Light transmission aggregometry (LTA) is the most common method used to assess platelet function. However, there is no universal standard for its performance. The Platelet Physiology Subcommittee of ...the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis formed a working party of experts with the aim of producing a series of consensus recommendations for standardizing LTA. Due to a lack of investigations that directly compared different methodologies to perform LTA studies, there were insufficient data to develop evidence-based guidelines. Therefore, the RAND method was used, which obtains a formal consensus among experts about the appropriateness of health care interventions, particularly when scientific evidence is absent, scarce and/or heterogeneous. Using this approach, each expert scored as "appropriate", "uncertain" or "inappropriate" a series of statements about the practice of LTA, which included pre-analytical variables, blood collection, blood processing, methodological details, choice of agonists and the evaluation and reporting of results. After presentation and public discussion at SSC meetings, the assessments were further refined to produce final consensus recommendations. Before delivering the recommendations, a formal literature review was performed using a series of defined search terms about LTA. Of the 1830 potentially relevant studies identified, only 14 publications were considered to be actually relevant for review. Based upon the additional information, 6 consensus statements were slightly modified. The final statements were presented and discussed at the SSC Meeting in Cairo (2010) and formed the basis of a consensus document, which is the subject of the present report. This article is protected by copyright. All rights reserved.
Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, ...pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors.
This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3weeks, as monotherapy or in combination with paclitaxel 80mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD.
No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000mg administered every 2weeks.
Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688)
It has become clear that platelets are not simply cell fragments that plug the leak in a damaged blood vessel; they are, in fact, also key components in the innate immune system, which is supported ...by the presence of Toll‐like receptors (TLRs) on platelets. As the cells that respond first to a site of injury, they are well placed to direct the immune response to deal with any resulting exposure to pathogens. The response is triggered by bacteria binding to platelets, which usually triggers platelet activation and the secretion of antimicrobial peptides. The main platelet receptors that mediate these interactions are glycoprotein (GP)IIb–IIIa, GPIbα, FcγRIIa, complement receptors, and TLRs. This process may involve direct interactions between bacterial proteins and the receptors, or can be mediated by plasma proteins such as fibrinogen, von Willebrand factor, complement, and IgG. Here, we review the variety of interactions between platelets and bacteria, and look at the potential for inhibiting these interactions in diseases such as infective endocarditis and sepsis.
Summary
Background
The ISTH bleeding assessment tool (ISTH‐BAT) was developed to record bleeding symptoms and to aid diagnosis in patients with a possible bleeding disorder.
Objectives
To investigate ...the utility of the ISTH‐BAT in predicting functional defects in platelet activation in participants with suspected inherited platelet function disorders.
Patients/Methods
Participants with clinical evidence of excessive bleeding and suspected inherited platelet function disorders and healthy volunteers were recruited to the Genotyping and Phenotyping of Platelets study (GAPP; ISRCTN 77951167). The ISTH‐BAT questionnaire was applied by a trained investigator prior to lumiaggregometry.
Results
One hundred participants were included (79 with suspected inherited platelet function disorders, and 21 healthy volunteers). The ISTH‐BAT score in participants with suspected inherited platelet function disorders (median 12; interquartile range IQR 8–16) was significantly higher than in healthy volunteers (median 0; IQR 0–0). There was no difference between participants with suspected inherited platelet function disorders with a platelet defect detected by lumiaggregometry (median 11; IQR 8–16) and those with normal platelet function (median 12; IQR 8–14) (P > 0.05). The ISTH‐BAT score was not associated with a demonstrable platelet defect on platelet function testing (area under the receiver operating characteristic curve = 0.501 95% confidence interval 0.372–0.630, P = 0.98 and odds ratio 1.01 95% confidence interval 0.93–1.09, P = 0.91).
Conclusions
The ISTH‐BAT is a powerful tool for documenting lifelong bleeding history. However, the score obtained is not predictive of the presence of a platelet defect on lumiaggregometry in patients with suspected inherited platelet function disorders.
Objective
To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early‐onset fetal growth restriction.
Design
A randomised placebo‐controlled trial.
Setting
Thirteen ...maternal–fetal medicine units across New Zealand and Australia.
Population
Women with singleton pregnancies affected by fetal growth restriction at 22+0 to 29+6 weeks.
Methods
Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 weeks, birth or fetal death (whichever occurred first).
Main Outcome Measures
The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre‐eclampsia.
Results
Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil‐treated, 39/57 (68.4%) placebo‐treated adjusted odds ratio (OR) 0.49, 95% CI 0.23–1.05 and had no effect on abdominal circumference Z‐scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil‐treated and 47/59 (79.7%) for placebo‐treated (adjusted OR 2.50, 95% CI 0.80–7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil‐treated and 33/59 (55.9%) for placebo‐treated (adjusted OR 1.93, 95% CI 0.84–4.45); and new‐onset pre‐eclampsia was 9/51 (17.7%) for sildenafil‐treated and 14/55 (25.5%) for placebo‐treated (OR 0.67, 95% CI 0.26–1.75).
Conclusions
Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta‐analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.
Tweetable
Maternal sildenafil use has no beneficial effect on growth in early‐onset FGR, but also no evidence of harm.
Tweetable
Maternal sildenafil use has no beneficial effect on growth in early‐onset FGR, but also no evidence of harm.
Reduced brain insulin signaling and low CSF-to-plasma insulin ratios have been observed in patients with Alzheimer disease (AD). Furthermore, intracerebroventricular or IV insulin administration ...improve memory, alter evoked potentials, and modulate neurotransmitters, possibly by augmenting low brain levels. After intranasal administration, insulin-like peptides follow extracellular pathways to the brain within 15 minutes.
We tested the hypothesis that daily intranasal insulin treatment would facilitate cognition in patients with early AD or its prodrome, amnestic mild cognitive impairment (MCI). The proportion of verbal information retained after a delay period was the planned primary outcome measure. Secondary outcome measures included attention, caregiver rating of functional status, and plasma levels of insulin, glucose, beta-amyloid, and cortisol.
Twenty-five participants were randomly assigned to receive either placebo (n = 12) or 20 IU BID intranasal insulin treatment (n = 13) using an electronic atomizer, and 24 participants completed the study. Participants, caregivers, and all clinical evaluators were blinded to treatment assignment. Cognitive measures and blood were obtained at baseline and after 21 days of treatment.
Fasting plasma glucose and insulin were unchanged with treatment. The insulin-treated group retained more verbal information after a delay compared with the placebo-assigned group (p = 0.0374). Insulin-treated subjects also showed improved attention (p = 0.0108) and functional status (p = 0.0410). Insulin treatment raised fasting plasma concentrations of the short form of the beta-amyloid peptide (A beta 40; p = 0.0471) without affecting the longer isoform (A beta 42), resulting in an increased A beta 40/42 ratio (p = 0.0207).
The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.
Climate change is altering the rate and distribution of primary production in the world's oceans. Primary production is critical to maintaining biodiversity and supporting fishery catches, but ...predicting the response of populations to primary production change is complicated by predation and competition interactions. We simulated the effects of change in primary production on diverse marine ecosystems across a wide latitudinal range in Australia using the marine food web model Ecosim. We link models of primary production of lower trophic levels (phytoplankton and benthic producers) under climate change with Ecosim to predict changes in fishery catch, fishery value, biomass of animals of conservation interest, and indicators of community composition. Under a plausible climate change scenario, primary production will increase around Australia and generally this benefits fisheries catch and value and leads to increased biomass of threatened marine animals such as turtles and sharks. However, community composition is not strongly affected. Sensitivity analyses indicate overall positive linear responses of functional groups to primary production change. Responses are robust to the ecosystem type and the complexity of the model used. However, model formulations with more complex predation and competition interactions can reverse the expected responses for some species, resulting in catch declines for some fished species and localized declines of turtle and marine mammal populations under primary productivity increases. We conclude that climate-driven primary production change needs to be considered by marine ecosystem managers and more specifically, that production increases can simultaneously benefit fisheries and conservation. Greater focus on incorporating predation and competition interactions into models will significantly improve the ability to identify species and industries most at risk from climate change.
Summary
The majority of patients with platelet function disorders (PFDs) have normal platelet counts and mild day‐to‐day bleeding symptoms, but are at risk of major hemorrhage at times of trauma, ...surgery, or childbirth. This group is challenging to investigate, because the assays are often time‐intensive and labour‐intensive, and interpretation is difficult, especially in patients with mild disorders. In addition, interuser variability in performance of the assays, including the currently accepted gold standard, light transmission aggregometry, makes the results difficult to compare between laboratories. Furthermore, a similar pattern of mucocutaneous bleeding is seen in disorders in other components of the hemostatic pathway, including type 1 von Willebrand disease (VWD). We have undertaken an extensive investigation of patients with clinically diagnosed excessive bleeding, using a genotyping and platelet phenotyping approach based on lumi‐aggregometry, and other specialist tests of platelet function, in combination with Sanger and next‐generation sequencing (NGS). We found a functional defect in ~ 60% of patients, the majority being associated with feedback pathways of platelet activation. Function‐disrupting mutations were identified in known and novel genes, and coinheritance with other genetic disorders of hemostasis, including type 1 VWD, was shown. A significant number of mutations are heterozygous and unlikely to cause extensive bleeding in isolation, consistent with incomplete penetrance of inheritance of bleeding disorders and a multifactorial etiology for excessive bleeding in many patients. Mucocutaneous bleeding is a complex trait, and this has important implications for NGS in the assessment of a PFD.
We present high-speed, three-colour photometry of seven short-period (P
orb≤ 95 min) eclipsing cataclysmic variables (CVs) from the Sloan Digital Sky Survey. We determine the system parameters via a ...parametrized model of the eclipse fitted to the observed light curve by χ2 minimization. Three out of seven of the systems possess brown dwarf donor stars and are believed to have evolved past the orbital period minimum. This is in line with the predictions that 40-70 per cent of CVs should have evolved past the orbital period minimum. Therefore, the main result of our study is that the missing population of post-period minimum CVs has finally been identified. The donor star masses and radii are, however, inconsistent with model predictions; the donor stars are approximately 10 per cent larger than expected across the mass range studied here. One explanation for the discrepancy is the enhanced angular momentum loss (e.g. from circumbinary discs); however, the mass-transfer rates, as deduced from white dwarf effective temperatures, are not consistent with enhanced angular momentum loss. We show that it is possible to explain the large donor radii without invoking enhanced angular momentum loss by a combination of geometrical deformation and the effects of starspots due to strong rotation and expected magnetic activity. Choosing unambiguously between these different solutions will require independent estimates of the mass-transfer rates in short-period CVs.
The white dwarfs in our sample show a strong tendency towards high masses. We show that this is unlikely to be due to selection effects. The dominance of high-mass white dwarfs in our sample implies that erosion of the white dwarf during nova outbursts must be negligible, or even that white dwarfs grow in mass through the nova cycle. Amongst our sample, there are no helium-core white dwarfs, despite predictions that 30-80 per cent of short-period CVs should contain helium-core white dwarfs. We are unable to rule out selection effects as the cause of this discrepancy.
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