Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ...ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.
Summary Background Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this ...treatment combination provided greater survival benefit than did chlorambucil or fludarabine. Methods 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. Findings There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p<0·0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0·006 and 0·04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0·00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (VH ) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
The EU Water Framework Directive (WFD) requires that the ecological and chemical status of water bodies in Europe should be assessed, and action taken where possible to ensure that at least "good" ...quality is attained in each case by 2015. This paper is concerned with the accuracy and precision with which chemical status in rivers can be measured given certain sampling strategies, and how this can be improved. High-frequency (hourly) chemical data from four rivers in southern England were subsampled to simulate different sampling strategies for four parameters used for WFD classification: dissolved phosphorus, dissolved oxygen, pH and water temperature. These data sub-sets were then used to calculate the WFD classification for each site. Monthly sampling was less precise than weekly sampling, but the effect on WFD classification depended on the closeness of the range of concentrations to the class boundaries. In some cases, monthly sampling for a year could result in the same water body being assigned to three or four of the WFD classes with 95% confidence, due to random sampling effects, whereas with weekly sampling this was one or two classes for the same cases. In the most extreme case, the same water body could have been assigned to any of the five WFD quality classes. Weekly sampling considerably reduces the uncertainties compared to monthly sampling. The width of the weekly sampled confidence intervals was about 33% that of the monthly for P species and pH, about 50% for dissolved oxygen, and about 67% for water temperature. For water temperature, which is assessed as the 98th percentile in the UK, monthly sampling biases the mean downwards by about 1 °C compared to the true value, due to problems of assessing high percentiles with limited data. Low-frequency measurements will generally be unsuitable for assessing standards expressed as high percentiles. Confining sampling to the working week compared to all 7 days made little difference, but a modest improvement in precision could be obtained by sampling at the same time of day within a 3 h time window, and this is recommended. For parameters with a strong diel variation, such as dissolved oxygen, the value obtained, and thus possibly the WFD classification, can depend markedly on when in the cycle the sample was taken. Specifying this in the sampling regime would be a straightforward way to improve precision, but there needs to be agreement about how best to characterise risk in different types of river. These results suggest that in some cases it will be difficult to assign accurate WFD chemical classes or to detect likely trends using current sampling regimes, even for these largely groundwater-fed rivers. A more critical approach to sampling is needed to ensure that management actions are appropriate and supported by data.
The total reactive phosphorus (TRP) and nitrate concentrations of the River Enborne, southern England, were monitored at hourly interval between January 2010 and December 2011. The relationships ...between these high-frequency nutrient concentration signals and flow were used to infer changes in nutrient source and dynamics through the annual cycle and each individual storm event, by studying hysteresis patterns. TRP concentrations exhibited strong dilution patterns with increasing flow, and predominantly clockwise hysteresis through storm events. Despite the Enborne catchment being relatively rural for southern England, TRP inputs were dominated by constant, non-rain-related inputs from sewage treatment works (STW) for the majority of the year, producing the highest phosphorus concentrations through the spring–summer growing season. At higher river flows, the majority of the TRP load was derived from within-channel remobilisation of phosphorus from the bed sediment, much of which was also derived from STW inputs. Therefore, future phosphorus mitigation measures should focus on STW improvements. Agricultural diffuse TRP inputs were only evident during storms in the May of each year, probably relating to manure application to land. The nitrate concentration–flow relationship produced a series of dilution curves, indicating major inputs from groundwater and to a lesser extent STW. Significant diffuse agricultural inputs with anticlockwise hysteresis trajectories were observed during the first major storms of the winter period. The simultaneous investigation of high-frequency time series data, concentration–flow relationships and hysteresis behaviour through multiple storms for both phosphorus and nitrate offers a simple and innovative approach for providing new insights into nutrient sources and dynamics.
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•River P concentrations dominated by sewage effluent for most of annually cycle•River N concentrations dominated by groundwater inputs•Major clockwise hystereses due to mobilisation of sewage-derived P in bed sediment•Large diffuse P inputs occurring during May storms, related to manure applications
This paper introduces new insights into the hydrochemical functioning of lowland river systems using field-based spectrophotometric and electrode technologies. The streamwater concentrations of ...nitrogen species and phosphorus fractions were measured at hourly intervals on a continuous basis at two contrasting sites on tributaries of the River Thames - one draining a rural catchment, the River Enborne, and one draining a more urban system, The Cut. The measurements complement those from an existing network of multi-parameter water quality sondes maintained across the Thames catchment and weekly monitoring based on grab samples. The results of the sub-daily monitoring show that streamwater phosphorus concentrations display highly complex dynamics under storm conditions dependent on the antecedent catchment wetness, and that diurnal phosphorus and nitrogen cycles occur under low flow conditions. The diurnal patterns highlight the dominance of sewage inputs in controlling the streamwater phosphorus and nitrogen concentrations at low flows, even at a distance of 7 km from the nearest sewage treatment works in the rural River Enborne. The time of sample collection is important when judging water quality against ecological thresholds or standards. An exhaustion of the supply of phosphorus from diffuse and multiple septic tank sources during storm events was evident and load estimation was not improved by sub-daily monitoring beyond that achieved by daily sampling because of the eventual reduction in the phosphorus mass entering the stream during events. The results highlight the utility of sub-daily water quality measurements and the discussion considers the practicalities and challenges of in situ, sub-daily monitoring.
In the face of emerging and re-emerging diseases, novel and innovative approaches to population scale surveillance are necessary for the early detection and quantification of pathogens. The last ...decade has seen the rapid development of wastewater and environmental surveillance (WES) to address public health challenges, which has led to establishment of wastewater-based epidemiology (WBE) approaches being deployed to monitor a range of health hazards. WBE exploits the fact that excretions and secretions from urine, and from the gut are discharged in wastewater, particularly sewage, such that sampling sewage systems provides an early warning system for disease outbreaks by providing an early indication of pathogen circulation. While WBE has been mainly used in locations with networked wastewater systems, here we consider its value for less connected populations typical of lower-income settings, and in assess the opportunity afforded by pit latrines to sample communities and localities. We propose that where populations struggle to access health and diagnostic facilities, and despite several additional challenges, sampling unconnected wastewater systems remains an important means to monitor the health of large populations in a relatively cost-effective manner.
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•Many populations are unconnected to centralised sewage systems in Lower Middle-Income countries.•Pit latrines are a common form of sewage disposal.•Communities can be successfully surveyed using a tailored wastewater-based epidemiology approach.•Environmental sampling in Lower Middle-Income countries requires robust sampling approaches.
•Wastewater sequencing was used to track SARS-CoV-2 variant frequencies in Liverpool.•Fine-scale differences in variant dynamics between parts of the city can be detected.•Wastewater and clinical ...variant dynamics are closely matched.•First detection of a new variant can occur in either wastewater or clinical samples.•Wastewater monitoring gives information unbiased by individual testing engagement.
Genomic surveillance of SARS-CoV-2 has provided a critical evidence base for public health decisions throughout the pandemic. Sequencing data from clinical cases has helped to understand disease transmission and the spread of novel variants. Genomic wastewater surveillance can offer important, complementary information by providing frequency estimates of all variants circulating in a population without sampling biases. Here we show that genomic SARS-CoV-2 wastewater surveillance can detect fine-scale differences within urban centres, specifically within the city of Liverpool, UK, during the emergence of Alpha and Delta variants between November 2020 and June 2021. Furthermore, wastewater and clinical sequencing match well in the estimated timing of new variant rises and the first detection of a new variant in a given area may occur in either clinical or wastewater samples. The study's main limitation was sample quality when infection prevalence was low in spring 2021, resulting in a lower resolution of the rise of the Delta variant compared to the rise of the Alpha variant in the previous winter. The correspondence between wastewater and clinical variant frequencies demonstrates the reliability of wastewater surveillance. However, discrepancies in the first detection of the Alpha variant between the two approaches highlight that wastewater monitoring can also capture missing information, possibly resulting from asymptomatic cases or communities less engaged with testing programmes, as found by a simultaneous surge testing effort across the city.
Intestinal dysbiosis is implicated in the origins of necrotising enterocolitis and late-onset sepsis in preterm babies. However, the effect of modulators of bacterial growth (e.g. antibiotics) upon ...the developing microbiome is not well-characterised. In this prospectively-recruited, retrospectively-classified, case-control study, high-throughput 16S rRNA gene sequencing was combined with contemporaneous clinical data collection, to assess the within-subject relationship between antibiotic administration and microbiome development, in comparison to preterm infants with minimal antibiotic exposure.
During courses of antibiotics, diversity progression fell in comparison to that seen outside periods of antibiotic use (-0.71units/week vs. + 0.63units/week, p < 0.01); Enterobacteriaceae relative abundance progression conversely rose (+ 10.6%/week vs. -8.9%/week, p < 0.01). After antibiotic cessation, diversity progression remained suppressed (+ 0.2units/week, p = 0.02).
Antibiotic use has an acute and longer-lasting impact on the developing preterm intestinal microbiome. This has clinical implications with regard to the contribution of antibiotic use to evolving dysbiosis, and affects the interpretation of existing microbiome studies where this effect modulator is rarely accounted for.
The Adolescent Brain Cognitive Development (ABCD) Study
is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track ...neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.
Electroconvulsive therapy (ECT) and ketamine treatment both induce rapidly acting antidepressant effects in patients with major depressive disorder unresponsive to standard treatments, yet their ...specific impact on emotion processing is unknown. Here, we examined the neural underpinnings of emotion processing within and across patients (N = 44) receiving either ECT (N = 17, mean age: 36.8, 11.0 SD) or repeated subanesthetic (0.5 mg/kg) intravenous ketamine therapy (N = 27, mean age: 37.3, 10.8 SD) using a naturalistic study design. MRI and clinical data were collected before (TP1) and after treatment (TP2); healthy controls (N = 31, mean age: 34.5, 13.5 SD) completed one MRI session (TP1). An fMRI face‐matching task probed negative‐ and positive‐valence systems. Whole‐brain analysis, comparing neurofunctional changes within and across treatment groups, targeted brain regions involved in emotional facial processing, and included regions‐of‐interest analysis of amygdala responsivity. Main findings revealed a decrease in amygdalar reactivity after both ECT and ketamine for positive and negative emotional face processing (p < .05 family wise‐error (FWE) corrected). Subthreshold changes were observed between treatments within the dorsolateral prefrontal cortex and insula (p < .005, uncorrected). BOLD change for positive faces in the inferior parietal cortex significantly correlated with overall symptom improvement, and BOLD change in frontal regions correlated with anxiety for negative faces, and anhedonia for positive faces (p < .05 FWE corrected). Both serial ketamine and ECT treatment modulate amygdala response, while more subtle treatment‐specific changes occur in the larger functional network. Findings point to both common and differential mechanistic upstream systems‐level effects relating to fast‐acting antidepressant response, and symptoms of anxiety and anhedonia, for the processing of emotionally valenced stimuli.
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