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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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Competing Interests: The authors report no conflict of interest.

Competing Interests: Conflict of Interest A.B. is a salaried employee and holds stock options of Invitae Corporation. B.A.S. is a salaried employee of Medical Science & Computing, LLC. All other authors declare no conflicts of interest.

Neuromuscular diseases are genetically highly heterogeneous, and differential diagnosis can be challenging. Over a 3-year period, we prospectively analyzed 268 pediatric and adult patients with a suspected diagnosis of inherited neuromuscular disorder (INMD) using comprehensive gene-panel analysis and next-generation sequencing. The rate of diagnosis increased exponentially with the addition of genes to successive versions of the INMD panel, from 31% for the first iteration (278 genes) to 40% for the last (324 genes). The global mean diagnostic rate was 36% (97/268 patients), with a diagnostic turnaround time of 4-6 weeks. Most diagnoses corresponded to muscular dystrophies/myopathies (68.37%) and peripheral nerve diseases (22.45%). The most common causative genes, TTN , RYR1 , and ANO5 , accounted for almost 30% of the diagnosed cases. Finally, we evaluated the utility of the differential diagnosis tool Phenomizer, which established a correlation between the phenotype and molecular findings in 21% of the diagnosed patients. In summary, comprehensive gene-panel analysis of all genes implicated in neuromuscular diseases facilitates a rapid diagnosis and provides a high diagnostic yield.

INTRODUCTION: Precision medicine is an approach to healthcare that is modifying clinical management by leveraging technological advances in genomics that assess a patient's genetic information to identify unique predispositions. While the civilian sector is integrating genomics widely to personalize diagnosis and treatment, the military medical environment has reacted more slowly. The operational requirements of military service encourage a tailored approach for focusing military precision medicine on occupation-specific conditions. Here, we present a survey of the genomic landscape related to military aerospace medicine. METHODS: We collated observations from genome-wide association studies (GWAS) relating genetic markers to conditions that may negatively influence flight operations and for which the U.S. Air Force School of Aerospace Medicine's Aeromedical Consult Service (ACS) provides aeromedical waiver guidance. Our sources for identifying relevant literature were the GWAS Catalog, the Atlas of GWAS Summary Statistics, and PubMed/Google Scholar searches. RESULTS: Using the ACS guidance as a starting point, we found 1572 papers describing 84 clinical conditions with genetic associations. The earliest aeromedical GWAS publication was in 2006, increasing to 225 publications in 2019. We identified 42,020 polymorphisms from more than 84 million participants across the studies. CONCLUSION: Our study revealed areas where deeper investigations into how genetic markers manifest in clinical diagnosis, prevention, or risk management could lead to increased medical readiness. Additionally, our results show those clinical areas for which guidance could include genetic risk considerations. Chapleau RR, Regn DD, de Castro MJ. Surveying the genomic landscape supporting the development of precision military aerospace medicine . Aerosp Med Hum Perform. 2022; 93(2):89-93.

Pressed by the accumulating knowledge in genomics and the proven success of the translation of cancer genomics to clinical practice in oncology, the Obama administration unveiled a $215 million commitment for the Precision Medicine Initiative (PMI) in 2016, a pioneering research effort to improve health and treat disease using a new model of patient-powered research. The objectives of the initiative include more effective treatments for cancer and other diseases, creation of a voluntary national research cohort, adherence to privacy protections for maintaining data sharing and use, modernization of the regulatory framework, and forging public-private partnerships to facilitate these objectives. Specifically, the DoD Military Health System joined other agencies to execute a comprehensive effort for PMI. Of the many challenges to consider that may contribute to the implementation of genomics-lack of familiarity and understanding, poor access to genomic medicine expertise, needs for extensive informatics and infrastructure to integrate genomic results, privacy and security, and policy development to address the unique requirements of military medical practice-we will focus on the need to establish education in genomics appropriate to the provider's responsibilities. Our hypothesis is that there is a growing urgency for the development of educational experiences, formal and informal, to enable clinicians to acquire competency in genomics commensurate with their level of practice. Several educational approaches, both in practice and in development, are presented to inform decision-makers and empower military providers to pursue courses of action that respond to this need., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed.

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.

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.

New genomic sequencing techniques have shown considerable promise in the field of neonatology, increasing the diagnostic rate and reducing time to diagnosis. However, several obstacles have hindered the incorporation of this technology into routine clinical practice. We prospectively evaluated the diagnostic rate and diagnostic turnaround time achieved in newborns with suspected genetic diseases using a rapid phenotype-driven gene panel (NeoSeq) containing 1870 genes implicated in congenital malformations and neurological and metabolic disorders of early onset (<2 months of age). Of the 33 newborns recruited, a genomic diagnosis was established for 13 (39.4%) patients (median diagnostic turnaround time, 7.5 days), resulting in clinical management changes in 10 (76.9%) patients. An analysis of 12 previous prospective massive sequencing studies (whole genome (WGS), whole exome (WES), and clinical exome (CES) sequencing) in newborns admitted to neonatal intensive care units (NICUs) with suspected genetic disorders revealed a comparable median diagnostic rate (37.2%), but a higher median diagnostic turnaround time (22.3 days) than that obtained with NeoSeq. Our phenotype-driven gene panel, which is specific for genetic diseases in critically ill newborns is an affordable alternative to WGS and WES that offers comparable diagnostic efficacy, supporting its implementation as a first-tier genetic test in NICUs.

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Although dietary and, in some cases, pharmacological treatment has been successful in preventing intellectual disability in PKU patients who are treated early, suboptimal outcomes have been reported, including bone mineral disease. In this systematic review, we summarize the available evidence on bone health in PKU patients, including data on bone mineral density (BMD) and bone turnover marker data. Data from cohort and cross-sectional studies of children and adults (up to 40 years of age) were obtained by searching the MEDLINE and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For each selected study, quality assessment was performed applying the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS I) tool. We found that mean BMD was lower in PKU patients than in reference groups, but was within the normal range in most patients when expressed as Z-score values. Furthermore, data revealed a trend towards an imbalance between bone formation and bone resorption, favoring bone removal. Data on serum levels of minerals and hormones involved in bone metabolism were very heterogeneous, and the analyses were inconclusive. Clinical trials that include the analysis of fracture rates, especially in older patients, are needed to gather more evidence on the clinical implications of lower BMD in PKU patients.

Lactose intolerance (LI) is characterized by the presence of primarily gastrointestinal clinical signs resulting from colonic fermentation of lactose, the absorption of which is impaired due to a deficiency in the lactase enzyme. These clinical signs can be modified by several factors, including lactose dose, residual lactase expression, concurrent ingestion of other dietary components, gut-transit time, and enteric microbiome composition. In many of individuals with lactose malabsorption, clinical signs may be absent after consumption of normal amounts of milk or, in particular, dairy products (yogurt and cheese), which contain lactose partially digested by live bacteria. The intestinal microbiota can be modulated by biotic supplementation, which may alleviate the signs and symptoms of LI. This systematic review summarizes the available evidence on the influence of prebiotics and probiotics on lactase deficiency and LI. The literature search was conducted using the MEDLINE (via PUBMED) and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and included randomized controlled trials. For each study selected, the risk of bias was assessed following the Cochrane Collaboration methodology. Our findings showed varying degrees of efficacy but an overall positive relationship between probiotics and LI in relation to specific strains and concentrations. Limitations regarding the wide heterogeneity between the studies included in this review should be taken into account. Only one study examined the benefits of prebiotic supplementation and LI. So further clinical trials are needed in order to gather more evidence.

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.

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.

Evidence suggests a role of long chain polyunsaturated fatty acids (LC-PUFA), in which animal foods are especially rich, in optimal neural development. The LC-PUFAs docosahexaenoic acid (DHA) and arachidonic acid, found in high concentrations in the brain and retina, have potential beneficial effects on cognition, and motor and visual functions. Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. The treatment of PKU consists of a phenylalanine-free diet, which limits the intake of natural proteins of high biological value. In this systematic review, we summarize the available evidence supporting a role for LC-PUFA supplementation as an effective means of increasing LC-PUFA levels and improving visual and neurocognitive functions in PKU patients. Data from controlled trials of children and adults (up to 47 years of age) were obtained by searching the MEDLINE and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For each selected study, the risk of bias was assessed applying the methodology of the Cochrane Collaboration. The findings indicate that DHA supplementation in PKU patients from 2 weeks to 47 years of age improves DHA status and decreases visual evoked potential P100 wave latency in PKU children from 1 to 11 years old. Neurocognitive data are inconclusive.

There is a physiological basis for the roles of selected nutrients, especially proteins, calcium, and vitamin D, in growth and development, which are at a maximum during the pediatric period. Milk and dairy products are particularly rich in this group of nutrients. The present systematic review summarizes the available evidence relating dairy product intake with linear growth and bone mineral content in childhood and adolescence. A search was conducted in the MEDLINE (via PubMed) and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included intervention-controlled clinical trials with dairy products in children from 1 January, 1926 to 30 June, 2018. The risk of bias for each study was assessed using the Cochrane methodology. The number of study participants, the type of study and doses, the major outcomes, and the key results of the 13 articles included in the review are reported. The present systematic review shows that supplementing the usual diet with dairy products significantly increases bone mineral content during childhood. However, the results regarding a possible relation between dairy product consumption and linear growth are inconclusive., (Copyright © American Society for Nutrition 2019.)

Background: Genomic sequencing has become a widely used tool in clinical and research settings in both civilian and military healthcare systems., Methods: In this paper, we consider potential military-specific implications of returning genomic sequencing secondary findings to ensure the proper protections, policies, and processes are in place for the use of this information., Results: We specifically use two examples to highlight potential military implications of the return of secondary findings., Conclusion: Clinicians and researchers are strongly encouraged to consider the military implications of the return of results for informed consent of service members or their families undergoing clinical or research genomic sequencing., (© 2018 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Rationale: Hypophosphatasia (HPP) is a very rare metabolic bone disease caused by loss-of-function mutations in the ALPL gene encoding the tissue nonspecific alkaline phosphatase. The severe neonatal form is considered lethal but insights into manifestations of the disease can help to increase our knowledge of the natural history for an early initiation of treatment and improvement of survival., Patient Concerns: We report the case of a newborn in which his fetal imaging showed findings of skeletal dysplasia disorder, considering initially achondroplasia as a potential diagnosis., Diagnosis: A definitive diagnosis compatible with perinatal lethal HPP was established in the 1st days due to the presentation at birth with thoracic and pulmonary hypoplasia, bone hypomineralization, and undetectable alkaline phosphatase. The genetic analysis identified a new heterozygous c.413G>C mutation and another 1 c.473-2G>C previously described in the ALPL gene., Outcomes: The patient died on the 4th day by clinical course complicated without having started enzyme replacement therapy (ERT). Retrospectively, previous analyzes of the parents already showed both a decreased alkaline phosphatase., Lessons: This report highlights the importance of prenatal differential diagnosis of bone dysplasia with the key biochemical marker of alkaline phosphatase in the parents. Substitutive ERT administered very soon after birth, seems to change the prognosis in these patients with neonatal HPP.

Background: In patients with phenylketonuria (PKU), a low-phenylalanine (Phe) diet supplemented with low-protein foods and a Phe-free amino acid mixture favors a dietary intake rich in carbohydrates, but little is known about how these molecules are metabolized in this setting. The objective of the present study was to analyze carbohydrate metabolism in patients with hyperphenylalaninemia., Methods: We conducted a multicenter cross-sectional study to investigate biochemical markers of basal and postprandial carbohydrate metabolism in PKU patients according to age, Phe tolerance, waist circumference and body mass index (BMI), diet, tetrahydrobiopterin (BH4) supplementation, and adherence to treatment. Basal biomarkers and anthropometric parameters were also evaluated in patients with mild hyperphenylalaninemia (MHPA) and in healthy controls., Results: A total of 83 patients aged 4-52 years were studied; 68.7% had PKU and 31.3% had MHPA. 68 healthy controls of similar sex and age were also evaluated Metabolic control was adequate in 71.9% of PKU patients. Fasting glucose levels (mean 80.77 ± 8.06 mg/dL) were high in just one patient, but fasting insulin levels, with a mean of 12.74 ± 8.4 mIU/L, were altered in 15 PKU patients (26.3%) and markedly higher than in patients with MPHA (p = 0.035). Fasting insulin levels and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were significantly higher than in healthy controls and correlated with body mass index, waist circumference, age, and also showed statistically significant differences according to diagnosis and Phe tolerance (p < 0.05). Patients under BH4 therapy had lower insulin levels and HOMA-IR. A higher mean carbohydrate intake from AA mixtures was observed in classic PKU patients. The caloric intake in the form of carbohydrates was also higher in PKU than MHPA patients (p = 0.038) and it was correlated with basal insulin (rho = 0.468, p = 0.006), HOMA-IR (rho = 0.423, p = 0.02), BMI (rho 0.533, p = 0.002), and waist circumference (rho 0.584, p = 0.0007)., Conclusions: This study shows that PKU patients are at risk of carbohydrate intolerance and insulin resistance, more evident in adults and overweight patients, probably related to their higher caloric intake in form carbohydrate content. A higher dependency of AA mixtures was demonstrated in PKU patients.

Large for gestational age (LGA) newborns have an increased risk of obesity, insulin resistance, and metabolic syndrome. Acylcarnitine profiles in obese children and adults are characterized by increased levels of C3, C5, and certain medium-chain (C12) and long-chain (C14:1 and C16) acylcarnitines. C2 is also increased in insulin-resistant states. In this 1-year observational study of 2514 newborns (246 LGA newborns, 250 small for gestational age (GA) newborns, and 2018 appropriate for GA newborns), we analyzed and compared postnatal acylcarnitine profiles in LGA newborns with profiles described for obese individuals. Acylcarnitine analysis was performed by tandem mass spectrometry on dried-blood spots collected on day 3 of life. LGA newborns had higher levels of total short-chain acylcarnitines (p < 0.001), C2 (p < 0.01) and C3 (p < 0.001) acylcarnitines, and all C12, C14, and C16 acylcarnitines except C12:1. They also had a higher tendency towards carnitine insufficiency (p < 0.05) and carnitine deficiency (p < 0.001). No significant differences were observed between LGA newborns born to mothers with or without a history of gestational diabetes. This novel study describes a postnatal acylcarnitine profile in LGA with higher levels of C2, C3, total acylcarnitines, and total short-chain acylcarnitines that is characteristic of childhood and adult obesity and linked to an unhealthy metabolic phenotype.

We describe the impact genomics has on the health and readiness of the military service member, highlight several examples of the current and future plans for genomic medicine within the military, discuss challenges to implementation and provide recommendations to address some of those challenges., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background & Aims: Nutritional supplementation with polyunsaturated fatty acids is important in preterm infants neurodevelopment, but it is not known if the omega-6/omega-3 ratio affects this process. This study was designed to determine the effects of a balanced contribution of arachidonic acid in very preterm newborns fed with formula milk., Methods: This was a randomized trial, in which newborns <1500 g and/or <32 weeks gestational age were assigned to one of two groups, based on the milk formula they would receive during the first year of life. Initially, 60 newborns entered the study, but ultimately, group A was composed of 24 newborns, who were given formula milk with an ω-6/ω-3 ratio of 2/1, and Group B was composed of 21 newborns, given formula milk with an ω-6/ω-3 ratio of 1/1. The infants were followed up for two years: growth, visual-evoked potentials, brainstem auditory-evoked potentials, and plasma fatty acids were periodically measured, and psychomotor development was assessed using the Brunet Lézine scale at 24 months corrected age. A control group, for comparison of Brunet Lézine score, was made up of 25 newborns from the SEN1500 project, who were fed exclusively with breast milk., Results: At 12 months, arachidonic acid values were significantly higher in group A than in group B (6.95 ± 1.55% vs. 4.55 ± 0.78%), as were polyunsaturated fatty acids (41.02 ± 2.09% vs. 38.08 ± 2.32%) achieved a higher average. Group A achieved a higher average Brunet Lézine score at 24 months than group B (99.9 ± 9 vs. 90.8 ± 11, p =0.028). The Brunet Lézine results from group A were compared with the control group results, with very similar scores registered between the two groups (99.9 ± 9 vs. 100.5 ± 7). There were no significant differences in growth or evoked potentials between the two formula groups., Conclusions: Very preterm infants who received formula with an ω-6/ω-3 ratio of 2/1 had higher blood levels of essential fatty acids during the first year of life, and better psychomotor development, compared with very preterm newborns who consumed formula with an ω-6/ω-3 of 1/1. Therefore, formula milk with an arachidonic acid quantity double that of docosahexaenoic acid should be considered for feeding very preterm infants., Trial Registration: ClinicalTrials.gov Identifier NCT02503020.

Background: Bacille Calmette-Guerin (BCG) vaccination has been suggested to have nonspecific beneficial effects in children from developing countries, reducing morbidity and mortality caused by unrelated pathogens., Objective: We aimed to assess the heterologous protective effects of BCG vaccination against respiratory infection (RI) and sepsis not attributable to tuberculosis in children born in Spain., Methods: We conducted a retrospective epidemiological study using data from the Official Spanish Registry of Hospitalizations (CMBD-HA) to identify differences in hospitalization rates (HR) in BCG-vaccinated children (Basque Country, where neonatal BCG is part of the immunization schedule and has a 100% coverage) as compared to non-BCG-vaccinated children (from the rest of Spain, where BCG is not used)., Results: A total of 464 611 hospitalization episodes from 1992 to 2011 were analyzed. The HR due to RI not attributable to tuberculosis in BCG-vaccinated children was significant lower compared to non-BCG-vaccinated children for all age groups, with a total preventive fraction (PF) of 41.4% (95% confidence interval: 40.3-42.5; P-value <.001). According to age group, PF was 32.4% (30.9-33.9; P-value <.001) for children under 1 year old, 60.1% (58.5-61.7; P-value <.001) for children between 1 and 4 years old, 66.6% (62.8-70.2; P-value <.001) for children between 5 and 9 years old, and 69.6% (63.3-75.0; P-value <.001) for children between 10 and 14 years old. The HR due to sepsis not attributable to tuberculosis in BCG-vaccinated children under 1 year of age was also significantly lower, with a PF of 52.8% (43.8-60.7; P-value <.001)., Conclusions: BCG vaccination at birth may decrease hospitalization due to RI and sepsis not related to tuberculosis through heterologous protection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of this study was to investigate the presence of premorbid Personality Disorder (PD) and its relationship with clinical correlates in patients with Delusional Disorder (DD). Eighty-six outpatients with DD whose diagnoses were confirmed using the Structured Clinical Interview for DSM-IV Axis I (SCID-I) Disorders (psychosis module) were evaluated for premorbid PD utilizing the Standardized Assessment of Personality (SAP). Psychopathology was assessed using Module B of SCID-I and the Positive and Negative Syndrome Scale (PANSS); psychosocial functioning was evaluated with the Global Assessment of Functioning scale. Premorbid intelligence was assessed using the Wechsler Adult Intelligence Scale-Third Edition, vocabulary subtest. A sociodemographic-clinical questionnaire was completed. Sixty-four percent of the patients had at least one premorbid PD, the most common being paranoid PD (38.4%), followed by schizoid PD (12.8%). The presence of at least one premorbid PD was significantly associated with higher scores for psychopathology, in particular, on the affective dimension of DD symptoms. However, the presence of premorbid PD was not associated with psychosocial functioning. Each of the premorbid PD was associated with different psychopathological profiles. Premorbid PD is a relevant phenomenon in DD, given its high prevalence and comorbidity, its influence on clinical correlates and its potential ability to predict specific sub-syndromes., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Weight gain is an undesirable side effect of second-generation antipsychotics (SGAs). We performed this study to examine the influence of SGAs on resting energy expenditure (REE) and the relationship of REE to weight gain in adolescent patients., Methods: Antipsychotic-naïve or quasi-naïve (<72 h of exposure to antipsychotics) adolescent patients taking olanzapine, quetiapine, or risperidone in monotherapy were followed up for one year. We performed a prospective study (baseline, 1, 3, 6, and 12 months after treatment) based on anthropometric measurements, bioelectrical impedance analysis, and indirect calorimetry (Deltatrac™ II MBM-200) to measure REE. We also analyzed metabolic and hormonal data and adiponectin concentrations., Results: Forty-six out of the 54 patients that started treatment attended at least 2 visits, and 16 completed 1 year of follow-up. Patients gained 10.8 ± 6.2 kg (60% in the form of fat mass) and increased their waist circumference by 11.1 ± 5.0 cm after 1 year of treatment. The REE/kg body mass ratio decreased (p = 0.027), and the REE/percentage fat-free mass (FFM) ratio increased (p = 0.007) following the fall in the percentage of FFM during treatment. Weight increase was significantly correlated with the REE/percentage FFM ratio at all the visits (1-3-6-12 months) (r = 0.69, p = 0.004 at 12 months)., Conclusions: SGAs seem to induce a hypometabolic state (reflected as decreased REE/kg body mass and increased REE/percentage FFM). This could explain, at least in part, the changes in weight and body composition observed in these patients., (Copyright © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Antipsychotic drug discontinuation is a key risk factor in psychotic relapses. Clinical relapse is related to poor outcome, especially in the earlier stages of psychotic illness. The attitude toward treatment during the acute phase of a first episode of psychosis has been proposed as one of the main determinants of treatment discontinuation. However, the relationship between attitude toward antipsychotic medication and treatment discontinuation in the adolescent population has not been properly assessed., Methods: Adolescents, aged 12-18 years old, consecutively admitted to an adolescent unit with a first lifetime admission for a first episode of psychosis were asked to participate in a randomized, flexible-dose, 6-month controlled trial of olanzapine vs. quetiapine. Attitude toward antipsychotic medication was assessed using the 10-item Drug Attitude Inventory (DAI). The outcome variable was all-cause treatment discontinuation over the 6-month follow- up. The study sample was composed of 42 patients [34 boys (82.9%), eight girls (17.1%), mean age ± SD: 16.1±1.3]., Results: Of the 42 patients, only 29 (69%) continued the medication throughout the entire 6-month follow-up, while 13 (31%) discontinued the medication. DAI scores were greater than zero at all assessments, indicating that the general attitude of the patients toward medication was positive. Higher DAI scores at baseline were related to lower all-cause treatment discontinuation [adjusted hazard ratio (HR) = 0.81 (95% CI: 0.68-0.96), P=0.016], while DAI scores at 15 days were unrelated to treatment discontinuation [adjusted HR=1.0 (95% CI: 0.82-1.23), P=0.998]., Conclusions: A better attitude toward antipsychotic medication at a first lifetime psychiatric admission for a first early-onset psychotic episode was significantly related to lower all-cause antipsychotic treatment discontinuation., (Copyright © 2008 Sociedad Española de Psiquiatría and Sociedad Española de Psiquiatría Biológica. Published by Elsevier Espana. All rights reserved.)

Objective: To examine the diagnostic stability and the functional outcome of patients with early-onset psychosis (EOP) over a 2-year follow-up period., Methods: A total of 24 patients (18 males (75%) and 6 females (25%), mean age +/- SD: 15.7 +/- 1.6 years) with a first episode of EOP formed the sample. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Social disability was measured with the Global Assessment of Functioning (GAF) disability scale. Diagnosis was assessed using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL), according to DSM-IV criteria. All diagnoses were re-assessed after 1 year and 2 years., Results: Schizophrenia had the highest prospective consistency (100% predictive value), while diagnostic stability was moderate for bipolar disorder (71.4%), and low for schizoaffective disorder (50%), schizophreniform and brief psychosis (50%), and psychosis not otherwise specified (NOS) (16.7%). The agreement between the baseline diagnoses and the 1-year follow-up diagnoses was 54.2%, whereas between the 1-year follow-up and the 2-year follow-up, it rose to 95.7%. Regardless of diagnosis, baseline negative symptoms were the only significant predictor of level of functioning at the 2-year follow-up (p = 0.010)., Conclusion: Our results highlight the primacy of the first-year follow-up diagnosis in predicting diagnostic stability of EOP.