Depression and all-cause mortality risk in HIV-infected and HIV-uninfected US veterans: a cohort study.

OBJECTIVES: The contribution of depression to mortality in adults with and without HIV infection is unclear. We hypothesized that depression increases mortality risk and that this association is stronger among those with HIV infection. METHODS: Veterans Aging Cohort Study (VACS) data were analysed from the first clinic visit on or after 1 April 2003 (baseline) to 30 September 2015. Depression definitions were: (1) major depressive disorder defined using International Classification of Diseases, Ninth Revision (ICD-9) codes; (2) depressive symptoms defined as Patient Health Questionnaire (PHQ)-9 scores ≥ 10. The outcome was all-cause mortality. Covariates were demographics, comorbid conditions and health behaviours. RESULTS: Among 129 140 eligible participants, 30% had HIV infection, 16% had a major depressive disorder diagnosis, and 24% died over a median follow-up time of 11 years. The death rate was 25.3 [95% confidence interval (CI) 25.0-25.6] deaths per 1000 person-years. Major depressive disorder was associated with mortality [hazard ratio (HR) 1.04; 95% CI 1.01, 1.07]. This association was modified by HIV status (interaction P-value = 0.02). In HIV-stratified analyses, depression was significantly associated with mortality among HIV-uninfected veterans but not among those with HIV infection. Among those with PHQ-9 data (n = 7372), 50% had HIV infection, 22% had PHQ-9 scores ≥ 10, and 28% died over a median follow-up time of 12 years. The death rate was 27.3 (95% CI 26.1-28.5) per 1000 person-years. Depressive symptoms were associated with mortality (HR 1.16; 95% CI 1.04, 1.28). This association was modified by HIV status (interaction P-value = 0.05). In HIV-stratified analyses, depressive symptoms were significantly associated with mortality among veterans with HIV infection but not among those without HIV infection. CONCLUSIONS: Depression was associated with all-cause mortality. This association was modified by HIV status and method of depression ascertainment.

Performance of the Pooled Cohort atherosclerotic cardiovascular disease risk score in hepatitis C virus-infected persons.

Chronic hepatitis C virus (HCV) infection has been associated with an increased risk for cardiovascular disease (CVD). The recommended Pooled Cohort atherosclerotic cardiovascular disease (ASCVD) risk equation for estimation of 10-year CVD risk has not been validated in HCV-infected populations. We examined the performance of the ASCVD risk score in HCV-infected persons, using the national Electronically Retrieved Cohort of HCV Infected Veterans to derive a cohort of HCV-infected and uninfected subjects without baseline ASCVD, hepatitis B, or HIV infection, and with low-density lipoprotein cholesterol level<190 mg/dL. Performance of the ASCVD risk equation was assessed by Cox proportional hazard regression, C-statistics and Hosmer-Lemeshow statistic. The cohort included 70 490 HCV-infected and 97 766 HCV-uninfected men with mean age of 55 years, 56% White and 29% Black. Incident CVD event rates were similar between the two groups (13.2 and 13.4 events/1000 person-years), with a higher incidence of coronary heart disease events in the HCV-uninfected group and of stroke events in the HCV-infected group. Adjusting for ASCVD risk score, HCV infection was associated with higher risk for an ASCVD event in the subgroup with baseline ASCVD risk ≥7.5% (HR: 1.19, P<.0001). C-statistics were poor in both the HCV-infected and uninfected groups (0.60 and 0.61, respectively). By Hosmer-Lemeshow test, the ASCVD risk equation overestimated risk amongst lower risk patients and underestimated risk amongst higher risk patients in both the HCV-infected and uninfected groups. Further investigation is needed to determine whether a modified equation to accurately predict ASCVD risk in HCV-infected persons is warranted.

Virologic response and haematologic toxicity of boceprevir- and telaprevir-containing regimens in actual clinical settings.

Effectiveness, safety and tolerability of boceprevir (BOC) and telaprevir (TPV) in actual clinical settings remain unknown. We determined rates of sustained virologic response (SVR) and haematologic adverse effects among persons treated with BOC- or TPV-containing regimens, compared with pegylated interferon/ribavirin (PEG/RBV). Using an established cohort of hepatitis C virus (HCV)-infected persons, Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), we identified those treated with a BOC- or TPV-containing regimen and HCV genotype 1-infected controls treated with PEG/RBV. We excluded those with HIV coinfection and missing HCV RNA values to determine SVR. Primary endpoints were SVR (undetectable HCV RNA ≥12 weeks after treatment completion) and haematologic toxicity (grade 3/4 anaemia, neutropenia and thrombocytopenia). We evaluated 2288 persons on BOC-, 409 on TPV-containing regimen and 6308 on PEG/RBV. Among these groups, respectively, 31%, 43% and 9% were treatment-experienced; 17%, 37% and 14% had baseline cirrhosis; 63%, 54% and 48% were genotype 1a. SVR rates among noncirrhotics were as follows: treatment naïve: 65% (BOC), 67% (TPV) and 31% (PEG/RBV); treatment experienced: 57% (BOC), 54% (TPV) and 13% (PEG/RBV); (P-value not significant for BOC vs TPV; P < 0.0001 for BOC or TPV vs PEG/RBV). Haematologic toxicities among BOC-, TPV- and PEG/RBV-treated groups were as follows: grade 3/4 anaemia 7%, 11% and 3%; grade 4 thrombocytopenia 2.2%, 5.4% and 1.7%; grade 4 neutropenia 8.2%, 5.6% and 3.4%. SVR rates are higher and closer to those reported in pivotal clinical trials among BOC- and TPV-treated persons compared with PEG/RBV-treated persons. Haematologic adverse events are frequent, but severe toxicity is uncommon.

Hepatitis C virus treatment and survival in patients with hepatitis C and human immunodeficiency virus co-infection and baseline anaemia.

The impact of pretreatment anaemia on survival in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is not known. Moreover, HCV treatment is offered less frequently to individuals with anaemia, due to haematological side effects of the treatment regimen. This study aimed to determine the effect of HCV treatment on survival among HCV/HIV co-infected individuals with pretreatment anaemia using the Electronically Retrieved Cohort of HCV-Infected Veterans (ERCHIVES). Individuals with HCV/HIV co-infection were included in current analyses. Participants were considered treated if they were prescribed ≥ 4 weeks of HCV treatment. All-cause mortality data were obtained using record linkage. Survival analyses were performed using Cox proportional hazard models. Among 5000 HCV/HIV co-infected individuals, 1671 (33.4%) had pretreatment anaemia. In a follow-up period of up to 7 years (19,500 person-years), individuals with anaemia had significantly higher mortality rate compared with those without anaemia [144.2 (95% CI: 134.5-154.7) vs 47.5 (44.0-51.2) per 1000 person-years, respectively]. Among individuals with anaemia, HCV treatment was associated with significantly lower mortality rate [66.6 (44.3-100.2) vs 149.6 (139.2-160.5) per 1000 person-years, for treated vs untreated, respectively]. Treatment remained associated with substantial survival benefit after taking into account the effect of multiple comorbidities (hazards ratio: 0.34, 95% CI: 0.21-0.62). These data suggest that HCV/HIV co-infected individuals with pretreatment anaemia have significantly higher mortality compared with those without anaemia. HCV treatment is associated with substantial survival benefit in this group. Additional studies are needed to determine strategies to improve HCV treatment rates among this group.

First report of sacbrood virus in honey bee (Apis mellifera) colonies in Brazil.

Sacbrood disease, an affliction of honey bees (Apis mellifera) characterized by brood that fails to pupate and subsequently dies, is an important threat to honey bee health. The disease is caused by the sacbrood virus (SBV), a positive-, single-stranded RNA virus in the order Picornavirales. Because of the economic importance of honey bees for both pollination and honey production, it is vital to understand and monitor the spread of viruses such as SBV. This virus has been found in many places across the globe, including recently in some South American countries, and it is likely that it will continue to spread. We performed a preliminary study to search for SBV in two apiaries of Africanized honey bees in the State of São Paulo, Brazil, using RT-PCR and Sanger sequencing and found the first evidence of SBV in honey bee colonies in Brazil. The virus was detected in larvae, foraging and nurse bees from two colonies, one of which had symptoms of sacbrood disease, at the beginning of the winter season in June 2011. No SBV was found in samples from nine other nearby colonies.

[Clinical usefulness of the reticulocyte hemoglobin equivalent in chronic hemodialysis patients]. / Utilidad clínica de la hemoglobina reticulocitaria equivalente en pacientes en hemodialisis crónica.

BACKGROUND: Iron deficiency is the main cause of failure to respond to erythropoietin (EPO) in haemodialysis patients. Several laboratory tests to detect the deficiency, ferritin and transferrin saturation (TSat) are the most commonly used but its limitations in this patient population are necessary to find other parameters to improve the identification of iron-deficient state. OBJECTIVE: To evaluate the ability of Reticulocyte Hemoglobin Equivalent (RET-He) to predict iron deficiency, taking as a reference standard to the increase of hemoglobin in response to iron intake. MATERIALS AND METHODS: 44 patients on chronic hemodialysis and fixed-dose EPO received 400 mg of intravenous iron. Were measured Hb, Ret-He, IRF, and ferritin prior to iron administration. After 20 to 30 days of completion of loading the patients were classified as responders if hemoglobin increased by at least 0.8 g / L and non-responders if this increase did not occur. RESULT: 25 patients were responders, the ROC curves analysis showed the Ret-He with the largest AUC of 0.862 similar to the AUC of 0.833 that showed the IST, but the first is more sensitive (72% CI 95%: 51-88% vs 52% 95% CI 31-72%) and similar specificity (94.7% CI 95%: 74-100% vs 100% 95% CI 82-100%). Ferritin AUC was 0.772 and finally the IRF AUC was 0.7. The Ret-He, to a cutoff of 29.5 pg was the best combination of sensitivity and specificity (72 and 94.7 respectively), and the sensitivity of the combination Ret-He/IST rose to 80% specificity 94.7%. CONCLUSIONS: According to these results it could consider to Ret-He and the Ret-He/IST combination of clinical utility for the identification of the iron deficit in patients in chronic haemodialysis.

Anti-pneumolysin activity of commercially available alpha 1-antitrypsin is due to cholesterol impurities.

Pneumolysin (PLY), the principal cytolytic toxin of Streptococcus pneumoniae, may be important in the pathogenesis of acute lung injury during pneumococcal pneumonia. However, the local host defenses that limit PLY injury to lung tissues have not been characterized. We investigated the ability of a commercial preparation of alpha 1-antitrypsin (alpha 1-AT), a major plasma anti-proteinase, to inhibit PLY. At normal plasma concentrations, the alpha 1-AT preparation prevented PLY injury to bovine pulmonary artery endothelial cells, rat alveolar epithelial cells, and human erythrocytes. The alpha 1-AT preparation selectively inhibited thiol-activated bacterial toxins; it was inactive against snake venom hemolysins, mastoparan, and oxygen-stable bacterial toxins. Biochemical characterization of the alpha 1-AT preparation and comparison with other available alpha 1-AT preparations revealed that this inhibitory activity was due to contamination with nanomolar concentrations of cholesterol. Characterization of non-immune human plasma anti-pneumolysin activity showed that beta-lipoprotein fractions contain the major inhibitory activity. We caution other investigators that the inhibition of bacterial virulence by these alpha 1-AT preparations may indicate toxin-mediated, rather than protease-mediated, mechanisms.

Polyamino acid enhancement of bacterial phagocytosis by human polymorphonuclear leukocytes and peritoneal macrophages.

Cationic polyamino acids are known to enhance a variety of cell-cell interactions by virtue of their ability to alter electrostatic forces of cell surfaces. In this study, the effect of polyamino acids on phagocytosis of 3H-labeled bacteria by human polymorphonuclear leukocytes (PMNs) and peritoneal macrophages was investigated. Negatively charged and neutral polyamino acids did not influence phagocytosis of unopsonized Staphylococcus epidermidis, whereas protamine, poly-L-arginine, and poly-L-lysine stimulated phagocytosis in a dose-dependent manner. At 50 micrograms/ml, greater than 30% uptake by PMNs was seen with each of these cationic polyamino acids. Although cationic polyamino acids promoted PMN and peritoneal macrophage phagocytosis of unopsonized S. epidermidis, Staphylococcus aureus M (encapsulated) and M variant (unencapsulated), and Escherichia coli J5, little effect was seen with the parent E. coli O111:B4 or a serotype O222:H16 strain. Pretreatment of bacteria and phagocytes separately demonstrated that the phagocytosis-promoting property of polyamino acids is manifest predominantly on the bacteria. Bacteria pretreated with cationic polyamino acids also elicited a PMN chemiluminescent response, and PMN-associated bacteria were killed, as determined by a fluorochrome microassay. Thus, cationic polyamino acids promote the phagocytosis and killing of many but not all bacterial strains, and in this respect polyamino acids function as opsonins.

Human peritoneal macrophage cytotoxicity mediated by cytophilic IgG.

Cells of the human mononuclear phagocyte system have recently been shown to possess cytophilic IgG molecules that promote phagocytosis of staphylococci bearing cell-wall protein A. In the present study, the possible mediation of a cytotoxic response to 51Cr-labeled sheep erythrocytes coated with protein A by cytophilic antibodies on human peritoneal macrophages was evaluated. The target cells were readily lysed by peritoneal macrophages. Cytotoxicity was blocked by pretreatment of macrophages with soluble protein or with anti-Fc F(ab')2 fragments. In contrast, cytotoxicity was not affected by cytochalasin B; this finding suggests that cytolysis is an extracellular event. Perturbation of cytophilic IgG with particle-bound protein A elicited a chemiluminescent response from peritoneal macrophages; however, experiments with scavengers of reactive oxygen species indicated that toxic oxygen radicals may not be required for cytotoxicity. The results indicate that cytophilic antibody-mediated cytotoxicity may contribute to cellular injury as well as host-defense aspects of the inflammatory process.

Peritoneal macrophages and opsonins: antibacterial defense in patients undergoing chronic peritoneal dialysis.

The antibacterial activity of phagocytic cells and opsonins in peritoneal dialysis effluents from 21 patients undergoing chronic peritoneal dialysis (CPD) was studied. Effluents contained an average of 12 x 10(6) cells per liter that were predominantly macrophages. Macrophages phagocytized and killed opsonized Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli as efficiently as did polymorphonuclear neutrophils (PMNs) from healthy donors. Macrophage chemiluminescence was one-third of that observed with donor PMNs. In the absence of opsonins, macrophages efficiently phagocytized and killed S. aureus by binding S. aureus cell wall protein A to macrophage surface IgG. Nine (43%) of 21 effluents failed to opsonize S. epidermidis, and none opsonized E. coli. When present, titers of S. epidermidis opsonins were 50- to 100-fold lower than that of normal serum. IgG and C3 concentrations in effluent reflected its opsonic capacity. Macrophages from patients undergoing CPD thus have intact phagocytic and bactericidal functions. However, the low level of opsonic molecules and inadequate numbers of macrophages in the peritoneal cavity may predispose patients undergoing CPD to peritonitis.

Influence of subinhibitory concentrations of penicillin, cephalothin, and clindamycin on Staphylococcus aureus growth in human phagocytic cells.

After an initial 2-h incubation with phagocytic cells, the growth of surviving intracellular Staphylococcus aureus was examined in the presence of subinhibitory concentrations of penicillin, cephalothin, and clindamycin. One-tenth of the minimal inhibitory concentrations of these antibiotics markedly reduced bacterial growth in normal polymorphonuclear leukocytes. In contrast, when human alveolar macrophages were studied, no inhibition of growth was seen. Subinhibitory concentrations of these antibiotics and polymorphonuclear leukocytes acted synergistically to reduce intracellular survival of S. aureus. This synergy did not appear to be dependent upon the microbicidal potential of the leukocyte respiratory burst, since no differences were found when polymorphonuclear leukocytes obtained from patients with chronic granulomatous disease were compared with those from normal donors.