Objective: Simulation-based interventions and education can potentially contribute to safer and more effective systems of care. We utilized in-situ simulation to highlight safety issues, regulatory requirements, and assess perceptions of safety processes by the plastic surgery office staff. Methods: A high-fidelity human patient simulator was brought to an office-based plastic surgery setting to enact a half-day full-scale, multidisciplinary medical emergency. Facilitated group debriefings were conducted after each scenario with special consideration of the principles of team training, communication, crisis management, and adherence to evidence-based protocols and regulatory standards. Abbreviated AHRQ Medical Office Safety Culture Survey was completed by the participants before and after the session. Results: The in-situ simulations had a high degree of acceptance and face validity according to the participants. Areas highlighted by the simulation sessions included rapid communication, delegation of tasks, location of emergency materials, scope of practice, and logistics of transport. The participant survey indicated greater awareness of patient safety issues following participation in simulation and debriefing exercises in 3 areas (P < 0.05): the need to change processes if there is a recognized patient safety issue (100% vs 75%), openness to ideas about improving office processes (100% vs 88%), and the need to discuss ways to prevent errors from recurring (88% vs 62%). Conclusions: Issues of safety and regulatory compliance can be assessed in an office-based setting through the short-term  use of in-situ simulation with facilitated debriefing and the review of audiovisual recordings by trained facilities inspectors. In 2005, the American Society of Anesthesiologists estimated that at least 10 million office-based procedures were performed annually, twice the number of office-based surgeries performed in 1995.5,22We hypothesized that to better gauge the ability of an office-based plastic surgery center to handle a medical emergency, we should simulate several medical emergencies in-situ and permit the clinic personnel to manage the events. We further hypothesized that simulation scenarios can contribute to increased awareness of safety issues by the office personnel. The advantages of in-situ simulation have been well described in hospital practices, ambulatory clinics, and recently, in office settings.20Much of the in-situ simulation has been utilized to advance the procedural responses of code teams and resuscitation personnel.AHRQ Medical Office Survey on Patient Safety administered to all participants before and after exposure to two simulation exercises.26In this feasibility study, we present a series of in-situ simulations that were structured to assess these unique challenges, customized to meet the needs of the participants, and reviewed to ensure that the scenarios and debriefings met and amplified guidelines of common agencies of accreditation. One of the outcome measures is the results of the With approval as an exempted study from the Beth Israel Deaconess Medical Center investigational review board, we conducted a needs assessment, planned pre- and postsurveys, designed scenarios, and structured debriefings to meet the needs of the office-based personnel and to conform to existing regulations of several accrediting agencies.The in-situ simulations were conducted in 2 free-standing office-based surgical centers in the Boston area, both of which specialized in plastic surgery procedures. Each facility performed about 1000 procedures per year. These procedures were performed using both general anesthesia and deep sedation as well as conscious sedation techniques. Both centers had previously received nationally recognized accreditation and had incorporated various safety equipment, protocols, and standards as outlined by these accrediting agencies. All medications and equipment used in the scenarios, for both routine and emergency situations, were the property of the office and remained in their normal locations for all of the scenarios. The only exception to the usual routine was the presence of a human patient simulator  with its monitor/emulator in place of the usual vital signs monitor. In one case, the automated external defibrillator was altered to allow the conductive pads to clip onto the mannequin during defibrillation.Office-based personnel consisted of reception staff, billing staff, managers, nurses, medical assistants, and surgeons. The level of training in emergency procedures was commensurate with each individual's professional training, although the lay office staff was current in their certification of basic life support (BLS).A specific, office-based Needs Assessment was performed during 2 initial visits to the facility prior to the in-situ simulation session.Several scenarios were developed to address perceived knowledge deficits and to strengthen team dynamics during complex medical emergencies. These scenarios were based on both the general requirements determined by the Needs Assessment as well as the specific suggestions during the previsits. The scenarios were crafted to represent technically challenging tasks to the medical personnel as well as require urgent actions from the administrative staff members.Once in the procedure room, the patient was represented by the human patient simulator. The scenario in the procedure room was designed to consist of several stages, but the transition to each stage as well as alterations in the scenario could be managed by the simulation experts and were reflective of the actions performed by the office personnel. In general, each scenario lasted 20 minutes. The scenarios ended when sufficient therapeutic maneuvers had been performed or when the outside emergency medical teams had arrived to assume care for the patient.Each scenario was followed by a structured debriefing. The debriefings were attended by all of the office personnel and had several overall goals . All of While individual performances were not assessed and no ratings were given, each debriefing did focus on examples of individual, team, and systemic problems that could impede rapid resolution of a crisis. Using video review of the scenarios, the debriefer could isolate specific instances of communication to either demonstrate useful examples or to encourage the group to suggest improvements in the choice of words or phrases. For example, team actions could be compared with existing ACLS (Advanced Cardiovascular Life Support) algorithms. The performance of certain tasks such as mask ventilation or chest compressions could be assessed for proper rate and chest excursion. Systemic issues such as the appropriate emergency telephone numbers, adequate written protocols, and explicit ingress and egress routes could be discussed in the context of the recorded scenario. Finally, a comparison between the performance of the office team could be made with existing benchmarks and specific recommendations of accrediting agency regulations.AHRQ Medical Office Survey on Patient Safety.Prior to the exposure to the 2 simulation exercises, all participants were administered the abbreviated version of the P value of less than 0.05 was considered to be statistically significant. All statistical analyses were performed with SAS version 9.3 .Responses from the survey were presented as frequencies and percentages. For the matched pairs, McNemar tests or Stuart-Maxwell tests were performed to examine the differences in participant survey responses before and after simulation sessions. The proportional differences among all respondents were compared using Fisher exact tests. All statistical tests were 2-sided, with a type I error of 0.05. A A total of 16 personnel in 2 plastic surgery offices participated in the half-day, in-situ simulation training exercise. After a brief introduction to the proposed schedule and a tour into the procedure room to meet a “healthy” mannequin on the operating table, the participants completed a safety culture survey and decided whether to allow for video recording of the sessions. The standardized (confederate) patient for the first scenario then arrived at the reception area and proceeded with the check in. The patient changed clothes and walked to the preprocedure area. One of the office nurses completed a screening questionnaire and physical examination. The surgeon and anesthesiologist then made their individual introductions, explanations and completed their own paperwork with the patient. The standardized (actor) patient then walked into the procedure room and a similarly dressed mannequin assumed the role of patient. After appropriate monitors were applied, the patient was prepped and draped for the procedure. A time out was performed. The specific stages of the scenario were then performed.AHRQ Medical Office Survey on Patient Safety, both prior to case scenarios and after the completion of the 2 scenarios (P < 0.05): the need to change processes if there is a recognized patient safety issue (100% vs 75%), openness to ideas about improving office processes (100% vs 88%), and the need to discuss ways to prevent errors from recurring (88% vs 62%). However, the rest of the survey responses did not show statistically significant differences between pre- and postintervention.Survey results were obtained from all participants who were administered the abbreviated version of the cenarios  and the cenarios . The preTwo scenarios were demonstrated during the simulation exercise. The first was a toxic reaction to a local anesthetic injection, which resulted in ventricular tachycardia and pulseless electrical activity. The second case was a reaction to general anesthetics known as MH.,33,34Team-based processes were evaluated according to the central principles of CRM as described by Gaba et al.30As team behaviors became bogged down, there appeared systems issues that contributed to the frustration and ineffectiveness of the participants. In the MH case, for example, there was a lack of large syringes and large bore needles in the accompanying kit. This lack of an adequate system slowed the rate at which dantrolene was able to be solubilized and administered to the patient. Also in the MH case, the lack of routine temperature monitoring frustrated the anesthesia provider and this lack of monitored temperature reading delayed the recognition of MH. While an increase in temperature is usually a late sign of MH, the participant ignored several early signs such as tachycardia, hypercarbia, and acidosis. Several minutes elapsed before the emergency was declared, and the appropriate emergency medical systems were activated.Once activated, the medical systems worked with varying degrees of effectiveness. A prepared kit for the treatment of MH was already in the procedure room and there were enough vials of dantrolene, but not enough syringes to reconstitute and administer the medication. Nurses were unfamiliar with the medication, the diluent, and the initial and total doses. As a result, the anesthesia provider had to guide the nurses but, in turn, failed to recognize electrocardiographic signs of hyperkalemia and of ventricular ectopy. Several of the office staff left to procure more dantrolene, but the operating room personnel were unaware of their whereabouts or their progress. In general, the scenario suffered for lack of an event manager who was able to fully coordinate multiple activities.During the debriefing, the office staff was able to identify further flaws in the systemic response to the emergency. After dialing 9-1-1, for example, the ambulance would arrive to the parking lot without knowing how to proceed to the procedure room. Even an enhanced ambulance emergency response system, such as the one that was available, does not provide directions within the building. The staff suggested that one of the reception staff would need to be in the parking lot to receive the ambulance and to direct the medical personnel. A route that would accommodate the width of a wheeled stretcher with a patient was devised. The need for periodic updates from the event manager in the procedure room to all the staff was emphasized, and the importance of the nonmedical personnel was reinforced.Following the scenarios and after a debriefing session that stressed the importance of leadership, communication, situational awareness, and elements of resuscitation, a number of specific recommendations were made to improve the process of crisis management . These 5All of the participants recognized the requirements for a coordinated manager of the medical emergency and for ready access to the written algorithms or protocols to help to plan for such an event. Most felt that their knowledge of ACLS was “rusty” and welcomed a refresher course or a series of simulations to periodically practice these resuscitative skills. While doctors and nurses were current with respect to ACLS certifications, the nonmedical office staff were not all current with BLS and felt that regular practice of BLS would be essential to be comfortable during a medical crisis.In addition to the regular practice of appropriate ACLS and BLS algorithms, the office-based group discussed several other improvements in their systems-based approach to a medical emergency . The off-While others have shown the utility of in-situ simulation35,40The in-situ nature of the simulation exercise allowed the office group to rehearse a response to an emergency with their own personnel and with their own equipment. The advantage of simulation when compared to a group discussion, for example, was that the personnel could physically handle the equipment and, thus, could detect any latent failures. These failures would not necessarily become clear during a discussion. The lack of sufficient syringes to mix the dantrolene, for instance, was an obvious systemic problem that became evident when the nurses had to actually mix the medication. We argue that these educational gaps causing systemic failures could have potentially been avoided through the use of a surgical safety checklist, which has been shown to increase safety and decrease cost in a hospital-based setting.38While the chosen scenarios represented both common occurrences in an office-based practice (medication side effect) as well as a rare, but potentially lethal condition (MH), the customized nature of the Needs Assessment does allow for the tailoring of the scenarios to the specific needs of the facility. For example, an office might want to practice a simulation of a recent adverse outcome that happened in their clinic or in the news. By modeling the scenario on an actual event, the staff can experience immediate appreciation or “buy-in” and can also relate their individual, team, and systems responses during simulation to an actual event. There is even the possibility to focus the debriefing on issues of individual performance , team behavior (leadership and communication), and systems processes (available resources and systems activation).Through slow motion review of recorded sessions, the debriefing can demonstrate that an emergency response does not occur until someone detects and declares an emergency. Furthermore, the evolution of a clinical problem into a full-blown crisis can be dissected during the debriefing. Latent failures can be demonstrated and preventative measures can be suggested that may be enough to avert a crisis. This ability to suspend time and to focus on the details is a distinct advantage of patient simulation with video review. This property can be utilized to improve the participant's understanding of the process with the hope of augmenting future participant actions.The advantage of a debriefing performed by people with knowledge of the requirements of the accrediting agencies is that all actions can be reviewed with an eye to the specific requirements. The debriefer can attest to the office performance that is up to specific standards. Agencies form regulations and inspectors document compliance with the regulations, but in-situ simulation can confirm actions that adhere to the standards. In the automotive industry, there are requirements that car manufactures provide brakes and there are inspectors who confirm that the brakes work, but only a road test can demonstrate that the driver can apply the brakes at the right time and circumstance. Office-based, in-situ simulation offers the ability to “road test” the required equipment and personnel in their own vehicle (office) in a realistic situation. The simulation exercise can document exemplary individual, team, and systems performances and can identify items for improvement. While this type of simulation remains voluntary at present, one could envision a time when regulatory agencies might ask for such simulation-based demonstrations of compliance with their patient safety policies.Issues raised during our simulation sessions can be explored further through similar simulation-based studies. Future investigations could be designed to assess knowledge and skills gaps, communication and organizational deficiencies, as well as system issues. We propose a number of potential lines of investigation. For example, knowledge of BLS and learning of these principles can be assessed using pre- and postexercise surveys. Basic life support motor skills, such as chest compression effectiveness, can be measured directly through the mannequin simulator, which can record compression rate, depth, and continuity. Communication skills such as percent closed-loop/read-back can be measured. Team training/CRM issues can be studied using video review with trained raters. Simulation scenarios can be designed to address teamwork, specifically assessing interactions between nurses, physicians, and nonmedical personnel. The adherence to checklists and algorithms for each of these parameters can also be measured. Systems issues can be explored through structured debriefings and surveys.A recent article by Arriaga et al demonstrated the usefulness of surgical-crisis checklists, similar to the use of crisis checklists in the airline industry.In conclusion, issues of safety and regulatory compliance can be assessed in an office-based plastic surgery setting through the short-term  use of in-situ simulation with facilitated debriefing and the review of audiovisual recordings by trained facilities inspectors.


Economic evaluation is used for effective resource allocation in health sector. Accumulated knowledge about economic evaluation of health programs in Bangladesh is not currently available. While a number of economic evaluation studies have been performed in Bangladesh, no systematic investigation of the studies has been done to our knowledge. The aim of this current study is to systematically review the published articles in peer-reviewed journals on economic evaluation of health and health-related interventions in Bangladesh.Literature searches was carried out during November-December 2008 with a combination of key words, MeSH terms and other free text terms as suitable for the purpose. A comprehensive search strategy was developed to search Medline by the PubMed interface. The first specific interest was mapping the articles considering the areas of exploration by economic evaluation and the second interest was to scrutiny the methodological quality of studies. The methodological quality of economic evaluation of all articles has been scrutinized against the checklist developed by Evers Silvia and associates.Of 1784 potential articles 12 were accepted for inclusion. Ten studies described the competing alternatives clearly and only two articles stated the perspective of their articles clearly. All studies included direct cost, incurred by the providers. Only one study included the cost of community donated resources and volunteer costs. Two studies calculated the incremental cost effectiveness ratio (ICER). Six of the studies applied some sort of sensitivity analysis. Two of the studies discussed financial affordability of expected implementers and four studies discussed the issue of generalizability for application in different context.Very few economic evaluation studies in Bangladesh are found in different areas of health and health-related interventions, which does not provide a strong basis of knowledge in the area. The most frequently applied economic evaluation is cost-effectiveness analysis. The majority of the studies did not follow the scientific method of economic evaluation process, which consequently resulted into lack of robustness of the analyses. Capacity building on economic evaluation of health and health-related programs should be enhanced. Resource scarcity is a common reality in the health sectors of low income countries. Given that the allocation and identification of additional resources is a major political decision and a long-term planning issue for government, many countries concentrate on more effectively utilizing the available resources instead. One method used for priority setting among health interventions is economic evaluation . Though Systematic reviews of economic evaluation studies have been carried out in various settings and in different areas of interest -8. WhileIn previous literature reviews in this area, the authors indicated a number of shortcomings in the published literature. In developing countries limited local capacity in undertaking economic evaluations and failure to monitor the quality of the studies has been observed . ExperieWhile a number of economic evaluation studies have been performed in Bangladesh, no systematic investigation on which intervention areas are explored by economic evaluation and the quality of the studies have not been done to our knowledge. The articles on economic evaluation of health and health-related interventions in Bangladesh will be scrutinized on the basis of a checklist, developed by Evers et al .Evers et al  publisheThe aim of this study is to systematically review the published literature on economic evaluation of health and health-related interventions in Bangladesh. The first specific interest is to map the articles by subject area under economic evaluation and the second interest is to assess the methodological quality of these studies.A comprehensive search strategy was developed to search Medline via the PubMed interface. The search was limited to all publications indexed from January 1, 1971 to December 30, 2008. The literature search was carried out during December 2008 with a combination of key words, MeSH terms and other free text terms as suitable for the purpose. The full search strategy is available in Additional file In addition we also searched minor databases such as Eldis, WHOLIS, World Bank, USAID, Management Sciences for Health (MSH), DFID and Centre for Reviews and Dissemination (CRD) database hosted at York University, and Google scholar. We also undertook hand searching of reference lists of relevant papers and reviews identified. However, the PubMed search covered all other search results.This study set out to identify and include all published articles that included an economic evaluation of health and related interventions in Bangladesh. We considered studies that used primary or secondary data. We limited our search to studies published in English language and related to humans.We excluded studies not conducted in humans, not in the health sector, and not in Bangladesh. Studies were excluded if they do not present any kind of cost or expenditure related data, or if they were editorial, review or methodological articles.This section is presented in three parts: the results of the search staretgy, a mapping of the economic evaluation literature and a review of the technical characteristics of the articles. With the mapping part, the main interest is to explore in which areas economic evaluation research has been done. Secondly, in the technical characteristics part, the interest is to observe if the reviewed studies have followed the methodological quality of economic evaluation.A total of 1784 abstract were identified from the search done in December, 2008. Two reviewers screened the abstracts individually and excluded 1731 titles and/or abstracts. Fifty-three full text articles were retrieved. After a second round of double screening, 12 articles were judged to be eligible for inclusion in the review  of studies in a matrix form is presented in additional file Though the number of articles increased over decades, a very few number of articles in total has been published during our period of investigation (1971-2008). The first article based on economic evaluation of health and health-related intervention in Bangladesh was published in year 1983 though our search period starts from 1971. Only, two studies . We found only one cost-minimization analysis and one cost-utility analysis.The methodological quality of economic evaluation of all articles has been assessed against the checklist developed by Evers Silvia et al . Table 1Ten studies described the competing alternatives clearly. The two studies (Reference number 9 and 12) which did not describe the alternatives clearly, tried to compare the programs with the do-nothing alternative, though it was not explicitly mentioned in the article. All studies posed a study question in answerable form and designed the economic study appropriately. All of the articles considered time horizon in their analyses and the time period ranged between one to seven years.Considering the perspective of the economic evaluation is important as this determines which costs and effects should be incorporated in the study. Only two authors stated the perspective of their articles clearly. However, after reviewing the articles, the perspective of the studies could be understood, though not explicitly mentioned. Some of the studies considered societal perspective. Such studies included cost components like costs  of health workers, capital cost, recurrent cost, training cost and cost borne by patients like, household out-of-pocket expenditure. However, there are some studies which considered provider's perspective.Any economic evaluation of health intervention should identify the costs incurred in accordance with intervention alternatives. All studies included direct cost, incurred by the providers. Nine articles included all major costs, such as, personnel cost, capital cost, recurrent cost. One article (reference number 1), which explicitly mentioned its perspective from a provider's point of view, did not include some important cost items, like, administrative and logistic costs. Another study (reference number 3), which took the societal perspective, did not include household cost and staff cost. Only one study (reference number 10) included the cost of community donated resources and volunteer costs, i.e., community donated time. All articles, except one with reference number 3 in additional file Measuring the cost data in appropriate physical unit is important. Only two studies (reference number 6 and 7) used the ingredient approach for stepwise resource allocation. These studies apportioned the joint or overhead cost. Nine studies used discounting for lifetime adjustment of capital and recurrent costs. Four studies  used the shared cost of health staffs to measure the percentage of time devoted by health workers. In most of the cases, the calculation of cost components is not clearly described. Capital costs, such as building and equipments; recurrent cost, like food, transport, medical supplies etc were not applied in a systematic manner. Nine studies stated the base year of the cost data. The currency used for cost valuation includes US dollars (5 studies), international dollar by one study (reference number 12) and local currency (6 studies).Most of the studies measured the outcomes using natural units, like proportion of patients cured, share of children immunized etc. Three of the studies employed health outcome as a measure of intervention effect. Two of these studies (reference number 4 and 6) used quality adjusted life years (QALYs) and one used (reference number 12) disability adjusted life years (DALYs) as outcome measurement. Most of the studies measured multiple outcomes of same intervention. The other outcome measurements, not mutually exclusive in the articles, used are patient cured (2 studies), knowledge improvement (3 studies), reduction in prevalence rate of worms (1 study), number of children immunized (2 studies), achieving 80% weight for height (1 study). Nine studies stated the sources of outcome data and multiple sources were used for collecting such information. In six of the studies, the authors implemented intervention programs and created outcome data in comparison with control groups. In other studies, secondary data sources have been used through reviewing published data or literature and estimation by Meta-analysis.Discounting has been applied in few studies. Costs have been discounted in three  and outcomes in two studies (reference number 11 and 12). In these studies either 3% or 5% discount rate was employed for costs. The outcome discounting rate was 3%. Two of the studies (reference number 11 and 12) referred to previous studies as a justification for considering the discounting rate, applied in their studies.Only two studies (reference number 11 and 12) calculated the incremental cost effectiveness ratio (ICER). For calculating ICER, these studies calculated the incremental cost per DALY averted. Both the studies that calculated ICER have compared their results with a benchmark ceiling rate. One study (reference number 11) used the World Bank ceiling ratio of cost per DALY averted which is $175 and the other study (reference number 12) used a ceiling ratio as I$ 29/DALY averted. However, one more study (reference number 6) mentioned that the ICER is important to be calculated, though not applied in that current study.Performing sensitivity analysis is vital to assess the robustness of the results to changes in assumptions and values of inputs. Six of the studies applied some sort of sensitivity analysis. Five of the studies performed one way sensitivity analysis considering uncertainty of single component  of economic evaluation. Only one study (reference number 10) applied sensitivity analyses applying changes in three different scenarios, namely lower estimate of effectiveness, full costs of implementation and worst-case scenario, i.e. combination of lower effectiveness and full cost.Two of the studies discussed affordability (reference number 7 and 12), of which one mentioned that 50% more patients can be treated using the existing budget which indicated the affordability of cost-effective intervention, whereas the second one referred to a real world budget constraint. Four studies discussed the issue of generalizability and three of those  mentioned that the findings of the studies can be replicable in different contexts. One study (reference number 6), on the contrary, proposed for testing in other countries to determine if the intervention is replicable elsewhere. Ethical and distribution issues are not discussed appropriately in most of the articles. However, the study by Taylor M (2003) referred to ethical consideration of collecting data (reference number 9).From the review of articles, we found that the research-base for economic evaluation of health and health-related interventions in Bangladesh is weak and the studies carried out in this area have many limitations.According to the mapping of the articles, we found few articles on economic evaluation of health and health-related intervention programs. At the same time these articles addressed a wide number of intervention areas. Thus there is shallow knowledge in a wide number of areas, with no single area or type of intervention being fully investigated. For the use of evidence as a basis for policy making, the same areas should be independently investigated by several research teams. However, this level of investment in economic evaluation should be supported by the use of these studies in health sector decision making.The contribution of the researchers from Bangladesh-based organizations appears negligible in the broader body of economic evaluation literature. In most of the articles, Bangladeshi researchers appeared as collaborative partners, not the principal investigator or first author. While appearing as a collaborator, their contribution to the research paper is not clearly described. A better understanding of the use and methodology of economic evaluation might help to enhance the translation of knowledge generated by economic evaluations in health sector decision making in Bangladesh.We have found that among the economic evaluation studies cost-effectiveness analysis is highly prevalent. This can be due to the availability of information on effectiveness in natural terms  from the programs and application of straight-forward methods in such evaluations. It has been further observed that although a number of studies were designed for performing CEA, the final analyses of many of these studies were done by comparing the cost and effectiveness ratio, which finally turned into a cost outcome study. Cost-utility analysis, on the other hand, is less frequently found, probably due to the relative difficulty and resource consumption needed for measuring health status, and in the consideration of quality and disability. However, we observed that the concepts of 'cost-effectiveness analysis' and 'cost-utility analysis' are often used interchangeably by the authors. Mislabeling the cost-minimization analysis (CMA) as the CEA was found in the review. The study by Ashworth A (1997) was designed as a CEA; the study used a fixed value for effectiveness measurement which is actually a CMA. Again, cost-benefit analysis for evaluating health and health-related interventions has not been carried out in Bangladesh.The economic evaluation studies, we reviewed are mainly limited to intervention programs. Several untouched areas can be identified such as disease-specific treatment alternatives, alternative drugs etc.The technical characteristics of the included studies show many limitations. Few published economic evaluations have consistently followed correct analytic procedure. In the figure below, we present how many of the 12 articles followed the criteria of being a scientifically good economic evaluation although the articles due a better job of meeting less technical issues. For instance, description of comparative intervention alternatives, appropriateness of study design and perspective taken are completed or at least addressed by most of the articles. Inclusion of all cost items, its measurement and valuing, which are fundamental and more technical issue in economic evaluation, is done by most of the articles. It indicates that the researchers are more familiar with costing techniques. On the other hand, more sophisticated issues, like incremental cost-effectiveness ratio, discounting of costs and effectiveness, sensitivity analysis, discussion on generasibility, ethical issues and affordability were not addressed by most of the articles. It needs to be emphasized here that though less technical issues are addressed by most of the articles; there are many shortcomings in their presentation. For instance, comparative alternatives, though described in the articles, but not in a structured way in many of them. See Figure Perspective of economic evaluation is an important issue which determines measurements of costs and outcomes of the interventions under investigation. In many studies, we found that though perspective was not clearly stated in some articles, all the studies had a perspective which could be found by reviewing. In some cases, all costs items have not been identified, which underestimates the actual costs of intervention. Traditionally, the studied did not estimated costs of donated items and volunteers' times which are very frequently applicable in a developing country context. However, exclusion of any important cost component can be due to lack of proper training about measurement techniques. Moreover, there is a lack of guideline for costing method with a common consensus of researchers and relevant expertise which can address the standard methodological as well as practical issues in Bangladesh.Irrespective of kinds of economic evaluation, the reviewed articles are routinely display a lack of transparency. In some cases it is difficult to understand which alternatives are being compared. We even observed when comparing a new intervention or alternative against no intervention, it has not been clearly mentioned in the article. Lack of transparency is found in using cost data from secondary sources. Though the cost and outcome data sources are mentioned in many articles, they mostly lacked a detail description of data collecting process by the sources. In addition, cost from secondary sources  needs to be converted by an appropriate exchange rate. In that case, price inflation over time and purchasing power parity (PPP) between countries needs to be considered. Some studies used US dollar rate, without considering the variation in purchasing power between Bangladesh and USA. PPP adjusted dollar rate needs to be applied instead of simple dollar exchange rate. Furthermore, discounting of costs and outcomes is not used often which consequently provides a biased estimation of economic evaluation. Incremental cost-effectiveness ratio calculation is often missing, which is fundamental for ranking the alternatives while making decision on effective resource allocation.To validate a study result, the researchers should conduct carry out a sensitivity analysis and triangulation of information. Most of the studies have done sensitivity analyses using only one dimension . However, for a better validation of the result multi-dimensional sensitivity analyses as well as uncertainty analyses should be done. Triangulation of results can be done by verifying with other relevant studies elsewhere.Most of the studies lack a discussion on generalisibility of the results, ethical consideration and affordability of the intervention programs. Since the intervention programs often are carried out on a pilot basis in a specific context, a discussion on generalisibility is important for scaling up the programs on the basis of the findings. If the interventions can be done without violating the ethical recommendation, should be clearly discussed. The distribution of outcomes of intervention programs across socioeconomic, age and gender groups etc. need to be discussed as well. Though an intervention program is cost-effective, it may not be affordable in a specific society. For fitting the economic evaluation study in a practical context, affordability of the intervention alternatives should be discussed.The economic evaluation is an aid to decision making, the quality of published work needs to be improved to ensure that the economic evaluations do not mislead decision makers. The weaknesses in health economic evaluation in Bangladesh may be due to lack of training on economic evaluation methods among the non-economist investigators and shortage of trained health economist in this area of research in Bangladesh. A country specific costing guideline with common consensus among the local researcher and relevant expertise is important for doing a economic evaluation of various health program. A uniform methodological guideline for conducting economic evaluation in Bangladesh is also needed.Economic evaluation should be focused on interventions that have major impact on population health. There are lack of economic evaluation studies in Bangladesh targeting MDGs, mainly Goal 4 and 5. Various public health programs in maternal and child health should be economically evaluated for scaling up through the country. This is needed to achieve the MDGs by 2015. None of the studies conducted economic evaluation targeting child health and maternal heath has been found. Various economic evaluation studies can be done targeting the national burden of disease, possible alternative interventions and investment in health.There are some limitations in this current review article. The study searched only the published literature in peer reviewed journals and included literature published in English only. Various gray literature items such as unpublished reports, conference proceedings and reports were not included in the search results. It is possible that more economic evaluation were done by Bangladeshi researchers which are not included here due to the specific inclusion and exclusion criteria.In this review we discovered that there are a very few economic evaluations of health interventions. There are many unexplored area such as economic evaluation of disease treatments and alternative drugs. However, one economic evaluation method  was applied most frequently. The majority of the studies did not follow the scientific method of economic evaluation process, which consequently resulted into a lack of robustness of the analyses.Based on the review of health economic evaluation articles, we recommend that capacity building on economic evaluation of health and health-related programs as well as health economics should be enhanced. Researchers and health sector stakeholders including policy makers and donors should identify important areas of economic evaluation considering national burden of diseases, possible alternative interventions and investment in health. Under the context of limited resources for health in Bangladesh and other developing countries, the use of robust economic evaluation of health and health-related interventions and programmes should be conducted routinely to help guide considerations for generalizability and potential scaling up.The authors declare that they have no competing interests.MEH was involved in concept and design, search strategy, data extraction, designing checklist, data analysis, interpretation of the data, preparing drafts and the manuscript. JK was involved in the analysis, interpreting the data and preparing drafts. SH was involved in conception and design, preparing and run the search strategy and retrieval of the abstract. RG was involved in data extraction, screening and adjuration full text, developing data extraction tool. HR was involved in conception and design and drafting of the manuscript. TK was involved in concept and design, developing data extraction tool and design and drafting of the manuscript. DW was involved in concept and design, search strategy, data extraction, designing checklist and overall guidance of the manuscript. All authors read and approved the final version of the manuscript.Search Strategy.Click here for fileList of selected articles for systematic review.Click here for fileStudies meet the inclusion criteria but are later deemed unsuitable for inclusion.Click here for fileMapping of included studies.Click here for file


The last decade has seen a number of methodological developments in meta-analysis of diagnostic test studies. However, it is unclear whether such developments have permeated the wider research community and on which applications they are being deployed. The objective was to assess the uptake and deployment of the main methodological developments in the meta-analysis of diagnostic tests, and identify the tests and target disorders most commonly evaluated by meta-analysis.Design - systematic review. Data Sources - Medline, EMBASE, CINAHL, Cochrane, PsychInfo, Global health, HMIC, and AMED were searched for studies published before 31st December 2008. Selection criteria - studies were included if they satisfied all of the following: evaluated a diagnostic test; measured test performance; searched two or more databases; stated search terms and inclusion criteria; used a statistical method to summarise performance. Data extraction - included the following data items: year; test; reference standard; target disorder; setting; statistical and quality methods.236 studies were included. Over the last 5 years the number of meta-analyses published has increased, but the uptake of new statistical methods lags behind. Pooling the sensitivity and specificity and using the SROC remain the preferred methods for analysis in 70% of studies, with the bivariate random effects and HSROC model being used in only 22% and 5% of studies respectively. In contrast, between 2006 and 2008 the QUADAS tool was used in 40% of studies. Broadly, radiological imaging was the most frequent category of tests analysed (36%), with cancer (22%) and infection (21%) being the most common categories of target disorder. Nearly 80% of tests analysed were those normally used in specialist settings.Although quality assessment in meta-analyses has improved with the introduction of QUADAS, uptake of the newer statistical methods is still lagging behind. Furthermore, the focus of secondary research seems to be in evaluating specialist tests in specialist settings, in contrast to the more routine tests and settings encountered in the majority of clinical practice. The application of meta-analysis to diagnostic tests has lagged behind its application to therapeutic trials ,2, emergIn contrast, test accuracy studies tend to be cross sectional in design ,5, in orHence two statistics, the sensitivity and specificity, are normally used when summarising a test's performance, and via Bayes' theorem  these haPrior to this, the main method for combining studies was to pool performance characteristics separately using the same fixed  and randThe potential to include other sources of heterogeneity in models has existed for some time. Yet, it is only in the last decade that two other approaches, the bivariate random effects model (BRM),19 and hDevelopments in statistical methodology have been mirrored by advances in methods for assessing the quality of studies for systematic reviews. This led to the publication of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool in 2004 . The StaThus, over the last decade, we have seen significant progress in the methodology used in the meta-analysis of diagnostic tests. Unfortunately, some of this progress has been at the cost of increased complexity that may inhibit its implementation. It is of interest to establish whether such developments have permeated the wider research community. The objective of this systematic review was to assess the uptake and deployment of the main methodological developments in the meta-analysis of diagnostic tests, and to identify the diagnostic tests and target disorders most commonly evaluated by meta-analysis.st December 2008. The search strategies for each of the databases are in Additional file A search strategy was developed aimed at retrieving articles in secondary research. The following databases were searched using an OVID interface: Medline, EMBASE, CINAHL, PsychInfo, Global Health, Cochrane, HMIC and AMED. The initial search strategy was conducted in October 2008 and again in September 2009 to identify studies published before the 31For the purpose of the review, a meta-analysis was considered to be a special type of systematic review in which the accepted methods used to construct a systematic review were followed and the results were aggregated by statistical methods. A number of other terms were also defined to remove ambiguity in the inclusion criteria and to aid reproducibility; the full details of these may be found in Additional file Studies were included if they satisfied all of the following criteria: the citation was an original study of a diagnostic or screening test; one of the objectives was to estimate an accepted performance measure of the test; two or more of the major electronic databases were searched; three or more search terms were explicitly stated in the methods; at least one statistical method was used to combine the studies and summarise the performance of the test.Data were abstracted on the following: year; test; reference standard; target disorder; patient setting; statistical methods and correlation; presence of heterogeneity; and quality assessment tool. Four statistical methods were specifically searched for as part of the appraisal: pooling of performance characteristics using a fixed effects  or randoThe selection, data extraction and the appraisal of studies were conducted by a single reviewer (BHW). A second reviewer (MQ) independently carried out the selection process on a 10% random sample drawn from the unduplicated set of citations and also independently extracted and appraised a 10% random sample of the included studies. The Kappa statistic was used to estimate the level of agreement ,28 interIn addition to inspection, the frequency distributions of the different methods used were compared. The baseline measures for comparison were: the number of studies applying a particular statistical method per year; and the proportion of the number included studies published per year reporting the method of interest. The respective frequency distributions were compared using the non-parametric Kolmogorov-Smirnov statistic (D)  and the The searches produced 6259 citations, which after removal of duplicate citations were reduced to 4336 studies. Screening of the titles and abstracts using the first criterion excluded a further 3288 studies  and the SROC curve . The year of publication of the seminal papers relating to each of these methods is also shown. It is of interest that the BRM was probably first proposed in 1993 , the samAn interesting question is whether using the new methods (BRM/HSROC) significantly alters the summary statistics from those derived using the more traditional methods (independent pooling/SROC). A number of studies reported using more than one statistical method to summarise the data. Yet, only one study explicitly compared the summary performance statistics derived from independent pooling with those from an HSROC curve model . In thisHaving been recently introduced, and presenting fewer technical barriers to its implementation, the uptake of the QUADAS tool by researchers provides a useful comparison with that of the new statistical methods figure . AlthougAn error that is sometimes made when implementing quality assessment tools is to sum the scores of the individual categories. Total scores are based on the implicit assumption that the different domains on quality are comparable on a linear scale, which has no validity. Yet, nearly half (49%) of the studies using the QUADAS tool reported an overall quality scores.The evidence tables for the individual studies may be found in Additional file The included studies frequently evaluated more than one test, on more than one target disorder, and in more than one setting. There were a total of 685 separate test evaluations, which were analysed in terms of category of test figure , categorRadiological imaging tests were the most common type of test appraised, with ultrasound (69), magnetic resonance (64) and computer tomography 53) being the most frequent technologies evaluated  and infection (145) were the most frequent categories of target disorder appearing in the included studies (figure 7 and infThe typical populations in which the tests would be applied in practice are shown in figure A description of the characteristics for the individual studies may be found in Additional file Over the past decade the number of meta-analyses published in diagnostic research has clearly increased. Although our stricter criteria excluded some of the earlier publications, the recent surge in reporting is both a reflection of increased interest in the field and greater attention to quality by investigators.Notwithstanding the obvious interest and likely improvement in standards, meta-analysis in diagnostic research still poses a number of difficulties to researchers. The studies appraised in this review seemed to demonstrate a lack of consensus on how best to aggregate results: in nearly two thirds of studies two or more statistical methods were used and in some instances up to four methods were employed.The SROC curve ,17 and pAs part of the normal process a delay between proposal and deployment by the wider research community should be expected. If the uptake of the SROC curve is representative, then figure Whereas pooling the sensitivity and the specificity or constructing an SROC curve may be easily achieved using, for example, a spreadsheet, the same cannot be said of either of the newer models. Both of these use maximum likelihood estimation of the population parameters and in the case of the HSROC model, Monte Carlo simulation may be required, particularly when a Bayesian approach is taken ,38. ThusTo widen access, software packages have recently become available which incorporate the BRM and HSROC models. These include: METANDI written in STATA ; METADASPerhaps an equally important issue is the relevance of the results produced by meta-analysis. The SROC curve model gives a performance curve with no indication of the corresponding threshold for individual points on the curve. The two newer models are able to produce summary estimates of the sensitivity and specificity. These take into account all possible variances within and between the studies analysed, yet do not say how a test may perform in any particular setting . RecentlThere has undoubtedly been a shift in the thinking on meta-analysis towards a multivariate approach, as it is considered more 'statistically rigorous' than other methods .Statistical rigour in itself may not be a sufficient argument for advocating uptake of the new bivariate methods; particularly, if the summary estimates generated are not significantly different from those derived from simpler univariate methods. There were no significant differences in the one study identified in this review that compared the two approaches . HoweverIt seems this new paradigm is going through an articulation process where its boundaries and uses are still being defined ,43,44. Oet al, and later Sandler [The distribution of tests analysed in the included studies is also telling, demonstrating incongruence between research and patient need. The diagnostic process has been notably analysed in the early work of Crombie, Hampton  Sandler -47. Thes Sandler -47. Yet, Sandler ,49.There is similar incongruence between the settings where most patients are seen in practice and the settings where the tests were analysed. The vast majority of patients in practice are either seen in a primary care or an emergency care setting ,51, but Designing a study to evaluate a clinical test particularly in a primary care setting is hampered by the availability of an adequate reference standard . The refAlso applying a suitable reference standard to primary care patients may be constrained by ethical considerations; particularly, if the patient population is considered low risk, but the reference standard carries potential hazards. This is not the case when the test is being used to stage an already identified cancer. Here there is a significant risk of inappropriate treatment and decreased life expectancy by not performing such a test for the patient. This, in part, explains the number of studies evaluating imaging technologies to stage patients with cancer.This study has some limitations. A single reviewer performed both the study selection and the data extraction. To measure the reproducibility, a second reviewer, blinded to the results, independently carried out each of these processes on two separate 10% random samples. Agreement between the reviewers was measured using the kappa statistic and this demonstrated 'good to excellent agreement' for both the study selection and data extraction. Nonetheless, this method is still more likely to yield errors over the preferred method of complete, independent replication of both steps by at least two reviewers.What may be considered a meta-analysis of diagnostic test studies is not without ambiguity. The definition used here was one, which encompassed sound systematic review principles and used recognised methods to aggregate the results. Inevitably such a definition leads to tight inclusion criteria and this is reflected by the number of studies included, which are perhaps fewer than might be expected from earlier reviews of the field .In summary, there is still limited uptake of the new statistical methods used in meta-analysis of diagnostic test studies. Although this should change with increased availability of statistical software, it remains unclear to what extent these methods will actually benefit clinical practice.More broadly, if the studies reviewed here are representative of diagnostic research in general, there appears to be a disconnect between the focus of investigators on specialist tests in specialist settings and the type of tests and settings actually encountered in the majority of clinical practice.The authors declare that they have no competing interests.Both BHW and MQ selected, extracted and appraised the data. BHW wrote the first draft. MQ commented on all drafts. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/11/27/prepubAppendix 1. search algorithms.Click here for fileAppendix 2. Detailed description of inclusion criteria.Click here for fileAppendix 3. Flowchart showing inclusion/exclusion decisions.Click here for fileAppendix 4. Set of included studies.Click here for fileAppendix 5. Evidence tables for individual studies.Click here for fileAppendix 6. Description of included studies.Click here for file


Routine Outcome Monitoring refers to regular measurements of clients’ progress in clinical practice, aiming to evaluate and, if necessary, adapt treatment. Clients fill out questionnaires and clinicians receive feedback about the results. Studies concerning feedback in youth mental health care are rare. The effects of feedback, the importance of specific aspects of feedback, and the mechanisms underlying the effects of feedback are unknown. In the present study, several potentially effective components of feedback from Routine Outcome Monitoring in youth mental health care in the Netherlands are investigated.We will examine three different forms of feedback through a three-arm parallel-group randomized controlled trial. 432 children and adolescents (aged 4 to 17 years) and their parents, who have been referred to mental health care institution Pro Persona, will be randomly assigned to one of three feedback conditions (144 participants per condition). Randomization will be stratified by age of the child or adolescent and by department. All participants fill out questionnaires at the start of treatment, one and a half months after the start of treatment, every three months during treatment, and at the end of treatment. Participants in the second and third feedback conditions fill out an additional questionnaire. In condition 1, clinicians receive basic feedback regarding clients’ symptoms and quality of life. In condition 2, the feedback of condition 1 is extended with feedback regarding possible obstacles to a good outcome and with practical suggestions. In condition 3, the feedback of condition 2 is discussed with a colleague while following a standardized format for case consultation. The primary outcome measure is symptom severity and secondary outcome measures are quality of life, satisfaction with treatment, number of sessions, length of treatment, and rates of dropout. We will also examine the role of being not on track (not responding to treatment).This study contributes to the identification of effective components of feedback and a better understanding of how feedback functions in real-world clinical practice. If the different feedback components prove to be effective, this can help to support and improve the care for youth.NTR4234Dutch Trial Register Quality of life will be measured with the KIDSCREEN. The KIDSatisfaction with treatment will be measured with the Jeugdthermometer,60. The The number of treatment sessions will be counted (quantitative variable) and the length of treatment will be registered in days (quantitative variable) for each client. Dropout rates will be calculated as the percentage of clients that abandon treatment  in each feedback group.In addition, we will examine whether being NOT moderates the association between the feedback intervention and symptom severity. We will determine whether each client is NOT by calculating the reliable change index (RCI) for theLastly, socio-demographic characteristics of the children, adolescents and parents  and clients’ diagnosis will be extracted from the electronic patient files and by asking additional questions.Literature indicates various effect sizes of feedback from ROM,21,27,62However, our previous experiences have shown that approximately 50% of the participants stop filling out questionnaires after one measurement (baseline assessment). Hence, the clinicians of these children, adolescents and parents do not receive feedback during treatment. It would not be desirable to impute 50% of the data as this would make the imputation highly unreliable. Therefore, we will invite twice as many children, adolescents and parents  to include the required number of 144 participants per condition of whom clinicians have received feedback during treatment (i.e. at least 50% of the measurements).Randomization of each participant to one of the three feedback conditions will be carried out using a computer-generated random number list with a blocked randomization scheme . An independent researcher will allocate the participants to the feedback conditions after the baseline assessment. To ensure that the distribution of parents and children and adolescents is similar across the three feedback conditions, randomization will be stratified by age of the child or adolescent (4 to 11 years old and 12 to 17 years old). To exclude confounding due to differences among departments, randomization will also be stratified by department .All analyses will be conducted using Mplus, becauseThis study protocol describes a three-arm parallel-group randomized controlled trial to investigate several potentially effective components of feedback from ROM in youth mental health care in the Netherlands. It is hypothesized that the more specific and concrete the feedback, the more and faster children’s and adolescents’ symptoms will decrease, the more children’s and adolescents’ quality of life will improve and the more children, adolescents and parents will be satisfied at the end of treatment. In addition, we expect to find a negative relationship between feedback condition and the duration of treatment. It is hypothesized that the more specific and concrete the feedback, the fewer sessions treatments will contain and the shorter treatments will be. Also, we expect that children, adolescents and parents will drop out of treatment less often when feedback is more specific and concrete. We expect that the largest effects of feedback will occur when clinicians additionally discuss the feedback with a colleague. Finally, we expect that feedback will be most effective for children and adolescents who are not progressing well in treatment.One of the strengths of this study is that we operationalize and directly compare three different forms of feedback to improve the design and delivery of feedback. The feedback conditions are derived directly from feedback theories and, to the best of our knowledge, the current study is the first to assess the effects of enhancing feedback with case consultation. Second, we focus not only on the effectiveness of different components of feedback, but also on the mechanisms through which feedback possibly works. We aim to understand why feedback is effective in some cases but not in others by testing whether not progressing well in treatment (i.e. not on track) moderates the effects of feedback. Third, we specifically investigate the effects of feedback in youth mental health care. We are thereby contributing to the limited knowledge about the effects of feedback and the importance of specific aspects of feedback for this particular population. Fourth, we actively involve parents in the study and combine self-reports with parent-reports. For children between 4 and 11 years old, parents fill out the questionnaires and clinicians will discuss the feedback with the parents. Hence, it is possible to assess the effects of different forms of feedback for young children and when only parents are receiving help (i.e. parenting skills training). Fifth, our study takes place in real-world clinical practice. The participating children, adolescents and parents are diverse in socio-demographic characteristics  and the children and adolescents have all kinds of mental health problems. The study has only one exclusion criterion (insufficient understanding of the Dutch language). The results of the study will, therefore, have good external validity.A limitation of the study is that differences in the care provided to participants in the second and third feedback conditions other than the intervention can arise (performance bias), because the intervention will be focused on the clinician. Since clinicians will not be blinded, it is possible that they will make additional efforts to improve treatment outcome when they receive feedback reports from the second and third feedback conditions instead of the first condition (control condition). Besides that, it is possible that effects from the third feedback condition will spill over to the second feedback condition. If clinicians have discussed several feedback reports with their colleagues (third feedback condition), they might guess what reactions their colleagues would have and what advice they would offer for clients who are not discussed (second feedback condition). Because each clinician will only have a couple of clients in each feedback condition, we think that such a spillover effect is unlikely. Furthermore, clients in the second and third feedback conditions may experience a placebo effect if their clinicians reveal that their feedback reports are being discussed with a colleague to improve treatment. In addition, due to technical and logistic restrictions, we are unable to check whether clinicians actually discuss the feedback with the children, adolescents and parents. However, we will remind the clinicians to discuss the feedback by sending them e-mail messages and we will ask clients at each measurement whether the feedback was discussed. Lastly, due to financial constraints, we will be unable to investigate the long-term effects of feedback in youth mental health care. Hence, further research should include follow-up measurements after treatment has ended.By investigating several potentially effective components of feedback from ROM in youth mental health care, we contribute to the identification of important aspects of feedback and to a better understanding of possible mechanisms underlying feedback effects . We also contribute to the knowledge about and possibilities for use of feedback in the real world, through which the results of our study will be immediately relevant for clinical practice. Moreover, we extend the knowledge to youth mental health care in the Netherlands.If the different components of feedback prove to be effective, the study will have strong practical relevance because the results will help to support the care for youth and to improve the treatments that children, adolescents and their parents receive. Clinicians might be better able to track the course of everyday treatments, signal potential treatment failures and adjust treatments accordingly by discussing the feedback with their clients. Eventually, treatments might have better outcomes, might contain fewer sessions and might become shorter. Also, children, adolescents and parents might drop out of treatment less often and might be more satisfied at the end of treatment. Consequently, there is potential for roll-out of the feedback with the most effective components across all youth departments of mental health care institutions throughout the Netherlands.aParents/caregivers might refer to any people who care for children and adolescents, e.g. biological parents, stepparents, adoptive parents, grandparents, other family members or guardians. Because children and adolescents are generally referred to mental health care with their biological parents or stepparents, we use the term ‘parents’ in the remainder of the study protocol.ROM: Routine Outcome Monitoring; NOT: Not On Track; TSM-Y: Treatment Support Measure–Youth Form; TSM-P: Treatment Support Measure–Parent Form; SDQ: Strengths and Difficulties Questionnaire; RCI: reliable change index.The authors declare that they have no competing interests.All authors contributed to the design of the study. MvS will be responsible for data collection, data analysis and for reporting the study results. GH, JWV and BT are supervisors and principal investigators. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/14/3/prepubExample of a feedback report.Click here for file


We propose, and offer evidence to support, the concept that many uterine leiomyomas pursue a self-limited life cycle. This cycle can be arbitrarily divided on the basis of morphologic assessment of the collagen content into 4 phases: (1) proliferation, (2) proliferation and synthesis of collagen, (3) proliferation, synthesis of collagen, and early senescence, and (4) involution. Involution occurs as a result of both vascular and interstitial ischemia. Interstitial ischemia is the consequence of the excessive elaboration of collagen, resulting in reduced microvascular density, increased distance between myocytes and capillaries, nutritional deprivation, and myocyte atrophy. The end stage of this process is an involuted tumor with a predominance of collagen, little to no proliferative activity, myocyte atrophy, and myocyte cell death. Since many of the dying cells exhibit light microscopic and ultrastructural features that appear distinct from either necrosis or apoptosis, we refer to this process as inanosis, because it appears that nutritional deprivation, or inanition, is the underlying cause of cell death. The disposal of myocytes dying by inanosis also differs in that there is no phagocytic reaction, but rather an apparent dissolution of the cell, which might be viewed as a process of reclamation as the molecular contents are reclaimed and recycled. The etiology of uterine leiomyomas (or fibroids) is unknown, and their pathogenesis has been incompletely determined. Because they are so common (80% in African-American women and 70% in Caucasian women in one study ), it wouThe histologic changes that characterize the smooth muscle cell response to vascular injury are similar to those that occur in uterine fibroids. Uterine fibroids are characterized by two primary histologic features: the proliferation of smooth muscle cells and the production of a collagenous matrix. While the mitotic activity of fibroids is variable and generally modest, the proliferative rate of many fibroids is greater than that of the adjacent myometrium . The colIt has been our observation that fibroids with extensive accumulation of collagen generally exhibit less mitotic activity. Based upon this observation and the conjectural analogy of fibroid development to the reparative response of smooth muscle cells in vascular injury, we hypothesized that the growth of uterine fibroids begins with a predominantly proliferative phase that either precedes or occurs concomitantly with the production of extracellular matrix. At some stage in the life of a fibroid, however, this progressive elaboration of matrix then seems to predominate over the proliferative response, resulting in the ultimate appearance of a hyalinized, involuted tumor. With this concept in mind, we have arbitrarily divided the development of fibroids into 4 hypothetical phases based upon the quantity of collagen present in the tumor. We have further hypothesized that the proliferative rate of the tumors would be the greatest in the early phases and would then diminish with progression to the final phase of involution.Fibroid tumor specimens were obtained by consent from women undergoing hysterectomy or myomectomy at the George Washington University Medical Center between June, 1996 and April, 1999, as part of the NIEHS Uterine Fibroid Study. Details of patient recruitment, demographics, and collection of gross pathology data have been previously reported [μm, and stained with hematoxylin and eosin. Representative sections were stained with Masson's trichrome stain to accentuate the collagen.Following fixation in 10% buffered formalin, representative sections of at least one and as many as six fibroid tumors were submitted from each patient. Up to six sections were taken from tumors that were of sufficient size, with four of these sections taken from the periphery of the tumor and two from the central portion of the tumor. Sections of myometrium and endometrium were also submitted from many of the patients. The fixed tissues were routinely processed, embedded in paraffin, sectioned at 4-5 A total of 2151 sections from 460 fibroid tumors were available for microscopic examination. The slides were examined with an Olympus BX50 microscope, using objectives ranging from 2x to 100x. An Olympus ocular micrometer WHN10x-H/22 was used for nuclear measurements. The magnifications cited in the figure legends represent the original objective magnification multiplied by the tube length magnification of 3.3. Phase 1 = no, or insignificant, collagen matrix Phase 2 = <10% collagen Phase 3 = 10–50% collagen Phase 4 = >50% collagen.On the basis of microscopic estimation of the area of the tumor occupied by extracellular matrix in H&E stained slides, we arbitrarily categorized the fibroid tumors into four phases as follows:When more than 1 section of the tumor was available, all sections were included in the estimation of percent collagen .The H&E stained sections of all tumors were scanned with the 20x objective of an Olympus BX50 microscope until a mitosis was identified, and then the number of mitoses in 10 high power (40x objective) fields was counted. Only structures consistent with the prometaphase, metaphase, anaphase, or telophase stages of mitosis were counted. When more than one section of a tumor was available, the mitotic counts from each section were added and the sum was divided by the number of sections to give an average mitotic count for each tumor.Gross tumor size data (<2 cm or ≥2 cm) were available for most (86%) of the tumors examined microscopically. Following assignment of Phase (1–4) for each tumor, the gross tumor sizes were obtained from the surgical pathology records for comparison of tumor size with tumor phase.Specimens for TEM were collected, with no identifiers or links to patient identification in accordance with guidelines by the National Institutes of Health Office of Human Subjects Research, at the time of hysterectomy or myomectomy at Duke University Medical Center in Durham, North Carolina. This on-site collection allowed for the immediate sectioning of tissue into 1 mm cubes and fixation in 2.5% glutaraldehyde. Following fixation, the tissues were processed routinely for TEM in a Lynx Automatic Tissue Processor  by buffer rinsing, postfixing in 1% osmium tetroxide, dehydrating in an ascending graded series of ethanols and acetone, and infiltrating and embedding in epoxy resin. Semithin sections  were cut and stained with toluidine blue, examined by a pathologist, and areas within the stained section chosen for thin sectioning (a 90 nm or “gold section”). Areas selected for thin sectioning were trimmed and cut and then placed on copper grids. The grids were examined on a Tecnai G2 12 BioTwin 120 KV TEM . Digital photomicrographs were taken from selected areas of interest.Descriptive statistics included means, standard errors of the mean, and minimum and maximum mitotic counts per tumor. Because mitotic counts were not normally distributed, counts were compared across phases using one-sided Mann-Whitney tests.Phasing of fibroids was based upon the microscopically estimated percent of total tumor area occupied by extracellular fibrous matrix in H&E stained slides. Small amounts of collagenous matrix around blood vessels and between muscle fascicles, unaccompanied by obvious spindle cell or fibroblastic proliferation, were considered to be part of the normal structural support and were not included in the total percentage. This perivascular and interfascicular matrix appeared to be a relatively minor component in most fibroids except for those tumors assigned to the Phase 1 category in which fibrous matrix was otherwise minimal. Collagen deposition within the tumors was variably interfascicular, intrafascicular, or a combination of the two . After aPhase 1 and Phase 2 tumors consist predominately of myocytes, whereas in Phase 3 and Phase 4 tumors, the balance is progressively tilted towards a predominance of dense extracellular matrix . As the P = 0.0003), Phases 2 and 3 (P = 0.0105), Phases 2 and 4 (P < 0.0001), and Phases 3 and 4 (P < 0.0001) were all statistically significant. Myometrial samples were also available from 67 of the patients. Out of the total of 287 myometrial samples, mitotic activity (1/10 HPF) was found in only one sample from each of two patients.Mitotic figures were infrequent in most tumors and were not identified in the Phase 4 tumors . Phase 3P = 0.0001. This finding correlates with our hypothesis that the growth of the tumors is the result of both the proliferation of myocytes and the accumulation of extracellular collagen. In addition, this result, in combination with the reduction in mitotic count in Phases 3 and 4, further supports our hypothesis that as the tumors grow and accumulate collagen, the proliferative rate of the myocytes eventually declines.Analysis of gross tumor size data revealed an increase in average size of tumors in Phases 3 and 4, as compared to Phases 1 and 2 . The treAt the interface between fascicles of myocytes and zones of collagenous matrix in leiomyomas, the myocytes often exhibit cytologic changes that are evident with the light microscope. Chief among these are the reduction of eosinophilic cytoplasm and the tendency of nuclei to become thinner and more pointed at the poles. The cytoplasmic pallor of these transformed myocytes is suggestive of a diminution in the number of myofilaments, which occupy most of the cytoplasm of normal smooth muscle cells . In addiIf the cytoarchitectural features of leiomyomas are compared to the myometrium itself, several differences are apparent. First, it is evident that the fascicular pattern of the myometrium becomes less well defined in leiomyomas, sometimes appearing microfascicular, sometimes disorganized and haphazardly fascicular, and sometimes relatively patternless. In addition, the parallel linear arrangement of normal myocytes usually noted in the myometrium is also replaced to varying degrees by a less orderly and sometimes completely disorganized pattern of cells in fibroid tumors . Since tIn some sections of myometrium, close examination of myometrial myocytes with the 40x or 100x objectives reveals lateral intercellular attachments between adjacent myocytes . We refeBy transmission electron microscopy, it is apparent, in side-by-side comparisons, that the cytoplasm of myometrial myocytes is more uniformly electron dense than the cytoplasm of leiomyoma tumor cells due to the greater concentration of thin myofilaments Figures . In contAn associated morphologic consequence of this transformation, seen with both the light and electron microscope, is that the transformed cells have less cytoplasm because of this reduction in myofilaments, and thus have a more slender, streamlined appearance. The nuclei also appear to be thinner and often have pointed ends, in contrast to the more frequently rounded ends of the myometrial cells Figures .By the examination of Masson's trichrome stained sections, it is apparent that the collagen in fibroids is produced by the myocytes themselves since there are no interspersed fibroblasts between the myocytes . In assoμm in length, while the nuclear lengths of the fibroid nuclei in this image  in the life of a fibroid, the excessive production of extracellular matrix reaches a maximum (>50% collagen), angiogenesis is reduced or at least fails to keep pace with the growth of the tumor, myocyte proliferation is greatly diminished or absent, and cellular atrophy occurs. This is the phase of involution, characterized by large areas of hyaline matrix with scattered islands of atrophic myocytes. Necrosis due to infarction is often seen in Phase 4, but infarction may occur in any phase. Likewise, apoptotic cells are occasionally noted. However, a third form of cell death, inanosis, the ultimate endpoint of atrophy and the consequence of nutritional deprivation, is a characteristic and defining feature of this final phase.In some respects, the process of inanosis occurring within fibroids can be considered ischemic in nature and in this respect likened to both necrosis and apoptosis which may occur as a result of ischemia. A fundamental difference between these processes, however, is the rapidity with which they occur. Necrosis and apoptosis are both relatively rapid consequences of severe to moderately severe ischemic injury, while the histologic features of inanosis suggest that this is a very slow atrophic process which probably progresses over days to months until cellular proteins have been depleted to the point that vital cellular functions can no longer be maintained. In fact, zones of necrosis are not infrequently found in fibroids, presumably resulting from more sudden and profound ischemia, and rare cells which appear apoptotic are noted among the myocytes of Phase 3 and 4 tumors. From a quantitative standpoint, however, the atrophic cells of inanosis are more commonly found in late phase fibroids than are apoptotic cells, and they occur more consistently than do zones of necrosis.μm or less, it is assumed that the cell is nonviable. This is based upon the fact that if all of the DNA of a human nucleus was condensed, it would occupy a volume equivalent to a cube measuring 1.9 μm on a side [μm. Thus, it must be assumed that cells having nuclei less than 2.356 μm in diameter, as well as nuclear pallor, have lost nucleic acid material, and that such loss would be incompatible with cell survival. As we have noted in our description of inanosis in μm, although admittedly it is always difficult to exclude tangential sectioning.In addition to pathogenetic differences, the morphologic features of inanosis, particularly the nuclear changes, are distinct from those of apoptosis. Apoptosis is a well-described and morphologically defined pattern of cell death. Other than cell shrinkage, there is very little similarity between apoptosis and inanosis by light microscopy. When the apoptotic cell shrinks, it also tends to retract from the surrounding tissue, rounds up and condenses the cytoplasm, whereas the atrophic cells of inanosis shrink to a more marked degree but usually maintain their shape and their connection with the surrounding stroma. While the apoptotic cell often exhibits hypereosinophilic cytoplasm, inanotic cells typically show cytoplasmic pallor, probably because of progressive depletion of cytoplasmic protein and organelles. Moreover, the nuclear changes are particularly different in that apoptotic cells characteristically condense their chromatin in peripheral aggregates against the nuclear membrane and then subsequently often fragment, whereas the myocyte tombstone nucleus is markedly reduced in size, pale staining, and nonfragmented. When the nuclear pallor of inanotic cells is marked and the nuclear size is diminished to 2 n a side . If thisMorphologic comparisons of inanosis with necrosis are more problematic than comparisons with apoptosis because necrosis is less well defined than apoptosis and also more variable in appearance. The histologic hallmarks of necrosis are usually considered to be the regional involvement of multiple contiguous cells, hypereosinophilia and swelling of the cytoplasm, variable nuclear changes including pyknosis, karyolysis, or karyorrhexis, and an accompanying inflammatory reaction because of the rupture of cell membranes with the release of cell contents. However, if the definition of necrosis is extended to include individual cell death with cytologic changes of cell shrinkage, nuclear and cytoplasmic pallor, and lack of inflammatory reaction, then inanosis would not be distinguishable from necrosis and would have to be considered as a variant of necrosis. At the least, however, there are a few features of inanosis that are not typically associated with necrosis. The degree of cell and nuclear shrinkage and pallor in inanosis is marked, the pattern of cell involvement is often mottled with viable cells between the dead cells, and there is no inflammatory reaction despite ultimate membrane degradation and release of cell contents. Necrotic cells probably do not achieve the marked degree of shrinkage seen in inanosis because there is often no preceding atrophy and because they are more rapidly eliminated by the enzymatic and phagocytic action of inflammatory cells attracted to the site by cytokines and the leakage of their cytoplasmic contents. Finally, it is of interest that autophagy, which we have shown by EM is clearly occurring in the late phase fibroid tumors, has been shown to be cytoprotective when the availability of oxygen and nutrients is poor, and in such environments is effective in inhibiting the induction of both apoptosis and necrosis .In this regard, the argument might also be made that inanosis is in fact autophagic cell death. While recognizing that there is no clear answer to this question, we favor the concept that autophagy is cytoprotective to cells deprived of nutrients, and that cell death in this circumstance is more likely related to a critical lack of oxygen and essential nutrients available to the cell in its environment, rather than being secondary to a self-destructive overzealous autophagic process. If nutritionally deprived cells, struggling to survive, possess the regulatory controls to suppress apoptosis, necrosis, and apparently the release of cytokines as suggested by the lack of inflammation, then it seems likely that autophagy would also be a finely tuned and regulated survival mechanism that would not promote the demise of the cell which it is designed to protect , 18.Comparative morphologic features of necrosis, apoptosis, and inanosis are summarized in In summary, the distinguishing features of inanosis in fibroids are the slowness of the process, the combined vascular and interstitial ischemic pathogenesis resulting from the elaboration of an extensive extracellular matrix, and the consequent cellular atrophy presumably due to nutritional and oxygen deprivation, which culminates in the formation of the hallmark cell, the myocyte tombstone. An alternative term for inanosis, combining these distinctive characteristics, is slow vasculointerstitial ischemic and atrophic cell death.Clearly there is no evidence of phagocytosis of the inanotic cells, nor is there any reason to hypothesize enzymatic digestion by leukocytes since there is no inflammatory reaction associated with inanosis. Perhaps there is an orderly, internal as well as extracellular, disposition process for the recycling of amino acids and other important molecules from the myocyte tombstones of inanosis. This process may be viewed as a type of reclamation in which the molecular contents of the cell are reclaimed by the body and recycled. Reclamation may be mediated by both lysosomal degradation and matrix metalloproteinases. The lack of an inflammatory reaction or recruitment of macrophages seems contrary to the notion that the extrusion of cytoplasmic contents will evoke an inflammatory reaction as occurs with necrosis. It could be argued that cytokines that might be released into the dense stroma do not reach the capillaries because of the dense fibrosis; however, there seems no reason for a starving cell to release cytokines. Since it has been reported that nutritional deprivation inhibits apoptosis in cells , it seemFrom a broader standpoint, might such a mechanism as reclamation be relevant to the routine removal of effete cells from our viscera as well, since we know that most of the cells in our body have a limited lifespan and are periodically replaced? Apoptotic cells are removed by phagocytosis, and yet phagocytes with apoptotic bodies are only infrequently encountered in histologic sections of viscera. And from the standpoint of energy efficiency, why would nature develop a system that would require the energy input of a second cell (such as a phagocyte) to remove senescent cells on a regular basis?We have presented morphologic studies to support our hypothesis of the contribution of collagen synthesis to both the enlargement and the eventual involution of uterine fibroids. The excessive elaboration of extracellular matrix ultimately results in hyalinization of both the smaller vessels and the interstitium, leading to reduced microvascular density, interstitial and vascular ischemia, and nutritional deprivation of the tumor myocytes. Atrophy through autophagy then develops as a survival mechanism for individual cells, until a critical point is reached when the nutritional deficits are incompatible with survival and inanotic cell death occurs. Inanosis differs from both apoptosis and necrosis in several respects, including the initiating factors, the slowness of the process, and the morphologic features. Future studies of immunohistochemical and molecular markers are needed to complement these morphologic observations and to provide additional evidence for the differentiation of inanosis from apoptosis and necrosis. Further elucidation of the process of inanosis may offer insights into the pathogenesis of cachexia in neoplastic diseases since nutritional deprivation may play a key role in each. Finally, disposition of inanotic cells seems to occur by a reclamation process of nonphagocytic, presumably enzymatic dissolution in which cellular molecules are reclaimed and recycled for utilization elsewhere.Our proposals and our concepts are based upon our observations and our attempt to understand the biology of these tumors. Although we believe that many fibroids undergo involutional changes later in their development, we neither propose that these changes occur in all fibroids, nor that the involutional changes occurring in some fibroids result in shrinkage or disappearance of those tumors. In fact, we have shown that the later phase tumors tend to be larger on average because of the accumulated collagenous matrix, and it is the gross size of these tumors that is recognized as one of the major determinants of their morbidity.