[Modification of immediate survival after in-hospital cardiac arrest during evenings and weekends]. / Modificación de la supervivencia inmediata tras parada cardiorrespiratoria intrahospitalaria en horario de tarde-noche y fin de semana.

OBJECTIVE: To determine whether cardiac arrests occurring at night or during the weekend, carry lower immediate survival. METHOD: An analysis of logistic regression was performed, adjusted for age, sex, time to care of the cardiac arrest and first monitored rhythm, to determine whether there are differences in immediate survival. RESULTS: The immediate survival of the cohort studied (n=121) was 32 patients (26%). A difference of 13% in immediate survival between both periods studied was found. The logistic regression analysis taking immediate survival as an effect, showed that suffering an in-hospital cardiac arrest during evenings or weekends was a variable that is not associated with a successful outcome. The OR: .48 (95% CI: .20-1.12; P=.08). CONCLUSIONS: Patients who suffer a cardiac arrest in our centre during evenings or weekends are more vulnerable.

[Treatment of encephalopathy by means of valproic acid with carglumic acid. Reply]. / Tratamiento de la encefalopatia inducida por acido valproico con acido carbaglumico. Replica.

TITLE: Tratamiento de la encefalopatia inducida por acido valproico con acido carbaglumico. Replica.

Association of General and Abdominal Obesity With Hypertension, Dyslipidemia and Prediabetes in the PREDAPS Study.

INTRODUCTION AND OBJECTIVES: Some anthropometric measurements show a greater capacity than others to identify the presence of cardiovascular risk factors. This study estimated the magnitude of the association of different anthropometric indicators of obesity with hypertension, dyslipidemia, and prediabetes (altered fasting plasma glucose and/or glycosylated hemoglobin). METHODS: Cross-sectional analysis of information collected from 2022 participants in the PREDAPS study (baseline phase). General obesity was defined as body mass index ≥ 30kg/m2 and abdominal obesity was defined with 2 criteria: a) waist circumference (WC) ≥ 102cm in men/WC ≥ 88cm in women, and b) waist-height ratio (WHtR) ≥ 0.55. The magnitude of the association was estimated by logistic regression. RESULTS: Hypertension showed the strongest association with general obesity in women (OR, 3.01; 95%CI, 2.24-4.04) and with abdominal obesity based on the WHtR criterion in men (OR, 3.65; 95%CI, 2.66-5.01). Hypertriglyceridemia and low levels of high-density lipoprotein cholesterol showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.49; 95%CI, 1.68-3.67 and OR, 2.70; 95%CI, 1.89-3.86) and with general obesity in men (OR, 2.06; 95%CI, 1.56-2.73 and OR, 1.68; 95%CI, 1.21-2.33). Prediabetes showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.48; 95%CI, 1.85-3.33) and with abdominal obesity based on the WC criterion in men (OR, 2.33; 95%CI, 1.75-3.08). CONCLUSIONS: Abdominal obesity indicators showed the strongest association with the presence of prediabetes. The association of anthropometric indicators with hypertension and dyslipidemia showed heterogeneous results.

[Treatment of encephalopathy by means of valproic acid with carglumic acid: two case reports and a review of the literature]. / Tratamiento de la encefalopatia por acido valproico con acido carbaglumico: descripcion de dos casos y revision de la bibliografia.

INTRODUCTION: Valproic acid (VPA) is a drug mainly used to treat epilepsy. Hyperammonaemic encephalopathy due to VPA is a rare but serious complication. The mechanism by which VPA influences the increase in ammonia consists in blocking the urea cycle, thereby inhibiting N-acetylglutamate synthase and diminishing acetyl coenzyme A. Generally, the treatment employed has been to withdraw VPA and to administer arginine, carnitine, antibiotics, glucose and protein restriction. Previous experience with carglumic acid is limited to reports of isolated cases of paediatric patients. CASE REPORTS: We report the cases of two adult patients with encephalopathy due to VPA who were treated with carglumic acid, in addition to the conventional measures. Following treatment with the drug, ammonia levels can be seen to return to normal values. In one of the two cases, owing to the existence of another cause of encephalopathy, no clinical improvement was observed. CONCLUSIONS: From the biochemical point of view, treating encephalopathy due to VPA with carglumic acid is a logical step, as it reverses the blockage of the urea cycle conditioned by VPA. The mechanism proposed as being the one by which brain toxicity and, therefore, encephalopathy are produced is the passage of ammonia in the form of glutamine to the inside of the cell, which then returns to ammonia and glutamate in the mitochondria and leads to oxidative stress. Carglumic acid must be considered an important part of the treatment in adult patients with hyperammonaemic encephalopathy due to VPA, although a randomised clinical trial needs to be conducted with the drug in order to test its efficacy.

TITLE: Tratamiento de la encefalopatia por acido valproico con acido carbaglumico: descripcion de dos casos y revision de la bibliografia.Introduccion. El acido valproico (VPA) es un farmaco principalmente usado en la epilepsia. La encefalopatia hiperamoniemica por VPA es una complicacion grave e infrecuente. El mecanismo por el que el VPA influye en la elevacion del amonio es bloqueando el ciclo de la urea, inhibiendo la N-acetilglutamato sintasa y disminuyendo la acetil coenzima A. De forma general, el tratamiento que se ha empleado ha sido la suspension del VPA y la administracion de arginina, carnitina, antibioticos, glucosa y restriccion proteica. La experiencia con acido carbaglumico se limita a comunicaciones de casos aislados de pacientes pediatricos. Casos clinicos. Descripcion de dos casos de pacientes adultos con encefalopatia por VPA tratados, ademas de las medidas convencionales, con acido carbaglumico. Tras el tratamiento con el farmaco se aprecia una normalizacion de los niveles de amonio. En uno de los casos, al existir otra causa de encefalopatia, no se aprecio mejora clinica. Conclusiones. Desde el punto de vista bioquimico es logico tratar la encefalopatia por VPA con acido carbaglumico, ya que revierte el bloqueo del ciclo de la urea condicionado por el VPA. El mecanismo propuesto por el que se produce la toxicidad cerebral y, por tanto, la encefalopatia, es el paso de amonio en forma de glutamina al interior celular, que retorna a amonio y glutamato en la mitocondria y genera estres oxidativo. El acido carbaglumico ha de considerarse como parte importante del tratamiento en pacientes adultos con encefalopatia hiperamoniemica por VPA, aunque es necesario realizar un ensayo clinico aleatorizado con el farmaco para comprobar su eficacia.

Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious Staphylococcus aureus Disease.

UNLABELLED: Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies. IMPORTANCE: Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.

[Medical expert consensus in AH on the clinical use of triple fixed-dose antihypertensive therapy in Spain]. / Consenso de médicos expertos en HTA sobre el uso clínico de la triple terapia antihipertensiva a dosis fija en España.

INTRODUCTION: The opinion of experts (different specialties) on the triple fixed-dose antihypertensive therapy in clinical practice may differ. MATERIALS AND METHODS: Online questionnaire with controversial aspects of the triple therapy answered by panel of experts in hypertension (HT) using two-round modified Delphi method. RESULTS: The questionnaire was completed by 158 experts: Internal Medicine (49), Nephrology (26), Cardiology (83). Consensus was reached (agreement) on 27/45 items (60%); 7 items showed differences statistically significant. Consensus was reached regarding: Predictive factors in the need for combination therapy and its efficacy vs. increasing the dose of a pretreatment, and advantage of triple therapy (prescription/adherence/cost/pressure control) vs. free combination. CONCLUSIONS: This consensus provides an overview of the clinical use of triple therapy in moderate-severe and resistant/difficult to control HT.

Meeting individualized glycemic targets in primary care patients with type 2 diabetes in Spain.

BACKGROUND: Information about the achievement of glycemic targets in patients with type 2 diabetes according to different individualization strategies is scarce. Our aim was to analyze the allocation of type 2 diabetic patients into individualized glycemic targets according to different strategies of individualization and to assess the degree of achievement of adequate control. METHODS: Cross-sectional analysis on 5382 type 2 diabetic patients in primary care setting in Spain between 2011 and 2012. Targets of HbA1c were assigned based on different strategies of individualization of glycemic targets: 1) the ADA/EASD consensus 2) The Spanish Diabetes Society (SED) consensus 3) a strategy that accounts for the risk of hypoglycemia (HYPO) considering the presence of a hypoglycemia during the last year and type of hypoglycemic treatment. Concordance between the different strategies was analyzed. RESULTS: A total of 15.9, 17.1 and 67 % applied to ADA/EASD recommendation of HbA1c target of <6.5, < 7 and <8 % (48, 53 and 64 mmol/mol), and 31.9 and 67.4 % applied to the SED glycemic target of <6.5 and <7.5 % (<48 and 58 mmol/mol). Using the HYPO strategy, 53.5 % had a recommended HbA1c target <7 % (53 mmol/mol). There is a 94 % concordance between the ADA/EASD and SED strategies, and a concordance of 41-42 % between these strategies and HYPO strategy. Using the three different strategies, the overall proportion of patients achieving glycemic targets was 56-68 %. CONCLUSIONS: Individualization of glycemic targets increases the number of patients who are considered adequately controlled. The proposed HYPO strategy identifies a similar proportion of patients that achieve adequate glycemic control than ADA/EASD or SED strategies, but its concordance with these strategies in terms of patient classification is bad.

Glycemic control in patients with type 2 diabetes mellitus in Spain. / Control glucémico en pacientes con diabetes mellitus tipo 2 en España.

OBJECTIVE: To evaluate the degree of glycemic control in patients with type 2 diabetes in Spain and identify factors associated with glycemic control. PATIENTS AND METHODS: This was a cross-sectional, multicenter, epidemiological study that used consecutive sampling and was conducted in primary care practices in Spain. A total of 5591 patients with type 2 diabetes mellitus lasting more than 1 year and who were treated with hypoglycemic agents for more than 3 months were included in the study. At a single visit, HbA1c levels were measured (A1cNow+ system) and demographic and clinical variables related to diabetes and its treatment were recorded. During the visit, CV risk factors (CVRF), the presence of target-organ damage (TOD), the presence of hypoglycemia and body weight changes within the previous year were recorded. RESULTS: We analyzed data from 5382 patients (mean age 66.7 [10.8] years, mean duration of the diabetes 8.8 [6.3] years). TOD was present in 43.6% of the patients and 59.1% were taking 2 or more drugs. The patients' mean HbA1c was 7.1 (1.1)%, and 48.6% had HbA1c levels <7.0%. The patients with HbA1c levels ≥7.0% had longer-standing diabetes, a higher prevalence of TOD and CVRF, used more complex therapies, experienced more hypoglycemic episodes in the previous year and had more weight gain. In the multivariate analysis, the absence of insulin treatment, the absence of abdominal obesity and atherogenic dyslipidemia, a duration of the diabetes <10 years and an age >70 years were associated with improved glycemic control. CONCLUSIONS: Patients with poorly controlled type 2 diabetes mellitus are highly prevalent in Spain. Factors associated with poorer glycemic control include the complexity of both the disease and the hypoglycemic therapy, a history of hypoglycemia and weight gain.

A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control.

Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long-term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response.

[Utility of the dead space fraction (Vd/Vt) as a predictor of extubation success]. / Valor de la fracción de espacio muerto (Vd/Vt) como predictor de éxito en la extubación.

PURPOSE: To determine the value of Vd/Vt as a predictor of extubation failure in patients with mechanical ventilation admitted to the intensive care units. DESIGN: A prospective, observational cohort study conducted from 1 September 2010 to 1 March 2011. SETTING: General intensive care unit (G-ICU) of a third level university hospital. PATIENTS OR PARTICIPANTS: The study included patients on mechanical ventilation (MV) for over 12 hours, and who in the process of weaning were subjected to low-level pressure support. Exclusion criteria were age under 18 years, ventilation via tracheotomy and patients failing to cooperate for different reasons. During the study, 392 patients were admitted to the G-ICU; of these, 214 required MV. The weaning process was started in 154 cases. Fifty-four patients were excluded from the study, and 24 were not extubated from MV. A total of 76 patients were finally extubated and analyzed. VARIABLES OF INTEREST: Vd/Vt was calculated as the ratio (PaCO(2)-Pє CO(2))/PaCO(2), with the recorded parameters. RESULTS: Logistic regression analysis showed a significant association between the Vd/Vt and extubation failure, with OR=1.52 (95%CI 1.11 to 2.09, p=0.008). The area under the ROC curve with respect to the prediction of extubation failure according to the Vd/Vt value was 0.94 (95%CI 0.86 to 0.98, p<0.0001). CONCLUSIONS: Vd/Vt is a powerful predictor of extubation failure in patients on MV.

Correlation of asymptomatic hyperuricaemia and serum uric acid levels with arterial stiffness in women with systemic lupus erythematosus without clinically evident atherosclerotic cardiovascular disease.

The objective of this article was to evaluate whether serum uric acid (SUA) correlates with arterial stiffness and inflammation markers in a cohort of women with systemic lupus erythematosus (SLE) without overt atherosclerotic cardiovascular diseases, who attended a community hospital. One hundred and two women with SLE were assessed as part of this cross-sectional study. Carotid-femoral pulse wave velocity (PWV) was measured using an automatic device (Complior). C-reactive protein (CRP), fibrinogen and homocysteine levels as well as other metabolic results were recorded. Duration and activity of SLE, damage accrual and treatments were recorded. SLE women were categorized as having or not having hyperuricaemia (HU) according to SUA levels (greater than or up to 6.2 mg/dl, respectively). A multiple linear regression analysis was used to determine the independent link between SUA levels and other variables. Women with SLE and HU (n = 15, 15%) had a worse cardiovascular risk profile that included ageing, hypertension, obesity, higher total cholesterol levels, renal failure and presence of metabolic syndrome. Also, the duration of SLE was increased and damage accrual was greater. In the unadjusted analysis, SUA levels correlated with PWV, CRP, fibrinogen and homocysteine. However, in a multivariate linear regression analysis, SUA levels independently correlated with the duration of SLE, creatinine, total cholesterol and homocysteine levels but did not correlate with PWV. In conclusion, SUA was associated with arterial stiffness, but not independently of age and homocysteine levels. Nevertheless, SUA might be an ancillary indicator of subclinical atherosclerosis in SLE women without clinically evident atherosclerotic cardiovascular disease.

Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention.

To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age

Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.

Prolonged survival after liver transplantation for Hodgkin's disease-induced fulminant liver failure.

A 30-year-old male with a past history of nodular lymphocyte predominance Hodgkin's disease in apparent complete remission for two years received a liver transplantation because of fulminant liver failure. Histopathological examination of the explanted liver showed massive infiltration by Hodgkin's disease. In spite of a nodal recurrence of Hodgkin's disease, the patient is alive and in excellent general condition six years after liver transplantation.

Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin's lymphoma autografted after a first relapse.

PURPOSE: To analyse outcome and prognostic factors for overall survival (OS) and time to treatment failure (TTF) in 357 patients with Hodgkin's lymphoma (HL) undergoing an autologous stem cell transplantation (ASCT) after a first relapse and reported to the The Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea (GEL/TAMO) Cooperative Group. METHODS: Two hundred and twenty males and 137 females with a median age of 29 years were autografted in second remission (n=181), first sensitive relapse (n=148) and first resistant relapse (n=28). RESULTS: Five-year actuarial TTF and OS were of 49% +/- 3% and 57% +/- 3%. Advanced stage at diagnosis, complementary radiotherapy before ASCT, a short first complete response (CR) and detectable disease at ASCT adversely influenced TTF. Year of transplant < or =1995, bulky disease at diagnosis, a short first CR, detectable disease at ASCT and > or =1 extranodal areas involved at ASCT were adverse factors for OS. CONCLUSIONS: ASCT constitutes a therapeutic option for HL patients after a first relapse. Promising results are observed in patients with low tumour burden at diagnosis, autografted after a long CR and without detectable disease at ASCT. Innovative approaches should be pursued for patients with risk factors at relapse.

Detection of transplant heart rejection by analysis of endomyocardial voltage.

These studies seek an alternative method with myocardial biopsy for rejection diagnosis. A pacemaker (Biotronik model Logos) was implanted into 16 patients to detect intramyocardial voltage. The recordings were classified in two groups according to results of myocardial biopsy. The results of the biopsy were classified according to the recommendations of the International Society for Heart and Lung Transplantation: namely, Group I: rejection < 2 (52 recordings) and Group II: rejection > or = 2 (9 recordings). The sensitive parameter for rejection detection was Tslew, which was deduced from the paced intracardial potential in the monopolar mode. The results were significant in both groups; the medium value of Tslew in group I was 96.7%, and the value for group II was 87.13% (P=.022). The sensitivity value in our patient group for detection of treatedable rejection was 78%; the negative predictive value was 95%. In conclusion the method is useful for rejection detection, but is necessary to make several recordings for the same patients during the first month post transplant, to obtain an individual baseline value.