To explore the evidence translation process during a 1-week national guideline development workshop  in Kenya.Nonparticipant observational study of the discussions of a multidisciplinary guideline development panel in Kenya. Discussions were aided by GRADE  grid.Three key thematic categories emerged: 1) “referral to other evidence to support or refute the proposed recommendations;” 2) “assessment of the presented research evidence;” and 3) “assessment of the local applicability of evidence.” The types of evidence cited included research evidence and anecdotal evidence based on clinician experiences. Assessment of the research evidence revealed important challenges in the translation of evidence into recommendations, including absence of evidence, low quality or inconclusive evidence, inadequate reporting of key features of the management under consideration, and differences in panelists’ interpretation of the research literature. A broad range of factors with potential to affect local applicability of evidence were discussed.The process of the “Child Health Evidence Week” combined with the GRADE grid may aid transparency in the deliberative process of guideline development, and provide a mechanism for comprehensive assessment, documentation, and reporting of multiple factors that influence the quality and applicability of guideline recommendations. In response to criticism that their process of guideline development has not always been made explicit Integrating global research evidence with locally relevant evidence and contextual factors has, however, rarely been undertaken in an explicit or structured fashion 1.1•Which aspects of the quality and nature of research evidence were key in shaping discussions?•Which aspects of local contextual factors influenced the acceptance or rejection of evidence and the final recommendations?We took advantage of efforts in Kenya to revise national guidelines for newborn and pediatric hospital care to examine the process of creating recommendations guided by the GRADE approach. The aim of the study was to document and characterize the discussions that took place among a multidisciplinary group of health care professionals who attended a week long meeting to review evidence and make guideline recommendations. Specifically, we explored the following two topics.22.1This was a descriptive study of the development of national guidelines for the management of common newborn and childhood illnesses in Kenya. Discussions between stakeholders attending a 5-day national guideline development workshop  held between 21st and 25th, June 2010, were observed, recorded, analyzed, and interpreted.2.2The organizers of the guideline development workshop (that included N.O. and M.E.) used a purposive sampling approach to select the guideline development panel after consultations with relevant stakeholders involved in the provision of newborn and pediatric care services in Kenya. Briefly, the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Program, working with the Ministry of Medical Services (MoMSs) identified leading individuals or key institutions of relevance to inpatient newborn and pediatric care . The MoMSs then sent letters requesting these individuals or those nominated by their departmental heads to join the guideline development panel. The invitation letters described the expected roles of the participants  and the research component of the workshop. Aiming at wide representation, the guidelines development panel finally consisted of 70 individuals .2.3The “Child Health Evidence Week” was a 1-week meeting of neonatal and pediatric stakeholders gathered to develop evidence-based guidelines for the hospital management of common newborn and childhood illnesses in Kenya www.jclinepi.com). Evidence summaries and draft recommendations were prepared for each of the clinical topics by a core team of 14 researchers and clinicians working in groups of 2 or 3. Evidence was summarized and packaged in three formats: systematic reviews, systematic reviews with summary-of-findings tables, and “graded-entry” formats   format and GRADE method to summarize the quality of the evidence and introduce possible additional considerations that might impact on the strength of recommendations. Each presentation was followed by a facilitated discussion. This initially focused on the formal evidence presented and subsequently, after presenting a draft recommendation, the wider issue of locally appropriate recommendations. Draft recommendations were then amended where necessary, and participants invited to vote for or against proposed recommendations. The voting process was aided by a modified GRADE grid 2.4Three investigators  independently observed and recorded comments made during the full workshop, focusing on discussions about research evidence, practitioner experiences and values, and context-specific issues that might influence acceptability and implementation of proposed recommendations.2.5Three investigators  independently reviewed their field notes of panel discussions, and grouped comments into a number of clusters. Groupings were guided by previously identified criteria for assessing the applicability of systematic review evidence 2.6Ethical approval for the conduct of this study was granted by the KEMRI scientific committee and National Ethics Review Committee in Kenya (SSC Protocol No 1770). The project was also presented to the Norwegian Regional Committee for Medical and Health Research Ethics, which did not find ethical clearance necessary for this type of study.3Overall, our observations of the deliberative process showed broad participation with most of the participants actively contributing in the debates. Outcomes of the deliberative process are illustrated with the pneumonia recommendation, where the panel voted against the proposal to replace benzyl penicillin/ampicillin with oral amoxicillin for the treatment of severe pneumonia despite moderate quality evidence suggesting equivalence between the treatments and additional factors favoring amoxicillin . This u1.“Referral to other evidence to support or refute a proposed recommendation.”2.“Assessment of the presented research evidence.” This category captures comments by the panelists reflecting a deeper assessment of the available research evidence.3.“Assessment of the local applicability of the evidence.” This category captures comments about whether the available evidence is applicable in the local setting.Three key themes  emerged The themes and subthemes with quotes from the field notes as illustrative examples are presented below.3.13.1.1Studies have shown that aminophylline is not better than salbutamol” (Asthma)“To demonstrate superiority of amoxicillin over co-trimoxazole, what is the absolute effect?” (Pneumonia)“We had a study at Kenyatta [National Referral Hospital]. We did 8-hour Kangaroo care per day. Comparing with conventional care, we found difference in growth of babies, length of stay was a little bit shorter” (Kangaroo care—unpublished report)“For nine of the 11 clinical topics, participants referred to other sources of research evidence to support or refute the draft recommendations . This inWe cannot say, [it] has not been tested. We are saving lives in the short-term. It is hard to act on this inconclusive evidence” (HIV-Pneumonia)“Should we even give a recommendation? Given the evidence, there is not enough to provide guidance. The earlier concerns may be valid, we do not know. So perhaps we should not change” “I beg to differ. We cannot apologize to these two patients if they die and say, we did not have the evidence” (Asthma)“The absence of relevant evidence and inconclusive state of evidence were frequently noted as reasons for participants’ inability to cast a vote based on sound evidence for or against proposed recommendations:3.1.2In private sector I have experienced that you discharge already at 1.5 kg with Kangaroo care, and they seem to do well” (Kangaroo care)“I am worried about taking out aminophylline. I had a patient last week in status asthmaticus who I am convinced survived only because of the aminophylline infusion we gave him” (Asthma)“In practice we use ready-to-use therapeutic foods [RTUFs] because we do not have F100. And it seems to be well accepted. If there are problems with the child taking it we mix e.g. with porridge” “Comments reflecting clinician’s experiences with proposed treatment options were observed in six of the 11 clinical topics , and incOf note, accounts of clinician’s experiences were observed more frequently in clinical conditions where existing practices were highly varied  and where the current research evidence base was weak or inconclusive .3.23.2.1The numbers were small in this study, giving us power problems. And the unblinding gives us a problem with interpretation” “The trial was stopped early. Should we try and find out the reasons for the high mortality?” “Is there mortality data on severe pneumonia?” (Pneumonia)“In the absence of good quality evidence are there other good reasons for adopting the policy?” (Pneumonia)“Selection bias of only studying children in hospital” (HIV-Pneumonia)“A range of issues reflecting participants’ scrutiny of the credibility of the evidence was noted in five of the 11 clinical topics , and incOpinions diverged more frequently in clinical conditions where the quality of evidence was low .3.2.2What is the maximum duration of Kangaroo care?” (Kangaroo care)“Clarification required on sequence—wash → dry → use alcohol hand rub (Hand washing)Question asked if inotropic support or mechanical ventilation were used: answer “no” Is ciprofloxacin recommended as p.o. [orally] or i.v. [intravenously]” (HIV-Pneumonia)“For those on breast milk, were they on plain or with fortifier” “The various fluids have different components, and we have no research to guide as to which is the better” “Comments seeking clarification of the features, or criticism of, the interventions being discussed were observed in nine of the 11 clinical topics . Aspects3.2.3In these studies you are lumping all malnourished shock patients together, and this is a problem. There are likely to be important subgroups” “Clarification on Papua New Guinea Study…showed no difference yet combination showed overall benefit of penicillin + gentamicin vs. chloramphenicol” (Pneumonia)“What about the morbid condition of the child—was this considered?” (Kangaroo care)“What was the definition of treatment failure?” (Pneumonia)“The Duke study had a similar sample size to the Asghar study yet was unable to show a difference of effect” (Pneumonia)“Given different patterns of resistance for different age groups, perhaps recommend cephalosporin for under 2-year olds, and penicillin plus chloramphenicol for the older ones?” (Meningitis)“Comments alluding to differences in participants’ interpretation of evidence were observed in all clinical topics , and inc3.33.3.1The science is there, fine. But if we change the recommendations we will need much training, for example, on the differentiation between the various severities of pneumonia” (Pneumonia)“I think feasibility is major issue. A mother who has just delivered needs so many other things, and having a baby with oxygen, fluids…” (Kangaroo care)“My concern is with the availability of IV [intravenous] salbutamol. If we take out aminophylline we have nothing” (Asthma)“Getting vascular access will be difficult for people with limited training” “Compliance for amoxicillin could be a problem” (Pneumonia)“…incubators are expensive and Kangaroo care will save money and space” (Kangaroo care)“Reference to the likely barriers and facilitators to effective implementation (adoption) of the proposed treatment options were observed in eight of the 11 clinical topics . Key fac3.3.2The risk of development of resistance across 3rd generation cephalosporins is highly relevant also in our setting, as we have experienced at Kenyatta hospital where resistance has emerged” “Many babies we receive at Kenyatta [National Referral Hospital] are hypothermic” (Kangaroo care)“Nyanza—salmonella common in malaria endemic areas” (Meningitis)“Outpatients in Kenya are staffed by clinical officers who are familiar with outpatient IMCI [Integrated Management of Childhood Illnesses]” “Comments where participants referred to knowledge about locally relevant practice-setting factors were observed in five of the 11 clinical topics . This in3.3.3Effective, safe, and accessible are the key components. If they are equally effective and safe, then accessibility is the issue” (Asthma)“The issue here, as I understand it, is not effectiveness but safety and toxicity…and the issue is not cost, both are cheap” (Asthma)“Costs of preparation of alcohol hand rub may be overweighed by costs of installing running water in all hospitals” (Hand washing)“Should consider costs—direct costs of good hand hygiene as well as money spent on morbidity due to poor hand hygiene” (Hand washing)“Comments reflecting judgments about likely benefits and harms of alternative treatments were observed in three of 11 clinical topics , and inc3.3.4My impression is that the attitude of the health professionals is an important factor” (Asthma)“Personal preference of medicated soaps due to the perfume” (Hand washing)“Need to consider cultural issues, e.g., uptake of alcohol hand rubs for Muslims” (Hand washing)“Acceptability, F100 may not appear as sufficient to give to an older child as is just milk. RTUF is solid, so potentially more acceptable” “References to health worker perspectives, attitudes, cultural issues, preferences, and acceptability of proposed interventions were observed in four of the 11 clinical topics :“My impr4Bellagio Child Survival Series published in 2003 and the Lancet Neonatal Survival Series published in 2005 identified low-cost interventions with proven effectiveness for improving neonatal survival The realization that failure to use research findings in health care has a negative impact on patient’s care has led to an increased emphasis on identifying ways to transfer evidence into practice. The The method for developing guidelines during the “Child Health Evidence Week” differed from the way guidelines are developed by established institutions in high-income countries Our observations revealed important challenges in the translation of evidence into recommendations. These included a lack of evidence, low quality or inconclusive evidence, limited cost data, inadequate reporting of features of treatments examined , and differences in panelists’ interpretation of research literature. This last challenge can be an additional barrier to the timely achievement of consensus in multidisciplinary panels. Similar challenges have been documented in related studies Explicit discussions focusing on trade-offs between likely benefits, harms, and budget impacts of treatments were sparse. This confirms previous findings that the net value of treatments (despite being an important determinant of patient’s choices and preferences) is frequently overlooked by guideline development panels The strengths of the present study include taking into account diverse opinions and experiences expressed by the multidisciplinary panel, the large panel size, which may have improved transparency, our real-time documentation of the decision-making process, and independent data collection and review of field notes by three investigators to minimize bias and error. Recognized limitations include the possible influence of professional status and expertise of panel members on aspects of evidence discussed (e.g., dominance of discussions by “powerful” members may skew viewpoints 5The present study gives insight into the many factors that influence the decision-making process in multidisciplinary guideline development groups. The findings also suggest that the process of the “Child Health Evidence Week” combined with the GRADE grid may aid transparency in the deliberative process of multidisciplinary guideline development groups in low-income settings, and provide a mechanism for comprehensive assessment, documentation, and reporting of the many factors that influence the quality and applicability of evidence-based guideline recommendations. Further studies on systematic methods to improve transparency and the rigor of how recommendations are derived from multiple evidence sources during guideline development are needed. In addition, a prospective study that assesses the impact of these methods for guideline development on patient’s outcomes is key.


Objectives. Fibromyalgia syndrome (FMS), characterized by subjective complaints without physical or biomarker abnormality, courts controversy. Recommendations in recent guidelines addressing classification and diagnosis were examined for consistencies or differences. Methods. Systematic searches from January 2008 to February 2013 of the US-American National Guideline Clearing House, the Scottish Intercollegiate Guidelines Network, Guidelines International Network, and Medline for evidence-based guidelines for the management of FMS were conducted. Results. Three evidence-based interdisciplinary guidelines, independently developed in Canada, Germany, and Israel, recommended that FMS can be clinically diagnosed by a typical cluster of symptoms following a defined evaluation including history, physical examination, and selected laboratory tests, to exclude another somatic disease. Specialist referral is only recommended when some other physical or mental illness is reasonably suspected. The diagnosis can be based on the (modified) preliminary American College of Rheumatology (ACR) 2010 diagnostic criteria. Discussion. Guidelines from three continents showed remarkable consistency regarding the clinical concept of FMS, acknowledging that FMS is neither a distinct rheumatic nor mental disorder, but rather a cluster of symptoms, not explained by another somatic disease. While FMS remains an integral part of rheumatology, it is not an exclusive rheumatic condition and spans a broad range of medical disciplines. Roughly 2% of the developed world's population meet either the 1990 classification or 2010 modified diagnostic criteria of the American College of Rheumatology (ACR) for fibromyalgia syndrome (FMS) . FMS pathttp://www.guideline.gov/), the Scottish Intercollegiate Guidelines Network (SGN) (http://www.sign.ac.uk/guidelines/index.html), and the Guidelines International Network (G-I-N) (http://www.g-i-n.net/) was conducted from January 2008 to February 2013, using the key words “Fibromyalgia” and “Fibromyalgia Syndrome.” Medline was also searched from January 2008 to February 2013 with the search terms “Guideline” (publication type) and “Fibromyalgia” (mesh). Because regular updates of guidelines are required by guideline clearing houses, the searches were limited to this period. A manual search of the guideline bibliographies and contacts to international FMS key opinion leaders was undertaken to verify that all published guidelines were identified.A systematic search of the US Agency for Healthcare Research and Quality (AHRQ) American National Guideline Clearing House (NGC)  was outlined.To be included in our analysis, the guidelines had to meet the following criteria.Guidelines that included FMS with other diagnoses, such as chronic fatigue syndrome, myalgic encephalomyelitis, or somatoform disorders, were excluded.Inclusion criteria and the composition of the steering committees and panels, search strategies, the classification of evidence and recommendations, the procedures for establishing recommendations, and the recommendations given by the guidelines that met inclusion criteria were assessed by two independent reviewers . All discrepancies were rechecked and consensus achieved by discussion. If needed a third reviewer was involved (Jacob N. Ablin).n = 19), not commissioned by a scientific society (n = 2) [The literature search yielded 24 citations . FMS opinion leaders reported two guidelines. Three of these met our inclusion criteria: the 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome , the gui (n = 2) .The Canadian guidelines were endorsed by the Canadian Pain Society (CPS) and the Canadian Rheumatology Association (CRA). The guidelines were developed by the Canadian Fibromyalgia Guidelines Committee (CFGC) .The German guidelines were initiated and coordinated by the German Interdisciplinary Association of Pain Therapy (DIVS). The DIVS, an umbrella organisation of 18 scientific societies, is dedicated to the improvement of interdisciplinary pain therapy. The methodological development of the guidelines was supported by the Association of the Scientific Medical Societies (AWMF), the umbrella organisation of 152 scientific medical societies in Germany. Nine scientific associations  and two national FMS self-help organisations participated in the guidelines development .The Israeli guidelines were developed by the Israeli fibromyalgia group, on behalf of the Israeli Rheumatology Association. This group was formed within the national rheumatology association and included a group of experts with both clinical and research interest in FMS .Details of the guideline groups are outlined in The development of the guidelines was funded by a private foundation (Canada), pharmaceutical companies , and the scientific societies involved . All three guideline groups comprised multidisciplinary teams representing healthcare professionals from relevant fields involved in the care of FM patients.Details of the composition of the methodologies to design levels of evidence and grades of recommendations are outlined in The levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence Based Medicine  by the CAll three countries justified the need for development of guidelines on the basis of the high prevalence of FMS and the association of reduced health-related quality of life of patients and high healthcare costs as well as controversies surrounding diagnosis and management , 11, 20.Recommendations concerning the definition, classification, clinical diagnosis, and general principles of care set out by all three guidelines were predominantly based on expert consensus, with very limited evidence available in the current literature.All three guidelines defined FMS by the 1990 classification criteria of the American College of Rheumatology (ACR) classification criteria [The Canadian guidelines stated that FMS is clinical construct of pain and other symptoms that cannot be explained by some other illness . The GerDetails of the recommended diagnostic workup are outlined in Currently there is no specific diagnostic laboratory test or biomarker available for the diagnosis of FMS. All three guidelines were in agreement that the diagnosis remains clinical and the purpose of the physical examination and limited laboratory investigations is to rule out some other alternative diagnoses. The Canadian guidelines  recommenhttp://dx.doi.org/10.1155/2013/528952).The German guidelines recommended the use of the fibromyalgia survey questionnaire  to assesBoth the Canadian and the German guidelines stated that, for most patients, the diagnosis can be established by a primary care physician. A referral to a specialist  should be limited to situations when there is a reasonable clinical suspicion of some other condition that is presenting similarly to FMS or when the patient presents particular treatment challenges , 13.All three guidelines emphasized that the diagnosis of FMS can coexist with a diagnosis of another somatic disease  or of a mental disorder  , 13, 20.The symptoms are not caused by an organic disease  but are instead based on a functional disorder.The legitimacy of the ailment should be acknowledged.The symptoms are persistent in nearly all patients.Total relief of symptoms is seldom achieved.The symptoms do not lead to disablement and do not shorten life expectancy.Most patients learn to adapt to the symptoms over time.The goals of treatment are improvement in quality of life, maintenance of function , and reduction of symptoms.The ability of the patient to modulate symptoms via self-management strategies should be emphasized .All three guidelines recommended that the diagnostic label “FM” or “FMS” should be communicated to patients after initial diagnosis and that patients should be provided with a clear explanation regarding the nature of the disorder, planned treatment strategy, and expected outcome , 11, 20.The German guidelines group developed a patient version of the guideline and handouts for patients and their significant others, which should be distributed to the patient after establishing the diagnosis .We have identified considerable consistency between three recently published FMS guidelines spanning three continents. This agreement observed for the classification and clinical steps to establishing a diagnosis of FMS should put to rest many of the contentious issues that have challenged the medical community regarding this condition . It shouThe diagnosis of FMS can be readily established in most cases by primary care physicians following a history of a typical cluster of symptoms and a defined diagnostic workup, including a complete medical history and physical examination and some simple and selected laboratory tests to exclude a somatic disease that sufficiently explains the symptoms. The modifier “sufficiently” in this definition is of critical importance and must be acknowledged: FMS often coexists with other disorders and the presence of such comorbidities must not be interpreted as ruling out a diagnosis of FMS. Thus, FMS is not a diagnosis of exclusion but rather a positive clinical diagnosis important to recognise, either independent of or in addition to other medical problems. In most patients diagnosed with FMS, more than one diagnosis is necessary to capture the whole spectrum of symptoms. Most importantly, other functional somatic syndromes , mental disorders , and somatic diseases  can be diagnosed , 20.A tender point examination is not obligatory for the diagnosis of FMS. This physical finding, subject to variable interpretation and which reflects an overall reduction in pain threshold, has at times been inappropriately used to establish a diagnosis of FMS. A referral to a specialist should be reserved for those selected patients in whom there is a suspicion of some other somatic disease and/or of mental disorder or when there are specific treatment challenges. Excessive healthcare utilization with referral to multiple specialists and repeated radiographic and laboratory investigations should be discouraged. The use of the (modified) ACR 2010 diagnostic criteria , 28, whiIt is reassuring that the concordance rates of the different diagnostic criteria of FMS are high (80–90%) , 30. ThiFMS, often disputed and challenged, has emerged as a clinical syndrome with a clear cluster of symptoms and comorbidities. Despite the ongoing paucity of biomarkers available for diagnosing and monitoring of this condition, a systematic evidence-based approach can lead to effective, patient-centered management with avoidance of unnecessary and harmful interventions.The cluster of symptoms that we today recognize as FMS has been described in the literature for over 200 years, with the specific diagnostic label of FMS introduced at the end of the 20th century . The recFibromyalgia Survey Questionnaire  contanis the symptom severity score and the widespread pain indexClick here for additional data file.


Decision-making is a dynamic process that begins with the accumulation of evidence and ends with the adjustment of belief. Each step is itself subject to a number of dynamic processes, such as planning, information search and evaluation. Furthermore, choice behavior reveals a number of challenging patterns, such as order effects and contextual preference reversal. Research in this field has converged toward a standard computational framework for the process of evidence integration and belief updating, based on sequential sampling models, which under some conditions are equivalent to normative Bayesian theory  and the fit with the data. Some of these papers also examine the neural mechanisms that implement the decisions. In a mathematically-oriented paper Heathcote and Love  examine The second group of six articles examines decisions that extend over a longer time-frame and which allow the subject to control the evidence accumulation process, and to form and update beliefs about the state of the environment. The study by Knox et al.  of exploThe next group of three articles addresses preference formation, in situations (risky choice and multi-attribute decisions) that do not set up an objective/normative criterion, but rather leaves this to the subject's control. Fiedler and Glockner  monitor Finally, two papers aim to provide novel or integrative frameworks for understanding dynamical decision making. Trueblood and Busemeyer  present We believe that this collection has revealed a number of important aspects of the nature of decision processes. More importantly, we hope that it will stimulate readers to keep probing these processes. Various key questions are still unresolved. How close are people to optimality when making decisions? Why does this vary so much between the cases of evidence and preference? Is the Bayesian framework a general one for all types of decisions . What are the neural mechanisms, and the nature of individual differences? Future research into these topics, should surely keep us stimulated for the near future.


The workshop was held in May 2011 in Nairobi, Kenya and was funded by the Canadian Global Health Research Initiatives (GHRI) and the US Centre for Disease Control and Prevention (CDC). At the end of the workshop participants came up with a framework to guide mHealth initiatives in the region and a plan to work together in scaling up evidence based mHealth interventions. The participants acknowledged the importance of the meeting in setting the pace for strengthening and coordinating mHealth initiatives and unanimously agreed to hold a follow up meeting after three months. There have been calls for more evidence on the effectiveness of mHealth interventions to improve health outcomes. The WelTel Kenya1 intervention evaluating the use of mobile phones to improve adherence to ART is the first randomized controlled trial to show the effectiveness of using mobile phones for viral suppression [High level adherence of 95% and above that can yield maximum viral suppression and reduce drug resistance to antiretroviral medications is still a challenge. Earlier studies with meta-analyses on adherence to anti-retroviral therapy (ART) in sub-Saharan Africa found that a pooled estimate of 77% of patients in African settings achieved adequate adherence (95% of prescribed pills), compared with 55% of patients in North American settings . HoweverInterventions using mobile phones to improve health outcomes such as adherence and retention in the ART programs are likely to be viable due to the wide access to mobile phones in most developing nations , the emeThe aim of the workshop was to bring together various stakeholders who included researchers, academicians, information, communication and technology programmers, policy makers and members from the civil society to:1) review evidence based mHealth research for HIV care and treatment; 2) review mHealth applications developed to support adherence and retention in ART programs; 3) develop an mHealth evidence based framework for scale up and 4) identify gaps in evidence and the areas where more research is needed.On the first day of the workshop the mHealth concept, ART adherence and retention challenges and the role of mHealth, evidence for HIV-related mHealth interventions and mHealth interventions in other areas were presented and discussed. The second day of the workshop was dedicated to building partnerships and developing a framework for mHealth strengthening to support HIV care and treatment and other health conditions.Fifty participants from twenty nine organizations in Kenya, Uganda, Zambia, Cameroon and Canada attended the workshop. They included researchers, policy makers, health care implementers, information, communication and technology programmers, academicians and civil society representatives. Although the workshop initially targeted thirty participants, the high demand necessitated a request for additional funding to accommodate more participants.There were seventeen brief presentations during the first day, in which thirteen mHealth projects either in progress or completed, were discussed . Some of1) Adherence to antiretroviral medications continues to be a serious problem. Lester et al., 2010 mobile phone adherence intervention conducted in Kenya report that only 66% of patients on ART in the control arm with viral loads available achieved viral suppression (<400 copies/ml) after one year . A studyThe second day of the workshop was dedicated to developing a strategic action plan for strengthening of mHealth interventions to support care and treatment of HIV and other conditions. The participants formed three discussion groups that formulated the following recommendations:1) To develop and submit a harmonized regional evidence-based ART adherence and retention mHealth intervention. A regional stepped wedge study design ,10 basedThe workshop generated greater interest for participation than expected which indicated the desire for a coordinated approach to implementing mHealth interventions in the region. It created a forum for participants to share and review mHealth interventions in the region. The evidence reviewed suggests that mobile phones can be used as monitoring and supporting tools to provide regular communication between patients and health care providers. A regional evidence-based cell phone intervention to support patient adherence and retention in ART programs was proposed. Participants acknowledged the importance of the workshop and agreed to hold a follow up meeting to reinforce the recommendations developed during this workshop.


Decisions to scale up population health interventions from small projects to wider state or national implementation is fundamental to maximising population-wide health improvements. The objectives of this study were to examine: i) how decisions to scale up interventions are currently made in practice; ii) the role that evidence plays in informing decisions to scale up interventions; and iii) the role policy makers, practitioners, and researchers play in this process.Interviews with an expert panel of senior Australian and international public health policy-makers (n = 7), practitioners (n = 7), and researchers (n = 7) were conducted in May 2013 with a participation rate of 84%.Scaling up decisions were generally made through iterative processes and led by policy makers and/or practitioners, but ultimately approved by political leaders and/or senior executives of funding agencies. Research evidence formed a component of the overall set of information used in decision-making, but its contribution was limited by the paucity of relevant intervention effectiveness research, and data on costs and cost effectiveness. Policy makers, practitioners/service managers, and researchers had different, but complementary roles to play in the process of scaling up interventions.This analysis articulates the processes of how decisions to scale up interventions are made, the roles of evidence, and contribution of different professional groups. More intervention research that includes data on the effectiveness, reach, and costs of operating at scale and key service delivery issues (including acceptability and fit of interventions and delivery models) should be sought as this has the potential to substantially advance the relevance and ultimately usability of research evidence for scaling up population health action. To maximise the impact of public health research, interventions found to be effective in improving health need to be scaled up and delivered on a population-wide basis. The transfer of new knowledge from public health research into practice, however, continues to be sub-optimal . On averScaling up is the process by which health interventions shown to be efficacious on a small scale and/or under controlled conditions are expanded under real world conditions into broader policy or practice ,7. UnderThe concept of scaling up is different from routine adoption as it involves an explicit intent to expand the reach of an intervention to new settings or target groups. Norton and Mittman  examinedSimilarly, a literature review and two-stage Delphi process with 14 senior Australian population health policy makers and researchers ,9 concluThough these recent studies, made up primarily of case studies, literature reviews and interviews with policy makers and practitioners ,11,12,16In light of these gaps in our knowledge, the objectives of the current study were to examine:i) how decisions to scale up population health interventions in high-income country contexts are made in practice;ii) the role that research evidence plays in informing decisions to scale up promising interventions; andiii) the roles policy makers, practitioners, and researchers play in the process of scaling up population health action.Purposeful sampling techniques were used as expert opinions were sought from senior policy makers, practitioners, and researchers . ExpertsInterviews were conducted by a research assistant with over 10 years’ experience in the conduct of qualitative methods and included a mix of open and closed questions to assess how these decision makers had made decisions to scale up interventions in practice, how evidence had informed their decisions and the respective roles policy makers, practitioners, and researchers had played in these scaling up processes. The interview questions addressed the aforementioned gaps in the knowledge base identified in previous research . All int1. How many years’ experience do you have in the development, implementation, and or evaluation of population health interventions? [Years]2. What is your current role? 3. Have you ever been involved in decision processes to scale up population health interventions into broader policy or practice?Prompt, if required: By scaling up we mean taking a health intervention shown to be efficacious on a small scale and or under controlled conditions and expanding it under real world conditions into broader policy or practice. Decision processes are processes by which decision makers identify information, evaluate alternatives, and make decisions on courses of action.) [Yes/No]4b. What formal processes, if any, were undertaken to inform decisions to scale up the intervention (or not)? 4c. What role did you personally have in the decision processes? 4d. How or by whom was the final decision to scale up the intervention (or not) made? (4e. What (if any) influence did research evidence have on the decision processes?4f. If research evidence did influence the decision processes, what type of research was used and how was it applied? 4g. What factors and information sources, if any, enabled decision-making about whether to scale up the intervention or not?4h. What factors were barriers to decision-making about whether to scale up the intervention or not?Prompt if necessary: intervention was scaled up, intervention abandoned, etc.)4i. What were the final outcomes of these decision processes?  you have been involved in previously.Prompts in required: how do they differ and why?)5. From your experience, what roles do policy makers and researchers play in process of scaling up population health interventions?  [Yes/No]7. Have you ever been responsible for implementing a process of scaling up a population health intervention into broader policy or practice? , with 7 of 8 policy makers, 7 of 7 practitioners/service managers, and 7 of 10 researchers approached agreeing to participate. Policy-makers (n = 7) possessed a mix of senior policy experience at the state, national, and international levels, and had a mean of 18 years’ experience in commissioning and/or conducting major intervention research trials and overseeing implementation of large-scale population health programs. Practitioners/service managers possessed extensive service development experience at local and regional levels and had a mean of 17.4 years’ experience in overseeing intervention research trials and expanding the implementation of prevention programs. The sample of researchers (n = 7) was a mix of Australian and international University based experts in public health, health services, and health promotion research with a mean of 22.1 years of experience. Four of the 21 respondents held senior public health or academic positions in Asia, Europe, or the United States.All of the policy makers and practitioners and 6 of the 7 researchers interviewed had been or were currently involved in decisions about whether to scale up population health interventions into policy and practice.Respondents were also asked how many times in the past 5 years they had been involved in decision processes to scale up population health interventions. Researchers most frequently reported involvement in between 1 and 6 cases and policy makers and practitioners most frequently reported involvement in 10 or more and 6 or more cases of decision processes, respectively.All of the policy makers and practitioners interviewed had been responsible for implementing scaled-up interventions into policy and practice, while 2 of 7 researchers had experienced such a responsibility.Respondents were asked to describe the most recent intervention for which they were involved in scaling up related decision processes Table . The 20 ‘It was an iterative process. We got technical expert advice from the market about the do-ability …which was very important because it was all very well coming up with the idea but without the practical, this is how much it will cost and yes it’s available, you can do it or you can’t do it, it was all kind of moot… It was also important for our minister to be able to say we had that consultation and we had that credibility with the public health community’ (PM).Respondents across professions reported that formal scaling up processes were generally iterative, and were run by policy makers and or practitioners: ‘The Minister is actually making a decision to fund a program. It’s not a conscious decision that they are scaling up… from research evidence into a state-wide program… The decision is about what advice policy makers give to the Minister and based on this advice the Minister makes a decision about whether to fund the program.’ (PM); and ‘…ultimately we had to take it to our minister as a package proposal’ (PM).Policy makers described the process of constructing a case for action for the consideration and endorsement of political leaders and senior executives in the form of parliamentary, ministerial, and executive briefings. Policy makers rarely made decisions in isolation and without first seeking senior endorsement of proposed approaches and associated budgets from senior delegates. One senior policy maker described the process as follows: ‘We formed a clinical advisory group with clinicians to formulate the model of care. Then we rolled it out. We then formed partnerships with each of the, what we call, clusters, groups of community health services. We formed partnerships with their executives where they gave us local advice’ (P/SM).It was observed that decisions to scale up interventions were almost always subject to processes of either internal and/or external consultation through organizations and/or stakeholder networks, using advisory committees, working parties, expert advice, and often involving researchers either directly or indirectly: I was consulted around interpreting the findings and being asked to give my opinion about recommendations for the future, but how those were considered with the processes that were followed to make the final decision internally I don’t know’ (R).Researchers agreed that while they might formulate recommendations, ultimate decisions to scale up interventions were generally made by policymakers and practitioners within government agencies, over which they had little control. Researchers reported that they collated and provided evidence to others in a number of forms and forums, including systematic reviews, intervention research results and expert advice, but they were not always sure how that evidence was then used by others to inform the decisions that were made about scaling up the intervention: ‘‘I was asked to sit on the steering committee for this play space initiative and then it was through that that I put forward or really advocated for consideration of our evidence-based intervention as part of the fleet of programs, chronic disease prevention and management programs that would be scaled up and delivered’ (R).Some researchers noted that their role in decision-making processes went beyond providing evidence, to one of advocating for particular approaches: ‘Politicians. One stroke of the pen, done’ (PM); and as a practitioner/service manager put it: ‘…obviously you need to have sufficient resources to enable it to happen, or at least have commitment that the resources will be available or can be attainable’ (P/SM).There was consistency in the view that the context for decisions about whether to scale up interventions is highly political, rapidly changing, and influenced by a variety of factors, inputs, and relationships, including individuals’ values, skills, and experience. Respondents across occupational groups noted that the most powerful influences over scaling up processes were political and resource related: as one policy maker put it: ‘The government doesn’t just make decisions on the basis of one research project… but about the overall body of evidence… And so I think in terms of research evidence in general, I think it had quite a strong influence but it’s not just the only factor, so it’s a kind of necessary but insufficient condition’ (R).Most decision-making processes associated with scaling population health interventions involved consideration of a variety of information sources, not just research evidence. Many respondents across occupation groupings observed that while research evidence was important, other contextual information or political influences also appeared to have a strong influence on the final outcome of decision processes. For example, alignment with government priorities and political imperatives, funding availability, leadership support, and support from stakeholders were thought to be particularly important influences by policy makers. Where research evidence was available, decisions were based on a body of evidence rather than a single study: ‘…I knew that I had to take into account the policy context, the relationships we had politically with Ministers and the relationship we had between different sectors’ (PM).A key theme identified by a number of policy makers acknowledged that research evidence was the starting point, but that: Plenty of critics were happy to say “well it’s never been done before, how do you know it will work?” That’s the reality of any large scale population-based intervention. Someone has to do it first. Someone had to legislate to make us wear seatbelts first’ (PM).Conversely, some policy makers suggested that from time to time decisions had been made without solid evidence, particularly where potential gains to the health of population are great: ‘‘Epidemiology or prevalence data provided a map or primary rationale for working in the setting’ (P/SM).The types of research evidence reported as having been used in decision processes varied greatly, and comprised epidemiological data, intervention research, systematic reviews, controlled trials, and local quasi-experimental pilot studies. Policy makers and practitioners noted that epidemiological evidence was used to determine the nature and scope of a problem and for surveillance purposes: ‘We also used the evidence available from systematic reviews to argue that if the intervention was delivered, a risk reduction outcome could be achieved’ (P/SM).Respondents frequently reported the use of evidence from systematic reviews where these were available to build a case for scaling up the intervention: ‘The evidence provided us with clues to what might be appropriate to include… so the sorts of things about how many call backs were required…who should we be targeting, so there was no single research study but it was elements of other sorts of bits and pieces of programs that we needed to make a judgment call on’ (PM).Policy makers and practitioners identified a paucity of intervention research in the literature to inform scaling up efforts, as one policy maker put it: ‘So few research studies provide the really nuts and bolts information that a policy maker would require’ (PM).When intervention research was available, this evidence alone rarely provided policy makers with all of the information they needed to scale up interventions: We used the local evidence we had gathered to show that the intervention could be delivered at no cost to service delivery and was acceptable to the service providers’ (P/SM).Research evidence was almost always adapted to context and situation. ‘Off the shelf’ interventions were generally not seen as appropriate by policy makers and practitioners unless they had been developed to suit the local context. Local evidence had a higher value because it was considered more likely to successfully translate into practice. Local evidence of efficacy or evidence from local pilots or replication studies was thought to be particularly persuasive: ‘Then we also looked at, as I mentioned, other health topics, like so if we looked for research where there had been some up scaling, whether or not it was specific to our health topic or not, but specific to the setting…’ (P/SM). Both policy makers and practitioners spoke of drawing on the evidence in relation to the principles of successful interventions or best practice population health approaches and theories, in cases where sufficient evidence was not available.A number of policy makers and practitioners observed that where direct evidence of effectiveness was not available, parallel evidence from other settings or health issues or countries was sometimes used: ‘‘…a lot of the research is grey when it comes from other departments and closely held so that always makes it difficult. There’s a lot of searching out the project managers, the project workers and talking to them personally…what their perspectives were, how they actually make things happen on the ground and then what are the process outcomes…’ (PM).Grey literature  was thought by policy makers and practitioners to be a particularly useful source of evidence as it often provided more ‘how to’ information than peer reviewed papers, although it could be difficult to access. Where this information was not available, advice and information was often directly sought from people who had implemented similar programs: I think one of the barriers was the lack of costing information. One of the other barriers was not having clear cut cost effectiveness data on $1 spent here is going to give you $5 in return. We had evidence that it was effective, but we didn’t have evidence that it was cost effective’ (PM).Respondents across occupational groupings in the sample, but particularly policy makers, stated that evidence of implementation costs and cost effectiveness had been rarely available to them from the research literature, and yet were needed to inform scaling up processes: ‘‘…need to assess current practice. Determine the factors that influenced decisions in the setting. What the provider attitudes are, the way things are organized organisational/infrastructure issues. What service models and systems can be used - framework for understanding? Support for specific arrangements and links to other programs, business arrangements, workforce funding. These feasibility issues were researched so decisions could be made about how to scale up the intervention’ (R).Many respondents across occupational groupings in the study sample observed that the value and importance of considering information in relation to the organisational fit of an intervention, and the acceptability and feasibility of the intervention to individuals and delivery agents: Scaling up processes that do not consider this information were seen by many respondents across occupation groupings as sub-optimal and more likely to meet system resistance, and less likely to be sustained in the longer term.Respondents across the sample perceived that policy makers, practitioners/service managers, and researchers had different but complementary roles to play in the process of scaling up population health interventions.‘I think they have been particularly critical in my experience because they can be that expert independent voice that is needed sometimes that you can roll out. Basically, a face behind the paper or someone that can actually put a voice to a paper in front of a power broker or someone that holds power’ (P/SM). It was clear that researcher-generated information contributed to the way policy makers and practitioners thought about an issue.Researchers played an important role in bringing evidence to the attention of opinion leaders and decision makers, by providing independent expert opinion and by advocating for particular interventions or issues. ‘…because I come originally from a practice background I am willing to kind of engage in broader discussions but I think a number of researchers would think that this is not their job’ (R).Some researchers stated that they participated in discussions with policy makers about ‘how to’ implement, while others typically confine their advice to ‘what’ to implement. It was suggested that there were limited rewards for researchers to participate in scaling up decision-making processes, as one respondent noted: ‘There’s the researchers that keep their hand in, they’re the go-to people, the people I can pick up the phone to. “I’ve got this issue with this, have you got any evidence around this, what’s your feeling, have you done some research in this area” and they understood the context that I was talking about because we had worked together because I knew they were working in the same field, we all kind of understood each other and I knew what they were doing and I knew their strengths and capacities. Those were the go-to people’ (PM).Policy makers also noted that there were certain researchers who were well connected with the policy context and were willing to assist in scaling up decision processes: ‘Well, my experience with researchers is that they never do research which is about scaling up. Research that’s about scaling up is probably less attractive to them than research that either proves something is effective or not…’ (PM).It was noted by a number of policy makers and practitioners that there was little evaluation conducted by researchers on scaled up interventions: ‘…providing the capacity for ongoing evaluation, which may be part of the plan that the policy makers come up with’ (R). This opportunity may be particularly salient where practitioners had dual roles as implementers and researchers. In this regard it was suggested that researchers could ensure that intervention evaluations were being implemented with some rigor.However, it was suggested by other respondents that there was scope for researchers to be engaged in ongoing evaluation for scaled up interventions: ‘There are the political factors that they [policy makers] have to be aware of, in terms of what the political consequences may be of a program being rolled out more broadly or continued, to elected the person at the top of the tree. There are probably internal political factors that have also got to pay attention to, in terms of their organisation and support for an area of work, what the consequences might be for continuing to scale or deliver a program. They are very dependent on partnerships and therefore they have got to think about what the consequences are for the important partnerships of scaling up’ (R).Policy makers play important roles in determining priorities, securing resources, and solidifying leadership and stakeholder support for action. They make decisions about what to implement and how to do it based on a variety of factors including the available evidence. Policy makers may also be involved in directing the implementation of interventions. As a researcher observed: ‘So I guess I lead the process, as the service director so I initiated some of the earlier discussions, seeking feedback from key stakeholders and gaining that leadership support and developing those relationships to actually support the process and then basically I developed the briefs, etc. to get it into the level. I had those high level decision meetings, etc.’ (P/SM).Practitioners/service managers in this study described a similar role to policy makers, but on a local level, as they sought executive endorsement of approaches to scaling up and had a particularly important role in building the relationships, systems, processes, and infrastructure that support the scaling up of population health interventions into practice. As one service manager put it: ‘Policy makers were trying to find the best range of tools to improve population health…’ (PM). It appeared that practitioners/service managers were driven by similar motivations as policy makers, but had a greater focus on meeting local community and stakeholder needs in scaling up processes. A practitioner observed that researchers often have a different motivation for involvement in scaling up processes: ‘The drivers are attracting funding and publishing papers not what the research leads to in a practical sense. I don’t know how often researchers think about how soon their research is going to be used or if in fact, it will be used’ (P/SM). This observation was confirmed by a researcher who said: ‘As a researcher, we’re not rewarded for it in any way really. So that’s another factor because everything we’re rewarded on is just the old metrics and there’s no money in any grant to do it…’ (R).Researchers, policy makers, and practitioners were observed to have different needs, interests, and values systems that impact on scaling up processes: As a policy maker observed: This is the first study to provide an analysis of how decisions to scale up population health interventions have actually occurred across a range of projects in developed country contexts. The study illustrates that decisions to scale up interventions are typically subject to iterative policy or practice-based decision-making processes, frequently involving engagement with internal and external stakeholders. Policy makers generally lead these processes, but are subject to decisions by fund holders and political leaders, who must be convinced of the relevant merits of action before any action can proceed; a theme that is consistent with the global health literature ,22.This study’s findings indicate that policy makers, practitioners, and researchers have different but complementary roles to play in scaling population health interventions. Consistent with observations of health policy processes in previous research ,17,23, rPractitioners/service managers in this study appeared to perform similar stakeholder management functions to policy makers, but on a local level. Practitioners described being at the ‘coal face’ of many scaling up processes, having a proximal role in facilitating practice change through stakeholder engagement, partnership building, and service development, and this contribution to scaling up may sometimes precede larger scale up, through testing of promising interventions on a local level prior to further expansion.While researchers provided information and advice to decision makers based on their assessments of the available evidence or the findings of their research, their greatest contribution to decisions about whether to and how to scale up interventions, was their influence on the way decision makers thought about issues, often communicated through their ongoing links with policy makers. As Brownson et al.  suggest,Co-production of research between researchers and end users of research such as policy makers and practitioners involves a different way of working in all parts of the research process , particuAn important observation by respondents in this study, again consistent with previous research ,16,17,29Encouragingly, interviews confirmed that evidence in many forms, including research evidence, was important to underpin many decisions related to scaling up population health interventions. Respondents’ descriptions of how evidence informed scaling up processes, that is, research being only one of many influences on decision making, appear to echo the use of research evidence in broader policy making processes previously described in the literature ,30-33.An interesting observation was that locally-generated research evidence was highly valued by policy makers and practitioners as it was perceived to be contextually relevant and more likely to translate into practice. Local evidence of efficacy or evidence from local pilots or replication studies was thought to be particularly persuasive. However, it is important to note that policy makers and practitioners in this study described using a ‘body of evidence’, rather than any single research study, as the empirical basis for scaling up an intervention. In most cases, decision makers noted that there were large gaps in the available evidence. They often described the need to search the grey literature and other sources of information, such as parallel evidence from other settings, and rely on practitioner knowledge and expert advice to fill in these gaps. Echoing these findings, recent interviews with 38 Australia policy makers conducted by Campbell et al.  found th.The costs of scaling up interventions are fundamental to decisions about public health program implementation ,39. CostRespondents across occupational groupings in the sample noted the tension between program fidelity, that is the extent to which the implementation of the intervention is consistent with intervention protocols previously found to be effective  and the Overall, this study confirms that a key challenge for the field of population health is to facilitate the timely provision of policy and practice relevant research evidence into scaling up decision processes. There is opportunity for more co-production of research that directly informs efforts to scale up population health action. This study also reinforces the importance of funding agencies and journals supporting the generation and publication of such applied research.The study findings are based on the substantial experience of senior policy makers, practitioners, and researchers, and provide a sound empirical basis for understanding the process of scaling up population health action in real world developed country contexts. This study also builds on the previous scalability research  by proviIn summary, to be appropriate for scaling up, population health interventions generally required evidence of effectiveness, had the potential for substantially expanded reach and system adoption, had evidence showing that they were acceptable to the target groups and settings, and could be delivered at an acceptable and sustainable cost.Though this is the first study to comprehensively examine how scaling up decision-making processes occur in the real world across a range of projects and settings, it did not examine the appropriateness of particular policies or programs for scaling up or otherwise. This study engaged a small number of expert participants, mainly from Australia, though it is important to note that a number of respondents were from Asia, Europe, and the United States and were recognized as international experts in their respective fields of expertise. While a larger sample or different set of respondents may have generated some differing views, the consistency, rigor, and detail of responses to the interviews, as well as the substantial experience of the experts lend confidence to the results. The considered approach taken in respondent selection, high response rate, and strong contributions from all respondents also add weight to the validity of the findings. There is, however, merit in determining if the findings identified amongst this select sample of experts can be replicated with a larger and more representative sample of policy makers, practitioners, and researchers.In order to achieve population-wide health improvements, population health interventions that have been found to be efficacious in research should be considered for widespread implementation. A better understanding of how decisions to scale up interventions are made in practice, the role of evidence, and the respective roles of policy makers, practitioners, and researchers have played in such processes can inform future intervention research design, intervention development, and scaling up decisions more broadly.At least part of the reason for the uneven dissemination of intervention research findings into population health practice appears to be lack of information relevant to the needs of decision makers when they are managing scaling up processes. The field is encouraged to address key evidence gaps to better inform scaling up processes, particularly publishing more intervention research that provides data on the effectiveness, reach, and costs of operating at scale as well as key service delivery issues including acceptability and fit of interventions and delivery models with the local context. Addressing these evidence gaps would advance the relevance and ultimately usability of research for policymakers and practitioners charged with scaling up population health action.The authors declare that they have no competing interests.AJM’s contribution to this paper included conceptualizing the study, developing data collection instruments, conducting content and thematic analysis of surveys and interviews, led the design of the manuscript, drafted and edited the manuscript taking into account input from co-authors and comments from journal peer reviewers. LK and CR contributed to the study design, design of the paper, reviewing and editing the manuscript. RN conducted interviews, contributed to reviewing and editing the manuscript. LW, AB and SR contributed to reviewing and editing the manuscript.


Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of the tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidyl-arginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function; hence, PPAD may be involved in deregulation of the host’s signalling network and immune evasion. Further, accumulating evidence suggests a role for autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contribute to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and the initiation of RA. In this review, we discuss evidence that PPAD may represent a mechanistic link between periodontitis and RA, diseases that are known to be significantly associated at the epidemiological level. Furthermore, 23 % of the US population age 65+ has been reported to suffer from severe PD. Together, development of both diseases brings considerable consequences for public health and for the quality of life of affected individuals.Rheumatoid arthritis (RA) and periodontal disease (PD) are two common chronic inflammatory diseases affecting humans worldwide. In 2003, the total cost attributable to arthritis and other rheumatic conditions in the United States was $128 billion, equivalent to 1.2 % of the 2003 U.S. gross domestic product , fimbrae, and haemagglutins, which enable the bacterium to colonise and invade periodontal pockets, and is therefore known as the “master manipulator” of the host homeostatic system , and regulation of gene expression via chromatin remodeling , 26. ApaThe citrullination process leads to alterations in intra- and inter-molecular interactions of protein targets possessing Arg residues essential for their structure. This may alter the three-dimensional architecture of modified proteins and their solubility in water, and may lead to the generation of neo-epitopes, thus breaching immunological tolerance to citrullinated proteins. In susceptible individuals, the process may initiate a cascade of events leading to the induction of RA , 23, 27.2+); thus, citrullination is likely to occur in conditions that lead to the mobilisation of free intracellular calcium, such as chemokine receptor ligation, cell death, and differentiation. Five different PADs  identified in humans are encoded by five paralogous genes clustered on chromosome 1p35–36. PAD1 and PAD3 are mainly found in epidermis and hair follicles; PAD2 is expressed in a variety of tissues, including muscle, brain, and haematopoietic cells; and human PAD4 (formerly known as PAD5) is found primarily in haematopoietic cells. PAD homologues for some or all of these enzymes have also been found in other mammals, with similar genomic organisation across species [Protein citrullination is carried out by peptidyl-arginine deiminases  3.5.3.15). The activity of mammalian PAD enzymes is dependent on high concentrations of calcium . Some enzymatic properties of PPAD differ significantly from those of the human PADs. Specifically, PPAD is active at a higher pH and does not require calcium for activity. PPAD also citrullinates C-terminal arginine residues and deiminates free arginine, while mammalian PADs lack these activities [P. gingivalis [P. gingivalis are devoid of citrullination, confirming that the citrullination of surface proteins is dependent on the activity of arginine gingipain proteases. Furthermore, recent data revealed that PPAD citrullinates peptides generated by the degradation of fibrinogen and α-enolase by P. gingivalis gingipains [P. gingivalis (W83) but not with the PPAD-null isogenic mutant [tivities . The prongivalis ••. Gingingipains . Citrullngipains  may intengipains . PPAD isc mutant ••.P. gingivalis precedes RA and that the bacterium is a likely factor in the initiation and maintenance of the autoimmune inflammatory responses that occur in this disease [P. gingivalis-PAD (PPAD), an enzyme expressed by P. gingivalis but absent in other prokaryotes [Recent findings indicate that infection with  disease . In thiskaryotes , may havP. gingivalis is the only known microorganism to produce PAD, and in inflamed P. gingivalis-infested periodontitis sites, PPAD may set in motion a chain of events that breaks immunotolerance to citrullinated proteins and leads to the development of RA. In line with this hypothesis, ACPA titres in RA patients have been shown to correlate with the presence of PD [ce of PD . Moreovece of PD •.P. gingivalis via bacterial adhesins. In keeping with this hypothesis, P. gingivalis rapidly generates fibrinogen-derived peptides with carboxy-terminal citrulline residues [P. gingivalis α-enolase [P. gingivalis-derived enolase. An increased level of antibodies specific for CEP-1 was detected in the chamber fluid of mice infected with P. gingivalis [P. gingivalis α-enolase [Aberrant citrullination has been observed in RA; however, it is still unclear whether citrullination in RA creates novel epitopes or uncovers cryptic ones in susceptible individuals. Among the potential autoantigens in RA that are efficiently citrullinated by human PADs are fibrinogen, enolase, vimentin, and collagen II (CII) , 39, 40•residues . A B cel-enolase . Therefongivalis ••. FinalP. gingivalis efficiently citrullinates its own proteins, and subcellular fractionation revealed that the majority of such proteins are associated with the periplasm, and with the outer and inner membrane fractions [P. gingivalis strain that expresses catalytically inactive PPAD and is thus devoid of autocitrullination (PPADC351A) did not induce an antibody response, confirming a specific immune response to citrullinated PPAD [P. gingivalis infection can uniquely prime the immune response in RA due to the appearance of autocitrullinated PPAD. The potential pathophysiologic role of autocitrullinated PPAD in RA opens up a novel area for future investigations.ractions . Althougractions , 42. Masractions ••. Thereted PPAD ••. Moreoted PPAD ••. Two PP. gingivalis not only exacerbates CIA but also appears to play a role in sensitising animals to early disease development [P. gingivalis was characterised by significantly greater bone and cartilage destruction in the affected joints. These clinical signs of arthritis manifested significantly earlier and were accompanied by a more severe disease course than in non-infected animals. The early onset and aggravated progression of CIA occurred only in animals inoculated with viable P. gingivalis. Infection with P. intermedia, another important pathogen associated with PDs [P. intermedia, inoculation with either heat-killed P. gingivalis or the purified cell membrane fraction from the same organism had no effect on either the rate or the severity of CIA. Taken together, these findings indicate the requirement for live P. gingivalis, which releases bacterial factors exerting a direct or indirect (via stimulation of host systems) effect on the host that ultimately triggers an autoimmune reaction. This hypothesis also drew on recent findings in which immunity to P. gingivalis, but not to P. intermedia (or Fusobacterium nucleatum), was shown to be significantly associated with the presence of RA-related autoantibodies in individuals at risk for the disease [In vivo studies have revealed a relationship between joint disease and PD, as mice with pre-existing periodontitis developed more severe arthritis at a faster rate than control animals , 44•. Moelopment ••. The awith PDs , had no  disease •.P. gingivalis oral infection prior to arthritis induction increases Th17 cell immune responses, including significant secretion of cytokines such as IL-1β, IL-6, IL-22, tumor necrosis factor-α, transforming growth factor-β, and IL-23. This observation suggests that chronic oral infection may influence RA development mainly through the activation of Th17-related pathways [Recent data revealed that chronic pathways .P. gingivalis is a potential risk factor in RA development. Recent data revealed that inoculation of animals with an isogenic P. gingivalis-PAD knockout strain (ΔPPAD) prior to immunisation with CII had no influence on clinical CIA development or progression [The induction of ACPA is dependent on deiminase activity; thus, PAD expressed by gression ••. HistoP. gingivalis because the level of anti-PPAD antibodies was very low. By contrast, the level of antibodies to citrullinated peptides (aCCP) and to enolase-derived citrullinated epitope (CEP-1), both of which are implicated in autoimmunity in RA, strongly increased in CIA mice infected with wild-type P. gingivalis [P. gingivalis infection increased the serum levels of specific IgG against CII, in contrast to either ΔPPAD or CIA control mice.The enzyme by itself is immunogenic in mice, as antibodies against PPAD were detected in animals inoculated with the wild-type strain, W83 ••. Moreongivalis ••. FinalCollectively, aggravation of these RA-associated pathologies is dependent on PPAD activity, which, either directly or indirectly (via the enhancement of inflammatory reactions and the release of host PADs), leads to the generation of citrullinated neo-epitopes, thus stimulating autoantibody production. In this context, one may hypothesise that pathological citrullination of proteins in gingival tissues by PPAD, within a chronic inflammatory environment in which the immune system is stimulated by bacteria-derived danger signals such as LPS, fimbriae, and peptidoglycan, breaks immune tolerance to citrullinated proteins and peptides, priming autoimmunity in a subset of patients with RA  Fig. 1)1).Fig. 1Notably, human PADs, PPAD, and citrullinated proteins have been detected in the oral mucosa and periodontium . Thus, iTogether, PD and RA are responsible for significant loss of function and morbidity in a large percentage of the population worldwide. Therefore, for many years, scientists have tried in vain to find a mechanistic link between both diseases in the hope of facilitating the development of a novel, effective treatment for both diseases. Based on these latest discoveries, we believe that PPAD could be a target for successful therapy or prevention of these crippling diseases.


Tumors of the spleen are rare compared to the incidence of such tumors in other parenchymatous organs. Their classification has varied with both time and author. They can be divided into two main categories: nonlymphoid and lymphoid. The most common nonlymphoid tumors are the vascular tumors which include benign and malignant haemangiomas, littoral cell angiomas, lymphangiomas and haemangioendotheliomas. The remaining nonlymphoid tumors, such as fibrosarcoma, neurinoma, and lipoma are very uncommon. The lymphoid tumors include Hodgkin’s and non Hodgkin’s lymphoma, histiocytic lymphoma and plasmacytoma. Metastatic tumors to the spleen mainly originate from melanoma, breast and lung lesions. However, metastases to the spleen are rare compared to those of other parenchymatous organs. Primary splenic neoplasms are uncommonly encountered in the practice of general surgical pathology, but when present they may require splenectomy for either diagnosis or treatment. The fragile spleen, hidden in its left upper quadrant recess, always presents an interesting and difficult challenge to the surgeon, while the presence of a neoplasm makes it an even harder challenge.No constant clinical features can be fitted to the entire group of splenic tumors. Splenomegaly is the commonest of findings. Upper quadrant discomfort, pain or tenderness may also be present. Anaemia, granulocytopenia and thrombocytopenia are also possible, depending on the localization and the size of the lesion. In case of malignancy, splenomegaly may be accompanied by signs of systemic involvement such as fever, cachexia and pleural infusion. Massive splenomegaly (over 3000 gr) may cause adjacent viscera displacement and pressure, leading to a variety of symptoms, including dyspnoea, shoulder pain and constipation. The most useful imaging test available today is the computed tomography (CT) scan. Histological examination following surgical removal, seems to be the most accurate technique to establish diagnosis.HaemangiomaLymphangiomaLittoral cell angiomaHaemangioendotheliomaBenignHaemangiosarcomaLittoral cell angiosarcomaMalignantHodgkin’s diseaseNon-Hodgkin’s lymphomaPlasmacytomaCastleman’s tumorLocalized reactive lymphoid hyperplasiaInflammatory pseudotumorLipoma, angiolipomaMalignant fibrous histiocytomaFibrosarcomaLeiomyosarcomaMalignant teratomaKaposi’s sarcomaSplenic haemangiomas Figure  remain tDiffuse haemangiomatosis of the spleen is a very rare variant of splenic haemangioma in which the spleen is diffusely replaced by blood vessels of varying caliber . TypicalLymphangioma of the spleen is even less common than haemangioma of the liver, with clinical manifestations ranging from insignificant incidental findings to large, symptomatic multicystic splenic masses requiring surgical intervention -10. The Littoral cell angioma (LCA) of the spleen is a vascular tumor that represents a lesion unique to the spleen, without a soft tissue counterpart . LCAs arPrimary angiosarcoma Figure  of the sRarely malignant splenic vascular tumors are encountered with the morphological features of littoral cell angioma, yet which display malignant nuclear cytology and an infiltrative or solid growth pattern . MacroscHaemangioendothelioma of the spleen is a controversial entity that may represent a vascular lesion with morphologic and clinical properties that are intermediate between those of the haemangioma and angiosarcoma , 23. TheThe spleen is often the site of secondary involvement by Hodgkin’s disease . OverallSplenic involvement is reported in 50-80% in patients with non-Hodgkin’s lymphoma. Primary splenic involvement is much less common. Usually a large spleen with small lesions, possibly microscopic, in other organs, raises the suspicion for a primary splenic origin. As in Hodgkin’s lymphoma, size and weight of the spleen may vary, while they do not correlate with the prognosis of the disease. Macroscopically there can be a diffuse involvement, small nodular lesions, large nodular lesions or a large tumor mass. Many infracts or blue subcapsular dots can be seen. The malignancy of these lesions can be rated following the Kiel pattern or the IWF  pattern. Benign lymphoid lesions may also cause splenomegaly and may mimic lymphoma. Reactive lymphoid hyperplasia and inflammatory pseudotumor have been briefly described. Angiofollicular lymphoid hyperplasia, also known as Castleman’s tumor may also affect the spleen, either as a solitary lesion or as a part of a diffuse lymphoid hyperplasia syndrome. Castleman’s tumor is thought to be a true lymphoid hamartoma, but does not resemble the follicular pattern of splenic hamartoma described by Berge. Primary plasmacytoma of the spleen is exceedingly rare and is not macroscopically recognizable, but is easily identified histologically as a plasma cell neoplasm. The spleen may be involved as a primary, isolated site or as a part of generalized myelomatosis.Lipoma of the spleen is a rare entity. Usually it appears as round mass of lipoid tissue. Angiolipomas have occasionally been reported as well. A number of cases of primary splenic malignant fibrous histiocytoma have also been described. This distinct, polymorphic sarcoma usually occurs in the soft tissues, but has also been found in a number of organs, including the spleen. Massive splenomegaly is usual, while these tumors tend to be very aggressive. Malignant fibrous histiocytoma may be misdiagnosed as fibrosarcoma or leiomyosarcoma, both of which occur in the spleen, but have not been well documented. Neurinoma or schwannoma of the spleen has also been described. There is a single report of a malignant teratoma, with papillary carcinoma, spindle cell carcinoma and cartilaginous tissue.Recently, incidence of Kaposi’s sarcoma has greatly increased, mainly in association with human immunodeficiency virus infection (HIV) and the acquired immunodeficiency syndrome (AIDS). It is a spindle cell malignant neoplasm, characterized by vascular spaces not generally lined by endothelial cells, which may contain blood. Kaposi’s sarcoma has not been described as a primary splenic tumor, but is seen in patients in whom the spleen is involved as part of a general sarcomatosis.Hamartomas or Splenomas of the spleen are rare, benign splenic lesions. They are not neoplasms, but dysplastic nodes that may be misdiagnosed as neoplasms. Most of the cases have been found as autopsy material. Their incidence has been estimated at 3 in 200.000 splenectomies. They occur equally in males and females, at all ages, but particularly in older people. Typically, they appear as well-circumscribed lesion, which appears darker than the surrounding spleen. Their size varies from a few mms to many cms. They are easily recognized microscopically, because of the distinct border and the slit like and tortuous endothelial-lined spaces. Sometimes they can cause splenomegaly, but hypersplenism is rare. Cases of rupture of a solitary splenic hamartoma, with life-threatening haemoperitoneum, have been reported in the literature.Splenic metastases are very rare. Berge reported the overall incidence of splenic involvement as 7.1% in 7165 autopsy cases with various cancers and the incidence of splenic metastasis from colon and rectal carcinomas as 4.4% and 1.6% respectively. However, he did not report any case of solitary splenic metastasis. Anatomical, histological and functional features of the spleen have been speculated as the reason of the rarity for solitary cancer metastasis. Particularly frequent carcinomas of origin are those of breast, lung and melanomas. Direct extension from retroperitoneal tumors and pancreatic carcinoma may be found. Virtually all primary tumors have been shown to be able to metastasize to the spleen, while in most cases splenic metastases occur as a component of disseminated disease. Most cases are reported as asymptomatic and the diagnosis is usually made by the imaging studies such as abdominal ultrasound (US) or computerized tomography (CT) during the evaluation of a rising CEA level in the postoperative follow-up period of colorectal cancer patients. However, splenomegaly, left pleural effusion, spontaneous rupture has been reported.Neoplasms of the spleen are rare entities, which may be a diagnostic challenge. Most of them are asymptomatic and are found incidentally after splenectomies. However, the fragile spleen as well as the malignant potency of a few splenic neoplasms makes their fast and accurate diagnosis imperative for more than a few patients.