Balancing the interests of patient data protection and medication safety monitoring in a public-private partnership.

Obtaining data without the intervention of a health care provider represents an opportunity to expand understanding of the safety of medications used in difficult-to-study situations, like the first trimester of pregnancy when women may not present for medical care. While it is widely agreed that personal data, and in particular medical data, needs to be protected from unauthorized use, data protection requirements for population-based studies vary substantially by country. For public-private partnerships, the complexities are enhanced. The objective of this viewpoint paper is to illustrate the challenges related to data protection based on our experiences when performing relatively straightforward direct-to-patient noninterventional research via the Internet or telephone in four European countries. Pregnant women were invited to participate via the Internet or using an automated telephone response system in Denmark, the Netherlands, Poland, and the United Kingdom. Information was sought on medications, other factors that may cause birth defects, and pregnancy outcome. Issues relating to legal controllership of data were most problematic; assuring compliance with data protection requirements took about two years. There were also inconsistencies in the willingness to accept nonwritten informed consent. Nonetheless, enrollment and data collection have been completed, and analysis is in progress. Using direct reporting from consumers to study the safety of medicinal products allows researchers to address a myriad of research questions relating to everyday clinical practice, including treatment heterogeneity in population subgroups not traditionally included in clinical trials, like pregnant women, children, and the elderly. Nonetheless, there are a variety of administrative barriers relating to data protection and informed consent, particularly within the structure of a public-private partnership

An International Study of the Ability and Cost-Effectiveness of Advertising Methods to Facilitate Study Participant Self-Enrolment Into a Pilot Pharmacovigilance Study During Early Pregnancy

Knowledge of the fetal effects of maternal medication use in pregnancy is often inadequate and current pregnancy pharmacovigilance (PV) surveillance methods have important limitations. Patient self-reporting may be able to mitigate some of these limitations, providing an adequately sized study sample can be recruited.To compare the ability and cost-effectiveness of several direct-to-participant advertising methods for the recruitment of pregnant participants into a study of self-reported gestational exposures and pregnancy outcomes.The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) pregnancy study is a non-interventional, prospective pilot study of self-reported medication use and obstetric outcomes provided by a cohort of pregnant women that was conducted in Denmark, the Netherlands, Poland, and the United Kingdom. Direct-to-participant advertisements were provided via websites, emails, leaflets, television, and social media platforms.Over a 70-week recruitment period direct-to-participant advertisements engaged 43,234 individuals with the study website or telephone system; 4.78% (2065/43,234) of which were successfully enrolled and provided study data. Of these 90.4% (1867/2065) were recruited via paid advertising methods, 23.0% (475/2065) of whom were in the first trimester of pregnancy. The overall costs per active recruited participant were lowest for email (€23.24) and website (€24.41) advertisements and highest for leaflet (€83.14) and television (€100.89). Website adverts were substantially superior in their ability to recruit participants during their first trimester of pregnancy (317/668, 47.5%) in comparison with other advertising methods (P<.001). However, we identified international variations in both the cost-effectiveness of the various advertisement methods used and in their ability to recruit participants in early pregnancy.Recruitment of a pregnant cohort using direct-to-participant advertisement methods is feasible, but the total costs incurred are not insubstantial. Future research is needed to identify advertising strategies capable of recruiting large numbers of demographically representative pregnant women, preferentially in early pregnancy

The decline and conservation of bumblebees

Declines in bumblebee species in the last 60 years are well documented in Europe, where they are primarily driven by habitat loss and declines in floral abundance and diversity resulting from agricultural intensification. Impacts of habitat degradation and fragmentation are likely to be compounded by the social nature of bumblebees and their largely monogamous breeding system which renders their effective population size low. Hence populations are susceptible to stochastic extinction events and inbreeding. In North America, catastrophic declines of some bumblebee species since the 1990s are probably attributable to the accidental introduction of a non-native parasite from Europe, a result of global trade in domesticated bumblebee colonies used for pollination of greenhouse crops. Given the importance of bumblebees as pollinators of crops and wildflowers, it is vital that steps be taken to prevent further declines. Suggested measures include tight regulation of commercial bumblebee use and targeted use of agri-environment schemes to enhance floristic diversity in agricultural landscapes

Unrelated Helpers in a Primitively Eusocial Wasp: Is Helping Tailored Towards Direct Fitness?

The paper wasp Polistes dominulus is unique among the social insects in that nearly one-third of co-foundresses are completely unrelated to the dominant individual whose offspring they help to rear and yet reproductive skew is high. These unrelated subordinates stand to gain direct fitness through nest inheritance, raising the question of whether their behaviour is adaptively tailored towards maximizing inheritance prospects. Unusually, in this species, a wealth of theory and empirical data allows us to predict how unrelated subordinates should behave. Based on these predictions, here we compare helping in subordinates that are unrelated or related to the dominant wasp across an extensive range of field-based behavioural contexts. We find no differences in foraging effort, defense behaviour, aggression or inheritance rank between unrelated helpers and their related counterparts. Our study provides no evidence, across a number of behavioural scenarios, that the behaviour of unrelated subordinates is adaptively modified to promote direct fitness interests

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism

Toll-like receptor 9 (TLR9) triggering is a promising novel strategy to combat cancer as it induces innate and adaptive immunity responses. B-cell lymphoma is unique in this context as tumor cells express TLR9 and may harbor latent Epstein-Barr virus (EBV), a gamma-herpesvirus with remarkable oncogenic potential when latent. Latent EBV may be promoted by TLR9 triggering via suppression of lytic EBV. Here, we elaborated an initial assessment of the impact of TLR9 triggering on EBV-positive and EBV-negative B-cell lymphoma using Burkitt's lymphoma (BL) cell lines as an in vitro model. We show that, independent of the presence of EBV, the TLR9 ligand oligodeoxynucleotide (ODN) CpG-2006 may or may not induce caspase-dependent cell death in BL cells. Moreover, ODN CpG-2006-induced cell death responses of BL cells were associated with TLR9 single-nucleotide polymorphisms (SNPs) rs5743836 or rs352140, which we detected in primary BL tumors and in peripheral blood from healthy individuals at similar frequencies. Thus, our findings suggest that the effect of TLR9 agonists on BL cells should be tested in vitro before installment of therapy and TLR9 SNPs in BL patients should be determined as potential biological markers for the therapeutic response to treatment targeting innate immunity

The C Allele of rs5743836 Polymorphism in the Human TLR9 Promoter Links IL-6 and TLR9 Up-Regulation and Confers Increased B-Cell Proliferation

In humans, allelic variants in Toll-like receptors (TLRs) associate with several pathologies. However, the underlying cellular and molecular mechanisms of this association remain largely unknown. Analysis of the human TLR9 promoter revealed that the C allele of the rs5743836 polymorphism generates several regulatory sites, including an IL-6-responding element. Here, we show that, in mononuclear cells carrying the TC genotype of rs5743836, IL-6 up-regulates TLR9 expression, leading to exacerbated cellular responses to CpG, including IL-6 production and B-cell proliferation. Our study uncovers a role for the rs5743836 polymorphism in B-cell biology with implications on TLR9-mediated diseases and on the therapeutic usage of TLR9 agonists/antagonists

“Medically unexplained” symptoms and symptom disorders in primary care: prognosis-based recognition and classification

Background: Many patients consult their GP because they experience bodily symptoms. In a substantial proportion of cases, the clinical picture does not meet the existing diagnostic criteria for diseases or disorders. This may be because symptoms are recent and evolving or because symptoms are persistent but, either by their character or the negative results of clinical investigation cannot be attributed to disease: so-called “medically unexplained symptoms” (MUS). MUS are inconsistently recognised, diagnosed and managed in primary care. The specialist classification systems for MUS pose several problems in a primary care setting. The systems generally require great certainty about presence or absence of physical disease, they tend to be mind-body dualistic, and they view symptoms from a narrow specialty determined perspective. We need a new classification of MUS in primary care; a classification that better supports clinical decision-making, creates clearer communication and provides scientific underpinning of research to ensure effective interventions. Discussion: We propose a classification of symptoms that places greater emphasis on prognostic factors. Prognosis-based classification aims to categorise the patient’s risk of ongoing symptoms, complications, increased healthcare use or disability because of the symptoms. Current evidence suggests several factors which may be used: symptom characteristics such as: number, multi-system pattern, frequency, severity. Other factors are: concurrent mental disorders, psychological features and demographic data. We discuss how these characteristics may be used to classify symptoms into three groups: self-limiting symptoms, recurrent and persistent symptoms, and symptom disorders. The middle group is especially relevant in primary care; as these patients generally have reduced quality of life but often go unrecognised and are at risk of iatrogenic harm. The presented characteristics do not contain immediately obvious cut-points, and the assessment of prognosis depends on a combination of several factors. Conclusion: Three criteria (multiple symptoms, multiple systems, multiple times) may support the classification into good, intermediate and poor prognosis when dealing with symptoms in primary care. The proposed new classification specifically targets the patient population in primary care and may provide a rational framework for decision-making in clinical practice and for epidemiologic and clinical research of symptoms