The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients.The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug.Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug.Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE). Coping with the outcomes of adverse drug events (ADEs) associated with the use of newly approved drugs, particularly in the elderly, has become a significant problem in both primary care and hospital settings in Australia, and is a major challenge for public health policy worldwide. One in every ten Australian patients who attend a GP in a primary care consultation has experienced an ADE in the preceding six months, and one in twenty has experienced a moderate to severe ADE . This trOlder patients are particularly vulnerable to adverse drug events because of multiple-drug regimens and age-associated changes in pharmacokinetics and pharmacodynamics . PrivileMany older patients suffer from illnesses targeted by newly approved drugs. However factors such as decreasing physiological resilience, the follow-on effects of cumulative morbidities, and effects of the increasing numbers of medications taken to manage these morbidities, together mean that the health profile of older populations is moving further and further away from the characteristics of the populations used in the clinical trials. Despite this lack of fit, it is patients in older age groups who are most frequently being prescribed new drugs as soon as they are approved. The potential for adverse drug events is greater when a new drug is prescribed soon after its release onto the market, and rapid uptake after release can place patients at risk of adverse drug reactions and serious drug interactions through co-prescribing .A recent Australian medical journal editorial called for the development of computerised systems that can deal with the reality that only limited numbers of highly selected patients are studied before a drug is approved for marketing . One sucPharmacovigilance systems rely on spontaneous reporting, and the large majority of adverse events are either not recognised or not reported ,8. It haThe Australian medical journal editorial referred to above identified the need for a computerised system that could focus on detecting early signals of potential ADEs . This paThis section addresses the generic methods underlying the proposed risk identification model. The section entitled Methods (Part 2) illustrates the application of these methods in the case of the clinical trials of the COX-2-selective NSAID rofecoxib and the patient groups who would have been the main target population for that arthritis drug.The first step uses data from reports of RCTs of a new drug. The RCT study design relies on the exercise of a range of controls to minimise bias, and this is done in order to achieve the internal validity that is seen as a scientific gold standard. However, internal validity is often achieved at the expense of external validity. The important issue of concern for older Australians taking new drugs is that though more within-trial controls contribute to an internally valid result, these controls frequently involve the exclusion of potential participants who have the very comorbidities and co-medications that commonly exist in older age groups.The RCT reports of a new drug are examined to identify whether there are age groups, gender, comorbidities and/or co-medications recorded as having been excluded from these clinical trials. Once exclusions are applied in an RCT, for whatever reason, this removes the possibility of gathering evidence on how the new drug will act in patients who, for example, suffer from one or more of the excluded morbidities, and/or who take one or more of the excluded medications.The examination of reports of clinical trials of new drugs should take into consideration the scope of the research questions posed, what data were sought, from whom they were sought, what endpoints were adjudicated, and what were the bases for outcome analyses. In this process, it is important to differentiate between those exclusions which are specifically related to the research questions being asked, and those exclusions which relate to other body systems. For example, a clinical trial of a new drug which is being evaluated for its specific effects on gastric mucosa may have a protocol that excludes persons already suffering from gastric morbidities such as ulceration or bleeding. The exclusion of patients with such gastric morbidities relates specifically to the research question which seeks to evaluate the new drug in relation to its effects on gastric mucosa. However, exclusion protocols relating to morbidities in other body systems are applied for different reasons, and can reduce the availability of important knowledge about the action of the new drug in patients who have those excluded morbidities.Access to information on the clinical trials of a new drug is via published research papers, but these may not always be available, as sometimes they can be withheld by the drug developer until after the drug is approved for marketing. The Australian Therapeutics Goods Administration (TGA) considers the results of Phase 1, 2 and 3 trials for a drug before it approves the registration of that drug for marketing in Australia. TGA approval is also a pre-requisite for any drug to be considered for inclusion in the PBS schedules. The TGA has recently commenced publishing an Australian Public Assessment Report (AusPAR) on each drug that is approved for marketing in Australia. These AusPAR reports are a valuable source of information as they include detailed summaries of the steps in the evaluation process that led the TGA to approve or not approve a prescription medicine submission. AusPARs are modelled on the similar EPAR public assessment report system implemented in the European Union .inter alia, descriptive information, in language intended for the lay public, concerning the purpose of the trial, the study design, the disease or condition being studied, the name of the drug, primary and secondary outcome measures, eligibility criteria, including exclusion protocols, and the trial protocol identifier. The results of all clinical trials carried out in the U.S. are required by law to be made available on the NIH website within 30 days of the approval of a new drug by the U.S. Food and Drug Administration (FDA). These results must include data on participating patient demographics, withdrawals and exclusions from the final analysis, and tables of values for primary and secondary outcome measures, including statistical analyses [Another significant source of RCT data is the U.S. National Institutes of Health (NIH) website. Since 2007, U.S. legislation has mandated that information about all clinical trials that are commenced in the U.S. must be made available on the NIH website with 2 months of the enrolment of the first patient. The sponsor or developer of the new drug must submit to the NIH data which include, analyses . The NIHanalyses . Some 50analyses ,16, so tThe outcome of the first part of the model process is a risk profile of patient groups whose ages, gender, comorbidities and co-medications were not included in the trial, and about whom there are effectively no data on the potential action and potential effects of that new drug.The second step uses de-identified administrative health data to establish the age groups and gender of selected subsets of current real-world Australian patients (e.g. patients over 65 years of age) who have the morbidity targeted by the new drug, and to establish what are the comorbidities suffered by these patients and what are the co-medications they are being prescribed. The process uses morbidity data drawn from the diagnoses fields of hospital separations records which have been linked with medications data drawn from PBS pharmaceutical dispensing records.Under a Memorandum of Understanding between the Western Australian Department of Health and the Commonwealth Department of Health and Ageing, the W.A. Department of Health Data Linkage Unit has established linkages between that State's hospital separations records and the PBS dispensing records held by the Commonwealth Department of Health and Ageing. Using the linked data, it is possible to establish which patient groups have the morbidity targeted by a new drug , and then establish what are the co-morbidities and co-medications associated with these patients . The result is a multi-source health profile of patients with the morbidity of interest.Linked morbidity data can also be sourced from the Commonwealth Department of Health and Ageing Medicare rebate data for approved consultations, procedures and diagnostic services. Using these data would improve and broaden the health profiling process. However, we were looking for proof of the concept, and worked only with two datasets described above.Part of the remit of the newly formed Australian Population Health Research Network is to link de-identified information from key administrative health datasets across State, Territorial and Commonwealth jurisdictions and health sectors to support population-based research. The anticipated outcome benefits are the capacity to improve the safety and quality of health care, assess the effectiveness of preventive interventions, enable longitudinal follow-up of research studies and surveys, and monitor trends in the patterns and costs of health care ,18. The The third step is to take the comorbidity and co-medications risk profile developed from the examination of exclusion protocols applied in RCTs of a new drug, and compare it with the comorbidity and co-medications risk profile developed from examination of the selected subsets of current real-world Australian patients who have the morbidity targeted by the new drug. Where these two risk profiles differ, for example, when there is one or more factors excluded in the clinical trials but present in the real-world population, there is likely to be limited information available about the action of the new drug in those real-world patient groups. The output of the comparison is a risk profile for the selected subsets of current Australian patients who have the morbidity targeted by a new drug, but who could potentially be at risk of an adverse drug event if they are prescribed that new drug in the context of their current age, gender, comorbidities and/or co-medications. The final output of the process is a warning advisory to be circulated to prescribers warning of the lack of information on the action of the new drug in the selected subsets of the national population, and warning that if the drug is prescribed, to closely monitor those patients to whom it is prescribed.When a new drug targets a morbidity experienced by a large number of older patients, implementing the model to assess potential risk should be a priority if the drug is proposed for listing in the PBS schedules, as this is usually the trigger for wide uptake.This section presents a practical application of the generic methods outlined in Methods (Part 1). The data analysed are from 14 clinical trials of the COX-2-selective NSAID rofecoxib, and the comorbidities and co-medications of an arthritis patient cohort aged 65 years and over in the State jurisdiction of Western Australia. These patients formed part of the potential receiving population for rofecoxib.We analysed clinical trial data from 14 RCTs of the COX-2-selective NSAID rofecoxib which were indicated as being available in Australia before February 2001, when rofecoxib was included in the PBS schedules -22, whicThe clinical trials of rofecoxib were checked for information on the trial category (safety/efficacy), trial design, aims and endpoints adjudicated, number of participants, their age range and health status, excluded comorbidities and co-medications, rofecoxib and comparator dosage levels, trial durations, and patient withdrawals. The principal focus was on the comorbidities and co-medications which disqualified arthritis patients from participation in the nine efficacy trials for patients with osteoarthritis (OA) and the two efficacy trials for patients with rheumatoid arthritis (RA).Persons of both genders aged 65 years and over, the age group of interest to us, were represented in the RCTs analysed. We took into account that the COX-2-selective NSAID rofecoxib was developed specifically to relieve the pain and inflammation of arthritis without the gastrointestinal morbidity associated with the use of non-selective NSAIDS to treat arthritis inflammation. As expected, there were consistent applications of gastric morbidity exclusion protocols specifically related to enabling the research questions to be asked. There were also applications of exclusion protocols related to enabling assessment of whether use of rofecoxib resulted in improvement in arthritis symptoms. For example, in an RCT evaluating rofecoxib for its specific effects on improving pain on walking, exclusion protocols required the capacity to walk for some measurable distance in order to be able to evaluate improvement.Of the exclusions relating to other body systems, we also noted the exclusion of participants who had suffered an unspecified active or recent hepatic disease. We recognised that this exclusion was related to ensuring the bioavailability of the new drug to be trialled. In retrospect, it could have been of value to extract de-identified patient data on the level of occurrence of hepatic disease in the over-65 age group with OA or RA. We also noted the consistent exclusion of prospective participants who had suffered one or more of a range of neoplastic events.However, of exclusion protocols relating to other body systems, what stood out in the examination of the reports on the clinical trials of rofecoxib was the exclusion of participants with vascular morbidities, and the exclusion of participants who were taking vascular medications. Patients with OA were excluded from participation in the analysed RCTs of rofecoxib if one or more of the following morbidities applied: adverse cardiovascular factors , adverse cerebrovascular factors , or severe renal impairment (creatinine clearance ≤ 30 ml/min). Patients with RA were excluded from participation in the analysed RCTs of rofecoxib if one or more of the following morbidities applied: adverse cardiovascular factors , adverse cerebrovascular factors , or severe renal impairment (creatinine clearance ≤ 30 ml/min).Figure This exclusion of patients being treated for cardiovascular (CVD), cerebrovascular (CVA) or renal disease meant that, as at February 2001, when rofecoxib was made available through the PBS, there were effectively no data available on the action of rofecoxib in patient groups who were being treated for these morbidities. It was this lack of data on the action of rofecoxib in the presence of CVD, CVA and renal disease, as applied to those arthritis patients in the 65 years and over age group, that was of interest to the researchers.The real-world current patient groups we selected were W.A. patients, male and female, who were aged 65 years and over in 1999 and 2000, and who had either OA or RA, the two major morbidities targeted by rofecoxib. The presence of either OA or RA was to be established based on de-identified PBS medications and hospital morbidity data, and co-morbidities and co-medications data were to be established through links to the OA or RA morbidity or medications data. The years 1999 and 2000 were chosen as arthritis patients in these two year cohorts would have formed the potential target population for rofecoxib.The project was granted institutional ethics approval by Deakin University, and this was accepted by the W.A. Department of Health (W.A. DoH) and the Commonwealth Department of Health and Ageing (DoHA).Using the Australian Statistics on Medicine, we selected a list of PBS Item Codes for high-use OA and RA medications dispensed in 1999 and 2000, and submitted the list to DoHA through the W.A. DoH Data Linkage Unit (DLU). We requested all PBS Item Codes linked to the patients, male or female, aged 65 years and over, who had been hospitalised with arthritis, as identified by a selected list of ICD-9-CM and ICD-10-AM arthritis diagnosis codes (see 3.2.2 below). We also requested person-level PBS dispensing data for non-hospitalised patients dispensed any of the selected high-use OA or RA medications, together with any other co-medications dispensed to these patients. We further requested data on all medications that had been dispensed in the previous year to those patients in the Year 1999 and Year 2000 cohorts who had been prescribed the selected OA or RA medications. Data supplied included age and gender variables.We received 1,370,073 PBS dispensing records definitively linked to W.A. patients aged 65 years and over who had been prescribed one or more of the selected OA or RA medications in 1999, together with data on any medications dispensed to these patients in 1998, plus any PBS medications that had been dispensed to W.A. patients aged 65 years and over who had an OA or RA hospital diagnosis in 1999. We also received 1,817,455 PBS dispensing records definitively linked to W.A. persons aged 65 years and over who had been prescribed one or more of the selected OA or RA medications in the year 2000, together with data on any medications dispensed to these patients in 1999, plus any PBS medications dispensed to W.A. patients aged 65 years and over who had an OA or RA hospital diagnosis in 2000.We also requested de-identified data for all the PBS medications dispensed to any patients who were prescribed rofecoxib between January 2003 and the end of September 2004, when rofecoxib was withdrawn for safety reasons, as we wished to examine what medications were being co-prescribed to patients who were prescribed rofecoxib during this period. We received 3,561,701 PBS medications records for this analysis.Though the medications data for the 1999 cohort were analysed, this paper will report only on the detailed analyses of the medications data from the 2000 cohort, the year prior to the inclusion of rofecoxib in the PBS schedules. As noted in the key outcomes discussed in Section 5, there was a difference of only 1.5% between the year 1999 and the year 2000 medications analyses. The decision to restrict the 1999 medications reporting was linked to issues associated with a change in ICD coding in that year in Western Australia (see 3.2.2 below), as the final cohort analyses for each year were designed to integrate both medications and morbidity data.Analysis of the January 2003 - September 2004 medications data is also addressed in Section 5.Using International Classification of Diseases (ICD) manuals, we selected a list of ICD-9-CM arthritis codes (for Jan-July 1999) and ICD-10-AM arthritis codes (July 1999 - Dec. 2000) which was submitted to the W.A. DoH DLU. The extraction specifications requested person-level hospitalisation morbidity data for all Year 1999 and Year 2000 patients, male or female, aged 65 years or over whose hospital separation records included any of the selected OA or RA ICD codes in either the primary diagnosis field or in any secondary diagnosis field. We also requested hospital morbidity data from any previous year's hospitalisation for those 1999 and 2000 patients.For the 1999 cohort, we received 27,580 hospital morbidity records definitively linked to W.A. patients aged 65 years and over. These records included hospital morbidity data from any patient hospitalisation episode in 1999, the previous year's hospital morbidity data for any 1999 patient who had a hospitalisation episode in 1998, plus 1999 hospital morbidity data linked to any patients who had been dispensed a selected OA or RA medication in 1999. For the 2000 cohort, we received 34,269 hospital morbidity records definitively linked to W.A. patients aged 65 years and over. These records included hospital morbidity data from any patient hospitalisation episode in 2000, the previous year's hospital morbidity data for any 2000 patient who had a hospitalisation episode in 1999, plus 2000 hospital morbidity data linked to any patients who had been dispensed a selected OA or RA medication in 2000.On analysis, the 1999 data showed significant inconsistencies at the rollover from ICD-9-CM to ICD-10-AM. The difference appears to be associated with a greater frequency of application of secondary arthritis diagnoses under ICD-9-CM, or a lower frequency of application of secondary arthritis diagnoses under ICD-10-AM. Given this inconsistency, we continued analysis with morbidity data from the year 2000 only.This section describes the analysis of the medication and morbidity data to support the identification of patients aged 65 years and over who would have potentially been at risk if they had been prescribed rofecoxib. It includes analyses of prescription medications dispensed to this age cohort in 2000, and hospital-confirmed morbidities experienced by this age cohort in 2000.The 1,817,455 dispensing records for the Year 2000 cohort were sorted into two groups: those for selected OA and RA medications, and all other medications. Using the Australian Statistics on Medicine, we selected a list of high-use CVD medications dispensed in 2000, and using this list we sorted all the non-OA/RA medications into three sub-groups: selected CVD medications, all medications dispensed ≥3,000 times, and medications dispensed <3,000 times. All medications dispensed <3,000 times were not further considered.There were 235,088 prescriptions dispensed for the selected OA and RA medications, 514,756 prescriptions dispensed for the selected CVD medications, and 653,793 prescriptions in the category of medications dispensed ≥3,000 times.Further analysis focused on the CVD medications group, as CVD medications and morbidities were subject to exclusion protocols in the RCTs of rofecoxib which were available prior to February 2001, when rofecoxib was included in the PBS schedules. All OA/RA medications and CVD medications were analysed to develop a person-level summary of these medications as dispensed in 2000.Of the 58,968 patients in the 2000 cohort aged 65 years and over who were prescribed OA/RA medications, 40,495 were co-prescribed CVD medications ; 5% of patients who were prescribed OA/RA medications and also had an OA/RA hospital diagnosis; and 47% of patients who were taking OA/RA medications suffered had hospital diagnoses for one or more of cardiovascular, cerebrovascular and renal disease  to ascertain what other medications were being taken by those persons during that period. Of the 38,010 persons prescribed rofecoxib in that period, 67% were also being co-prescribed medications to treat CVD, a potential indicator of a lack of awareness of the link between cardiovascular risk and use of the rofecoxib arthritis drug. Prior to its voluntary safety withdrawal in September 2004, it has been estimated that rofecoxib was implicated in more than a thousand ADEs in Australian patients, of which about 30% resulted in deaths .It is essential that there is a timely source of risk information concerning new drugs, and this source must be independent of the product information provided by the new drug's manufacturer, or by representatives of that manufacturer who visit medical practices. Identification of likely or possible risk should be undertaken before there is the opportunity for a problem to be realised.Had we assembled all the relevant information we now know to have been available in Australia before the PBS listing of rofecoxib, we could have identified the discrepancies between the profile of the OA/RA patients included in the analysed rofecoxib RCTs and the profile of the local OA/RA patient groups aged 65 years and over. The restriction of cardiovascular, cerebrovascular and renal disease exposure in rofecoxib trial patients, and the limitation of cardiovascular adjudication in most of the analysed RCTs, could together have served to indicate a significant shortfall in knowledge about the action and effects of rofecoxib in those disease contexts, and pointed to the potential risk of ADEs in patients with these diseases if they were to be prescribed the drug. These patients could then have been advised to take a different NSAID, paracetamol, or other treatment option. The rofecoxib-associated morbidity and mortality adverse events in Australian patients could have been reduced using data that was available before they occurred.Implementing the model process described in this paper before a newly released drug is included in Australian PBS schedules could support production of a profile of patient groups potentially at risk of an ADE if prescribed that new drug in the context of their age, gender, comorbidities and/or co-medications. This risk information could then be communicated to prescribers, and would serve to promote caution until more is known about that new drug. This, in turn, would have the potential to reduce ADEs at the time when the risk is greatest.Prospective identification of risk would make a valuable contribution to the health of the increasing numbers of older patients with multiple morbidities who are being co-prescribed new drugs soon after they are released.The authors declare that they have no competing interests.MW conceived the idea, worked with CP to design the study, and wrote the draft paper. SR designed and undertook all the statistical analyses of the hospital and pharmaceutical data. CP worked on the design of the study, provided interpretative feedback to MW and SR during the statistical analyses, and revised the draft paper. LE worked with MW and CP at the design stage, and revised the draft paper. All authors have read and approved the final manuscript.MTW  undertook work for this project when she was a Research Fellow at Deakin University. Her principal academic focus is on developing systems to support reduction of medication-related adverse events in older persons. CMP (PhD MFM MBBS FRACGP FACRRM FAICD FACHI) is Adjunct Associate Professor in General Practice, Monash University, and a practicing GP and Emergency Medicine specialist. He is Director of Research, Melbourne East General Practice Network, Visiting Fellow, Australian National University, and Clinical Lead, National E-Health Transition Authority. He joined the project as he was interested in how IT could be used to support reduction of medication-related adverse events in older patients in the primary care setting. SCR (BSc Hons) joined the project when he was Research Officer, School of Population Health, University of Western Australia. He has been involved in statistical analyses of linked administrative health data for over 10 years. EJE  is Associate Professor, Sociology of Health, Deakin University. She has had a long-term involvement in improvements in public health and quality of life, and she was interested to see if we could develop a tool that would assist in improving the quality of life for older persons.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/361/prepub


This article addresses first the definition of a (care) pathway, and then follows a description of theories since the 1950s. It ends with a discussion of theoretical advantages and disadvantages of care pathways for patients and professionals. The objective of this paper is to provide a theoretical base for empirical studies on care pathways.Pubmed and other literature databases, and with the keywords integrated care pathway, clinical pathway, critical pathway, theory, research, and evaluation. One of the inspirational sources was the website of the European Pathway Association (EPA) and its journal International Journal of Care Pathways. The authors visited several sites for this paper. These are mentioned as illustration of a concept or theory. Most of them have English websites with more information. The URLs of these websites are not mentioned in this paper as a reference, because the content of them changes fast, sometimes every day.The knowledge for this chapter is based on several books on pathways, which we found by searching in the digital encyclopedia Wikipedia. Although this is not usual in scientific publications, this method was used because books are not searchable by databases as Pubmed. From 2005, we performed a literature search on  In 2007, Vanhaecht et al.  defined “A care pathway is a complex intervention for the mutual decision-making and organisation of care processes for a well-defined group of patients during a well-defined period.Defining characteristics of care pathways include:an explicit statement of the goals and key elements of care based on evidence, best practice, and patients’ expectations and their characteristics;the facilitation of the communication among the team members and with patients and families;the coordination of the care process by coordinating the roles and sequencing the activities of the multidisciplinary care team, the patients and their relatives;the documentation, monitoring, and evaluation of variances and outcomes, andthe identification of the appropriate resources.The aim of a care pathway is to enhance the quality of care across the continuum by improving risk-adjusted patient outcomes, promoting patient safety, increasing patient satisfaction, and optimizing the use of resources.”This paper is based on this authoritative definition from the European Pathway Association (EPA) with the following comments. The expression ‘care pathway’ is leading, not the words “integrated care pathway”, ‘clinical pathway’ or ‘care street’. The term “integrated care pathway” is longer than necessary. Care pathways (as defined above) are per definition integrated. Fragmented care pathways cannot exist. The term ‘clinical pathway’ is reserved for the path within a clinic, or a 24-hour department of a hospital. A care pathway is longer and includes outpatient department’s activities, discharge from the hospital and after-care. A transmural pathway or disease management pathway [The term ‘care street’ is a pathway within a specific architectural setting. If the latter follows and facilitates the “sequencing activities of the Multidisciplinary Team” (see definition above), then it is a care street. Good examples of care streets are seen at the Eye Hospital Rotterdam, the Coxa Hospital for hip and knee patients in the Finnish city of Tampere and the Shouldice Hernia Centre at Thornhill, Canada, which annually treats 7000 hernia patients. If a hospital or hospital division focuses on certain patient groups such as the examples mentioned here, it is a focused factory, a term that Skinner introduced in 1974. A traditional name is a categorial hospital for, for instance, rehabilitation or epilepsy. The annex of the Reinier de Graaf Hospital in The Hague in the Netherlands is an example of a focused factory designed exclusively for elective, not complicated and not-emergent interventions.The concept of a care pathway is one of the concepts from the field of Health Operations Management , described by Vissers and Beech as the analysis, design, planning and control of all the steps necessary to provide a service to a client . They dia care plan for each individual patient (patient planning and protocol);the planning of care in care pathways (patient group planning and control);the capacity planning of professionals, equipment and space (resource planning and control);the planning of the number of patients to be treated and care activities to be carried out (patient volume planning and control), andthe long-term policy of the institution (strategic planning).They emphasize the connection between these five levels. They point out the expected difficulties in introducing care pathways without taking into account any changes in scheduling systems for individual patients (level 1) and for example the capacity planning of the number of professionals and equipment (level 3). And if a pathway increases the number of patients entering the system, this will lead to decision on level 4 and 5.Vissers and Beech distinguish two types of logistic management of care processes:managing care units, andthe management of care processes, for instance with care pathways.A care unit can be a health centre, an outpatient clinic, a day care centre, a laboratory, a radiology department, an operating room or a nursing ward. In such a unit logistic management is aimed at optimizing the occupancy rate of professionals and equipment. For professionals, for example, it is about avoiding gaps in the appointment schedule and about equipment such as a CT scan not being used. When managing care processes in institutions, it is important to optimize the total flow time, or the total amount of time a patient is under treatment within the institution. One approach can contradict the other if the care pathway planning (see level 2 above) and the capacity planning are not geared to one another.Although the use of care pathways seems new for health services, the thoughts on this already exist for decades within the (defence) industry. In the 1950s, the critical path method  (CPM) beThis diagram shows the starting point (circle one) as well as the end (circle 2) of a care pathway in an emergency department. The arrow in between indicates an activity (e.g. triage) that lasts up to five minutes.Connecting all activities within a project shows how the duration of a project can be shortened by starting activities sooner or increasing parallelism. In later years, the graphical display of care pathways has become an art in itself. Mould et al. provide a fascinating overview of this . The CPMThe Six Sigma approach has five steps that together form the word DMAIC:Define: defining the problem and coordinating the project organisation;Measure: making the process performance concrete, i.e. a baseline run;Analyse: underpinning the causes of the problem;Improve: re-designing and optimizing the work process;Control: implementing and securing the improvements.The method is particularly suited for high volume standard processes and possibilities for precise result measurement. The benefits of Six Sigma occur in the way bottlenecks and results can be interpreted in figures. In the 1990s, Six Sigma spread all over the world thanks to its success with large US companies. Since 2008, the UMC Groningen and the Reinier de Graaf Hospital are two of the hospitals in the Netherlands working with Six Sigma.Parallel to the development of Six Sigma, Toyota managed to become one of the ten largest companies in the world thanks to ‘lean production’. And thanks to its lean production focused on creating value, the company reduced the intermediate supply and the waiting times for the activities within the factory. The Just-In-Time (JIT) concept is a part of this management philosophy. Another concept that fits in is COUP or the “Customer Order Uncoupling Point”: the point where the customer order requirements penetrate a company. Before COUP, purchase and production are based on stock. After COUP, they are based on the customer order. Translated into care pathways, this means, on the one hand, a planning without the professional actually knowing the particular patient and, on the other hand, a planning for specific patient needs. The advantage of a ‘lean’ management philosophy is that several techniques can be combined.In the 1980s, Toyota combined its approach with Six Sigma from Motorola. Vissers and Beech  mention In the 1990s, besides toyotism, the concept of business process redesign (BPR) came up. This was started by the articles of the Americans Hammer  and DaveThey have customers, either within or outside the company; andThey run throughout the organisation and often go beyond department limits.Davenport and Short also emphasize the importance of information technology to design these processes and to track whether they keep running the way they were designed to. For the redesign of processes, Davenport and Short mention four goals:cost reduction;flow rate reduction;improvement of the quality of service; andimprovement of job satisfaction.Their articles had an enormous impact on corporate America. Many articles and books relied on BPR. American and Canadian Hospitals introduced BPR in the 1990s [The Goal [Another development related to CPM and PERT is the Theory of Constraints (ToC). The Israeli business consultant Goldratt has presented this theory in 1986 in his book The Goal . The ToCGoldratt distinguishes five focusing steps:Identify the limiting factors .Decide how the limiting process is used (ensuring that the limiting process does not waste time doing things that it should not do).Ensure that all processes are adapted to the limiting process .Expand the limiting process (if possible and necessary—permanent increase of capacity).If, as a result of these steps, the bottleneck has moved, start over from step 1.The five focusing steps are aimed at continuous improvement around the bottlenecks. In ToC literature this is known as the Process of Ongoing Improvement (POOGI). In 1216 (!) pages the ToC Handbook  publisheThe past ten years, care pathways were given a boost in the Netherlands because of the creation of multidisciplinary guidelines, on which they can be based. A good example are the integrated cancer care pathways, established in 2009 and based on the in previous years established multidisciplinary guidelines for doctors, nurses and other professionals . AlthougIn recent years, health care providers in the Netherlands developed many new care pathways. They are process innovations that focus on improving the organization of care processes. These innovations can be distinguished from product innovations like new, scientifically proven diagnostics, treatment with drugs and equipment. Sometimes a product innovation necessitates a process innovation, for example, if oral rather than intravenous drug therapy becomes possible by a new drug entering the market. Process innovations also differ from system innovations, with different legislation, financing and legal responsibilities. Sometimes a new care pathway is not possible, because a system innovation is not realized simultaneously. If, for example, an emergency physician is not authorized by law to admit a patient (as is the case in the Netherlands) but first has to ask a surgeon for permission, a new care pathway will not lead to a shorter time of stay for patients in the emergency department.Nowadays, in addition to new care pathways four other process innovations are also counting, namely the specialized outpatient clinic, the one-stop shop, task transfer and telecare. The specialized outpatient clinic (cf. the aforementioned focused factory), is visited by patients with similar care needs and different diseases. This clinic has a multidisciplinary character. A good example is the Falls Clinic, where patients are seen after a fall by, for example, a geriatrician and a nurse and if necessary by a neurologist, ophthalmologist or orthopaedic surgeon. A good example of a Fall Clinic is the Kennemer Gasthuis in Haarlem in the Netherlands. When this outpatient care takes place in one single day, it is the aforementioned one-stop-shop. Both the specialized outpatient clinic and the one-stop-shop usually require the design of care pathways to, within and from these units.Task transfer from, for example, a general practitioner to a nurse practitioner or from a cardiologist to a physician's assistant is also a process innovation. The care pathways to be developed often play a major role in achieving a division of tasks between initially present professionals and newcomers. Telecare as a process innovation is to replace a face-to-face contact between patient and professional by a contact via the internet, where both parties are separated in time and space. In this case the website could take over parts of the interaction by autonomously asking questions and draw preliminary conclusions based on the responses of the patient.Telecare also requires the design of a pathway with:a division of tasks between the patient, the website and the professional;easy transition from a remote contact to a face-to-face contact and vice versaa maximum flow time for answering e-mail or other messages, e.g. four hours.Care pathways differ because patients, flow times and guidelines differ. Furthermore, there is a difference between acute and elective care pathways. The last one differs from emergency care, since the starting time of care can be planned and for common interventions the duration can be planned too, within reasonable reliability margins. There are hospitals that year after year show stable waiting times for procedures that can be planned, such as cataract and bypass surgery. Although over time, there is an increase in capacity of professionals, rooms and equipment, the access time remains a few weeks. If so, a newly developed care pathway, in combination with a catch-up effort, can help.In emergency care this is less often the case. The starting time of care is difficult to plan, it is often hardly or not postponable and duration of elective care can also vary enormously. If a provider offers both elective and emergent care, the first mentioned care could still be delayed due to the priority of an emergency patient. With the differences between emergent care and elective care it is theoretically interesting to offer two separate care pathways for both developments within separate units. The law of large numbers makes it appealing to concentrate all emergent  care in one department, the EAU (Emergent Admission Unit). In five Dutch hospitals such EAUs have since been set up, all working with their own emergent care pathways.The concept of care pathways has its roots in the above-mentioned management theories: Critical Path Method, Lean Six Sigma, Business Process Redesign and the Theory of Constraints.These theories mention the following general theoretical advantages:Shortening the duration of the production process by reducing waiting time between divisions of the same organization and by simultaneously running sub-processes that take place analogously ;The increase in coherence due to explicit analysis of the relationships and interactions between departments that are involved in the production;Reducing the risk of errors (particularly Lean Six Sigma);The reduction of the cost of the production process through standardization, by avoiding employee waiting times and underutilization of equipment, and by avoiding duplication ;Increasing the job satisfaction of employees as job descriptions and responsibilities derived from the work process become clearer . Clarity within the set framework offers more autonomy, allowing employees to start a routine act independently without waiting for the approval of superiors.Each of the above management theories yielded substantial savings for large companies as shown to us by the cited references. But some disadvantages are mentioned too:The dehumanisation of work because employees rarely have room for own creativity, for the whole production process is set up in phases and provided with a maximum duration;The increase in costs because data collection on the production process and control of errors and defects are expensive;Reduction of job satisfaction because employees do not get enough time for their activity and have no extra time to relieve stress;Reduction of job satisfaction because the variation in work decreases.Theoretical advantages of care pathways for patients and professionals:Do the mentioned advantages also apply to patients and health professionals, who are involved in the care pathway?Advantage 1 is shortening the duration of the production process with faster diagnosis by parallelization of sub-processes every patient benefits. The earlier the diagnosis is established, the sooner treatment can begin and the shorter the period of uncertainty without diagnosis. If the treatment time is also shortened, a patient will recover faster.Advantage 2 is the increased coherence. Greater consistency of care between different professionals provides a better overview for the patient, reduces the risk of opposing opinions and therapies, and increases the opportunity for patient empowerment.Advantage 3 is reducing the risk of errors. Naturally, the reduced chance of errors in diagnosis and treatment works in favour of the patient.Advantage 4 is the reduction of costs. Avoiding duplication  is also in favour of patients, professionals and others. Shortening hospitalization and reducing the number of outpatient visits lead to reduction of costs.The last advantage is related to increasing job satisfaction. When frameworks and protocols are clearly defined and coordinated between occupational groups, there is more room for freedom of action. With this increased autonomy, a nurse can start acting independently and work ahead. Dedicated, passionate professionals provide better care for the patient.Care pathways also have theoretical disadvantages as mentioned here above. The first disadvantage is the dehumanization of work. The relationship between the health professional and the patient is less personal, the care pathway reduces the patient's choices. Furthermore, a maximum time for each patient may compromise the quality of care. Because of these time limits some care providers in Holland compare nursing according to a care pathway with stopwatch nursing and with wash streets for cars. The second disadvantage is an increase in costs. Checking for errors and defects is a costly activity and brings the professional in the position of being controlled, which could easily turn into mistrust. Furthermore, the control of errors and defects may lead to more limited access to the care pathway for patients with poor physical condition. For these patients have greater risk of, for example, postoperative infections, and a higher mortality risk. The third disadvantage is that a care pathway may lead to lower job satisfaction. If professionals get too little time to prepare and too little contact time within the care pathway, this reduces the probability of a correct diagnosis and treatment, and increases the likelihood of poor communication between patient and professional. It diminishes the dedicateness and passion of professionals. The last disadvantage is the decline of diversity in the professional work. If experienced professionals rely too much on routine, because they work within one single care pathway and always see the same types of patients, there is a chance of increasing indifference, cynicism and reduced empathy with the patient.So far the advantages and disadvantages of care pathway as deducted for general theories.In the 1950s and 1990s of the last century, the mentioned Critical Path Method, Six Sigma, Lean, Business Process Redesign, and the Theory of Constraints led to a shift compared with the paradigm of Taylor's scientific management (based on preproduction and subsequent costing of products and services) and compared with the bureaucracy model of Max Weber  . Care paIt is not surprising that there is a period of approximately fifty years between the scientific development of the Critical Path Method and the present innovative pathways in health services. In the history of science, there are often decades between discovery  and innovation . In the U.S. health care there appears to be a period of seventeen years between the discovery of a drug or other innovation and its application in health care [Applying care pathways in health services may lead to advantages and disadvantages for patients and health professionals. For managers and policy-makers this implies that their effort should be focused on maximizing the advantages and minimizing the disadvantages. For  researchers this implies that they use the right definitions to describe care pathway within a context of integrated care, disease management and health care innovation. The list of advantages and disadvantages of care pathways in this paper could be used as a checklist in empirical evaluation studies.John Bowers, Professor of Management Science, Stirling Management School, University of Stirling, UKJan Swinkels, MD, PhD, Psychiatrist, Professor in Clinical Guideline Development in Health Care, Academic Medical Centre, PO Box 22660,1100 DD Amsterdam, The NetherlandsClaire Whittle, Associate Dean, Academic Affairs and Business Development, Faculty of Education, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham B9 5SS, UK


Cardiovascular diseases are a public health concern everywhere, especially ischemic or coronary heart diseases (CHD) which are on top of causes list of mortality and morbidity in both genders globally. From which nearly 80% can be because of modifiable risks. In Egypt, there is a lack of studies on the knowledge of people about coronary heart diseases and its modifiable risks. So, this research reported here we designed to measure the dimensions of peoples knowledge about CHD and their attitude towards prevention, and to identify the main risk reduction barriers.By using comprehensive cross-sectional, descriptive research design, all adult individuals attending the family health clinic at Suez Canal University Hospital were eligible for inclusion with total number 125 participants. An interview questionnaire designed and used to collect data.The study revealed that (10.4%) of participants had a history of CHD, and (7.2%) had a family history of CHD. 79.2% Had a satisfactory total knowledge about CHD, and (94.4%) had a positive total attitude towards prevention. Risk reduction barriers as a medical setting barriers were (24%), patient related barriers were (22.4%). Community-societal barriers were almost the same as knowledge barriers which were around (16%). At last the systemic-organizational barriers were (9.6%).The findings settled that, total knowledge about CHD was satisfactory but lower than the level total of attitude. More effort the health system needs to improve the settings and engage patients in their plans and breaking related barriers, with development of health education programs based on needs assessment. Further studies we recommend to explore the reasons and follow up the changes. Cardiovascular diseases are a public health concern everywhere, especially ischaemic or coronary heart diseases (CHD) which are on top of causes list of mortality and morbidity in both genders globally  CHD is aGlobally and within the region the sedentary life, high fat diet, high blood pressure, smoking, diabetes, obesity, dyslipidaemia and stress are the main risks which lead to increased prevalence of CHD and especially in Egypt  The WorlThe region countries are suffering from a tow fold burden, from both infectious and non-infectious diseases, where shortly the non-infectious diseases will be the most. And as shown from the data that CHD will impose the highest within the cardiovascular diseases and the country′s burden of disease in men and women , 5. It iPresence of the different risk factors affects the CHD mortality, specially high blood pressure, cholesterol level, smoking, physical inactivity, stress and diet. Up to 90% of mortality cases have a risk factor or more because of their different living style , 6.Where in Egypt the major risk factors prevalence are as the following; smoking is nearly 48% for men and 4% for women, hypertension is almost 31% . DM is 7Where is a fairly long time between exposure to a risk factor and development of disease, so there is a need to focus efforts on the risk factors that predict disease. As well the risk factors distribution within the population is needed for planning of prevention.Health systems need a preventive tactics which focus on the population as a whole, and specifically on the people at high risk of certain diseases. Prevention can be effective but it is usually missed. More than half of deaths because of CHD occurred outside the health facilities for that, the role of primary prevention is increasing and risk factors identification and barriers to risks reduction is getting more valuable  StartingMen, as well as women should be more aware of their own risk of developing CHD and of the manifestations of CHD. Doctors should ask patients more deeply and comprehensively about their illnesses understanding, beliefs, and attitudes to check their knowledge , and defIn Egypt, there is a lack of studies on the knowledge of people about coronary heart diseases and its modifiable risk factors. So, this research reported here was designed to measure the dimensions of people;s knowledge about CHD and their attitude towards prevention, and to identify the main risk reduction barriers. This study will contribute to the existed knowledge and will add more understanding to the risk factors that we can prevent and control. As well as a step for breaking down the barriers.This study aimed to identify People's knowledge about coronary heart disease, their attitude towards prevention and main risk reduction barriers. That was achieved through measuring their knowledge and attitude towards CHD, its risk factors and identification of the main barriers for achieving the risks reduction.Study design: we used the comprehensive descriptive cross-sectional study design to assess the knowledge, attitude about CHD, the possibly related variables and the main risk reduction barriers.Study setting: This study was carried out in Ismailia governorate, Egypt. It has a population  of about 750,000, on the west bank of the Suez Canal, nearly halfway between Port Said to the north and Suez to the south.Population and fieldwork: All adult individuals, males and females, attending the family health clinic at Suez Canal university hospital within the inclusion criteria, 18 and older and willing to take part in during the time of the study. On obtaining the official permits, and after preparation of the study tools, the data collection ran for 3 days per week (clinic working days) over 3 weeks duration. The researcher approached eligible individuals according to inclusion criteria, explained to them the purpose of the study, asked their willingness to take part in, and obtained their verbal consent. All participants interviewed using the questionnaire form, and the responses marked by the researcher to avoid any bias in data collection.Sampling: Through a comprehensive random sample within the determined time of the data collection, all individuals fulfilling the inclusion criteria were included: 125 participants, 51 males and 74 females, with no refusal cases for taking part in the interview.Data collection tool: the interview questionnaire we designed based on relevant literature, experts’ opinions and field-testing. It consisted of Personal data (demographic characteristics and socioeconomic data), Medical history, Family history, Knowledge about coronary heart disease, Attitude towards prevention and lastly Barriers for risk reduction. With timing of 10-15 minutes to be marked.Scoring: For the knowledge items scoring was carried out by evaluating the total knowledge through responding to 12 questions asking about the different aspects of knowledge. Disease definition, presentation, main risk factors, fatality and seriousness, early treatment and control, and lastly the main risk factors relative to the incidence of the disease. Right or positive answer was given 2 points and wrong or negative answer was given 1 point. Resulted in a scale for weighting the total knowledge (lowest score was 12 and highest score was 24). Satisfactory level of knowledge chose to be over 75% of total score (>18 points)In The same principle the total attitude was scored as the following. 1 point was given to the answer (insignificant), and 5 points were given to the answer (very Important), 4, 3 and 2 points were given to the answers  respectively. Answering 5 questions reflecting the attitude aspect Resulted in a scale for weighting the total attitude towards prevention (lowest score was 5 and highest score was 25). Positive attitude chose to be over 75% of total score (>18.75=19 points)Ethical considerations and human rights: A verbal consent was taken from all the studied individuals before the beginning of the study. Complete confidentiality of the data ensured. The investigator provided counseling to participants if needed or requested. Participants had the right to leave and stop the questionnaire.Data analysis: Statistical analysis carried out by using SPSS -V18.0 statistical software packages.Frequencies and cross tabulations were generated and A chi-square test was used to see if there is a relationship between the categorical variables. Chi-square test, is assuming that the expected value for each cell is five or higher, and statistical significance was considered at p-value <0.05.The socio-demographic characteristics of study participants are described in As shown in About participants’ attitudes towards prevention of CHD, The main barriers preventing from achieving risk reduction as in The association between the total knowledge and socio-demographic characteristics of study participants as in The association between the total attitude and socio-demographic characteristics of study participants reflected the association between total attitude to marital status, job and special habits. But for the association between the total attitudes, medical and family histories there was only an association with family history of chronic heart disease. Also there was an association between the total knowledge and the total attitude.This study aimed to identify people's knowledge about coronary heart disease, their attitude towards prevention and main risk reduction barriers. In disagreement with the study prevalence findings for CHD and risk factors in participants, an American report in 2003 showed that a large part of the US population had multiple risk factors for heart disease . MoreoveIn studying the knowledge of the studied sample, in the present study, about the risk factors related to CHD, smoking was the most recognized factor by most of the studied participants. Besides, most of them had a positive attitude towards smoking cessation as a preventive measure for CHD. Explained by the increased preventive measures targeting smoking, also spreading awareness among the population all over the country through all mass media Another explanation was the higher number female participants in the present study, who were mostly non-smokers.About the knowledge of the modifiable risk factors among all participants, the studied factors were recognized by half of the participants. The total knowledge score found to be satisfactory by most of the participants. Moreover, the data showed that most of them had a positive attitude towards all preventive measures. However, the study also reported several barriers to prevention and achieving risk reduction. In this context, surveys of CHD prevention-related services such as: smoking cessation advice, treatment of lipid disorders, physical activity assessment and counseling are disappointing . We shouKnowledge about the disease presentation was correct among most of the participants in the present study. This higher awareness might be because of that chest pain, which is one of the most important symptoms in CHD, and the most feared symptoms. The high-level of awareness about this symptom we quietly expected it, and was in line with the current trends. Patient with a recent onset of chest pain, especially when the symptoms are constant, should be transported immediately to the emergency .Also agreed with the present study findings, the data reported on the signs and symptoms of heart attack and stroke in New York State 2003 had showed that recognition of symptoms ranged from 42% to 93%. Chest pain or discomfort has been the most often recognized symptoms (93%)  Further,Although a good percentage of the studied participants recognized the disease presentation, only slightly more than half recognized the seriousness of the disease while most of the participants recognized the importance of early treatment and control. Such inconsistency might lead to the delay in time for treatment. For that It should be kept in mind that knowing the disease presentation is not the only factor that affects the time to treatment, other factors also need to be considered .Within this study, a satisfactory total knowledge level about CHD was revealed among four fifths of the participants. Also, most of them had a positive total attitude. These figures are higher than the similar ones in other studies. Surveys conducted by the AHA between 1997 and 2003 have shown that the awareness of heart disease ranges from 30% in 1997 to 46% in 2003. Excellent awareness was reported by less than half of the population .About the attitude towards CHD, in 1997, a telephone survey of 1000 US households found that only 8% of population respondents identified heart disease as their greatest health concern. The same survey showed that less than one third identified heart disease as the leading cause of death . These fAccording to the present study findings, the association between attitude towards prevention among participants, their personal and family histories revealed no association except for the association with the family history of coronary heart disease. This is in disagreement with the claim that, patients who did not experience chest pain during the acute event had significantly different attitudes than those who did .In the present study, obviously the total knowledge score was associated to marital status and educational level. However, it was not associated to age, gender and income level, which in contrast with 2003 results where were people from lower income and certain age groups lag behind the rest in their recognition of these symptoms .The findings are also in line with the results of a study done in two New England communities where knowledge was higher among more educated individuals . SimilarIn the present study, the relation between participants’ attitude towards prevention and their socio-demographic characteristics pointed that, there was no association between attitude and gender. As well as between age and total attitude, where there was no association. These findings are in contrast with the results of 2005 which had also suggested that educating women and interpreting the symptoms of CHD remain significant obstacles in reducing decision time . Also, oThe data of the present study showed that, there was an association between knowledge about CHD and attitude towards prevention among participants in the current study. This means that increased knowledge would lead to improved attitude. This is in line with the findings that have emphasized that, interventions based on simple messages, for example knowledge about disease presentations and dealing with it is still being recommended . Lastly,Finally, this study only examined modifiable risk factors and did not include other fixed risk factors, for example age, gender and family history of coronary heart diseases , 17.It is concluded that, the level of satisfactory knowledge about CHD and positive attitude towards prevention were higher than expected, but with no statistical significance related to gender or education. There were a highly reported percentage of medical setting related barriers and patient related barriers that were preventing from achieving the risk reduction actions. Therefore, it is recommended to strength the role of doctors in the development and application of health prevention and promotion programs towards CHD and engage patients and families into the risk reduction plans. Further in-depth studies are needed for more accurate results and confirming the findings and cover the limits of the quantitative studies, by using focus group discussions or interviews and using qualitative methods as well.


Although the number of newly detected leprosy cases has decreased globally, a quarter of a million new cases are detected annually and eradication remains far away. Current options for leprosy prevention are contact tracing and BCG vaccination of infants. Future options may include chemoprophylaxis and early diagnosis of subclinical infections. This study compared the predicted trends in leprosy case detection of future intervention strategies.Mycobacterium leprae (“no BCG”); no BCG with chemoprophylaxis; and no BCG with early diagnosis.Seven leprosy intervention scenarios were investigated with a microsimulation model (SIMCOLEP) to predict future leprosy trends. The baseline scenario consisted of passive case detection, multidrug therapy, contact tracing, and BCG vaccination of infants. The other six scenarios were modifications of the baseline, as follows: no contact tracing; with chemoprophylaxis; with early diagnosis of subclinical infections; replacement of the BCG vaccine with a new tuberculosis vaccine ineffective against Without contact tracing, the model predicted an initial drop in the new case detection rate due to a delay in detecting clinical cases among contacts. Eventually, this scenario would lead to new case detection rates higher than the baseline program. Both chemoprophylaxis and early diagnosis would prevent new cases due to a reduction of the infectious period of subclinical cases by detection and cure of these cases. Also, replacing BCG would increase the new case detection rate of leprosy, but this effect could be offset with either chemoprophylaxis or early diagnosis.M. leprae, it is crucial to continue developing immuno- and chemoprophylaxis strategies and an effective test for diagnosing subclinical infections.This study showed that the leprosy incidence would be reduced substantially by good BCG vaccine coverage and the combined strategies of contact tracing, early diagnosis, and treatment of infection and/or chemoprophylaxis among household contacts. To effectively interrupt the transmission of  Leprosy is a contagious disease that will remain prevalent, despite the declining number of patients worldwide over the last century. With approximately 250,000 new cases detected annually, leprosy is far from being eradicated. Leprosy can be treated with drugs after disease detection.Some cases can be prevented with a tuberculosis vaccine (BCG) that cross-reacts with the bacterium responsible for leprosy, but this vaccine might be replaced in the future. Furthermore, preventive drugs can reduce the number of new cases among people in contact with infectious patients, but this strategy has not yet become established in common practice. Also, a new test is under development for the detection of infections before the appearance of symptoms.In this study, we used a computer model to assess the effectiveness of seven possible leprosy control activities. Our results showed that the decline in incidence of leprosy would slow down or halt with the introduction of a new tuberculosis vaccine that is ineffective against leprosy. However, this effect could be offset by the implementation of effective tests for early diagnosis or the routine administration of preventative drugs to contacts of patients. The global new case detection rate of leprosy has dropped considerably during last century, but with approximately 250,000 new cases detected annually, leprosy is far from being eradicated Other recent developments however, are cause for concern. For example, the integration of leprosy control activities into general health care programs has in many countries led to the cessation of active case finding and contact tracing. Consequently, diagnosis is delayed and patients are therefore infectious for a longer period causing more people in contact with patients to become infected.Mycobacterium lepraeAnother concern is that a new vaccine may replace the current Bacillus Calmette-Guérin (BCG) tuberculosis vaccine, which is given to infants to prevent tuberculosis (TB), but which also protects against leprosy Although the short-term effectiveness of new interventions can be assessed in trials, extrapolation to long-term effectiveness in the general population is difficult, due to the complex impact on transmission dynamics. Hence, dynamic simulation models are necessary to assess the possible impact of different intervention strategies on future trends in the new case detection rate of leprosy.We have developed a microsimulation model that simulates the transmission and control of leprosy (the SIMCOLEP model), taking into account the population structure of households For the COLEP trial (ISRCTN 61223447), on which the data of this modeling study is largely based, ethical clearance was obtained from the Ethical Review Committee of the Bangladesh Medical Research Council in Dhaka (ref. no. BMRC/ERC/2001–2004/799). All subjects were informed verbally in their own language and invited to participate. Written consent was requested from each adult. For children consent from a parent or guardian was given.The microsimulation model simulates the life history of fictitious individuals An individual that is susceptible to leprosy is defined as an individual that developed leprosy sometime during their lifetime, after acquiring the infection. The large majority (say 80–95%) of the population is assumed not to be susceptible to leprosy Random ; Household susceptibility ; Dominant (susceptibility is inherited by a dominant gene); Recessive (susceptibility is inherited by a recessive gene); Household & dominant (50% of susceptibility is determined by the Household and 50% by a dominant gene); Household & recessive inheritance (50% of susceptibility is determined by the Household and 50% by a recessive).The mechanisms underlying leprosy susceptibility are currently unknown Random it turned out that 20% susceptibles provided the best fit, whereas this was 10% for the other mechanisms. For Household this 10% was established by assuming on average 25% of the households contain on average 40% susceptible individuals.As described in a previous paper The quantification of the model is based on the leprosy situation in 2003 and the control program of the last decades in the Nilphamari and Rangpur districts of Bangladesh For a full and detailed description of the model, we refer to our previous paper In the study we considered seven potential intervention scenarios for the future control of leprosy. The baseline scenario was the current leprosy control program in the Bangladesh study area, as described above. The other scenarios were modifications of the baseline control program. These other six scenarios were: 1) no contact tracing; 2) with a single chemoprophylactic dose of rifampicin, which cured 50% of subclinical cases, for each individual in contact with a leprosy patient In our intervention scenarios, contact tracing, chemoprophylactic treatment and early diagnosis were performed only on household members. Contact tracing was repeated three times in three consecutive years with a 10% probability of loss to follow-up and a 90% of symptomatic cases being detected. Early diagnosis was performed in the same schedule as the contact tracing with three consecutive visits to the household. Chemoprophylactic treatment was given only once after examination, in which 90% of symptomatic cases will be detected.The simulation of interventions was started based on the quantification of 2003, because a detailed data set i.e. early diagnosis lowest; then no BCG & early diagnosis; then chemoprophylaxis; then baseline; then no BCG & chemoprophylaxis together with no contact tracing; and finally no BCG had the highest new case detection rate.Both the cessation of contact tracing and the replacement of BCG vaccine by a tuberculosis vaccine ineffective for leprosy (no BCG) would have detrimental effects on the rate of decline in leprosy . Twenty-Both chemoprophylaxis and early diagnosis were predicted to have substantial effects on the new case detection of leprosy . With noEarly diagnosis of infection allows the detection of subclinical cases, of which part would be detected later or never at all. These subclinical cases are added to the number of detected cases. This is seen in the results of this intervention. The introduction of early diagnosis would increase the total number of detected cases in the first 18 years, simply because of the detection of previously undetectable subclinical cases. Over time however, the total number of new cases  would finally drop below the number detected in the baseline control program . In FiguThis study used a microsimulation model to compare the future outcomes of different leprosy intervention programs. The baseline program consists of passive case detection, treatment with MDT, contact tracing, and infant BCG vaccination. The predicted rate of decline in new case detection depends on the intervention scenario chosen over the next 50 years. Early diagnosis and/or chemoprophylaxis added to the baseline program can result in a considerable reduction in the new case detection rate. Furthermore, these interventions were predicted to compensate for the adverse effect of replacing BCG by a leprosy-ineffective tuberculosis vaccine.Our microsimulation modeling approach was able to capture individual (stochastic) processes. Complex infection dynamics could thus be simulated on an individual basis. Aggregating the model outcomes enabled the analysis of trends at the population level. The quantification of the model was based on an area, Nilphamari and Rangpur districts in Bangladesh, where leprosy is highly endemic and which has a well-organized control program The use of our microsimulation model is limited to interventions on a household basis. A future challenge would be to extend the modeling to interactions between households. This requires data from molecular epidemiology studies, for which techniques only recently have been developed and field tested The absence of data on the households in the years prior to the COLEP trial makes a quantitative validation of the results impossible. Therefore, the conclusions of our study are only qualitative, i.e. ranking of the intervention strategies. However, these can be used to prioritize implementation and fundamental research into chemoprophylactic treatment and early diagnosis. We are confident that our results will apply to Bangladesh and many other regions in the world.M. leprae in the population. Nevertheless, we argue that the qualitative results, i.e. the ranking of the intervention strategies, will not differ when implemented in a currrently less intensive control program.The current leprosy control program in the Nilphamari and Rangpur districts of Bangladesh is more extensive than usual. The primary advantage of this program is the active tracing of individuals that had been in contact with newly diagnosed leprosy patients. Contact tracing is not common in leprosy control programs. Our modelling showed that contact tracing and subsequent treatment of newly found patients could, in itself, contribute to a reduction in the transmission of The primary concern of this study was to estimate the relative, not the absolute, impact of the various interventions and take into account alternative hypotheses for mechanisms of susceptibility to leprosy. We compared the results based on different hypothesized mechanisms for susceptibility, because each of these mechanisms could be valid The new interventions chemoprophylaxis and early diagnosis (which necessarily include contact tracing) were predicted to have a clear added impact for leprosy control. We assumed that the effect of chemoprophylaxis with a single dose rifampicin (SDR) could prevent 50% of subclinical infections to develop leprosy. This assumption was based on the outcome of the COLEP trial and represented the overall effect of SDR in the contacts M. leprae in the population. Part of the better performance of early diagnosis compared to chemoprophylaxis was that the early diagnosis strategy comprised three consecutive annual tests with 70% sensitivity, compared to a single round of rifampicin with a cure rate of 50%. Thus, more subclinical cases could be cured after the early diagnosis than with chemoprophylaxis. Meima et al.Our modeling showed that identification and treatment of subclinical infections among household contacts had the largest effect in reducing transmission of et al.Our study shows that BCG may have an important effect on the reduction of the case detection of leprosy. Previously, Meima M. leprae, it is crucial to continue developing immuno- and chemoprophylaxis strategies and an effective test for diagnosing subclinical infections.We showed that the leprosy incidence would be reduced substantially by good BCG vaccine coverage and the combined strategies of contact tracing, early diagnosis, and treatment of infection and/or chemoprophylaxis among household contacts. To effectively interrupt the transmission of


From early infancy onwards, young children appear motivated to engage reciprocally with others and share psychological states during dyadic interactions. Although poor reciprocity is one of the defining features of autism spectrum disorders (ASDs), few studies have focused on the direct assessment of real-life reciprocal behavior; consequently, our knowledge of the nature and the development of this core feature of autism is still limited. In this study, we describe the phenomenon of reciprocity in infant-caregiver interaction by analyzing family movies taken during the first year of life of 10 infants with ASD and 9 infants with typical development (TD). We analyzed reciprocal behaviors by means of a coding scheme developed for this purpose ). Infants with ASD displayed less motor activity during the first semester and subsequently fewer vocalizations, compared to TD infants. Caregivers of ASD infants showed in the second semester shorter periods of involvement and a reduction of affectionate touch. These results suggest that from the first months of life a nonsynchronic motor-vocal pattern may interfere in different ways with the development of reciprocity in the primary relationship between infants later diagnosed with ASD and their caregivers. Reciprocity can be defined as an interactive condition in which two individuals mutually respond to each other while performing activities together . This atSome studies on early autism, both retrospective and prospective, have described behavioral difficulties that are in some way linked with the concept of reciprocity. Palomo et al.  suggesteThis evidence of an early alteration in parent-infant interaction suggests that the first signs of ASD could be better understood by observing interactive dynamics rather than the increase or decrease in single behaviors of one member of the dyad. As stated by Thomas and Martin  and by AOn the basis of these assumptions, we have hypothesized that reciprocity can be better understood by analyzing dyadic behaviors that occur in simple caregiver-infant interactions observed in family home videos, a valid method for observing ecological interactions from the first stages of life. To describe interactions specifically in terms of reciprocity, we have developed the caregiver-infant reciprocity scale (CIRS) which consists of items referring to mutual exchanges (such as involvement or responsiveness) and single or molecular behaviors . The CIRS was developed in order to describe and evaluate how infants try to involve and to respond to the other's bids; according to the literature , 11, we We studied retrospective home movies from the first year of life of two groups of children. The first group was composed of 10 children (M/F: 9/1) with a diagnosis of autism spectrum disorder (ASD) performed by a child psychiatrist according to the DSM-IV-TR criteria  and confnaive to the children's diagnoses. Only sequences where the child was involved in an interaction with a visible caregiver were selected for the study. Sequences were selected in terms of situation type. We included face-to-face interactions in various circumstances, such as bath time, nutrition time, and play time. We also included face-to-face interactions per se . Birthday parties and sequences with several adults and/or children simultaneously present in the video were excluded.Families were asked to provide any videotape recorded during their child's first year of life. Copies of the videos were made and coded with an ID number to preserve confidentiality. Written informed consent was collected from participating families. The selection of the video clips was carried out by a research assistant t-test was performed to check that the selected material was comparable across groups in terms of total duration and number and type of situations. In accordance with other studies in the literature [A terature , 21, 22 We developed the caregiver-infant reciprocity scale (CIRS) on the basis of previous research using the infant caregiver behavior scale (ICBS) developed by Muratori et al.  and the The Observer XT 10.0′ , a profek were ≥ 0,70. The mean Intercoder reliability, calculated directly by the Observer XT, showed satisfactory agreement (k = 0.81). In order to verify the ongoing agreement, 25% of the collection of sequences were coded by both coders. The mean Intercoder agreement calculated on these sequences was k = 0,84, and the values of k were ≥ 0,70. In all cases of discordance between coders, a third coder's (FA) advice was used.Two coders (NC and VC), with an undergraduate degree in psychology, were trained to use the coding system, by observing and coding videos of both TD infants and infants with ASD, who were not included in the study. The two-month training period enabled the coders to become familiar with the meaning of the items, to identify them correctly, and to acquire ability in coding procedures. In addition, the coders were required to achieve a satisfactory level of agreement between them (Cohen's Kappa ≥ 0.70) and with an expert clinician (FA) in two matched sequences for each age range. The tolerance window regarding time discrepancy between coding was set at 1 s for event behaviors and at 3 s for state behaviors. The coding recorded outside these windows was reported as a coding error and was considered a disagreement. In order to avoid any interpretation biases, the two coders were blind to group membership. Intercoders agreement was calculated for each item, and the values of Due to the different length of video sequences of each child, the frequencies and the duration of each behavior were converted, respectively, to a ratio number of behaviors per time (hereinafter rate/min) and to a percentage duration (hereinafter % duration) calculated between the total duration of a behavior and the duration of the sequences available for the same subject , 21. Twot-test for independent samples in order to detect “between group” differences (separately for T1 and T2) and Student's t-test for paired samples to detect “within group” differences between age periods (separately for ASD and TD). Statistical analysis was performed using SPSS version 16.0 [P < 0.05.Rates and percentages of all CIRS items were compared using Student's ion 16.0 . Level oResults are reported in Both at T1 and at T2 there were no significant differences between groups in the rate/min and in the percentage duration of the infant states . At T1 iAs for caregiver behaviors , both atIn TD infants , a signiIn infants with ASD , no signCaregivers of infants with ASD  showed avice versa.This study described both segmental and longitudinal peculiarities in the context of the early developing relationship between a small group of infants with ASD and their primary caregivers. Considering the small sample size, it provides a provisional in-depth model for understanding the onset and the perpetuation of deficits in social reciprocity. First of all, we found that while the time the dyads spent in involvement and responsiveness did not differ across groups, quite opposite trajectories emerged during the first year of life, suggesting that two different reciprocity profiles may be under construction in infants with ASD compared to TD infants see . In contMoreover, the analysis of events suggests several qualitative differences in the behaviors used by the infants in order to involve or to respond to the caregiver. First, the early significantly reduced amount of activating behaviors  and total motor behaviors in infants with ASD highlights the lack of motor activity used by these infants both to engage or to respond to caregivers' bids . The redIn the second six months, the same activating and motor behaviors significantly increase in infants with ASD as well as in TD infants, although they remain at a slightly lower level in ASD, and attuned motor activity significantly increases only in TD infants. This longitudinal data might suggest that, even if there is an improvement of motor activity in ASD, these children make less use of it to be attuned to others. We could hypothesize that the pattern, composed of an early lower level of motor activity and a subsequent nonincrease in attuned motor activity, could represent the expression or the substrate of ASD difficulties in reciprocity, which in TD infants relies on the significant increase of attuned behaviors—with motor activity.While in the first six months we only found differences in items referring to motor activity, during the second six months of life, lower rates in the amount of vocalizations—total significantly distinguished ASD from TD . This diThis result, showing an atypical pattern of vocalization development during the first year of life, is comparable to that of a prospective study by Ozonoff et al.  on sibliAs for caregiver behaviors, the most significant result was the reduction, between T1 and T2, of affectionate touch in the ASD group. Affectionate touch refers to caregivers touching the infant in an affectionate way . A natural and progressive decrease in caregivers' affectionate touch during the first year of life of typical children has been described by Ferber et al. . We alsot-test, but it was not possible to perform a formal statistical test of the interaction between these differences. Given the small sample size and the limited power of the statistical analysis, results should be considered a testable hypothesis for future adequately powered studies.The first and most relevant limitation is represented by the small sample size, as the Type I error cannot be ruled out and the results may not survive multiple comparison tests. Moreover, we have described different patterns in the two groups by carrying out separate analyses of differences between and within groups through Student's naive context, which varies across subjects and reduces the comparability of the sequences in terms of opportunity for reciprocal exchanges. To reduce the bias of the wide variability of video sequences, we chose situations of interaction between infant and caregiver as similar to each other as possible, selecting the video material specifically on the basis of the scenes which were filmed.A second limitation is the quality of the videotapes recorded by parents in a Finally, a further limitation is the absence of a control group consisting of infants with non-ASD neurodevelopmental disorders . In our study, ASD and TD groups were not matched based on IQ, thus we cannot exclude the possibility that the differences are in part due to this factor. Therefore, we are aware that this study lacks evidence for the specificity of the abnormalities found in infants with ASD.To summarize, the present study suggests that infants with early onset autism spectrum disorders may display both motor and vocal impairments. We hypothesize that a nonsynchronic motor-vocal pattern may interfere in different ways with the development of reciprocity in the primary relationship between infants later diagnosed with ASD and their caregivers. Differences in motor activity patterns are evident by the end of the first six months of life, and we suggest that they may have a role in the lack of initiative and in difficulties in having an active role in purposeful interactions as well as in reciprocal responses. On the other hand, a reduction of vocalizations across time and in comparison with TD infants may be seen as a red flag of atypical social development.Given the limitations, these findings should be regarded as very preliminary, encouraging further research in this direction with a dual purpose: to evaluate if the differences we have highlighted withstand more powerful statistical analysis by increasing the sample size and to determine the specificity of the results by introducing a control group of infants with non-ASD developmental disorders. Moreover, future research addressing the topic of infants' motor-vocal development might benefit from a prospective approach which would enable the use of standardized observations of infants at risk.If this nonsynchronic motor-vocal pattern observed in infants later diagnosed with ASD were to be confirmed by future studies, its early identification might provide useful information for determining infants at risk for ASD and starting a timely intervention.