Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c.

Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race and emphasize a need to consider the effects of race when developing anti-thrombotic drugs

Quasi-Monte Carlo Integration for Affine-Parametric, Elliptic PDEs: Local Supports and Product Weights

ISSN:0036-1429ISSN:1095-717

Comparison of propofol and dexmedetomidine infused overnight to treat hyperactive and mixed ICU delirium: a protocol for the Basel ProDex clinical trial

Delirium is a neurobehavioural disturbance that frequently develops particularly in the intensive care unit (ICU) population. It was first described more than half a century ago, where it was already discovered as a state that might come along with serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. However, in most cases, there is still lack of proof for causal relationship. Its presence frequently remains unrecognised due to suggested predominance of the hypoactive form. Furthermore, in the general ICU population, it has been shown that the duration of delirium is associated with worse long-term cognitive function. Due to the multifactorial origin of delirium, we have several but no incontestable treatment options. Nonetheless, delirium bears a high burden for patient, family members and the medical care team.The Basel ProDex Study targets improvement of hyperactive and mixed delirium therapy in critically ill patients. We will focus on reducing the duration and severity of delirium by implementing dexmedetomidine into the treatment plan. Dexmedetomidine compared with other sedatives shows fewer side effects representing a better risk profile for delirium treatment in general. This could further contribute to higher patient safety.The aim of the BaProDex Trial is to assess the superiority of dexmedetomidine to propofol for treatment of hyperactive and mixed delirium in the ICU. We hypothesise that dexmedetomidine, compared with propofol administered at night, shortens both the duration and severity of delirium.; The Basel ProDex Study is an investigator-initiated, one-institutional, two-centre randomised controlled clinical trial for the treatment of delirium with dexmedetomidine versus propofol in 316 critically ill patients suffering from hyperactive and mixed delirium. The primary outcome measure is delirium duration in hours. Secondary outcomes include delirium-free days at day 28, death at day 28, delirium severity, amount of ventilator days, amount of rescue sedation with haloperidol, length of ICU and hospital stay, and pharmaceutical economic analysis of the treatments. Sample size was estimated to be able to show the superiority of dexmedetomidine compared with propofol regarding the duration of delirium in hours. The trial will be externally monitored according to good clinical practice (GCP) requirements. There are no interim analyses planned for this trial.; This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the International Conference on Harmonization- Good Clinical Practice (ICH-GCP) or Europäische Norm International Organization for Standardization (ISO EN 14155; as far as applicable) as well as all national legal and regulatory requirements. Only the study team will have access to trial specific data. Anonymisation will be achieved by a unique patient identification code. Trial data will be archived for a minimum of 10 years after study termination. We plan to publish the data in a major peer-reviewed clinical journal.; ClinicalTrials.gov Identifier: NCT02807467 PROTOCOL VERSION: Clinical Study Protocol Version 2, 16.08.2016

Impact of amount of fluid for circulatory resuscitation on renal function in patients in shock: evaluating the influence of intra-abdominal pressure, renal resistive index, sublingual microcirculation and total body water measured by bio-impedance analysis on haemodynamic parameters for guidance of volume resuscitation in shock therapy: a protocol for the VoluKid pilot study–an observational clinical trial

Abstract Background All forms of shock, particularly septic shock, that involve insufficient blood supply to tissues to meet metabolic demands are main causes of morbidity and mortality worldwide and develop in one third of patients admitted to the intensive care unit (ICU). This alarmingly high incidence underlines the importance of further research in this field. Uncertainty remains about the undeceiving parameters for guidance of fluid resuscitation to avoid acute kidney injury (AKI) and renal replacement therapy. However, there are consequences of fluid overload (e.g. organ oedema and high interstitial pressures). This proposed study aims to establish a new framework of parameters for the guidance of fluid resuscitation in shock therapy focusing on the first 72 h, amending the currently used parameters (i.e. cardiac output, heart rate, blood pressure, central venous pressure) with an array of additional measurements including assessment of total body water (TBW), renal vascular resistance (renal resistive index (RRI)), intra-abdominal pressure (IAP) and microcirculatory blood flow (MBF). Methods This observational cohort study includes patients in shock presenting to the ICU. In addition to routine parameters (i.e. cardiac output, heart rate, blood pressure, central venous pressure) for volume resuscitation, MBF will be recorded using sublingual incident dark field microscopy, IAP, RRI seen in duplex-sonography and TBW will be estimated using bio-impedance analysis for correlation and eventually signalling of AKI and need for renal replacement therapy. Follow-up measurements will be taken at set intervals up to 72 h post admittance. To investigate the association between the newly investigated parameters and the occurrence of an AKI, we will compare the difference between measurements taken after admittance to the ICU and baseline values in patients with and without AKI using a two-sample t test. A linear regression model will be constructed to investigate the first and secondary outcome. Results Between January 2016 and August 2017, a total of 33 patients were recruited. The final results are expected in the second half of 2018. Conclusions The VoluKid study will investigate a new approach to assess volaemia and parameters indicating AKI in patients in shock who undergo volume resuscitation in the ICU. Trial registration The study was registered at ClinicalTrials.gov (Identifier: NCT02666404) on January 18, 2016, and at the Swiss National Clinical Trial Portal (SNCPT; Identifier: SNCTP000001693) on February 13, 2016

Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial

International audienceAbstract Background Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO 2 ) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO 2 with patients’ outcome. Methods Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO 2  300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. Results 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO 2 -AUC), for hyperoxemia was significantly associated with mortality ( p = 0.003). Conclusions In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration : clinicaltrials.gov NCT02908308 , Registered September 20, 2016

Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial

International audienc