Temporal changes in secondary prevention and cardiovascular outcomes after revascularization for peripheral arterial disease in Denmark: a nationwide cohort study

Background:Patients with peripheral arterial disease (PAD) are at increased risk of cardiovascular morbidity and mortality. Medical prevention with antithrombotic and statin therapies is a mainstay of treatment to prevent adverse outcomes; nevertheless, patients with PAD are often undertreated. This study describes the temporal changes in medical prevention and adverse outcomes in a national cohort of patients with symptomatic PAD after revascularization.Methods:We identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark, from 2000 to 2016. We examined temporal changes in the use of aspirin, clopidogrel, and statins and 1-year cause-specific hazard ratios for adverse clinical outcomes, after adjusting for procedure type, treatment indication, age, sex, and cardiovascular risk factors. The analyses were performed overall and within strata of index procedure (endovascular versus surgical), treatment indication, age, sex, and high-risk comorbidities.Results:Between 2000 and 2016, we identified 32 911 patients who underwent revascularization for symptomatic PAD. The mean age was 69 years and increased over time, as did the burden of comorbidity. The cumulative incidence of medication use increased between 2000 to 2004 and 2013 to 2016, respectively, from 57.3% to 64.3% for aspirin, 3.6% to 24.8% for clopidogrel, and 36.2% to 77.1% for statins. Concurrently, the 1-year outcome rates declined. Compared with 2000 to 2004, the adjusted hazard ratios in 2013 to 2016 were 0.73 (95% CI, 0.62-0.84) for major adverse cardiovascular events, 0.92 (95% CI, 0.85-1.00) for major adverse limb events, 0.60 (95% CI, 0.48-0.74) for myocardial infarction, 0.94 (95% CI, 0.75-1.18) for ischemic stroke, 0.92 (95% CI, 0.75-1.12) for major bleeding, 0.54 (95% CI, 0.39-0.76) for cardiovascular death, and 0.80 (95% CI, 0.72-0.88) for all-cause death. These improvements in prognosis were most prominent from 2000 to 2004 to 2005 to 2008 and occurred in all strata of index procedure, treatment indication, sex, age, and comorbidity. In contrast, the adjusted hazard ratio for major amputations was 1.00 (95% CI, 0.90-1.11) when comparing 2013 to 2016 to 2000 to 2004.Conclusions:Medical prevention of adverse events has increased considerably over time in patients who underwent revascularization for symptomatic PAD. This increase was accompanied by reductions in all adverse outcomes, except major amputations.Diabetes mellitus: pathophysiological changes and therap

Impacto de sulfentrazona, isoxaflutol e oxyfluorfem sobre a microbiota de dois solos florestais

Questões referentes à aplicação de herbicidas em pré-emergência das plantas daninhas na cultura do eucalipto merecem destaque devido ao impacto dessa prática no ambiente, principalmente sobre a atividade microbiana do solo e micro-organismos benéficos, como os fungos micorrízicos e os solubilizadores de fosfatos. Objetivou-se estudar o impacto da aplicação dos herbicidas sulfentrazona, isoxaflutol e oxyfluorfem sobre a colonização micorrízica, biomassa e atividade microbiana de dois solos florestais cultivados com eucalipto. O ensaio foi conduzido em casa de vegetação utilizando um solo argiloso e um solo francoarenoso distribuídos em vasos de 12 dm³. O esquema fatorial utilizado foi 4 x 3, sendo três herbicidas (sulfentrazona, isoxaflutol e oxyfluorfem) mais a testemunha e três avaliações (5, 20 e 70 dias após a aplicação - DAA), no delineamento inteiramente casualizado com quatro repetições. Após a aplicação dos herbicidas na dose recomendada para a cultura transplantaram-se as mudas do híbrido de Eucalyptus grandis x E. urophylla. Avaliaram-se a biomassa microbiana, a taxa respiratória do solo, o quociente metabólico e o potencial de solubilização de fosfato inorgânico aos 5, 20 e 70 DAA. Aos 70 DAA verificou-se a colonização micorrízica e a viabilidade de esporos. Os herbicidas sulfentrazona, isoxaflutol e oxyfluorfem, bem como o tempo decorrido da aplicação afetaram os indicadores microbiológicos de maneira diferenciada. No solo franco-arenoso, o sulfentrazona foi mais prejudicial à biomassa microbiana, à colonização micorrízica e aos micro-organismos solubilizadores de fosfato inorgânico. No solo argiloso, no entanto, a aplicação dos três herbicidas não afetou a biomassa microbiana, mas reduziu a colonização radicular do eucalipto por fungos micorrízicos arbusculares e o potencial de solubilização de fosfato inorgânico. O herbicida sulfentrazona se destacou por provocar aumento do número de esporos não viáveis de fungos micorrízicos arbusculares nesse solo

Clinical review: Update on hemodynamic monitoring - a consensus of 16.

Contains fulltext : 96739.pdf (publisher's version ) (Open Access)Hemodynamic monitoring plays a fundamental role in the management of acutely ill patients. With increased concerns about the use of invasive techniques, notably the pulmonary artery catheter, to measure cardiac output, recent years have seen an influx of new, less-invasive means of measuring hemodynamic variables, leaving the clinician somewhat bewildered as to which technique, if any, is best and which he/she should use. In this consensus paper, we try to provide some clarification, offering an objective review of the available monitoring systems, including their specific advantages and limitations, and highlighting some key principles underlying hemodynamic monitoring in critically ill patients

Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis

Rationale: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown.Objectives: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis.Methods: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203).Measurements and Main Results: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival.Conclusions: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.Diabetes mellitus: pathophysiological changes and therap

Supplementary Material for: Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

<b><i>Purpose:</i></b> We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. <b><i>Methods:</i></b> Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce <i>Escherichia coli</i> endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. <b><i>Results:</i></b> We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced <i>E. coli</i> endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). <b><i>Conclusions:</i></b> Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock

Supplementary Material for: The Specific Organism: Not Bacterial Gram Type: Drives the Inflammatory Response in Septic Shock

Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns