•Network parameter ensembles achieve robust GIC modelling and network characterisation.•Transfer functions using the ensemble methodology bypass conductivity assumptions.•Only geomagnetic field and ...measured GIC data are needed for ensemble approaches.•Full networks can be calibrated using sparse magnetometer and node measurements.•Uncertainty in GIC estimation applicable to operational application is quantified.
Typical geomagnetically induced current (GIC) modelling assumes the induced quasi-DC current at a node in the transmission network is linearly related to the local geoelectric field by a pair of network parameters. Given a limited time-series of measured geomagnetic and GIC data, an empirical method is presented that results in a statistically significant generalised ensemble of parameter estimates with the error in the estimates identified. The method is showcased for different transmission networks and geomagnetic storms and, where prior modelling exists, shows improved GIC estimation. Furthermore, modelled networks can be locally characterised and probed without any further network knowledge. Insights include network parameter variation, effective network directionality and response. Merging the network parameters and geoelectric field estimation, a transfer function is derived which offers an alternative approach to assessing transformer exposure to GICs.
This paper describes the use of a class of nonlinear smoothers for the identification of interesting phenomena in narrow band very low frequency (VLF) transmission phase caused by perturbation events ...in the D region of the ionosphere. The LULU smoothers, named for their smoothing of upward (L) and downward (U) peaks in a signal, usually used for image processing tasks, are described, and examples are shown where these operators are used to automatically isolate and identify features in the phase of narrow band transmissions received at high and high‐middle latitudes (Antarctica and Marion Island, respectively). Identification of solar flare events, electromagnetic ion cyclotron wave precipitation, and substorm injection events are demonstrated, showing the potential for this technique to be used for space weather monitoring.
Key Points
We demonstrate the use of LULU operators for event detection in narrow band VLF signal phase
LULU is used to identify solar flares, EMIC wave precipitation events, and substorms from VLF phase
We show that events could be isolated without the explicit need for estimating a quiet day curve
Abstract
Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of ...feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second‐tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false‐positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG‐CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl‐CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl‐CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.
In the present work low-cycle fatigue experiments were carried out on thermo-mechanically processed AA6082 and AA7075 sheets to evaluate mechanical properties under cyclic loading. Different cooling ...rates imposed by use of tempered forming tools after solutionizing and subsequent aging treatment led to the formation of precipitates with differing sizes and morphologies. Specimens thermo-mechanically processed in tools with temperatures of 24 °C and 200 °C showed superior mechanical properties under both monotonic and cyclic loading. Different behavior was observed for the specimens formed in the tool with a temperature of 350 °C. Based on thorough analysis of prevalent microstructural features, processing-property-damage relationships are established pointing at the major impact of the thermal history on the final performance of the high-strength aluminum alloys in focus.
To pave the way for healthy aging in early treated phenylketonuria (ETPKU) patients, a better understanding of the neurological course in this population is needed, requiring easy accessible ...biomarkers to monitor neurological disease progression in large cohorts. The objective of this pilot study was to investigate the potential of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as blood biomarkers to indicate changes of the central nervous system in ETPKU. In this single-center cross-sectional study, GFAP and NfL concentrations in serum were quantified using the Simoa
®
multiplex technology in 56 ETPKU patients aged 6–36 years and 16 age matched healthy controls. Correlation analysis and hierarchical linear regression analysis were performed to investigate an association with disease-related biochemical parameters and retinal layers assessed by optical coherence tomography. ETPKU patients did not show significantly higher GFAP concentrations (mean 73 pg/ml) compared to healthy controls (mean 60 pg/ml
, p
= 0.140). However, individual pediatric and adult ETPKU patients had GFAP concentrations above the healthy control range. In addition, there was a significant association of GFAP concentrations with current plasma tyrosine concentrations (r = −0.482,
p
= 0.036), a biochemical marker in phenylketonuria, and the retinal inner nuclear layer volume (r = 0.451,
p
= 0.04). There was no evidence of NfL alterations in our ETPKU cohort. These pilot results encourage multicenter longitudinal studies to further investigate serum GFAP as a complementary tool to better understand and monitor neurological disease progression in ETPKU. Follow-up investigations on aging ETPKU patients are required to elucidate the potential of serum NfL as biomarker.
Extreme geomagnetic disturbances occur rarely but can have great impact on technological systems such as power supply networks. Long‐term planning for extreme events requires the estimation of event ...impact for occurrence periods greater than the length of observed data. With this in mind an analysis of extreme geomagnetic events observed in South Africa (middle geomagnetic latitude) is performed over four solar cycles (1974–2015). An algorithm to identify active periods with minimum SYM‐H ≤−100 nT is demonstrated. The sum of induced electric field over the course of each event is used to characterize the severity of each active period. It is found that the severity index (accumulated electric field magnitude ΣE) shares a highly linear relationship with accumulated SYM‐H over each event. The index ΣE is lognormal distributed, with tail deviating greater than lognormal, confirming heavy‐tailed occurrence. A general Pareto distribution is fitted to the tail of the distribution and extrapolated to calculate the return levels of extreme events. Return levels of once in 100 and once in 200 year events are estimated to be 9.4 × 104 mV/km min and 1.09 × 105 mV/km min, respectively. The top three events, in ascending order of severity, are the March 1989 storm, the events of late October 2003, and the April 1994 event—a long interval of coronal‐hole driven disturbances, bookended by two intense geomagnetic storms.
Plain Language Summary
Planning for future extreme events like catastrophic floods or geomagnetic storms is difficult if the interval measured over is shorter than the planning period. This research deals with such a case. We only have 41 years' worth of data, but we wanted to know how extreme the once‐in‐a‐hundred‐years and once in 200 years events will be. To solve this, we quantify the severity of each significant event over the 41 year period by a single number, by adding up electric field induced in the Earth's surface by the geomagnetic perturbations over the course of an event. This collection of numbers—one for each event—is analyzed with statistical methods to guess how extreme the once in a 100 and once in 200 year events will be. The induced electric field tells us something about the effect that a geomagnetic storm will have on power network infrastructure, so this research enables power companies in South Africa to plan for future events. The methods used here are clearly explained so that this study can be reproduced by other researchers in different parts of the world.
Key Points
Intense storms over four solar cycles are identified and their severity quantified by accumulated induced geoelectric field and SYM‐H
Accumulated E field, accumulated SYM‐H, and event duration all show similarly shaped fat‐tailed distributions over four solar cycles
Accumulated E field at Hermanus is estimated for 1/100 and 1/200 year occurrence
During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for ...phenylalanine hydroxylase, tetrahydrobiopterin; BH
), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0-4 years with BH
-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin.
All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only ('sapropterin extension' group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period ('sapropterin continuous' group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the 'sapropterin continuous' group (95% CI 28.9, 48.6; p < 0.0001). In the 'sapropterin extension' group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI - 2.8, 13.8; p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters.
Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH
-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH
-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment. Trial registration ClinicalTrials.gov, NCT01376908. Registered 17 June 2011, https://clinicaltrials.gov/ct2/show/NCT01376908 .
An integrative framework from information privacy and relationship marketing arenas was employed to investigate whether a traditional business-to-business relationship marketing framework could be ...applied to the information-intensive online business-to-consumer channel. Roles of consumers' privacy concerns and perceived e-tailer's reputation on their trust in, commitment toward, and purchase intent toward a services e-tailer were examined. Effects of opt-in versus opt-out choice strategies on consumers' privacy concerns and trust were also studied. Results showed that the strongest relationships leading to online purchase intent were those between trust in and commitment toward an e-tailer and between firm reputation and trust. Privacy concerns influenced purchase intent with strong negative effects, both directly and indirectly through trust. No difference was observed in respective direct effects of choice strategy on privacy concerns, nor were strategies found to moderate reputation on privacy concerns or trust. Managerial implications are discussed.
To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated ...disease (MOGAD) optic neuritis (ON).
All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGAD
) cohort and patients with ≥18 years in the adult (MOGAD
) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained.
Twenty MOGAD
(10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGAD
(34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 μm; GCIPL: 0.42±0.09 and 0.44±0.13 mm
, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGAD
and 31% MOGAD
ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome.
Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.
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