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OpenMC is an open source Monte Carlo neutral particle transport application that has recently been ported to GPU using the OpenMP target offloading model. We examine the performance of OpenMC at scale on the Frontier, Polaris, and Aurora supercomputers, demonstrating that performance portability has been achieved by OpenMC across all three major GPU vendors (AMD, NVIDIA, and Intel). OpenMC’s GPU performance is compared to both the traditional CPU-based version of OpenMC as well as several other state-of-the-art CPU-based Monte Carlo particle transport applications. We also provide historical context by analyzing OpenMC’s performance on several legacy GPU and CPU architectures. This work includes some of the first published results for a scientific simulation application at scale on a supercomputer featuring Intel’s Max series “Ponte Vecchio” GPUs. It is also one of the first demonstrations of a large scientific production application using the OpenMP target offloading model to achieve high performance on all three major GPU platforms.

Celeritas [1] is a new Monte Carlo (MC) detector simulation code designed for computationally intensive applications (specifically, High Lumi- nosity Large Hadron Collider (HL-LHC) simulation) on high-performance heterogeneous architectures. In the past two years Celeritas has advanced from prototyping a GPU-based single physics model in infinite medium to implementing a full set of electromagnetic (EM) physics processes in complex geometries. The current release of Celeritas, version 0.3, has incorporated full device-based navigation, an event loop in the presence of magnetic fields, and detector hit scoring. New functionality incorporates a scheduler to offload electromagnetic physics to the GPU within a Geant4-driven simulation, enabling integration of Celeritas into high energy physics (HEP) experimental frameworks such as CMSSW. On the Summit supercomputer, Celeritas performs EM physics between 6 and 32 faster using the machine’s Nvidia GPUs compared to using only CPUs. When running a multithreaded Geant4 ATLAS test beam application with full hadronic physics, using Celeritas to accelerate the EM physics results in an overall simulation speedup of 1.8–2.3× on GPU and 1.2× on CPU.

The random ray method is a recently developed neutron transport method that can be used to perform efficient full-core, general-purpose, high-fidelity 3D simulations of nuclear reactors. While Tramm et al. have so far documented the new random ray algorithm in several publications, one critical detail has not yet been published: how to best determine the volume of each source region (or cell) of the simulation. As the “true” analytical constructive solid geometry cell volumes are typically not known a priori they must be computed by the application at runtime, which is not straightforward in TRRM as different rays are used each power iteration such that the sampled volume of each cell also changes between iterations. In the present study, we analyze two different on-the-fly stochastic methods for computing the cell volumes and quantify their impacts on the accuracy of scalar flux estimates. We find that the “na¨ıve” stochastic volume estimator (which arises naturally from the derivation of the Method of Characteristics), is highly biased and can result in over 1,000 pcm error in eigenvalue. Conversely, we find that the “simulation averaged” estimator is unbiased and is therefore equivalent to the use of analytical cell volumes even when using a coarse ray density. Thus, the new simulation averaged method is a critical (and as yet undocumented) component of the TRRM algorithm, and is therefore vital information for those in the reactor physics community working to implement random ray solvers of their own.

Celeritas is a new computational transport code designed for high-performance simulation of high-energy physics detectors. This work describes some of its current capabilities and the design choices that enable the rapid development of efficient on-device physics. The abstractions that underpin the code design facilitate low-level performance tweaks that require no changes to the higher-level physics code. We evaluate a set of independent changes that together yield an almost 40% speedup over the original GPU code for a net performance increase of 220× for a single GPU over a single CPU running 8.4M tracks on a small demonstration physics app.

Whole-body and spine dual-energy X-ray absorptiometry was done in 63 patients with osteogenesis imperfecta aged 5 to 63 y, and the results were compared with OI types and collagen defects. Bone mineral content (BMC)-for-age, bone area (BA)-for-age, bone mineral density (BMD)-­for-age, and BMC-for-BA were reduced, especially in patients with OI III/IV and/or in those with a qualitative collagen defect. BA-for-height was normal. Some patients with OI I and/or a quantitative collagen defect had BMD at or above -2 z-scores. We conclude (i) that both BMC and BMD differ significantly between OI types and collagen defects, (ii) that reduced BMC-for-age in OI patients is due mainly to reduced height (“short bones”) and reduced BMC-for-BA (“light bones”), whereas BA-for-height (“bone width”) is normal, (iii) that most OI patients have lower than average BMC, but in some mildly affected patients brittleness may exist with only small reductions in BMC. [ABSTRACT FROM AUTHOR]

Markers of bone formation [C-terminal and N-terminal propeptides of procollagen I (PICP, PINP), osteocalcin and alkaline phosphatase] and bone resorption [C-terminal cross-linked telopeptide of collagen I (ICTP) and hydroxypyridinium cross-links, pyridinoline (Pyr) and deoxypyridinoline (Dpyr)] were measured in 78 osteogenesis imperfecta (OI) patients to investigate bone metabolism in vivo and relate marker concentrations to phenotype and in vitro collagen I defects, as shown by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). PICP and PINP were generally low, and the serum levels were lower in all children and adults with mild OI and a quantitative collagen defect than in patients with severe OI and a qualitative collagen I defect. ICTP, Pyr and Dpyr were generally normal or reduced, but elevated in severely affected adults with a qualitative collagen I defect. The in vivo findings correlated with in vitro results of collagen I SDS-PAGE. Bone turnover is reduced in OI children and mildly affected OI adults, whereas bone resorption is elevated in severely affected adults. These findings may prove helpful for diagnosis and decision-making regarding therapy in OI. [ABSTRACT FROM AUTHOR]

Introduction: Current literature lacks consensus on initial assessments and routine follow-up care of patients with alpha-mannosidosis (AM). A Delphi panel was conducted to generate and validate recommendations on best practices for initial assessment, routine follow-up care, and integrated care coordination of patients with AM., Methods: A modified Delphi method involving 3 rounds of online surveys was used. An independent administrator and 2 nonvoting physician co-chairs managed survey development, anonymous data collection, and analysis. A multidisciplinary panel comprising 20 physicians from 12 countries responded to 57 open-ended questions in the first survey. Round 2 consisted of 11 ranking questions and 44 voting statements. In round 3, panelists voted to validate 60 consensus statements. The panel response rate was ≥95% in all 3 rounds. Panelists used 5-point Likert scales to indicate importance (score of ≥3) or agreement (score of ≥4). Consensus was defined a priori as ≥75% agreement with ≥75% of panelists voting., Results: Consensus was reached on 60 statements, encompassing 3 key areas: initial assessments, routine follow-up care, and treatment-related follow-up. The panel agreed on the type and frequency of assessments related to genetic testing, baseline evaluations, quality of life, biochemical measures, affected body systems, treatment received, and integrated care coordination in patients with AM. Forty-nine statements reached 90% to 100% consensus, 8 statements reached 80% to 85% consensus, and 1 statement reached 75% consensus. Two statements each reached consensus on 15 baseline assessments to be conducted at the initial follow-up visit after diagnosis in pediatric and adult patients., Conclusion: This is the first Delphi study providing internationally applicable, best-practice recommendations for monitoring patients with AM that may improve their care and well-being., Competing Interests: Declaration of competing interest NG is a member of advisory boards and principal investigator for clinical trials. She received consulting fees, research funding, and/or travel reimbursement from BioMarin, Chiesi Farmaceutici S.p.A, Sanofi Genzyme, Takeda, Ultragenyx Pharmaceutical Inc., Regenxbio, JCR Pharma. BKB has received consulting fees and/or honoraria from Alexion, Aro, Astellas, Biomarin, Chiesi, Horizon, JCR Pharma, Jnana, Maze, Moderna, Orchard, Passage Bio, Sanofi, Takeda, Travere, and Ultragenyx. She has conducted clinical trials funded by Biomarin, Denali, Homology Medicines, JCR Pharma, Sangamo, Takeda and Ultragenyx. CF has served as an advisor or consultant for Horizon Therapeutics, Travere, Sanofi Genzyme, Takeda, Avrobio and Chiesi. He has received grants for clinical research from Travere, Passage Bio, REGENXBIO, Sanofi Genzyme, Takeda, JNANA, Denali, and JCR. MM is a member of an advisory board and received consulting fees from BioMarin, Chiesi Farmaceutici S.p.A, Takeda. MGC was a member of an advisory board for Chiesi Farmaceutici S.p.A. MALR does not have any competing interests relative to the subject of this work. PJ is an employee of Nicklaus Childrens Hospital. AML received consulting fees from Alexion, BioMarin, Chiesi Farmaceutici S.p.A., Sanofi Genzyme, and Shire. He has conducted clinical trials for alpha-mannosidosis funded by Chiesi Farmaceutici S.p.A. GT does not have any competing interests relative to the subject of this work. JEGO is a is a member of an advisory board and received consulting fees from Chiesi Farmaceutici S.p.A, Sanofi, Takeda and PTC. KMS is a member of advisory boards and received consulting fees, research funding, and/or travel reimbursement from BioMarin, Chiesi Farmaceutici S.p.A, Sanofi Genzyme, Takeda. CE has been a member of medical advisory boards and received honoraria from Sanofi-Genzyme, Biomarin, Takeda and Amicus Therapeutics. WAH has been an advisory board member for Beam, Zevra, Kriya, Sanofi, and Ultragenyx. RG reports honoraria, consulting fees, speaker fees, research funding, and/or travel reimbursement from Allievex, Amicus, Avrobio, Azafaros, BioMarin, Chiesi, Idorsia, Janssen, JCR, Lysogene, Novartis, Paradigm, Passage Bio, PTC, Regenxbio, Sanofi, Takeda, and Ultragenyx. SSC does not have any competing interests relative to the subject of this work. JBH received consulting fees/speaker honoraria and/or travel expenses from Chiesi Farmaceutici S.p.A., Amicus, Genzyme, and Takeda. CL has received travel grants, speakers fee, and honorarium for advisory boards from BioMarin, Chiesi, Amicus, Alexion, Sanofi, Kyowa Kirin, and Takeda. MMc has consulted and received honoraria in the past 2 years for several pharmaceutical companies including Horizon Therapeutics, Biomarin Pharmaceuticals, Eton Pharmaceuticals, Acer Therapeutics, Ultragenyx, Applied Therapeutics, Jnana Therapeutics, Alexion, and Chiesi. He has been a site PI for clinical trials sponsored by Aeglea Biotherapeutics, Reneo Pharmaceuticals, PTC Therapeutics, Homology Medicines, Horizon Therapeutics, Arcturus Therapeutics, Jnana Therapeutics, Synlogic Therapeutics, and Biomarin Pharmaceutical. FBL does not have any competing interests relative to the subject of this work. MS has received unrestricted grants and travel honoraria from Actelion, Alexion, Azafaros, BioMarin, Chiesi, DENALI, Sanofi Genzyme, Takeda, Ultragenyx, Paradigm, Orchard, and PTC Therapeutics. VRS does not have any competing interests relative to the subject of this work. NM received consulting fees/speaker honoraria and/or travel grants from Amicus, BioMarin, Lysogene, JCR, Orphazyme, Sanofi Genzyme, Takeda, and Chiesi Farmaceutici S.p.A., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gaucher disease (GD) is a lysosomal storage disorder with glucocerebroside accumulation in the macrophages. The disease is divided into three types based on neurocognitive involvement with GD1 having no involvement while the acute (GD2) and chronic (GD3) are neuronopathic. The non-neurological symptoms of GD3 are well treated with enzyme replacement therapy (ERT) which has replaced hematopoietic stem cell transplantation (HSCT). ERT is unable to prevent neurological progression as the enzyme cannot cross the blood-brain barrier. In this retrospective study, we report the general, neurocognitive, and biochemical outcomes of three siblings with GD3 after treatment with ERT or HSCT. Two were treated with HSCT (named HSCT1 and HSCT2) and one with ERT (ERT1). All patients were homozygous for the c.1448 T > C, (p.Leu483Pro) variant in the GBA1 gene associated with GD3. ERT1 experienced neurocognitive progression with development of seizures, oculomotor apraxia, perceptive hearing loss and mental retardation. HSCT1 had no neurological manifestations, while HSCT2 developed perceptive hearing loss and low IQ. Chitotriosidase concentrations were normal in plasma and cerebrospinal fluid (CSF) for HSCT1 and HSCT2, but both were markedly elevated in ERT1. We report a better neurological outcome and a normalization of chitotriosidase in the two siblings treated with HSCT compared to the ERT-treated sibling. With the advancements in HSCT over the past 25 years, we may reconsider using HSCT in GD3 to achieve a better neurological outcome and limit disease progression., Competing Interests: Declaration of competing interest All the authors have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Molybdenum cofactor deficiency classically presents in neonates with intractable seizures; however, milder cases generally present before age 2 years with developmental delays and may go undiagnosed. Early diagnosis, and safe, US Food and Drug Administration-approved substrate replacement are critical to preserve neurologic function. This article discusses 2 children who presented with late-onset molybdenum cofactor deficiency type A.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women., (© 2023 SSIEM.)

X-linked adrenoleukodystrophy (XALD) is the most common leukodystrophy. It has an estimated incidence of around 1/17.000, and a variable phenotype. Following the passage of Aidens Law, New York became the first state to implement a newborn screening for XALD in 2013. Since then, 38 American states, Taiwan, and the Netherlands have included XALD in their NBS program, and Japan and Italy have ongoing pilot studies. Screening for XALD allows for early, potentially lifesaving treatment of adrenal insufficiency and cerebral demyelination but is also a complex subject, due to our limited understanding of the natural history and lack of prognostic biomarkers. Screening protocols and algorithms vary between countries and states, and results and experiences gained so far are important for the future implementation of XALD NBS in other countries. In this review, we have examined the algorithms, methodologies, and outcomes used, as well as how common challenges are addressed in countries/states that have experience using NBS for XALD. We identified 14 peer-reviewed reports on NBS for XALD. All studies presented methods for detecting XALD at birth by NBS using a combination of mass spectrometry and ABCD1 gene sequencing. This has allowed for early surveillance of presymptomatic XALD patients, and the possibility for early detection and timely treatment of XALD manifestations. Obstacles to NBS for XALD include how to deal with variants of unknown significance, whether to screen females, and the ethical concerns of an NBS for a disease where we have limited understanding of natural history and phenotype/genotype correlation., Competing Interests: Declaration of Competing Interest Sabine Grønborg has previously served on an advisory board for Bluebird Bio. None of the other authors have competing interest statements., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary carnitine deficiency (PCD) can be lethal. Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for β-oxidation. The reported prevalence of PCD in the Faroe Islands of 1:300 is the highest in the world. The Faroese PCD patient cohort has been closely monitored and we now report results from a 10-year follow-up study of 139 PCD patients. Four patients have died of natural causes since diagnosis. There were no signs of cardiac complications related to PCD. 70.5% reported an effect of L-carnitine treatment. 33.7% reported current symptoms with fatigue and low stamina being the most common. 65.1% had experienced side effects during L-carnitine treatment. Most common side effects were fish odor, abdominal pain, and diarrhea. The overall mean L-carnitine dosage was 66.3 mg/kg/day. Free p-carnitine was similar between male and female patients on L-carnitine-18.6 and 18.8 μmol/L, respectively. L-carnitine supplementation seems to be a safe and effective treatment when suffering from PCD. PCD patients in the Faroe Islands are alive and doing well more than 10 years after diagnosis., Competing Interests: Rannvá K. Abrahamsen, Jan Rasmussen, and Allan M. Lund declare that they have no conflict of interest., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Strict metabolic control with dietary treatment during pregnancy is essential for women with phenylketonuria (PKU), as elevated levels of phenylalanine (Phe) are toxic to the developing fetus. Maternal delay in achievement of the recommended Phe level during pregnancy is associated with delayed development of the child. However, the extent to which risk is changed by later or less stringently performed dietary treatment is unclear. The aim of this study was to investigate the impact of Phe levels and time of initiation of a Phe-restricted diet in pregnant women with PKU on birth weight, head circumference and later development of their children. Birth data were obtained from the medical records of women with PKU giving birth in the period 1980-2020. Later development was investigated by interviewing the mothers about their children's development and health. We included 79 children of 41 women with PKU. The women showed good adherence with the diet and had mean blood Phe levels within target range (248 ± 62 μmol/L). The children's development was not affected by fluctuations in the women's Phe levels, that occurred especially in first trimester. Despite maternal Phe levels being within target range, 19 children (26.8%) had low birth weight below 10th percentile. This study indicates that with dietary treatment, the children are born with the same prospect for normal development and health as children born to non-PKU mothers. This is despite maternal fluctuations in the Phe levels during first trimester., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background & Aim: Preterm infants risk deficits of long-chain polyunsaturated fatty acids (LCPUFAs) that may contribute to morbidities and hamper neurodevelopment. We aimed to determine longitudinal serum fatty acid profiles in preterm infants and how the profiles are affected by enteral and parenteral lipid sources., Methods: Cohort study analyzing fatty acid data from the Mega Donna Mega study, a randomized control trial with infants born <28 weeks of gestation (n = 204) receiving standard nutrition or daily enteral lipid supplementation with arachidonic acid (AA):docosahexaenoic acid (DHA) (100:50 mg/kg/day). Infants received an intravenous lipid emulsion containing olive oil:soybean oil (4:1). Infants were followed from birth to postmenstrual age 40 weeks. Levels of 31 different fatty acids from serum phospholipids were determined by GC-MS and reported in relative (mol%) and absolute concentration (μmol l -1 ) units., Results: Higher parenteral lipid administration resulted in lower serum proportion of AA and DHA relative to other fatty acids during the first 13 weeks of life (p < 0.001 for the 25th vs the 75th percentile). The enteral AA:DHA supplement increased the target fatty acids with little impact on other fatty acids. The absolute concentration of total phospholipid fatty acids changed rapidly in the first weeks of life, peaking at day 3, median (Q1-Q3) 4452 (3645-5466) μmol l -1 , and was positively correlated to the intake of parenteral lipids. Overall, infants displayed common fatty acid trajectories over the study period. However, remarkable differences in fatty acid patterns were observed depending on whether levels were expressed in relative or absolute units. For example, the relative levels of many LCPUFAs, including DHA and AA, declined rapidly after birth while their absolute concentrations increased in the first week of life. For DHA, absolute levels were significantly higher compared to cord blood from day 1 until postnatal week 16 (p < 0.001). For AA, absolute postnatal levels were lower compared to cord blood from week 4 throughout the study period (p < 0.05)., Conclusions: Our data show that parenteral lipids aggravate the postnatal loss of LCPUFAs seen in preterm infants and that serum AA available for accretion is below that in utero. Further research is needed to establish optimal postnatal fatty acid supplementation and profiles in extremely preterm infants to promote development and long-term health., Clinical Trial Registry: ClinicalTrials.gov, identifier: NCT03201588., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2&#95;293-1insT, one deletion c.122&#95;(228 + 1&#95;229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options., (© The Author(s) 2022. Published by Oxford University Press.)

The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Introduction: Nicotinamide adenine dinucleotide (NAD) is an essential cosubstrate/coenzyme in multiple cellular redox processes and a substrate in several non-redox reactions. NADSYN1 encodes NAD synthetase 1, an enzyme in the NAD de novo synthesis pathway and the Preiss-Handler pathway, and biallelic pathogenic variants causes NAD deficiency associated with vertebral, cardiac, renal and limb defects. Szot et al. and Kortbawi et al. have reported a total of seven patients with NADSYN1 associated congenital NAD deficiency disorder with the oldest patient being seven years old., Patient Data: We present a male patient age 30 with a height of 130 cm and numerous skeletal malformations including segmentation defects of the spine, rib anomalies and unequal leg length as well as bilateral ptosis, cleft palate and asymmetric dysmorphic facial features. The patient underwent surgery for an aortic stenosis due to a bicuspid valve. No malformations of the kidneys or urinary tract were identified., Results: Trio exome sequencing revealed a homozygous missense variant in NADSYN1 c.1717G > A (p.Ala573Thr). Both parents were unaffected carriers of the variant. Analysis of NAD levels showed that the patient had a lower NAD pool compared to his unaffected siblings. The NAD pool rose approximately 25% after supplementation with nicotinamide, a NAD precursor for the salvage pathway., Conclusion: The variant was previously reported in four patients and functional analyses by Szot et al. support the pathogenicity of the variant. We report an adult patient with NADSYN1 associated congenital NAD deficiency disorder and expand the phenotypic spectrum. We also present analysis of the NAD levels before and after supplementation with nicotinamide., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Alpha-mannosidosis (AM), an autosomal recessive disorder caused by pathogenic biallelic variants in the MAN2B1 gene, leads to lysosomal alpha-mannosidase deficiency and accumulation of mannose-rich oligosaccharides. Velmanase alfa (VA), a recombinant human lysosomal alpha-mannosidase, is the first enzyme replacement therapy for non-neurological symptoms of AM. Previously, a potential relationship was identified between three MAN2B1 genotype/subcellular localization subgroups (G1, G2, and G3) and AM disease severity. In VA-treated patients with AM, it is unknown if a relationship exists between MAN2B1 genotype/subcellular localization subgroups, antidrug antibodies (ADAs), and infusion-related reactions (IRRs). This pooled analysis evaluated data from 33 VA-treated patients with AM to investigate this relationship. Overall, 10 patients were positive for ADAs, 4 of whom had treatment-emergent ADAs (G1: 3/7 [43%]; G2: 1/17 [6%]; G3: 0/9). Treatment-emergent ADA-positive patients with relatively high titers ( n  = 2; G1: 1012 U/ml and G2: 440 U/ml) experienced mild/moderate IRRs that were well-managed; patients with lower titers ( n  = 2) experienced no IRRs. Overall, changes from baseline in serum oligosaccharides and immunoglobulin G levels did not vary between ADA-positive and ADA-negative patients, suggesting a similar effect of VA treatment regardless of ADA status in most patients. Clinical outcomes (3MSCT and 6MWT) were also similar in most patients regardless of ADA status. While further studies are needed, these data suggest a relationship between MAN2B1 genotype/subcellular localization subgroups and ADA development, with G1 and G2 subgroups more likely to develop ADAs and IRRs. Regardless, this study suggests that ADAs have limited effect on the clinical impact of VA in most patients with AM., Competing Interests: Line Gutte Borgwardt has received consulting fees from Chiesi, the sponsor of the study; Ferdinando Ceravolo was an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Giulia Zardi has received consulting fees from Chiesi Farmaceutici S.p.A., the sponsor of the study; Andrea Ballabeni is an employee of Chiesi Farmaceutici S.p.A., the sponsor of the study; Allan Meldgaard Lund has received consulting fees and/or honoraria/travel support from Amicus, BioMarin, Chiesi, Sanofi Genzyme, Shire/Takeda, Recordati, and Sobi as well as grant/research support from Sanofi Genzyme and Shire/Takeda., (© 2022 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Effraimidis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are structurally related neuropeptides that are widely expressed in vertebrate tissues. The two neuropeptides are pleiotropic and have been associated with migraine pathology. Three PACAP and VIP receptors have been described: PAC1, VPAC1, and VPAC2. The localization of these receptors in relation to VIP and PACAP in migraine-relevant structures has not previously been shown in mice. In the present study, we used fluorescence immunohistochemistry, well-characterized antibodies, confocal microscopy, and three-dimensional reconstruction to visualize the distribution of PACAP, VIP, and their receptors in the basal blood vessels (circle of Willis), trigeminal ganglion, and brain stem spinal trigeminal nucleus (SP5) of the mouse CNS. We demonstrated a dense network of circularly oriented VIP fibers on the basal blood vessels. PACAP nerve fibers were fewer in numbers compared to VIP fibers and ran along the long axis of the blood vessels, colocalized with calcitonin gene-related peptide (CGRP). The nerve fibers expressing CGRP are believed to be sensorial, with neuronal somas localized in the trigeminal ganglion and PACAP was found in a subpopulation of these CGRP-neurons. Immunostaining of the receptors revealed that only the VPAC1 receptor was present in the basal blood vessels, localized on the surface cell membrane of vascular smooth muscle cells and innervated by VIP fibers. No staining was seen for the PAC1, VPAC1, or VPAC2 receptor in the trigeminal ganglion. However, distinct PAC1 immunoreactivity was found in neurons innervated by PACAP nerve terminals located in the spinal trigeminal nucleus. These findings indicate that the effect of VIP is mediated via the VPAC1 receptor in the basal arteries. The role of PACAP in cerebral arteries is less clear. The localization of PACAP in a subpopulation of CGRP-expressing neurons in the trigeminal ganglion points toward a primary sensory function although a dendritic release cannot be excluded which could stimulate the VPAC1 receptor or the PAC1 and VPAC2 receptors on immune cells in the meninges, initiating neurogenic inflammation relevant for migraine pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lund and Hannibal.)

MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome., (© 2022 SSIEM.)

Aim: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy., Method: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements., Results: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs., Interpretation: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency., What This Paper Adds: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B 6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy., (© 2021 Mac Keith Press.)

Background and Aims: Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism., Methods: The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function., Results: Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days., Conclusion: Rifaximin does not alter inflammation or metabolism in patients with AH., Competing Interests: FB and NK have received an unrestricted grant from Norgine Denmark A/S for a clinical trial (NCT01739040) conducted in the same period as the present trial (2013-2017). Activities regarding that study was without relation to the present study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: The aim of the study was to evaluate the relationships between intake of mother's own milk (MOM), compared with intake of pasteurized donor milk (DM), and postnatal growth, incidence of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD), in extremely preterm infants., Methods: Swedish population-based cohort of surviving extremely preterm infants born 2004 to 2007. Exposure to MOM and DM was investigated from birth until 32 weeks postmenstrual age (PMA) in 453 infants. Primary outcome variables were change in z-score (Δ) from birth to 32 weeks PMA for weight, length, and head circumference (HC). Secondary outcomes were incidence of ROP and BPD. Mixed models adjusting for confounders were used to investigate the association between exposures and outcomes., Results: Infants' mean gestational age (GA) was 25.4 weeks. Unadjusted, MOM (per 10 mL · kg-1 · day-1) was associated with Δweight and ΔHC with beta estimates of 0.03 z-score units (95% CI, 0.02-0.04, P < 0.001) and 0.03 z-score units (95% CI, 0.01-0.05, P = 0.003), respectively. After adjustment for predefined confounders, the association remained significant for Δweight and ΔHC. A similar pattern was found between Δweight and each 10% increase of MOM. Unadjusted, a higher intake of MOM (mL · kg-1 · day-1) was significantly associated to a lower probability of any ROP and severe ROP; however, these associations did not remain in the adjusted analyses. No associations were found between MOM (mL · kg-1 · day-1) and BPD. Moreover, no associations were found between DM and growth or morbidity outcomes., Conclusions: An increased intake of MOM, as opposed to DM (and not formula feeding), was associated with improved postnatal weight gain and HC growth from birth until 32 weeks PMA in extremely preterm infants. Interventions aiming at increasing early intake of unpasteurized MOM for extremely preterm infants should be encouraged., Competing Interests: M.D. holds the copyright to the Nutrium software. The remaining authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides., Objective: The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?., Material and Methods: 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry., Results: Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP))., Conclusion: CGMP can be a relevant supplement for the treatment of PKU., Competing Interests: Erik Jensen was the industrial supervisor for the above described PhD project, and his mandatory obligation was to contribute with inputs to study design, formulation of test diets and study manuscript according to agreements and ethical standard. However, Erik Jensen did not have the final decision about these issues and this affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. Erik Jensen has sent a written signed statement regarding this (separate file).

Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme.

Background: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1., Methods: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only)., Findings: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment., Interpretation: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy., Funding: Swedish Orphan Biovitrum (Sobi)., Competing Interests: Declaration of interests US, MLC, AMD, CdL, CD-V, AML, MSc, MSp, and RV were principal investigators in the study with institution contracts including investigator fees from Swedish Orphan Biovitrum (Sobi). AML reports travel grants from Sobi. CdL reports honoraria for consulting activity and scientific event grant from Sobi. CD-V reports honoraria for consulting activity, and research and travel grants from Nutricia, Sobi, and Medifood; and grants from Vitaflo and Sanofi Genzyme, educational courses with Orphan Europe/Recordati and Takeda, and has been an advisory board member for Promethera, Reneo Pharmaceuticals, and Ultragenix. US reports honoraria for consulting activity from Nutricia, Sobi, Reneo, Alexion, and Shire. MSc, MSp, RV, and MLC report honoraria for consulting activity from Sobi. AMD reports honoraria and travel grants from Sobi, Nutricia, and Vitaflo. ES, JS, and MR are employees and shareholders of Sobi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Lack of arachidonic acid (AA) and docosahexaenoic acid (DHA) after extremely preterm birth may contribute to preterm morbidity, including retinopathy of prematurity (ROP)., Objective: To determine whether enteral supplementation with fatty acids from birth to 40 weeks' postmenstrual age reduces ROP in extremely preterm infants., Design, Setting, and Participants: The Mega Donna Mega trial, a randomized clinical trial, was a multicenter study performed at 3 university hospitals in Sweden from December 15, 2016, to December 15, 2019. The screening pediatric ophthalmologists were masked to patient groupings. A total of 209 infants born at less than 28 weeks' gestation were tested for eligibility, and 206 infants were included. Efficacy analyses were performed on as-randomized groups on the intention-to-treat population and on the per-protocol population using as-treated groups. Statistical analyses were performed from February to April 2020., Interventions: Infants received either supplementation with an enteral oil providing AA (100 mg/kg/d) and DHA (50 mg/kg/d) (AA:DHA group) or no supplementation within 3 days after birth until 40 weeks' postmenstrual age., Main Outcomes and Measures: The primary outcome was severe ROP (stage 3 and/or type 1). The secondary outcomes were AA and DHA serum levels and rates of other complications of preterm birth., Results: A total of 101 infants (58 boys [57.4%]; mean [SD] gestational age, 25.5 [1.5] weeks) were included in the AA:DHA group, and 105 infants (59 boys [56.2%]; mean [SD] gestational age, 25.5 [1.4] weeks) were included in the control group. Treatment with AA and DHA reduced severe ROP compared with the standard of care (16 of 101 [15.8%] in the AA:DHA group vs 35 of 105 [33.3%] in the control group; adjusted relative risk, 0.50 [95% CI, 0.28-0.91]; P = .02). The AA:DHA group had significantly higher fractions of AA and DHA in serum phospholipids compared with controls (overall mean difference in AA:DHA group, 0.82 mol% [95% CI, 0.46-1.18 mol%]; P < .001; overall mean difference in control group, 0.13 mol% [95% CI, 0.01-0.24 mol%]; P = .03). There were no significant differences between the AA:DHA group and the control group in the rates of bronchopulmonary dysplasia (48 of 101 [47.5%] vs 48 of 105 [45.7%]) and of any grade of intraventricular hemorrhage (43 of 101 [42.6%] vs 42 of 105 [40.0%]). In the AA:DHA group and control group, respectively, sepsis occurred in 42 of 101 infants (41.6%) and 53 of 105 infants (50.5%), serious adverse events occurred in 26 of 101 infants (25.7%) and 26 of 105 infants (24.8%), and 16 of 101 infants (15.8%) and 13 of 106 infants (12.3%) died., Conclusions and Relevance: This study found that, compared with standard of care, enteral AA:DHA supplementation lowered the risk of severe ROP by 50% and showed overall higher serum levels of both AA and DHA. Enteral lipid supplementation with AA:DHA is a novel preventive strategy to decrease severe ROP in extremely preterm infants., Trial Registration: ClinicalTrials.gov Identifier: NCT03201588.

Purpose: Choline is an essential nutrient for fetal and infant growth and development. Parenteral nutrition used in neonatal care lack free choline but contain small amounts of lipid-bound choline in the form of phosphatidylcholine (PC). Here, we examined the longitudinal development of serum free choline and metabolically related compounds betaine and methionine in extremely preterm infants and how the concentrations were affected by the proportion of parenteral fluids the infants received during the first 28 postnatal days (PNDs)., Methods: This prospective study included 87 infants born at gestational age (GA) < 28 weeks. Infant serum samples were collected PND 1, 7, 14, and 28, and at postmenstrual age (PMA) 32, 36, and 40 weeks. The serum concentrations of free choline, betaine, and methionine were determined by 1 H NMR spectroscopy., Results: The median (25th-75th percentile) serum concentrations of free choline, betaine, and methionine were 33.7 (26.2-41.2), 71.2 (53.2-100.8), and 25.6 (16.4-35.3) µM, respectively, at PND 1. The choline concentration decreased rapidly between PND one and PND seven [18.4 (14.1-26.4) µM], and then increased over the next 90 days, though never reaching PND one levels. There was a negative correlation between a high intake of parenteral fluids and serum-free choline., Conclusion: Circulating free choline in extremely preterm infants is negatively affected by the proportion of parenteral fluids administered., Trial Registration: ClinicalTrials.gov Identifier NCT02760472, April 29, 2016, retrospectively registered.