We describe on-chip circuits specially designed and fabricated for the purpose of measuring the effect of AC NBTI on an individual, well-defined device in the wide frequency range on a single wafer. The circuits are designed to allow measurements in multiple modes, specifically, DC and AC NBTI (both interrupted and on-the-fly), on a single pFET and on a CMOS inverter, as well as charge-pumping characterization of the stressed pFET. The results indicate that AC NBTI is independent of the frequency in the 1 Hz -2 GHz range. The voltage and stress time acceleration is observed to be identical for both AC and DC NBTI stress.

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Background Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B12 deficiency have been detected by clinical symptoms and only few of them trough NBS programs. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions. Methods A screening strategy using the usual primary markers followed by the analysis of MMA, MCA and Hcys as second tier-test in the first dried blood spot (DBS) was developed and evaluated. Results During the period 2015–2018 a total of 258,637 newborns were screened resulting in 130 newborns with acquired vitamin B12 deficiency (incidence 1:1989), 19 with genetic disorders (incidence 1:13,613) and 13 were false positive. No false negatives were notified. Concerning the second-tier test, the percentage of cases with MMA above the cut-off levels, both for genetic and acquired conditions was very similar (58% and 60%, respectively). Interestingly, the percentage of cases with increased levels of Hcys was higher in acquired conditions than in genetic disorders (87% and 47%, respectively). In contrast, MCA was high only in 5% of the acquired conditions versus in 53% of the genetic disorders, and it was always very high in all patients with propionic acidemia. Conclusions When screening for methylmalonic acidemia and homocystinuria, differential diagnosis with acquired vitamin B12 deficiency should be done. The results of our strategy support the inclusion of this acquired condition in the NBS programs, as it is easily detectable and allows the adoption of corrective measures to avoid the consequences of its deficiency.

Short-chain enoyl-CoA hydratase (ECHS1) is a mitochondrial beta-oxidation enzyme involved in the metabolism of acyl-CoA fatty acid esters, as well as in valine metabolism. ECHS1 deficiency has multiple manifestations, including Leigh syndrome early at birth or in childhood with poor prognosis, to cutis laxa, exercise-induced dystonia and congenital lactic acidosis.Here we describe the case of a newborn with mutations in ECHS1 that caught our attention after the incidental finding of 3-hydroxy-butyryl\3-hydroxy-isobutyryl\malonylcarnitine (C4OH\C3DC) and tiglylcarnitine (C5:1) on blood spot in the newborn screening (NBS) program. Diagnosis was suspected based on the analysis of organic acids on dried urine spot. A moderate increase of 2-methyl-2,3-dihydroxybutyric acid, was detected, which is a known marker of this disease. Exome analysis showed c.404A>G (p.Asn135Ser) mutation in homozygosis in the ECHS1 gene. The child was therefore admitted to the hospital. Initial examination showed little response to auditory stimuli and mild hypertonia of the extremities. Clinical deterioration was evident at 4 months of age, including neurological and cardiac involvement, and the patient died at 5 months of age. This case illustrates how an incidental detection in the NBS Program can lead to the diagnosis ECHS1 deficiency. Although it is a severe disease, with no treatment available, early detection would allow adequate genetic counseling avoiding the odyssey that suffered most of these families.

BackgroundIn Spain, the Strategy for Assistance in Normal Childbirth (SANC) promoted a model of care, which respects the physiological birth process and discards unnecessary routine interventions, such as episiotomies. We evaluated the rate of episiotomy use and perineal trauma as indicators of how selective introduction of the SANC initiative has impacted childbirth outcomes in hospitals of Catalonia.MethodsCross-sectional study of all singleton vaginal term deliveries without instrument registered in the Minimum Basic Data Set (MBDS) of Catalonia in 2007, 2010 and 2012. Hospitals were divided into types according to funding (public or private), and four strata were differentiated according to volume of births attended.Episiotomies and perineal injury were considered dependent variables. The relationship between qualitative variables was analysed using the chi-squared test, and Student’s t-test was used for quantitative variables. Comparison of proportions was performed on the two hospital groups between 2007 and 2012 using a Z-test. Logistic regression models were used to analyse the relationship between episiotomy or severe perineal damage and maternal age, volume of births and hospital type, obtaining odds ratios (OR) and 95% confidence intervals (CI).ResultsThe majority of normal singleton term deliveries were attended in public hospitals, where maternal age was lower than for women attended in private hospitals. Analysis revealed a statistically significant (P < 0.001) decreasing trend in episiotomy use in Catalonia for both hospital types. Private hospitals appeared to be associated with increased episiotomy rate in 2007 (OR = 1.099, CI: 1,057–1,142), 2010 (OR = 1.528, CI: 1,472–1,587) and 2012 (OR = 1.459, CI: 1,383–1,540), and a lower rate of severe perineal trauma in 2007 (OR = 0.164, CI: 0.095–0.283), 2010 (OR = 0.16, CI: 0.110–0.232) and 2012 (OR = 0.19, CI: 0.107–0.336). Regarding severe perineal injury, when independent variables were adjusted, maternal age ceased to have a significant correlation in 2012 (OR = 0.994, CI: 0.970–1.018).ConclusionsEpisiotomy procedures during normal singleton vaginal term deliveries in Catalonia has decreased steadily since 2007. Study results show a stable incidence trend below 1% for severe perineal trauma over the study period.