HLA-C*07 is associated with symptomatic HIV-1-associated neurocognitive disorders (HAND) and immune dysregulation.

BACKGROUND: HIV-1-associated neurocognitive disorders (HAND) in stable patients undergoing antiretroviral therapy (ART) may result from ongoing immune dysregulation and chronic inflammation. A contributing factor may result from the unstable HLA class I allele, HLA-C*07. OBJECTIVE: To assess the genetic profile of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigens (HLA), and immune activation or senescence markers and their association with HAND in stable HIV-1 patients receiving ART. METHODS: An observational cross-sectional study was carried out with 96 patients with asymptomatic or symptomatic HAND. HLA and KIR as well as immune activation/senescence biomarkers in peripheral blood cells were assessed by SSO-Luminex typing and flow cytometry, respectively. RESULTS: HLA-C*07 is associated with symptomatic HAND. The frequency of two copies of HLA-C*07 was higher in patients with symptomatic than with asymptomatic HAND (12.0 vs. 2.2%, ρ < 0.001). The percentage of senescent CD8+CD28- T-cells was higher in patients with two copies of HLA-C*07 (ρ < 0.05). In patients with symptomatic HAND, the percentages of non-senescent CD8+CD28+ T cells were inversely proportional to the number of copies of the HLA-C*07 (ρ < 0.05). CONCLUSION: Patients with symptomatic HAND showed a higher frequency of the homozygotic unstable HLA-C*07 allotype, which could be associated with neurocognitive complications. Two copies of HLA-C*07 were associated with immune senescent T lymphocyte profiles characterized by the loss of CD28 expression.

The phagocytosis dysfunction in lupus nephritis is related to monocyte/macrophage CPT1a.

Macrophages must remove apoptotic cells to shield tissues from the deleterious components of dying cells. The development of chronic inflammation and autoimmune symptoms in systemic lupus is influenced by a deficiency in phagocytosis of apoptotic cells but the underlying mechanism is still unknown. Modifications in monocyte/macrophage phenotype brought on by an increase in their inflammatory phenotype would cause them to decrease the expression of CPT1a, which would reduce their ability to phagocytose, aggravating kidney damage in lupus nephritis. We aim to demonstrate that the deficiency of CPT1A in the immunological system determines lupus. For this purpose, we will monitor CPT1a expression in blood monocytes and phagocytosis and CPT1a expression of macrophages isolated from kidneys and the inflammatory state in kidneys in two experimental models of lupus nephritis such as lupus induced pristane model and in the OVA-IC in vivo model. Additionally, we will test if reestablishing CPT1a expression in tissue macrophages restores the lost phagocytic function. We evidenced that blood monocytes and macrophages isolated from kidneys in the two in vivo models have a reduced expression of CPT1a and a reduced phagocytosis. Phagocytosis could be restored only if macrophage administration leads to an increase in CPT1a expression in kidney macrophages. A new cell therapy to reduce kidney nephritis in lupus could be developed based on these results.

Remdesivir plus dexamethasone is associated to improvement in the clinical outcome of COVID-19 hospitalized patients regardless of their vaccination status.

INTRODUCTION: Remdesivir seems to reduce the risk of hospitalization and improve clinical outcome in hospitalized patients with COVID-19. OBJECTIVES: To compare the clinical outcome of COVID-19 hospitalized patients treated with remdesivir plus dexamethasone versus dexamethasone alone, according to their vaccination status. MATERIAL AND METHODS: A retrospective observational study was carried out in 165 patients hospitalized for COVID-19 from October 2021 to January 2022. Multivariate logistic regression, Kaplan-Meier and the log-rank tests were used to evaluate the event (need for ventilation or death). RESULTS: Patients treated with remdesivir plus dexamethasone (n=87) compared with dexamethasone alone (n=78) showed similar age (60±16, 47-70 vs. 62±37, 51-74 years) and number of comorbidities: 1 (0-2) versus 1.5 (1-3). Among 73 fully vaccinated patients, 42 (47.1%) were in remdesivir plus dexamethasone and 31 (41%) in dexamethasone alone. Patients treated with remdesivir plus dexamethasone needed intensive care less frequently (17.2% vs. 31%; p=0.002), high-flow oxygen (25.3% vs. 50.0%; p=0.002) and non-invasive mechanical ventilation (16.1% vs. 47.4%; p<0.001). Furthermore, they had less complications during hospitalization (31.0% vs. 52.6%; p=0.008), need of antibiotics (32.2% vs. 59%; p=0.001) and radiologic worsening (21.8% vs. 44.9%; p=0.005). Treatment with remdesivir plus dexamethasone (aHR, 0.26; 95% CI: 0.14-0.48; p<0.001) and vaccination (aHR 0.39; 95% CI: 0.21-0.74) were independent factors associated with lower progression to mechanical ventilation or death. CONCLUSIONS: Remdesivir in combination with dexamethasone and vaccination independently and synergistically protects hospitalized COVID-19 patients requiring oxygen therapy from progression to severe disease or dead.

NGAL release from peripheral blood mononuclear cells protects against acute kidney injury and prevents AKI induced fibrosis.

We propose the use of a peripheral blood mononuclear cell therapy based on cell NGAL release to be used in the clinical setting for acute kidney injury (AKI) and the derived fibrosis. First, we designed a procedure whereby PBMC overexpress NGAL and anti-inflammatory agents when subjected to repetitive anoxia/reoxygenation (PBMC (A/R)). Using an in vivo AKI model, we observed that PBMC(A/R) reduces BUN and creatinine levels in blood and inflammation, enhances anti-inflammation, induces proliferation of tubular epithelial cells and reduces AKI-induced fibrosis. Flow cytometry analysis evidenced that monocytes are the only cells accumulated in the injured kidney and phenotype analysis of freshly isolated kidney macrophages, revealed that the healing phenotype is maintained the time needed for recovery. NGAL release from PBMC(A/R) determines the beneficial effect of the therapy since administration of a NGAL antibody previous to the therapy or injection of PBMC(A/R) obtained from NGAL KO animals abolished the beneficial effects. CD11b-NGAL positive cells were enhanced in tissue after PBMC (A/R) therapy and were produced by the injected monocytes. In an in vitro model with tubular epithelial cells (NRK52e) we proved that NGAL release by PBMC(A/R) induced epithelial proliferation and activation of PI3K/Akt pathway.

Moderate to Intense Physical Activity Is Associated With Improved Clinical, CD4/CD8 Ratio, and Immune Activation Status in HIV-Infected Patients on ART.

BACKGROUND: Physical activity has anti-inflammatory effects and reduces morbidity and mortality in the general population, but its role in the clinical, CD4/CD8 ratio, and immune activation status of HIV-infected patients has been poorly studied. METHODS: A cross-sectional study was carried out in a cohort of 155 HIV-infected patients on stable antiretroviral therapy (ART) to compare clinical, biochemical, CD4/CD8 ratio, and immune activation status according to their physical activity in the last 2 years (sedentary/low vs moderate/intense) assessed by the iPAQ. A binary logistic regression and mixed analysis of variance were performed to evaluate the impact of levels of physical activity on CD4/CD8 ratio. RESULTS: In our series, 77 (49.7%) out of 155 patients were sedentary, and 78 (50.3%) practiced moderate/intense physical activity. Moderate/intense physical activity was associated with better metabolic control (lower body mass index, P = .024; glucose, P = .024; and triglyceride, P = .002) and CDC HIV stage (P = .046), lower CD8+ (P =  .018), CD4+CD8+ (P = .026), CD4+CD86+ (P = .045), CD4+HLA-DR+ (P = .011), CD8+HLA-DR+ (P = .048) T lymphocytes and CD16+HLA-DR+ natural killer cells (P = .026), and higher CD3+CD4+ T lymphocytes (P = .016) and CD4/CD8 ratio (P = .001). Sedentary lifestyle (odds ratio [OR], 2.12; P = .042), CD4 nadir (OR, 1.005; P < .001), and CD8+CD38+ T cells (OR, 1.27; P = .006) were independently associated with low CD4/CD8 ratio (<0.8). Earlier and more intense CD4/CD8 ratio recovery was observed in patients with higher physical activity in the 2-year follow-up with a significant interaction between these variables: F(2, 124) = 3.31; P = .049; partial η2 = 0.042. CONCLUSIONS: Moderate to high physical activity is associated with beneficial health effects, improvement in metabolic profile, and reduction of chronic inflammation in patients with HIV. Although more studies and clinical trials are needed to confirm these findings, a healthy lifestyle including at least moderate physical activity should be recommended to HIV patients on stable ART.

Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages.

Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and anti-inflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality.

Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model.

Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.

Subclinical atherosclerosis and immune activation in young HIV-infected patients with telomere shortening.

BACKGROUND: To date, available data on premature aging in young HIV-infected adults are scarce and no reports offer comprehensive assessment of telomere shortening (TS) in relation to subclinical atherosclerosis (SCA). In this study, we investigate if telomere shortening and immune activation markers are associated with SCA, which is one of the main degenerative diseases in young HIV-infected adults. METHODS: A descriptive cross-sectional study was carried out in 149 HIV-infected patients on stable antiretroviral regimen (ART). Carotid intima-media thickness (cIMT) was estimated by carotid ultrasound. Quantitative singleplex PCR was performed to evaluate TS. The expression of activation/senescence markers was evaluated by multiparametric flow cytometry. RESULTS: TS was observed in 73 patients (49%). Higher cIMT was observed in patients with TS than those without it (0.86 vs. 0.80 mm; p=0.041). Patients under the age of 50 (defined as young adults) with TS showed higher absolute numbers of activated lymphocyte T cells CD8+CD38+ (3.94 vs. 2.34 cell/µl; p=0.07) and lymphocyte B cells CD19+CD38+ (3.07 vs. 2.10 cell/µl; p=0.004) compared to those without TS. In the multivariate analysis, the only factor independently associated with TS was the absolute number of lymphocyte T cells CD8+CD38+ T cells (OR = 1.18; 95%-CI = 1.00-1.39; p = 0.05). CONCLUSION: Young HIV-infected adults show premature biological aging with accentuated immune activation. Chronic inflammation with excessive T-cells activation could be associated to TS, premature aging, and SCA in young HIV-infected adults.

Activating Killer-Cell Immunoglobulin-Like Receptors Are Associated With the Severity of Coronavirus Disease 2019.

BACKGROUND: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. METHODS: We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls. RESULTS: The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, P < 7.7 × 10-9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; P < .002; Pc = 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells. CONCLUSIONS: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.

CPT1a gene expression reverses the inflammatory and anti-phagocytic effect of 7-ketocholesterol in RAW264.7 macrophages.

BACKGROUND: Macrophage are specialized cells that contributes to the removal of detrimental contents via phagocytosis. Lipid accumulation in macrophages, whether from phagocytosis of dying cells or from circulating oxidized low-density lipoproteins, alters macrophage biology and functionality. It is known that carnitine palmitoyl transferase 1-a (CPT1a) gene encodes an enzyme involved in fatty acid oxidation and, therefore, lipid content. However, the potential of CPT1a to activate macrophage phagocytic function have not been elucidated. METHODS: Using a murine macrophage cell line, RAW264.7, we determine if intracellular accumulation of 7-ketocholesterol (7-KC) modulates macrophage phagocytic function through CPT1a gene expression. In addition, the effects of CPT1a genetic modification on macrophage phenotype and phagocytosis has been studied. RESULTS: Our results revealed that CPT1a gene expression decreased by the accumulation of 7-KC at the higher dose of 7-KC. This was concomitant with an impair ability to phagocytize bioparticles and an inflammatory phenotype. GW3965 treatment, which have shown to facilitate the efflux of cholesterol, eliminated the intracellular lipid droplets of 7-KC-laden macrophages, increased the gene expression of CPT1a, diminished the gene expression of the inflammatory marker iNOS and restored macrophage phagocytosis. Furthermore, CPT1a Knockdown per se was detrimental for macrophage phagocytosis whereas transcriptional activation of CPT1a heightened the uptake of bioparticles. CONCLUSIONS: Altogether, our findings indicate that downregulation of CPT1a by lipid content modulates macrophage phagocytosis and inflammatory phenotype.

CPT1a downregulation protects against cholesterol-induced fibrosis in tubular epithelial cells by downregulating TGFß-1 and inflammasome.

BACKGROUND: Dyslipidemia causes renal damage; however, the detailed molecular mechanism has not been clarified. It is known that carnitine palmitoyl transferase 1-a (CPT1a) gene encodes an enzyme involved in fatty acid oxidation and, therefore, lipid content. In the present study, we investigated whether the accumulation of lipids induced by 7-ketocholesterol (7-KC) in tubular epithelial cells produce a fibrotic and inflammatory response through CPT1a. METHODS: Using an epithelial cell line, NRK-52E, we determine if intracellular accumulation of 7-KC modulates profibrotic and inflammatory events through CPT1a gene expression. In addition, the direct effects of CPT1a genetic modification has been studied. RESULTS: Our results revealed that high levels of 7-KC induce increased expression of CPT1a, TGF-ß1, α- SMA and NLRP3 that was correlated with lipid content. GW3965 treatment, which have shown to facilitate the efflux of cholesterol, eliminated the intracellular lipid droplets of 7-KC laden cells and decreased the expression of CPT1a, TGF-ß1, α- SMA and NLRP3. Furthermore, CPT1a Knockdown and C75 pre-treatment increased lipid content but decreased TGF-ß1, α- SMA and NLRP3. CONCLUSIONS: Our findings reveal that the profibrotic effect of 7-KC on renal epithelial cells are mediated by CPT1a overexpression, which acts on TGF-ß1, α-SMA and NLRP3. Thus, CPT1a downregulation protects against 7-KC-induced fibrosis in tubular epithelial cells by downregulating TGF-ß1, α- SMA and NLRP3.

Association Between Erectile Dysfunction and Carotid Subclinical Atherosclerosis in HIV-Infected Patients.

BACKGROUND: Erectile dysfunction (ED) is frequent in HIV-infected patients, and it can be associated with atherosclerosis and cardiovascular events. So, the objective was to evaluate whether the presence of moderate-severe ED was a marker of subclinical atherosclerosis (SCA) in HIV-infected patients. METHODS: A cross-sectional study was conducted in a cohort of HIV-infected patients. The presence of ED was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. The presence of SCA was determined by calculating the mean carotid intima-media thickness with Doppler ultrasound. A logistic regression analysis was performed to check the variables associated with SCA. RESULTS: One hundred thirty-nine men of 45 (10) years of age were included, of which 130 (94.9%) received antiretroviral therapy. In 30 (22%) patients, the Framingham score was higher than 10%. In 36 (25.9%) patients, ED was detected in a moderate-severe degree and in 53 (38.1%), SCA was detected. In the multivariate analysis, variables independently associated with the presence of SCA were as follows: older age [odds ratio (OR) = 1.22, confidence interval (CI) 95%: 1.1 to 1.35, P < 0.001] and moderate-severe ED (OR = 4.68, CI 95%: 1.18 to 18.5; P = 0.028). Variables associated with moderate-severe ED were as follows: age (OR = 1.107, CI 95%: 1.041 to 1.17, P < 0.001) and having antibodies for hepatitis C virus (OR = 5.12, CI 95%: 1.54 to 17.03, P < 0.001). CONCLUSIONS: HIV-Infected patients often have moderate-severe ED, especially the elderly and coinfected patients with hepatitis C virus. ED can be an early clinical manifestation of incipient atherosclerosis, so its presence should involve a deep control of cardiovascular risk factors and using a regimen with a better atherogenic profile.

T cell senescence predicts subclinical atherosclerosis in HIV-infected patients similarly to traditional cardiovascular risk factors.

The main objective of this study is to evaluate the predictive capacity of T cell activation/senescence in subclinical atherosclerosis (SCA) in a group of HIV-infected patients. So, a cross-sectional analysis was performed on 91 long-term triple-ART therapy HIV-infected patients from an observational and prospective cohort. Carotid Intima Media Thickness (cIMT) was measured. Binary logistic regression was used to evaluate independent variables associated with SCA. Compared to patients without SCA, patients with SCA (60.4%) were older (41.33 ±â€¯9.04 vs. 51.73 ±â€¯8.44 years old, p < 0.001) and showed Framingham risk score (2.63 ±â€¯3.127 vs. 7.66 ±â€¯5.84, p = 0.008), as well as higher numbers of CD4+CD8+ double positive T cells (0.50 ±â€¯0.42% vs. 0.81 ±â€¯0.79%, p = 0.037), CD8+CD28- T cells (41.70 ±â€¯16.96% vs. 50.22 ±â€¯16.15%, p = 0.018), higher expression of CD28 on CD8+CD28+ T cells (1865 ±â€¯789 vs. 2243 ±â€¯917 MFI, P = 0.046). In contrast, they showed lower expression of CD38 on CD19+ B cells (65.38 ±â€¯27.47% vs. 42.67 ±â€¯30.26%, P < 0.001). Logistic multivariable analysis showed that Framingham risk score >10% (OR = 14.84, CI95% 1.63-125; p = 0.016) and numbers of CD8+CD28- T cells (OR = 1.032, CI 95% 1-1.065; p = 0.045) were independent factors associated with SCA. Patients with CD8+CD28- T cells ≥59% compared to those <59% had higher risk of SCA (OR = 4, CI95% 1.19-13.3, p = 0.024). Interestingly, 27.4% of patients with low Framingham risk score had elevated levels of CD8+CD28- T cells. In conclusion, immune senescence represented by accumulation of CD8+CD28- T cells may contribute to improve the predictive capacity of the Framingham risk score, especially when the scores are low and can explain, at least in part, the higher prevalence of SCA observed in long-term ART-treated stable HIV infected patients.

Low-Level Viremia Is Associated With Clinical Progression in HIV-Infected Patients Receiving Antiretroviral Treatment.

BACKGROUND: The objective of this study was to investigate the long-term impact of low-level viremia (LLV) on all-cause mortality, AIDS and non-AIDS events (NAEs), and virological failure in patients receiving antiretroviral therapy (ART). METHODS: We analyzed ART-naive adults from the cohort of the Spanish AIDS Research Network (CoRIS) who initiated ART from 2004 to 2015 and achieved plasma viral load (VL) below 50 copies per milliliter. LLV50-199 was defined as 2 consecutive VL between 50 and 199 copies per milliliter, and LLV200-499 as 2 consecutive VL between 50 and 499 copies per milliliter with at least one between 200 and 499 copies per milliliter. Multivariable Cox models were used to estimate the association of LLV with AIDS events/death, non-AIDS events, and virological failure. RESULTS: Of 5986 patients included, 237 (4.0%) experienced LLV50-199 and 168 (2.8%) developed LLV200-499. One hundred seventy-one patients died or developed an AIDS event, 245 had any serious NAE and 280 had virological failure. LLV200-499 was strongly associated with a higher risk of both AIDS events/death [adjusted hazard ratio (aHR), 2.89; 95% confidence interval (CI), 1.41 to 5.92] and virological failure (aHR, 3.25; 95% CI: 1.77 to 5.99), whereas no differences were observed between LLV50-199 and no LLV neither for AIDS events/death (aHR, 1.84; 95% CI: 0.89 to 3.82) nor virological failure (aHR, 1.42; 95% CI: 0.78 to 2.58). LLV was not associated with the occurrence of any serious NAE. CONCLUSIONS: In this cohort, LLV200-499 was strongly associated with AIDS events/death and virological failure, but not with any serious NAE. Therefore, vigorous treatment should be implemented in patients with more than 200 copies per milliliter.

Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis.

BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP) and sepsis. In this paper, we examined the ability of MR-proADM to predict organ damage and long-term mortality in sepsis patients, compared to that of procalcitonin, C-reactive protein and lactate. METHODS: This was a prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to internal service department. The association between biomarkers and 90-day mortality was assessed by Cox regression analysis and Kaplan-Meier curves. The accuracy of biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: A total of 148 patients with severe sepsis, according to the criteria of the campaign to survive sepsis, were enrolled. Eighty-five (57.4%) had sepsis according to the new criteria of Sepsis-3. MR-proADM showed the best AUROC to predict sepsis as defined by the Sepsis-3 criteria (AUROC of 0.771, 95% CI 0.692-0.850, p <0.001) and was the only marker independently associated with Sepsis-3 criteria (OR = 4.78, 95% CI 2.25-10.14; p < 0.001) in multivariate analysis. MR-proADM was the biomarker with the best AUROC to predict mortality in 90 days (AUROC of 0.731, CI 95% 0.612-0.850, p <0.001) and was the only marker that kept its independence [hazard ratio (HR) of 1.4, 95% CI 1.2-1.64, p <0.001] in multivariate analysis. The cut-off point of MR-proADM of 1.8 nmol/L (HR of 4.65, 95% CI 6.79-10.1, p < 0.001) was the one that had greater discriminative capacity to predict 90 days mortality. All patients with MR-proADM concentrations ≤0.60 nmol/L survived up to 90 days. In patients with SOFA ≤ 6, the addition of MR-proADM to SOFA score increased the ability of SOFA to identify non-survivors, AUROC of 0.65 (CI 95% 0.537-0.764) and AUROC of 0.700 (CI 95% 0.594-0.800), respectively (p < 0.05 for both). CONCLUSIONS: MR-proADM is a good biomarker in the early identification of high risk septic patients and may contribute to improve the predictive capacity of SOFA scale, especially when scores are low.

[Nomogram to predict a poor outcome in emergency patients with sepsis and at low risk of organ damage according to Sepsis-related Organ Failure Assessment (SOFA)]. / Nomograma para predecir mal pronóstico en pacientes procedentes de urgencias con sepsis y bajo riesgo de daño orgánico evaluado mediante SOFA.

OBJECTIVES: To develop a nomograph to predict a poor outcome (death during hospitalization or a hospital stay longer than 15 days) in emergency patients with sepsis and at low risk of organ damage according to Sepsis-related Organ Failure Assessment (SOFA). MATERIAL AND METHODS: Prospective, observational study carried out in a single universitary hospital. All patients admitted from the emergency department with sepsis and SOFA scores of 6 or lower were enrolled. We used bivariate logistic regression analysis to develop a predictive nomogram. RESULTS: A total of 174 patients were included. Seventeen patients (9.8%) died during hospitalization and the average hospital stay was greater than 15 days in 29 (16.7%) patient. The outcome was poor in a total of 42 patients (24.1%);. Independent variables that were significantly associated with a poor outcome were SOFA score (odds ratio [OR], 1.3; 95% CI, 1.06-1.71; P<.05), C-reactive protein (CRP) concentration (OR, 1.04; 95% CI, 1.0-1.09; P<.05), N-terminal fragment of brain natriuretic peptide (NT-proBNP) concentration over 1330 ng/mL (OR, 2.64; 95% CI, 1.17-6.22; P<.05), and septic shock (OR, 8.3; 95% CI, 1.16-166.5; P<.05). For a SOFA score of 2 or more the crude OR was 4.44 (95%, CI, 1.91-10.34) and the OR adjusted for other variables was 3.08 (95% CI, 1.24-7.69). CONCLUSION: A high percentage of patients predicted to be at low risk of organ failure had poor outcomes, associated with SOFA score, the presence of septic shock, CRP concentration, and elevated NT-proBNP concentration. The SOFA score by itself is an inadequate prognostic tool in patients at low risk of organ damage. Other clinical and analytical variables are required to complement the SOFA score.

OBJETIVO: Elaborar un nomograma que permita predecir el mal pronóstico (mortalidad durante el ingreso o estancia media > 15 días) en pacientes procedentes de urgencias con sepsis y baja probabilidad de daño orgánico evaluado por SOFA (Sepsis-related Organ Failure Assessment). METODO: Estudio observacional prospectivo realizado en un único hospital. Se incluyeron de forma consecutiva pacientes del servicio de urgencias con sepsis y SOFA igual o inferior a 6 puntos. Se realizó un análisis de regresión logística binaria y se elaboró un nomograma predictivo. RESULTADOS: Se incluyeron 174 pacientes. Diecisiete (9,8%) pacientes fallecieron durante la hospitalización y 29 (16,7%) tuvieron una estancia media prolongada. En total, 42 (24,1%) pacientes tuvieron mal pronóstico. Las variables independientes de mal pronóstico fueron: la puntuación SOFA (OR 1,3; IC 95% 1,06-1,71; p < 0,05), las concentraciones de proteína C reactiva (PCR) (OR 1,04; IC 95% 1-1,09; p < 0,05), NT-proBNP > 1.330 ng/ml (OR 2,64; IC 95% 1,17-6,22; p < 0,05) y la presencia de shock séptico (OR 8,3; IC 95% 1,16-166,5; p < 0,05). Si tenemos en cuenta el índice SOFA >= 2, la OR cruda fue 4,44 (IC 95% 1,91-10,34) y ajustada por el resto de variables fue de 3,08 (IC 95%, 1,24-7,69). CONCLUSIONES: Una elevada proporción de pacientes con baja probabilidad de tener daño orgánico tuvieron mal pronóstico en relación con la puntuación en la escala SOFA, la presencia de shock séptico, concentraciones de PCR y NTproBNP. La utilización de la escala pronóstica SOFA en pacientes con bajo riesgo es insuficiente para predecir el pronóstico en estos pacientes y se hace necesario complementarla con otras variables clínicas y analíticas.

The N-terminal pro brain natriuretic peptide is the best predictor of mortality during hospitalization in patients with low risk of sepsis-related organ failure. / El fragmento N-terminal del propéptido natriurético cerebral es el mejor predictor de mortalidad intrahospitalaria en pacientes con sepsis y bajo riesgo de lesión orgánica.

INTRODUCTION: The purpose of this study was to investigate the value of N-terminal pro brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and procalcitonin (PCT) in predicting mortality in septic patients during hospitalization with mortality risk<10% evaluated by Sepsis-related Organ Failure Assessment (SOFA). MATERIAL AND METHODS: Prospective, observational study performed in sepsis patients with SOFA risk<10%. We obtained levels of biomarkers in the first 72h after admission in hospital. All patients were monitored during hospitalization or until death. We used ROC curves to determine area under curve (AUC) and identify the best cutoff concentrations to predict mortality. RESULTS: A total of 174 patients were analyzed. Seventeen (9.8%) patients died during hospitalization. The AUC of NT-proBNP was 0.793 (95% CI 0.686-0.9; P<.0005) compared to AUC of CRP (0.728; 95% CI 0.617-0.839; P=.004) and AUC of PCT (0.684; 95% CI 0.557-0.811; P=.019). Factors independently associated with in-hospital mortality were NT-proBNP>1,330pg/ml (OR=23.23; 95% CI 2.92-182.25; P=.003) and to have predisposing factors (OR=3.05; 95% CI 1.3-9.3; P=.044) CONCLUSIONS: In patients with low mortality risk according to SOFA score, NT-proBNP obtained in the first 72h after admission prove to be a powerful predictor of mortality. Their implementations in clinical practice would improve the predictive ability of clinical severity scores.

Basolateral sorting and transcytosis define the Cu+-regulated translocation of ATP7B to the bile canaliculus.

The Cu(+) pump ATP7B plays an irreplaceable role in the elimination of excess Cu(+) by the hepatocyte into the bile. The trafficking and site of action of ATP7B are subjects of controversy. One current proposal is that an increase in intracellular Cu(+) results in the translocation of ATP7B to the lysosomes and excretion of excess Cu(+) through lysosomal-mediated exocytosis at the bile canaliculus. Here, we show that ATP7B is transported from the trans-Golgi network (TGN) to the bile canaliculus by basolateral sorting and endocytosis, and microtubule-mediated transcytosis through the subapical compartment. Trafficking ATP7B is not incorporated into lysosomes, and addition of Cu(+) does not cause relocalization of lysosomes and the appearance of lysosome markers in the bile canaliculus. Our data reveal the pathway of the Cu(+)-mediated transport of ATP7B from the TGN to the bile canaliculus and indicates that the bile canaliculus is the primary site of ATP7B action in the elimination of excess Cu(.)

The CD4/CD8 Ratio is Inversely Associated with Carotid Intima-Media Thickness Progression in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Treatment.

Inversion of the CD4/CD8 ratio (<1) has been identified as a surrogate marker of immunosenescence and an independent predictor of AIDS events in HIV-infected patients and mortality in the general population. We aimed to assess the association between the CD4/CD8 ratio and carotid intima-media thickness (cIMT) progression in treated HIV-infected patients as a marker of coronary heart disease. A longitudinal study was conducted during 3 years in 96 virally suppressed HIV-infected patients receiving antiretroviral treatment (ART). We analyzed the associations between the CD4/CD8 ratio, cardiovascular risk factors, and antiretroviral treatment (ART) and progression of subclinical atherosclerosis assessed using cIMT at baseline and after 3 years. Finally, 96 patients completed the study. Seventy six (79.1%) patients were male, aged 44 ± 10 years; 39 (40.6%) were on treatment with protease inhibitors; 49 (51.04%) with nonnucleoside reverse transcriptase inhibitors, 6 (6.25%) with integrase inhibitors, 3 (3.12%) with maraviroc, and 2 (2.08%) just with nucleoside reverse transcriptase inhibitors. The mean of ART exposition was 6.9 ± 5.9 years. Twenty six (27%) patients had family history of ischemic heart disease, 51 (53.12%) were smokers, 12 (12.5%) were hypertensive, 4 (4.16%) had type 2 diabetes, 23 (23.9%) had dyslipidemia, and 31 (32.3%) were infected with hepatitis C virus. Baseline cIMT was significantly associated with age (rho = 0.497; p < .001), basal glucemia (rho = 0.323; p = .001), triglycerides (rho = 0.232; p = .023), Framingham risk score (rho = 0.324; p = .001), CD4/CD8 ratio (rho = -0.176; p = .05), and dyslipidemia (0.72 ± 0.16 mm vs. 0.63 ± 0.11 mm; p = .029). In multivariable analysis where cardiovascular risk factor and ART were included, cIMT progression was inversely associated with CD4/CD8 ratio [odds ratio (OR) = 0.283; confidence interval (95% CI) 0.099-0.809; p = .019]. In conclusion, the inversion of CD4/CD8 ratio in treated HIV-infected patients is independently associated with cIMT progression, a marker of coronary heart disease. Therefore, it might be clinically useful as predictor of cardiovascular events.