Evaluation of community-wide interventions: The ecologic case-referent study design

In a setting of long-standing, community-wide and generally accepted prevention activities like youth health care services in The Netherlands, evaluative research in the form of experimental studies is hardly possible. Furthermore, as most interventions will bear fruit only after several years and the effects are often described in rather vague terms, even nonexperimental study designs are fraught with possible difficulties. Although a study design using aggregate data is generally considered inferior or 'incomplete', in many cases, especially in health services research, this approach can be the only one feasible to evaluate the effectiveness of preventive programmes and interventions. In this article we present the ecologic case-referent design as a potentially expedient and valid method for estimating the ecologic effect of a population-wide intervention on the outcome rate in those populations. In this case-referent design, many variables are measured at the individual level, whereas the main exposure variable is measured at an aggregate or ecologic level. Using recently published studies as an example, the advantages and drawbacks of the design are discussed using the randomised controlled trial design as the referent study design

Prediction of response to biological treatment with monoclonal antibodies in severe asthma

In recent years, major developments have occurred in severe asthma management. Different asthma phenotypes and subgroups have been identified and new treatment options have become available. A total of five monoclonal antibodies are currently approved in severe asthma treatment: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. These drugs have been shown to reduce exacerbations and to have an oral corticosteroid-sparing effect in many severe asthma patients. However, biological treatment is not successful in all patients and should be discontinued in non-responsive patients. Treating the right patient with the right biologic, and therefore biologic response prediction, has become a major point of interest in severe asthma management. A variety of response outcomes is utilized in the different clinical trials, as well as a huge range of potential predicting factors. Also, regarding the timing of the response evaluation, there are considerable differences between studies. This review summarizes the results from studies on predicting responses and responders to biological treatment in severe asthma, taking into account clinical, functional and inflammatory parameters assessed prior to the start of treatment as well as following a few months of therapy. In addition, future perspectives are discussed, highlighting the need for more research to improve patient identification and treatment responses in the field of biological treatment in severe asthma

Cumulative Corticosteroid Sparing Effect of Anti-Interleukin-5/5Ra In Eosinophilic Asthma

BACKGROUND: Anti-interleukin (IL)-5/IL-5 receptor α (IL-5Ra) therapy has been shown to reduce maintenance oral corticosteroid (OCS) dose in severe eosinophilic asthma. However, the effect on cumulative OCS exposure is currently unknown. Neither is it known how prior OCS exposure affects response to anti-IL-5/5Ra treatment. We aimed primarily to compare the cumulative OCS exposure over a 2-year period before and after anti-IL-5/5Ra initiation, and secondarily to investigate whether duration and cumulative OCS exposure prior to anti-IL-5/5Ra influence the ability to discontinue OCS within 2 years of anti-IL-5/5Ra therapy. METHODS: This real-world nationwide observational registry-based study evaluated all dispensed OCS from 389 adults with severe eosinophilic asthma included in the Dutch Severe Asthma Registry (RAPSODI) 2 years before and 2 years after initiating anti-IL-5/5Ra. The Wilcoxon signed-rank test and multivariable regression analyses were used. RESULTS: Median (interquartile range) cumulative OCS exposure in the 2 years before and after anti-IL-5/5Ra initiation decreased from 2.715 (1.150–5.539) to 1.050 (0.300–3.640) g (p<0.001). 52% of patients were able to discontinue OCS within 2 years after anti-IL-5/5Ra therapy, which was independently predicted by lower and shorter prior OCS exposure. CONCLUSIONS: This real-world study showed that anti-IL-5/5Ra therapy leads to a significant reduction in cumulative OCS exposure over a 2-year period. Patients with lower and shorter OCS exposure were more likely to completely eliminate OCS. Since cumulative exposure increased progressively prior to anti-IL-5/5Ra initiation, our data suggest that early intervention leads to a better long-term prognosis in patients with severe eosinophilic asthma

Pesticide exposure: the hormonal function of the female reproductive system disrupted?

Some pesticides may interfere with the female hormonal function, which may lead to negative effects on the reproductive system through disruption of the hormonal balance necessary for proper functioning. Previous studies primarily focused on interference with the estrogen and/or androgen receptor, but the hormonal function may be disrupted in many more ways through pesticide exposure. The aim of this review is to give an overview of the various ways in which pesticides may disrupt the hormonal function of the female reproductive system and in particular the ovarian cycle. Disruption can occur in all stages of hormonal regulation: 1. hormone synthesis; 2. hormone release and storage; 3. hormone transport and clearance; 4. hormone receptor recognition and binding; 5. hormone postreceptor activation; 6. the thyroid function; and 7. the central nervous system. These mechanisms are described for effects of pesticide exposure in vitro and on experimental animals in vivo. For the latter, potential effects of endocrine disrupting pesticides on the female reproductive system, i.e. modulation of hormone concentrations, ovarian cycle irregularities, and impaired fertility, are also reviewed. In epidemiological studies, exposure to pesticides has been associated with menstrual cycle disturbances, reduced fertility, prolonged time-to-pregnancy, spontaneous abortion, stillbirths, and developmental defects, which may or may not be due to disruption of the female hormonal function. Because pesticides comprise a large number of distinct substances with dissimilar structures and diverse toxicity, it is most likely that several of the above-mentioned mechanisms are involved in the pathophysiological pathways explaining the role of pesticide exposure in ovarian cycle disturbances, ultimately leading to fertility problems and other reproductive effects. In future research, information on the ways in which pesticides may disrupt the hormonal function as described in this review, can be used to generate specific hypotheses for studies on the effects of pesticides on the ovarian cycle, both in toxicological and epidemiological settings

The secular trends in male:female ratio at birth in postwar industrialized countries.

Finnish investigators [Vartiainen et al. Environmental Chemicals and Changes in Sex Ratio: Analysis Over 250 Years in Finland. Environ Health Perspect 107:813-815 (1999)] presented the sex ratio of all newborn babies from 1751 to 1997 in order to evaluate whether Finnish long-term data are compatible with the hypothesis that the decrease in the ratio of male to female births after World War I and World War II in industrial countries is caused by environmental factors. They found an increase in the proportion of males from 1751 to 1920, which was interrupted by peaks in male births during World War I and World War II and followed by a decrease thereafter, similar to the trends in many other countries. The turning point of male proportion, however, preceded the period of industrialization and introduction of pesticides and hormonal drugs. Thus, a causal association between these environmental exposures and this decrease is unlikely. In addition, none of the various family parameters (e.g., paternal age, maternal age, age difference in parents, birth order) could explain the historical time trends. Vartiainen et al. concluded that at present it is unknown how these historical trends could be mediated. The postwar secular decline of the male:female ratio at birth is not an isolated phenomenon and parallels the decline of perinatal morbidity and mortality, congenital anomalies, and various constitutional diseases. This parallelism indicates a common etiology and may be caused by reduction of conceptopathology, as a correlate to increasing socioeconomic development. An inverted dose response or the dose-response fallacy due to vanishing male conceptuses explains the low sex ratios before World War I and World War II in newborns from black parents and from the lowest socioeconomic classes