A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension.

PURPOSE: Clinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients. METHODS: We searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects. RESULTS: Of 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01). CONCLUSION: Current evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.

Long-term modelling of crop yield, nitrogen losses and GHG balance in organic cropping systems.

Although organic cropping systems are promoted for their environmental benefits, little is known about their long-term impact on nitrogen (N) fate in the soil-plant-atmosphere system. In this paper, we analyze two long-term experiments: DOK in Switzerland (39-yr) and Foulum organic in Denmark (19-yr). Four treatments were considered in each experiment: two conventional treatments with (CONFYM) or without manure (CONMIN), organic with manure (BIOORG) and unfertilized treatment (NOFERT) at DOK; conventional (CGL-CC+IF) and three organic treatments, one with cover crops only (OGL+CC-M) and two including cover crops and grass-clover with (OGC+CC+M) or without manure (OGC+CC-M), at Foulum. STICS model was used to simulate crop production, N surplus, nitrate leaching, gaseous N losses and changes in soil organic N. It was calibrated in the conventional treatments and tested in organic systems. The crop production, N surplus and soil organic N stocks were satisfactorily predicted. The mean N surplus greatly differed between treatments at DOK, from -58 (NOFERT) to +21 kg N ha-1 yr-1 (CONFYM), but only from -9 (OGL+CC-M) to +21 kg N ha-1 yr-1 (OGC+CC+M) in Foulum. Soil N pools declined continuously in both sites and treatments at a rate varying from -18 to -78 kg N ha-1 yr-1, depending on fertilization and crop rotation. The decline was consistent with the observed N surpluses. Although not all simulations could be tested against field observations and despite of prediction uncertainties, simulations confirm the hypothesis that environmental performances resulting from C and N cycles depend more on specificities of individual than nominal treatments. Significant correlations appeared between long-term N surplus and soil N storage and between total N fertilization and total N gaseous losses. Results showed in both experiments that arable organic systems do not systematically have lower N surplus and N losses than conventional ones, providing opportunity for increasing N use efficiency of these systems.

Measuring the accuracy of agro-environmental indicators.

Numerous agro-environmental indicators have been developed by agronomists and ecologists during the last 20 years to assess the environmental impact of farmers' practices, and to monitor effects of agro-environmental policies. The objectives of this paper were (i) to measure the accuracy of a wide range of agro-environmental indicators from experimental data and (ii) to discuss the value of different information typically used by these indicators, i.e. information on farmers' practices, and on plant and soil characteristics. Four series of indicators were considered in this paper: indicators of habitat quality for grassland bird species, indicators of risk of disease in oilseed rape crops, indicators of risk of pollution by nitrogen fertilizer, and indicators of weed infestation. Several datasets were used to measure their accuracy in cultivated plots and in grasslands. The sensitivity, specificity, and probability of correctly ranking plots were estimated for each indicator. Our results showed that the indicators had widely varying levels of accuracy. Some show very poor performance and had no discriminatory ability. Other indicators were informative and performed better than random decisions. Among the tested indicators, the best ones were those using information on plant characteristics such as grass height, fraction of diseased flowers, or crop yield. The statistical method applied in this paper could support researchers, farm advisers, and decision makers in comparing various indicators.

Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock.

PURPOSE: Guidelines for shock recommend mean arterial pressure (MAP) targets for vasopressor therapy of at least 65 mmHg and, until recently, suggested that patients with underlying chronic hypertension and atherosclerosis may benefit from higher targets. We conducted an individual patient-data meta-analysis of recent trials to determine if patient variables modify the effect of different MAP targets. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials of higher versus lower blood pressure targets for vasopressor therapy in adult patients in shock (until November 2017). After obtaining individual patient data from both eligible trials, we used a modified version of the Cochrane Collaboration's instrument to assess the risk of bias of included trials. The primary outcome was 28-day mortality. RESULTS: Included trials enrolled 894 patients. Controlling for trial and site, the OR for 28-day mortality for the higher versus lower MAP targets was 1.15 (95% CI 0.87-1.52). Treatment effect varied by duration of vasopressors before randomization (interaction p = 0.017), but not by chronic hypertension, congestive heart failure or age. Risk of death increased in higher MAP groups among patients on vasopressors > 6 h before randomization (OR 3.00, 95% CI 1.33-6.74). CONCLUSIONS: Targeting higher blood pressure targets may increase mortality in patients who have been treated with vasopressors for more than 6 h. Lower blood pressure targets were not associated with patient-important adverse events in any subgroup, including chronically hypertensive patients.

Zebra rocks: compaction waves create ore deposits.

Nature has a range of distinct mechanisms that cause initially heterogeneous systems to break their symmetry and form patterns. One of these patterns is zebra dolomite that is frequently hosting economically important base metal mineralization. A consistent generic model for the genesis of these periodically banded rocks is still lacking. In this contribution, we present for the first time a fully consistent mathematical model for the genesis of the pattern by coupling the reactive fluid-solid system with hydromechanics. We show that visual banding develops at a given stress and host-rock permeability indicating that the wavelength and occurrence of the pattern may be predictable for natural settings. This finding offers the exciting possibility of estimating conditions of formation of known deposits as well as forecasting potential exploration targets.

Vasopressor use following traumatic injury: protocol for a systematic review.

INTRODUCTION: Worldwide, traumatic casualties are projected to exceed 8 million by year 2020. Haemorrhagic shock and brain injury are the leading causes of death following trauma. While intravenous fluids have traditionally been used to support organ perfusion in the setting of haemorrhage, recent investigations have suggested that restricting fluid therapy by tolerating more severe hypotension may improve survival. However, the safety of permissive hypotension remains uncertain, particularly among patients who have suffered a traumatic brain injury. Vasopressors preferentially vasoconstrict blood vessels that supply non-vital organs and capacitance vessels, thereby mobilising the unstressed blood volume. Used as fluid-sparing adjuncts, these drugs can complement resuscitative measures by correcting hypotension without diluting clotting factors or increasing the risk for tissue oedema. METHODS AND ANALYSIS: We will identify randomised control trials comparing early resuscitation with vasopressors versus placebo or standard care in adults following traumatic injury. Data sources will include MEDLINE, EMBASE, CENTRAL, clinical trial registries and conference proceedings. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction and risk of bias assessment. We will assess the overall quality of the data for each individual outcome using the GRADE approach. ETHICS AND DISSEMINATION: We will report this review in accordance with the PRISMA statement. We will disseminate our findings at critical care and trauma conferences and through a publication in a peer-reviewed journal. We will also use this systematic review to create clinical guidelines (http://www.magicapp.org), which will be disseminated in a standalone publication. TRIAL REGISTRATION NUMBER: CRD42016033437.

Early vasopressor use following traumatic injury: a systematic review.

OBJECTIVES: Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury. RESULTS: Of 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function. CONCLUSIONS: Existing data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation. TRIAL REGISTRATION NUMBER: CRD42016033437.

The Max b-HLH-LZ can transduce into cells and inhibit c-Myc transcriptional activities.

The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc, the cDNA of a designed mutant of the b-HLH-LZ of c-Myc named Omomyc. The overall mode of action of Omomyc consists in the sequestration of Max and the concomitant competition of the Omomyc/Max complex with the endogenous c-Myc/Max heterodimer. This leads to the inhibition of the transactivation of Myc target genes involved in proliferation and metabolism. While this body of work has provided extraordinary insights to guide the future development of new cancer therapies that target c-Myc, Omomyc itself is not a therapeutic agent. In this context, we sought to exploit the use of a b-HLH-LZ to inhibit c-Myc in a cancer cell line in a more direct fashion. We demonstrate that the b-HLH-LZ domain of Max (Max*) behaves as a bona fide protein transduction domain (PTD) that can efficiently transduce across cellular membrane via through endocytosis and translocate to the nucleus. In addition, we show that the treatment of HeLa cells with Max* leads to a reduction of metabolism and proliferation rate. Accordingly, we observe a decrease of the population of HeLa cells in S phase, an accumulation in G1/G0 and the induction of apoptosis. In agreement with these phenotypic changes, we show by q-RT-PCR that the treatment of HeLa cells with Max* leads to the activation of the transcription c-Myc repressed genes as well as the repression of the expression of c-Myc activated genes. In addition to the novel discovery that the Max b-HLH-LZ is a PTD, our findings open up new avenues and strategies for the direct inhibition of c-Myc with b-HLH-LZ analogs.