Prognostic factors in left-sided endocarditis: results from the andalusian multicenter cohort

Despite medical advances, mortality in infective endocarditis (IE) is still very high. Previous studies on prognosis in IE have observed conflicting results. The aim of this study was to identify predictors of in-hospital mortality in a large multicenter cohort of left-sided IE.Methods An observational multicenter study was conducted from January 1984 to December 2006 in seven hospitals in Andalusia, Spain. Seven hundred and five left-side IE patients were included. The main outcome measure was in-hospital mortality. Several prognostic factors were analysed by univariate tests and then by multilogistic regression model. Results.The overall mortality was 29.5% (25.5% from 1984 to 1995 and 31.9% from 1996 to 2006; Odds Ratio 1.25; 95% Confidence Interval: 0.97-1.60; p = 0.07). In univariate analysis, age, comorbidity, especially chronic liver disease, prosthetic valve, virulent microorganism such as Staphylococcus aureus, Streptococcus agalactiae and fungi, and complications (septic shock, severe heart failure, renal insufficiency, neurologic manifestations and perivalvular extension) were related with higher mortality. Independent factors for mortality in multivariate analysis were: Charlson comorbidity score (OR: 1.2; 95% CI: 1.1-1.3), prosthetic endocarditis (OR: 1.9; CI: 1.2-3.1), Staphylococcus aureus aetiology (OR: 2.1; CI: 1.3-3.5), severe heart failure (OR: 5.4; CI: 3.3-8.8), neurologic manifestations (OR: 1.9; CI: 1.2-2.9), septic shock (OR: 4.2; CI: 2.3-7.7), perivalvular extension (OR: 2.4; CI: 1.3-4.5) and acute renal failure (OR: 1.69; CI: 1.0-2.6). Conversely, Streptococcus viridans group etiology (OR: 0.4; CI: 0.2-0.7) and surgical treatment (OR: 0.5; CI: 0.3-0.8) were protective factors.Conclusions Several characteristics of left-sided endocarditis enable selection of a patient group at higher risk of mortality. This group may benefit from more specialised attention in referral centers and should help to identify those patients who might benefit from more aggressive diagnostic and/or therapeutic procedures.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

Three-year multicenter surveillance of community-acquired Listeria monocytogenes meningitis in adults

BACKGROUND. Listeria monocytogenes is the third most frequent cause of bacterial meningitis. The aim of this study is to know the incidence and risk factors associated with development of acute community-acquired Lm meningitis in adult patients and to evaluate the clinical features, management, and outcome in this prospective case series. METHODS. A descriptive, prospective, and multicentric study carried out in 9 hospitals in the Spanish Network for Research in Infectious Diseases (REIPI) over a 39-month period. All adults patients admitted to the participating hospitals with the diagnosis of acute community-acquired bacterial meningitis (Ac-ABM) were included in this study. All these cases were diagnosed on the basis of a compatible clinical picture and a positive cerebrospinal fluid (CSF) culture or blood culture. The patients were followed up until death or discharge from hospital. RESULTS. Two hundred and seventy-eight patients with Ac-ABM were included. Forty-six episodes of Lm meningitis were identified in 46 adult patients. In the multivariate analysis only age (OR 1.026; 95% CI 1.00-1.05; p = 0.042), immunosuppression (OR 2.520; 95% CI 1.05-6.00; p = 0.037), and CSF/blood glucose ratio (OR 39.42; 95% CI 4.01-387.50; p = 0.002) were independently associated with a Lm meningitis. The classic triad of fever, neck stiffness and altered mental status was present in 21 (49%) patients, 32% had focal neurological findings at presentation, 12% presented cerebellum dysfunction, and 9% had seizures. Twenty-nine (68%) patients were immunocompromised. Empirical antimicrobial therapy was intravenous ampicillin for 34 (79%) of 43 patients, in 11 (32%) of them associated to aminoglycosides. Definitive ampicillin plus gentamicin therapy was significantly associated with unfavourable outcome (67% vs 28%; p = 0.024) and a higher mortality (67% vs 32%; p = 0.040).The mortality rate was 28% (12 of 43 patients) and 5 of 31 (16.1%) surviving patients developed adverse clinical outcome. CONCLUSIONS Elderly or immunocompromised patients, and a higher CSF/blood glucose ratio in patients with Ac-ABM must alert clinicians about Lm aetiology. Furthermore, we observed a high incidence of acute community-acquired Lm meningitis in adults and the addition of aminoglycosides to treatment should be avoid in order to improve the patients' outcome. Nevertheless, despite developments in intensive care and antimicrobial therapy, this entity is still a serious disease that carries high morbidity and mortality rates.

Acquisition and cross-transmission of Staphylococcus aureus in European intensive care units

Objective. To study the acquisition and cross-transmission of Staphylococcus aureus in different intensive care units (ICUs). Methods. We performed a multicenter cohort study. Six ICUs in 6 countries participated. During a 3-month period at each ICU, all patients had nasal and perineal swab specimens obtained at ICU admission and during their stay. All S. aureus isolates that were collected were genotyped by spa typing and multilocus variable-number tandem-repeat analysis typing for cross-transmission analysis. A total of 629 patients were admitted to ICUs, and 224 of these patients were found to be colonized with S. aureus at least once during ICU stay (22% were found to be colonized with methicillin-resistant S. aureus [MRSA]). A total of 316 patients who had test results negative for S. aureus at ICU admission and had at least 1 follow-up swab sample obtained for culture were eligible for acquisition analysis. Results. A total of 45 patients acquired S. aureus during ICU stay (31 acquired methicillin-susceptible S. aureus [MSSA], and 14 acquired MRSA). Several factors that were believed to affect the rate of acquisition of S. aureus were analyzed in univariate and multivariate analyses, including the amount of hand disinfectant used, colonization pressure, number of beds per nurse, antibiotic use, length of stay, and ICU setting (private room versus open ICU treatment). Greater colonization pressure and a greater number of beds per nurse correlated with a higher rate of acquisition for both MSSA and MRSA. The type of ICU setting was related to MRSA acquisition only, and the amount of hand disinfectant used was related to MSSA acquisition only. In 18 (40%) of the cases of S. aureus acquisition, cross-transmission from another patient was possible. Conclusions. Colonization pressure, the number of beds per nurse, and the treatment of all patients in private rooms correlated with the number of S. aureus acquisitions on an ICU. The amount of hand disinfectant used was correlated with the number of cases of MSSA acquisition but not with the number of cases of MRSA acquisition. The number of cases of patient-to-patient cross-transmission was comparable for MSSA and MRSA.

Construcción y validación de un cuestionario para medir conductas, conocimientos y actitudes sobre la higiene de las manos en personal sanitario en formacion.

Background: Hand hygiene in the health context is a complex behaviour. There have been rarely given the role of the knowledge and attitudes as predictors of hand hygiene behaviour. The main objective of this work is the description of the development of a questionnaire on hand hygiene and the analysis of their measurement properties. Method: An instrument which was designed and validated a questionnaire. It was held in January 2009. It finally has had 50 items that assess risk behaviour intention before and after contact with the patient, declarative knowledge and attitudes about hand hygiene. It has been applied to 431 students of health sciences at the University of Granada. Results: There were three factor analysis, ultimately obtaining a general convergence value that explains 46.01% of the total variance and high reliability (a=0,843). There is correlation between knowledge and behavior intentions before and after patient contact (p <0.01).In turn, the attitude correlates only with behavioral intention before (p <0.05). The hand hygiene behavior refers to a higher mean after the completion of various health activities before the same (4.26 and 3.96 respectively). Both declarative knowledge and attitudes significantly predict behavioral intention, in particular the conduct before the contact with the patient (R2 = 0.100, standardized Beta 0.256 for knowledge and 0.145 for attitudes). Conclusions: The questionnaire shows high internal consistency. We have obtained a valid tool for assessing risk behavior, knowledge and attitudes about students’ hand hygiene in health sciences. The tool detects deficiencies in basic skills in students.

Ki-67 MIB1 labelling index and the prognosis of primary TaT1 urothelial cell carcinoma of the bladder.

Aims: To evaluate whether ki-67 labelling index (LI) has independent prognostic value for survival of patients with bladder urothelial tumours graded according to the 2004 World Health Organisation classification. Methods: Ki-67 LI was evaluated in 164 cases using the grid counting method. Non-invasive (stage Ta) tumours were: papilloma (n = 5), papillary urothelial neoplasia of low malignant potential (PUNLMP; n = 26), and low (LG; n = 34) or high grade (HG; n = 15) papillary urothelial carcinoma. Early invasive (stage T1) tumours were: LG (n = 58) and HG (n = 26) carcinoma. Statistical analysis included Fisher and x2 tests, and mean comparisons by ANOVA and t test. Univariate and multivariate survival analyses were performed according to the Kaplan–Meier method with log rank test and Cox’s proportional hazard method. Results: Mean ki-67 LI increased from papilloma to PUNLMP, LG, and HG in stage Ta (p,0.0001) and from LG to HG in stage T1 (p = 0.013) tumours. High tumour proliferation (.13%) was related to greater tumour size (p = 0.036), recurrence (p = 0.036), progression (p = 0.035), survival (p = 0.054), and high p53 accumulation (p = 0.015). Ki-67 LI and tumour size were independent predictors of disease free survival (DFS), but only ki-67 LI was related to progression free survival (PFS). Cancer specific overall survival (OS) was related to ki-67 LI, tumour size, and p27kip1 downregulation. Ki-67 LI was the main independent predictor of DFS (p = 0.0005), PFS (p = 0.0162), and cancer specific OS (p = 00195). Conclusion: Tumour proliferation measured by Ki-67 LI is related to tumour recurrence, stage progression, and is an independent predictor of DFS, PFS, and cancer specific OS in TaT1 bladder urothelial cell carcinoma.

Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

Granada Virus: a Natural Phlebovirus Reassortant of the Sandfly Fever Naples Serocomplex with Low Seroprevalence in Humans

A new member of the phlebovirus genus, tentatively named Granada virus, was detected in sandflies collected in Spain. By showing the presence of specific neutralizing antibodies in human serum collected in Granada, we show that Granada virus infects humans. The analysis of the complete genome of Granada virus revealed that this agent is likely to be a natural reassortant of the recently described Massilia virus (donor of the long and short segments) with ayet unidentified phlebovirus (donor of the medium segment)

Hypermethylated 14-3-3-sigma and ESR1 gene promoters in serum as candidate biomarkers for the diagnosis and treatment efficacy of breast cancer metastasis

Background: Numerous hypermethylated genes have been reported in breast cancer, and the silencing of these genes plays an important role in carcinogenesis, tumor progression and diagnosis. These hypermethylated promoters are very rarely found in normal breast. It has been suggested that aberrant hypermethylation may be useful as a biomarker, with implications for breast cancer etiology, diagnosis, and management. The relationship between primary neoplasm and metastasis remains largely unknown. There has been no comprehensive comparative study on the clinical usefulness of tumor-associated methylated DNA biomarkers in primary breast carcinoma and metastatic breast carcinoma. The objective of the present study was to investigate the association between clinical extension of breast cancer and methylation status of Estrogen Receptor1 (ESR1) and Stratifin (14-3-3-σ) gene promoters in disease-free and metastatic breast cancer patients. Methods: We studied two cohorts of patients: 77 patients treated for breast cancer with no signs of disease, and 34 patients with metastatic breast cancer. DNA was obtained from serum samples, and promoter methylation status was determined by using DNA bisulfite modification and quantitative methylation-specific PCR. Results: Serum levels of methylated gene promoter 14-3-3-σ significantly differed between Control and Metastatic Breast Cancer groups (P < 0.001), and between Disease-Free and Metastatic Breast Cancer groups (P < 0.001). The ratio of the 14-3-3-σ level before the first chemotherapy cycle to the level just before administration of the second chemotherapy cycle was defined as the Biomarker Response Ratio [BRR]. We calculated BRR values for the "continuous decline" and "rise-and-fall" groups. Subsequent ROC analysis showed a sensitivity of 75% (95% CI: 47.6 - 86.7) and a specificity of 66.7% (95% CI: 41.0 - 86.7) to discriminate between the groups for a cut-off level of BRR = 2.39. The area under the ROC curve (Z = 0.804 ± 0.074) indicates that this test is a good approach to post-treatment prognosis. Conclusions: The relationship of 14-3-3-σ with breast cancer metastasis and progression found in this study suggests a possible application of 14-3-3-σ as a biomarker to screen for metastasis and to follow up patients treated for metastatic breast cancer, monitoring their disease status and treatment response.

CD209 in inflammatory bowel disease: a case-control study in the Spanish population

BACKGROUND The etiology of Ulcerative Colitis (UC) and Crohn's Disease (CD), considered together as Inflammatory Bowel Diseases (IBD), involves environmental and genetic factors. Although some genes are already known, the genetics underlying these diseases is complex and new candidates are continuously emerging. The CD209 gene is located in a region linked previously to IBD and a CD209 functional polymorphism (rs4804803) has been associated to other inflammatory conditions. Our aim was to study the potential involvement of this CD209 variant in IBD susceptibility. METHODS We performed a case-control study with 515 CD patients, 497 UC patients and 731 healthy controls, all of them white Spaniards. Samples were typed for the CD209 single nucleotide polymorphism (SNP) rs4804803 by TaqMan technology. Frequency comparisons were performed using chi2 tests. RESULTS No association between CD209 and UC or CD was observed initially. However, stratification of UC patients by HLA-DR3 status, a strong protective allele, showed that carriage of the CD209_G allele could increase susceptibility in the subgroup of HLA-DR3-positive individuals (p = 0.03 OR = 1.77 95% CI 1.04-3.02, vs. controls). CONCLUSION A functional variant in the CD209 gene, rs4804803, does not seem to be influencing Crohn's disease susceptibility. However, it could be involved in the etiology or pathology of Ulcerative Colitis in HLA-DR3-positive individuals but further studies are necessary.

Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component

BACKGROUND This study assesses the validity and reliability of the Spanish version of DN4 questionnaire as a tool for differential diagnosis of pain syndromes associated to a neuropathic (NP) or somatic component (non-neuropathic pain, NNP). METHODS A study was conducted consisting of two phases: cultural adaptation into the Spanish language by means of conceptual equivalence, including forward and backward translations in duplicate and cognitive debriefing, and testing of psychometric properties in patients with NP (peripheral, central and mixed) and NNP. The analysis of psychometric properties included reliability (internal consistency, inter-rater agreement and test-retest reliability) and validity (ROC curve analysis, agreement with the reference diagnosis and determination of sensitivity, specificity, and positive and negative predictive values in different subsamples according to type of NP). RESULTS A sample of 164 subjects (99 women, 60.4%; age: 60.4 +/- 16.0 years), 94 (57.3%) with NP (36 with peripheral, 32 with central, and 26 with mixed pain) and 70 with NNP was enrolled. The questionnaire was reliable [Cronbach's alpha coefficient: 0.71, inter-rater agreement coefficient: 0.80 (0.71-0.89), and test-retest intra-class correlation coefficient: 0.95 (0.92-0.97)] and valid for a cut-off value > or = 4 points, which was the best value to discriminate between NP and NNP subjects. DISCUSSION This study, representing the first validation of the DN4 questionnaire into another language different than the original, not only supported its high discriminatory value for identification of neuropathic pain, but also provided supplemental psychometric validation (i.e. test-retest reliability, influence of educational level and pain intensity) and showed its validity in mixed pain syndromes.

Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry

There is little literature about the clinical presentation and time-course of postoperative venous thromboembolism (VTE) in different surgical procedures. RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic acute VTE. In this analysis, we analysed the baseline characteristics, thromboprophylaxis and therapeutic patterns, time-course, and three-month outcome of all patients with postoperative VTE. As of January 2006, there were 1,602 patients with postoperative VTE in RIETE: 393 (25%) after major orthopaedic surgery (145 elective hip arthroplasty, 126 knee arthroplasty, 122 hip fracture); 207 (13%) after cancer surgery; 1,002 (63%) after other procedures. The percentage of patients presenting with clinically overt pulmonary embolism (PE) (48%, 48%, and 50% respectively), the average time elapsed from surgery to VTE (22 +/- 16, 24 +/- 16, and 21 +/- 15 days, respectively), and the three-month incidence of fatal PE (1.3%, 1.4%, and 0.8%, respectively), fatal bleeding (0.8%, 1.0%, and 0.2%, respectively), or major bleeding (2.3%, 2.9%, and 2.8%, respectively) were similar in the three groups. However, the percentage of patients who had received thromboprophylaxis (96%, 76% and 52%, respectively), the duration of prophylaxis (17 +/- 9.6, 13 +/- 8.9, and 12 +/- 11 days, respectively) and the mean daily doses of low-molecular-weight heparin (4,252 +/- 1,016, 3,260 +/- 1,141, and 3,769 +/- 1,650 IU, respectively), were significantly lower in those undergoing cancer surgery or other procedures. In conclusion, the clinical presentation, time-course, and three-month outcome of VTE was similar among the different subgroups of patients, but the use of prophylaxis in patients undergoing cancer surgery or other procedures was suboptimal.

New aspects in celiac disease

Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA-DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.

Testing of Diagnostic Methods for Detection of Influenza Virusfor Optimal Performance in the Context of an Influenza Surveillance Network

Influenza surveillance networks must detect early the viruses that will cause the forthcoming annual epidemics and isolate the strains for further characterization. We obtained the highest sensitivity (95.4%) with a diagnostic tool that combined a shell-vial assay and reverse transcription-PCR on cell culture supernatants at 48 h, and indeed, recovered the strain

Toscana virus in Spain

Toscana virus (TOSV, Phlebovirus, family Bunyaviridae) infection is one of the most prevalent arboviruses in Spain. Within the objectives of a multidisciplinary network, a study on the epidemiology of TOSV was conducted in Granada, in southern Spain. The overall seroprevalence rate was 24.9%, significantly increasing with age. TOSV was detected in 3 of 103 sandfly pools by viral culture or reverse transcription-polymerase chain reaction from a region of the L gene. Nucleotide sequence homology was 99%-100% in TOSV from vectors and patients and 80%-81% compared to the Italian strain ISS Phl.3. Sequencing of the N gene of TOSV isolates from patients and vectors indicated 87%-88% and 100% homology at the nucleotide and amino acid levels, respectively, compared to the Italian strain. These findings demonstrate the circulation of at least 2 different lineages of TOSV in the Mediterranean basin, the Italian lineage and the Spanish lineage.