Mapping ongoing European research activities examining the infectious aetiology of chronic conditions


Corresponding author: J. C. Semenza, European Centre for Disease Prevention and Control (ECDC), Office of the Chief Scientist, Tomtebodavagen 11A, 171 83 Stockholm, Sweden


Clin Microbiol Infect


Chronic conditions contribute to the majority of the mortality and morbidity burden in Europe. The extent to which infectious agents are responsible for the chronic disease burden remains elusive. The complex nature of the natural history of chronic conditions calls for an overview of ongoing research activities linking infectious agents with these conditions in order to guide research endeavours, direct research funding, steer prevention efforts, and point health policy towards promising interventions. A selection of websites hosted by institutions either financing or conducting research within the European Union was screened for ongoing research activities examining infectious aetiology of chronic conditions. The searches were conducted until September 2011, applying search strategies and inclusion criteria predefined in a study protocol. In total, 25 research activities met the inclusion criteria. Of those, ten activities were focused to investigate infectious aetiology of cancer, four focused on type 2 diabetes mellitus, and 11 focused on a wide spectrum of other chronic conditions. The identified research projects did not cover areas such as mental and behavioural disorders. Infectious agents analysed included enteroviruses, Epstein-Barr virus, human rhinoviruses, P. gingivalis, human papillomaviruses, cytomegalovirus, Helicobacter spp. and human parvovirus. Only three projects specifically addressed therapeutic interventions. Ultimately, linking infectious agents with chronic conditions may translate into prevention efforts with vaccinations or treatment strategies with antimicrobial agents, and could, thus, eventually reduce the heavy disease burden from chronic conditions. However, little translational research on therapeutic interventions was found in our search and should be fostered, particularly for more established infectious-chronic disease associations.


Chronic conditions are responsible for the greatest burden of ill health in Europe, accounting for 77% of the morbidity and 86% of the mortality [1]. The aetiological origin of some chronic conditions is not well understood [2,3]. Elucidating the natural history of disease can help avert the initial (or subsequent) infection, prevent the onset or progression of disease, evade disability and avoid premature death. Infectious agents have been suspected for long to be causally linked to chronic conditions. Indeed, scientific advances over the last 30 years have led to an increase in the number of recognized infectious agents associated with the aetiology of chronic conditions [4]. For example, peptic ulcer and gastric cancer have been associated with Helicobacter pylori infection, liver cirrhosis and cancer have been associated with hepatitis B virus or hepatitis C virus infection, cervical cancer with human papillomavirus infection, lyme arthritis and neuroborreliosis with Borrelia burgdorferi infection, and lymphoma with Epstein-Barr virus (EBV) infection [5–8].

Infectious agents can cause a chronic condition through a variety of pathways [3]; they can act directly or act in concert with a co-factor (or trigger) in a complex series of events, which ultimately progress to chronic disease [5,9]. There may be environmental, host and other microbial factors that contribute to the disease process. Pathogens might be cleared rapidly after having interacted with their target, such as in the case of Guillain-Barré syndrome, rheumatic heart disease or Reiter’s syndrome [3]. Co-infections may also play a role in the pathology. Often technical laboratory difficulties hamper the identification of new and rare causative agents for which no effective diagnostic assays exist [5]. Thus, causally linking infectious agents to chronic conditions has proven to be challenging. Establishing causal links between infectious agents and chronic conditions requires considerable research efforts and sustainable funding.

In order to help guide the future research enterprise in this field we conducted a review of ongoing research activities and networks addressing the infectious aetiology of chronic conditions. Such a scoping exercise can uncover the diversity of aetiological microbes and chronic conditions under investigation, the range of pathogenic mechanisms and the diagnostic methods under development. It can also identify research needs, obstacles and opportunities for the detection, prevention and treatment of chronic conditions caused by an infectious agent. The goal was to inform the policy debate on future directions with regards to funding and prioritization and to assure sustainability and interdisciplinary cooperation for translational research on treatment and prevention. The scope was limited to the European Union (EU) in order to complement expert assessments and literature reviews that had been done elsewhere [2,3]. As the EU is preparing a 7-year financial and activity framework (2014–2020), an insight into ongoing EU activities can contribute to the policy-making process. Moreover, a snap shot of participating organizations in the current research activities can contribute to the discussion on existing collaborative schemes between European and overseas research institutions. Tackling the infectious origin of chronic conditions is scientifically and technically challenging, but preventing and treating infections early can potentially reduce the human, economic and societal costs of chronic conditions.


In order to indentify ongoing research activities within the EU27, websites of WHO programmes and projects within EU member states, EU institutions, international and national research networks and financiers were screened (Table 1). International medical were also assessed profession associations (focusing on cancer, cardiovascular disease and diabetes), national institutions for disease control (focusing on EU5: France, Germany, Italy, Spain and the United Kingdom), national health ministries (in EU5), and medical universities and research institutions (EU top 10 within the top 50 ranking at the Times higher education ranking 2010 for Life Sciences). The searches were conducted in English, German and French in May 2011 and were updated in September 2011.

Table 1.   Data sources searched and number and type of research initiatives identified
Data sourcesNumber of websites searchedType of research initiatives identified
Individual projectCollaborative projectResearch group
  1. (EU5)a: France, Germany, Italy, Spain and the United Kingdom

WHO and WHO agencies3001
EU institutions8180
International research councils, networks and financiers9300
International medical professional associations4000
Local institutions for disease control (EU5)a5000
Health ministries (EU5)5000
National research councils, networks and financiers (EU5)9200
Medical universities (EU top 10 ranked)10109

The methodology applied for the searches is detailed in the study protocol, which lists inclusion and exclusion criteria for the search, the search strategy and keywords, and the actual websites examined (Appendix S1). In brief, each website was screened by one reviewer, any doubt regarding the inclusion or exclusion of a research activity was discussed with a second reviewer, and any discrepancies in the decision between the reviewers was reconciled by a third reviewer. The search strategies employed depended on whether the websites were hosted by institutions financing or conducting research (Appendix S2): the search strategy for websites of institutions financing research were examined for information regarding recipients of funds in the field of infectious aetiology of chronic conditions by navigating through pages and documents listing funded projects in areas of interest (e.g. chronic conditions and infectious diseases). If a funded research activity was identified, further information on the project was searched for on the receiving party’s website. If a search function was available, funding-related keywords were used in combination with disease-related, infection-related and association-related keywords (for a list of the keywords used, see Appendix S1). Similarly, websites of institutions conducting research were screened for information regarding ongoing research activities in the field of infectious aetiology of chronic conditions by navigating through the pages of research units conducting research in the areas of interest. Again, if a search function was available, disease-related, infection-related and association-related keywords were used (Appendix S1). For institutions that both finance and conduct research, both search strategies described above were applied.


Out of the 25 research activities identified, ten projects were classified as belonging to research groups or units, eight were collaborative research projects, and seven were described as individual research projects (Table 1). The details of the research activities are presented in Table 2, in the following order: international/European-funded collaborative projects, individual projects executed by a single institution or several institutions located with one country? A detailed description of the research activities by organization is available in Appendix S2.

Table 2.   Ongoing research activities related to the association between chronic disease and infectious aetiology
Name of research projectType of research projectDisease areaInfectious agentsGoal and focusSource
ICE and ICBResearch units at WHO agencyCancerMultiple, latest update: not available
PEVNET: Persistent virus infection as a cause of pathogenic inflammation in type 1 diabetes – an innovative research program of biobanks and expertiseCollaborative FP7 project (6 EU countries)Diabetes mellitus type 1EnterovirusGoal: to provide the information necessary for proving causality in the enterovirus-diabetes association. Focus: persistent enterovirus infection leading to inflammation and tissue damage in the pancreas and its role in mediating the inflammatory response that causes T1DM. Time line: January 2011 – December 2015., update: January 2011
MAARS: Microbes in Allergy and Autoimmunity Related to the SkinCollaborative FP7 project (6 EU countries + Israel)Atopic dermatitis and psoriasisThe microbiome on the skinGoal: to identify key microbes and molecular targets to develop novel intervention strategies in order to decrease and prevent the burden of allergy and autoimmunity. Focus: effect of the microbiome on the skin on autoimmunity and allergy
Time line: April 2011 – March 2015., latest update: March 2011
INTRICATE: Infectious triggers of chronic autoimmunityCollaborative FP7 project (5 EU countries + USA)Systemic vasculitisNot specifiedGoal: to understand autiommunity and to translate the results into clinical applications. Focus: investigating the role of infection in the aetiology of the autoimmune disease systemic vasculitis.
Time line: November 2010 – October 2014., latest update: not available
PreDicta: Post-infectious immune reprogramming and its association with persistence and chronicity of respiratory allergic diseasesCollaborative FP7 project (9 EU countries + Switzerland)Respiratory allergiesHuman rhinovirusesGoal: to evaluate the hypothesis that repeated infections reprogramme the immune system towards a persistent inflammatory pattern leading to respiratory allergies.
Focus: role of pathogens, altered host-pathogen interactions and other mechanisms involved in a reprogramming, development of relevant diagnostic and therapeutic strategies.
Time line: October 2010 – November 2015., latest update: not available
Gums & Joints: Protein citrullination as a link between periodontal diseases and rheumatoid arthritis and target for development of novel drugs to treat RACollaborative FP7 project (7 EU countries)Rheumatoid arthritis P. gingivalis Goal: to investigate possible causative link between RA and periodontal diseases is based on the ability of P. gingivalis to citrullinate proteins and thereby generate autoantigens that drive autoimmunity.
Focus: to study susceptibility factors and immune responses in RA and periodontal diseases.
Time line: November 2010 – October 2014., latest update: not available
ALLFUN: Fungi in the setting of inflammation, allergy and autoimmune diseases: translating basic science into clinical practicesCollaborative FP7 project (7 EU countries + Switzerland)Allergy and inflammatory diseaseAirborne or commensal fungiGoal: to identify novel biomarkers for immunological disorders.
Focus: to identify the cellular and molecular mechanisms by which ubiquitous airborne or commensal fungi contribute to immune homeostasis or its dysregulation, leading to allergy and inflammatory diseases.
Time line: December 2010 -November 2013., latest update: June 2011
FLORINASH: The role of intestinal microflora in non-alcoholic fatty liver diseaseCollaborative FP7 project (4 EU countries)Non-alcoholic fatty liverIntestinal microfloraGoal: to gain knowledge about the biological processes and mechanisms responsible for the development of non-alcoholic fatty liver disease.
Focus: identification of validated biomarkers, targets and molecules for therapeutic interventions, and additional knowledge about the role of intestinal microflora in the control of non-alcoholic fatty liver disease.
Time line: January 2010 – December 2014., latest update: not available
DIAPREPP: Diabetes type 1 prediction, early pathogenesis and preventionCollaborative FP7 project (7 EU countries)Diabetes mellitus type 1EnterovirusGoal: to determine mechanisms of autoimmunization against islet antigens.
Focus: investigation of the effects of infections on islet and immune cells.
Time line: April 2008 to August 2011., latest update: not available
Cancerbiome; Characterization of the cancer-associated microbiomeIndividual FP7 projectColorectal cancerIntestinal microfloraGoal: to study intestinal bacteria and explore their impact on colorectal cancer and various other diseases.
Time line: July 2011 – July 2016., latest update: June 2011
Do gut bacteria have a role in the aetiology of type 2 diabetes?Individual projectDiabetes mellitus type 2Gastrointestinal floraGoal: to reveal if gut bacteria have a role in the aetiology of T2DM.
Time line: the project received funding in 2011., latest update: not available
Dissecting the possibility of an infectious aetiology of type-1 diabetesIndividual projectDiabetes mellitus type 1EnterovirusGoal: to investigate the potential link between infectious agents and T1DM.
Time line: the project received funding in 2010., latest update: not available
The role of human papillomaviruses and their oncoproteins in non-melanoma skin cancerIndividual projectNon-melanoma skin cancerHuman papillomavirusesGoal: to assess the role of cutaneous HPV in non-melanoma skin cancer in both immunosuppressed organ transplant recipients and immunocompetent patients.
Time line: May 2007 – March 2011., latest update: not available
Epstein-Barr virus infection in multiple sclerosis and control subjects: an HLA association studyIndividual projectMultiple sclerosisEpstein-Barr virusGoal: to investigate the seroprevalence rates between concordant and discordant MS sibling pairs, to investigate whether or not EBV seronegativity in normal control subjects is associated with human leukocyte antigen (HLA) haplotypes that are protective for MS, to establish whether or not adults who are developing infectious mononucleosis are more likely to carry extended HLA haplotypes associated with MS genetic susceptibility compared with subjects with asymptomatic EBV seroconversion, and to establish whether or not people with MS are more likely to be carrying HLA haplotypes that have been shown to predispose to infectious mononucleosis.
Time line: September 2009 to August 2012., latest update: not available
CWL35Individual projectTeenage and young adult leukaemia, lymphoma and central nervous system tumoursNot specifiedGoal: to address the paucity of information on the causes of teenage and young adult leukaemia, lymphoma and central nervous system tumours by carrying out a programme of aetiological research focusing on infections.
Focus: cancer dataset available from the North West Cancer Intelligence Service, UK, including 7000 individuals aged 15 to 24 years diagnosed between 1996 and 2006 will be utilized for structural equation modelling and latent variable analyses to investigate the timing of infection using a validated surrogate measure.
Time line: January 2009 – December 2012., latest update: not available
CMV pathogenesis in inflammation and cancerResearch groupInflammation, cardiovascular disease, cancerCytomegalovirusGoal: to understand the biological role of CMV in inflammation and cancer and to develop new treatment strategies for patients suffering from inflammatory disease and cancer by targeting CMV.
Focus: role of CMV infection is explored in different patient groups: inflammation, cardiovascular disease, cancer, and organ transplant patients., latest update: not available
Characterization of the carcinogenic properties of bacterial genotoxinsResearch groupCancerCytolethal distending toxin producing bacteriaGoal: to study carcinogenic properties of bacterial genotoxins.
Focus: to understand CDT internalization pathway, an essential step for the toxin to exert its genotoxic activity, characterize a novel survival pathway induced by CDT intoxication, assess the carcinogenic potential of infection with CDT-producing bacteria in in vivo models., latest update: November 2009
Molecular mechanisms of viral oncogenesisResearch groupCancerEpstein-Barr virusGoal: investigate molecular mechanisms of viral oncogenesis.
Focus: mechanism by which EBV proteins expressed in malignant cells modify the cellular environment and regulate the interaction of the infected cells with the host immune system., latest update: November 2009
Aetiological epidemiology unitResearch groupCancerNot specifiedGoal: to investigate aetiology of certain malignancies and the long-term risks of cancer in individuals who have suffered from a particular disease or have received potentially carcinogenic treatments., latest update: August 2011
Oncogenic herpes virusesResearch groupCancer (focus on lymphomas)Epstein-Barr virusGoal: to investigate mechanisms leading to the development of virus-associated cancers.
Focus: contribution of EBV to the pathogenesis of various B-cell lymphomas., latest update: not available
The Maloy LaboratoryResearch groupIntestinal inflammation Helicobacter spp.Goal: to understand how immune responses are controlled in the intestine and how host-pathogen interactions contribute to intestinal pathology.
Focus: experimental models of intestinal inflammation induced by infection with the intestinal bacterium Helicobacter hepaticus., latest update: not available
The Powrie mucosal immunology groupResearch groupColon cancer, inflammatory bowel diseaseCommensal bacteriaGoal: to investigate factors that control the mutualistic relationship between commensal bacteria and the intestinal immune system and how a dysregulation may result in IBD.
Focus: T cell-dendritic cell interactions, cytokine networks in the intestine and how these influence the balance between effector and regulatory T-cell responses. The link between intestinal inflammation and colon cancer is explored as well as innate and adaptive immune responses in IBD patients., latest update: not available
Immune responses to parvovirus and their role in inflammatory arthritisIndividual projectInflammatory arthritisHuman parvovirusGoal: investigation of CD8 and CD4 epitopes to human parvovirus.
Focus: search for evidence of cross-reactivity and autoimmunity in adults with acute arthropathy following parvovirus infection., latest update: not available
Multiple sclerosisResearch groupMultiple sclerosisNot specified (viruses)Goal: to understand the molecular basis for the Major Histocompatibility Complex association in MS and how MHC genes interact with environmental factors, such as viruses., latest update: not available
The Kullberg laboratoryResearch groupInflammatory bowel disease Helicobacter hepaticus Goal: to define the mechanisms by which interactions between bacterial antigens, dendritic cells, and CD4 + T cells trigger colitis in disease-susceptible individuals and suppress development of disease in disease-resistant hosts.
Focus: pathogenic and disease-protective immune response to H. hepaticus, with special emphasis on CD4 + T-cell responses., latest update: not available

The European Commission [10] was a major funding source of research within this area, through the seventh Framework Programme for Research and Technological Development (FP7). Participation of countries from the EU was not evenly distributed in the research networks and consortiums; some countries (e.g. the UK, Sweden, Germany and France) were over-represented.

In the consortiums funded by international/European organizations, non-EU countries (e.g. Israel, Switzerland and the USA) participated as well.

The ongoing research activities identified in the current study were concentrated to a few disease areas: neoplasms (primarily cancer) and the endocrine system (primarily diabetes (Table 2). Out of the 25 research activities identified, ten focused on infectious aetiology of cancer, four on the infectious aetiology of type 2 diabetes mellitus (T2DM), and the remaining 11 focused on the infectious aetiology of a wide spectrum of chronic conditions. However, none of the identied research activities focused on infectious aetiology of blood conditions, endocrine conditions (other than diabetes) mental conditions, or congenital malformations.

The research for a large number of projects focused on mechanisms by which interactions between bacteria and viruses enhance susceptibility and trigger chronic disorders (e.g. investigating the mechanisms leading to the development of virus-associated cancers). Only three (13%) mentioned intervention or therapeutic strategies (MAARS, FLORINASH, cytomegalovirus (CMV) pathogenesis in inflammation and cancer).

Some research activities focused on multiple agents while others did not specify the infectious agent. Infectious agents affecting the digestive system were investigated in six research projects (enterovirus, three projects; intestinal/gastrointestinal (micro) flora, three projects) and the contribution of EBV to the aetiology of chronic conditions was researched in three projects. A number of projects investigated single infectious agents, for example, the microbiome on the skin, human rhinoviruses, P. gingivalis, airborne or commensal fungi, human papillomaviruses, cytomegalovirus, cytolethal distending toxin-producing bacteria, Helicobacter spp., commensal bacteria, and human parvovirus.

Thirty-two publications originating from the ongoing research activities were identified, of which 16 were published in 2011. Based on the information provided in the titles and abstracts, six of these publications were likely to be experimental in vitro or in vivo studies. The remaining ten publications were, for example, epidemiological studies or reviews assessing infectious aetiology of chronic conditions.


Elucidating the pathogenesis of chronic conditions with an infectious aetiology is essential to advance the field. Understanding the natural history of disease and the underlying molecular mechanisms is a foundation for the development of novel treatment regimens. However, some of the associations between infectious agents and chronic conditions are now well established. For example, epidemiological studies have been instrumental in confirming the association between Campylobacter infection and Guillain-Barre syndrome, H. pylori infection and peptic ulcers, EBV and malignant disease (e.g. Burkitt’s lymphoma and Hodgkin’s disease), human herpes virus-8 and Kaposi’s sarcoma, hepatitis B virus and hepatocellular carcinoma, and human papilloma virus (HPV) and cervical cancer [2]. It is desirable that discoveries in basic research are translated rapidly and efficiently into meaningful health outcomes, such as the antimicrobial treatment for H. pylori and Campylobacter or the HPV vaccine currently available. Thus, intervention studies examining prevention and/or treatment strategies for these pathogens through vaccination or antimicrobial treatment should be advanced [7,11]. For these specific pathogens, we identified the following research activities: H. pylori infection and the mechanism of intestinal inflammation and the mechanism of EBV-induced carcinogenesis. Translational research projects targeting these health outcomes with randomized trials or cost-benefit analyses for treatment and prevention were under-represented in our scoping exercise. Thus, even for those pathogens that have convincingly been associated with a chronic condition, the research activities we identified tended to focus on mechanistic and basic research questions rather than translating these insights into public health benefits.

A number of therapeutic interventions or prevention strategies have already been developed for a few infectious agents. They include H. pylori or HPV and neoplasms [12,13], T. cruzi and chronic conditions of the circulatory system [14], C. trachomatis and chronic conditions of the genitourinary system [15], and H. pylori or T. whipplei and chronic conditions of the digestive system [16]. Two of these infectious agents are being investigated by research consortia (Table 2).

From a public health perspective it would be desirable to translate basic research into epidemiological studies, but in this review only three research projects mention interventions. Large pan-European population cohorts and health-related registries can be an opportunity for collaborative research activities regarding risk factors and the aetiology of chronic conditions. However, these study populations should also be used for longitudinal studies to assess the cost-effectiveness of vaccination and antimicrobial treatment of infections that might result in chronic conditions later in life.

Some of the collaborative research projects, funded by the European Union research program (FP7), investigated the associations between infectious agents and chronic conditions. The projects employed a range of novel approaches (e.g. research design and intervention strategies) to obtain a better understanding of the associations and to translate research into practical clinical applications. The FP7 programme will continue to provide funding for research until 2013. However, in contrast to previous years, the call for 2012 did not contain proposals within the field of infectious aetiology of chronic conditions [17].

The new WHO strategy for the prevention and control of non-communicable diseases for 2012–2016 states that there is a strong relationship between several non-communicable diseases and infectious diseases [11]. However, none of the identified actions for the WHO and member states specifically aim to explore the aetiology of non-communicable diseases.

It is important to underscore that for certain categories of diseases the evidence of casual inference between infectious agents and chronic conditions is weak and we observed that current research does not cover this gap. Research projects on blood, endocrine and mental disorders, as well as congenital malformations, were not identified in our search.


Many of the reviewed websites for ongoing research initiatives were not regularly updated. Thus, recently initiated research activities may not have been captured. Health research is typically funded by a number of public bodies, charities and industry. Although we did not explicitly review the charity sector (see annex A for the ones included) or pharmaceutical research, they should, at least in part, be captured as part of the funding for universities in peer reviewed publications which were not in the focus of this study as we wanted to capture CURRENT research activities. Nevertheless, intervention research could inadvertently be under-represented in our sample. Completed research from previous funding cycles (EU commission FP 4, 5 and 6) should be captured in the publications that were identified or on the university websites. On a disaggregated member state level, the search was limited to the EU5 countries, as these represent the largest economies in Europe, and to the universities with the highest ranked life science research within the EU. Therefore, the aggregated data on participation of different countries in research collaborative projects may be biased and some countries may be over-represented. Despite these limitations, this review marks the current trends in the research activities within the field of infectious aetiology of chronic conditions in the EU.


This scoping exercise revealed that of the 25 research initiatives examined, eight were collaborative efforts with a number of scientific partners. It is precisely those multidisciplinary initiatives that on their websites mention translational research, therapeutic strategies and interventions (Table 2). A successful strategy to tackle the infectious origin of chronic conditions relies on an interdisciplinary approach that combines basic research with therapeutic strategies and integrates laboratory methods with epidemiological studies and surveillance. Such a strategy will advance pathogen discovery, laboratory detection methods, treatment and prevention. Synergistic networks between research groups, combining multidisciplinary research strategies, require longitudinal planning and programme management. For the EU, the added value of enhanced research collaboration is to tackle limitations imposed by scattered funding and fragmentation between national programmes and to contribute to sustainable and long-lasting funding. Overall, the ongoing research activities identified in this scoping exercise were impressive and will contribute to increasing the knowledge around infectious aetiology of chronic conditions. Nevertheless, there are disease areas where further research is needed in order to establish the role of infectious agents (e.g. endocrine, nutritional and metabolic conditions). Research on uncertain associations may lead to a better understanding of the mechanisms leading to disease progression. However, based on our assessment, it would be advisable to accelerate the development of therapeutic options, encompassing vaccines and other alternatives, specifically for the more well-established infectious-chronic disease associations. This is particularly important in the EU setting, with ageing populations and increasing disease burden and healthcare costs.

In light of diminishing resources for public health due to the economic downturn it is crucial to proceed strategically with the most promising approach [18–20]. The most fruitful tactic is based on crosscutting collaborations, integrating laboratory sciences with epidemiological studies, and disease surveillance (both chronic and infectious). Directing resources to treatment and prevention of well-established associations will increase the yield of investment in biomedical research and public health.


We would like to thank Grigorij Kogan from the European Commission, Directorate-General for Research and Innovation and Ana-Belen Escriva from ECDC for technical help with the search.

Transparency Declaration

This work was conducted by the European Centre for Disease Prevention and Control and by contractors hired to support data collection and analysis. ECDC is an international public health agency, with no financial interests in the outcome of the studies. No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JCS and ST conceived of the study and IS, EM, and SO carried out the search. All authors contributed to data analysis and writing of the manuscript.