Defining tetrahydrobiopterin responsiveness in phenylketonuria: Survey results from 38 countries.

BACKGROUND: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world. METHODS: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). RESULTS: We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. CONCLUSION: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.

EcoAnthromes of Alberta: An example of disturbance-informed ecological regionalization using remote sensing.

Humans influence ecosystems on magnitudes that often exceed that of natural forces such as climate and geology; however, frameworks rarely include anthropogenic disturbance when delineating unique ecological regions. A critical step toward understanding, managing and monitoring human-altered ecosystems is to incorporate disturbance into ecological regionalizations. Furthermore, quantitative regionalization approaches are desirable to provide cost-effective, repeatable and statistically sound stratification for environmental monitoring. We applied a two-stage multivariate clustering technique to identify 'EcoAnthromes' across a large area - the province of Alberta, Canada - at 30 m spatial resolution, and using primarily remotely sensed inputs. The EcoAnthrome clusters represent regions with unique ecological characteristics based on a combination of natural ecological potential (e.g., climatic and edaphic factors) and disturbance, both natural and anthropogenic. Compared to existing expert-derived Natural Subregions in Alberta, the model-based EcoAnthromes showed greater class separation and explained more variance for an assortment of variables related to land cover, disturbance and species intactness. The EcoAnthromes successfully separated important ecological regions that are defined by complex assemblages of topography, climate and disturbance, such as gravel-bed river valleys, boreal forests, grasslands, post-fire recovery areas and highly disturbed agricultural, industrial and urban landscapes. In addition to presenting a flexible method for EcoAnthrome regionalization, we group and describe the EcoAnthromes created for Alberta and discuss how they can complement expert-derived regionalizations to aid in environmental management efforts, such as species recovery planning and monitoring for threatened species.

Pharmacokinetics of a novel extended half-life glycoPEGylated factor IX, nonacog beta pegol (N9-GP) in previously treated patients with haemophilia B: results from two phase 3 clinical trials.

INTRODUCTION: Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (FIX) with an extended half-life developed for routine prophylaxis and the prevention and treatment of bleeding episodes in patients with haemophilia B. AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP. METHODS: Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL-1 ) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg-1 or 40 IU kg-1 in adolescents/adults and 40 IU kg-1 in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed. RESULTS: Incremental recoveries were 0.02 (IU mL-1 )/(IU kg-1 ) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL-1 for adolescents/adults and 0.17 IU mL-1 for children at steady-state after weekly dosing at 40 IU kg-1 . The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL-1 at all times and 6.4 days week-1 in children. CONCLUSION: N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product.

INTRODUCTION: Health-related quality of life (HRQoL) of individuals with haemophilia has greatly improved with the use of factor replacement and routine prophylaxis. AIM: To explore the HRQoL of individuals with haemophilia B treated with nonacog beta pegol, an extended half-life recombinant factor IX, in a single-blind, randomized multinational phase III pivotal trial (paradigm(™) 2) and its open-label extension (paradigm(™) 4). METHODS: In the pivotal trial, adolescents and adults with haemophilia B were allocated to 28-week on-demand treatment or randomized to 52 weeks of prophylaxis with 10 or 40 IU kg(-1) nonacog beta pegol administered every seven days. In the extension trial, patients could continue on the same treatment or switch to the alternate dosing regimen at any time. HRQoL was assessed with the HAEMO-QOL/HAEM-A-QOL age-specific questionnaires and the EQ-5D. RESULTS: In the pivotal trial, adults receiving 40 IU kg(-1) prophylaxis reported significant improvements in the 'HAEM-A-QOL Total' score (-6.4 ± 8.5, P = 0.017) and in 'Sport' (-15.3 ± 8.5, P = 0.020), 'Feeling' (-15.2 ± 18.3, P = 0.010) and 'Partnership' (-9.6 ± 15.5, P = 0.046) domain scores; no significant improvements were seen in the other arms. At the pivotal trial end, fewer patients reported problems in the EQ-5D 'Mobility' and 'Pain/Discomfort' dimensions, in particular those receiving prophylaxis. In the extension trial, adult patients switching from 10 to 40 IU kg(-1) prophylaxis showed significant improvements in 'HAEM-A-QOL Total' score (-12.5 ± 8.7, P = 0.016) and 'Physical health' domain (-23.1 ± 14.4, P = 0.016). CONCLUSION: Prophylactic treatment with nonacog beta pegol 40 IU kg(-1) once weekly leads to HRQoL benefits in individuals with haemophilia B; this might be related to fewer bleeding episodes and higher FIX activity levels.

Neonatal circumcision in severe haemophilia: a survey of paediatric haematologists at United States Hemophilia Treatment Centers.

Neonatal circumcision in patients with severe haemophilia has not been well studied. We performed a survey of paediatric haematologists from Hemophilia Treatment Centers (HTC) across the United States to better understand the attitudes toward and management of neonatal circumcision in haemophilia patients. Response rate to our survey was 40% (n = 64/159). Thirty-eight percent of respondents (n = 24) said that they would allow this procedure in the newborn period but in many cases this was against medical advice. The most reported concern regarding neonatal circumcision in haemophilia patients was the risk of development of an inhibitor (n = 25; 39%) followed by the concern for bleeding (n = 22; 34%) and issues related to vascular access in the neonate (n = 11; 17%). All respondents recommended at least one preprocedure dose of factor replacement. Twenty-two percent (n = 14) of respondents did not use more than one dose of factor replacement but 32% (n = 21) used 1-2 postoperative doses. The remainder of paediatric haematologists surveyed recommended between 3-5 (16%; n = 10) and 6-10 (3%, n = 2) additional days postoperatively. There was wide variation in both techniques of circumcision as well as adjuvant haemostatic agents used. Only 22% of respondents said that they had an established protocol for management of circumcision in the newborn haemophilia patient. These survey results highlight the need for evidence-based guidelines regarding the optimal management of circumcision in neonates with severe haemophilia.

Intellectual and neurological functioning in Morquio syndrome (MPS IVa).

Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6-sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored.

Diffuse interlobular septal thickening in a coal miner.

Diffuse interlobular septal thickening (DIST) is an abnormality seen on high-resolution CT (HRCT) scanning of the thorax. While DIST may be present to variable extents in a number of lung conditions, it is uncommon as a predominant finding except in a few entities. This report features an ex-coal miner, thought to have coal workers' pneumoconiosis (CWP), in whom the HRCT scan showed no evidence of CWP and instead showed DIST. The patient's condition progressed incessantly towards death from severe secondary pulmonary hypertension. The case links fatal pulmonary hypertension to DIST, a pattern not previously described in coal workers.

A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research.

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.

Recombinant factor XIII prophylaxis is safe and effective in young children with congenital factor XIII-A deficiency: international phase 3b trial results.

Essentials Prophylaxis is the standard of care for congenital factor XIII-A (FXIII-A) deficiency. Six children with FXIII-A deficiency received once-monthly prophylaxis with recombinant FXIII-A. Prophylaxis was well tolerated and no anti-FXIII antibodies were detected. Prophylaxis was effective with an annualized bleeding rate of zero. SUMMARY: Background Factor XIII deficiency is a rare, severe congenital bleeding disorder. Monthly prophylaxis with recombinant FXIII A-Subunit (rFXIII) has demonstrated favorable safety and efficacy in patients aged ≥ 6 years, and may similarly benefit younger children. Objective To evaluate the long-term safety and efficacy of rFXIII in children aged < 6 years with congenital FXIII A-subunit deficiency. Patients/methods Six children, who had previously completed a single-dose pharmacokinetic trial of rFXIII, received 35 IU kg-1 rFXIII every 28 days (± 2 days) for a minimum of 52 weeks, and were evaluated for bleeding and adverse events. The Berichrom FXIII activity assay was used to monitor FXIII activity. Results The children, three girls and three boys, had an average age of 3.0 years (range: 1-4 years) at enrollment. The total treatment duration was 1.8-3.5 years, giving a total of 16.6 patient-years. No antibody development, thromboembolic events or allergic reactions occurred. There were 93 mild and seven moderate adverse events. Two adverse events (lymphopenia and gastroenteritis) were reported as probably or possibly related to rFXIII in two children. Two serious adverse events, unrelated to rFXIII, were reported in a single child, each related to head injury, and neither resulting in intracranial hemorrhage. The geometric mean FXIII activity trough was 0.19 IU mL-1 . No bleeding episodes requiring treatment with an FXIII-containing hemostatic agent occurred during the trial; thus, the annualized bleeding rate was 0. Conclusions Consistent with data from older age groups, prophylaxis with rFXIII appears to be safe and effective in young children with congenital FXIII A-subunit deficiency.

The complete European guidelines on phenylketonuria: diagnosis and treatment.

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial.

UNLABELLED: Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys ≤ 12 years. A 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys ≤ 12 years with hemophilia B. SUMMARY: Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm(™) 5, enrolled and treated 25 children (aged ≤ 12 years) with hemophilia B (FIX ≤ 2%). Patients were stratified by age (0-6 years and 7-12 years), and received once-weekly prophylaxis with 40 IU kg(-1) nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated.

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles.

BACKGROUND: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. AIM: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. METHODS: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. RESULTS: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. CONCLUSIONS: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence.

Absence of mutations in the VHL gene but frequent loss of heterozygosity at 3p25-26 in non-small cell lung carcinomas.

In this study we have examined 79 primary non-small cell lung tumours for the presence of mutations of the VHL gene as well as for allelic imbalance at the gene surrounding loci. While allelic imbalance was found in 83% of specimens, frequently affecting the whole 3p25-p26 region, no mutations were detected in the VHL coding region. The fractional regional loss (FRL) was significantly higher in squamous cell carcinomas (0.746) than adenocarcinomas (0.493) (Wilcoxon P=0.002). This is the first investigation of the VHL gene mutational status in primary lung tumours. Our results indicate that mutation is not a common means of VHL inactivation in NSCLC.

Acute severe asthma treated by mechanical ventilation: a comparison of the changing characteristics over a 17 yr period.

Recorded cases of asthma have increased in recent years. It is unclear, however, whether this apparent increase in prevalence is accompanied by an increase in severity of the disorder. One potential measure of asthma severity is the requirement for mechanical ventilation. This paper examines those patients ventilated for severe asthma in a district general hospital over a 17 yr period. Since the methods used to assess asthma attacks and the criteria for instituting mechanical ventilation in this hospital did not alter between 1973 and 1992 (Jones criteria), it was possible to compare directly characteristics of all ventilated patients during the study period. The comparison showed that there was a significant increase between the two study periods in the number of patients who required mechanical ventilation. Moreover, in the more recent period both the subjective speed of onset of the asthma attack and the objective time between admission and ventilation were significantly shorter. However, despite this increase in asthma severity the mortality and morbidity in the more recent study period were lower. Overall the results of this study support the view that, in the population served by our district general hospital, asthma has increased in severity. This increased severity is indicated by an increase in the number of patients requiring mechanical ventilation and in the rapidity with which attacks evolved. However, for patients in whom ventilation was required, improved care has lowered both morbidity and mortality.

CT scanning of the paranasal sinuses--the effect of reducing mAs.

High quality CT scans are required prior to fibreoptic endoscopic sinus surgery (FESS) surgery and in many institutions such scans are performed using a high mAs technique. Consequently, the investigation imparts a radiation dose to the patient and in particular to the eye. Such a radiation dose is a possible source of morbidity. We believe that the mAs, and consequently the radiation dose, can be considerably reduced without affecting scan quality. The present study compares the quality of sinus CT scans performed at two mAs values, 40 and 60. Scan quality was assessed in terms of the ability to visualize clearly important anatomical structures and in terms of overall perceived quality. We show that mAs values as low as 40 can be used without adversely affecting the diagnostic quality of the examination.

The characteristics and significance of thoracic lymphadenopathy in parapneumonic effusion and empyema.

The occurrence of significant mediastinal lymphadenopathy together with pleural effusion or empyema inevitably raises concern about the presence of intrathoracic malignancy or granulomatous disease. Lymph node enlargement may also occur when pneumonia is accompanied by a parapneumonic effusion or empyema. Features that allow "benign" lymph node enlargement to be distinguished from malignant causes have not previously been determined. The present study aims to establish the CT characteristics of enlarged nodes in parapneumonic effusion. The appearances of mediastinal lymph nodes were recorded in 50 consecutive patients with parapneumonic effusion/empyema. 18 (36%) had mediastinal lymphadenopathy (node size greater than 1 cm). The mean number of enlarged nodes was 1.9 (range 1-3) and the mean size was 1.4 cm (2 cm maximum). Seven patients had a single involved site, nine patients two sites and two patients three sites. The right paratracheal area was most commonly involved and the subcarinal area contained the largest nodes. The presence of enlarged nodes did not correlate with biochemical and microbiological stage of pleural infection, length of history, or extent of consolidation. This study shows that mediastinal lymphadenopathy is commonly associated with parapneumonic effusion and that multiple sites may be involved. The degree of enlargement is moderate although lymphadenopathy of greater than 2 cm size should raise the possibility of other pathology.

The effects of alcohol on speed perception in a closed-course driving situation.

The present study examined the effect of alcohol on the perception of speed in a closed-course driving situation. Male subjects (N = 24) classified with respect to previous drinking experience were used in the experiment. Each subject was tested on a speed estimation task at blood alcohol levels (BALs) of 0 and 100 mg/dl. Subjects were required to decelerate from a constant speed of 30 mph to a target speed of 20 mph under two conditions: using their speedometer and being deprived of its use. Of interest were the subjective judgments made under the latter conditions. Results show that there was no significant effect of alcohol on the perception of speed. The expected interaction between previous drinking experience and alcohol dose was found to be nonsignificant. Overall, a significant difference in performance between the two speedometer conditions indicated that subjects overestimated the target speed when they were not given access to their speedometer. Possible explanations and implications of these findings are discussed and future directions for research are suggested.

Lithium mania: play and learn.

The authors describe an instructional game, Lithium Mania, which they developed to assist in teaching psychiatric clients who were taking lithium about their medication. This game can be used in a formal or recreational setting. The goal of learning made fun was to increase compliance and decrease recidivism.