| 1. |
- Fu, Zhongjie, et al.
(författare)
-
FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP
- 2023
-
Ingår i: Angiogenesis. - : Springer Science and Business Media LLC. - 0969-6970 .- 1573-7209. ; 26:3, s. 409-21
-
Tidskriftsartikel (refereegranskat)abstract
- Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).
|
|
| 2. |
- Klevebro, Susanna, et al.
(författare)
-
Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants
- 2024
-
Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 43:5, s. 1162-1170
-
Tidskriftsartikel (refereegranskat)abstract
- 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 inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants. Methods: A retrospective exploratory study of infants (n = 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 identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. 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 up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-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).
|
|
| 3. |
|
|
| 4. |
- Morsing, Eva, et al.
(författare)
-
Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation
- 2022
-
Ingår i: Acta Paediatrica, International Journal of Paediatrics. - : Wiley. - 0803-5253 .- 1651-2227. ; 111:6, s. 1167-1175
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. Methods: Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. Results: We studied 383 children born at a median of 23.3 (range 21.9–23.9) weeks, with a median birthweight of 565 (range 340–874) grams. Three-quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). Conclusion: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.
|
|
| 5. |
- Nilsson, Anders K., 1982, et al.
(författare)
-
Sphingolipidomics of serum in extremely preterm infants : Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity
- 2021
-
Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1866:7
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to severe ROP development.METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures.RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change.CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.
|
|
| 6. |
- Pivodic, Aldina, 1978, et al.
(författare)
-
Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity
- 2022
-
Ingår i: British Journal of Ophthalmology. - : BMJ Publishing Group Ltd. - 0007-1161 .- 1468-2079. ; 106:11, s. 1573-1580
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights.METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions.RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%.CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
|
|
| 7. |
- Pivodic, Aldina, 1978, et al.
(författare)
-
Evaluation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) in a randomised controlled trial aiming for prevention of severe ROP: A substudy of the Mega Donna Mega trial
- 2022
-
Ingår i: BMJ Open Ophthalmology. - : BMJ. - 2397-3269. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective The current grading of retinopathy of prematurity (ROP) does not sufficiently discriminate disease severity for evaluation of trial interventions. The published ROP Activity Scales (original: ROP-ActS and modified: mROP-ActS), describing increasing severity of ROP, versus the categorical variables severe ROP, stage, zone and plus disease were evaluated as discriminators of the effect of an ROP preventive treatment. Methods and analysis The Mega Donna Mega trial investigated ROP in infants born <28-week gestational age (GA), randomised to arachidonic acid (AA) and docosahexaenoic acid (DHA) supplementation or no supplementation. Of 207 infants, 86% with finalised ROP screening were included in this substudy. ROP-ActS versus standard variables were evaluated using Fisher's non-parametric permutation test, multivariable logistic and linear regression and marginal fractional response models. Results The AA:DHA group (n=84) and the control group (n=93) were well balanced. The maximum ROP-ActS measurement was numerically but not significantly lower in the AA:DHA group (mean: 4.0 (95% CI 2.9 to 5.0)) versus the control group (mean: 5.3 (95% CI 4.1 to 6.4)), p=0.11. In infants with any ROP, the corresponding scale measurements were 6.8 (95% CI 5.4 to 8.2) and 8.7 (95% CI 7.5 to 10.0), p=0.039. Longitudinal profiles of the scale were visually distinguished for the categories of sex and GA for the intervention versus control. Conclusions The preventive effect of AA:DHA supplementation versus no supplementation was better discriminated by the trial's primary outcome, severe ROP, than by ROP-ActS. The sensitivity and the linear qualities of ROP-ActS require further validations on large data sets and perhaps modifications. Trial registration number NCT03201588.
|
|
| 8. |
- Pivodic, Aldina, 1978, et al.
(författare)
-
Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics
- 2020
-
Ingår i: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 138:1, s. 21-29
-
Tidskriftsartikel (refereegranskat)abstract
- Importance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness. Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment. Design, Setting, and Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models. Main Outcomes and Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data. Conclusions and Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.
|
|
| 9. |
- Pivodic, Aldina, et al.
(författare)
-
Prognostic Value of Parenteral Nutrition Duration on Risk of Retinopathy of Prematurity
- 2023
-
Ingår i: JAMA ophthalmology. - : American Medical Association (AMA). - 2168-6165 .- 2168-6173. ; 141:8, s. 716-716
-
Tidskriftsartikel (refereegranskat)abstract
- Importance The prognostic impact of parenteral nutrition duration (PND) on retinopathy of prematurity (ROP) is not well studied. Safe prediction models can help optimize ROP screening by effectively discriminating high-risk from low-risk infants.Objective To evaluate the prognostic value of PND on ROP; to update and validate the Digital ROP (DIGIROP) 2.0 birth into prescreen and screen prediction models to include all ROP-screened infants regardless of gestational age (GA) and incorporate PND; and to compare the DIGIROP model with the Weight, IGF-1, Neonatal, and ROP (WINROP) and Postnatal Growth and ROP (G-ROP) models.Design, Setting, and Participants This retrospective study included 11 139 prematurely born infants from 2007 to 2020 from the Swedish National Registry for ROP. Extended Poisson and logistic models were applied. Data were analyzed from August 2022 to February 2023.Main Outcomes and Measures Any ROP and ROP requiring treatment were studied in relation to PND. ROP treatment was the outcome in DIGIROP models. Sensitivity, specificity, area under the receiver operating characteristic curve, and adjusted OR (aOR) with 95% CI were the main measures. Internal and external validations were performed.Results Of 11 139 screened infants, 5071 (45.5%) were girls, and the mean (SD) gestational age was 28.5 (2.4) weeks. ROP developed in 3179 infants (29%), treatment was given in 599 (5%), 7228 (65%) had PND less than 14 days, 2308 (21%) had PND for 14 days or more, and 1603 (14%) had unknown PND. PND was significantly correlated with ROP severity (Spearman r = 0.45; P < .001). Infants with 14 days or more of PND vs less than 14 days had faster progression from any ROP to ROP treatment (adjusted mean difference, −0.9 weeks; 95% CI, −1.5 to −0.3; P = .004). Infants with PND for 14 days or more vs less than 14 days had higher odds of any ROP (aOR, 1.84; 95% CI, 1.62-2.10; P < .001) and of severe ROP requiring treatment (aOR, 2.20; 95% CI, 1.73-2.80; P < .001). Among all 11 139 infants, the DIGIROP 2.0 models had 100% sensitivity (95% CI, 99.4-100). The specificity was 46.6% (95% CI, 45.6-47.5) for the prescreen model and 76.9% (95% CI, 76.1-77.7) for the screen model. G-ROP as well as the DIGIROP 2.0 prescreen and screen models showed 100% sensitivity on a validation subset (G-ROP: sensitivity, 100%; 95% CI, 93-100; DIGIROP prescreen: sensitivity, 100%; 95% CI, 93-100; DIGIROP screen: sensitivity, 100%; 95% CI, 93-100), whereas WINROP showed 89% sensitivity (95% CI, 77-96). Specificity for each prediction model was 29% (95% CI, 22-36) for G-ROP, 38% (95% CI, 32-46) for DIGIROP prescreen, 53% (95% CI, 46-60) for DIGIROP screen at 10 weeks, and 46% (95% CI, 39-53) for WINROP.Conclusion and Relevance Based on more than 11 000 ROP-screened infants born in Sweden, PND of 14 days or more corresponded to a significantly higher risk of having any ROP and receiving ROP treatment. These findings provide evidence to support consideration of using the updated DIGIROP 2.0 models instead of the WINROP or G-ROP models in the management of ROP.
|
|
| 10. |
- Pivodic, Aldina, 1978, et al.
(författare)
-
Prognostic Value of Parenteral Nutrition Duration on Risk of Retinopathy of Prematurity Development and Validation of the Revised DIGIROP Clinical Decision Support Tool
- 2023
-
Ingår i: JAMA ophthalmology. - : AMER MEDICAL ASSOC. - 2168-6165 .- 2168-6173. ; 141:8, s. 716-724
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The prognostic impact of parenteral nutrition duration (PND) on retinopathy of prematurity (ROP) is not well studied. Safe prediction models can help optimize ROP screening by effectively discriminating high-risk from low-risk infants. OBJECTIVE To evaluate the prognostic value of PND on ROP; to update and validate the Digital ROP (DIGIROP) 2.0 birth into prescreen and screen prediction models to include all ROP-screened infants regardless of gestational age (GA) and incorporate PND; and to compare the DIGIROP model with the Weight, IGF-1, Neonatal, and ROP (WINROP) and Postnatal Growth and ROP (G-ROP) models. DESIGN, SETTING, AND PARTICIPANTS This retrospective study included 11 139 prematurely born infants from 2007 to 2020 from the Swedish National Registry for ROP. Extended Poisson and logistic models were applied. Data were analyzed from August 2022 to February 2023. MAIN OUTCOMES AND MEASURES Any ROP and ROP requiring treatment were studied in relation to PND. ROP treatment was the outcome in DIGIROP models. Sensitivity, specificity, area under the receiver operating characteristic curve, and adjusted OR (aOR) with 95% CI were the main measures. Internal and external validations were performed. RESULTS Of 11 139 screened infants, 5071 (45.5%) were girls, and the mean (SD) gestational age was 28.5 (2.4) weeks. ROP developed in 3179 infants (29%), treatment was given in 599 (5%), 7228 (65%) had PND less than 14 days, 2308 (21%) had PND for 14 days or more, and 1603 (14%) had unknown PND. PND was significantly correlated with ROP severity (Spearman r = 0.45; P < .001). Infants with 14 days or more of PND vs less than 14 days had faster progression from any ROP to ROP treatment (adjusted mean difference, -0.9 weeks; 95% CI, -1.5 to -0.3; P = .004). Infants with PND for 14 days or more vs less than 14 days had higher odds of any ROP (aOR, 1.84; 95% CI, 1.62-2.10; P < .001) and of severe ROP requiring treatment (aOR, 2.20; 95% CI, 1.73-2.80; P < .001). Among all 11 139 infants, the DIGIROP 2.0 models had 100% sensitivity (95% CI, 99.4-100). The specificity was 46.6%(95% CI, 45.6-47.5) for the prescreen model and 76.9%(95% CI, 76.1-77.7) for the screen model. G-ROP as well as the DIGIROP 2.0 prescreen and screen models showed 100% sensitivity on a validation subset (G-ROP: sensitivity, 100%; 95% CI, 93-100; DIGIROP prescreen: sensitivity, 100%; 95% CI, 93-100; DIGIROP screen: sensitivity, 100%; 95% CI, 93-100), whereas WINROP showed 89% sensitivity (95% CI, 77-96). Specificity for each prediction model was 29% (95% CI, 22-36) for G-ROP, 38%(95% CI, 32-46) for DIGIROP prescreen, 53%(95% CI, 46-60) for DIGIROP screen at 10 weeks, and 46%(95% CI, 39-53) for WINROP. CONCLUSION AND RELEVANCE Based on more than 11 000 ROP-screened infants born in Sweden, PND of 14 days or more corresponded to a significantly higher risk of having any ROP and receiving ROP treatment. These findings provide evidence to support consideration of using the updated DIGIROP 2.0 models instead of the WINROP or G-ROP models in the management of ROP.
|
|
| 11. |
|
|
| 12. |
- Yanagida, Keisuke, et al.
(författare)
-
Sphingosine 1-Phosphate Receptor Signaling Establishes AP-1 Gradients to Allow for Retinal Endothelial Cell Specialization
- 2020
-
Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 52:6, s. 779-
-
Tidskriftsartikel (refereegranskat)abstract
- Transcriptional mechanisms that drive angiogenesis and organotypic vascular endothelial cell specialization are poorly understood. Here, we show that retinal endothelial sphingosine 1-phosphate receptors (S1PRs), which restrain vascular endothelial growth factor (VEGF)-induced angiogenesis, spatially restrict expression of JunB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs). Mechanistically, VEGF induces JunB expression at the sprouting vascular front while S1PR-dependent vascular endothelial (VE)-cadherin assembly suppresses JunB expression in the nascent vascular network, thus creating a gradient of this TF. Endothelial-specific JunB knockout mice showed diminished expression of neurovascular guidance genes and attenuated retinal vascular network progression. In addition, endothelial S1PR signaling is required for normal expression of b-catenin-dependent genes such as TCF/LEF1 and ZIC3 TFs, transporters, and junctional proteins. These results show that S1PR signaling restricts JunB function to the expanding vascular front, thus creating an AP-1 gradient and enabling organotypic endothelial cell specialization of the vascular network.
|
|
