The vaginal microbiota and its association with human papillomavirus,Chlamydia trachomatis,Neisseria gonorrhoeae and Mycoplasma genitalium infections: a systematic review and meta-analysis

Background

The vaginal microbiota may modulate susceptibility to human papillomavirus (HPV), Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium infections. Persistent infection with a carcinogenic HPV is a prerequisite for cervical cancer, and C. trachomatis, N. gonorrheae and M. genitalium genital infections are all associated with pelvic inflammatory disease and subsequent infertility issues.

Alternative methods to analyse the impact of HIV mutations on virological response to antiviral therapy

Background  

Principal component analysis (PCA) and partial least square (PLS) regression may be useful to summarize the HIV genotypic information. Without pre-selection each mutation presented in at least one patient is considered with a different weight. We compared these two strategies with the construction of a usual genotypic score.     

Estimation of dynamical model parameters taking into account undetectable marker values

Background  

Mathematical models are widely used for studying the dynamic of infectious agents such as hepatitis C virus (HCV). Most often, model parameters are estimated using standard least-square procedures for each individual. Hierarchical models have been proposed in such applications. However, another issue is the left-censoring (undetectable values) of plasma viral load due to the lack of sensitivity of assays used for quantification. A method is proposed to take into account left-censored values for estimating parameters of non linear mixed models and its impact is demonstrated through a simulation study and an actual clinical trial of anti-HCV drugs.     

Surveillance of γδ T Cells Predicts Cytomegalovirus Infection Resolution in Kidney Transplants

Cytomegalovirus (CMV) infection in solid-organ transplantation is associated with increased morbidity and mortality, particularly if a CMV mutant strain with antiviral resistance emerges. Monitoring CMV–specific T cell response could provide relevant information for patient care. We and others have shown the involvement of Vδ2^neg γδ T cells in controlling CMV infection. Here, we assessed if Vδ2^neg γδ T cell kinetics in peripheral blood predict CMV infection resolution and emergence of a mutant strain in high–risk recipients of kidney transplants, including 168 seronegative recipients receiving organs from seropositive donors (D+R−) and 104 seropositive recipients receiving antithymocyte globulins (R+/ATG). Vδ2^neg γδ T cell percentages were serially determined in patients grafted between 2003 and 2011. The growing phase of Vδ2^neg γδ T cells was monitored in each infected patient, and the expansion rate during this phase was estimated individually by a linear mixed model. A Vδ2^neg γδ T cell expansion rate of ˃0.06% per day predicted the growing phase. The time after infection at which an expansion rate of 0.06% per day occurred was correlated with the resolution of CMV DNAemia (r=0.91; P<0.001). At 49 days of antiviral treatment, Vδ2^neg γδ T cell expansion onset was associated with recovery, whereas absence of expansion was associated with recurrent disease and DNAemia. The appearance of antiviral–resistant mutant CMV strains was associated with delayed Vδ2^neg γδ T cell expansion (P<0.001). In conclusion, longitudinal surveillance of Vδ2^neg γδ T cells in recipients of kidney transplants may predict CMV infection resolution and antiviral drug resistance.     

Total fluid intake of children and adolescents: cross-sectional surveys in 13 countries worldwide

Purpose

To describe total fluid intake (TFI) according to socio-demographic characteristics in children and adolescents worldwide.

Methods

Data of 3611 children (4–9 years) and 8109 adolescents (10–18 years) were retrieved from 13 cross-sectional surveys (47 % males). In three countries, school classes were randomly recruited with stratified cluster sampling design. In the other countries, participants were randomly recruited based on a quota method. TFI (drinking water and beverages of all kinds) was obtained with a fluid-specific record over 7 consecutive days. Adequacy was assessed by comparing TFI to 80 % of adequate intake (AI) for total water intake set by European Food Safety Authority. Data on height, weight and socio-economic level were collected in most countries.

Results

The mean (SD) TFI ranged from [1.32 (0.68)] to [1.35 (0.71)] L/day. Non-adherence to AIs for fluids ranged from 10 % (Uruguay) to >90 % (Belgium). Females were more likely to meet the AIs for fluids than males (4–9 years: 28 %, OR 0.72, p = 0.002; 10–18 years: 20 %, OR 0.80, p = 0.001), while adolescents were less likely to meet the AI than children (OR 1.645, p < 0.001 in males and OR 1.625, p < 0.001 in females).

Conclusions

A high proportion of children and adolescents are at risk of an inadequate fluid intake. This risk is especially high in males and adolescents when compared with females or children categories. This highlights water intake among young populations as an issue of global concern.

     

Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Société Française de Greffe de Moelle (SFGM)

To assess the place of allogeneic hematopoietic stem cell transplantation (HSCT) in the advanced stage of acute myeloid leukemia (AML), we retrospectively analyzed 379 consecutive patients who underwent allogeneic HSCT for advanced AML. The median follow-up of the entire cohort was 7.5 years. Sixty-nine patients (18%) were transplanted with primary resistant disease. Three hundred and ten (82%) were relapsed patients, 94 (30%) of whom were in untreated relapse, 67 (22%) in refractory relapse and 149 (48%) in 2nd or 3rd complete remission at time of transplantation. The 5-year probabilities of overall survival (OS), disease-free survival (DFS), and transplant-related mortality (TRM) were 22 +/- 4%, 20 +/- 4%, 45 +/- 6%, respectively. In multivariate analysis, we demonstrated the favorable impact on OS, DFS and TRM of two factors over which we have no control (age <15 years, complete remission achievement) and three factors over which we have some control (female donor, acute and chronic graft-versus-host disease). The results of this study suggest that the graft-versus-leukemia effect is important in advanced AML and that new HSCT modalities are needed for some patients with this indication.     

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.The variability in the biology of human populations poses significant challenges in understanding different disease outcomes and developing successful therapeutics. The sources of this variation are likely the consequence of genetics, epigenetics, and the history of antigenic exposure (1, 2). As therapies targeting immune function are developed to improve clinical outcomes in cancer, viral and bacterial infections, autoimmune diseases, and transplantation, identifying the sources of immunological variation and finding biomarkers for immune health and dysfunction are crucial for their success (3).An important source of immunological variation is known to be the sex of the individual. Males experience a greater severity and prevalence of bacterial, viral, fungal, and parasitic infections than females, who also exhibit a more robust response to antigenic challenges such as infection and vaccination (4, 5). This stronger immune response in females could also explain why they more frequently develop immune-mediated pathologies during influenza infection, such as an overproduction of cytokines (cytokine storm) that contribute to an increase in capillary permeability and lung failure (6). Furthermore, females are at a higher risk for developing autoimmune diseases. In this later context, it is interesting to note that a recent study showed that females had, on average, 1.7 times the frequency of self-specific T cells as males (7). Despite the fact that initial observations relating the sex of the individual with the immune response were made many years ago (8), little is known about the mechanisms underlying these differences.Some sex-specific variations in the immune response can be directly attributed to sex hormones (9). In humans, sex steroids can bind to intracellular receptors located in immune cells such as monocytes, B cells, and T cells and activate hormone-responsive genes, suggesting that they can directly affect sex-related differences in both innate and adaptive immune responses (10). Whereas estrogens are associated with inflammation and can stimulate proliferation and differentiation of lymphocytes and monocytes, androgens suppress the activity of immune cells by increasing the synthesis of anti-inflammatory cytokines (11, 12).To date, no clear associations have been found between biological and clinical differences in the immune response between males and females in humans. In one study, results from public gene expression data (13) showed that many of the genes induced by a yellow fever vaccine were preferentially activated in females (14). However, whether these differences correlate with poor antibody outcomes remains to be determined.In this study, we sought to determine whether we could identify biomarkers from peripheral blood that could explain the sex-related differences in the serological response to the trivalent inactivated seasonal influenza vaccine (TIV) in both young and older cohorts.Young and older females had higher neutralizing antibodies than age-matched males, consistent with previous reports (15). Females also showed higher expression of inflammatory markers. However, none of these specific sex-related differences correlated with the observed disparities in the antibody response to TIV. Nevertheless, using a machine learning approach, we identified a set of genes previously shown to be regulated by testosterone and participating in lipid biosynthesis, whose expression was negatively associated with antibody responses to TIV in the male subjects in our study. Moreover, males with high levels of serum testosterone and expressing related gene signatures in blood cells showed the lowest neutralizing responses to TIV. These results suggest that testosterone might be immunosuppressive in vivo in humans, and indicate that its effect on an influenza vaccine and other immune responses could be due to the regulation of genes implicated in the metabolism of lipids.     

Fairness in cost‐benefit analysis: A methodology for health technology assessment

We evaluate the introduction of various forms of antihypertensive treatments in France with a distribution‐sensitive cost‐benefit analysis. Compared to traditional cost‐benefit analysis, we implement distributional weighting based on equivalent incomes, a new concept of individual well‐being that does respect individual preferences but is not subjectively welfarist. Individual preferences are estimated on the basis of a contingent valuation question, introduced into a representative survey of the French population. Compared to traditional cost‐effectiveness analysis in health technology assessment, we show that it is feasible to go beyond a narrow evaluation of health outcomes while still fully exploiting the sophistication of medical information. Sensitivity analysis illustrates the relevancy of this richer welfare framework, the importance of the distinction between an ex ante and an ex post approach, and the need to consider distributional effects in a broader institutional setting.     

Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400 x 10(6) cells/l

OBJECTIVE: To analyse immunological markers associated with CD4+ lymphocyte T-cell count (CD4+) evolution during 12-month follow-up after treatment discontinuation. METHOD: Prospective observational study of chronically HIV-1 infected patients with CD4+ above 400 x 10(6) cells/l. RESULTS: CD4+ changes took place in two phases: an initial rapid decrease in the first month (-142 x 10(6) cells/l on average), followed by a slow decline (-17 x 10(6) cells/l on average) The second slope of CD4+ decline was not correlated with the first and only baseline plasma HIV RNA was associated with it. The decline in CD4+ during the first month was steeper in patients with higher CD4+ and weaker plasma HIV RNA baseline levels. Moreover, the decline was less pronounced (P < 10(-4)) in patients with CD4+ nadir above 350 x 10(6) cells/l (-65 x 10(6) cells/l per month) in comparison with those below 350 x 10(6) cells/l (-200 x 10(6) cells/l per month). A high number of dendritic cells (DCs) whatever the type was associated with high CD4+ at the time of treatment interruption and its steeper decline over the first month. Moreover, the myeloid DC level was stable whereas the lymphoid DC count, which tended to decrease in association with decrease in CD4+, was negatively correlated with the HIV RNA load slope. CONCLUSIONS: The results support the use of the CD4+ nadir to predict the CD4+ dynamic after treatment interruption and consideration of the CD4+ count after 1-month of interruption merely reflects the 12-month level of CD4+. Although DCs seem to be associated with the CD4+ dynamic, the benefit of monitoring them has still to be defined.     

Treatment of dyslipidaemia in HIV-infected persons

Accumulating evidence suggests that HIV-infected individuals have an increased risk of cardiovascular events. This risk seems to be at least partially mediated by dyslipidaemia, which is related to the use of highly active antiretroviral therapy (HAART). As HIV-infected individuals live longer due to HAART, their cardiovascular risk will invariably increase. Because HAART is likely to be used indefinitely, HAART-related dyslipidaemia has emerged as a major cardiovascular concern. This article summarises the evaluation of dyslipidaemia and cardiovascular risk in HIV-infected individuals, the potential pathophysiological and genetic mechanisms involved in HAART-related dyslipidaemia and the current treatment approaches. In general, dyslipidaemia is evaluated and treated as in HIV-negative persons. The first step is cardiovascular risk assessment and the determination of target lipid levels. A healthier lifestyle and, in particular, smoking cessation should be promoted. Lowering levels of low-density lipoprotein cholesterol (or, in the setting of significant hypertriglyceridaemia, non-high-density lipoprotein cholesterol) is the primary target of intervention. Switching HAART to a more lipid-favourable regimen should be considered if this does not jeopardise virological control. Many patients will need lipid-lowering drug therapy. Appropriate low-density lipoprotein cholesterol target levels may be more difficult to reach than in the HIV-negative population, and the potential for drug interactions when using lipid-lowering agents together with HAART needs to be considered. The identification of HAART strategies with no or minimal metabolic toxicity, and the identification of the safest and most efficacious lipid-lowering therapies for HIV-infected individuals with dyslipidaemia are important research goals.