Simvastatin in the Acute Respiratory Distress Syndrome

Background

Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS.

Methods

In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety.

Results

The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug.

Conclusions

Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.)

Tiotropium Respimat inhaler and the risk of death in COPD

Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.

Sporting Justice: An Arbitrator's Perspective

Drawing on my experience of a number of sports dispute resolution tribunals in the UK and Ireland (such as Sports Resolutions UK; Just Sport Ireland; the Football Association of Ireland’s Disciplinary Panel and the Gaelic Athletic Association’s Dispute Resolution Authority) I intend to use this paper to review the legal arguments typically made in sports-related arbitrations. These points of interest can be summarised as a series of three questions: the fairness question; the liability question; the penalty question.

In answer to the fairness question, the aim is to give a brief outline on best practice in establishing a "fair" sports disciplinary tribunal. The answer, I believe, is always twofold in nature: first, and to paraphrase Lord Steyn in R v Secretary of State For The Home Department, Ex Parte Daly [2001] UKHL 26 at [28] "in law, context is everything" – translated into the present matter, this means that in sports disciplinary cases, the more serious the charges against the individual (in terms of reputational damage, economic impact and/or length of sanction); the more tightly wrapped the procedural safeguards surrounding any subsequent disciplinary hearing must be. A fair disciplinary system will be discussed in the context of the principles laid down in Article 8 of the World Anti-Doping Code which, in effect, acts as sport’s Article 6 of the ECHR on a right to a fair trial.

Following on from the above, in the 60 or so sports arbitrations that I have heard, there are two further points of interest. First, the claim before the arbitral panel will often be framed in an argument that, for various reasons of substantive and procedural irregularity, the sanction imposed on the appellant should be quashed ("the liability"). Second, and in alternative, that the sanction imposed was wholly disproportionate ("the penalty").

The liability issue usually breaks down into two further questions. First, what is the nature of the legal duty upon a sports body in exercising its disciplinary remit? Second, to what extent does a de novo hearing on appeal cure any apparent defects in a hearing of first instance? The first issue often results in an arbitral panel debating the contra preferentum approach to the interpretation of a contested rule i.e., the sports body’s rules in question are so ambiguous that they should be interpreted in a manner to the detriment of the rule maker and in favour of the appellant. On the second matter, it now appears to be a general principle of sports law, administrative law and even human rights law that even if a violation of the principles of natural justice takes place at the first instance stage of a disciplinary process, they may be cured on de novo appeal. Authority for this approach can be found at the Court of Arbitration for Sport and in particular in CAS 2009/A/1920 FK Pobeda, Aleksandar Zabrcanec, Nikolce Zdraveski v UEFA at para 87.

The question on proportionality asks what, aside from precedent found within the decisions of the sports body in question, are the general legal principles against which a sanction by a sports disciplinary body can be benchmarked in order to ascertain whether it is disproportionate in length or even irrational in nature?

On the matter of (dis)proportionality of sanction, the debate is usually guided by the authority in Bradley v the Jockey Club [2004] EWHC 2164 (QB) and affirmed at [2005] EWCA Civ 1056. The Bradley principles on proportionality of sports-specific sanctions, recently cited with approval at the Court of Arbitration for Sport, will be examined in this presentation.

Finally, an interesting application of many of the above principles (and others such as the appropriate standard of proof in sports disciplinary procedures) can be made to recent match-fixing or corruption related hearings held by the British Horse Racing Authority, the integrity units of snooker and tennis, and at the Court of Arbitration for Sport.

Genetically Determined Height and Coronary Artery Disease

Background: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. 
Methods: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. 
Results: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. 
Conclusions: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.

RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.

CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).

Predicting polarization signatures for double-detonation and delayed-detonation models of Type Ia supernovae

Calculations of synthetic spectropolarimetry are one means to test multidimensional explosion models for Type Ia supernovae. In a recent paper, we demonstrated that the violent merger of a 1.1 and 0.9 M⊙ white dwarf binary system is too asymmetric to explain the low polarization levels commonly observed in normal Type Ia supernovae. Here, we present polarization simulations for two alternative scenarios: the sub-Chandrasekhar mass double-detonation and the Chandrasekhar mass delayed-detonation model. Specifically, we study a 2D double-detonation model and a 3D delayed-detonation model, and calculate polarization spectra for multiple observer orientations in both cases. We find modest polarization levels (<1 per cent) for both explosion models. Polarization in the continuum peaks at ∼0.1–0.3 per cent and decreases after maximum light, in excellent agreement with spectropolarimetric data of normal Type Ia supernovae. Higher degrees of polarization are found across individual spectral lines. In particular, the synthetic Si II λ6355 profiles are polarized at levels that match remarkably well the values observed in normal Type Ia supernovae, while the low degrees of polarization predicted across the O I λ7774 region are consistent with the non-detection of this feature in current data. We conclude that our models can reproduce many of the characteristics of both flux and polarization spectra for well-studied Type Ia supernovae, such as SN 2001el and SN 2012fr. However, the two models considered here cannot account for the unusually high level of polarization observed in extreme cases such as SN 2004dt.

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. 
METHODS We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. 
RESULTS The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). 
CONCLUSIONS The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039.)