Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol.

Purpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes. Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects. Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0-18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17×10-9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54×10-8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3×10-5), but not with rs116702638. Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.

Platelet response to aspirin in UK and Irish pregnancy cohorts: a genome-wide approach.

A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pregnant women taking low dose aspirin. Objectives were to (i) develop pregnancy-specific 95% reference intervals for a range of laboratory based platelet function tests (PFTs); (ii) select an optimal and acceptable PFT that reflected aspirin's COX-1 inhibition in women with confirmed aspirin adherence in pregnancy; and (iii) identify genomic variants that may influence pregnant women's platelet response to aspirin.The study included two independent cohorts of pregnant women. A range of PFTs and matched phenotyping with urinary 11-dehydrothromboxane B2 (11DTXB2) and nuclear magnetic resonance (NMR) spectroscopy detection of urinary salicyluric acid as a measure of aspirin adherence were performed. Genome-wide data was acquired from the UK Biobank Axiom® (Thermo Fisher Scientific). 11DTXB2 in combination with adherence testing with NMR salicyluric acid was an accurate and acceptable testing strategy for detecting biochemical aspirin responsiveness in pregnant women, with the provision of relevant reference ranges. GWAS meta-analysis found no significant single nucleotide polymorphisms in association with response to aspirin in pregnancy. Further evaluation in relation to effective dosing of aspirin in pregnancy and optimizing the benefits to specific subgroups should now be a priority for future research.

North Sea spring bloom-associated Gammaproteobacteria fill diverse heterotrophic niches.

BACKGROUND: The planktonic bacterial community associated with spring phytoplankton blooms in the North Sea is responsible for a large amount of carbon turnover in an environment characterised by high primary productivity. Individual clades belonging to the Gammaproteobacteria have shown similar population dynamics to Bacteroidetes species, and are thus assumed to fill competing ecological niches. Previous studies have generated large numbers of metagenome assembled genomes and metaproteomes from these environments, which can be readily mined to identify populations performing potentially important ecosystem functions. In this study we attempt to catalogue these spring bloom-associated Gammaproteobacteria, which have thus far attracted less attention than sympatric Alphaproteobacteria and Bacteroidetes. METHODS: We annotated 120 non-redundant species-representative gammaproteobacterial metagenome assembled genomes from spring bloom sampling campaigns covering the four years 2010-2012 and 2016 using a combination of Prokka and PfamScan, with further confirmation via BLAST against NCBI-NR. We also matched these gene annotations to 20 previously published metaproteomes covering those sampling periods plus the spring of 2009. RESULTS: Metagenome assembled genomes with clear capacity for polysaccharide degradation via dedicated clusters of carbohydrate active enzymes were among the most abundant during blooms. Many genomes lacked gene clusters with clearly identifiable predicted polysaccharide substrates, although abundantly expressed loci for the uptake of large molecules were identified in metaproteomes. While the larger biopolymers, which are the most abundant sources of reduced carbon following algal blooms, are likely the main energy source, some gammaproteobacterial clades were clearly specialised for smaller organic compounds. Their substrates range from amino acids, monosaccharides, and DMSP, to the less expected, such as terpenoids, and aromatics and biphenyls, as well as many 'unknowns'. In particular we uncover a much greater breadth of apparent methylotrophic capability than heretofore identified, present in several order level clades without cultivated representatives. CONCLUSIONS: Large numbers of metagenome assembled genomes are today publicly available, containing a wealth of readily accessible information. Here we identified a variety of predicted metabolisms of interest, which include diverse potential heterotrophic niches of spring bloom-associated Gammaproteobacteria. Features such as those identified here could well be fertile ground for future experimental studies.

Tight Adherence (Tad) Pilus Genes Indicate Putative Niche Differentiation in Phytoplankton Bloom Associated Rhodobacterales.

The multiple interactions of phytoplankton and bacterioplankton are central for our understanding of aquatic environments. A prominent example of those is the consistent association of diatoms with Alphaproteobacteria of the order Rhodobacterales. These photoheterotrophic bacteria have traditionally been described as generalists that scavenge dissolved organic matter. Many observations suggest that members of this clade are specialized in colonizing the microenvironment of diatom cells, known as the phycosphere. However, the molecular mechanisms that differentiate Rhodobacterales generalists and phycosphere colonizers are poorly understood. We investigated Rhodobacterales in the North Sea during the 2010-2012 spring blooms using a time series of 38 deeply sequenced metagenomes and 10 metaproteomes collected throughout these events. Rhodobacterales metagenome assembled genomes (MAGs) were recurrently abundant. They exhibited the highest gene enrichment and protein expression of small-molecule transporters, such as monosaccharides, thiamine and polyamine transporters, and anaplerotic pathways, such as ethylmalonyl and propanoyl-CoA metabolic pathways, all suggestive of a generalist lifestyle. Metaproteomes indicated that the species represented by these MAGs were the dominant suppliers of vitamin B12 during the blooms, concomitant with a significant enrichment of genes related to vitamin B12 biosynthesis suggestive of association with diatom phycospheres. A closer examination of putative generalists and colonizers showed that putative generalists had persistently higher relative abundance throughout the blooms and thus produced more than 80% of Rhodobacterales transport proteins, suggesting rapid growth. In contrast, putative phycosphere colonizers exhibited large fluctuation in relative abundance across the different blooms and correlated strongly with particular diatom species that were dominant during the blooms each year. The defining feature of putative phycosphere colonizers is the presence of the tight adherence (tad) gene cluster, which is responsible for the assembly of adhesive pili that presumably enable attachment to diatom hosts. In addition, putative phycosphere colonizers possessed higher prevalence of secondary metabolite biosynthetic gene clusters, particularly homoserine lactones, which can regulate bacterial attachment through quorum sensing. Altogether, these findings suggest that while many members of Rhodobacterales are competitive during diatom blooms, only a subset form close associations with diatoms by colonizing their phycospheres.

Cultivable Winogradskyella species are genomically distinct from the sympatric abundant candidate species.

Winogradskyella is a genus within the phylum Bacteroidetes with a clear marine origin. Most members of this genus have been found associated with marine animals and algae, but also with inorganic surfaces such as sand. In this study, we analyzed genomes of eleven species recently isolated from surface seawater samples from the North Sea during a single spring algae bloom. Corresponding metagenomes yielded a single Candidatus species for this genus. All species in culture, with the exception of W. ursingii, affiliated with a Winogradskyella lineage characterized by large genomes (~4.3 ± 0.4 Mb), with high complexity in their carbohydrate and protein degradation genes. Specifically, the polysaccharide utilization loci (PULs) were diverse within each individual strain, indicating large substrate versatility. Although present in the North Sea, the abundances of these strains were at, or below, the detection limit of the metagenomes. In contrast, the single species, classified as Candidatus W. atlantica, to which all North Sea MAGs belonged, affiliated with a lineage in which the cultivated representatives showed small genomes of ~3.0-3.5 Mb, with the MAGs having ~2.3 Mb. In Ca. W. atlantica, genome streamlining has apparently resulted in the loss of biosynthesis pathways for several amino acids including arginine, methionine, leucine and valine, and the PUL loci were reduced to a single one for utilizing laminarin. This as-yet uncultivated species seems to capitalize on sporadically abundant substrates that are released by algae blooms, mainly laminarin. We also suggest that this streamlined genome might be responsible for the lack of growth on plates for this Candidatus species, in contrast to growth of the less abundant but coexisting members of the genus.

Taxonomic study of nine new Winogradskyella species occurring in the shallow waters of Helgoland Roads, North Sea. Proposal of Winogradskyella schleiferi sp. nov., Winogradskyella costae sp. nov., Winogradskyella helgolandensis sp. nov., Winogradskyella vidalii sp. nov., Winogradskyella forsetii sp. nov., Winogradskyella ludwigii sp. nov., Winogradskyella ursingii sp. nov., Winogradskyella wichelsiae sp. nov., and Candidatus "Winogradskyella atlantica" sp. nov.

Evaluation of bacterial succession with cultivation-dependent strategies during a spring phytoplankton bloom in the North Sea led to the isolation of 41 strains that affiliated with the genus Winogradskyella. Fifteen of the strains were selected for a taxonomic study after discarding clonal cultures. A thorough phylogenetic, genomic and phenotypic analysis of the isolates indicated that they represented eight new species that coexisted in North Sea waters. Molecular data revealed the existence of an as yet uncultivated novel species recurrently binned from the North Sea metagenomes. The metagenome-assembled genomes (MAGs) of this new Winogradskyella were used to classify it as a new Candidatus species. This study represented a new example of the use of the tandem approach of whole cell mass spectrometry linked to 16S rRNA gene sequencing in order to facilitate the discovery of new taxa by high-throughput cultivation, which increases the probability of finding more than a single isolate for new species. In addition, we demonstrated the reasons for classifying MAGs representing recurrently retrieved heterotrophic species that evade cultivation even after an important high-throughput effort. The taxonomic study resulted in the classification of eight new species and one new Candidatus species of the genus Winogradskyella for which we propose the names W. schleiferi sp. nov., W. costae sp. nov., W. helgolandensis sp. nov., W. vidalii sp. nov., W. forsetii sp. nov., W. ludwigii sp. nov., W. ursingii sp. nov., W. wichelsiae sp. nov., and Candidatus "W. atlantica" sp. nov.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genetic associations with clozapine-induced myocarditis in patients with schizophrenia.

Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10-6), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10-7; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10-5). Combining clinical and genetic factors together increased the proportion of variability accounted for (r2 0.73, P = 9.8 × 10-9). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy.

OBJECTIVE: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). METHODS: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. RESULTS: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). SIGNIFICANCE: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.

Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.

BACKGROUND: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen. METHODS: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge. FINDINGS: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference - 0.7%, 95% CI - 2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)). INTERPRETATION: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions.

Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink.

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10-5 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10-9 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

Reforestation of agricultural land in the tropics: The relative contribution of soil, living biomass and debris pools to carbon sequestration.

Tropical regions of the world experience high rates of land-use change and this has a major influence on terrestrial carbon (C) pools and the global C cycle. We assessed land-use change from agriculture to reforested plantings (with endemic species), up to 33 years of age, using 10 paired sites in the wet tropics, Australia. We determined the impacts on 0-50 cm below-ground C (soil organic C (SOC), charcoal C, humic organic C, particulate organic C, resistant organic C), C stored in roots (fine and coarse), C stored in living above-ground biomass and debris C pools. Reforested areas accumulated ecosystem C at a rate of 7.4 Mg ha-1 yr-1. Reforestation plantings contained, on average, 2.3 times more ecosystem C than agricultural areas (102 Mg ha-1 and 233 Mg ha-1, respectively). Most of the C accumulation was in living above-ground and below-ground biomass (60 and 30%, respectively) with a smaller amount in debris pools (16%). Apart from C in roots, soil C accumulation was not obvious across sites ranging from 8 to 33 years since reforestation, relative to the agricultural baseline. Differences in SOC (and associated SOC pools) to a depth of 50 cm, did exist between reforested areas and adjacent agriculture at some sites, however there was not a consistent trend in SOC associated with reforestation. Local site-based factors (e.g. soil texture and mineralogy, land-use history and microbial activity) appear to have a strong influence on the direction of the change in SOC. While reforestation in the tropics has great potential to accumulate C in biomass in living vegetation, and debris pools, it is likely to take approximately 50 years before C stocks of reforested areas resemble natural ecosystems. Accumulation of SOC through reforestation is difficult to achieve, highlighting the need to conserve carbon pools in remnant forests in the tropics.

Role of a pre-operative radiological scoring system in determining resectability for potentially resectable hilar cholangiocarcinoma.

AIMS: Cholangiocarcinoma is a rare cancer arising from the biliary tree. Case series indicate that 25-40% of all borderline resectable primary tumours are potentially resectable. The Memorial Sloane Kettering System (MSKCC) stratifies patients for resectability by longitudinal and radial extension of the hilar tumour. The Bismuth-Corlette system describes the longitudinal extension of the tumour within the biliary duct system. We sought to validate and, if possible, augment these two scores within an independent validation cohort. METHODS: Patients diagnosed with hilar cholangiocarcinoma between January 2009 and December 2016 were analysed from a prospectively held database. Patients with distal cholangiocarcinoma, peripheral cholangiocarcinoma and gallbladder cancer were excluded. Comparison of surgical findings to pre-operative radiological imaging was undertaken at the time of surgery. RESULTS: The validation cohort was formed of 198 patients, of which, 55 (27.8%) patients underwent resection. Logistic regression analyses identified that BC score, MSKCC score, age at diagnosis and left artery involvement were all significant independent predictor's univariately. BC score explained 28% of the variability in resectability compared to 26% explained by MSKCC. In combination, the model consisting of BC score, age at diagnosis and left artery involvement explained 39% of variability in resectability compared to the 34% explained same model including MSKCC score instead of BC score. CONCLUSION: In this cohort an augmented BC score, incorporating left hepatic artery involvement, is more discriminative in predicting resectability than the current MSKCC system.

Pacing during a cross-country mountain bike mass-participation event according to race performance, experience, age and sex.

This study describes pacing strategies adopted in an 86-km mass-participation cross-country marathon mountain bike race (the 'Birkebeinerrittet'). Absolute (km·h-1) and relative speed (% average race speed) and speed coefficient of variation (%CV) in five race sections (15.1, 31.4, 52.3, 74.4 and 100% of total distance) were calculated for 8182 participants. Data were grouped and analysed according to race performance, age, sex and race experience. The highest average speed was observed in males (21.8 ± 3.7 km/h), 16-24 yr olds (23.0 ± 4.8 km/h) and those that had previously completed >4 Birkebeinerrittet races (22.5 ± 3.4 km/h). Independent of these factors, the fastest performers exhibited faster speeds across all race sections, whilst their relative speed was higher in early and late climbing sections (Cohen's d = 0.45-1.15) and slower in the final descending race section (d = 0.64-0.98). Similar trends were observed in the quicker age, sex and race experience groups, who tended to have a higher average speed in earlier race sections and a lower average speed during the final race section compared to slower groups. In all comparisons, faster groups also had a lower %CV for speed than slower groups (fastest %CV = 24.02%, slowest %CV = 32.03%), indicating a lower variation in speed across the race. Pacing in a cross-country mountain bike marathon is related to performance, age, sex and race experience. Better performance appears to be associated with higher relative speed during climbing sections, resulting in a more consistent overall race speed.

Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies.

Overexpression of the HER2 gene is predictive of treatment benefit with trastuzumab therapy for breast cancer (BC) patients. The study objective was to investigate whether all eligible patients with HER2-positive BC initiated trastuzumab therapy. A systematic search was conducted through PubMed, Web of Science PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Library. From 2651 studies identified, 107 observational studies were included for full text review, of which 26 met the inclusion criteria and an additional 7 studies were identified through citation searching. Two independent reviewers extracted data for accuracy and completeness. From 33 observational studies, 14,644 patients were exposed to trastuzumab therapy. Age range varied across studies; the youngest cohort had a median age of 50 and the oldest had a median age of 84. Sample sizes ranged from 11 to 1928 and included patients from 10 countries. Studies were heterogenous and few studies accounted for confounders. We identified large variability in uptake of trastuzumab in HER2-positive early BC patients (9.1-100%) and metastatic BC patients (50.8-84.0%). The pooled uptake was 71.3% (95% CI 64.6-77.9%), with high heterogeneity (I2 = 99.05%). The most conservative predictors of higher uptake included younger age (OR 2.09; 95% CI 1.36-3.20) and lower Charlson Comorbidity Index of patients (OR 1.62; 95% CI 1.32-1.99). In addition, tumour characteristics including higher tumour grade (OR 1.73; 95% CI 1.23-2.45), larger tumour size (OR 1.80; 95% CI 1.54-2.10), advanced tumour stage (OR 2.07; 95% CI 1.44-2.96) and hormone receptor negative tumor (OR 1.54; 95% CI 1.35-1.77) were associated with higher uptake. The uptake of trastuzumab therapy varied widely between studies and across subgroups suggesting that there may be some inequalities in the use of this agent. However, our findings should be interpreted with caution due to study heterogeneity and potential confounding, and thus additional studies of individual level data which control for confounders are needed to understand more about inequalities in uptake.

Variants in genes coding for glutathione S-transferases and asthma outcomes in children.

Our hypothesis was that children with mutations in genes coding for glutathione S-transferases (GST) have worse asthma outcomes compared with children with active type genotype. Data were collected in five populations. The rs1695 single nucleotide polymorphism (GSTP1) was determined in all cohorts (3692 children) and GSTM1 and GSTT1 null genotype were determined in three cohorts (2362 children). GSTT1 null (but not other genotypes) was associated with a minor increased risk for asthma attack and there were no significant associations between GST genotypes and asthma severity. Interactions between GST genotypes and SHS exposure or asthma severity with the study outcomes were nonsignificant. We find no convincing evidence that the GST genotypes studied are related to asthma outcomes.

TEMPORARY REMOVAL: Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

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