Infant mortality in Brazil attributable to inborn errors of metabolism associated with sudden death: a time-series study (2002-2014).

BACKGROUND: The literature suggests that 0.9 to 6% of infants who die unexpectedly may have had a metabolic disorder. At least 43 different inborn errors of metabolism (IEMs) have been associated with sudden death (SUDI). To date, the frequency of IEM-associated SUDI has not been studied in Brazil. The present study sought to characterize infant mortality related to IEMs known to cause SUDI disaggregated by each of the regions of Brazil. METHODS: This was a descriptive, cross-sectional, population-based study of data obtained from the Brazilian Ministry of Health Mortality Information System (SIM). Death records were obtained for all infants (age < 1 year) who died in Brazil in 2002-2014 in whom the underlying cause of death was listed as ICD-10 codes E70 (Disorders of aromatic amino-acid metabolism), E71 (Disorders of branched-chain amino-acid metabolism and fatty-acid metabolism), E72 (Other disorders of amino-acid metabolism), or E74 (Other disorders of carbohydrate metabolism), which are known to be associated with SUDI. RESULTS: From 2002 to 2014, 199 deaths of infants aged < 1 year were recorded in the SIM with an underlying cause corresponding to one of the IEMs of interest. The prevalence of IEM-related deaths was 0.67 per 10,000 live births (0.58-0.77). Of these 199 deaths, 18 (9.0%) occurred in the North of Brazil, 43 (21.6%) in the Northeast, 80 (40.2%) in the Southeast, 46 (23.1%) in the South, and 12 (6.0%) in the Center-West region. Across all regions of the country, ICD10-E74 was predominant. CONCLUSIONS: This 13-year time-series study provides the first analysis of the number of infant deaths in Brazil attributable to IEMs known to be associated with sudden death.

Universal newborn screening: A roadmap for action.

Newborn screening (NBS) prevents morbidity and mortality by screening babies for selected disorders in the first days of life so that early diagnosis and treatment can be initiated. Congenital disorders impact an estimated 8 million or 6% of annual births worldwide, and of the top five that contribute 25% to the global burden of these disorders, three can be identified and managed by NBS. There are determined pockets of activity in Latin America, Sub-Saharan Africa, and the Asia Pacific region, where partnerships among government, non-governmental organizations, academia, the private sector and civil society are developing novel NBS programs that are both saving lives and preventing disability in those who survive.

A randomized, controlled clinical trial to evaluate the immunogenicity of a PreS/S hepatitis B vaccine Sci-B-Vac™, as compared to Engerix B®, among vaccine naïve and vaccine non-responder dialysis patients.

BACKGROUND: Dialysis patients have a suboptimal response to hepatitis B (HBV) vaccination. This study aimed to compare the immunogenicity of two vaccines: the third-generation Sci-B-Vac™ vs. the second-generation Engerix B®. The cohort included two groups of dialysis patients: naïve and previously vaccinated non-responders. Primary endpoints were antibody titers ≥10 IU/L at 3 and 7 month post-vaccination. Secondary objectives were seroprotection rates in vaccine-naïve patients and in previously vaccinated non-responders. METHODS: Eighty-six patients were assigned to vaccine (Sci-B-Vac™ or Engerix B®) using computer-generated randomization, stratified by age, gender, diabetes, and previous HBV vaccination. Sci-B-Vac™ was administered in three doses, 10 µg, at 0, 1, and 6 months in naïve patients; or 20 µg in previously vaccinated non-responders. Engerix B® included four doses, 40 µg at 0, 1, 2, and 6 months. RESULTS: Each group had 43 patients. Seroconversion was 69.8% with Engerix B® vs. 73.2% with Sci-B-Vac™. Antibody titers at 7 months were higher with Sci-B-Vac™ (266.4 ± 383.9, median 53.4) than with Engerix® (193.2 ± 328.9, median 19). However, these differences were not significant, perhaps due to a suboptimal sample size. CONCLUSIONS: This study suggests comparable immunogenicity for both vaccines. Thus, we cannot reject the null hypothesis that there is no difference in seroconversion by vaccine type. It is noteworthy that naïve patients were vaccinated with a standard dose of Sci-B-Vac™, while Engerix B® was administered at a double dose. Similarly, although mean antibody titer levels in the Sci-B-Vac™ group were higher than in the Engerix® group, this difference did not reach significance. Consequently, a future clinical trial should recruit a larger cohort of patients, using a standard double-dose protocol in both groups.

Enhancing noise-induced switching times in systems with distributed delays.

The paper addresses the problem of calculating the noise-induced switching rates in systems with delay-distributed kernels and Gaussian noise. A general variational formulation for the switching rate is derived for any distribution kernel, and the obtained equations of motion and boundary conditions represent the most probable, or optimal, path, which maximizes the probability of escape. Explicit analytical results for the switching rates for small mean time delays are obtained for the uniform and bi-modal (or two-peak) distributions. They suggest that increasing the width of the distribution leads to an increase in the switching times even for longer values of mean time delays for both examples of the distribution kernel, and the increase is higher in the case of the two-peak distribution. Analytical predictions are compared to the direct numerical simulations and show excellent agreement between theory and numerical experiment.

Did AIDS mortality decrease the number of lifetime sexual partners in Kenya: an ecological analysis?

We assessed if there has been a decline in the median number of reported lifetime sexual partners in Kenya following the AIDS epidemic. The Wilcoxon rank-sum test was used to compare the median and interquartile range (IQR) of the number of lifetime sexual partners for men aged 20-54 years in the 1993 and 2008 Kenyan Demographic Health Surveys. The median number of sexual partners in 1993 increased rapidly to 10 partners reported at age 30 years then plateaued at this level. In 2008, the median number of sexual partners plateaued at around half the value of the 1993 plateau. The median number of lifetime sexual partners for men aged 20-54 years declined from 10 (IQR 4-20) in 1993 to 3 (IQR 2-7) in 2008 (P < 0·001). This decline could be due to a combination of the effects of AIDS mortality and a misreporting bias.

Mucopolysaccharidosis type II: identification of 30 novel mutations among Latin American patients.

In this study, 103 unrelated South-American patients with mucopolysaccharidosis type II (MPS II) were investigated aiming at the identification of iduronate-2-sulfatase (IDS) disease causing mutations and the possibility of some insights on the genotype-phenotype correlation The strategy used for genotyping involved the identification of the previously reported inversion/disruption of the IDS gene by PCR and screening for other mutations by PCR/SSCP. The exons with altered mobility on SSCP were sequenced, as well as all the exons of patients with no SSCP alteration. By using this strategy, we were able to find the pathogenic mutation in all patients. Alterations such as inversion/disruption and partial/total deletions of the IDS gene were found in 20/103 (19%) patients. Small insertions/deletions/indels (<22 bp) and point mutations were identified in 83/103 (88%) patients, including 30 novel mutations; except for a higher frequency of small duplications in relation to small deletions, the frequencies of major and minor alterations found in our sample are in accordance with those described in the literature.

Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis.

Introduction: Pompe disease (PD) is a glycogen disorder caused by the deficient activity of acid alpha-glucosidase (GAA). We sought to review the latest available evidence on the safety and efficacy of recombinant human GAA enzyme replacement therapy (ERT) for infantile-onset PD (IOPD). Methods: We systematically searched the MEDLINE (via PubMed) and Embase databases for prospective clinical studies evaluating ERT for IOPD on pre-specified outcomes. Meta-analysis was also performed. Results: Of 1,722 articles identified, 16 were included, evaluating 316 patients. Studies were heterogeneous and with very low certainty of evidence for most outcomes. A moderate/high risk of bias was present for most included articles. The following outcomes showed improvements associated with alglucosidase alfa, over natural history of PD/placebo, for a mean follow-up of 48.3 months: left ventricular (LV) mass {mean change 131.3 g/m2 [95% confidence interval (CI) 81.02, 181.59]}, time to start ventilation (TSV) [HR 0.21 (95% CI: 0.12, 0.36)], and survival [HR 0.10 (95% CI: 0.05, 0.19)]. There were no differences between the pre- and post-ERT period for myocardial function and psychomotor development. Adverse events (AEs) after ERT were mild in most cases. Conclusion: Our data suggest that alglucosidase alfa potentially improves LV mass, TSV, and survival in IOPD patients, with no important safety issues. Systematic Review Registration: PROSPERO identifier (CRD42019123700).

Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy.

Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6-1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.

Quantitation of cell-associated borrelial DNA in the blood of Lyme disease patients with erythema migrans.

Bloodstream invasion is an important event in the pathogenesis of the more serious manifestations of Lyme disease. The number of spirochetes in the blood of infected patients, however, has not been determined, and, therefore, it is unknown whether the number of spirochetes can be correlated with particular clinical or laboratory features. This study was designed to measure the level of Borrelia burgdorferi in the plasma of Lyme disease patients and correlate these levels with selected clinical and laboratory findings. Nested and quantitative polymerase chain reaction (qPCR) was employed to detect cell-associated flaB gene DNA in the plasma of untreated early Lyme disease patients with erythema migrans (EM). Twenty-nine (45.3%) of 64 patients had evidence of B. burgdorferi in their plasma by at least one of the PCR methods. For the 22 qPCR-positive patients, the mean number of flaB gene copies per mL of plasma was 4,660, with a range of 414 to 56,000. The number of flaB gene copies did not significantly correlate with any of the clinical, demographic, or laboratory variables assessed. For reasons discussed, we suggest caution in extrapolating an estimate of the number of viable Borrelia in plasma from the observed number of flaB copies.

Burden of phenylketonuria in Latin American patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. If untreated, the complications of PKU lead to significant neucognitive and neuropsychiatric impairments, placing a burden on both the individual's quality of life and on the healthcare system. We conducted a systematic literature review to characterize the impact of PKU on affected individuals and on healthcare resources in Latin American (LATAM) countries. METHODS: Searches of the global medical literature as well as regional and local medical literature up to September 2021. Observational studies on patients with PKU from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias. RESULTS: 79 unique studies (47 cross-sectional studies, 18 case series, 12 case reports, and two cohort studies) with a total of 4090 patients were eligible. Of these studies, 20 had data available evaluating early-diagnosed PKU patients for meta-analysis of burden outcomes. Intellectual disability in the pooled studies was 18% [95% Confidence Interval (CI) 0.04-0.38; I2 = 83.7%, p = 0.0133; two studies; n = 114]. Motor delay was 15% [95% CI 0.04-0.30; I2 = 74.5%, p = 0.0083; four studies; n = 132]. Speech deficit was 35% [95% CI 0.08-0.68; I2 = 93.9%, p < 0.0001; five studies; n = 162]. CONCLUSIONS: There is currently evidence of high clinical burden in PKU patients in LATAM countries. Recognition that there are many unmet neuropsychological needs and socioeconomic challenges faced in the LATAM countries is the first step in planning cost-effective interventions.

Investigation of genotypes of Borrelia burgdorferi in Ixodes scapularis ticks collected during surveillance in Canada.

The genetic diversity of Borrelia burgdorferi sensu stricto, the agent of Lyme disease in North America, has consequences for the performance of serological diagnostic tests and disease severity. To investigate B. burgdorferi diversity in Canada, where Lyme disease is emerging, bacterial DNA in 309 infected adult Ixodes scapularis ticks collected in surveillance was characterized by multilocus sequence typing (MLST) and analysis of outer surface protein C gene (ospC) alleles. Six ticks carried Borrelia miyamotoi, and one tick carried the novel species Borrelia kurtenbachii. 142 ticks carried B. burgdorferi sequence types (STs) previously described from the United States. Fifty-eight ticks carried B. burgdorferi of 1 of 19 novel or undescribed STs, which were single-, double-, or triple-locus variants of STs first described in the United States. Clonal complexes with founder STs from the United States were identified. Seventeen ospC alleles were identified in 309 B. burgdorferi-infected ticks. Positive and negative associations in the occurrence of different alleles in the same tick supported a hypothesis of multiple-niche polymorphism for B. burgdorferi in North America. Geographic analysis of STs and ospC alleles were consistent with south-to-north dispersion of infected ticks from U.S. sources on migratory birds. These observations suggest that the genetic diversity of B. burgdorferi in eastern and central Canada corresponds to that in the United States, but there was evidence for founder events skewing the diversity in emerging tick populations. Further studies are needed to investigate the significance of these observations for the performance of diagnostic tests and clinical presentation of Lyme disease in Canada.

Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity.

Mucolipidosis II (ML II alpha/beta), or I-cell disease, is a rare genetic disease in which activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent. GlcNAc-phosphotransferase is a multimeric enzyme encoded by two genes, GNPTAB and GNPTG. A spectrum of mutations in GNPTAB has been recently reported to cause ML II alpha/beta. Most of these mutations were found to be private or rare. However, the mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We analysed 44 patients who were either homozygous or compound heterozygous for this deletion (22 Italians, 8 Arab-Muslims, 1 Turk, 3 Argentineans, 3 Brazilians, 2 Irish travellers and 5 Portuguese) and 16 carriers (15 Canadians and 1 Italian) for three intragenic polymorphisms: c.-41_-39delGGC, c.18G>A and c.1932A>G as well as two microsatellite markers flanking the GNPTAB gene (D12S1607 and D12S1727). We identified a common haplotype in all chromosomes bearing the c.3503_3504delTC mutation. In summary, we showed that patients carrying the c.3503_3504delTC deletion presented with a common haplotype, which implies a common origin of this mutation. Additionally, the level of diversity observed at the most distant locus indicates that the mutation is relatively ancient (around 2063 years old), and the geographical distribution further suggests that it probably arose in a peri-Mediterranean region.

Evidence that L-carnitine and selenium supplementation reduces oxidative stress in phenylketonuric patients.

It is well established that the involvement of reactive species in the pathophysiology of several neurological diseases, including phenylketonuria (PKU), a metabolic genetic disorder biochemically characterized by elevated levels of phenylalanine (Phe). In previous studies, we verified that PKU patients (treated with a protein-restricted diet supplemented with a special formula not containing L-carnitine and selenium) presented high lipid and protein oxidative damage as well as a reduction of antioxidants when compared to the healthy individuals. Our goal in the present study was to evaluate the effect of Phe-restricted diet supplemented with L-carnitine and selenium, two well-known antioxidant compounds, on oxidative damage in PKU patients. We investigated various oxidative stress parameters in blood of 18 treated PKU patients before and after 6 months of supplementation with a special formula containing L-carnitine and selenium. It was verified that treatment with L-carnitine and selenium was capable of reverting the lipid peroxidation, measured by thiobarbituric acid-reactive species, and the protein oxidative damage, measured by sulfhydryl oxidation, to the levels of controls. Additionally, the reduced activity of glutathione peroxidase was normalized by the antioxidant supplementation. It was also verified a significant inverse correlation between lipid peroxidation and L-carnitine blood levels as well as a significant positive correlation between glutathione peroxidase activity and blood selenium concentration. In conclusion, our results suggest that supplementation of L-carnitine and selenium is important for PKU patients since it could help to correct the oxidative stress process which possibly contributes, at least in part, to the neurological symptoms found in phenylketonuric patients.

Locomotor training using a robotic device in patients with subacute spinal cord injury.

STUDY DESIGN: Quasi experiment; single experimental group with matched historical control. OBJECTIVES: To evaluate the effect of an additive robotic-assisted gait training (RAGT) using the Lokomat system on the neurological and functional outcomes of patients with subacute spinal cord injury (SCI). SETTING: Department of Physical Medicine and Rehabilitation. METHODS: A total of 28 subacute SCI patients were treated by RAGT, 2-3 times a week, 30-45 min every treatment, concomitantly with regular physiotherapy. As control, for each patient, we matched a comparable patient treated in the same department in previous years, according to age, severity of injury, level of injury and cause. The main outcomes were: the AIS (American Spinal Injury Association impairment scale) the spinal cord independence measurement (SCIM) score, the walking index for SCI II (WISCI II) and functional ambulation category scale (FAC). RESULTS: At the end of rehabilitation, both groups showed a significant improvement in both the FAC score and the WISCI score (P<0.01) without differences between the groups. Functional abilities, according to the SCIM score, were also improved, with a significant interaction effect; the RAGT patients improve by 30±20 points, which was significantly greater gain as compared with the controls, 21±14 points (P=0.05). This improvement was mainly due to the change in the SCIM motor subscales. CONCLUSION: RAGT is an important additional treatment to improve the functional outcome of subacute SCI patients. Larger, controlled studies are still required to determine the optimal timing and protocol design for the maximal efficacy of RAGT in SCI patients.

Predictors of insulin regimens and impact on outcomes in youth with type 1 diabetes: the SEARCH for Diabetes in Youth study.

OBJECTIVES: To describe the insulin regimens used to treat type 1 diabetes mellitus (T1DM) in youth in the United States, to explore factors related to insulin regimen, and to describe the associations between insulin regimen and clinical outcomes, particularly glycemic control. STUDY DESIGN: A total of 2743 subjects participated in the SEARCH for Diabetes in Youth study, an observational population-based study of youth diagnosed with T1DM, conducted at 6 centers. Data collected during a study visit included clinical and sociodemographic information, body mass index, laboratory measures, and insulin regimen. RESULTS: Sociodemographic characteristics were associated with insulin regimen. Insulin pump therapy was more frequently used by older youth, females, non-Hispanic whites, and families with higher income and education (P = .02 for females, P < .001 for others). Insulin pump use was associated with the lowest hemoglobin A1C levels in all age groups. A1C levels were >7.5% in >70% of adolescents, regardless of regimen. CONCLUSIONS: Youth using insulin pumps had the lowest A1C; A1C was unacceptably high in adolescents. There is a need to more fully assess and understand factors associated with insulin regimens recommended by providers and the influence of race/ethnicity, education, and socioeconomic status on these treatment recommendations and to develop more effective treatment strategies, particularly for adolescents.

Correlation between pinocytosis and hydroosmosis induced by neurohypophyseal hormones and mediated by adenosine 3',5'-cyclic monophosphate.

The isolated urinary bladder of the toad responds to neurohypophyseal hormone with a net increase of water transport from the mucosal to the serosal solution in the presence of an osmotic gradient. This response is mediated intracellularly by cyclic 3',5'-adenosine monophosphate (AMP). The present study demonstrates that hydroosmotically active substances such as oxytocin, dibutyryl cyclic 3',5'-AMP, and theophylline, but not hydroosmotically inactive substances, induce the uptake of horseradish peroxidase from the mucosal solution. Peroxidase taken up by the mucosal cells is demonstrable in small tubules and vesicles, and eventually accumulates in lysosomes. The uptake of peroxidase from the serosal solution into similar bodies in the mucosal cells is not hormone-dependent. It is also shown that peroxidase does not penetrate the tight junction from either the mucosal or serosal solution. These results extend previous findings which implicated the apical membrane of the mucosal epithelium as the site affected by neurohypophyseal hormones. A mechanism based on secretory phenomena is proposed as a framework for future investigations of apical membrane permeability changes and pinocytosis.

Oxytocin: crystal data of a seleno analog.

The sulfur atom in position 6 of deamino-oxytocin (1-beta-mercapto-propionic acid-oxytocin) was replaced by selenium. The crystals of the resulting deamino-6-seleno-oxytocin are similar to those of the "wet" form of deamino-oxytocin, but they are stable upon prolonged exposure to air.