Methodological Insights on Biomarker-Based Patient Selection: A Review of Scientific Advice Procedures at the European Medicines Agency.

Biomarkers play a pivotal role in the selection and enrollment of trial participants. Particularly, predictive biomarkers help tailor medical care to individual patients; however, also prognostic biomarkers require consideration at the design stage. At the time of initiating a clinical trial, there may be uncertainty about whether a biomarker is predictive or prognostic, and the trial design may need to account for this.

Facilitating Next-Generation Pre-Exposure Prophylaxis Clinical Trials Using HIV Recent Infection Assays: A Consensus Statement from the Forum HIV Prevention Trial Design Project.

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared.

Individualized Positive End-expiratory Pressure and Regional Gas Exchange in Porcine Lung Injury.

Background: In acute respiratory failure elevated intraabdominal pressure aggravates lung collapse, tidal recruitment, and ventilation inhomogeneity. Low positive end-expiratory pressure (PEEP) may promote lung collapse and intrapulmonary shunting, whereas high PEEP may increase dead space by inspiratory overdistension. The authors hypothesized that an electrical impedance tomography-guided PEEP approach minimizing tidal recruitment improves regional ventilation and perfusion matching when compared to a table-based low PEEP/no recruitment and an oxygenation-guided high PEEP/full recruitment strategy in a hybrid model of lung injury and elevated intraabdominal pressure.

Disentangling estimands and the intention-to-treat principle.

Randomized controlled trials (RCTs) aim at providing reliable estimates of treatment benefit. Missing data and nonadherence to treatment are distinct problems that can substantially impede this task. In practice, the fact that the handling of missing data due to nonadherence affects the question that is addressed is often ignored.

CD66b Overexpression and Loss of C5a Receptors as Surface Markers for Staphylococcus aureus-Induced Neutrophil Dysfunction.

Neutrophil granulocytes constitute the main component of innate immunity in the clearance of bacterial infections. However, during systemic inflammation, immunoparalysis may occur resulting in neutrophil dysfunction. This study presents a new in vitro model for analyzing the dysfunction of human peripheral blood neutrophils resulting from the interaction with Staphylococcus aureus components in whole blood.

Choosing Appropriate Estimands in Clinical Trials.

Lack of adherence to study protocol and missing data are often unavoidable in clinical trials, and both increase the need to differentiate between the ideal treatment effect if the medication is taken as directed and the treatment effect in presence of the actual adherence pattern. In this regard, estimands have become the focus of attention. An estimand is simply that which is being estimated.

Spline-based procedures for dose-finding studies with active control.

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose-response relationship and to find the smallest target dose concentration d(*), which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose-response function with the expected efficacy of the active control has to be estimated.

Florbetapir (18F) for brain amyloid positron emission tomography: highlights on the European marketing approval.

Florbetapir (18F) for brain amyloid positron emission tomography (PET) imaging has been recently approved in Europe to estimate β-amyloid neuritic plaque density in the brain when the subject is still alive. Such density is one of the key issues for the definitive diagnosis of Alzheimer's disease (AD) at autopsy. This capability of florbetapir (18F) is regarded as a significant improvement in the diagnostic procedures for adult patients with cognitive impairment who are being evaluated for AD and other causes of cognitive impairment.

Pumpless extracorporeal CO(2) removal restores normocapnia and is associated with less regional perfusion in experimental acute lung injury.

Background: Lung protective ventilation may lead to hypoventilation with subsequent hypercapnic acidosis (HA). If HA cannot be tolerated or occurs despite increasing respiratory rate or buffering, extracorporeal CO2-removal using a percutaneous extracorporeal lung assist (pECLA) is an option. We hypothesised that compensation of HA using pECLA impairs regional perfusion.

Estimation of the treatment effect in the presence of non-compliance and missing data.

Treatment non-compliance and missing data are common problems in clinical trials. Non-compliance is a broad term including any kind of deviation from the assigned treatment protocol, such as dose modification, treatment discontinuation or switch, often resulting in missing values. Missing values and treatment non-compliance may bias study results.

The effect of pumpless extracorporeal CO2 removal on regional perfusion of the brain in experimental acute lung injury.

Background: Lung-protective mechanical ventilation with low tidal volumes (V(T)) is often associated with hypercapnia (HC), which may be unacceptable in patients with brain injury. CO2 removal using a percutaneous extracorporeal lung assist (pECLA) enables normocapnia despite low V(T), but its effects on regional cerebral blood flow (rCBF) remain ambiguous. We hypothesized that reversal of HC by pECLA impairs rCBF in a porcine lung injury model.

Phenotyping of Staphylococcus aureus reveals a new virulent ST398 lineage.

Staphylococcus aureus sequence type (ST)398, which is commonly found as a colonization strain in pig farming, is emerging more frequently as the cause of human infections. In this study, we analysed ST398 of porcine and human origin at the genetic, protein and immunogenic levels. Although genetic analysis of the genes encoding the major virulence factors revealed the presence of the same genes in all strains studied, the results demonstrated spa type crossing alterations in adhesion abilities in addition to a strongly enhanced lysis activity directly linked to impaired clearance attributable to polymorphonuclear leukocytes (PMNs).

CD66b overexpression and homotypic aggregation of human peripheral blood neutrophils after activation by a gram-positive stimulus.

Neutrophils represent the main component of innate immunity in the clearance of bacterial infections. To pass the tissue and to localize and reach the site of infection, the peripheral blood neutrophils have to pass through a complex receptor-mediated interaction with the endothelial layer. Under pathophysiological conditions, such as severe sepsis, this process is impaired and often characterized by neutrophil aggregation.

Tidal recruitment assessed by electrical impedance tomography and computed tomography in a porcine model of lung injury*.

Objectives: To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung injury model.

Design: Randomized, controlled, prospective experimental study.

Setting: Academic research laboratory.

Repinotan, a selective 5-HT1A-R-agonist, antagonizes morphine-induced ventilatory depression in anesthetized rats.

Background: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT(1A)-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT(1A)-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown.

Effects of spontaneous breathing during airway pressure release ventilation on cerebral and spinal cord perfusion in experimental acute lung injury.

Background: Systemic-blood flow, cerebral-blood flow, and spinal cord blood flow can be affected by mechanical ventilation. We investigated the effect of spontaneous breathing on cerebral and spinal blood flow during airway pressure release ventilation (APRV) with and without spontaneous breathing.

Methods: Twelve pigs with oleic-acid-induced lung injury were ventilated with APRV with or without spontaneous breathing in random order.

The Entropy Module and Bispectral Index as guidance for propofol-remifentanil anaesthesia in combination with regional anaesthesia compared with a standard clinical practice group.

This study was designed to investigate the impact of the Entropy Module and Bispectral Index (BIS) monitoring on drug consumption and recovery times compared with standard anaesthetic practice in patients undergoing orthopaedic surgery using a combination of regional and general anaesthesia as performed by an experienced anaesthesiologist. We hypothesised that electroencephalogram monitoring would lead to a lower drug consumption as well as shorter recovery times. With institutional review board approval and written informed consent, 90 adult patients undergoing surgery to the upper or lower extremity received regional anaesthesia for post- and intraoperative pain control and were randomised to receive general anaesthesia by propofol/remifentanil infusion controlled either solely by clinical parameters or by targeting Entropy or BIS values of 50.

Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury.

Background: Trials have provided conflicting results regarding the effect of different ventilatory strategies on the outcomes of patients with the acute respiratory distress syndrome (ARDS) and acute lung injury.

Purpose: To determine whether ventilation with low tidal volume (Vt) and limited airway pressure or higher positive end-expiratory pressure (PEEP) improves outcomes for patients with ARDS or acute lung injury.

Data Sources: Multiple computerized databases (through March 2009), reference lists of identified articles, and queries of principal investigators.

The counteraction of opioid-induced ventilatory depression by the serotonin 1A-agonist 8-OH-DPAT does not antagonize antinociception in rats in situ and in vivo.

Background: Spontaneous breathing during mechanical ventilation is gaining increasing importance during intensive care but is depressed by narcotics, such as opioids. Serotonin 1A-receptor (5-HT(1A)-R) agonists have been shown to antagonize opioid-induced ventilatory depression, but both enhancement and attenuation of nociceptive reflexes have been found with different experimental models. To clarify contradictory findings, we simultaneously determined dose-response functions of the standard 5-HT(1A)-R-agonist 8-OH-DPAT and two different opioids for spontaneous ventilation and nociception.

Effects of spinal anaesthesia versus epidural anaesthesia for caesarean section on postoperative analgesic consumption and postoperative pain.

Background And Objective: Regional anaesthesia is commonly used for elective caesarean section. The aim of this study was to investigate whether there is a positive effect of either spinal or epidural anaesthesia on postoperative analgesic requirements and pain relief.

Methods: The analgesic effect of either spinal or epidural induction of perispinal anaesthesia have been compared in 132 women (ASA I or II) scheduled for elective caesarean section, all having epidural catheterization for perioperative anaesthesia and postoperative analgesia.

Cardiorespiratory effects of spontaneous breathing in two different models of experimental lung injury: a randomized controlled trial.

Introduction: Acute lung injury (ALI) can result from various insults to the pulmonary tissue. Experimental and clinical data suggest that spontaneous breathing (SB) during pressure-controlled ventilation (PCV) in ALI results in better lung aeration and improved oxygenation. Our objective was to evaluate whether the addition of SB has different effects in two different models of ALI.

Electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury.

Objective: To determine the validity of functional electric impedance tomography to monitor regional ventilation distribution in experimental acute lung injury, and to develop a simple electric impedance tomography index detecting alveolar recruitment.

Design: Randomized prospective experimental study.

Setting: Academic research laboratory.

Spontaneous breathing during airway pressure release ventilation in experimental lung injury: effects on hepatic blood flow.

Objective: Positive pressure ventilation can affect systemic haemodynamics and regional blood flow distribution with negative effects on hepatic blood flow. We hypothesized that spontaneous breathing (SB) with airway pressure release ventilation (APRV) provides better systemic and hepatic blood flow than APRV without SB.

Design: Animal study with a randomized cross-over design.

Electrical impedance tomography guided ventilation therapy.

Purpose Of Review: Computed tomography (CT) in patients with acute respiratory distress syndrome has shown that intrapulmonary gas is not homogeneously distributed. Although regional ventilation can be studied by isotope and magnetic resonance techniques while aeration of the lungs can be imaged using CT, these techniques are not available at the bedside. Recently, electrical impedance tomography has been introduced as a true bedside technique which provides information on regional ventilation distribution.