Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease.

BACKGROUND: Sebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3-5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials. METHODS: We recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed. RESULTS: Analyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective. CONCLUSION: 5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the 'trough' periods before the next dosing, even with this intensive regimen.

A newborn Screening Programme for Inborn errors of metabolism in Galicia: 22 years of evaluation and follow-up.

BACKGROUND: There is a notable lack of harmonisation in newborn screening (NBS) programmes worldwide. The Galician programme for early detection of inborn errors of metabolism (IEM) was one of the first NBS programmes in Europe to incorporate mass spectrometry (July 2000). This programme currently screens for 26 IEMs in dried blood and urine samples collected 24-72 h after birth. RESULTS: In its 22-year history, this programme has analysed samples from 440,723 neonates and identified 326 cases of IEM with a prevalence of 1:1351. The most prevalent IEMs were hyperphenylalaninaemia (n = 118), followed by medium chain acyl-CoA dehydrogenase deficiency (MCADD, n = 26), galactosaemia (n = 20), and cystinurias (n = 43). Sixty-one false positives and 18 conditions related to maternal pathologies were detected. Urine samples have been identified as a useful secondary sample to reduce the rate of false positives and identify new defects. There were 5 false negatives. The overall positive value was 84.23%. The fatality rate over a median of 12.1 years of follow-up was 2.76%. The intelligence quotient of patients was normal in 95.7% of cases, and school performance was largely optimal, with pedagogic special needs assistance required in < 10% of cases. Clinical onset of disease preceded diagnosis in 4% of cases. The age at which first NBS report is performed was reduced by 4 days since 2021. CONCLUSIONS: This study highlights the benefits of collecting urine samples, reduce NBS reporting time and expanding the number of IEMs included in NBS programmes.

Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders.

Rare diseases are infrequent, but together they affect up to 6-10 % of the world's population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants' responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Morquio A Syndrome: Identification of Differential Patterns of Molecular Pathway Interactions in Bone Lesions.

Mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) is a rare autosomal recessive lysosomal storage disease (LSD) caused by deficiency of a hydrolase enzyme, N-acetylgalactosamine-6-sulfate sulfatase, and characterized clinically by mainly musculoskeletal manifestations. The mechanisms underlying bone involvement in humans are typically explored using invasive techniques such as bone biopsy, which complicates analysis in humans. We compared bone proteomes using DDA and SWATH-MS in wild-type and MPS IVA knockout mice (UNT) to obtain mechanistic information about the disease. Our findings reveal over 1000 dysregulated proteins in knockout mice, including those implicated in oxidative phosphorylation, oxidative stress (reactive oxygen species), DNA damage, and iron transport, and suggest that lactate dehydrogenase may constitute a useful prognostic and follow-up biomarker. Identifying biomarkers that reflect MPS IVA clinical course, severity, and progression have important implications for disease management.

Characterization of the plasma proteomic profile of Fabry disease: Potential sex- and clinical phenotype-specific biomarkers.

Fabry disease (FD) is a X-linked rare lysosomal storage disorder caused by deficient α-galactosidase A (α-GalA) activity. Early diagnosis and the prediction of disease course are complicated by the clinical heterogeneity of FD, as well as by the frequently inconclusive biochemical and genetic test results that do not correlate with clinical course. We sought to identify potential biomarkers of FD to better understand the underlying pathophysiology and clinical phenotypes. We compared the plasma proteomes of 50 FD patients and 50 matched healthy controls using DDA and SWATH-MS. The >30 proteins that were differentially expressed between the 2 groups included proteins implicated in processes such as inflammation, heme and haemoglobin metabolism, oxidative stress, coagulation, complement cascade, glucose and lipid metabolism, and glycocalyx formation. Stratification by sex revealed that certain proteins were differentially expressed in a sex-dependent manner. Apolipoprotein A-IV was upregulated in FD patients with complications, especially those with chronic kidney disease, and apolipoprotein C-III and fetuin-A were identified as possible markers of FD with left ventricular hypertrophy. All these proteins had a greater capacity to identify the presence of complications in FD patients than lyso-GB3, with apolipoprotein A-IV standing out as being more sensitive and effective in differentiating the presence and absence of chronic kidney disease in FD patients than renal markers such as creatinine, glomerular filtration rate and microalbuminuria. Identification of these potential biomarkers can help further our understanding of the pathophysiological processes that underlie the heterogeneous clinical manifestations associated with FD.

Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.

Background: Metabolic decompensation episodes (DEs) in Maple Syrup urine disease (MSUD) result in brain accumulation of toxic branched-chain amino acids (BCAAs) and their respective branched-chain α-keto acids that could induce neuroinflammation, disturb brain bioenergetics, and alter glutamate and glutamine synthesis. These episodes require immediate intervention to prevent irreversible neurological damage. Intravenous (IV) administration of BCAA-free solution could represent a powerful alternative for emergency treatment of decompensations. Methods: This pediatric series discusses the management of DEs in MSUD patients with IV BCAA-free solution, as an emergency treatment for DEs or as a prophylactic in cases requiring surgery. Clinical evolution, amino acid profile and adverse effects were evaluated. Results: We evaluated the use of BCAA-free solution in 5 DEs in 5 MSUD pediatric patients, all with significantly elevated plasma leucine levels at admission (699-3296 µmol/L) and in 1 episode of risk of DE due to surgery. Leucine normalization was achieved in all cases with resolution or improvement of clinical symptoms following IV BCAA-free solution. The duration of administration ranged from 3-20 days. Administration of IV BCAA-free solution at the beginning of a DE could reverse depletion of the amino acids that compete with BCAAs for the LAT1 transporter, and the observed depletion of alanine, despite IV alanine supplementation. No related adverse events were observed. Conclusions: Administration of standardized IV BCAA-free solution in emergency settings constitutes an important and safe alternative for the treatment of DEs in MSUD, especially in pediatric patients for whom oral or enteral treatment is not viable.

The Consensus Definition of Bronchopulmonary Dysplasia Is an Adequate Predictor of Lung Function at Preschool Age.

BACKGROUND: Recent attempts to refine the definition bronchopulmonary dysplasia (BPD) have based its predictive capacity on respiratory outcome in the first 2 years of life, eliminating the pre-existing requirement of 28 days of oxygen therapy prior to 36 weeks postmenstrual age (PMA). The objective of this study was to assess the utility of the 2001 consensus definition in predicting impaired lung function at preschool age. METHODS: This cohort study included children aged 4-6 years old who were born at gestational age (GA) <32 weeks or bodyweight <1500 g. Univariate and multivariate analyses were performed to assess differences in antenatal and neonatal variables between BPD and non-BPD children. All participants underwent incentive spirometry. Lung function parameters were contrasted with the Global Lung Function Initiative (GLI-2012) reference equations and, together with antenatal and neonatal variables, compared among the different subgroups (no BPD, mild BPD, and moderate-to-severe BPD). A multivariate model was generated to identify independent risk factors for impaired lung function. RESULTS: GA, hemodynamically significant patent ductus arteriosus, and late sepsis were independent risk factors for the development of BPD. A total of 119 children underwent incentive spirometry. All lung function parameters were significantly altered relative to reference values. Greater impairment of lung function was observed in the mild BPD vs. the no BPD group (forced expiratory volume in the first 0.75 seconds [FEV0.75]: -1.18 ± 0.80 vs. -0.55 ± 1.13; p = 0.010), but no difference in forced vital capacity (FVC) was observed (-0.32 ± 0.90 vs. -0.18 ± 1; p = 0.534). The moderate-to-severe BPD group exhibited the most severe FEV0.75 reduction (FEV0.75: -2.63 ± 1.18 vs. -0.72 ± 1.08; p = 0.000) and was the only condition with FVC impairment (FVC: -1.82 ± 1.12 vs. -0.22 ± 0.87; p = 0.000). The multivariate analysis identified a diagnosis of moderate-to-severe BPD as an independent risk factor for lung function impairment. CONCLUSION: The 2001 consensus definition of BPD has adequate predictive capacity for lung function measured by spirometry at 4-6 years of age. Moderate-to-severe BPD was the best predictor of respiratory impairment. Children with mild BPD showed greater alteration of FEV0.75 than those without BPD.

Plasma Proteomic Analysis in Morquio A Disease.

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal disease caused by mutations in the gene encoding the enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS), and is characterized by systemic skeletal dysplasia due to excessive storage of keratan sulfate (KS) and chondroitin-6-sulfate in chondrocytes. Although improvements in the activity of daily living and endurance tests have been achieved with enzyme replacement therapy (ERT) with recombinant human GALNS, recovery of bone lesions and bone growth in MPS IVA has not been demonstrated to date. Moreover, no correlation has been described between therapeutic efficacy and urine levels of KS, which accumulates in MPS IVA patients. The objective of this study was to assess the validity of potential biomarkers proposed by other authors and to identify new biomarkers. To identify candidate biomarkers of this disease, we analyzed plasma samples from healthy controls (n=6) and from untreated (n=8) and ERT-treated (n=5, sampled before and after treatment) MPS IVA patients using both qualitative and quantitative proteomics analyses. The qualitative proteomics approach analyzed the proteomic profile of the different study groups. In the quantitative analysis, we identified/quantified 215 proteins after comparing healthy control untreated, ERT-treated MPSIVA patients. We selected a group of proteins that were dysregulated in MPS IVA patients. We identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: fetuin-A, vitronectin, alpha-1antitrypsin, and clusterin. Further studies of cartilage and bone samples from MPS IVA patients will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

Evaluation of Body Composition, Physical Activity, and Food Intake in Patients with Inborn Errors of Intermediary Metabolism.

Children with inborn errors of intermediary metabolism (IEiM) must follow special diets that restrict their intake of essential nutrients and may compromise normal growth and development. We evaluated body composition, bone mineral density, physical activity, and food intake in IEiM patients undergoing dietary treatment. IEiM patients (n = 99) aged 5-19 years and healthy age- and sex-matched controls (n = 98) were recruited and underwent dual-energy X-ray absorptiometry to evaluate anthropometric characteristics and body composition. Data on food intake and physical activity were also collected using validated questionnaires. The height z-score was significantly lower in IEiM patients than controls (-0.28 vs. 0.15; p = 0.008), particularly in those with carbohydrate and amino acid metabolism disorders. Significant differences in adiposity were observed between patients and controls for the waist circumference z-score (-0.08 vs. -0.58; p = 0.005), but not the body mass index z-score (0.56 vs. 0.42; p = 0.279). IEiM patients had a significantly lower total bone mineral density (BMD) than controls (0.89 vs. 1.6; p = 0.001) and a higher risk of osteopenia (z-score < -2, 33.3% vs. 20.4%) and osteoporosis (z-score < -2.5, 7.1% vs. 0%), but none presented fractures. There was a significant positive correlation between natural protein intake and BMD. Our results indicate that patients with IEiM undergoing dietary treatment, especially those with amino acid and carbohydrate metabolism disorders, present alterations in body composition, including a reduced height, a tendency towards overweight and obesity, and a reduced BMD.

Human Milk Concentrations of Minerals, Essential and Toxic Trace Elements and Association with Selective Medical, Social, Demographic and Environmental Factors.

This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and infant formula (IF) and evaluate associations with medical, social, environmental, and demographic variables. A prospective, case series study of 170 nursing mothers was made. HM samples were obtained from full-term (colostrum, intermediate and mature HM) and preterm (mature HM) mothers. Variables of interest were assessed by a questionnaire. For comparison, IF samples (n = 30) were analyzed in a cross-sectional study. Concentrations of 35 minerals, essential and toxic trace elements were quantified, 5 for the first time: thallium in HM and IF; strontium in preterm HM; and gallium, lithium and uranium in IF. In preterm and full-term HM, levels of selenium (p < 0.001) were significantly lower than recommended and were associated with low birth weight (p < 0.002). Cesium and strontium concentrations were significantly higher than recommended (p < 0.001). Associations were observed between arsenic and residence in an urban area (p = 0.013), and between lead and smoking (p = 0.024) and well-water consumption (p = 0.046). In IF, aluminum, vanadium, and uranium levels were higher than in HM (p < 0.001); uranium, quantified for the first time, was 100 times higher in all types of IF than in HM. Our results indicate that concentrations of most trace elements were within internationally accepted ranges for HM and IF. However, preterm infants are at increased risk of nutritional deficiencies and toxicity. IF manufacturers should reduce the content of toxic trace elements.

Treatment adherence in tyrosinemia type 1 patients.

BACKGROUND: While therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease. RESULTS: This observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively). CONCLUSIONS: Despite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.

Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.

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).

Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA.

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls (n = 6) and from untreated (n = 5) and ERT-treated (n = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

Incidence, Treatment, and Outcome Trends of Necrotizing Enterocolitis in Preterm Infants: A Multicenter Cohort Study.

Background: Data regarding the incidence and mortality of necrotizing enterocolitis trends are scarce in the literature. Recently, some preventive strategies have been confirmed (probiotics) or increased (breastfeeding rate). This study aims to describe the trends of necrotizing enterocolitis incidence, treatment, and mortality over the last decade in Spain. Methods: Multicenter cohort study with data from the Spanish Neonatal Network-SEN1500 database. The study period comprised from January 2005 to December 2017. Preterm infants <32 weeks of gestational age at birth without major congenital malformations were included for analysis. The main study outcomes were necrotizing enterocolitis incidence, co-morbidity (bronchopulmonary dysplasia, late-onset sepsis, cystic periventricular leukomalacia, retinopathy of prematurity, acute kidney injury), mortality, and surgical/non-surgical treatment. Results: Among the 25,821 included infants, NEC incidence was 8.8% during the whole study period and remained stable when comparing 4-year subperiods. However, more cases were surgically treated (from 48.8% in 2005-2008 to 70.2% in 2015-2017, p < 0.001). Mortality improved from 36.7% in the 2005-2008 to 26.6% in 2015-2017 (p < 0.001). Breastfeeding rates improved over the studied years (24.3% to 40.5%, p < 0.001), while gestational age remained invariable (28.5 weeks, p = 0.20). Prophylactic probiotics were implemented during the study period in some units, reaching 18.6% of the patients in 2015-2017. Conclusions: The incidence of necrotizing enterocolitis remained stable despite the improvement regarding protective factors frequency. Surgical treatment became more frequent over the study period, whereas mortality decreased.

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management.

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA.

Effects of Nutritional Education Interventions on Metabolic Risk in Children and Adolescents: A Systematic Review of Controlled Trials.

Childhood obesity is a global public health issue and is linked to metabolic syndrome, which increases the risk of comorbidities such as type 2 diabetes, cardiovascular diseases and cancer. Social, economic and cultural factors influence changes in nutrition and lifestyle characterized by poorer diets and reduced physical activity. This systematic review summarizes the evidence for nutritional education interventions to improve metabolic risks in children and adolescents. Systematic searches of the databases Medline (via PubMed) and Scopus were conducted following PRISMA guidelines. The risk of bias for each study was assessed following the methodology of the Cochrane Collaboration. Ten case-controlled and randomized controlled studies testing nutritional educational interventions targeting children and adolescents from the general population were eligible for inclusion. The sample size was 3915 and the age range was 7-20 years. The duration of intervention ranged from 12 weeks to 20 years. All the studies that provided data on abdominal obesity reported differences in favour of the intervention. However, data on the effects on the remaining components of metabolic syndrome remain inconclusive. These results support the role of nutritional education interventions as a strategy to reduce central adiposity and its possible unhealthy consequences in children and adolescents.

The Impact of Postnatal Systemic Steroids on the Growth of Preterm Infants: A Multicenter Cohort Study.

Postnatal steroids, often used to prevent and treat bronchopulmonary dysplasia, may influence the growth of preterm infants, although data are scarce in the literature. This is a multicenter cohort study including surviving preterm infants <32 weeks at birth (n = 17,621) from the Spanish Neonatal Network SEN1500 database, without major congenital malformations. Linear regression models were adjusted for postnatal steroids, respiratory severity course (invasive mechanical ventilation at 28 days), progression to moderate-severe bronchopulmonary dysplasia (O2 at 36 weeks), length of stay, sex, gestational age and z-scores at birth. A subgroup analysis depending on the timing of administration, ventilation status at 28 days and moderate-severe BPD diagnosis was also performed. Overall, systemic postnatal steroids were not independently associated with poorer weight gain (0.1; 95% CI: -0.05 to 0.2 g/kg/day), linear growth (0; 95% CI: -0.03 to 0.01 cm/week) or head circumference growth (-0.01; 95% CI: -0.02 to 0 cm/week). Patients who received steroids after 28 days or who were not O2 dependent at 36 weeks after having received steroids gained more weight (0.22; 95% CI: 0.04 to 0.4 and 0.2; 95% CI: 0.004 to 0.5 g/kg/day, respectively). Globally, systemic postnatal steroids had no significant adjusted effect on postnatal growth.

Proteomic Analysis in Morquio A Cells Treated with Immobilized Enzymatic Replacement Therapy on Nanostructured Lipid Systems.

Morquio A syndrome, or mucopolysaccharidosis type IVA (MPS IVA), is a lysosomal storage disease due to mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Systemic skeletal dysplasia and the related clinical features of MPS IVA are due to disruption of cartilage and its extracellular matrix, leading to an imbalance of growth. Enzyme replacement therapy (ERT) with recombinant human GALNS, alpha elosulfase, provides a systemic treatment. However, this therapy has a limited impact on skeletal dysplasia because the infused enzyme cannot penetrate cartilage and bone. Therefore, an alternative therapeutic approach to reach the cartilage is an unmet challenge. We have developed a new drug delivery system based on a nanostructure lipid carrier with the capacity to immobilize enzymes used for ERT and to target the lysosomes. This study aimed to assess the effect of the encapsulated enzyme in this new delivery system, using in vitro proteomic technology. We found a greater internalization of the enzyme carried by nanoparticles inside the cells and an improvement of cellular protein routes previously impaired by the disease, compared with conventional ERT. This is the first qualitative and quantitative proteomic assay that demonstrates the advantages of a new delivery system to improve the MPS IVA ERT.

The Effect of Morbidity and Sex on Postnatal Growth of Very Preterm Infants: A Multicenter Cohort Study.

BACKGROUND: Extrauterine growth restriction is common in the preterm infant, and it is associated with poor neurodevelopment. Nutrition plays an important role in postnatal growth, but growth is also influenced by other factors like co-morbidity, and, also, there might be sex differences. METHODS: This is a cohort study including preterm infants < 32 weeks at birth (n = 21,825) from the Spanish Neonatal Network database. The effect of sex and morbidity (patent ductus arteriosus, bronchopulmonary dysplasia, necrotizing enterocolitis and late-onset sepsis) on weight gain as well as linear and head growth from birth to discharge/death was assessed with linear regression models adjusted by gestational age and Z-scores at birth. RESULTS: The 4 selected morbidities had an independent effect on all 6 growth parameters studied, which was greater in the case of necrotizing enterocolitis: changes in weight, length and head Z-scores were -0.60 (95% CI: -0.66 to -0.55), -0.62 (95% CI: -0.70 to -0.54) and -0.63 (95% CI: -0.71 to -0.56), respectively. Weight gain and linear growth were overall more affected than head growth. Girls lost slightly more weight Z-scores (-0.03; 95% CI: -0.06 to -0.002) than boys after adjustment by morbidity. There were no significant gender differences regarding linear and head growth velocity (cm/week), although girls lost more head Z-scores (-0.14; 95% CI: -0.18 to -0.10). CONCLUSIONS: Main co-morbidities associated with prematurity have an impact on postnatal growth. Head growth is less affected than length and weight. Girls are at slightly higher risk of postnatal weight and head restriction after adjustment by morbidity.