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Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL–based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 activation in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies and Natural Killer cells.

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C+ NK cells associate with reduced incidence of infection in CMV+ KTR. Expansions of adaptive NKG2C+ NK cells were reported in posttransplant CMV-infected KTR. To further explore this issue, NKG2C+ NK, CD8+, and TcRγδ T cells were analyzed pretransplant and at different time points posttransplant for ≥24 mo in a cohort of CMV+ KTR (n = 112), stratified according to CMV viremia detection. In cryopreserved samples from a subgroup (n = 49), adaptive NKG2C+ NK cell markers and T cell subsets were compared after a longer follow-up (median, 56 mo), assessing the frequencies of CMV-specific T cells and viremia at the last time point. Increased proportions of NKG2C+ NK, CD8+, and TcRγδ T cells were detected along posttransplant evolution in viremia(+) KTR. However, the individual magnitude and kinetics of the NKG2C+ NK response was variable and only exceptionally detected among viremia(–) KTR, presumably reflecting subclinical viral replication events. NKG2C+ expansions were independent of KLRC2 zygosity and associated with higher viral loads at diagnosis; no relation with other clinical parameters was perceived. Increased proportions of adaptive NKG2C+ NK cells (CD57+, ILT2+, FcεRIγ–) were observed after resolution of viremia long-term posttransplant, coinciding with increased CD8+ and Vδ2– γδ T cells; at that stage CMV-specific T cells were comparable to viremia(–) cases. These data suggest that adaptive NKG2C+ NK cells participate with T cells to restore CMV replication control, although their relative contribution cannot be discerned.

Acute appendicitis is one of the most prevalent causes of an acute abdomen. Although the cause of appendicitis is not completely understood, the theory of luminal obstruction is a popular belief, with appendicoliths being a common etiology. While appendicoliths are quite common, giant appendicoliths >2 cm are rare. Although previous reports cite only two or three other occurrences of giant appendicoliths, we found at least 11 reported cases in the literature. We present a young male diagnosed preoperatively on computed tomography to have a large appendiceal mass of 2.2 cm. This case is presented for the rarity of giant appendicoliths along with a review of the literature.

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C

Apathy is a frequent finding in both acute and chronic neurological conditions, and it is defined as a general reduction in motivation, as manifested by reduced goal-directed behaviours, cognitions, and emotions. This chapter reviews the frequency, diagnostic process, clinical correlates, and treatment of apathy in Alzheimer’s disease and traumatic brain injury, as examples of relevant chronic neurodegenerative and acute conditions, respectively.

Background: Human cytomegalovirus (HCMV) infection has been recently associated with a low risk of multiple sclerosis (MS), yet the basis behind this observation remains uncertain. In this study, we aimed to determine in MS patients whether HCMV induces modifications in the peripheral B cell compartment. Methods: HCMV serostatus was determined in 73 MS patients (55 relapsing-remitting MS (RRMS); 18 progressive MS (PMS)) and 30 healthy controls, assessing their B cell immunophenotype and cytokine production (GM-CSF, IL-6, IL-10, and TNFα) by flow cytometry. Results: HCMV seropositivity in untreated MS patients (n = 45) was associated with reduced switched memory B cells, contrasting with an opposite effect in PMS. Expansions of transitional B cells were observed in HCMV(+) IFNβ-treated RRMS patients but not in HCMV(-) cases (p < 0.01), suggesting that HCMV may influence the distribution of B cell subsets modulating the effects of IFNβ. Considering the B cell functional profile, HCMV(-) PMS displayed an increased secretion of proinflammatory cytokines (IL-6, TNFα) as compared to HCMV(+) PMS and RRMS cases (p < 0.001). Conclusions: Our study reveals an influence of HCMV infection on the phenotype and function of B cells, promoting early differentiation stages in RRMS and reducing the proinflammatory cytokine profile in advanced MS forms, which might be related with the putative protective role of this virus in MS. This work was supported by grants FIS/PI17/00254, SAF 2016-80363-C2-1-R (Spanish Ministry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Program (PCIN-2015-191-C02-01), and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness.

espanolEste articulo es tudia y reexamin a la figura del controvertido lider afroamericano Alexander Crummell, cuya influencia ha sido ignorada por muchos estudiosos. Sus ideas , escritas en la pos guerra, sobre el progreso de los ciudadanos afroamericanos influyeron en algunos de sus contemporaneos como Booker T. Washington y en otros posteriores tales como W . E. B. Du Bois. El articulo tambien ofrece una interpretacion de dos de los discursos mas famosos de Crummell sobre el futuro de su raza . Estos sugieren posibles soluciones a l as tensiones y problemas vividos por los afroamericanos al terminar la guerra civi EnglishThe following article offers a study and reassessment of the controversial figure of Alexander Crummell, an African Americ an leader whose influence has been neglected by most scholars. His postbellum ideas on the advancement of black people influenced some of his contemporaries like Booker T. Washington and even late r leaders such as W. E. B. DuBois. The article also offers an interpretation of two of Crummell’s most famous speeches on the future of his race, which suggest possible solutions to the tensions and problems experienced by his people after the end of the C ivil Wa

BACKGROUND AND PURPOSE: Cytomegalovirus (CMV) infection has recently been associated with a lower multiple sclerosis (MS) susceptibility, although it remains controversial whether it has a protective role or is merely an epiphenomenon related to westernization and early-life viral infections. We aimed to evaluate whether CMV serostatus may differ in patients with early MS as compared with patients with non-early MS, analyzing the putative association of this virus with MS clinical course and humoral immune responses against other herpesviruses. METHODS: Multicentric analysis was undertaken of 310 patients with MS (early MS, disease duration ≤5 years, n = 127) and controls (n = 155), evaluating specific humoral responses to CMV, Epstein-Barr virus and human herpesvirus-6, as well as T-cell and natural killer (NK)-cell immunophenotypes. RESULTS: Cytomegalovirus seroprevalence in early MS was lower than in non-early MS or controls (P < 0.01), being independently associated with disease duration (odds ratio, 1.04; 95% confidence interval, 1.01-1.08, P < 0.05). CMV+ patients with MS displayed increased proportions of differentiated T-cells (CD27-CD28-, CD57+, LILRB1+) and NKG2C+ NK-cells, which were associated with a lower disability in early MS (P < 0.05). CMV+ patients with early MS had an age-related decline in serum anti-EBNA-1 antibodies (P < 0.01), but no CMV-related differences in anti-human herpesvirus-6 humoral responses. CONCLUSIONS: Low CMV seroprevalence was observed in patients with early MS. Modification of MS risk attributed to CMV might be related to the induction of differentiated T-cell and NK-cell subsets and/or modulation of Epstein-Barr virus-specific immune responses at early stages of the disease. This work was supported by grants FIS/PI14/00177,FIS/PI17/00254 and SAF 2013-49063-C2-1-R (SpanishMinistry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Pro-gram (PCIN-2015-191-C02-01) and Red Española de Esclerosis Múltiple from the Instituto de Salud CarlosIII, European Regional Development Fund (grant RD16/0015/0011) and Spanish Ministry of Economyand Competitiveness.

CD69 regulates lymphocyte egress from the thymus and lymph nodes through cis-interactions and the downregulation of surface sphingosine-1-phosphate (S1P) receptor-1 (S1P1). However, its role in the regulation of cell egress from bone marrow has not been extensively studied. We show here that CD69 targeting induced rapid and massive mobilization of BM leukocytes, which was inhibited by desensitization to S1P with FTY720. This mobilization was reproduced with anti-human CD69 mAb treatment of mice expressing human CD69. In this strain, the mobilization occurred to the same extent as that induced by AMD3100. The anti-human CD69 treatment highly increased LSK and CLP cell proliferation and numbers, both in the periphery and in the BM, and also augmented S1P1 and CXCR4 expression. Additionally, increased mTOR, p70S6K, S6, and 4E-BP1 phosphorylation was detected after in vivo anti-CD69 treatment in the bone marrow. Importantly, mTOR inhibition with rapamycin inhibited anti-huCD69-induced mobilization of hematopoietic stem and progenitor cells (HSPCs). Together, our results indicated that CD69 targeting induces not only mobilization but also high proliferation of HSPCs, and thus is crucial for precursor cell replenishment over time. These results suggest that anti-CD69 mAbs are putative novel candidates for mobilization strategies.

NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-γ secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcγR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV+ individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-α and IFN-γ) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350+ particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF-α production but induced minimal IFN-γ secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350+ particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350+ particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-α but not cytotoxicity or IFN-γ production, potentially favoring the progression of viral infection.

Additional file 1: Table 1. Proportions of B cell subsets in controls and MS patients according to HCMV serostatus.

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(-), and PLZF(-) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(-) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(-) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(-) CD56dim NK cells in HCMV(+) and increased PLZF(-) CD56bright NK cells in HCMV(-) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(-) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS. This work was supported by grants FIS/PI17/00254, SAF 2016-80363-C2-1-R (Spanish Ministry of Economy and Competitiveness and FEDER), the EU FP7-MINECO Infect-ERA Program (PCIN-2015-191-C02-01), and Red Española de Esclerosis Múltiple (REEM) from the Instituto de Salud Carlos III, the European Regional Development Fund (Grant RD16/0015/0011), and the Spanish Ministry of Economy and Competitiveness.

Background and objectives: Percentages of blood CD19 + CD5 + B cells and CD8 + perforin + T lymphocytes can predict response to Interferon (IFN)-beta treatment in relapsing-remitting multiple sclerosis (RRMS) patients. We aimed to standardize their detection in a multicenter study, prior to their implementation in clinical practice. Methods: Fourteen hospitals participated in the study. A reference centre was established for comparison studies. Peripheral blood cells of 105 untreated RRMS patients were studied. Every sample was analyzed in duplicate in the participating centre and in the reference one by flow cytometry. When needed, participating centres corrected fluorescence compensations and negative cut-off position following reference centre suggestions. Concordance between results obtained by participating centres and by reference one was evaluated by intraclass correlation coefficients (ICC) and Spearman correlation test. Centre performance was measured by using z-scores values. Results: After results review and corrective actions implementation, overall ICC was 0.86 (CI: 0.81-0.91) for CD19 + CD5 + B cell and 0.89 (CI: 0.85-0.93) for CD8 + perforin + T cell quantification; Spearman r was 0.92 (0.89-0.95; p < 0.0001) and 0.92 (0.88-0.95; p < 0.0001) respectively. All centres obtained z-scores 5 0.5 for both biomarkers. Conclusion: Homogenous percentages of CD19 + CD5 + B cells and CD8 perforin + T lymphocytes can be obtained if suitable compensation values and negative cut-off are pre-established.

Although depression is a treatable cause of suffering, disability and death, its identifcation and treatment continue to be a challenge in clinical practice and a severe problem for global public health. The main objective of this study was to investigate the frequency with which mental health professionals use scales to assess depressive patients in Argentina and to determine the reasons that constrain such practice. Between July and September 2012 a national survey was conducted by e-mail. Professionals registered in the database of the Argentine Association of Psychiatrists were invited to participate in the survey. Responses were obtained from 243 professionals. Of the total respondents, only 8.7% said they always used scales to assess depressive patients. The reasons recorded by most respondents why scales were not used were: lack of time and the belief that they do not help in clinical practice. Despite the fact that treatment guidelines for depression recommend the use of scales to optimize the assessment and treatment of depressive disorders, this does not seem to be the usual behavior in clinical practice in our country.

11 páginas, 7 figuras, 9 tablas., The status of European legislation regarding inland water quality after the enactment of the Water Framework Directive (WFD) originated scientific effort to develop reliable methods, primarily based on biological parameters. An important aspect of the process was to ensure that quality assessment was comparable between the different Member States. The Intercalibration process (IC), required in the WFD ensures the unbiased application of the norm. The presented results were developed in the context of the 2nd IC phase. An overview of the reservoir type definition of the Lake Mediterranean Geographical Intercalibration Group, where four types were considered divided by both alkalinity and climate, togetherwith the results for selection of MaximumEcological Potential sites (MEP) are presented. MEP reservoirs were selected based on pressure and biological variables. Three phytoplankton-based assessment methods were intercalibrated using data from Mediterranean countries. The Mediterranean Assessment System for Reservoirs Phytoplankton (Spain), the New Mediterranean Assessment System for Reservoirs Phytoplankton (Portugal and Cyprus) and the New Italian Method (Italy) were applied. These three methods were compared through option 3 of the Intercalibration Guide. The similarity of the assessments was quantified, and the Good/Moderate (GM) boundaries assessed. All three methods stood as comparable at the GM boundary except for theMASRP in siliceous wet reservoirs, which was slightly stricter. Finally, the main taxonomic groups represented in the phytoplankton community atMEP conditionswere identified, aswell as theirmain changes with an increasing trophic status.MEP sites are dominated by chrysophytes in siliceouswet reservoirs and by the diatoms Cyclotella and Achnanthes in calcareous ones. Cyanobacteria take over the community in both calcareous and siliceous wet reservoirs as eutrophication increases. In summary, the relevance and reliability of the quality assessment methods compared were confirmed both from an ecological perspective and a health risk management point of view., The authors thank all data providers during the IC process, namely the SpanishMinistry of Agriculture, Food and Environment (MAGRAMA), the Division of Hydrometry of the Water Development Department of the Ministry of Agriculture, Natural resources and Environment (MANREWWD) of Cyprus and the Università degli Studi di Sassari, Dipartamento di Scienze Botaniche, Ecologiche e Geologiche (DiSBEG) from Italy. The final boundary comparison was performed based on the data from the three above countries, but data was also submitted by the Portuguese J. Pahissa et al. / Science of the Total Environment 538 (2015) 169–179 177 Environment Agency (former PortugueseWater Institute) (Portugal), Aristotle University of Thessaloniki (Greece), the Ministerul Mediului și Pădurilor (MMP) and the National Administration “Apele Române” (Romania) and the Rhône Méditerranée Corse Water Agency (France). Additionally, the close collaboration and feedback provided by Vasiliki Tsiaoussi and OtiliaMihail were essential for the intercalibration process.

Environmental influences are critical for the expression of genes putatively related to the behavioral and cognitive phenotypes of schizophrenia. Among such factors, psychosocial stress has been proposed to play a major role in the expression of symptoms. However, it is unsettled how stress interacts with pathophysiological pathways to produce the disease. We studied 21 patients with schizophrenia and 21 healthy controls aged 18 to 50 years with 3T-fMRI, in which a period of 6 min of resting state acquisition was followed by a block design, with three blocks of 1-min control-task, 1-min stress-task and 1-min rest after-task. Self-report of stress and PANSS were measured. Limbic structures were activated in schizophrenia patients by simple tasks and remained active during, and shortly after stress. In controls, stress-related brain activation was more time-focused, and restricted to the stressful task itself. Negative symptom severity was inversely related to activation of anterior cingulum and orbitofrontal cortex. Results might represent the neurobiological aspect of hyper-reactivity to normal stressful situations previously described in schizophrenia, thus providing evidence on the involvement of limbic areas in the response to stress in schizophrenia. Patients present a pattern of persistent limbic activation probably contributing to hypervigilance and subsequent psychotic thought distortions. Fil: Castro, Mariana Nair. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Villarreal, Mirta Fabiana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bolotinsky, N.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Papávero, E.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Goldschmidt, M.G.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Costanzo, E.Y.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Drucaroff, Lucas Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Wainsztein, A.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: de Achaval, Delfina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Pahissa, J.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Bär, K.-J.. Friedrich-Schiller-Universität; Alemania Fil: Nemeroff, C.B.. University of Miami; Estados Unidos Fil: Guinjoan, Salvador Martín. Universidad de Buenos Aires. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina

Chagas disease has been increasingly diagnosed in non-endemic countries. This is a prospective observational study performed at the Tropical Medicine Units of the International Health Program of the Catalan Health Institute, Barcelona (PROgrama de Salud Internacional del Instituto Catalán de la Salud, PROSICS Barcelona, Spain), that includes all patients with Chagas disease who attended from June 2007 to May 2012. Clinical and epidemiological data were collected. Overall, 1274 patients were included, the mean age of the patients was 37.7 years, 67.5% were women and 97% came from Bolivia. Thirteen patients had immunosuppressive conditions. The prevalence of cardiac involvement was 16.9%, lower than in previous studies performed in endemic areas (20–60%). Cardiac alterations were found in 33.8% of symptomatic and 14.1% of asymptomatic patients. The prevalence of digestive involvement was 14.8%. The rate of digestive involvement is very different among previous studies because of different diagnostic tools and strategies used. Barium enema alterations were found in 21.4% of symptomatic and 10.3% of asymptomatic patients, and oesophageal alterations were found in 3.7% of symptomatic and in 2.3% of asymptomatic patients. As shown in previous studies, Chagas disease in non-endemic countries affects younger patients and has lower morbidity.

The effectiveness of daptomycin versus vancomycin for treating experimental methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) catheter-related infection by antibiotic-lock technique was assessed.One MSSA strain and one clinical MRSA isolate were used. A preliminary in vitro study determined the minimum biofilm eradication concentration (MBEC) of vancomycin and daptomycin. An intravenous catheter was implanted in New Zealand white rabbits. Infection was induced by 24 h locking the catheter with 0.3 mL of broth culture containing MSSA or MRSA. The 24 h of antibiotic-lock treatment groups were: control, vancomycin 10 mg/mL, daptomycin 5 mg/mL and daptomycin 50 mg/mL.Daptomycin showed greater in vitro activity than vancomycin against biofilm bacteria (MBECs of vancomycin and daptomycin for MSSA,2000 mg/L and 7 mg/L; MRSA,2000 mg/L and 15 mg/L). Daptomycin 5 mg/mL achieved significant reductions relative to vancomycin 10 mg/mL in log10 cfu recovered from catheter tips for both strains (P 0.05). Only daptomycin 50 mg/mL achieved negative catheter tip cultures (up to 75% in MSSA and 85% in MRSA, P 0.05), showing the greatest median log10 cfu reduction compared to controls (6.07 in MSSA and 6.59 in MRSA, P 0.05).Daptomycin 50 mg/mL showed the highest activity against both strains biofilms.

Spontaneous bacterial peritonitis (SBP) in liver transplantation (LT) recipients who progress to cirrhosis has received little attention. We investigated the adequacy of empirical treatment with third-generation cephalosporins for SBP in this population and the impact of transplantation on the evolution of the infection. We performed a cohort study with 138 SBP episodes: 19 in LT patients and 119 in non-LT patients. The etiology of SBP was identified for 73.7% of the episodes in LT patients and for 38.7% of the episodes in non-LT patients (P = 0.004). The main microorganisms in recipients were Escherichia coli (35.7%) and Streptococcus pneumoniae (21.4%). The etiologies did not differ in non-LT patients. The cephalosporin sensitivity was similar in the 2 groups (85.7% versus 78.4%, P = 0.7). LT recipients developed renal failure (57.9% versus 25.2%, P = 0.004) and encephalopathy (42.1% versus 22%, P = 0.08) more often than non-LT patients, and the mortality rates during episodes (52.6% versus 13.4%, P 18 odds ratio (OR) = 6.1 and being an LT recipient (OR = 4.45). At 6 months, the risk factors for mortality were a MELD score > 18 (OR = 3.08), being an LT recipient (OR = 3.47), a known etiology (OR = 2.08), and the presence of hepatocellular carcinoma (OR = 3.73).

Current therapeutic options for Chagas' disease are limited to benznidazole and nifurtimox, which have been associated with low cure rates in the chronic stage of the disease and which have considerable toxicity. Posaconazole has shown trypanocidal activity in murine models.We performed a prospective, randomized clinical trial to assess the efficacy and safety of posaconazole as compared with the efficacy and safety of benznidazole in adults with chronic Trypanosoma cruzi infection. We randomly assigned patients to receive posaconazole at a dose of 400 mg twice daily (high-dose posaconazole), posaconazole at a dose of 100 mg twice daily (low-dose posaconazole), or benznidazole at a dose of 150 mg twice daily; all the study drugs were administered for 60 days. We assessed antiparasitic activity by testing for the presence of T. cruzi DNA, using real-time polymerase-chain-reaction (rt-PCR) assays, during the treatment period and 10 months after the end of treatment. Posaconazole absorption was assessed on day 14.The intention-to-treat population included 78 patients. During the treatment period, all the patients tested negative for T. cruzi DNA on rt-PCR assay beyond day 14, except for 2 patients in the low-dose posaconazole group who tested positive on day 60. During the follow-up period, in the intention-to-treat analysis, 92% of the patients receiving low-dose posaconazole and 81% receiving high-dose posaconazole, as compared with 38% receiving benznidazole, tested positive for T. cruzi DNA on rt-PCR assay (P0.01 for the comparison of the benznidazole group with either posaconazole group); in the per-protocol analysis, 90% of the patients receiving low-dose posaconazole and 80% of those receiving high-dose posaconazole, as compared with 6% receiving benznidazole, tested positive on rt-PCR assay (P0.001 for the comparison of the benznidazole group with either posaconazole group). In the benznidazole group, treatment was discontinued in 5 patients because of severe cutaneous reactions; in the posaconazole groups, 4 patients had aminotransferase levels that were more than 3 times the upper limit of the normal range, but there were no discontinuations of treatment.Posaconazole showed antitrypanosomal activity in patients with chronic Chagas' disease. However, significantly more patients in the posaconazole groups than in the benznidazole group had treatment failure during follow-up. (Funded by the Ministry of Health, Spain; CHAGASAZOL ClinicalTrials.gov number, NCT01162967.).

Data from published studies regarding risk factors for liver biopsy (LB)–related infectious complications in liver transplant recipients are inconsistent. We carried out a retrospective cohort study analyzing consecutive LBs for orthotopic liver transplant patients at a tertiary hospital (2001-2011): there were 667 LB procedures (575 percutaneous procedures and 92 transjugular procedures) in 286 liver transplant recipients. There were 20 complications in 19 patients (overall incidence = 3.0%): 10 were infectious complications (8 cases of bacteremia and 2 cases of peritonitis). The causal microorganisms were mainly Pseudomonas aeruginosa (4 patients) and Enterobacteriaceae (4 patients). All complications occurred with biopsies performed in patients hospitalized for more than 48 hours (381 biopsies for 201 patients); hence, only this group was included in the risk factor analysis. The variables associated with the development of infectious complications after LB were the presence of impaired biliary drainage at the time of biopsy (40% versus 15.1%, P = 0.03) and low albumin levels (2.4 versus 3.1 g/dL, P = 0.01). In conclusion, according to our experience, infectious complications secondary to LB in liver transplant recipients are related to hospitalization at the time of biopsy, particularly in the presence of impaired biliary drainage and low albumin levels. Liver Transpl 20:552–556, 2014. © 2014 AASLD.

Personality disorders are common in nonpsychotic siblings of patients with schizophrenia, and some personality traits in this group may be associated with an increased risk for full-blown psychosis. We sought to establish if faulty right-hemisphere activation induced by social cognitive tasks, as previously described in patients with schizophrenia, is associated with specific personality symptoms in their unaffected siblings. We observed that cluster B personality symptoms in this group were inversely related to activation in the right temporo parietal junction (rTPJ, a structure critical in social cognitive processing) in response to a basic emotion processing task and also to social competence, whereas in contrast to our initial hypothesis, cluster A traits were not associated with right hemisphere activation during emotion processing or with social competence. These findings suggest the existence of clinical traits in at-risk individuals which share a common neurobiological substrate with schizophrenia, in regards to social performance. Fil: Goldschmidt, Micaela Giuliana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Villarreal, Mirta Fabiana. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: de Achaval, Delfina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Drucaroff, Lucas Javier. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Costanzo, Elsa Y.. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Castro, Mariana Nair. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pahissa, Jaime. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Camprodon, Joan. Massachusetts General Hospital. Laboratory for Neuropsychiatry & Neuromodulation; Estados Unidos Fil: Nemeroff, Charles B.. University of Miami; Estados Unidos Fil: Guinjoan, Salvador Martín. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Psicología; Argentina

Invasive fungal infections (IFI) represent a serious threat for patients undergoing solid organ transplantation (SOT). IFI in SOT has a significant incidence and mortality not due to negligence. The management of IFI in SOT involves specific recommendations and has been individualized to the type of transplant and patient. The current review presents an overview of epidemiology, diagnosis, treatment and prevention of IFI in TOS. Depending on risk factors for different IFIs and transplant type, this paper includes the main recommendations based on previous publications and on the opinion of the authors on the prophylaxis and treatment of these patients. These recommendations highlight epidemiology changes and the emergence of new antifungals. The current document has focused mainly on Candidaspp. and Aspergillusspp., with a special mention to the rest of yeasts and moulds that are common in SOT.

Clostridium difficile-associated disease (CDAD) is the most common cause of nosocomial diarrhea. Information about CDAD in solid organ transplant (SOT) recipients is scarce. To determine its epidemiology and risk factors, we conducted a cohort study in which 4472 SOT patients were prospectively included in the RESITRA/REIPI (Spanish Research Network for the Study of Infection in Transplantation) database between July 2003 and July 2006. Forty-two episodes of CDAD were diagnosed in 36 patients. The overall incidence was 0.94%. Median onset of infection was 31.5 days (range 6–741); in half the cases, onset occurred during the first month after transplantation. In 26% of cases, there was no previous antibiotic use. Independent risk factors for CDAD using Cox regression analysis were previous use of first- and second-generation cephalosporins (HR 3.68; 95%CI 1.8–7.52; P

Aim and method The aim of this study was to describe the clinical characteristics and outcome of pandemic influenza A H1N1/2009 (pH1N1) infection, in a retrospective cohort of pediatric patients with kidney and/or liver transplant and confirmed pH1N1 infection from June to December 2009, diagnosed in 2 Spanish teaching hospitals. Results Forty-nine patients were included. Pneumonia was diagnosed in 4 patients (8.2%), and 3 of them required respiratory support. There were no related deaths. Conclusion Antiviral treatment within 48 h was associated with a lower likelihood of pneumonia (0/38, 0%) than treatment started after 48 h (4/11, 36.3%) (P

Background Despite the reported decrease in the incidence and mortality rates of central nervous system (CNS) infections after the introduction of highly active antiretroviral therapy (HAART), few studies have focused on the global incidence and the relationship of these diseases with immune reconstitution inflammatory syndrome (IRIS) in the developed world. Methods A descriptive cohort study of all consecutive adult HIV-infected patients with CNS opportunistic infections diagnosed between 2000 and 2010 in a tertiary hospital in Spain was carried out. Demographic, clinical, laboratory, and microbiological data were recorded. Patients were followed up until death or loss to follow-up or until 30 July 2011, when the study finished. The significance of differences in the incidence rate between early and late HAART periods was determined using the Mantel–Haenszel test. Survival distribution was estimated using the Kaplan–Meier method. Results A total of 110 cases of CNS infections were diagnosed. The incidence of CNS opportunistic infections decreased from 9 cases per 1000 HIV-infected patients per year in the early HAART period to 3.8 in the late HAART period (P = 0.04). Overall, the estimated mean survival time was 58.8 months (95% confidence interval 47.1–70.6 months). Of the 110 patients, 18 (16.4%) met the criteria of IRIS, 10 (55.6%) were paradoxical and eight (44.4%) were unmasking. IRIS was not associated with a higher mortality rate. Conclusions The annual incidence of CNS infections decreased progressively during the period of study. The mortality rate associated with these diseases remains high despite HAART. The development of IRIS associated with neurological infections had no influence on prognosis.

To assess the effectiveness of simplification to a dual antiretroviral regimen containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced HIV-1-infected patients.Retrospective analysis of 131 HIV-1-infected patients on suppressive antiretroviral treatment (HIV-RNA50 copies/mL) who switched to a maintenance dual antiretroviral regimen, containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV-RNA50 copies/mL. The percentage of patients remaining free of therapeutic failure was estimated using the time-to-loss-of-therapeutic-response algorithm, by intent-to-treat analysis.Median baseline characteristics of the patients were 14 years on antiretroviral therapy, five prior HAART regimens and 10 different drugs, 24 months on a suppressive regimen and 522 CD4+ cells/mL. Reasons for simplification to dual therapy were nucleoside reverse transcriptase inhibitor-related toxicity (46.6%), removal of lamivudine/emtricitabine due to resistance (16.8%), simplification from regimens containing a dual PI, enfuvirtide or tipranavir (20.6%) and simplification from other complex regimens (16.0%). Darunavir (58.0%), lopinavir (16.8%) or atazanavir (13.0%) were the preferred PIs, used in combination with tenofovir (50.4%), raltegravir (22.1%) or etravirine (12.2%). At the end of follow-up (median 14 months), 90.1% of patients remained free of therapeutic failure; corresponding data at treatment weeks 24, 48 and 96 were 93.6% (95% CI, 89.3-97.9), 90.9% (95% CI, 84.9-95.9) and 87.4% (95% CI, 80.7-94.1), respectively. Two (1.5%) patients had virological failure and 11 (8.4%) discontinued treatment due to side effects or were lost to follow-up.Simplification to a dual-therapy regimen including a PI/r might be useful to enhance convenience and/or diminish toxicity in selected treatment-experienced patients.

In the context of solid organ transplantation, screening of potential organ donors is crucial, and should be performed with great rigor to minimize the risk of transmission of certain infectious processes. This review aims to update understanding of the possible pathologies involved, as well as of emerging infections that, as a result of globalization, are gaining increasing prominence on a daily basis.

BACKGROUND Few data exist on the implications of widespread use of 7-valent pneumococcal conjugate vaccine in children in the invasive pneumococcal disease (IPD) in HIV-infected adults. We conducted a multicenter study to analyze differences in clinical presentation of IPD between HIV-infected and non-HIV-infected adults in the prevaccine and postvaccine era. METHODS Study of all cases of IPD in HIV-infected adults diagnosed since 1996 to 2010. Episodes were classified into prevaccine (1996-2001), early postvaccine (2002-2004), and late postvaccine period (2005-2010). For each case, we identified an HIV-negative control patient with IPD matched by hospital, age, and vaccine period. RESULTS Two hundred twenty-one episodes of IPD in HIV-infected patients were diagnosed. The incidence of IPD decreased from 7.81 to 3.69 episodes per 1000 patient-years (-53%; 95% confidence interval: -65% to -36%, P < 0.001) between prevaccine and late postvaccine period. There was an 81% (95% confidence interval: -88% to -69%, P < 0.001) decrease of IPD caused by vaccine serotypes. In late postvaccine period IPD in HIV-infected patients was associated to higher rates of respiratory failure (28.4% vs. 48.4%, P = 0.011), greater intensive care unit admission (8.2% vs. 21.7%, P = 0.02) and a higher need for mechanical ventilation (5.9% vs. 16.3%, P = 0.033). In the prevaccine period, non-HIV-infected patients had a more severe illness than in those with HIV infection; however, these differences disappeared in the late postvaccine period. CONCLUSIONS In the late postvaccine era, the incidence of IPD in HIV-infected patients has decreased, however, clinical presentation seems to have changed to a more severe illness. The widespread use of highly active antiretroviral therapy, polyssacharide vaccine, and 7-valent pneumococcal conjugate vaccine has contributed to these changes.

The shortage of organs for transplantation has prompted the investigation of extended criteria donors, such as donors with transmissible infectious diseases. Here we report our recent experience with liver transplantation using organs from donors who were serologically positive for Chagas disease. We also provide a review of the literature and emphasize donor screening and preventive measures. Liver Transpl 17:1304–1308, 2011. © 2011 AASLD.

Background In haematopoietic stem cell transplant (HSCT) recipients, cytomegalovirus (CMV) infection contributes significantly to morbidity and mortality in both the early and late post-transplant period. Ganciclovir (GCV) is the treatment of choice for CMV, but requires intravenous administration, a fact that complicates its long-term use. Oral valganciclovir (VGCV) and intravenous GCV were recently shown to have similar efficacy for pre-emptive CMV treatment in solid organ transplant recipients, but relatively limited data are available in HSCT recipients. The objectives of this study were to compare the efficacy of VGCV versus intravenous GCV or foscarnet (FOS) for pre-emptive therapy of active CMV infection in allogeneic HSCT and to determine the incidence of adverse effects and relapses. Methods This was a 2-year prospective, comparative cohort study in which 237 episodes of pre-emptive therapy for active CMV infection were collected in 166 allogeneic HSCT recipients out of 717 included in the Spanish Network for Research on Infection in Transplantation (RESITRA/REIPI) database. Intravenous GCV was the first-line treatment in 112 episodes, intravenous FOS in 38 episodes, and oral VGCV in 87 episodes. Results VGCV was used as pre-emptive therapy for active CMV infection in 87 episodes. Excluding episodes considered as relapse, VGCV was as successful (91.4% [74/81]) as GCV (83.7% [87/14]) or FOS (75.8% [25/33]). In the VGCV arm, 7 (8.6%) cases were considered treatment failures: 4 (4.9%) because of adverse events, 1 (1.2%) due to persistent viral activity and 2 (2.5%) based on clinical decision. There were also 6 (7.4%) cases of recurrent infection. No statistically significant differences were found when compared to GCV or FOS. Conclusions In allogeneic HSCT recipients, VGCV seemed effective and safe in the pre-emptive therapy of active CMV infection.

A prospective observational study evaluated the effectiveness of combining antibiotic-lock therapy and systemic antibiotics for Gram-negative bacilli long-term catheter-related bacteremia. In 46 uncomplicated episodes, the most frequently isolated microorganisms were Pseudomonas aeruginosa (15), Enterobacter cloacae (12), Escherichia coli (10), and Klebsiella spp. (8). Cure was achieved in 95% of cases.

The aims of this study were to compare the characteristics of adult patients with left‐sided infective endocarditis (LSIE) diagnosed and treated in a tertiary‐care hospital with those of patients referred from a second‐level community hospital, and to establish the accuracy of diagnosis and adequacy of treatment in referred patients and the influence of this factor on outcome. A prospective observational cohort study was conducted at Hospital Universitari Vall d’Hebron, a 1000‐bed teaching hospital in Barcelona (Spain) and a referral centre for cardiac surgery. One hundred and fourteen of 337 (34%) episodes of LSIE treated in our hospital occurred in transferred patients. As compared with patients diagnosed in our hospital, transferred patients acquired LSIE within the healthcare system less often (16.7% vs. 38.1%, p

Two new species related to Candida glabrata, i.e., Candida nivariensis and Candida bracarensis, have been proposed. The occurrence of these species among isolates collected in a Spanish mycology reference laboratory in 2008-2009 was reviewed. In addition, strains recovered as part of an active population-based surveillance of candidemia conducted in Barcelona between 2002 and 2003 were also analyzed. Among 143 clinical isolates received in 2008-2009, three (2%) were identified as C. bracarensis and none as C. nivariensis through sequencing of their ribosomal DNA. Of the 31 strains initially identified as C. glabrata in the 2002-2003 population-based study (0.38 cases/100,000 population), none were found to belong to these related new species. Results from in vitro susceptibility studies of C. bracarensis isolates were comparable to those found with C. glabrata. Since new and cryptic species have been described, periodic surveillance including the use of molecular identification methods seems to be necessary in order to determine their frequency, geographical distribution and susceptibility profile.

The aim of this study was to assess whether the clinical characteristics, management, and outcomes of infective endocarditis differ in women and men through a prospective observational cohort study at a single tertiary care teaching hospital. From January 2000 to December 2008, 271 new cases of infective endocarditis were diagnosed (183 in men, 88 in women) according to modified Duke criteria, and patients were followed for 1 year. Women were older than men (mean age 63 +/- 16 vs 58 +/- 18 years, p = 0.006); more women were taking immunosuppressants (14% vs 3%, p = 0.006) and had mitral valve involvement (52% vs 36%, p = 0.02). However, more men had human immunodeficiency virus infection than women. There were no gender differences in Charlson index, regurgitation severity, culprit pathogens, or major complications. When surgery was indicated, women were less likely to undergo the procedure (26% vs 47%, relative risk [RR] 0.4, 95% confidence interval [CI] 0.2 to 0.7), p = 0.001). Mortality tended to be higher in women in the hospital (32% vs 23%, RR 1.58, 95% CI 1 to 2.5, p = 0.05) and at 1 year (38% vs 26%, RR 1.7, 95% CI 1.0 to 2.9, p = 0.04). Surgical treatment was a protective factor against death in the hospital (RR 0.18, 95% CI 0.04 to 0.77, p = 0.02) and at 1 year (RR 0.12, 95% CI 0.03 to 0.48, p = 0.03) after adjustment for age, gender, Charlson index, infection by Staphylococcus aureus, severity at presentation, heart failure, acute renal failure, stroke, and the ejection fraction. In conclusion, women with infective endocarditis were slightly older than men but showed similar co-morbidities. Women underwent surgery less frequently and consequently had worse prognosis than men.

Objective: Guidelines recommendation to extend treatment duration in genotype 1 hepatitis C virus (HCV)/HIV-coinfected patients who clear the virus later than treatment week 4 is not evidence-based. Our main objective was to study the ability of week 12 viral response [early virologic response (EVR)] to predict long-term outcome in patients treated for 48 weeks. Design: Multicenter retrospective cohort analysis. Methods: Genotype 1 HCV treatment-naive, HIV-coinfected adult patients with compensated liver disease who started combination therapy with fixed-dose pegylated-interferon (pegIFN) alfa-2a or weight-based pegIFN alfa-2b plus ribavirin were included. Univariate and forward stepwise logistic regression analysis were used to identify predictors of sustained viral response (SVR) and relapse. Results: By intention-to-treat analysis, 31.3% (87/278) of patients achieved an SVR. SVR rate was more than three-fold higher in patients who cleared the virus by week 12 of treatment compared with late responders. Among 123 end-of-treatment responders, 36 (29.3%) relapsed. Relapse risk increased in patients with cirrhosis, in those with ribavirin dose reductions and in late responders: more than 65% of patients who cleared the virus between weeks 12 and 24 relapsed following 48 weeks of treatment compared with 10% of those attaining a complete EVR (

Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456 ms) in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants (TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of significant QTc prolongation. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar relative risk of SCD. Lower doses of risperidone had a higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc prolongation with sertindole is significant and this drug has not been approved by the Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been associated with QTc prolongation but no cases of TdP have been reported with the use of these agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT syndrome and TdP include: female gender, concomitant cardiovascular disease, substance abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital Long QT syndrome. Careful selection of the psychotropic and identification of patient's risk factors for QTc prolongation is applicable in current clinical practice.

European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints classify Candida strains with a fluconazole MIC ≤ 2 mg/liter as susceptible, those with a fluconazole MIC of 4 mg/liter as representing intermediate susceptibility, and those with a fluconazole MIC > 4 mg/liter as resistant. Machine learning models are supported by complex statistical analyses assessing whether the results have statistical relevance. The aim of this work was to use supervised classification algorithms to analyze the clinical data used to produce EUCAST fluconazole breakpoints. Five supervised classifiers (J48, Correlation and Regression Trees [CART], OneR, Naïve Bayes, and Simple Logistic) were used to analyze two cohorts of patients with oropharyngeal candidosis and candidemia. The target variable was the outcome of the infections, and the predictor variables consisted of values for the MIC or the proportion between the dose administered and the MIC of the isolate (dose/MIC). Statistical power was assessed by determining values for sensitivity and specificity, the false-positive rate, the area under the receiver operating characteristic (ROC) curve, and the Matthews correlation coefficient (MCC). CART obtained the best statistical power for a MIC > 4 mg/liter for detecting failures (sensitivity, 87%; false-positive rate, 8%; area under the ROC curve, 0.89; MCC index, 0.80). For dose/MIC determinations, the target was >75, with a sensitivity of 91%, a false-positive rate of 10%, an area under the ROC curve of 0.90, and an MCC index of 0.80. Other classifiers gave similar breakpoints with lower statistical power. EUCAST fluconazole breakpoints have been validated by means of machine learning methods. These computer tools must be incorporated in the process for developing breakpoints to avoid researcher bias, thus enhancing the statistical power of the model.

This study describes the grammar-related behaviours of three experienced non-native teachers of English working in state secondary schools in Catalonia and investigates what beliefs may explain, from the teachers' point of view, these behaviours; it also examines what factors in their turn determine these beliefs. The results uncover three essentially different approaches to metatalk, which have their origins in complex and varied relationships between cognitive, experiential and contextual factors.

Objectives Gentamicin is often used to treat listeriosis, particularly in patients with meningitis; nonetheless, some clinicians question this practice because of the drug's associated nephrotoxicity and inability to cross the blood-brain barrier. The aim of this study was to evaluate predictors of mortality and the impact of aminoglycosides on outcome in patients with listeriosis. Methods We conducted a retrospective study of all non-pregnant adult patients with Listeria monocytogenes infection detected in sterile body fluids between 1983 and 2006. Early mortality was defined as death occurring between days 3 and 14 after admission, and late mortality as in-hospital death after 14 days. Results Of 118 episodes, 16 were excluded because patients died in the first 48 h. Among the 102 patients analysed, 33 (32%) had received combined beta-lactam and aminoglycoside therapy and 69 (68%) beta-lactam monotherapy. Both groups had similar demographic and clinical features, and rate of appropriate initial therapy. Overall mortality was 21/102 (20.6%). Early overall mortality was 11.8%: 27.3% (9/33) in the combined group and 4.3% (3/69) in the monotherapy group (P = 0.003). Late mortality was 8.8%. In the multivariate analysis, the factors predicting early mortality were renal failure, previous corticosteroid therapy and age >65 years, whereas neoplastic disease and coma were associated with late mortality. Gentamicin administration did not decrease early mortality, but seemed to increase it. In the late mortality analysis, gentamicin use had no impact. In an analysis with the propensity score method for the use of aminoglycosides, combined therapy with this antibiotic was associated with an increasing trend for early mortality (OR 3.40, 95% CI 0.82-14.07). Conclusions The addition of aminoglycosides to treatment for listeriosis did not improve the patients' outcome.

Background. To study the feasibility of a response-guided therapy for chronic hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus (HIV) in a tertiary care hospital. Methods. Treatment duration was individualized on the basis of week 4 and week 12 virologic response. Sixty patients were enrolled and received pegylated interferon alfa-2b (1.5 μg/kg per week) plus weight-based ribavirin (800-1400 mg/day). Patients who achieved a rapid virologic response, defined as viral load

Definimos la docencia de la patologia infecciosa en los estudios de grado de medicina como el conjunto de actividades destinadas a proporcionar al alumno un nivel de competencia en esta area (conocimientos, habilidades y actitudes) adecuado para un medico recien licenciado, asi como a dotarle de una base solida para poder adquirir en el futuro las competencias propias de un especialista. En el momento actual, la ubicacion, la dimension y las competencias de la patologia infecciosa en el grado de medicina son muy heterogeneas en las distintas facultades espanolas. La proxima incorporacion al espacio europeo de educacion superior, con la necesaria adecuacion de los planes de estudio, comportara una mejor definicion de los contenidos y objetivos docentes de esta materia. El ultimo documento de la Conferencia de Decanos de Facultades de Medicina identifica claramente la asignatura de patologia infecciosa y la situa en el modulo de patologias medicas dentro del bloque de formacion clinica humana. En nuestra opinion, la patologia infecciosa debe plantearse como una asignatura troncal situada preferentemente en el segundo semestre del quinto curso y disponer de un minimo de 6 y un maximo de 9 creditos ECTS, entre teoricos y practicos, distribuidos equitativamente en creditos presenciales, semipresenciales y de formacion autonoma. La asignatura debe tener una integracion horizontal con la mayoria de asignaturas que conforman el bloque clinico y una integracion vertical con la asignatura de microbiologia. La coordinacion de la asignatura y la imparticion de la mayor parte de los creditos deben corresponder a especialistas con actividad clinica en enfermedades infecciosas.

BACKGROUND The aim of this study was to describe the characteristics of health care-associated infective endocarditis (HAIE) and to establish the risk factors for mortality. METHODS We conducted a prospective, observational cohort study. HAIE was defined according to the following conditions: (1) symptom onset >48 h after hospitalization or within 6 months after hospital discharge; or (2) ambulatory manipulations causing endocarditis. RESULTS Eighty-three episodes of HAIE (accounting for 28.4% of all cases of endocarditis) were diagnosed. Compared with patients with community-acquired endocarditis, patients with HAIE were older (median age +/- standard deviation, 65.3 +/- 16.4 years vs. 57.8 +/- 17.0 years; P = .001), were in poorer health before disease onset (Charlson index, 2.5 +/- 2.3 vs. 1.7 +/- 2.1; P = .006), had more staphylococcal (55.4% vs. 28.3% of cases) and enterococcal infections (22.9% vs. 7.7% of cases; P < .005), underwent fewer surgeries (22.9% vs. 45.9% of cases; P < .005), and experienced a higher rate of in-hospital (45.8% vs. 22.0%) and 1-year mortality (59.5% vs. 29.6%; P < .005). In the HAIE cohort, independent predictors of in-hospital death were stroke (odds ratio [OR], 8.95; 95% confidence interval [CI], 2.04-39.31; P = .004), congestive heart failure (OR, 5.48; 95% CI, 1.77-17.03; P = .003), surgery indicated but not performed (OR, 3.74; 95% CI, 1.22-11.45; P = .021), and enterococcal infection (OR, 0.18; 95% CI, 0.04-0.78; P = .022). Independent predictors of 1-year mortality were surgery indicated but not performed (OR, 7.81; 95% CI, 2.06-29.67; P = .003), acute renal failure (OR, 7.18; 95% CI, 1.32-39.18; P = .023), and enterococcal infection (OR, 0.18; 95% CI, 0.04-0.81; P = .026). For the series overall (292 episodes), HAIE was an independent predictor of in-hospital (OR, 2.83; 95% CI, 1.34-5.98; P = .007) and 1-year mortality (OR, 2.59; 95% CI, 1.25-5.39; P = .011). CONCLUSIONS HAIE is an important health problem associated with considerable mortality. New strategies to prevent HAIE should be assessed.

Transmission of infection from donor to recipient is a potential complication of transplantation. More data on this issue are needed to expand the insufficient donor pool. This study evaluates the incidence of donor nonviral infection, transmission from infected donors and the effect of donor infection on 30-day recipient survival. Data from 211 infected donors contributing to 292 (8.8%) of 3322 consecutive transplant procedures within RESITRA (Spanish Research Network for the Study of Infection in Transplantation) were prospectively compiled and analyzed. Lung was the most likely transplanted organ carried out with an infected donor and Staphylococcus aureus was the most commonly isolated microorganism. In more than a half of donors, the lung was the site of infection. Donor-to-host transmission was documented in 5 patients out of 292 (1.71%), 2 of whom died of the acquired infection (40%). Nonetheless, there was no difference in 30-day patient survival when comparing transplant procedures performed with organs from infected or uninfected donors. In conclusion, donor infection is not an infrequent event, but transmission to the recipient is quite low. Hence, with careful microbiological surveillance and treatment, the number of organs available for transplantation may be increased.

Background. Cytomegalovirus (CMV) infection causes morbidity in solid organ transplant (SOT) recipients, either by direct injury or in association with chronic allograft rejection or other opportunistic infections. Ganciclovir is the treatment of choice, but this agent requires intravenous administration, which affects its feasibility for long-term use. Valganciclovir, which has an oral bioavailability of 60%, has proven to be useful for prophylaxis of CMV infection in high-risk SOT recipients and for treating retinitis in persons with acquired immunodeficiency syndrome. Objective. To compare the efficacy of valganciclovir (alone or as sequential therapy after a regimen of intravenous ganciclovir) with intravenous ganciclovir alone for preemptive therapy or treatment of CMV disease (viral syndrome or focal disease) in SOT recipients and to determine the incidence of adverse effects and relapses. Methods. In this 2-year prospective, comparative cohort study, 376 episodes of preemptive therapy or treatment of CMV disease were recorded among 334 of 3467 SOT recipients included in the Spanish Network for Research on Infection in Transplantation (RESITRA) database. Intravenous ganciclovir was the first-line treatment in 170 episodes; valganciclovir followed by intravenous ganciclovir was administered in 82 episodes, and valganciclovir alone was administered in 112 episodes. Results. Valganciclovir was used as preemptive therapy or treatment for CMV disease in 84 and 28 episodes, respectively. Duration of treatment was longer in valganciclovir recipients than in ganciclovir recipients for both preemptive therapy (21 vs. 15 days; P

Contains fulltext : 53715.pdf (Publisher’s version ) (Closed access) We report on the correlation of the outcomes for two cohorts of patients who had been treated for candidemia (126 episodes) or oropharyngeal candidiasis (110 episodes) with various doses of fluconazole and the MIC of fluconazole obtained by using the EUCAST standard for fermentative yeasts. Of 145 episodes caused by an isolate with a fluconazole MIC < or =2 mg/liter, 93.7% (136 of 145) responded to fluconazole treatment. The response for those infected with a strain with a MIC of 4 mg/liter was 66% but reached 100% when the dose was greater than 100 mg/day, whereas the response for those infected with strains with MICs > or =8 mg/liter was only 12%. Hence, a MIC of 2 mg/liter or 4 mg/liter was able to predict successful treatment. A cure rate of 93.9% (140 of 149) was achieved when the dose/MIC ratio was > or =100 but fell to 14.6% (16 of 109) when the ratio was less. The dose/MIC required to achieve a response rate of 50% (the 50% effective concentration) was 43.7 for the cohort of patients with oropharyngeal candidiasis. Classification and regression analysis indicated that a dose/MIC of 35.5 was the threshold for the prediction of cure or failure. However, an increase in exposure above this threshold further increased the probability of cure, and all patients were cured when the dose/MIC exceeded 100. Monte Carlo simulations showed a probability of target attainment of 99% at MICs < or =2 mg/liter and a pharmacodynamic target of a dose/MIC ratio of 100, which was equivalent to an unbound fraction of the fluconazole area under the curve versus the MIC of 79.

Removal of central venous catheters (CVCs) from candidaemic patients is considered the reference standard of care, although this practice is not always possible. The impact of prompt catheter removal on outcome was investigated by analysing data from an active population-based surveillance study in Barcelona, Spain. Patients with candidaemia and a CVC were identified between January 2002 and December 2003. Cases with CVC removal within 2 days were classified as having early CVC removal. Outcome, defined as in-hospital mortality 2–30 days after diagnosis of candidaemia, was determined among hospitalised adults using univariate, Kaplan–Meier and multivariate logistic regression analysis. Outpatients, paediatric patients and those who died or were discharged within 2 days were excluded. The study identified 265 patients with candidaemia and a CVC. Median time from diagnosis of candidaemia to catheter removal was 1 day (range 0–29 days). Overall, 172 patients met the criteria for inclusion in the outcome study. Patients with early CVC removal differed significantly from those with delayed CVC removal. According to univariate, Kaplan–Meier and multivariate analysis, the marker most predictive of in-hospital mortality among candidaemic patients with CVCs was severity of illness. These data suggest that timing of CVC removal may best be determined after carefully considering the risks and benefits to individual patients.