Multi-GeV Electron Acceleration in Wakefields Strongly Driven by Oversized Laser Spots.

Experiments were performed on laser wakefield acceleration in the highly nonlinear regime. With laser powers P<250 TW and using an initial spot size larger than the matched spot size for guiding, we were able to accelerate electrons to energies E_{max}>2.5 GeV, in fields exceeding 500 GV m^{-1}, with more than 80 pC of charge at energies E>1 GeV. Three-dimensional particle-in-cell simulations show that using an oversized spot delays injection, avoiding beam loss as the wakefield undergoes length oscillation. This enables injected electrons to remain in the regions of highest accelerating fields and leads to a doubling of energy gain as compared to results from using half the focal length with the same laser.

Hepatobiliary circulation and dominant urinary excretion of homogentisic acid in a mouse model of alkaptonuria.

Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production. The aim of this study was to investigate the phe-tyr metabolite content of key biofluids and tissues in AKU mice on and off nitisinone to gain new insights into the biodistribution of metabolites in these altered metabolic states. The data show for the first time that HGA is present in bile in AKU (mean [±SD] = 1003[±410] µmol/L; nitisinone-treated AKU mean [±SD] = 45[±23] µmol/L). Biliary tyrosine, 3(4-hydroxyphenyl)pyruvic acid (HPPA) and 3(4-hydroxyphenyl)lactic acid (HPLA) are also increased on nitisinone. Urine was confirmed as the dominant elimination route of HGA in untreated AKU, but with indication of biliary excretion. These data provide new insights into pathways of phe-tyr metabolite biodistribution and metabolism, showing for the first time that hepatobiliary excretion contributes to the total pool of metabolites in this pathway. Our data suggest that biliary elimination of organic acids and other metabolites may play an underappreciated role in disorders of metabolism. We propose that our finding of approximately 3.8 times greater urinary HGA excretion in AKU mice compared with patients is one reason for the lack of extensive tissue ochronosis in the AKU mouse model.

Equipping for risk: Lessons learnt from the UK shale-gas experience on assessing environmental risks for the future geoenergy use of the deep subsurface.

findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH4). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane. The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term.

Habitat traits and predation interact to drive abundance and body size patterns in associated fauna.

Habitat-forming organisms provide three-dimensional structure that supports abundant and diverse communities. Variation in the morphological traits of habitat formers will therefore likely influence how they facilitate associated communities, either via food and habitat provisioning, or by altering predator-prey interactions. These mechanisms, however, are typically studied in isolation, and thus, we know little of how they interact to affect associated communities. In response to this, we used naturally occurring morphological variability in the alga Sargassum vestitum to create habitat units of distinct morphotypes to test whether variation in the morphological traits (frond size and thallus size) of S. vestitum or the interaction between these traits affects their value as habitat for associated communities in the presence and absence of predation. We found morphological traits did not interact, instead having independent effects on epifauna that were negligible in the absence of predation. However, when predators were present, habitat units with large fronds were found to host significantly lower epifaunal abundances than other morphotypes, suggesting that large frond alga provided low-value refuge from predators. The presence of predators also influenced the size structure of epifaunal communities from habitat units of differing frond size, suggesting that the refuge value of S. vestitum was also related to epifauna body size. This suggests that habitat formers may chiefly structure associated communities by mediating size-selective predation, and not through habitat provisioning. Furthermore, these results also highlight that habitat traits cannot be considered in isolation, for their interaction with biotic processes can have significant implications for associated communities.

Approach-avoidance biases to self-harm cues in young people with self-harm.

BACKGROUND: The urge to self-harm can be likened to craving in addictive behaviours. However, it remains unclear whether cognitive mechanisms involved in craving, such as attentional biases to cues, also underpin the urge to self-harm. METHODS: A Dot Probe Task was used to investigate attentional biases to self-harm cues in young people aged 16-25 with self-harm. Cues were shown for either 0.2 s or 2 s. Dot Probe Task performance in the Self-harm group (N = 50) was compared with age-matched Healthy Controls (N = 50) and age- and negative-affect (Depression Anxiety Stress Scale-21) matched controls with no self-harm (N = 50). RESULTS: The Self-harm group showed significantly greater avoidance of self-harm cues than Healthy Controls at 2 s. The Negative Affect group showed significantly less difficulty disengaging from self-harm cues than the Self-harm group and Healthy Controls at 2 s. There were no between-group differences in attentional bias at 0.2 s. LIMITATIONS: Study limitations that may affect attentional biases in the Self-harm group include not measuring indicators of recovery and recruiting only from the community potentially missing more severe self-harm presentations in clinical settings. CONCLUSIONS: Avoidance of self-harm cues in young people with self-harm may reflect conflict around self-harm behaviour, consistent with ambivalence models of craving. An ability to disengage from self-harm cues may be a protective factor in young people with higher levels of negative affect who do not self-harm. Whether these attentional biases represent a quantifiable marker of treatment response or susceptibility to relapse in individuals with self-harm remains an area for future investigation.

Ocean current patterns drive the worldwide colonization of eelgrass (Zostera marina).

Currents are unique drivers of oceanic phylogeography and thus determine the distribution of marine coastal species, along with past glaciations and sea-level changes. Here we reconstruct the worldwide colonization history of eelgrass (Zostera marina L.), the most widely distributed marine flowering plant or seagrass from its origin in the Northwest Pacific, based on nuclear and chloroplast genomes. We identified two divergent Pacific clades with evidence for admixture along the East Pacific coast. Two west-to-east (trans-Pacific) colonization events support the key role of the North Pacific Current. Time-calibrated nuclear and chloroplast phylogenies yielded concordant estimates of the arrival of Z. marina in the Atlantic through the Canadian Arctic, suggesting that eelgrass-based ecosystems, hotspots of biodiversity and carbon sequestration, have only been present there for ~243 ky (thousand years). Mediterranean populations were founded ~44 kya, while extant distributions along western and eastern Atlantic shores were founded at the end of the Last Glacial Maximum (~19 kya), with at least one major refuge being the North Carolina region. The recent colonization and five- to sevenfold lower genomic diversity of the Atlantic compared to the Pacific populations raises concern and opportunity about how Atlantic eelgrass might respond to rapidly warming coastal oceans.

Coherent Control of Trapped-Ion Qubits with Localized Electric Fields.

We present a new method for coherent control of trapped ion qubits in separate interaction regions of a multizone trap by simultaneously applying an electric field and a spin-dependent gradient. Both the phase and amplitude of the effective single-qubit rotation depend on the electric field, which can be localized to each zone. We demonstrate this interaction on a single ion using both laser-based and magnetic-field gradients in a surface-electrode ion trap, and measure the localization of the electric field.

Host genetic identity determines parasite community structure across time and space in oyster restoration.

Intraspecific variation in host susceptibility to individual parasite species is common, yet how these effects scale to mediate the structure of diverse parasite communities in nature is less well understood. To address this knowledge gap, we tested how host genetic identity affects parasite communities on restored reefs seeded with juvenile oysters from different sources-a regional commercial hatchery or one of two wild progenitor lines. We assessed prevalence and intensity of three micro- and two macroparasite species for 4 years following restoration. Despite the spatial proximity of restored reefs, oyster source identity strongly predicted parasite community prevalence across all years, with sources varying in their relative susceptibility to different parasites. Oyster seed source also predicted reef-level parasite intensities across space and through time. Our results highlight that host intraspecific variation can shape parasite community structure in natural systems, and reinforce the importance of considering source identity and diversity in restoration design.

The Outreach Virtual Fracture Clinic - a Pilot Report of the Initial Nine Months.

The virtual fracture clinic (VFC) enables the safe, cost-effective delivery of high-quality patient-centred fracture care, whilst reducing hospital footfall. Within our institution, an Outreach VFC was launched, accepting a pre-defined range of trauma referrals from the outreach centre's emergency department (ED). The initial nine months' worth of cases referred to the Outreach VFC were assessed. The injury pattern, time to review, treatment plan and discharge destination of each referred patient were examined. A total of 822 patients were referred to the Outreach VFC during its initial nine months in operation. Owing to COVID-19-related alterations in the patient pathway, 58.1% of patients were referred on to fracture clinic/ED, with 34.4% of patients being referred for physiotherapy input. 44.9% of patients were reviewed at the Outreach VFC within 72 hours of ED presentation, with 88.6% of patients reviewed within 7 days. The Outreach VFC pilot initiative saved the Dublin Midlands Hospitals Group approximately €83,022 over nine months. The Outreach VFC model represents a novel approach to trauma care delivery with advantages for patient and hospital alike. Rural communities serve to benefit from its future implementation and the remote management of orthopaedic trauma. The Outreach VFC model provides a means of delivering safe and timely orthopaedic care whilst maintaining high levels of patient satisfaction.

An exploration of values-based radiography from the perspective of the service user.

INTRODUCTION: This article presents the patient outcomes of a CoRIPS funded study which investigated the values of patients in both a diagnostic and therapeutic setting. Little work has been conducted to ascertain patient values and these have previously been presumed. METHOD: The study used focus groups, conducted by two experienced researchers, to allow participants the opportunity to discuss their values during imaging examinations and therapeutic treatments. The resultant discussions were audio recorded and transcribed before a thematic analysis was conducted. A sample of the data was reviewed by both researchers to demonstrate credibility and confirmability. RESULTS: The main themes identified were related to radiographer professional skills, communication and compassion. Both diagnostic and therapeutic participants shared values despite the difference in their examinations and treatments. They valued being seen as an individual and felt that radiographer communication contributed to this. Patients value being able to access information to help them prepare for their examination or treatment. During the examination they value the skills of the radiographer which they assumed. The patients also value the radiographer taking their time over the examination as they relate this the quality of the examination or treatment. After the imaging or treatment they valued being able to see their images and have their questions answered. Patient responses suggested that their values were not always met in practice. CONCLUSION: The values of the patients were successfully explored using focus groups. Patient values relate to radiographer professional skills, communication and compassion. Patients do not always have their values met during their examinations and treatments. Radiographers in practice should be mindful that patients value being treated as individuals and be provided with information throughout their imaging and treatment. Recommendations for practice were identified.

The effect of warming on seagrass wasting disease depends on host genotypic identity and diversity.

Temperature increases due to climate change have affected the distribution and severity of diseases in natural systems, causing outbreaks that can destroy host populations. Host identity, diversity, and the associated microbiome can affect host responses to both infection and temperature, but little is known about how they could function as important mediators of disease in altered thermal environments. We conducted an 8-week warming experiment to test the independent and interactive effects of warming, host genotypic identity, and host genotypic diversity on the prevalence and intensity of infections of seagrass (Zostera marina) by the wasting disease parasite (Labyrinthula zosterae). At elevated temperatures, we found that genotypically diverse host assemblages had reduced infection intensity, but not reduced prevalence, relative to less diverse assemblages. This dilution effect on parasite intensity was the result of both host composition effects as well as emergent properties of biodiversity. In contrast with the benefits of genotypic diversity under warming, diversity actually increased parasite intensity slightly in ambient temperatures. We found mixed support for the hypothesis that a growth-defense trade-off contributed to elevated disease intensity under warming. Changes in the abundance (but not composition) of a few taxa in the host microbiome were correlated with genotype-specific responses to wasting disease infections under warming, consistent with the emerging evidence linking changes in the host microbiome to the outcome of host-parasite interactions. This work emphasizes the context dependence of biodiversity-disease relationships and highlights the potential importance of interactions among biodiversity loss, climate change, and disease outbreaks in a key foundation species.

The influence of erosion sources on sediment-related water quality attributes.

Suspended fine sediment has a significant impact on freshwater quality variables such as visual clarity (VC). However, freshwater quality is related to the attributes of the catchment sources contributing fine sediment to the stream network. Here, the extent to which an array of sources defined spatially according to erosion process and geological parent material may be discriminated and classified based on sediment-related water quality (SRWQ) attributes that potentially affect VC was examined. Erosion sources were sampled across two New Zealand catchments representing six types of erosion and eight parent materials. Erosion source measurements focused on particle size, organic matter content, and light beam attenuation (which is convertible to VC). The source data were analysed to: 1) evaluate source variability using a combination of Kruskal-Wallis and principal component analysis; 2) reclassify sources using a Random Forest model; and 3) demonstrate how erosion source affects VC for a range of theoretical sediment concentrations (SC) using a simple empirical model. The results indicate that SRWQ attributes show significant variation across erosion sources. The extent to which attributes differed between sources often related to whether there was a strong association between a specific erosion process and parent material. The 19 a priori source classifications were reduced to 5 distinct sources that combined erosion process and parent material (i.e., bank erosion-alluvium; mass movement-ancient volcanics; mass movement-sedimentary; surficial erosion; gully-unconsolidated sandstone). At low SC, the impact of erosion source on VC became most evident ranging from 2.6 to 5.6 m at SC of 5 g m-3. These findings show how catchment sources of sediment, in addition to sediment concentration, influence VC, and highlight the need to consider quality as well as quantity of material supplied to stream networks when planning erosion control.

Atmosphere-Snow Exchange Explains Surface Snow Isotope Variability.

The climate signal imprinted in the snow isotopic composition allows to infer past climate variability from ice core stable water isotope records. The concurrent evolution of vapor and surface snow isotopic composition between precipitation events indicates that post-depositional atmosphere-snow humidity exchange influences the snow and hence the ice core isotope signal. To date, however, this is not accounted for in paeleoclimate reconstructions from isotope records. Here we show that vapor-snow exchange explains 36% of the summertime day-to-day δ18O variability of the surface snow between precipitation events, and 53% of the δD variability. Through observations from the Greenland Ice Sheet and accompanying modeling we demonstrate that vapor-snow exchange introduces a warm bias on the summertime snow isotope value relevant for ice core records. In case of long-term variability in atmosphere-snow exchange the relevance for the ice core signal is also variable and thus paleoclimate reconstructions from isotope records should be revisited.

FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study.

BACKGROUND: Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone. METHODS: Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of 'dose-limiting toxicity' (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing. DISCUSSION: Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen's use in alcoholism and guidelines for the management of opiate dependence. TRIAL REGISTRATION: Clinicaltrials.gov NCT05161351. Registered on 16 December 2021.

Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria.

Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701-900 (105), 901-1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.

The association between lumbar paraspinal muscle functional cross-sectional area on MRI and regional volumetric bone mineral density measured by quantitative computed tomography.

Osteosarcopenia is a common condition among elderly and postmenopausal female patients. Site-specific bone mineral density is more predictive of bone-related complications. Few studies have investigated muscle-bone associations. Our results demonstrated that in women, significant positive associations between paraspinal muscles FCSA and vBMD exist at different lumbosacral levels. These regional differences should be considered when interpreting bone-muscle associations in the lumbar spine. INTRODUCTION: There is increasing evidence between bone and muscle volume associations. Previous studies have demonstrated comorbidity between osteoporosis and sarcopenia. Recent studies showed that sarcopenic subjects had a fourfold higher risk of concomitant osteoporosis compared to non-sarcopenic individuals. Although site-specific bone mineral density (BMD) assessments were reported to be more predictive of bone-related complications after spinal fusions than BMD assessments in general, there are few studies that have investigated level-specific bone-muscle interactions. The aim of this study is to investigate the associations between muscle functional cross-sectional area (FCSA) on magnetic resonance imaging (MRI) and site-specific quantitative computed tomography (QCT) volumetric bone mineral density (vBMD) in the lumbosacral region among spine surgery patients. METHODS: We retrospectively reviewed a prospective institutional database of posterior lumbar fusion patients. Patients with available MRI undergoing posterior lumbar fusion were included. Muscle measurements and FCSA were conducted and calculated utilizing a manual segmentation and custom-written program at the superior endplate of the L3-L5 vertebrae level. vBMD measurements were performed and calculated utilizing a QCT pro software at L1-L2 levels and bilateral sacral ala. We stratified by sex for all analyses. RESULTS: A total of 105 patients (mean age 61.5 years and 52.4% females) were included. We found that female patients had statistically significant lower muscle FCSA than male patients. After adjusting for age and body mass index (BMI), there were statistically significant positive associations between L1-L2 and S1 vBMD with L3 psoas FCSA as well as sacral ala vBMD with L3 posterior paraspinal and L5 psoas FCSA. These associations were not found in males. CONCLUSIONS: Our results demonstrated that in women, significant positive associations between the psoas and posterior paraspinal muscle FCSA and vBMD exist in different lumbosacral levels, which are independent of age and BMI. These regional differences should be considered when interpreting bone and muscle associations in the lumbar spine.

A Pleistocene legacy structures variation in modern seagrass ecosystems.

Distribution of Earth's biomes is structured by the match between climate and plant traits, which in turn shape associated communities and ecosystem processes and services. However, that climate-trait match can be disrupted by historical events, with lasting ecosystem impacts. As Earth's environment changes faster than at any time in human history, critical questions are whether and how organismal traits and ecosystems can adjust to altered conditions. We quantified the relative importance of current environmental forcing versus evolutionary history in shaping the growth form (stature and biomass) and associated community of eelgrass (Zostera marina), a widespread foundation plant of marine ecosystems along Northern Hemisphere coastlines, which experienced major shifts in distribution and genetic composition during the Pleistocene. We found that eelgrass stature and biomass retain a legacy of the Pleistocene colonization of the Atlantic from the ancestral Pacific range and of more recent within-basin bottlenecks and genetic differentiation. This evolutionary legacy in turn influences the biomass of associated algae and invertebrates that fuel coastal food webs, with effects comparable to or stronger than effects of current environmental forcing. Such historical lags in phenotypic acclimatization may constrain ecosystem adjustments to rapid anthropogenic climate change, thus altering predictions about the future functioning of ecosystems.

Temporal adaptations in the phenylalanine/tyrosine pathway and related factors during nitisinone-induced tyrosinaemia in alkaptonuria.

BACKGROUND: Adaptations within the phenylalanine (PHE)/tyrosine (TYR) pathway during nitisinone (NIT) are not fully understood. OBJECTIVE: To characterise the temporal changes in metabolic features in NIT-treated patients with alkaptonuria. PATIENTS AND METHODS: Serum (s) and 24-urine (u) homogentisic acid (sHGA, uHGA24), TYR (sTYR, uTYR24), PHE (sPHE, uPHE24), hydroxyphenylpyruvate (sHPPA, uHPPA24), hydroxyphenyllactate (sHPLA, uHPLA24) and sNIT were measured at baseline (V1) and until month 48 (V6) in 69 NIT-treated patients, recommended to reduce protein intake. The 24-h urine urea (uUREA24), creatinine (uCREAT24) and body weight were also measured. Amounts of tyrosine metabolites in total body water (TBW) were derived by multiplying the serum concentrations by 60% body weight, and sum of TBW and urine metabolites resulted in combined values (c). RESULTS: uUREA24 and uCREAT24 decreased between V1 and V6 during NIT, whereas body weight and sNIT increased. Linear regression coefficient between uUREA24 and uCREAT24 was extremely strong (R = 0.84). sPHE, TBWPHE and cPHE24 increased gradually from V1 to V6. A decrease in cTYR24/cPHE24, sTYR/sPHE and TBWTYR/TBWPHE was seen from V2 to V6. Serum, 24-urine and combined TYR, HPPA and HPLA either remained stable or decreased from V2 to V6. DISCUSSION: The gradual increase in PHE suggests adaptation to increasing TYR during NIT therapy. The decrease in protein intake resulted in decreased muscle mass and increased weight gain. CONCLUSION: Progressive adaptation by decreasing PHE conversion to TYR occurs over time during NIT therapy. A low protein diet results in loss of muscle mass but also weight gain suggesting an increase in fat mass.

Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria.

BACKGROUND: Although changes in the tyrosine pathway during nitisinone therapy are known, a complete characterization of the induced tyrosinaemia is lacking to improve disease management. PATIENTS AND METHODS: Our research aims were addressed by 24-h blood sampling. 40 patients with alkaptonuria (AKU), treated with 0, 1, 2, 4 and 8 mg nitisinone daily (n = 8), were studied over four weeks. Serum homogentisic acid (sHGA), tyrosine (sTYR), phenylalanine (sPHE), hydroxyphenylpyruvate (sHPPA), hydroxyphenyllactate (sHPLA) and nitisinone (sNIT) were measured at baseline and after four weeks. RESULTS: sNIT showed a clear dose-proportional response. sTYR increased markedly but with less clear-cut dose responses after nitisinone. Fasting and average 24-h (Cav) sTYR responses were similar. Individual patient sTYR 24-h profiles showed significant fluctuations during nitisinone therapy. At week 4, sTYR, sHPPA and sHPPL all showed dose-related increases compared to V0, with the greatest difference between 1 and 8 mg nitisinone seen for HPLA, while there was no change from V0 in sPHE. sHGA decreased to values around the lower limit of quantitation. DISCUSSION: There was sustained tyrosinaemia after four weeks of nitisinone therapy with significant fluctuations over the day in individual patients. Diet and degree of conversion of HPPA to HPLA may determine extent of nitisinone-induced tyrosinaemia. CONCLUSION: A fasting blood sample is recommended to monitor sTYR during nitisinone therapy Adaptations in HPPA metabolites as well as the inhibition of tyrosine aminotransferase could be contributing factors generating tyrosinaemia during nitisinone therapy.