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Background: To study whether the association between the CD4/CD8 ratio variation over time and the develop‑ ment of clinical outcomes vary in late presenters (CD4 count<350/µL or AIDS event at enrolment) or advanced presenters (CD4 count<200/µL or AIDS event at enrolment). Methods: We included ART-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) enrolled between January 2004 up to November 2018 and with at least 6 months of follow-up. We used extended Cox pro‑ portional hazard models to estimate the hazard ratios (HRs) for the association between CD4/CD8 ratio over time and a composite endpoint of the occurrence of the frst AIDS event, frst serious non-AIDS event or overall mortality occurring from 6 months after enrolment. HRs in non-late, late and advanced presenters were obtained by including an interaction term between late presentation status and CD4/CD8 ratio over time. Results: Of 10,018 participants, 55.6% were late presenters and 26.5% were advanced presenters. Compared with CD4/CD8 ratio>0.4, CD4/CD8 ratio≤0.4 over time was associated with an increased risk of experiencing the compos‑ ite endpoint in non-late (HR 1.90; 95%CI 1.48, 2.43), late (HR 1.94; 1.46, 2.57) and advanced presenters (HR 1.72; 1.26, 2.34). Similarly, CD4/CD8 ratio≤0.4 over time was associated with a higher risk of developing an AIDS event (HR 3.31; 2.23, 4.93 in non-late; HR 2.75; 1.78, 4.27 in late and HR 2.25; 1.34, 3.76 in advanced presenters) or serious non-AIDS event (HR 1.39; 0.96, 2.02 in non-late, HR 1.62; 1.10, 2.40 in late and HR 1.49; 0.97, 2.29 in advanced presenters) as well as with a higher risk of overall mortality (HR 1.49; 0.92, 2.41 in non-late, HR 1.80; 1.04, 3.11 in late and HR 1.61; 0.92, 2.83 in advanced presenters) compared to CD4/CD8>0.4, regardless of the late presentation status. Conclusions: A low CD4/CD8 measured over time is associated with increased risk of morbidity and mortality in people living with HIV independently of thei

Objectives: To evaluate whether simplification of antiretroviral treatment to dual therapy (DT) negatively impacts immune recovery (IR), immune activation and inflammation (IA/I), and HIV reservoir. Methods: An open-label, single-centre, randomized controlled trial conducted in adult virologically suppressed HIV-infected patients on triple therapy (TT) with elvitegravir-cobicistat, emtricitabine and tenofovir alafenamide or dolutegravir (DTG), abacavir, and lamivudine (3TC). Participants were ran domized to continue TT or switch to DTG, or darunavir/cobicistat (DRVc) plus 3TC. IR was assessed by CD4þ/CD8þ ratio at 48 and 96 weeks. Changes in immune activation, proliferation, exhaustion, senes cence, and apoptosis in CD4þ and CD8þ T cells, plasma sCD14, hsCRP, D-dimers, b2-microglobulin, IL-6, TNF-a and IP-10 levels, cell-associated HIV-DNA (CA-DNA), and unspliced HIV-RNA (usRNA) were also analysed. Results: One hundred and fifty-one participants were enrolled. Fourteen patients did not complete the follow up. In the ITT and PP analysis, the IR was similar between the treatment arms. In the ITT analysis, the median increase in CD4þ/CD8þ ratio was 0.10, 0.04, and 0.07 at week 48, and 0.09, 0.05, and 0.08 at week 96 for TT, DTG/3TC, and DRVc/3TC, respectively. After adjusting for confounding factors, the slopes of changes in CD4þ/CD8þ ratio over time were independent of treatment (F ¼ 1.699; p ¼ 0.436) and related only to baseline values (F ¼ 756.871; p ¼ 0.000). There were no differences in IA/I, CA-DNA, or usRNA between treatment arms. Discussion: Both IR and IA/I, CA-DNA, and usRNA were similar in the three treatment groups, regardless of maintaining TT or simplifying to DTG/3TC or DRVc/3TC in virologically suppressed HIV-infected pa tients.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/ recipient mismatch (D+/R-) transplant recipients.

Acinetobacter baumannii y Pseudomonas aeruginosa son bacilos Gram-negativos (BGN) no fermentadores, y paradigmas de las resistencias microbianas, encontrándose dentro del grupo de microorganismos denominados ESKAPE por la Organización Mundial de la Salud (OMS) (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, P. aeruginosa, y especies de Enterobacter). Las infecciones causadas por estos patógenos son comunes en las Unidades de Cuidados Intensivos (UCI), así como en pacientes con alteraciones anatómicas y/o funcionales de órganos en el caso de la P. aeruginosa, y están asociadas con elevadas tasas de morbi-mortalidad, estancias hospitalarias prolongadas, así como costes elevados. El aumento exponencial de las resistencias microbianas al que nos enfrentamos mundialmente, lleva en ocasiones, a que no existan alternativas terapéuticas óptimas en el tratamiento de estas infecciones. En este contexto, la OMS publicó en 2017 una alerta mundial sobre la necesidad urgente de búsqueda de nuevas alternativas terapéuticas para la prevención, diagnóstico y tratamiento de este tipo de infecciones. En este trabajo, nos centramos en una de las alternativas no antimicrobianas a explorar, en concreto en la inmunoterapia como coadyuvante a antimicrobianos, ya sea mediante linfocitos de memoria o mediante inmunoglobulinas enriquecidas en IgM. La modulación de la respuesta inmune se ha demostrado como una estrategia terapéutica ventajosa en la prevención y tratamiento de infecciones, la supresión de respuestas autoinmunes e inflamatorias y/o la estimulación de la inmunidad antitumoral en pacientes con cáncer. En este trabajo se describe la caracterización de modelos murinos de neumonía no letales por cepas clínicas multirresistentes de A. baumannii y P. aeruginosa con diferentes patrones de resistencia a colistina. Además, se describe la respuesta inmune celular desencadenada por este tipo de infecciones, con la finalidad última de ser capaces de modular

Outer membrane complex (OMC) vaccines, which contain antigens from the bacterial outer membrane, have been developed for multiple Gram-negative bacteria. However, OMC vaccines demonstrate high endotoxin activity due to the presence of lipopolysaccharide in the bacterial outer membrane, thus precluding their use in humans. We isolated OMCs from an LPS-deficient strain of A. baumannii (IB010) which completely lacks LPS due to a mutation in the lpxD gene. OMCs from IB010 demonstrated a more than 10,000-fold reduction in endotoxin activity compared to OMCs from wild type A. baumannii. Vaccination with IB010 OMCs produced similar levels of antigen-specific IgG and IgM after two administrations compared to wild type OMCs, and resulted in a similar reduction in post-infection spleen bacterial loads and serum pro-inflammatory cytokine levels. Vaccination with IB010 OMCs provided significant protection against infection compared to control mice, indicating the LPS-free OMCs could contribute to vaccine strategies for preventing infection by A. baumannii.

Epstein-Barr virus, a member of the Herpesviridae family, is responsible for the infectious mononucleosis clinical syndrome, which mainly includes the pharyngitis, fever, and lymphadenopathy triad after incubation for 30-50 days. The liver is involved in 80-90% of patients in a self-limiting transient manner, with jaundice being much more uncommon (5%). From a hematological standpoint it may manifest aplastic anemia, neutropenia, and thrombocytopenia. We report a case of infectious mononucleosis that included severe acute hepatitis and was associated with severe hemolytic anemia secondary to cold agglutinins. After exclusion of other etiologies, and given the clinical suspicion of the above association, which was later confirmed by lab tests, empiric therapy was initiated with antiviral agents (aciclovir + valganciclovir) and corticoids, which resulted in a progressive clinical improvement until complete remission. Therefore, we believe that this case report will reinforce the clinical evidence in support of the above combined therapy for serious infectious mononucleosis as a step prior to liver transplantation.

Objectives This study aims to analyze the mortality and the length of ICU stay (LOS) of A. baumannii VAP compared to respiratory colonization in patients with mechanical ventilation (MV). Methods A prospective cohort study was performed in an ICU of adult patients (February 2010–June 2011). One hundred patients on MV with A. baumannii in lower respiratory airways were recruited, and classified as VAP or airways colonization according to CPIS criteria, with a punctuation 6. LOS, 30-days mortality, A. baumannii bacteremia, and clinical features including antibiotic therapy were recorded. Multivariate analysis (linear and Cox regression) and survival analysis (Kaplan-Meier curves) were performed. Results Fifty-seven VAP and 43 colonized A. baumannii patients were analyzed. Among the A. bau- mannii strains, 99% were non-susceptible to carbapenems and the MIC 90 of colistin was 0.12 mg/l. Therapy was appropriate in 94.6% of VAP patients, most of them with colistin 6 MIU/day, although in 13 (23.6%) cases colistin was started 48 hours after the onset of VAP. Mortality was similar in both groups (VAP 24.6% vs. colonized 27.9%, p = 0.7). Bacteremia and acute kidney insufficiency were associated with decreased survival (p = 0.02 and p = 0.04, respectively) in VAP patients. LOS was 21.5 (11.5–42.75) vs. 9 (6–22) days for VAP and colonized patients (p = 0.004). VAP (p = 0.003) and age (p = 0.01) were independently related to a longer LOS. Conclusions Multidrug-resistant A. baumannii VAP treated with colistin does not have a different mortality compared to lower airways colonization, among patients on mechanical-ventilation, in a set- ting of high susceptibility to colistin of A. baumannii.

Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX. We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.

Acinetobacter baumannii can acquire resistance to the cationic peptide antibiotic colistin through complete loss of lipopolysaccharide (LPS) expression. The activities of the host cationic antimicrobials LL-37 and human lysozyme against multidrug-resistant clinical isolates of A. baumannii that acquired colistin resistance through lipopolysaccharide loss were characterized. We demonstrate that LL-37 has activity against strains lacking lipopolysaccharide that is similar to that of their colistin-sensitive parent strains, whereas human lysozyme has increased activity against colistin-resistant strains lacking LPS.