a higher likelihood of later autism spectrum disorder diagnosis in extremely preterm children without documented brain injuries or genetic disorders.

Background Two risk factors for severe retinopathy of prematurity (ROP) in extremely preterm infants are thrombocytopenia and low levels of arachidonic acid (AA) and docosahexaenoic acid (DHA). To date, these risk factors have not been linked. Method Infants born < 28 weeks gestational age (GA) from 2016 to 2019 were randomized to postnatal enteral AA/DHA supplementation or standard care (controls). Levels of AA and DHA, platelet counts ( < 100 x 109/L defined as thrombocytopenia) and platelet-related proteins in the infants' first four weeks of life were evaluated for their association with severe ROP. Results The mean birthweight of 178 included infants was 806 +/- 200 grams, and the mean GA was 25.6 +/- 1.4 weeks. During the first four postnatal weeks, 20.2% of AA/DHA-supplemented infants had thrombocytopenia versus 27.7% of controls (p = 0.29). In infants with thrombocytopenia, fewer AA/DHA-supplemented infants developed severe ROP than non-supplemented controls, 29.4% (5/17) versus 65.4% (17/26) (p = 0.031). Thrombocytopenia and serum levels of AA and DHA correlated with several platelet-related proteins involved in angiogenesis and ROP, such as platelet-derived growth factor subunits A and B and vascular endothelial growth factor. Conclusions AA and DHA supplementation is associated with less severe ROP in thrombocytopenic infants, possibly by modulating platelet activation and function. Impact Postnatal enteral supplementation with arachidonic acid (AA) and docosahexaenoic acid (DHA) to extremely preterm infants reduces the risk of severe retinopathy of prematurity (ROP) in infants with thrombocytopenia. The impact of AA and DHA might be, at least in part, mediated through altered platelet activation. We found that AA and DHA may reduce the risk of severe ROP, possibly by modulating platelet-related proteins involved in angiogenesis. Our findings strongly support that supplementing AA and DHA to extremely preterm infants is crucial and can significantly impact their health.