Large-scale forcing of the European Slope Current and associated inflows to the North Sea

Drifters drogued at 50?m in the European Slope Current at the Hebridean shelf break follow a wide range of pathways, indicating highly variable Atlantic inflow to the North Sea. Slope Current pathways, timescales and transports over 1988–2007 are further quantified in an eddy-resolving ocean model hindcast. Particle trajectories calculated with model currents indicate that Slope Current water is largely ''recruited'' from the eastern subpolar North Atlantic. Observations of absolute dynamic topography and climatological density support theoretical expectations that Slope Current transport is to first order associated with meridional density gradients in the eastern subpolar gyre, which support a geostrophic inflow towards the slope. In the model hindcast, Slope Current transport variability is dominated by abrupt 25–50?% reductions of these density gradients over 1996–1998. Concurrent changes in wind forcing, expressed in terms of density gradients, act in the same sense to reduce Slope Current transport. This indicates that coordinated regional changes of buoyancy and wind forcing acted together to reduce Slope Current transport during the 1990s. Particle trajectories further show that 10–40?% of Slope Current water is destined for the northern North Sea within 6 months of passing to the west of Scotland, with a clear decline in this Atlantic inflow over 1988–2007. The influence of variable Slope Current transport on the northern North Sea is also expressed in salinity, which declines through the hindcast period, and there is evidence for a similar freshening trend in observational records. A proxy for Atlantic inflow may be found in sea level records. Variability of Slope Current transport is implicit in mean sea level differences between Lerwick (Shetland) and Torshavn (Faeroes), in both tide gauge records and a longer model hindcast spanning 1958–2013. Potential impacts of this variability on North Sea biogeochemistry and ecosystems, via associated changes in seasonal stratification and nutrient fluxes, are discussed

Determination of cystathionine beta-synthase activity in human plasma by LC-MS/MS: potential use in diagnosis of CBS deficiency

Cystathionine β-synthase (CBS) deficiency is usually confirmed by assaying the enzyme activity in cultured skin fibroblasts. We investigated whether CBS is present in human plasma and whether determination of its activity in plasma could be used for diagnostic purposes. We developed an assay to measure CBS activity in 20 μL of plasma using a stable isotope substrate - 2,3,3-2H serine. The activity was determined by measurement of the product of enzyme reaction, 3,3-2H-cystathionine, using LC-MS/MS. The median enzyme activity in control plasma samples was 404 nmol/h/L (range 66–1,066; n = 57). In pyridoxine nonresponsive CBS deficient patients, the median plasma activity was 0 nmol/ho/L (range 0–9; n = 26), while in pyridoxine responsive patients the median activity was 16 nmol/hour/L (range 0–358; n = 28); this overlapped with the enzyme activity from control subject. The presence of CBS in human plasma was confirmed by an in silico search of the proteome database, and was further evidenced by the activation of CBS by S-adenosyl-L-methionine and pyridoxal 5′-phosphate, and by configuration of the detected reaction product, 3,3-2H-cystathionine, which was in agreement with the previously observed CBS reaction mechanism. We hypothesize that the CBS enzyme in plasma originates from liver cells, as the plasma CBS activities in patients with elevated liver aminotransferase activities were more than 30-fold increased. In this study, we have demonstrated that CBS is present in human plasma and that its catalytic activity is detectable by LC-MS/MS. CBS assay in human plasma brings new possibilities in the diagnosis of pyridoxine nonresponsive CBS deficiency

Large-scale forcing of the European Slope Current and associated inflows to the North Sea

Drifters drogued at 50?m in the European Slope Current at the Hebridean shelf break follow a wide range of pathways, indicating highly variable Atlantic inflow to the North Sea. Slope Current pathways, timescales and transports over 1988–2007 are further quantified in an eddy-resolving ocean model hindcast. Particle trajectories calculated with model currents indicate that Slope Current water is largely ''recruited'' from the eastern subpolar North Atlantic. Observations of absolute dynamic topography and climatological density support theoretical expectations that Slope Current transport is to first order associated with meridional density gradients in the eastern subpolar gyre, which support a geostrophic inflow towards the slope. In the model hindcast, Slope Current transport variability is dominated by abrupt 25–50?% reductions of these density gradients over 1996–1998. Concurrent changes in wind forcing, expressed in terms of density gradients, act in the same sense to reduce Slope Current transport. This indicates that coordinated regional changes of buoyancy and wind forcing acted together to reduce Slope Current transport during the 1990s. Particle trajectories further show that 10–40?% of Slope Current water is destined for the northern North Sea within 6 months of passing to the west of Scotland, with a clear decline in this Atlantic inflow over 1988–2007. The influence of variable Slope Current transport on the northern North Sea is also expressed in salinity, which declines through the hindcast period, and there is evidence for a similar freshening trend in observational records. A proxy for Atlantic inflow may be found in sea level records. Variability of Slope Current transport is implicit in mean sea level differences between Lerwick (Shetland) and Torshavn (Faeroes), in both tide gauge records and a longer model hindcast spanning 1958–2013. Potential impacts of this variability on North Sea biogeochemistry and ecosystems, via associated changes in seasonal stratification and nutrient fluxes, are discussed

Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial

BACKGROUND: Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known. OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12. METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment—Evaluation for Depression) trial. Participants defined as having “low” serum vitamin B-12 (vitamin B-12 ≥150 and <220 ng/L) or “marginal” serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD). RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was −0.01 (95% CI: −0.06, 0.04; P = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95% CI: 387, 535 μg/L; P < 0.001). CONCLUSIONS: Supplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism. This trial was registered at www.isrctn.com as ISRCTN37558856

Maternal SARS-CoV-2 sero-surveillance using newborn dried blood spot (DBS) screening specimens highlights extent of low vaccine uptake in pregnant women

SARS-CoV-2 vaccine uptake in pregnant women is believed to be low and lags behind the general population contributing to increased hospital admissions, and poor maternal and fetal outcomes. However, there is a paucity of information on the SARS-CoV-2 serostatus of pregnant women to help inform policy planning and assess impact of interventions to improve vaccine uptake in this at-risk group. We analyzed 8,683 residual, anonymized newborn screening dried bloodspot (DBS) specimens during a 15-month period (October 2020 to December 2021) in Wales (UK) for SARS-CoV-2 IgG-antibodies. We compared newborn DBS antibody-positive rates to the percentage number of pregnant women vaccinated and the percentage number of antibody-positive adults. In December 2021, 47.8% of women in Wales had received two doses of the vaccine by their delivery date; however, only 41.1% of DBS specimens had high antibody concentrations. Results indicate that a proportion of pregnant women remain at higher-risk of COVID complications, particularly given the reduction in antibody neutralization of Omicron versus the Delta variant. Our study demonstrates the utility of newborn screening DBS specimens to monitor SARS-CoV-2 serostatus in pregnant women representing maternal vaccination and natural infection in almost real-time, defining the immunity gap and impact of any interventions

Correction: Folate Augmentation of Treatment – Evaluation for Depression (FolATED): protocol of a randomised controlled trial

This correction reports changes in our protocol since its publication. These include changes to authorship and acknowledgements, together with improvements to study design and procedures, and correction of an internal inconsistency. The improvements relate to the exclusion criteria, assessments carried out at screening, and mode of data collection

Cystic fibrosis newborn screening: the importance of bloodspot sample quality

Objective Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality. Design Longitudinal birth cohort. Setting Wales 1996–2016. Patients Children with CF. Interventions Identification of all CF patients with triangulation of multiple data sources to detect false negative cases. Main outcome measures False negative cases. Results Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases—all were classified as small/insufficient or poor quality. Conclusions The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality

Current state and innovations in newborn screening: continuing to do good and avoid harm

In 1963, Robert Guthrie’s pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, ‘second-tier’ methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening

Performance of laboratory tests used to measure blood phenylalanine for the monitoring of patients with phenylketonuria

Analysis of blood phenylalanine is central to the monitoring of patients with phenylketonuria (PKU) and age‐related phenylalanine target treatment‐ranges (0‐12 years; 120‐360 μmol/L, and >12 years; 120‐600 μmol/L) are recommended in order to prevent adverse neurological outcomes. These target treatment‐ranges are based upon plasma phenylalanine concentrations. However, patients are routinely monitored using dried bloodspot (DBS) specimens due to the convenience of collection. Significant differences exist between phenylalanine concentrations in plasma and DBS, with phenylalanine concentrations in DBS specimens analyzed by flow‐injection analysis tandem mass spectrometry reported to be 18% to 28% lower than paired plasma concentrations analyzed using ion‐exchange chromatography. DBS specimens with phenylalanine concentrations of 360 and 600 μmol/L, at the critical upper‐target treatment‐range thresholds would be plasma equivalents of 461 and 768 μmol/L, respectively, when a reported difference of 28% is taken into account. Furthermore, analytical test imprecision and bias in conjunction with pre‐analytical factors such as volume and quality of blood applied to filter paper collection devices to produce DBS specimens affect the final test results. Reporting of inaccurate patient results when comparing DBS results to target treatment‐ranges based on plasma concentrations, together with inter‐laboratory imprecision could have a significant impact on patient management resulting in inappropriate dietary change and potentially adverse patient outcomes. This review is intended to provide perspective on the issues related to the measurement of phenylalanine in blood specimens and to provide direction for the future needs of PKU patients to ensure reliable monitoring of metabolic control using the target treatment‐ranges