Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Dosing regimen optimisation for oseltamivir in immunocompromised paediatric patients with influenza: Extrapolation of efficacy.

AIMS: To optimise the dosing regimen of oseltamivir for immunocompromised (IC) paediatric patients (<18 years) with influenza, we used an extrapolation approach alongside clinical data. METHODS: Efficacy was extrapolated from adult IC patients to paediatric IC patients by leveraging existing efficacy, safety, pharmacokinetic (PK)/pharmacodynamic (PD), and disease-progression models of oseltamivir and oseltamivir carboxylate (OC). Data of IC paediatric patients from two studies (NV25719 and NV20234) were included in the population PK (n = 30), PK/PD analysis (n = 22) and disease modelling approach (n = 36). Simulations were performed to identify the optimal dosing regimen. RESULTS: Clearance of oseltamivir (CL) and OC (CLM ) were similar in IC and otherwise-healthy (OwH) patients <10 years, but decreased by 44.4% (95% CI: 26.8-62.0) and 49.1% (95% CI: 34.5-63.8), respectively, in IC patients aged 10-17 years versus OwH patients. There were no notable exposure-response relationships for any of the virologic PD analyses. Thus, no additional benefit was seen with oseltamivir carboxylate exposures higher than achieved with the conventional dose (75 mg twice daily, age- and weight-adjusted for children <13 years). The disease model illustrated that doses above the conventional oseltamivir dose had limited impact on viral kinetics in IC paediatric patients and a prolonged treatment duration of 10 days was favoured to limit potential viral rebound. CONCLUSION: An oseltamivir dosage recommendation (conventional dose, twice daily for 10 days) was established in IC paediatric patients with influenza, based on extrapolation of efficacy from IC adults, leveraging population PK, PK/PD, and disease modelling, whilst taking resistance and safety data into account.

Early Outcomes After Mitral Valve Repair versus Replacement in the Elderly: A Propensity Matched Analysis.

BACKGROUND: To compare early outcomes of mitral valve repair versus replacement in elderly patients with degenerative mitral valve disease. METHODS: A retrospective review of prospectively collected clinical data of patients over 75 years of age, who underwent mitral valve surgery for degenerative disease, between 2010 and 2013, was carried out. Those undergoing mitral valve repair and replacement were propensity matched to adjust for baseline clinical differences. RESULTS: A total 260 patients were identified: mitral valve repair was undertaken in 145 and replacement in 115 patients. After propensity matching, 78 patients were included in each group. In the entire, unmatched population, in-hospital mortality was significantly higher in those undergoing replacement compared with those undergoing repair (9.6% vs 1.4%, p=0.003). In-hospital death occurred in six (7.7%) of the propensity matched replacement group and none in the repair group (p=0.012). Amongst the propensity matched groups, probability of survival at 1, 2 and 3 years were 0.94, 0.90 and 0.86 respectively for the repair group and 0.85, 0.77 and 0.69 for the replacement group: the HR for death between replacement and repair is 2.5 (1.2-5.4), p=0.012. CONCLUSIONS: Within the limitations imposed by retrospective analyses, our study demonstrates that, in elderly patients with degenerative disease of the mitral valve, repair is associated with improved short-term and mid-term outcomes compared with mitral valve replacement.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Usefulness of the STOP-Bang Questionnaire in a Cardiac Surgical Population.

OBJECTIVE: The aim of this study was to assess the predictive accuracy of the STOP-Bang questionnaire in relation to obstructive sleep apnea (OSA) detected by nocturnal oximetry, as well as postoperative outcomes, in a population undergoing cardiac surgery. DESIGN: A prospective observational cohort study. SETTING: The specialist cardiothoracic center at the Royal Papworth Hospital, Cambridge University Health Partners, United Kingdom. PARTICIPANTS: All adult patients, undergoing elective coronary artery bypass grafting with or without cardiac valve surgery between March 2013 and July 2014 were included. The authors excluded patients participating in other interventional studies, those who had a tracheostomy before surgery, and those who required emergency surgery or were due to be admitted on the day of surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Cardiac surgical patients were screened for the risk of OSA with the use of STOP-Bang questionnaire. The presence of OSA prior to surgery was assessed with overnight oximetry. The predictive performance of the STOP-Bang questionnaire was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC)-receiver operating characteristic curve (ROC). Multiple-logistic regression models were used to assess for associations between the STOP-Bang scores and postoperative outcomes. The STOP-Bang questionnaire discriminated poorly between mild OSA (AUC-ROC 0.57 [95% confidence interval (CI) 0.47-0.67]) and moderate/severe OSA (AUC-ROC 0.82 (95% CI 0.69-0.95)]. Accuracy was increased by modifying the cut-off value to 6 or greater, with sensitivity and specificity of 75% and 77%, respectively. A STOP-Bang score indicating the possibility of OSA was not significantly associated with prolonged intensive care unit lengths of stay (hazard ratio [HR] 1.1; 95% CI 0.99-1.19; p = 0.08) or postoperative complications (odds ratio [OR] 1.0; 95% CI 0.59-1.72; p = 0.98). CONCLUSIONS: In the study population, a STOP-Bang questionnaire score of 3 or greater had limited predictive value for identifying cardiac surgical patients at high risk of OSA. STOP-Bang scores were not significantly associated with worse postoperative outcomes. A STOP-Bang score of 6 or greater could help identify patients in need of a sleep study to confirm the presence of OSA as such patients may be at increased risk of postoperative complications.

A genome-wide association analysis for porcine serum lipid traits reveals the existence of age-specific genetic determinants.

BACKGROUND: The genetic determinism of blood lipid concentrations, the main risk factor for atherosclerosis, is practically unknown in species other than human and mouse. Even in model organisms, little is known about how the genetic determinants of lipid traits are modulated by age-specific factors. To gain new insights into this issue, we have carried out a genome-wide association study (GWAS) for cholesterol (CHOL), triglyceride (TRIG) and low (LDL) and high (HDL) density lipoprotein concentrations measured in Duroc pigs at two time points (45 and 190 days). RESULTS: Analysis of data with mixed-model methods (EMMAX, GEMMA, GenABEL) and PLINK showed a low positional concordance between trait-associated regions (TARs) for serum lipids at 45 and 190 days. Besides, the proportion of phenotypic variance explained by SNPs at these two time points was also substantially different. The four analyses consistently detected two regions on SSC3 (124 Mb, CHOL and LDL at 190 days) and SSC6 (135 Mb, CHOL and TRIG at 190 days) with highly significant effects on the porcine blood lipid profile. Moreover, we have found that SNP variation within SSC3, SSC6, SSC10, SSC13 and SSC16 TARs is associated with the expression of several genes mapping to other chromosomes and related to lipid metabolism. CONCLUSIONS: Our data demonstrate that the effects of genomic determinants influencing lipid concentrations in pigs, as well as the amount of phenotypic variance they explain, are influenced by age-related factors.

Hyperreflective Material Boundary Remodeling in Neovascular Age-Related Macular Degeneration: A Post Hoc Analysis of the AVENUE Trial.

OBJECTIVE: To describe the spatial and temporal characteristics of hyperreflective material (HRM) on spectral-domain OCT (SD-OCT) in neovascular age-related macular degeneration (nAMD) during antiangiogenic treatment and explore associations with best-corrected visual acuity (BCVA) and macular atrophy (MA). DESIGN: Retrospective regrading of SD-OCT-images from the multicenter, randomized controlled AVENUE trial (NCT02484690, conducted from August 2015 to September 2017). PARTICIPANTS: Treatment-naive nAMD patients enrolled from 50 sites in the US. METHODS: Retrospective regrading and secondary analysis. MAIN OUTCOME MEASURES: Spectral-domain OCT images from 207 study eyes that fit criteria for the present analysis were graded for HRM features, its evolution, and associated hypertransmission into choroid (HTC), a proxy for MA. The appearance of a well-defined hyperreflective inner boundary that separated persistent HRM from the neurosensory retina continuous with the adjacent retinal pigment epithelium layer was defined as hyperreflective material boundary remodeling (HRM-BR). Patterns of HRM composition/evolution were defined as follows: (1) no subretinal HRM at baseline, (2) fully resolved, (3) persistent with complete HRM-BR, or (4) partial/absent HRM-BR. Associations of HRM patterns with BCVA and HTC were analyzed. Predictive factors for complete HRM-BR were explored. RESULTS: Of 207 included eyes, subretinal HRM was present in 159 (76.8%) at baseline and persisted until month 9 in 118 (57.0%) eyes. Of these 118 eyes, 44.9% developed complete HRM-BR and had similar BCVA outcomes by month 9 compared with no/fully resolved subretinal HRM. Partial/absent HRM-BR had a strong negative association with BCVA outcome (-6.1 ETDRS letters; P = 0.016) and a higher frequency of intralesional HTC (69.2%) compared with eyes with complete HRM-BR (20.8%) at month 9. Older age (odds ratio [OR], 0.96; P = 0.054) and presence of intralesional HTC (OR, 0.06; P = 0.010) at baseline were associated with lower odds of complete HRM-BR at month 9. CONCLUSIONS: In nAMD eyes under antiangiogenic treatment, complete HRM-BR occurred frequently and was associated with better BCVA than when HRM-BR was only partial/absent. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH-Results from a prospective discovery and validation biomarker study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors.

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. CLINICAL TRIALS REGISTRATION: NCT04363736.

A strong quantitative trait locus for wing length on chromosome 2 in a wild population of great reed warblers.

Wing length is a key character for essential behaviours related to bird flight such as migration and foraging. In the present study, we initiate the search for the genes underlying wing length in birds by studying a long-distance migrant, the great reed warbler (Acrocephalus arundinaceus). In this species wing length is an evolutionary interesting trait with pronounced latitudinal gradient and sex-specific selection regimes in local populations. We performed a quantitative trait locus (QTL) scan for wing length in great reed warblers using phenotypic, genotypic, pedigree and linkage map data from our long-term study population in Sweden. We applied the linkage analysis mapping method implemented in GridQTL (a new web-based software) and detected a genome-wide significant QTL for wing length on chromosome 2, to our knowledge, the first detected QTL in wild birds. The QTL extended over 25 cM and accounted for a substantial part (37%) of the phenotypic variance of the trait. A genome scan for tarsus length (a body-size-related trait) did not show any signal, implying that the wing-length QTL on chromosome 2 was not associated with body size. Our results provide a first important step into understanding the genetic architecture of avian wing length, and give opportunities to study the evolutionary dynamics of wing length at the locus level.

A web application to perform linkage disequilibrium and linkage analyses on a computational grid.

MOTIVATION: Unravelling the genetic architecture of complex traits requires large amounts of data, sophisticated models and large computational resources. The lack of user-friendly software incorporating all these requisites is delaying progress in the analysis of complex traits. METHODS: Linkage disequilibrium and linkage analysis (LDLA) is a high-resolution gene mapping approach based on sophisticated mixed linear models, applicable to any population structure. LDLA can use population history information in addition to pedigree and molecular markers to decompose traits into genetic components. Analyses are distributed in parallel over a large public grid of computers in the UK. RESULTS: We have proven the performance of LDLA with analyses of simulated data. There are real gains in statistical power to detect quantitative trait loci when using historical information compared with traditional linkage analysis. Moreover, the use of a grid of computers significantly increases computational speed, hence allowing analyses that would have been prohibitive on a single computer. AVAILABILITY: The authors have implemented LDLA within the freely available GridQTL software (www.gridqtl.org.uk).

Effect of family relatedness on characteristics of estimated IBD probabilities in relation to precision of QTL estimates.

BACKGROUND: A random QTL effects model uses a function of probabilities that two alleles in the same or in different animals at a particular genomic position are identical by descent (IBD). Estimates of such IBD probabilities and therefore, modeling and estimating QTL variances, depend on marker polymorphism, strength of linkage and linkage disequilibrium of markers and QTL, and the relatedness of animals in the pedigree. The effect of relatedness of animals in a pedigree on IBD probabilities and their characteristics was examined in a simulation study. RESULTS: The study based on nine multi-generational family structures, similar to a pedigree structure of a real dairy population, distinguished by an increased level of inbreeding from zero to 28% across the studied population. Highest inbreeding level in the pedigree, connected with highest relatedness, was accompanied by highest IBD probabilities of two alleles at the same locus, and by lower relative variation coefficients. Profiles of correlation coefficients of IBD probabilities along the marked chromosomal segment with those at the true QTL position were steepest when the inbreeding coefficient in the pedigree was highest. Precision of estimated QTL location increased with increasing inbreeding and pedigree relatedness. A method to assess the optimum level of inbreeding for QTL detection is proposed, depending on population parameters. CONCLUSIONS: An increased overall relationship in a QTL mapping design has positive effects on precision of QTL position estimates. But the relationship of inbreeding level and the capacity for QTL detection depending on the recombination rate of QTL and adjacent informative marker is not linear.

Mid-term follow-up after aortic valve replacement with the Carpentier Edwards Magna Ease prosthesis.

BACKGROUND: Approximately 250,000 heart valve operations are performed annually worldwide. An intensive research and development effort has led to progressively more advanced heart valve prostheses. The Carpentier-Edwards Perimount Magna Ease (CEPME) prosthesis represents the latest iteration of the Edwards Perimount series of aortic tissue valves. The current study aims to evaluate the midterm performance of this bioprosthesis. METHODS: Five hundred and eighteen patients with aortic stenosis underwent aortic valve replacement with the CEPME valve at Papworth Hospital between August 2008 and November 2011. After a minimum of 3 years from the index operation, eligible patients were retrospectively and consecutively recruited to participate. Recruitment was closed after 100 eligible patients had completed all study assessments. Investigations at follow-up included echocardiography, and NYHA status. Primary endpoints included valve performance measures. RESULTS: The mean age was 72 years, 64% were male and median follow-up was 5.1 years. NYHA status had improved in 66% of patients. The average postoperative peak and mean pressure gradients decreased by 51.2 mmHg (64.5%) and 31.8 mmHg (59.4%), with a significant improvement in NYHA status. The frequency of moderate aortic regurgitation was 3%. There was no evidence for structural valve deterioration. CONCLUSIONS: The CEPME has excellent mid-term durability. Its use effectively improves haemodynamics and functional capacity.

Pharmacokinetics and Pharmacodynamics of Conventional-Dose vs Triple-Dose Oseltamivir in Severely Immunocompromised Children With Influenza.

This randomized phase 1b study evaluated the pharmacokinetics/pharmacodynamics of conventional-dose (30-75 mg twice daily [BID]) vs triple-dose (90-225 mg BID; weight-adjusted) oseltamivir for treatment of influenza in severely immunocompromised children <13 years. Oseltamivir carboxylate (OC) Cmax and AUC0-12h were ~2-fold higher with triple-dose vs conventional-dose oseltamivir. Increased dose/exposure of oseltamivir/OC did not improve virological outcomes or reduce viral resistance. Median time to cessation of viral shedding was similar with triple-dose and conventional-dose oseltamivir (150.7 vs 157.1 hours, respectively); median time to alleviation of baseline fever was longer with conventional-dose oseltamivir (28.4 vs 11.3 hours). No new safety signals were identified.

Prediction of multilocus identity-by-descent.

Previous studies have enabled exact prediction of probabilities of identity-by-descent (IBD) in random-mating populations for a few loci (up to four or so), with extension to more using approximate regression methods. Here we present a precise predictor of multiple-locus IBD using simple formulas based on exact results for two loci. In particular, the probability of non-IBD X(ABC) at each of ordered loci A, B, and C can be well approximated by X(ABC) = X(AB)X(BC)/X(B) and generalizes to X(123...k) = X(12)X(23...)X(k)(-1,k)/X(k-2), where X is the probability of non-IBD at each locus. Predictions from this chain rule are very precise with population bottlenecks and migration, but are rather poorer in the presence of mutation. From these coefficients, the probabilities of multilocus IBD and non-IBD can also be computed for genomic regions as functions of population size, time, and map distances. An approximate but simple recurrence formula is also developed, which generally is less accurate than the chain rule but is more robust with mutation. Used together with the chain rule it leads to explicit equations for non-IBD in a region. The results can be applied to detection of quantitative trait loci (QTL) by computing the probability of IBD at candidate loci in terms of identity-by-state at neighboring markers.

Medication and patient factors associated with adherence to pulmonary hypertension targeted therapies.

The aims of this study were to investigate the medication adherence of patients on pulmonary hypertension (PH)-targeted therapies and uncover factors that might influence adherence values. Patients taking at least one specialist medicine (sildenafil, tadalafil, bosentan, ambrisentan, iloprost, epoprostenol, treprostinil) completed a Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire. Participants' MMAS-8 scores were used to estimate overall medicine adherence. Potential adherence co-factor data were collected from patient databases and hospital discharge summaries. The MMAS-8 questionnaire was completed by 263 patients (mean age = 61.6 ± 14.8 years, 70.6% women). Data from MMAS-8 showed that 47.9% reported high adherence, 40.3% moderate adherence, and 11.8% low adherence. Factors associated with adherence as measured by the MMAS-8 included: older age; taking monotherapy; and having a higher number of co-morbidities or concurrent medicines. Higher administration frequency, greater length of time on targeted therapy, and use of a compliance aid had a negative association with adherence. Overall adherence to PH specialist medicines is relatively high but a proportion of patients report sub-optimal adherence behavior. A number of factors may help to recognize susceptible patients.

Prediction of postpercutaneous coronary intervention myocardial infarction: insights from intravascular imaging, coronary flow, and biomarker evaluation.

BACKGROUND: Percutaneous coronary intervention-induced myocardial infarction (PMI) has prognostic significance. Identifying patients at high risk for PMI is desirable as it may alter strategy and facilitate early preventative therapy. We therefore sought to establish whether preprocedural demographic, interventional (plaque characteristics and coronary microcirculatory function), and inflammatory, endothelial damage, and platelet-derived biomarker data could predict the risk of PMI. PATIENTS AND METHODS: We performed target vessel pressure wire to assess fractional flow reserve, index of microcirculatory resistance (IMR) and coronary flow reserve, plaque characterization by virtual histology intravascular ultrasound, and assayed peripheral biomarkers before uncomplicated PCI in 88 patients. We then analyzed post-PCI cardiac troponin level to adjudicate PMI based on the third universal definition of myocardial infarction. RESULTS: Overall incidence of PMI was 27%. Women [10/15 (66%) vs. 14/73 (19%), P<0.001] and those with low body mass (27.1±3.9 vs. 29.7±5.5 kg/m; P=0.02) were at significantly higher risk of PMI. Preprocedural coronary flow reserve was lower in individuals with a subsequent PMI (1.8±1.2 vs. 2.1±1.3. P=0.03), and patients with higher pre-PCI IMR were more likely to sustain PMI [IMR>22: 10/23 (44%) vs. ≤22: 14/65 (22%), P=0.04], although neither was predictive after multivariate analysis. Plaque characterization by virtual histology intravascular ultrasound did not discriminate those at risk of PMI. However, peripheral venous interleukin (IL)-18 and IL-8 levels were independently negatively and positively associated with PMI, respectively. CONCLUSION: Women and those with low BMI, particularly when associated with high IL-8 and low IL-18 levels, appear to be at increased risk of PMI.

Clinical trial protocol for TRANSFORM-UK: A therapeutic open-label study of tocilizumab in the treatment of pulmonary arterial hypertension.

Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.