Effects of an economic downturn on construction partnering

Over the economic downturn in recent years, there has been a trend for construction clients to revert to traditional competitive procurement strategies. This is despite authoritative calls for an increase in collaborative working and partnering practices, heralded as the means to drive efficiencies and innovation. Clients may feel that the only way to assure themselves that they are not paying too much is to market-test their projects in a highly competitive environment. This study seeks to provide an insight into the effects of the recent economic downturn on collaborative working, with particular emphasis on manifestation in the practice and positioning of trust within such relationships. Eight interviews were carried out with senior industry professionals, all experienced in partnering and collaborative working practices. Individuals have responded with a quest for job security, which has in turn developed risk-averse work practices and affected the establishment of short-term collaborative relationships. Organisations have returned to traditional competitive procurement methods, seeking to reduce risk in their practices and maintain control in uncertain times. Sceptical considerations of collaboration have re-emerged; the abuses of collaborative relationships for financial benefits, employing austerity as leverage, have become contemporary legend if not fact

Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1)

Background: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients and methods: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m&lt;sup&gt;2&lt;/sup&gt; on day 1) was administered alone or with ganetespib (150 mg/m&lt;sup&gt;2&lt;/sup&gt; on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Results: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease &gt;6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Conclusion: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients &gt;6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.</p

The Pfam protein families database

Pfam is a comprehensive collection of protein domains and families, represented as multiple sequence alignments and as profile hidden Markov models. The current release of Pfam (22.0) contains 9318 protein families. Pfam is now based not only on the UniProtKB sequence database, but also on NCBI GenPept and on sequences from selected metagenomics projects. Pfam is available on the web from the consortium members using a new, consistent and improved website design in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/), as well as from mirror sites in France (http://pfam.jouy.inra.fr/) and South Korea (http://pfam.ccbb.re.kr/)

Fever management with or without a temperature control device after out‐of‐hospital cardiac arrest and resuscitation (TEMP‐CARE): A study protocol for a randomized clinical trial

Background: Fever is associated with brain injury after cardiac arrest. It is unknown whether fever management with a feedback‐controlled device impacts patient‐centered outcomes in cardiac arrest patients. This trial aims to investigate fever management with or without a temperature control device after out‐of‐hospital cardiac arrest. Methods: The TEMP‐CARE trial is part of the 2 × 2 × 2 factorial Sedation, Temperature and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial, a randomized, international, multicenter, parallel‐group, investigator‐initiated, superiority trial that will evaluate sedation strategies, temperature management, and blood pressure targets simultaneously in nontraumatic/nonhemorrhagic out‐of‐hospital cardiac arrest patients following hospital admission. For the temperature management component of the trial described in this protocol, patients will be randomly allocated to fever management with or without a feedback‐controlled temperature control device. For those managed with a device, if temperature ≥37.8°C occurs within 72 h post‐randomization the device will be started targeting a temperature of ≤37.5°C. Standard fever treatment, as recommended by local guidelines, including pharmacological agents, will be provided to participants in both groups. The two other components of the STEPCARE trial evaluate sedation and blood pressure strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. A physician blinded to the intervention will determine the neurological prognosis following European Resuscitation Council and European Society of Intensive Care Medicine guidelines. The primary outcome is all‐cause mortality at six months post‐randomization. To detect a 5.6% absolute risk reduction (90% power, alpha .05), 3500 participants will be enrolled. Secondary outcomes include poor functional outcome at six months, intensive care‐related serious adverse events, and overall health status at six months. Conclusion: The TEMP‐CARE trial will investigate if post‐cardiac arrest management of fever with or without a temperature control device affects patient‐important outcomes after cardiac arrest

Sedation, temperature and pressure after cardiac arrest and resuscitation—The STEPCARE trial: A statistical analysis plan

Background: Basic management for patients who have suffered a cardiac arrest and are admitted to an intensive care unit (ICU) after resuscitation includes setting targets for blood pressure and managing sedation and temperature. However, optimal targets and management are unknown. Methods: The STEPCARE (Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation) trial is a multicenter, parallel‐group, randomized, factorial, superiority trial in which sedation, temperature, and blood pressure strategies will be studied in three separate comparisons (SED‐CARE, TEMP‐CARE, and MAP‐CARE). The trial population will be adults admitted to intensive care who are comatose after resuscitation from out‐of‐hospital cardiac arrest. The primary outcome will be all‐cause mortality, and the secondary outcomes will be poor functional outcome (modified Rankin Scale 4–6), Health‐Related Quality of Life using EQ‐VAS, and specific serious adverse events in the intensive care unit predefined for each trial. All outcomes will be assessed at 6 months after randomization. The prognosticators, outcome assessors, statisticians, data managers, steering group, and manuscript writers will be blinded to treatment allocation. This statistical analysis plan includes a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Analyses will be conducted according to the intention‐to‐treat principle, that is, all randomized participants with available data will be included. The analyses will be performed independently by two statisticians following the present plan. Conclusion: This statistical analysis plan describes the statistical analyses for the STEPCARE trial in detail. The aim of this predefined statistical analysis plan is to minimize the risk of analysis bias

Continuous deep sedation versus minimal sedation after cardiac arrest and resuscitation (SED‐CARE): A protocol for a randomized clinical trial

Background: Sedation is often provided to resuscitated out‐of‐hospital cardiac arrest (OHCA) patients to tolerate post‐cardiac arrest care, including temperature management. However, the evidence of benefit or harm from routinely administered deep sedation after cardiac arrest is limited. The aim of this trial is to investigate the effects of continuous deep sedation compared to minimal sedation on patient‐important outcomes in resuscitated OHCA patients in a large clinical trial. Methods: The SED‐CARE trial is part of the 2 × 2 × 2 factorial Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) trial, a randomized international, multicentre, parallel‐group, investigator‐initiated, superiority trial with three simultaneous intervention arms. In the SED‐CARE trial, adults with sustained return of spontaneous circulation (ROSC) who are comatose following resuscitation from OHCA will be randomized within 4 hours to continuous deep sedation (Richmond agitation and sedation scale (RASS) −4/−5) (intervention) or minimal sedation (RASS 0 to −2) (comparator), for 36 h after ROSC. The primary outcome will be all‐cause mortality at 6 months after randomization. The two other components of the STEPCARE trial evaluate sedation and temperature control strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. Neurological prognostication will be performed according to European Resuscitation Council and European Society of Intensive Care Medicine guidelines by a physician blinded to the allocation group. To detect an absolute risk reduction of 5.6% with an alpha of 0.05, 90% power, 3500 participants will be enrolled. The secondary outcomes will be the proportion of participants with poor functional outcomes 6 months after randomization, serious adverse events in the intensive care unit, and patient‐reported overall health status 6 months after randomization. Conclusion: The SED‐CARE trial will investigate if continuous deep sedation (RASS −4/−5) for 36 h confers a mortality benefit compared to minimal sedation (RASS 0 to −2) after cardiac arrest

Fever management with or without a temperature control device after out-of-hospital cardiac arrest and resuscitation (TEMP-CARE): A study protocol for a randomized clinical trial.

peer reviewed[en] BACKGROUND: Fever is associated with brain injury after cardiac arrest. It is unknown whether fever management with a feedback-controlled device impacts patient-centered outcomes in cardiac arrest patients. This trial aims to investigate fever management with or without a temperature control device after out-of-hospital cardiac arrest. METHODS: The TEMP-CARE trial is part of the 2 × 2 × 2 factorial Sedation, TEmperature and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial, a randomized, international, multicenter, parallel-group, investigator-initiated, superiority trial that will evaluate sedation strategies, temperature management, and blood pressure targets simultaneously in nontraumatic/nonhemorrhagic out-of-hospital cardiac arrest patients following hospital admission. For the temperature management component of the trial described in this protocol, patients will be randomly allocated to fever management with or without a feedback-controlled temperature control device. For those managed with a device, if temperature ≥37.8°C occurs within 72 h post-randomization the device will be started targeting a temperature of ≤37.5°C. Standard fever treatment, as recommended by local guidelines, including pharmacological agents, will be provided to participants in both groups. The two other components of the STEPCARE trial evaluate sedation and blood pressure strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. A physician blinded to the intervention will determine the neurological prognosis following European Resuscitation Council and European Society of Intensive Care Medicine guidelines. The primary outcome is all-cause mortality at six months post-randomization. To detect a 5.6% absolute risk reduction (90% power, alpha .05), 3500 participants will be enrolled. Secondary outcomes include poor functional outcome at six months, intensive care-related serious adverse events, and overall health status at six months. CONCLUSION: The TEMP-CARE trial will investigate if post-cardiac arrest management of fever with or without a temperature control device affects patient-important outcomes after cardiac arrest

Higher versus lower mean arterial blood pressure after cardiac arrest and resuscitation (MAP-CARE): A protocol for a randomized clinical trial.

peer reviewed[en] BACKGROUND: In patients resuscitated after cardiac arrest, a higher mean arterial pressure (MAP) may increase cerebral perfusion and attenuate hypoxic brain injury. Here we present the protocol of the mean arterial pressure after cardiac arrest and resuscitation (MAP-CARE) trial aiming to investigate the influence of MAP targets on patient outcomes. METHODS: MAP-CARE is one component of the Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) 2 x 2 x 2 factorial randomized trial. The MAP-CARE trial is an international, multicenter, parallel-group, investigator-initiated, superiority trial designed to test the hypothesis that targeting a higher (>85 mmHg) (intervention) versus a lower (>65 mmHg) (comparator) MAP after resuscitation from cardiac arrest reduces 6-month mortality (primary outcome). Trial participants are adults with sustained return of spontaneous circulation who are comatose following resuscitation from out-of-hospital cardiac arrest. The two other components of the STEPCARE trial evaluate sedation and temperature control strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. Neurological prognostication will be performed according to European Resuscitation Council and European Society of Intensive Care Medicine guidelines by a physician blinded to allocation group. The sample size of 3500 participants provides 90% power with an alpha of 0.05 to detect a 5.6 absolute risk reduction in 6-month mortality, assuming a mortality of 60% in the control group. Secondary outcomes will be poor functional outcome 6 months after randomization, patient-reported overall health 6 months after randomization, and the proportion of participants with predefined severe adverse events. CONCLUSION: The MAP-CARE trial will investigate if targeting a higher MAP compared to a lower MAP during intensive care of adults who are comatose following resuscitation from out-of-hospital cardiac arrest reduces 6-month mortality

Continuous deep sedation versus minimal sedation after cardiac arrest and resuscitation (SED-CARE): A protocol for a randomized clinical trial.

peer reviewed[en] BACKGROUND: Sedation is often provided to resuscitated out-of-hospital cardiac arrest (OHCA) patients to tolerate post-cardiac arrest care, including temperature management. However, the evidence of benefit or harm from routinely administered deep sedation after cardiac arrest is limited. The aim of this trial is to investigate the effects of continuous deep sedation compared to minimal sedation on patient-important outcomes in resuscitated OHCA patients in a large clinical trial. METHODS: The SED-CARE trial is part of the 2 × 2 × 2 factorial Sedation, Temperature and Pressure after Cardiac Arrest and Resuscitation (STEPCARE) trial, a randomized international, multicentre, parallel-group, investigator-initiated, superiority trial with three simultaneous intervention arms. In the SED-CARE trial, adults with sustained return of spontaneous circulation (ROSC) who are comatose following resuscitation from OHCA will be randomized within 4 hours to continuous deep sedation (Richmond agitation and sedation scale (RASS) -4/-5) (intervention) or minimal sedation (RASS 0 to -2) (comparator), for 36 h after ROSC. The primary outcome will be all-cause mortality at 6 months after randomization. The two other components of the STEPCARE trial evaluate sedation and temperature control strategies. Apart from the STEPCARE trial interventions, all other aspects of general intensive care will be according to the local practices of the participating site. Neurological prognostication will be performed according to European Resuscitation Council and European Society of Intensive Care Medicine guidelines by a physician blinded to the allocation group. To detect an absolute risk reduction of 5.6% with an alpha of 0.05, 90% power, 3500 participants will be enrolled. The secondary outcomes will be the proportion of participants with poor functional outcomes 6 months after randomization, serious adverse events in the intensive care unit, and patient-reported overall health status 6 months after randomization. CONCLUSION: The SED-CARE trial will investigate if continuous deep sedation (RASS -4/-5) for 36 h confers a mortality benefit compared to minimal sedation (RASS 0 to -2) after cardiac arrest