Serum cytokine responses over the entire clinical-immunological spectrum of human leishmania (l.) infantum chagasi infection

The clinical-immunological spectrum of human Leishmania (L.) infantum chagasi infection in Amazonian Brazil was recently reviewed based on clinical, DTH, and IFAT (IgG) evaluations that identified five profiles: three asymptomatic (asymptomatic infection, AIsubclinical resistant infection, SRIand indeterminate initial infection, III) and two symptomatic (symptomatic infection, SIAmerican visceral leishmaniasis, AVLand subclinical oligosymptomatic infection, SOI). TNF-alpha, IL-4, IL-6, and IL-10 serum cytokines were analyzed using multiplexed Cytometric Bead Array in 161 samples from endemic areas in the Brazilian Amazon: SI [AVL] (21 cases), III (49), SRI (19), SOI (12), AI (36), and a control group [CG] (24). The highest IL-6 serumlevels were observed in the SI profile (AVL)higher IL-10 serum levels were observed in SI than in SOI or CG and in AI and III than in SOIhigher TNF-alpha serum levels were seen in SI than in CG. Positive correlations were found between IL-6 and IL-10 serum levels in the SI and III profiles and between IL-6 and TNF-alpha and between IL-4 and TNF-alpha in the III profile. These results provide strong evidence for associating IL-6 and IL-10 with the immunopathogenesis of AVL and help clarify the role of these cytokines in the infection spectrum.Instituto Evandro Chagas (Secretaria de Vigilancia em Saude, Ministerio da Saude, Brazil)Nucleo de Medicina Tropical (Universidade Federal do Para, Brazil)Laboratorio de Investigacao Medica (LIM)-50 (Hospital de Clinicas (HC)-Faculdade de Medicina (FM)-Universidade de Sao Paulo (USP), Brazil)Sao Paulo Research Foundation (FAPESP) [2006/56319-1]Parasitology Department, Evandro Chagas Institute, Surveillance Secretary of Health, Ministry of Health, Ananindeua, PA, BrazilAlbert Einstein Israelite Hospital, São Paulo, SP, BrazilDivision of Immunology, Federal University of São Paulo, São Paulo, SP, BrazilPathology Department, Medical School of São Paulo University, São Paulo, SP, BrazilTropical Medicine Nucleus, Federal University of Pará, Belém, PA, BrazilDivision of Immunology, Federal University of São Paulo, São Paulo, SP, BrazilFAPESP: 2006/56319-1Web of Scienc

Serum Cytokine Responses over the Entire Clinical-Immunological Spectrum of Human Leishmania (L.) infantum chagasi

The clinical-immunological spectrum of human Leishmania (L.) infantum chagasi infection in Amazonian Brazil was recently reviewed based on clinical, DTH, and IFAT (IgG) evaluations that identified five profiles: three asymptomatic (asymptomatic infection, AI; subclinical resistant infection, SRI; and indeterminate initial infection, III) and two symptomatic (symptomatic infection, SI; American visceral leishmaniasis, AVL; and subclinical oligosymptomatic infection, SOI). TNF-α, IL-4, IL-6, and IL-10 serum cytokines were analyzed using multiplexed Cytometric Bead Array in 161 samples from endemic areas in the Brazilian Amazon: SI [AVL] (21 cases), III (49), SRI (19), SOI (12), AI (36), and a control group [CG] (24). The highest IL-6 serum levels were observed in the SI profile (AVL); higher IL-10 serum levels were observed in SI than in SOI or CG and in AI and III than in SOI; higher TNF-α serum levels were seen in SI than in CG. Positive correlations were found between IL-6 and IL-10 serum levels in the SI and III profiles and between IL-6 and TNF-α and between IL-4 and TNF-α in the III profile. These results provide strong evidence for associating IL-6 and IL-10 with the immunopathogenesis of AVL and help clarify the role of these cytokines in the infection spectrum

Proteins of Leishmania (Viannia) shawi confer protection associated with Th1 immune response and memory generation

<p>Abstract</p> <p>Background</p> <p><it>Leishmania (Viannia) shawi </it>parasite was first characterized in 1989. Recently the protective effects of soluble leishmanial antigen (SLA) from <it>L. (V.) shawi </it>promastigotes were demonstrated using BALB/c mice, the susceptibility model for this parasite. In order to identify protective fractions, SLA was fractionated by reverse phase HPLC and five antigenic fractions were obtained.</p> <p>Methods</p> <p>F1 fraction was purified from L. (V.) shawi parasite extract by reverse phase HPLC. BALB/c mice were immunized once a week for two consecutive weeks by subcutaneous routes in the rump, using 25 μg of F1. After 1 and 16 weeks of last immunization, groups were challenged in the footpad with L. (V.) shawi promastigotes. After 2 months, those same mice were sacrificed and parasite burden, cellular and humoral immune responses were evaluated.</p> <p>Results</p> <p>The F1 fraction induced a high degree of protection associated with an increase in IFN-γ, a decrease in IL-4, increased cell proliferation and activation of CD8⁺T lymphocytes. Long-term protection was acquired in F1-immunized mice, associated with increased CD4⁺central memory T lymphocytes and activation of both CD4⁺and CD8⁺T cells. In addition, F1-immunized groups showed an increase in IgG2a levels.</p> <p>Conclusions</p> <p>The inductor capability of antigens to generate memory lymphocytes that can proliferate and secrete beneficial cytokines upon infection could be an important factor in the development of vaccine candidates against American Tegumentary Leishmaniasis.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

How appealing is "Free"?

Many marketing strategies seem based on the notion that consumers respond more strongly to products that are being offered for free than a rational calculation would predict. Such a preference would be consistent with some existing research on ways that marketing takes advantage of irrational behavior, and research findings in mental accounting and budgeting might bear on the apparent irrational appeal of free. A series of experiments on people’s preferences produced mixed results. One experiment suggested that a cheaper, but inferior, movie, was preferred over a more expensive better one when that movie was free, but not when it was similarly discounted but not free. However, other experiments did not reveal any consumer preference for free items in a variety of hypothetical choices, from buy-one-get-one-free offers to free gifts with magazine subscriptions. Overall, the results do not support a view that free items have a markedly powerful effect on choices, at least relative to equivalent discounts

Understanding sick leave risk in a lifecourse framework. A register-based birth cohort study of Norwegians born 1967–1976

Background Sick leave rates in Norway and in the Western world in general are quite high, and despite the identification of a wide array of risk factors, much of the individual variation in sick leave remains unexplained. Health, education, occupation, individual abilities and traits, are all in part determined by conditions during the early lifecourse, and are also strong predictors of sick leave. However, few studies take a lifecourse approach to studying sick leave, instead often focusing only on more contemporary risk factors. One line of research has studied the importance of physical fitness on sick leave risk, though focusing primarily on adult fitness levels; poor fitness in adolescence could arguably have more far-reaching consequences, through its impact on educational and occupational attainment. A second line of research has focused on identifying pathways linking adult social position to sick leave, though these studies have rarely taken into account the individual and social conditions that precede adult conditions. Thus, it is difficult to say whether the observed findings are causal because early lifecourse factors could be confounding the association, and it also obscures the lifelong processes that lead to adult sick leave risk. Another line of work has focused on the role that social interaction may play in accounting for the patterns of clustering of sick leave risk, with some suggesting that this mechanism could account for observed sex differences in sick leave behavior. This research has mostly focused on the influence of neighborhoods and workplaces, but this norm-based mechanism could also be operating within families, with parents influencing offspring, and siblings influencing one another. Aim In this thesis, I sought to first identify pathways linking exposures to sick leave risk through occupational and educational trajectories while taking into account contributions of early lifecourse factors. In Paper I, we aimed to assess the impact of adolescent aerobic fitness on sick leave in adulthood, through the mediating variables education and work-related factors (industry and enterprise-mean sick leave level). We restricted the analysis to musculoskeletal diagnoses. In Paper II, the main exposure is adult social position, and the mediating variable is physical workload. Here we focused on taking into account early personality development and childhood and adolescent social conditions. Second, we sought to investigate possible familial social interaction, focusing in Paper III on intergenerational transmission of sick leave, and sex-specific differences, and on sibling transmission from an older to a younger sibling in Paper IV. To account for the reverse causality problems and correlated effects in Paper IV, we used a dynamic Cox survival model that allowed for the incorporation of frailty and lagged time-dependent exposures. Study population We used four different study samples of employed individuals for the four papers based on certain selection criteria. All participants were identified from a national birth cohort study comprising all individuals born alive in Norway from 1967 through 1976. In Paper I, the sample was restricted to 227,201 males with available aerobic fitness information data from the National Conscription Database. In Paper II, the sample was restricted to 3,328 individuals from the birth cohort who had also participated in the Nord-Trøndelag Health Study (HUNT3, 2006–2008). In Paper III, we restricted the sample to 78,887 individuals, born 1974–1976, whose parents had been employed when the participants were 18. In Paper IV, our sample was 19,634 participants with one older sibling, where both siblings had been employed for at least four months. Statistical methods Data on exposures, outcomes and covariates were obtained from national registries, including the event-history database FD-Trygd (with data from 1992 through 2009) and from HUNT3. Our data thus spanned several decades, with some containing information on daily eventhistories. The natural methodological choice for such a data structure is survival analysis, which was used for Papers I, II and VI. Due to the exposures of interest in the four papers having been being measured at different time-points, the respective follow-up periods also differed, ranging from 1 to 15 years. In Paper I, we used a traditional epidemiological approach to mediation analysis by fitting a Cox regression model with and without the mediators, while controlling for possible confounders (parental education, intelligence, BMI, and musculoskeletal fitness). In Paper II, we applied a counterfactual approach to mediation, based on an Aalen’s additive hazards model. The model controlled for possible confounders (childhood and adolescent social position and neuroticism). In this analysis, we sought to identify the proportion of sick leave cases that could be reduced among individuals in the lowest adult social positions, if one could intervene to improve their physical workload so that it was the same as the physical workload of those with the highest adult social position. In Paper III, we estimated the additive risk difference in those exposed to parental sick leave at age 18, compared to those not exposed, using binomial regression, in a model controlling for several early lifecourse confounders. To elucidate whether the association was likely attributable to social interaction, we considered the strength of the parental-offspring associations in different constellations of parent-offspring sex and diagnostic categories. In Paper IV, we fit a dynamic Cox regression model for recurrent events, to study whether sick leave hazard increased following exposure to an older sibling’s sick leave episode. The model included both sibling sick leave and past sick leave history as time-dependent covariates. The latter was included in order to try to incorporate propensity to sick leave into the model. The model also controlled for a wide array of early life course and other time-dependent confounders. Results Aerobic fitness at age 18 was moderately associated with sick leave hazard 5 to 15 years later. Poor and medium fitness increased the rate of non-injury sick leave, but decreased the rate of injury sick leave. While the association between aerobic fitness and sick leave appeared to be mediated through education and work-related factors, the indirect pathway had a negative sign for non-injury sick leave, but a positive sign for injury-sick leave. In Paper II we found that if we could perform an intervention that would change the physical workload of the lowest social group to that of the highest, we could reduce 24% of the extra sick leave episodes due to the social gradient for women, and 30% for men. To our knowledge, this study is the first to show that the link between social position and sick leave through physical workload was confounded by neuroticism and childhood and adolescent social position, especially for women. In Paper III, we found evidence of a parent-offspring association of sick leave. Parental sick leave in adolescence was associated with offspring sick leave 15 years later, though we found no evidence of a stronger additive association for women than for men. The sick leave risk was generally stronger for exposure to sick leave in same-sex parent, and sick leave in same-diagnostic category. In Paper IV, we found that exposure to sibling sick leave was followed by an increased sick leave rate. The hazard also increased with increasing levels of exposure in a dose-response manner. Controlling for a dynamic covariate of past sick leave history only reduced the estimates slightly. However, we found that the pattern was substantially weakened when we re-analyzed the data from time-of-first sick leave episode to time-to-recurrent episodes, suggesting that most of the association could be due to an unobserved propensity to sick leave. Conclusion In conclusion, a greater understanding of the ways in which educational and occupational pathways interact with individual factors across the lifecourse is required. Adolescent aerobic fitness level was a risk factor for sick leave, and while this link appeared to be mediated through educational and work-related factors, and possibly also moderated, future studies should clarify this relation using causal mediation approaches that suited for survival outcomes and that can incorporate interactions between the exposure and mediator. This thesis further suggests that interventions aimed at reducing physical workload could reduce the social gradient in health. Additionally, we found that the link between adult social position and sick leave, and the mediating path through work conditions, may in part be due to personality factors and early life social conditions. This has implications for policy, but also for which variables future studies ought to consider in their analysis, since leaving them out will tend to show an inflated effect of adult social position on sick leave. In addition, a greater understanding of possible social influence within families is warranted. While we found that adolescent exposure to parent sick leave was associated with sick leave in adulthood, and sibling exposure was followed by an increased sick leave hazard, we could not rule out confounding. Studies that are able to adequately control for shared genetic vulnerability in family studies of sick leave, or studies that use a causal inference approach that evades this issue (i.e., natural experiments), are needed. Findings from the sibling study suggest that social interaction studies that do not take into account frailty may be biased. Further, it is still unaddressed which mechanisms are accounting for this possible social interaction—norms, information, or health behavior—which would also be important for intervention efforts

The gender gap in sickness absence from work and the influence of parental absence on offspring absence 15 years later: register-based cohort of Norwegians born in 1974–1976

Background Women have shown consistently higher levels of sickness absence from work in comparison to men, but explanations for this gender gap have not been completely understood. Life-course studies suggest that health and health-related social benefits in adult age are influenced by early life experiences. We aimed to estimate intergenerational associations with a 15-year time gap between parents’ and offspring sickness absences, pursuing the hypothesis that this parental influence would have a stronger impact for women than for men. Methods All persons born alive between 1974 and 1976 in Norway were followed up in several national registries. Employed persons considered to be at risk of sickness absence and also with parents at risk of sickness absence (n = 78 878) were followed in the calendar year of their 33rd birthday with respect to spells lasting >16 days. The probability of one or more spells during this year constituted the one-year risk under study. Additive risk differences in association with an exposure (parental sickness absence 15 years earlier) were estimated in a binomial regression analysis. The estimates were adjusted for parental socioeconomic factors. Results The 1-year sickness absence risk was higher for women (30.4 %) than for men (12.3 %). The crude risk differences between those exposed and those unexposed to parental sickness absence were similar in percentage points (PP) for women (3.8; 95 % confidence interval (CI) 2.6 to 4.9) and men (3.8; 95 % CI 2.9 to 4.6). The risk differences were moderately attenuated after adjustment for parental education and father’s income to 3.4 PP (2.2 to 4.5) for women and 2.8 PP (2.0 to 3.7) for men. Male absence was more strongly associated with the father’s than with the mother’s sickness absence, while associations for women were stronger for the same diagnostic groups as their parents. Conclusions Parental sickness absence was moderately associated with sickness absence in the next generation. Bias from unmeasured confounders cannot be entirely dismissed. Contrary to our hypothesis, associations were not stronger for women than for men. If parental sickness absence has a long-term causal effect, preventive measures could have an impact over generations

Adult social position and sick leave: the mediating effect of physical workload

Objective This study aimed to quantify how much of the adult social gradient in sick leave can be attributed to the mediating role of physical workload while accounting for the role of childhood and adolescent social position and neuroticism. Methods Our sample consisted of 2099 women and 1229 men from a Norwegian birth cohort study (born 1967–1976) who participated in the Nord-Trøndelag Health Study (2006–2008) (HUNT3). Data on sick leave (defined as >16 calendar days; 2006–2009) and social position during childhood, adolescence, and adulthood were obtained from national registers. Study outcome was time-to-first sick leave spell. Physical workload and neuroticism were self-reported in HUNT3. Mediating effects through physical workload were estimated using a method based on the additive hazards survival model. Results A hypothetical change from highest to lowest group in adult social position was, for women, associated with 51.6 [95% confidence interval (95% CI) 24.7–78.5] additional spells per 100 000 person-days at risk, in a model adjusted for childhood and adolescent social position and neuroticism. The corresponding rate increase for men was 41.1 (95% CI 21.4–60.8). Of these additional spells, the proportion mediated through physical workload was 24% (95% CI 10–49) and 30% (95% CI 10–63) for women and men, respectively. Conclusions The effect of adult social position on sick leave was partly mediated through physical workload, even while accounting for earlier life course factors. Our findings provide support that interventions aimed at reducing physical workload among those with lower adult social position could reduce sick leave risk