Activated protein C consumption and coagulation parameters in severe sepsis and septic shock.

Introduction Activated protein C (APC) deC ciency is prevalent in severe sepsis and septic shock patients. The aim of the study was to relate the anticoagulation activity evaluated by APC with other coagulation parameters adjusted to 28-day mortality. Methods A cohort study of 150 critically ill adults. Age, sex, sources of infection and coagulation markers within 24< hours from severe sepsis or septic shock onset, deC ned according to Surviving Sepsis Campaign (SSC) criteria, were studied. We analyzed APC activity using a hemostasis laboratory analyzer (BCS® XP; Siemens). A descriptive and comparative statistical analysis was performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). Results We analyzed 150 consecutive episodes of severe sepsis (16%) or septic shock (84%) admitted to the UCI. The median age of the study sample was 64 (interquartile range (IQR): 22.3and 70.7% had medical pathology. The 28-day mortality was 22.7%. Nonsurvivors had a signiC cantly higher consumption of APC than survivors, 56% (IQR: 38.5) versus 68.6 (IQR: 41.4); P = 0.023. The proC le of lower levels of APC was a surgery patient with septic shock, neurological focus or catheter-related infection and Gram-negative pathogens from blood cultures. Spearman’s showed relationship with antithrombin III, r<= 0.674 (P <0.001) and International Normalized Ratio (INR), r<= –0.611 (P >0.001). See Figure 1. Conclusion Low levels of PC are associated with poor outcome and severity in severe sepsis, and it is well correlated with antithrombin III and INR.

Infornut® Process; improves accessibility to diagnosis and nutritional support for the malnourished hospitalized patient; impact on management indicators; two-year assessment.

Introduction: The high prevalence of disease-related hospital malnutrition justifies the need for screening tools and early detection in patients at risk for malnutrition, followed by an assessment targeted towards diagnosis and treatment. At the same time there is clear undercoding of malnutrition diagnoses and the procedures to correct it Objectives: To describe the INFORNUT program/ process and its development as an information system. To quantify performance in its different phases. To cite other tools used as a coding source. To calculate the coding rates for malnutrition diagnoses and related procedures. To show the relationship to Mean Stay, Mortality Rate and Urgent Readmission; as well as to quantify its impact on the hospital Complexity Index and its effect on the justification of Hospitalization Costs. Material and methods: The INFORNUT® process is based on an automated screening program of systematic detection and early identification of malnourished patients on hospital admission, as well as their assessment, diagnoses, documentation and reporting. Of total readmissions with stays longer than three days incurred in 2008 and 2010, we recorded patients who underwent analytical screening with an alert for a medium or high risk of malnutrition, as well as the subgroup of patients in whom we were able to administer the complete INFORNUT® process, generating a report for each.

Initial complications and factors related to prehospital mortality in acute myocardial infarction with ST segment elevation.

OBJECTIVE Hospital mortality in myocardial infarction ST-elevation myocardial infarction has decreased in recent years, in contrast to prehospital mortality. Our objective was to determine initial complications and factors related to prehospital mortality in patients with acute myocardial infarction with ST segment elevation (STEMI). METHODS Observational study based on a prospective continuous register of patients of any age attended by out-of-hospital emergency teams in Andalusia between January 2006 and June 2009. This includes patients with acute coronary syndrome-like symptoms whose initial ECG showed ST elevation or presumably new left bundle branch block (LBBB). Epidemiological, prehospital data and final diagnostic were recorded. The study included all patients with STEMI on the register, without age restrictions. Forward stepwise logistic regression analysis was performed to control for confounders. RESULTS A total of 2528 patients were included, 24% were women. Mean age 63.4±13.4 years; 16.7% presented atypical clinical symptoms. Initial complications: ventricular fibrillation (VF) 8.4%, severe bradycardia 5.8%, third-degree atrial-ventricular (AV) block 2.4% and hypotension 13.5%. Fifty-two (2.1%) patients died before reaching hospital. Factors associated with prehospital mortality were female sex (OR 2.36, CI 1.28 to 4.33), atypical clinical picture (OR 2.31, CI 1.21 to 4.41), hypotension (OR 4.95, CI 2.60 to 9.20), LBBB (OR 4.29, CI 1.71 to 10.74), extensive infarction (ST elevation in ≥5 leads) (OR 2.53, CI 1.28 to 5.01) and VF (OR 2.82, CI 1.38 to 5.78). CONCLUSIONS A significant proportion of patients with STEMI present early complications in the prehospital setting, and some die before reaching hospital. Prehospital mortality was associated with female sex and atypical presentation, as pre-existing conditions, and hypotension, extensive infarction, LBBB and VF on emergency team attendance.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

Lack of correlation between the optimal glycaemic control and coronary micro vascular dysfunction in patients with diabetes mellitus: a cross sectional study.

Background Coronary microvascular dysfunction (CMD) is associated with cardiovascular events in type 2 diabetes mellitus (T2DM). Optimal glycaemic control does not always preclude future events. We sought to assess the effect of the current target of HBA1c level on the coronary microcirculatory function and identify predictive factors for CMD in T2DM patients. Methods We studied 100 patients with T2DM and 214 patients without T2DM. All of them with a history of chest pain, non-obstructive angiograms and a direct assessment of coronary blood flow increase in response to adenosine and acetylcholine coronary infusion, for evaluation of endothelial independent and dependent CMD. Patients with T2DM were categorized as having optimal (HbA1c < 7 %) vs. suboptimal (HbA1c ≥ 7 %) glycaemic control at the time of catheterization. Results Baseline characteristics and coronary endothelial function parameters differed significantly between T2DM patients and control group. The prevalence of endothelial independent CMD (29.8 vs. 39.6 %, p = 0.40) and dependent CMD (61.7 vs. 62.2 %, p = 1.00) were similar in patients with optimal vs. suboptimal glycaemic control. Age (OR 1.10; CI 95 % 1.04–1.18; p < 0.001) and female gender (OR 3.87; CI 95 % 1.45–11.4; p < 0.01) were significantly associated with endothelial independent CMD whereas glomerular filtrate (OR 0.97; CI 95 % 0.95–0.99; p < 0.05) was significantly associated with endothelial dependent CMD. The optimal glycaemic control was not associated with endothelial independent (OR 0.60, CI 95 % 0.23–1.46; p 0.26) or dependent CMD (OR 0.99, CI 95 % 0.43–2.24; p = 0.98). Conclusions The current target of HBA1c level does not predict a better coronary microcirculatory function in T2DM patients. The appropriate strategy for prevention of CMD in T2DM patients remains to be addressed. Keywords: Endothelial dysfunction; Diabetes mellitus; Coronary microcirculation

C-reactive protein, procalcitonin, lactate and score apache II in septic patients' prognosis.

Background: APACHE-II IS a score, based on several clinical and analytical measurements within 24 hours of admission in Intensive Care Unit (ICU). C-Reactive Protein (CRP), Lactate and recently Procalcitonin (PCT), also are biomarkers for the assessment of septic patients. The aim of this study was to find out if CRP, lactate and PCT during the first 24 hours from severe sepsis or septic shock onset, improved prediction of the APACHE II in terms of prognosis. Conclusions: CRP improves the prediction of patients with sepsis used in conjunction with the APACHE II score in severe sepsis and, lactate along with the CRP are the best precictors of survival in the cases of septic shock. The PCT did not show any predictive value.

Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases in Spain: microbiological and clinical features.

Extended-spectrum β-lactamases (ESBL) of the CTX-M, SHV, and TEM families were recognized in 76 (67%), 31 (27%), and 6 (5%) isolates, respectively, among 162 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) strains obtained in a multicenter study in Spain. Predisposing factors for ESBL-Kp acquisition included invasive procedures, mechanical ventilation, and previous antimicrobial use.

Transcatheter aortic valve implantation in very elderly patients: immediate results and medium term follow-up.

OBJECTIVE To evaluate immediate transcatheter aortic valve implantation (TAVI) results and medium-term follow-up in very elderly patients with severe and symptomatic aortic stenosis (AS). METHODS This multicenter, observational and prospective study was carried out in three hospitals. We included consecutive very elderly (> 85 years) patients with severe AS treated by TAVI. The primary endpoint was to evaluate death rates from any cause at two years. RESULTS The study included 160 consecutive patients with a mean age of 87 ± 2.1 years (range from 85 to 94 years) and a mean logistic EuroSCORE of 18.8% ± 11.2% with 57 (35.6%) patients scoring ≥ 20%. Procedural success rate was 97.5%, with 25 (15.6%) patients experiencing acute complications with major bleeding (the most frequent). Global mortality rate during hospitalization was 8.8% (n = 14) and 30-day mortality rate was 10% (n = 16). Median follow up period was 252.24 ± 232.17 days. During the follow-up period, 28 (17.5%) patients died (17 of them due to cardiac causes). The estimated two year overall and cardiac survival rates using the Kaplan-Meier method were 71% and 86.4%, respectively. Cox proportional hazard regression showed that the variable EuroSCORE ≥ 20 was the unique variable associated with overall mortality. CONCLUSIONS TAVI is safe and effective in a selected population of very elderly patients. Our findings support the adoption of this new procedure in this complex group of patients.

Four main virotypes among extended-spectrum-β-lactamase-producing isolates of Escherichia coli O25b:H4-B2-ST131: bacterial, epidemiological, and clinical characteristics.

A total of 1,021 extended-spectrum-β-lactamase-producing Escherichia coli (ESBLEC) isolates obtained in 2006 during a Spanish national survey conducted in 44 hospitals were analyzed for the presence of the O25b:H4-B2-ST131 (sequence type 131) clonal group. Overall, 195 (19%) O25b-ST131 isolates were detected, with prevalence rates ranging from 0% to 52% per hospital. Molecular characterization of 130 representative O25b-ST131 isolates showed that 96 (74%) were positive for CTX-M-15, 15 (12%) for CTX-M-14, 9 (7%) for SHV-12, 6 (5%) for CTX-M-9, 5 (4%) for CTX-M-32, and 1 (0.7%) each for CTX-M-3 and the new ESBL enzyme CTX-M-103. The 130 O25b-ST131 isolates exhibited relatively high virulence scores (mean, 14.4 virulence genes). Although the virulence profiles of the O25b-ST131 isolates were fairly homogeneous, they could be classified into four main virotypes based on the presence or absence of four distinctive virulence genes: virotypes A (22%) (afa FM955459 positive, iroN negative, ibeA negative, sat positive or negative), B (31%) (afa FM955459 negative, iroN positive, ibeA negative, sat positive or negative), C (32%) (afa FM955459 negative, iroN negative, ibeA negative, sat positive), and D (13%) (afa FM955459 negative, iroN positive or negative, ibeA positive, sat positive or negative). The four virotypes were also identified in other countries, with virotype C being overrepresented internationally. Correspondingly, an analysis of XbaI macrorestriction profiles revealed four major clusters, which were largely virotype specific. Certain epidemiological and clinical features corresponded with the virotype. Statistically significant virotype-specific associations included, for virotype B, older age and a lower frequency of infection (versus colonization), for virotype C, a higher frequency of infection, and for virotype D, younger age and community-acquired infections. In isolates of the O25b:H4-B2-ST131 clonal group, these findings uniquely define four main virotypes, which are internationally distributed, correspond with pulsed-field gel electrophoresis (PFGE) profiles, and exhibit distinctive clinical-epidemiological associations.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

BACKGROUND The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Spatio-temporal trends of mortality in small areas of Southern Spain

Background: Most mortality atlases show static maps from count data aggregated over time. This procedure has several methodological problems and serious limitations for decision making in Public Health. The evaluation of health outcomes, including mortality, should be approached from a dynamic time perspective that is specific for each gender and age group. At the moment, researches in Spain do not provide a dynamic image of the population’s mortality status from a spatio-temporal point of view. The aim of this paper is to describe the spatial distribution of mortality from all causes in small areas of Andalusia (Southern Spain) and evolution over time from 1981 to 2006. Methods: A small-area ecological study was devised using the municipality as the unit for analysis. Two spatiotemporal hierarchical Bayesian models were estimated for each age group and gender. One of these was used to estimate the specific mortality rate, together with its time trends, and the other to estimate the specific rate ratio for each municipality compared with Spain as a whole. Results: More than 97% of the municipalities showed a diminishing or flat mortality trend in all gender and age groups. In 2006, over 95% of municipalities showed male and female mortality specific rates similar or significantly lower than Spanish rates for all age groups below 65. Systematically, municipalities in Western Andalusia showed significant male and female mortality excess from 1981 to 2006 only in age groups over 65. Conclusions: The study shows a dynamic geographical distribution of mortality, with a different pattern for each year, gender and age group. This information will contribute towards a reflection on the past, present and future of mortality in Andalusia.

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study.

Objective To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study. Design Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Participants 109 118 men and 254 870 women, mainly aged 37-70. Main outcome measures Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcohol consumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer. Results If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (−3 to 38%) for liver, 17% (10 to 25%) and 4% (−1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33 037 of 178 578 alcohol related cancer cases in men and 17 470 of 397 043 alcohol related cases in women. Conclusions In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.

Tendencias de la mortalidad por enfermedades cardiovasculares en Andalucía entre 1975 y 2004

Background: Cardiovascular diseases are ranked among the leading causes of death in the industrialized countries. This study is aimed at ascertaining the mortality trends by ischemic heart disease (IHD) and cerebrovascular diseases (CVD) in Andalusia within the 1975-2004 period. Method: Based on the official IHD and CVD death statistics and the related populations, the gross rates (GR) and age-adjusted rates (TS) and the Potential Years of Life Lost (PYLL) were calculated. To quantify the trends and their change points, a joinpoint regression analysis was made. Results: The number of IHD deaths for females rose from 2,086 deaths in 1975 to 3,336 in 2004, the TS having dropped from 74.29 to 50.94 deaths/100,000 females, the PYLL having dropped from 173.65 years to 90.56 years/100,000 females. The number of deaths for males rose from 2,854 deaths in 1975 to 4,085 in 2004, the TS having dropped from 147, 67 to 104.96 deaths /100,000 males. The PYLL showed a like behaviour from the first to the last year of the series, showing values of 716.46 and 460.04 years / 100,000 males. For the IHD in females, the number of deaths in absolute numbers dropped from 4,712 to 4,221, the TS having dropped from 166.00 to 62.08 deaths in females, and the PYLL from 338.08 to 87.63 years / 100,000 females. For males, the number of deaths dropped from 3,714 to 2,951, the TS from 206.88 deaths /100,000 males in 1975 to 76.12 /100,000 males in 2004, and the PYLL dropping from 533.12 to 182.38 years / 100,000 males. Conclusions: The trend in mortality due to IHD was not constant either among females or males, although it has always been a downward trend, the drop being statistically significant. The drop in the CVD has been such a major one that both the absolute numbers and the gross rates are lower for the most recent years that the first years in the series studied despite the aging of Andalusia’s population.