Bacillus thuringiensis and apparition of resistance of the codling moth Cydia pomonella to the C. pomonella granulovirus have, for example, been described. In contrast with the situation for pests, the durability of biological control of plant diseases has hardly been studied and no scientific reports proving the loss of efficiency of biological control agents against plant pathogens in practice has been published so far. Knowledge concerning the possible erosion of effectiveness of biological control is essential to ensure a durable efficacy of biological control agents on target plant pathogens. This knowledge will result in identifying risk factors that can foster the selection of strains of plant pathogens resistant to biological control agents. It will also result in identifying types of biological control agents with lower risk of efficacy loss, i.e., modes of action of biological control agents that does not favor the selection of resistant isolates in natural populations of plant pathogens. An analysis of the scientific literature was then conducted to assess the potential for plant pathogens to become resistant to biological control agents.The durability of a control method for plant protection is defined as the persistence of its efficacy in space and time. It depends on (i) the selection pressure exerted by it on populations of plant pathogens and (ii) on the capacity of these pathogens to adapt to the control method. Erosion of effectiveness of conventional plant protection methods has been widely studied in the past. For example, apparition of resistance to chemical pesticides in plant pathogens or pests has been extensively documented. The durability of biological control has often been assumed to be higher than that of chemical control. Results concerning pest management in agricultural systems have shown that this assumption may not always be justified. Resistance of various pests to one or several toxins of  The durability of a control method for plant protection is defined as the persistence of its efficacy in space and time. Erosion of effectiveness of conventional plant protection methods has been widely studied in the past. The durability of chemical control has for instance been studied because of the frequent and recurrent apparition of resistance to fungicides in major plant pathogenic fungal populations . The breBacillus thuringiensis (Bt) has been described shortly after the market approval of products based on various strains of this bacterium. McGaughey was the first to observe resistance in the field to Bt toxins in the Indian meal moth Plodia interpunctella, a major post-harvest pest of grain . It may also depend on the specific mode of action of biocontrol agents. Various modes of action are involved in the protective effect of biocontrol agents against plant pathogens. Although the number of studies done on this subject is important, knowledge of the precise mode of action of biocontrol agents is still partial. However, it is generally considered that there are three main ways for a biocontrol agent to control a plant pathogen : first, The main objective of this review is to assess the potential for plant pathogens to become resistant to biocontrol agents. To this end, an analysis of the scientific literature was conducted and scientific papers reporting the diversity of efficacy of biocontrol agents toward plant pathogens or those describing the ability of plant pathogens to produce natural mutants with reduced susceptibility under the selection pressure exerted by biocontrol agents were analyzed. The link between a potential loss of efficacy of a biocontrol agent and its mode of action was carefully explored.Identifying publications focused on this topic proved to be a challenging task. A survey of the Web of Science database between 1973 and the end of 2014, using the keyword combination [ AND ((pathogen OR disease) AND plant)], yielded 7872 references on biological control against plant diseases. Entering keywords describing the diversity of efficacy of biocontrol agents toward plant pathogens, i.e., [(divers* OR variab* OR variation) AND (resist* OR toleran* OR susceptib* OR sensitiv* OR insensitiv* OR defense)], allowed to refine this survey to 593 references. However, the analysis of this subset yielded only six relevant references. A second subset was generated from the initial 7872 references by entering keywords describing the durability of efficacy of biocontrol agents toward plant pathogens, i.e., (durability OR durable OR sustainable OR sustainability). Among the 274 references obtained, only one was relevant. Efforts to improve the keyword combinations failed to yield any additional references, a situation presumably reflecting the scarcity of studies specifically dedicated to this topic. The set of seven references was then complemented with studies including a comparison of biocontrol efficacy for two or more strains of a given plant pathogen. Attempts to automate this search with keywords failed, probably due to the fact that such comparisons were not the focus of these studies. Eventually, additional references were obtained through direct consultation with scientists implicated in biocontrol of plant pathogens. It is thus likely that the final set of 30 references analyzed in the present review may not be exhaustive, but it already provided quite illustrative examples  and 2,4-diacetylphloroglucinol , two compounds produced by antagonistic strains of fluorescent Pseudomonas spp. present in the wheat rhizosphere  was observed, with isolates of some anastomosis groups being less sensitive than others , P. medicaginis being less sensitive than P. aphanidermatum and P. torulosum  differed considerably in their sensitivity to 2,4-DAPG. The difference of susceptibility among Pythium species to various natural toxic compounds produced by biocontrol agents and the fact that several of these species could occur at the same time in a similar specific place may impact the success or at least the regularity of the effectiveness of biological control conferred by these antibiotic-producing bacterial strains.This diversity of sensitivity to antimicrobial compounds produced by biocontrol agents was also observed among different anastomosis groups within a species or different species of plant pathogens that could occur and can infect plants at the same time. For instance, variation in sensitivity among 18 isolates of n others . This waensitive , for kanorulosum , for the species , and for species . One strAgrobacterium tumefaciens, the causal agent of crown gall on many dicotyledonous plants, by biocontrol agent A. rhizogenes strain K84, which produces the antibiotic agrocin 84  that hyperparasitizes the fungus Cryphonectria parasitica and reduces its pathogenicity on chestnut trees, resulting in hypovirulent isolates of the fungus , the protective efficacy of B. subtilis QST713 was found to range from 40 to 86% on tomato leaves and from 0 to 80% on lettuce leaves , which was shown to control powdery mildew of barley mainly through induced resistance and especially by enhancing expression of leaf-specific thionin in leaves (Podosphaera xanthii (syn. Sphaerotheca fuliginea) and on leaf disks for 116 isolates of Pseudoperonospora cubensis revealed limited diversity among isolates of either species  sachalinensis, whose mode of action is generally associated with plant-induced resistance . The same results were observed for all five strains of B. cinerea, regardless of their initial phenotype of sensitivity to the antibiotic  in an experimental evolution study on melon leaves treated with an extract from roots of Chinese rhubarb  was able to rapidly adapt to the effect of the antibiotic-producing biocontrol agents tested. However, in the case of the pyrrolnitrin-producing biocontrol agent, a detrimental effect for the plant pathogen of the resistance to pyrrolnitrin would limit the risk of complete loss of efficacy. Based on the study with physcion, it is likely that this plant extract will have a low to moderate risk for resistance development of powdery mildew and downy mildew of cucurbits. Additional studies with other biocontrol agents having different modes of action would be necessary to infer a possible link between the durability of efficacy of a biocontrol agent and its mode of action. Similarly, additional studies with other plant pathogens would allow to generate hypotheses about a possible link between the durability of biological control and specific traits related to the plant pathogen.To our knowledge, the three experimental evolution studies described here are the only examples illustrating the potential of plant pathogens to adapt to the effect of biocontrol agents. In two of these studies, the fungal pathogen  was also shown to provide resistance to toxins produced by antagonistic bacteria P. fluorescens and Pantoea agglomerans , or MSF (major facilitator superfamily) transporters. These membrane proteins are able to transport a wide range of compounds and can evacuate outside of the cells diverse toxic metabolites. The tolerance conferred by these transporters is quite low but it is significant because it provides time for pathogens to activate some mechanisms of detoxification . ABC traudomonas . Severaludomonas . Multidrudomonas . Ajouz elomerans . TherefoMycosphaerella graminicola to a sublethal dose of 1-hydroxyphenazine, an antibiotic produced by the biocontrol bacterium Pseudomonas, led to increased production by the fungus of catalases, peroxidases, and superoxide-dismutases and an increase in melanin synthesis, allowing the degradation of the antibiotic and the protection of the fungus , that still produces agrocin 84 but lacks the region necessary for the transfer of the plasmid pAgK84. The judicious use of biocontrol agents and particularly of the new strain K1026 should minimize the risk of pAgK84 transfer into pathogenic Agrobacterium strains and thus help to preserve the effectiveness of A. radiobacter as a biocontrol agent against crown gall.Finally, natural plasmid transfer between bacteria was also shown to provide a possible mechanism for plant pathogens to become resistant to biocontrol agents. This was the case for example for the soilborne bacterium d pAgK84 . The resol agent . To miniFusarium udum to maintain a slow growth and the production of conidia in presence of the hyperparasitic bacterium Bacillus subtilis AF1 . For example, ABC transporter activity has been implicated in the tolerance of  sativum , of B. cof grape  and of Go tubers . SimilarGcABC-G1 . This alGcABC-G1 .Botrytis cinerea is for instance able to detoxify the alpha-tomatine, a phytoanticipin found in tomato plants  involves the production of reactive oxygen species that leads to cell death and it is generally consider as a signal to induce the synthesis of antimicrobial compounds like phytoalexins. It usually prevents the fungal penetration into host tissue but it has been shown that HR facilitates the colonization of the plants by necrotroph fungal pathogens like rotiorum  or Rhizoa solani . These pa solani .P. fluorescens 2–79 and Q72a80 to persist in the wheat rhizosphere  levels of sensitivity to biocontrol agents, regardless of the complexity of their mode of action. Certain pathogens also have the potential to adapt in a few generation to the selection pressure exerted by biocontrol agents. Available information is sufficient to suggest that the assumption that durability of biological control is necessarily higher than that of chemical control may not always be justified. However, it is not sufficient to draw conclusions about the existence of specific traits related to the plant pathogen or related to the biocontrol agent that could explain the loss of effectiveness of a biocontrol agent in practice.There is much need for further studies on issues related to this topic. Among them, the establishment of baseline sensitivity  would be helpful in future surveys of biocontrol agents. Such monitoring is carried out routinely for fungicide resistance in fungal plant pathogens world-wide . It is aIn addition to the population approach described above, experimental evolution studies are also needed to evaluate the ability of plant pathogens to evolve under the selection pressure exerted by a biocontrol agent. This approach will result in identifying risk factors that can foster the selection of strains of plant pathogens resistant to biocontrol agents. Various biocontrol agents and different plant pathogens must be tested in the future. This will result in identifying types of biocontrol agents with lower risk of efficacy loss, i.e., modes of action of biocontrol agents that does not favor the selection of resistant isolates in natural populations of plant pathogens. Even though all biocontrol agents should create selection pressure on target populations of plant pathogen, some modes of action may present a clear opportunity for pathogens to evolve resistance. For example, a mechanism involving antibiosis would, by analogy with the fungicides, be considered a high risk to be overcome, whereas a multiple or a more complex mode of action would indicate relatively low risk. This knowledge is essential to ensure a durable efficacy of biocontrol agents on target plant pathogens.Even if the data are too sparse to suggest general statement on the use of biocontrol agents in practice, this review highlights the necessity for careful management of their use once they become commercially available in order to avoid repeating the mistakes made with chemical fungicides. For instance, we should consider alternating or combining biocontrol agents with different mechanisms of action. In addition to possibly ensure the durability of biological control, the combination of several biocontrol agents have shown to improve the efficacy and reduce the variability of efficacy . The conSignificant research efforts are also needed to anticipate the potential failure of biological control and integrate durability concerns in the screening procedure of new biocontrol agents. According to the results mentioned in this review, caution should be applied when screening and selecting isolates of biocontrol agents, to ensure a wide representation of the targeted plant pathogen population. To test the efficacy of potential biocontrol agents or to screen for new biocontrol agents against plant diseases, most studies continue to use a single isolate or relatively few isolates. Innovative screening procedures based on the known mode of action have already been developed . We mustThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Introduction Health facilities assessments are an essential instrument for health system strengthening in low- and middle-income countries. These assessments are used to conduct health facility censuses to assess the capacity of the health system to deliver health care and to identify gaps in the coverage of health services. Despite the valuable role of these assessments, there are currently no minimum standards or frameworks for these tools.Methods We used a structured keyword search of the MEDLINE, EMBASE and HealthStar databases and searched the websites of the World Health Organization, the World Bank and the International Health Facilities Assessment Network to locate all available health facilities assessment tools intended for use in low- and middle-income countries. We parsed the various assessment tools to identify similarities between them, which we catalogued into a framework comprising 41 assessment domains.Results We identified 10 health facility assessment tools meeting our inclusion criteria, all of which were included in our analysis. We found substantial variation in the comprehensiveness of the included tools, with the assessments containing indicators in 13 to 33 (median: 25.5) of the 41 assessment domains included in our framework. None of the tools collected data on all 41 of the assessment domains we identified.Conclusions Not only do a large number of health facility assessment tools exist, but the data they collect and methods they employ are very different. This certainly limits the comparability of the data between different countries’ health systems and probably creates blind spots that impede efforts to strengthen those systems. Agreement is needed on the essential elements of health facility assessments to guide the development of specific indicators and for refining existing instruments. A large number of health facility assessment tools currently exist, using different methodologies and indicators and limiting the comparability and comprehensiveness of health systems data.Consensus is needed on specific indicators for monitoring the capacity and functionality of health facilities in low- and middle-income countries.The need to move beyond individual health services and strengthen health systems has become a critical component of global public health and international development . CompareMost would agree that to improve population health, health services must be available, accessible, efficacious and used by the population. To achieve this, comprehensive interventions are needed that strengthen not only service delivery, but also the laws and policies that influence the functionality of a health system and the health-seeking behaviour of the population. To achieve those reforms, one needs a pragmatic assessment of where gaps or weaknesses exist within the system using rigorous and valid methodologies to determine the above-listed factors. Collecting data at the level of health facilities allows for a detailed assessment of the various components that function (or do not) at the level of service delivery, which is a useful level of analysis for identifying the weaknesses within a national health system  health systems building blocks  or healtThe fact that health facility assessments are often patchy or incomplete is problematic for achieving important health gains in LMIC. Major investments in initiatives to scale up health services necessarily rely on reliable, accurate and comprehensive information on both capacities and gaps in health services availability to prioritize interventions and ensure equitable access to care. To achieve this, there is a need to ensure the development of evidence-based policies and interventions to improve the performance of health systems in LMIC  when necThis study asked whether the vagaries of health system assessments have a common root: the quality and comprehensiveness of health facility assessment tools. To answer this question, we performed a comparative analysis of the different tools that are currently used to assess the administrative and service delivery capabilities of health facilities in LMICs, charting their similarities and differences. We hypothesized that if a genuine consensus on health system strengthening existed, then the assessment tools used to assess the capabilities at the point of actual service delivery  ought to be quite similar, allowing perhaps for differences of form but few if any differences of substance.The MEDLINE, EMBASE and HealthStar databases were searched for articles published in English using the keywords and search strategy described in Appendix 1, developed with the assistance of a medical librarian. To locate non–peer-reviewed reports, a keyword search was conducted in the following databases: (1) the The inclusion criteria were the presence of an assessment tool, checklist or questionnaire that evaluated the availability of health resources or services at the health facility level. All questionnaires, regardless of the level of care evaluated , were included, consistent with WHO’s definition of health systems as being inclusive of ‘all organizations, people, and actions whose primary intent is to promote, restore or maintain health’ . We exclThe analysis of these assessments was conducted using a health systems framework to contextualize them in the essential capacities of health systems in LMIC. We used the WHO’s health systems building blocks as an organizing framework  and treaData were extracted into an Excel  database from all included reports using a thematic analysis of the health services included in the assessment tools by one reviewer (JWN). All the tools were analysed twice: the first time to compile a list of the assessment indicators present in each of the tools and the second time to evaluate which of these indicators were measured by each of the assessment tools. Each extracted indicator was categorized into a broader domain reflecting a group of health services. For instance, an indicator measuring the availability of surgical instruments was included under the domain ‘surgery’. Each of these domains was then mapped to the health systems building blocks contained in the health systems framework. Using the defined list of assessment domains and their indicators, a second reviewer screened 30% of the assessment tools to ensure consistency in the data extracted. Disagreements in data extraction were resolved through discussions among two reviewers until consensus was achieved.A recently published review of health facility assessment tools examined four of the assessments included in our study for the purpose of developing indicators of newborn care  of the 41 assessment domains. The majority of the differences fell within the areas of health services delivery, with considerable variation in the types of health services assessed and with a preference towards assessments of services at the primary care or community level rather than secondary-level services such as surgery or intensive care. A summary of the assessment domains and tools is included in Eight of the included assessments contained some form of basic information concerning the organization, ownership and leadership of health facilities. These data consisted of basic descriptive data of the ownership of the facility, department heads and basic questions of how the facility was organized and run. While these data were frequently available, they were generally very basic indicators of ownership or leadership of the facility and provided little in the way of measuring the quality of leadership, which may well be beyond the scope of these tools.Only two assessments collected information on how the health facility was financed and only five collected information on whether user fees were charged. Countries where the health system is financed through governmental schemes may account for the absence of these questions in some assessments  and only three collected data on the availability of emergency staff in-house 24 hours a day.Significant variation was uncovered in the assessment of diagnostic services, essential medicines and laboratory services. All of these domains have the potential for expansive lists of assessment criteria , although most used a selective sampling rather than an exhaustive list. For example, most assessments included indicators for basic equipments such as a stethoscope, blood pressure cuff and adult scale.Assessments of diagnostic services (including laboratory and diagnostic imaging) were frequently included, although again the specificity of these assessments varied. All 10 of the assessment tools evaluated the availability of some form of laboratory services, while only 7 assessed the availability of diagnostic imaging. These assessments ranged from indicators for specific analytical tests and equipment to general questions of capacity .Our results located two kinds of information and research of relevance to this building block: health information systems and clinical practice guidelines.Eight of the included assessments in our review contained assessments of different aspects of health information systems. Caseload data  were the most frequently collected and were included in eight of the tools, while assessments of communicable disease surveillance systems were the second most frequently collected data in six of the tools. Other data collected were less consistent across the assessments, such as vital statistics, patient charts and vaccination activity.Seven of the included assessments contained indicators for assessing the availability of evidence-based guidelines for relevant health conditions. These guidelines were often integrated into assessments of service availability, assessing services for the availability of essential resources and equipment as well as relevant clinical practice guidelines. Five of the included tools assessed whether clinicians had received continuing medical education or training in specific areas, generally over the past two years.The delivery of health services is the point of contact between patients and the health care system, where diagnosis and treatment occur. Not surprisingly, service delivery accounts for the bulk of the data collected by the assessments included in our review, collected across a large number of different clinical domains. The range of clinical services evaluated are in some ways misleading as some tools included only single indicators of complex, yet poorly defined packages of services rather than specific measures .All of the assessment tools also included some form of basic structural assessments, such as the condition of walls, floors and heating/cooling systems. As a basic structure constitutes an integral component of a health facility, this is included as an element of the health services delivery building block. Another key infrastructure assessment, the hospital bed census, was included in six of the included assessment tools, representing a significant absence of basic structural information in these tools.Nutrition services were included in five assessments, including indicators for malnutrition screening services and therapeutic feeding. Environmental health services were less frequently included in assessment tools, with only three of the included assessments containing relevant indicators. One assessment included indicators for the availability of water and food inspection services, although this was not included in any others, nor does it seem a particularly relevant focus for health facilities. The other two assessments that included environmental health services were both related to malaria bed net distribution.Health system strengthening requires reliable, accurate and comparable data sources across the health system to identify gaps in coverage and to identify priority health needs. The monitoring and evaluation of the health system necessitate a focus on how inputs and processes  contribute to outputs  and their impact on relevant health indicators . The absence of any of these data sources results in incomplete information and unreliable assessments of priority areas , this momentum appears to have left much of the essential health systems data behind. The results of our literature review located only four publications that implemented a standardized assessment in peer-reviewed publications; this low number may be the result of our search strategy, but it appears that there is either little awareness or little use of the tools currently in existence. A likely explanation is that although there is extensive experience in using these assessments by donors and ministries of health, the evidence base for these tools appears to be severely lacking and appears to be based on a restricted set of preferences or priorities rather than on a rigorous evaluation of the essential functions of health facilities or health systems.Second, we noted a preference towards the evaluation of primary care services, with secondary and tertiary care being absent from many assessments, despite a need for these services in LMIC  or the Alma Ata Declaration , which may also reflect donor or organizational priorities oriented towards specific kinds of programmes. This is an important finding, as these tools appear designed to assess the programmes that donors fund rather than initiatives that are led and monitored by the countries themselves.Only one of the tools included in our review (HeRAMS) made use of an explicit framework to guide the assessment of available health resources and services. While the HeRAMS framework is explicit, it also does not clearly link to a broader health systems framework. This is, in part, because of the nature of the tool’s initial deployment in the Darfur region of Sudan, an area of ongoing conflict rather than stable development.This review provides a systematic catalogue of the broad domains employed in the assessment of health facilities. This catalogue should provide a foundation for the development of more detailed assessment indicators based on these domains and with the goal of making future assessments reflective of the essential characteristics of well-functioning health systems.A significant number of gaps were uncovered that would likely lead to an incomplete assessment of the administrative or health service delivery functions of health facilities, which should raise serious concerns. While some building blocks are perhaps easier to quantify  than others , each is important for ensuring that health systems evolve comprehensively and not disproportionately. Furthermore, many of the included indicators were evaluated differently, leading to concerns not only of incomparability among the tools, but also a lack of agreement of how best to measure specific functions or services.Assessments of the leadership of a health facility, for example, often allow one to guess or infer other features of the facilities. A public hospital run by an international non-governmental organization may have access to different supply chains or human resources than a public hospital run by the ministry of health, for example. Combined with relevant geographic and population demographic information, this information allows for important analyses of equity in the distribution of health services and resources and the identification of underserved populations when health facilities and population data are compared , but rather to generate a framework of essential assessment domains, linked to health systems building blocks, that could be applied in the development of future assessments. To that end, we feel justified in excluding these service-specific assessments, in favour of this more comprehensive approach.Further studies that expand on this work could also consider including additional databases for their search, which may result in additional references being located in peer-reviewed journals and in the grey literature. This project’s findings are representative of the search strategy employed and expanding on the databases or keywords may result in additional sources, such as those in languages other than English.Our approach utilized a broad health systems framework as the foundation for aligning health facilities assessment domains with a broader objective of health systems strengthening. In doing so, we have identified common domains that ought to be included as part of a health facilities census, which should guide the development of more specific assessment indicators to correspond to each of these domains similar to those service-specific tools mentioned above. Our review and recommendations fall short of prescribing particular indicators or assessment strategies; rather, we propose this as the next step in the evolution of these assessments: defining the indicators that best align with countries’ packages of health services and the information needs of specialists working in these areas of health service delivery to ensure that detailed assessments of specialized health services are comparable among countries.Our results should be interpreted to recognize that different agencies  have a desire to exert ownership of their own data collection tools and processes, structured in a way that makes sense for the delivery or support of their own programmes. Rather than proposing the development of one tool that should be universally applied, our results propose a broad framework to be populated with internationally accepted indicators and basic datasets that can be used to guide the development of these tools, thereby ensuring a more comprehensive and coherent approach.This review highlights a fundamental problem in the collection of health facilities and health services availability data: the absence of common assessment tools yields incomparable data making it difficult, if not impossible, to track progress towards increasing access to health services, globally. Our review found 10 different health facility assessment tools currently in use. Our comparative analysis of these tools revealed that there are significant gaps in the areas evaluated by many of them, often orienting their focus towards primary care rather than the broader health system.This review provides a framework in the form of 41 assessment domains linked to health systems building blocks that should guide the development of new health facilities assessment tools and the refinement of existing ones. Furthermore, these assessment domains provide a useful starting point for defining more detailed assessments that correspond to specialized health services. Future developments in this area should integrate existing specialized indicators into assessment tools to enhance the comparability of the data collected and to align these data with existing standards.No specific funding was obtained for this project. Jason Nickerson was supported by a University of Ottawa Admission Scholarship and an Ontario Ministry of Training, Colleges, and Universities Ontario Graduate Scholarship. Amir Attaran was supported by a Social Sciences and Humanities Research Council Canada Research Chair. Peter Tugwell was supported by a Canadian Institutes for Health Research Canada Research Chair.Conflict of interest statement. None declared.


Brazilian Bioethanol Science and Technology Laboratory (CTBE) one of the laboratories of the Brazilian Center of Research in Energy and Materials (CNPEM) has as one of its main goals contribute to the development of the process of obtaining second generation ethanol ( GII ) mainly from lignin cellulosic fractions of cane sugar.The To achieve this goal leads its own line of research, develop partnerships with other public and private institutions or acting as national laboratory offers its facilities of laboratories and process development pilot plant to researchers involved in projects to produce ethanol, energy and chemicals from lignocelluloses materials.The activities of CTBE are based on research and development line that integrates the current process of obtaining first-generation ethanol ( GI ) of the sugars extracted from cane sugar coupled with the second generation process of deconstruction of lignocelluloses fractions (bagasse and straw), enzymatic hydrolysis of cellulose and fermentation of pentose and hexoses.The production of ethanol GII although technically demonstrated, at the present time not achieved results that enable production at competitive costs.The critical barriers to overcome to achieve this goal are:• Pretreatment: efficient fractionation of lignocelluloses material for better recovery and hydrolysis of pentose and cellulignin.• Hydrolases: Obtaining a more efficient and productive hydrolases complex;• Enzymatic hydrolysis: optimization of hydrolysis of cellulose;• Ethanol from pentose: development of pentose fermentation to ethanol.The negative impact of these barriers on the process of obtaining second-generation ethanol will be discussed. The research lines proposed for overcome it and improve the performance of this process integrated with first generation ethanol will be presented.


Ameloblastic fibrodentinoma is a rare benign mixed odontogenic neoplasm usually occurring in the first two decades of life. It is more common in males and the most common site of occurrence is in the mandibular premolar molar area. This report presents a case of ameloblastic fibrodentinoma in a 12-year-old boy in the maxillary anterior region, a less common site for the occurrence of ameloblastic fibrodentinoma. A 12-year-old boy presented with a midline diastema in 11 and 21 region and a swelling in the palatal aspect of 11 and 12. Intraoral periapical radiograph showed the presence of rarefaction of bone on the mesial aspect of the cervical and middle third of the root of 11. Excision biopsy was done. The specimen was processed and stained with hematoxylin and eosin. Microscopic examination showed islands, chords and strands of odontogenic epithelium in a primitive ectomesenchyme resembling dental papilla. The odontogenic epithelium exhibited peripheral ameloblast-like and central stellate reticulum-like cells. The presence of dentinoid material was seen adjacent to the odontogenic epithelium in some foci. The lesion was diagnosed as ameloblastic fibrodentinoma. Ameloblastic fibrodentinoma also called dentinoma, arising from the odontogenic epithelium and ectomesenchyme, is a rare benign mixed odontogenic tumor with an occurrence of less than 1% of the odontogenic tumors [The majority of these hamartomatous lesions were observed during the first two decades of life, but it has been reported in older individuals as well. Ameloblastic fibrodentinoma is a slow growing asymptomatic lesion with both central and peripheral counterparts. There is a distinct male preponderance with a male: female ratio of 3 : 1 and it is usually seen in the mandibular premolar molar area . SometimA 12-year-old boy came to the Department of Oral Medicine and Radiology with a chief complaint of a growth of the gingiva on the palatal aspect of 11. The growth appeared along with the eruption of the upper front teeth. At the time of eruption, there was midline diastema in 11 and 21 region with a nodule of tissue in between, which the patient pinched out 1 year back Figures . He gaveExcisional biopsy of the lesion was done. The gross specimen was a granulomatous tissue in the nasopalatine region in a cavitary space with regular margins and smooth floor . The tisOn microscopic examination of the specimen, islands, chords, and strands of odontogenic epithelium in a primitive ectomesenchyme resembling dental papilla were observed. The odontogenic epithelium exhibited peripheral ameloblast-like and central stellate reticulum-like cells. Presence of dentinoid material was seen adjacent to the odontogenic epithelium in some foci . A finalAmeloblastic fibrodentinoma is a slow growing, asymptomatic lesion, generally occurring in the first two decades of life, with the posterior region of the mandible being the most common site of occurrence . It is sAmeloblastic fibrodentinoma is an odontogenic tumor with or without formation of dental hard tissues. Radiographically, it presents as a well-defined radiolucency with varying degrees of radioopacity. Our radiograph also showed the presence of a well-defined radiolucency in relation to the mesial aspect of the cervical and middle third of the root of 11 surrounded by a corticated border without any detectable radioopacities within the radiolucency.Histologically ameloblastic fibrodentinoma is composed of proliferating epithelium embedded in a cellular ectomesenchymal tissue that resembles dental papilla, and the proliferating epithelium exhibits varying degrees of inductive changes on the mesenchyme, leading to the formation of varying amounts of dentin . If therConfusion exists on the nature and interrelationship of the mixed odontogenic tumors. Some authors are of the view that all the three mixed odontogenic tumors are interrelated and that ameloblastic fibrodentinoma is an intermediate stage between ameloblastic fibroma and ameloblastic fibroodontoma depending on the degree of histodifferentiation , 10. TheBased on the stage of development, ameloblastic fibrodentinoma can be histologically divided into immature and mature type. The malignant counterpart of ameloblastic fibrodentinoma is ameloblastic fibrodentinosarcoma. The mechanism of malignant transformation of ameloblastic fibrodentinoma is unknown. Multiple surgical procedures of recurrent lesions have been suggested as an important factor for the malignant transformation. Metastasis of the malignant counterpart is also uncommon .This case presented a rarity in that the lesion presented clinically as a case of gingival enlargement in the palatal aspect of the maxillary anterior region. Presence of a well-defined radiolucency on radiographic examination suggested that it was a case of false gingival enlargement, and the histopathologic examination confirmed the case as ameloblastic fibrodentinoma. Hence, this case is unique because of the fact that an intraosseous ameloblastic fibrodentinoma presented as a false gingival enlargement in the anterior maxillary region, a less common site for the occurrence of ameloblastic fibrodentinoma. This case highlights the importance of thorough evaluation of any gingival enlargement to rule out the possibility of an underlying neoplastic process.


The medical fields of otolaryngology and head and neck are evolving rapidly. For the past years, much new knowledge and many techniques have been introduced into the basic researches and clinical practices of otolaryngology and head and neck for a comprehensive understanding of diseases and practical clinical applications. Just recall the recent development of many medical devices designed for enabling techniques and surgery, including the newly designed hearing aids and coagulative surgical instruments; the trend of newly developed technologies is likely to be a constant flow. In addition, many distinct diagnostic modalities and research approaches have also been invented to investigate the underlying phenomenon and mechanisms of diseases. The cornucopia of all novel technologies and approaches serve as important blessings for both doctors and patients in the fields of otolaryngology and head and neck. This special issue is to showcase the diversity and advances in recent progress that contributes to the different subspecialties of otolaryngology and head and neck surgery.Recent advances both in basic and clinical studies have introduced new concepts and technologies to be applied in otolaryngology and head and neck surgery. In this special issue, several special topics regarding the applications of hearing devices and vestibular evoked myogenic potential, the surgical tools for potentiating the procedure of thyroidectomy, and identification of the novel therapeutic agents and underlying mechanism of head and neck cancer will be presented. One article of each field will be selected as the representative example of the progress. These articles will demonstrate the current advance of medical development in otolaryngology and head and neck surgery.An article will discuss the role of screening of cognitive function in old adults because of the efficacy of using hearing aid assistance. Previous studies had found that hearing loss is associated with poorer cognitive function. This study examined cognitive function in elderly hearing aid users. The study investigated whether the screening cognitive function should be considered in the individuals with hearing impairment. On the other hand, for the adult patients with unilateral microtia and atresia, many devices of implantable hearing amplification have been created for hearing ability rehabilitation. An article in this special will give a comprehensive review of the development, the progress, and the technical advantages of the different types of implantable hearing devices available. After understanding the pros and cons of each specific type of devices, it is easy to make the clinical decision of recommending a device to match the need of patients.Apart from the hearing ability, the vestibular function, another essential component of the 8th cranial nerve, has also drawn much attention of researchers and clinicians. An article included in this special issue will demonstrate the use of skull tap vestibular evoked myogenic potentials of diagnosing cerebellopontine angle tumor. The tap vestibular evoked myogenic potentials (tap VEMPs) are another method of inducing VEMPs by tapping method in contrary to the traditional one of using auditory stimulation. In the diagnosis and pretreatment evaluation of cerebellopontine angle tumor, the involvement and the extent of tumor are critical for the following treatments and can be clearly identified by clinical physiological examinations. In this article, the tap VEMPs could be successfully induced in some of the recruited patients. It shows a potential of clinical utility of combining both AC VEMP and tap VEMPs in the evaluation of patients suffering from cerebellopontine angle tumors. Salvia miltiorrhiza Bunge. It has been documented to be an antiproliferative reagent on various human cancer cells. This research aims to evaluate its role in nasopharyngeal carcinoma. By showing the effects of antiproliferation and apoptosis induction, Tan IIA is believed to be a potential candidate of exploring the anticancer drugs. On the other hand, bleeding is always a major concern in the procedure of thyroidectomy. Many distinct skills have been developed to control bleeding, and multiple devices and surgical instruments have been created to facilitate the hemostasis. Ligasure and bipolar thermofusion are two surgical tools that have been widely used to achieve hemostasis during thyroidectomy. In an article included in this special issue, the comparison between these two techniques will be addressed when more than 2122 lobectomies were performed within 8 years. The experience earned from the large patient population provides convincing evidence of using these distinct surgical tools for bleeding control of thyroidectomy.With the innovation of many tools of basic research, the understanding of molecular and cellular mechanism has achieved a profound advancement in the head and neck cancer. An article in this special issue will address the importance of finding novel and potential therapeutic reagents that target the mitochondria-dependent pathway. Tanshinone IIA (Tan IIA) is an active phytochemical retrieved from the dried root ofThe researches and development of new technologies and knowledge of the field of otolaryngology and head and neck surgery are committed to improving excellent medical care in all subspecialties to the patient groups worldwide. It is also committed to educating the health provider and investigators in the basics and the clinical practices of otolaryngology and head and neck surgery for the further progress in each subspecialty. The current knowledge and understanding have led to the exploration of new mechanism underlying the diseases and also development of novel therapies, surgical techniques, and tools to change the way of clinical practices. It is believed that the evolvement of medical researches and clinical health care may substantially improve the clinical outcomes and life quality of patients.Tsung-Lin Yang Robert L. Ferris Tetsuya OgawaPeter Hwang Michael Tong Mu-Kuan Chen


Lactobacillus jensenii TL2937  in the late 1990s, initial investigations were focused on understanding their role, stimulating immune responses against infectious agents. Yet, the human body is home to a myriad of TLR agonistic bacteria that have not only established symbiosis with the immune system but also likely contribute to the induction and maintenance of immune homeostasis by dampening immune responses. In fact, stimulation of TLRs might be critically involved in this process and ultimately contribute to preventing development of inflammatory and autoimmune diseases. Sander De Kivit and colleagues present an overview of those aspects, notably outlining the role of gut epithelial TLRs in the induction of immunity and the maintenance of tolerance . Alexandra Zanin-Zhorov and colleagues described an immune regulatory mechanism conferred by TLR expression on T cells, which the authors review herein and discuss in the context of TLR-induced T cell effector functions . The rolThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Anorexia Nervosa (AN) and restrictive eating disorders present a significant burden of disease within the Australian Community with AN having the highest mortality rate of all psychiatric disorders. Family Based Treatment for Adolescent Anorexia Nervosa (FBT) has the best evidence worldwide for successful treatment outcome and sustained recovery.In October 2012, The Children Health Services District established a specialised weekly clinic to provide FBT for community based treatment of AN. Multidisciplinary staff with a background in Family therapy were trained in FBT. The aim was to develop a specialist service targeted at a high risk and resource-intensive population.Prior to establishing the clinic in this form Family based Treatment was provided at three separate community clinics. The intention of establishing a single clinic was to facilitate greater access to supervision and increase model fidelity, increase the capacity of the service, enhance the sense of team cohesion and increase the overall number of referrals.The presentation will outline the outcomes from the first two years of this specialist clinic. These include, a reduction in length of stay in hospital inpatient units, an increased proportion of families completing FBT, reduced length of time in treatment and an increased identification of anorexia nervosa with corresponding increased referrals into FBT.


This work analyzes and implements finite axonal transmission speeds in two-dimensional neural populations. The biological significance of this is found in the rate of spatiotemporal change in voltage across neuronal tissue, which can be attributed to phenomena such as delays in spike propagation within axons, neurotransmitter activation and the time courses of neuron polarization and refraction. The authors build upon the finite transmission speed work in .Linear analysis about a spatially homogeneous resting state of the neural population dynamics is performed. The analyses of the resulting analytical expressions guide the parameter selection for simulations. For simulation, computation of the transmission-delayed convolution between the kernel and firing rates is performed with a fast Fourier transform as in .The Neural Field Simulator  is used We find Turing patterns appear when starting the simulations with the derived conditions for stationary instability. This is shown in Figure


Plasmodium naturally infect humans. Some species cause non-specific symptoms that can sometimes progress rapidly to severe and fatal outcomes. Early diagnosis and appropriate treatment interrupts progression and cures disease. Confirmation of diagnosis of malaria currently relies on microscopy, or on application of rapid diagnostic tests (RDTs) that are becoming increasingly widely available and are recommended to confirm infection before treating it. The diagnosis of malaria by itself is not sufficient to optimise individual therapies because there is a growing problem of multidrug resistance in parasites . This limits the use of some drugs or combinations by severely compromising their efficacy.Five species of Diagnostic strategies for management of malaria can therefore be improved in several ways. First by an increase in sensitivity of detection of parasites that should improve of the thresholds for detection by the current generation of RDTs because they cannot identify low parasitaemias. Second, a diagnostic that can differentiate all the naturally infecting species of parasite needs to be developed. Finally, rapid (point-of-care) assessment of the drug resistance status of parasites will add greatly to the treatment strategies available to manage individual patients. Technological platforms that can deliver information that is currently missing for the personalised management of malaria infections are being developed and these advances will be presented and discussed in the context of the global burden of disease caused by malaria.


Lateralization of brain and behavior in both humans and non-human animals is a topic that has fascinated neuroscientists since its initial discovery in the mid of the nineteenth century Broca, . HemisphBased on these observations, the present Frontiers in Cognition Research Topic aimed to further investigate the relationship of lateralization and cognitive systems in the vertebrate brain. Overall, the Research Topic encompasses more than 30 novel publications, ranging from Original Research Articles to Reviews and Mini Reviews, Perspective Articles and Hypothesis and Theory Articles. From the beginning, the present Research Topic was conceptualized with a comparative multi-disciplinary inter-species approach in mind. This idea is reflected in the broad diversity of animal models included in the Research Topic, ranging from invertebrates (Frasnelli, Taken together, the wide variety of cognitive systems in different species covered in the present Research Topic highlights the enormous importance of understanding how and why the vertebrate brain is asymmetrically organized for almost any subfield within cognitive neuroscience. We hope that the excellent papers assembled in the present Research Topic will help to stimulate more research aimed at understanding the complex mechanisms underlying the interaction between hemispheric asymmetries in stimulus perception and higher cognitive systems.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


BMC Biology addresses this issue with live imaging of gut explants from mouse embryos.The complex physiology of the gastrointestinal tract is regulated by intricate neural networks embedded within the gut wall. How neural crest cells colonize the intestine to form the enteric nervous system is of great interest to developmental biologists, but also highly relevant for understanding gastrointestinal disorders. A recent paper in http://www.biomedcentral.com/1741-7007/12/23.See research article:  BMC Biology by Young and colleagues ]? Or]? Oret an vitro . In thiShedding light on the cellular and molecular mechanisms that control the colonization of the intestine by neural crest cells is of obvious medical importance. A number of conditions are thought to result from deficits in the migration and ultimately the colonization of the gut by neural crest cells and the normal development of the ENS. Foremost among them is Hirschsprung’s disease, a congenital neurodevelopmental deficit of the ENS, which occurs in 1:4,500 live births and is characterized by absence of enteric ganglia from the distal colon. In addition, a number of ill-defined conditions, termed collectively as functional gastrointestinal disorders, are thought to originate from subtle changes in the connectivity of enteric neurons. Therefore, understanding the mechanisms that regulate the migration of neural crest cells and how they may influence the connectivity of enteric neurons is critical for deciphering the pathogenesis of a broad range of congenital and acquired deficits of enteric neural activity and digestive function.


Access to the endodontic lesion located between the central and lateral incisors was achieved by reflection of a full mucoperiosteal flap. Granulomatous tissue as well as aberrant root was removed and the surface of the root and adjacent coronal region were reshaped. Three years later, the patient was orthodontically treated. Seven years after completion of surgical/orthodontic management, the tooth remained asymptomatic and functional with normal periodontium/vital pulp. Radiographically, the healing of the lesion was observed. Actually, vitality of the invaginated tooth and communication between the invagination and the root canal were the most important factors in determining such minimally invasive treatment protocol. Depending on the anatomy of the root canal system, surgical amputation of an invaginated root can be performed to achieve a successful outcome in Oehler’s type III dens invaginatus cases, even though it is associated with apical periodontitis.The developmental abnormality of tooth resulting from the infolding of enamel/dentin into the root is called dens invaginatus. Management of such cases is usually challenging due to the morphological complexity of root canal system. This report presents a rare treatment protocol of a clinical case of Oehler’s  Malformations of teeth with variations involving either the crown or the root or both are described as dental hard tissue anomalies , 2. DensType I is an enamel-lined minor invagination confined to the crown without extending beyond the cemento-enamel junction. Type II describes the extension of the invagination into the root, beyond the cemento-enamel junction ending in a blind sac. Some type II cases may communicate with the dental pulp. Type III includes penetration of the root by the invagination to form an additional apical or lateral foramen, usually without an immediate communication with the dental pulp [Oehler classified dens invaginatus into three distinct types according to the depth of invagination and its communication with the periodontal ligament or periapical tissues; tal pulp , 6. type III cases, treatment procedures are usually chosen from the following procedures: root canal treatment of the invagination only [Based on the complex root canal anatomy and the shape of the pulp in the ion only , endodonion only , combineion only , intentiion only , and extion only .The following unique case report describes a successful surgical aberrant root amputation of an invaginated extra-root with an endodontic lesion in a vital maxillary lateral incisor.A 16-year-old male was referred to private clinic by a general dentist for evaluation and treatment of the maxillary right lateral incisor with enlarged clinical crown. The patient described moderate pain associated with the involved tooth. At the time of clinical evaluation, the patient’s symptoms had subsided. His medical history was not contributory and there was no history of trauma. The involved tooth was caries free and responsive to thermal and electrical pulp tests while the adjacent teeth were also responding. The clinical crown was larger than the contralateral tooth, especially the mesiodistal aspect. Crown appeared to be intact with a small palatal tuberculum without a pit or foramen coecum and revealed no discoloration, but mesial tilting of clinical crown with a slight depression on palatal surface near the mesial marginal ridge was evident . No tendtype III dens invaginatus and associated chronic periradicular periodontitis. Radiographic examination revealed large periradicular radiolucency along the mesial surface adjacent to the mesial aspect of the tooth. There was a mesially directed radiopaque enamel-lined tract, which is related to the periapical radiolucency. Enamel lined tract was separated from the main root canal. The abnormal hard tissue structure of invaginated root was extending from the mesial aspect of the middle third of the main root canal to the cervical distal margin of the adjacent central incisor. The diagnosis was a vital tooth with The treatment plan included the surgical amputation of bucally-located anomalous root-like structure of dens invaginatus. Under local anesthesia, a full mucoperiosteal flap was elevated; access to the pathological area was obtained between left central and lateral incisors. The lesion was curetted and the specimen was sent for histopathological examination. The abnormal hard tissue structure of invaginated root with groove was removed using a tapered diamond fissure and finishing burs under continuous irrigation with saline solution. The surface of the main root adjacent to the cervical region was reshaped and smoothed while exposure of the dentinal tubules was minimized. The flap was replaced and sutured . The palThe histologic diagnosis of the biopsy material was granulation tissue with severe chronic inflammation. A postoperative four-year periapical radiography taken during orthodontic treatment showed resolution of the periradicular radiolucency while the tooth remained asymptomatic and continued to give a positive response to cold test. Periodontal probing depths were found to be within normal limits . Seven-yTreatment of dens invaginatus is undoubtedly an endodontic challenge, especially because of the complicated morphology of tooth and the complexity of associated root canal system. It is therefore important to identify the morphologic character of the canal before treating a tooth with dens invaginatus associated with pulp pathosis .type III dens invaginatus, the pulp is confined within the wall of the invagination process, there is usually no communication between the root canal and the invagination itself. Although the invagination may seem to be completely lined by enamel, the apical portion of the invagination is more often lined only by cementum [In cases of Oehlers’ cementum . Bactericementum . Following eruption, teeth with dens invaginatus, lose the main blood supply of the connective tissue in the invaginated space which subsequently results in necrosis of the tissue within the invaginated tract and this in turn, leads to the development of periradicular inflammation  and the The presence of communication between the invagination and the pulp may be an important prognostic value, but in the present case, it was presumed that such communication does not exist. On the other hand, communication between the invagination and the oral environment was not apparent clinically, but the abnormal shape of an invaginated root caused a plaque-retentive area prompting the development of a localized advanced periodontitis that may lead to occurrence of periradicular lesion.type III dens invaginatus with endodontic failure or in teeth, which cannot be treated non-surgically because of anatomical problems or failure to gain access to entire root canal system [Researchers suggested that pulp necrosis and periradicular pathosis may occur in permanent incisors with abnormal crown or incisors with root groove defect , 15. Furl system . type III dens invaginatus besides the diagnosis of periradicular lesion, pulp health was retained after endodontic treatment [Despite the complex anatomy of the reatment  or combireatment . To the type III dens invaginatus associated with an apical lesion without interfering with the vitality of the main root.The present case report describes the successful surgical treatment of an extra-root of a


There is a paucity of data about whether our treatment philosophy is different for our patients as compared with what we would have wanted for ourselves, or while acting as surrogate decision-makers for our loved ones.An anonymous survey was sent to all the members of Australia and New Zealand Intensive Care Society and the College of Intensive Care Medicine (CICM). The first section comprised a hypothetical case scenario spanning over 6 weeks of ICU stay for a patient. At four different stages of the ICU stay, responders were requested to answer multiple-choice questions regarding the philosophy of treatment, based on their perceived prognosis of the patient at that particular time. The following two sections contained the same set of questions with the hypothetical scenario of responders acting as surrogate decision-makers for the patient and that of responders being patients themselves, in the same situation. The responses were compared amongst three sections at each stage using the chi-square test.A total of 115 responses were received from the fellows of CICM. The results are presented in Tables Of the ICU physicians who would withdraw care for their patient, the majority would also want the same for themselves. The disparity between decision to continue to treat the patients versus treating self or family increased with increasing length of stay.


In cluster headache (CH) during the active period we described a facilitated temporal summation (TS) of nociceptive signals at spinal level linked to a defective suprapinal control of pain and followed by a normalization of the values during the remission period. TS of sWe studied 10 episodic CH patients during both active and remission period and 17 healthy subjects (HS). Two types of stimulation blocks were delivered during the fMRI scanning according to the stimulation paradigms previously determined to evoke both the TST of the NWR (SUMM) and the NWR single response (SING).The analysis of the hemodynamic signals showed a comparable activation of sensory and pain related areas in both CH (during active and remission period) and HS. The most relevant differences emerged in the deactivation of both posterior cingulate cortex (PCC) and bilateral angular gyrus (AG) and in the activation of the anterior cingulate cortex (ACC). CH during the active phase showed a lack of deactivation of PCC and AG and a more relevant activation of the ACC when compared to CH during the remission phase and HS.PCC, AG and ACC are considered to be pivotal in default mode network (DMN), with a high activity correlated to the rest and reactive deactivation during most tasks where the attention is directed externally. Our data have demonstrated that in CH during the active phase of the disease, the facilitation in temporal processing of nociceptive stimuli is linked to a defective functioning of the DMN. Interestingly, both these abnormalities are dependent on the clinical activity of the disease.Written informed consent to publication was obtained from the patient(s).


To compare the similarities among the multimorbidity patterns identified in primary care patients from two European regions (Spain and the Netherlands) with similar organisational features of their primary care systems, using validated methodologies.This observational, retrospective, multicentre study analysed information from primary care electronic medical records. Multimorbidity patterns were assessed using exploratory factor analysis of the diagnostic information of patients over 14 years of age. The analysis was stratified by age groups and sex.The analysis of Dutch data revealed a higher prevalence of multimorbidity which corresponds with the clustering of a higher number of diseases in each of the patterns. Relevant clinical similarities were found between both countries for three multimorbidity patterns that were previously identified in the original Spanish study: cardiometabolic, mechanical and psychiatric-substance abuse. In addition, the clinical evolution towards complexity of the cardiometabolic pattern with advancing age -already demonstrated in the original study- was corroborated in the Dutch context. A clear association between mechanical and psychosocial disorders was unique to the Dutch population, as well as the recurrent presentation of the psychiatric-substance abuse pattern in all age and sex groups.The similarities found for the cardiometabolic, mechanical and psychiatric-substance abuse patterns in primary care patients from two different European countries could offer initial clues for the elaboration of clinical practice guidelines, if further evidenced in other contexts. This study also endorses the use of primary care electronic medical records for the epidemiologic characterization of multimorbidity. Multimorbidity, which refers to the coexistence of two or more chronic conditions, is highly prevalent in older populations and, in absolute numbers, even more common in the adult population Lately, the global move towards the primary care-led management of chronic diseases has incorporated the analysis of multimorbidity patterns into the research agenda, with the goal of providing health and social care professionals with a better clinical and epidemiological understanding of the synergies and effects associated with coexisting diseases Further knowledge regarding the similarities and differences between the patterns obtained in different countries is expected to pave the way for the establishment of a sound and rigorous methodology for the identification of patterns of multimorbidity.The present work aims to assess the similarities among the multimorbidity patterns identified in primary care patients from two European regions (Spain and the Netherlands) with similar organisational features of their primary care systems, using validated methods.Data for the Spanish population were obtained from electronic medical records of people over 14 years of age who consulted their general practitioner at least once in 2008 at any of the 19 primary health care centres included in this study. The centres were located in two north-eastern regions of Spain and had more than two years of experience using electronic records by all general practitioners and nurses Data for the Dutch population derived from the Registration Network Family Practices of The Netherlands  Both primary care databases contain basic demographics as well as all relevant health problems affecting the present functional status of patients and/or their future functioning coded using the International Classification of Primary Care (ICPC) To facilitate the management of diagnostic information, diseases were grouped according to the Expanded Diagnostic Clusters (EDC) of the ACG system in both contexts. This system groups ICPC codes into 260 EDCs based on the clinical, diagnostic and therapeutic similarities of diseases All information was anonymised using a unique patient identifier. The Spanish database was approved by the Clinical Research Ethics Committee of Aragon (CEICA). In the Netherlands, no ethical approval is necessary when analysing anonymised data The statistical analysis applied to the Dutch data was the same as that performed in the original Spanish study, and previously by other authors The extraction of the disease patterns was based on the principal factor method, and the number of factors to extract was established using a scree plot To determine which health problems (EDCs) belonged to each of the multimorbidity patterns, those with scores equal to or greater than 0.25 for each factor were selected. To calculate the prevalence of the patterns according to the most common definition of multimorbidity, an individual was assigned a specific pattern of multimorbidity if he/she presented at least two of the diseases included in the pattern. The entire analysis was stratified by age groups  and sex.As in the original work in the Spanish setting, only diagnoses with a prevalence equal to or greater than 1% in each age and sex group were included in the analyses so as to increase the epidemiological interest of the study.The STATA 12.0 software was used to conduct the statistical analysis.The Dutch study population consisted of 79,291 individuals and the Spanish one of 275,682, with a slightly smaller proportion of middle age individuals in the latter group . MultimoIn the original Spanish study In total, 6.3% of young Dutch men were assigned to at least one of the three factors obtained for this age group . Factor Over a quarter of Dutch men in this age group (27.3%) were assigned to at least one of the two identified factors . The firTwo thirds of the men in this age group (66.9%) were assigned to at least one of the two factors identified for this group . Factor At least one of the three factors identified for young Dutch women were present in 12% of this group . Factor Two patterns affecting more than a quarter of these women (26.2%) were identified . Factor Almost two out of three women (64.8%) were assigned to at least one of the three factors identified in this age group . The firIn this first population-based study comparing multimorbidity patterns in two different European regions, relevant similarities were found for three of the five patterns identified in the original Spanish study, namely the cardiometabolic, mechanical and psychiatric-substance abuse. The analysis of Dutch data revealed a higher prevalence of multimorbidity which corresponds with the clustering of a higher number of diseases in each of the patterns.To date, very few studies focusing on disease patterns encompass populations covering broad age ranges. This study attempts to take into account health problems throughout the entire lifespan, supporting the generalizability of the findings The pattern with highest similarities in the Spanish and Dutch results was the cardiometabolic one. This pattern, as shown in the Spanish study The greater complexity of multimorbidity patterns in the Dutch population starting at middle age could be partly explained by the use of different diagnostic protocols in the two countries. In this regard, it is worth mentioning that in 2010 functional payments for the total episode of care were introduced in general practice in the Netherlands for specific conditions  and cardiovascular risk management, under the premise that this new payment system would improve the position of the patient and the quality of care In the Dutch population, a mechanical component was evident in young and elderly women and in men up to middle age, comparable to the Spanish mechanical pattern. Diseases such as arthropathy, cervical and low back pain, varicose veins of the lower extremities, gastro-oesophageal reflux, anxiety and obesity coincided in both studies and confirm previous results found by other authors Two of the diseases associated with the psychiatric-substance abuse pattern described in young Spanish men (substance use and anxiety/neuroses) together with other psychosocial conditions were also present in the Dutch population, but in all age and sex groups. The recurrent presentation of this cluster of psychosocial problems in the Dutch population could be a consequence of the development in the past 15 years of the Dutch mental health sector; about half of Dutch adults with a serious mental or addictive disorder receive care and two-thirds of them receive satisfactory care The main strengths of the present study are the similarities concerning the study populations and the organisational features of primary care in both the Spanish and Dutch contexts. Both studies were based on primary care populations served by general practitioners who systematically register diagnoses using ICPC. Moreover, the public nature of both health care systems and the high access of citizens, as well as the one-year observation periods guarantee that selection bias is reduced. Still, several limitations need to be considered.Diagnostic habits and registration of clinical data may vary in the two countries, due to differences in the level of professional training, the degree of implementation or content of clinical practice guidelines, the use of active protocols for detecting certain diseases, organisational factors, etc. Indeed, the Dutch general practice holds an outstanding position regarding quality assurance and guideline implementation with respect to other European countries Another limitation, also mentioned in the original Spanish study, was the cross-sectional design used in both studies, limiting the establishment of causal relationships and/or the evolution of patterns over time The study of the Dutch patterns from the perspective of the pathophysiology of the identified disease interactions was out of the scope of this study, focused rather on comparing the multimorbidity patterns obtained in two different health care contexts. As a consequence, Dutch patterns lacked specific clinical labels.The assessment of the differences/similarities between the results obtained in both countries was largely qualitative and descriptive. A statistical analysis of such differences does not seem very relevant in this study since, given the large numbers, all differences are expected to be statistically significant. Therefore, a qualitative comparison seems to be more pertinent and better adapted to the clinical appraisal of the associations and interactions among diseases.The similarities found for certain multimorbidity patterns in primary care patients from two different European countries could offer initial clues for the elaboration of clinical practice guidelines, if further evidenced in other contexts. This has been repeatedly mentioned and urgently requested by the scientific community This study also endorses the use of primary care electronic medical records for the epidemiologic characterization of multimorbidity. Moreover, electronic medical records would enable a longitudinal approach to the multimorbidity phenomenon.File S1Combined file of supporting figures. Figure A - Scree plots for the different age and sex groups in the Spanish setting. Figure B - Scree plots for the different age and sex groups in the Dutch setting.(DOC)Click here for additional data file.


The purpose of this study was to utilize the Context, Input, Process and Product (CIPP) evaluation model as a comprehensive framework to guide initiating, planning, implementing and evaluating a revised undergraduate medical education programme. The eight-year longitudinal evaluation study consisted of four phases compatible with the four components of the CIPP model. In the first phase, we explored the strengths and weaknesses of the traditional programme as well as contextual needs, assets, and resources. For the second phase, we proposed a model for the programme considering contextual features. During the process phase, we provided formative information for revisions and adjustments. Finally, in the fourth phase, we evaluated the outcomes of the new undergraduate medical education programme in the basic sciences phase. Information was collected from different sources such as medical students, faculty members, administrators, and graduates, using various qualitative and quantitative methods including focus groups, questionnaires, and performance measures. The CIPP model has the potential to guide policy makers to systematically collect evaluation data and to manage stakeholders’ reactions at each stage of the reform in order to make informed decisions. However, the model may result in evaluation burden and fail to address some unplanned evaluation questions. The CIPP model addresses all the steps of an education programme, even when the programme is still being developed.Context evaluation is very important in convincing the faculty members and policymakers at the onset of a major programme reform.Input evaluation might be helpful in saving precious resources which might be lost by performing evaluation at the end of the programme.The CIPP model provides ongoing information to decision-makers to ensure that the implemented programme is on the track.The CIPP evaluation model may fail to address some important but unplanned evaluation questions and may result in evaluation burden.The past two decades have witnessed an international call for fundamental changes in medical education programmes ‒3. Many The use of the Context, Input, Process and Product (CIPP) evaluation model has been thoroughly recognized in a variety of educational and non-educational evaluation settings ‒13. AddiThe CIPP evaluation model addresses all phases of an education programme renewal , accommoThis article elaborated the use of the CIPP evaluation model as a comprehensive framework to help to initiate, develop, install, and evaluate a new undergraduate medical education programme in a period of eight years. We examined five specific research questions:How does the CIPP evaluation model effectively facilitate the management of the stakeholders’ reactions during the undergraduate medical education programme reform?What are the needs of the undergraduate medical students and the community?What is an appropriate model for an undergraduate medical education programme to address the identified needs?What are the strengths and weaknesses of the new undergraduate medical education programme?To what extent has the new undergraduate medical education programme achieved its outcomes in basic science phases?This study was conducted at the School of Medicine of Tehran University of Medical Sciences. This school, which is one of the largest and oldest among Iranian medical schools, delivered a traditional Flexnerian undergraduate medical education programme for a long period of time. This programme was composed of two and half years of basic sciences, one year of pathophysiology, a two-year clerkship, and an 18-month internship. The idea of reform in the traditional programme was raised seriously in the early 2000s when the change seemed inevitable in our institution in response to profound contextual changes and the recommendations of the Iranian Ministry of Health and Medical Education.This longitudinal evaluation project started from 2006. The entire process was supervised by Educational Development Office of the School of Medicine. Fig. In order to understand the necessity and scope of the change, we conducted a comprehensive context evaluation from 2006 to 2009 which comprised five projects. The projects included exploring the challenges of the traditional programme from the stakeholders’ viewpoint, evaluating the quality of the traditional programme in graduates’ perceptions, assessing the educational environment from the students’ perspectives using the Dundee Ready Education Environment Measure (DREEM) inventory, self-study of the traditional programme in comparison with the national undergraduate medical education standards and evaluating the competency of medical students in clinical skills through an objective structured clinical examination Table .In a two-year input evaluation project, we carried out three consecutive activities. In order to set down a sound model for the revised undergraduate medical education programme, the responsible taskforce reviewed the relevant literature on authoritative medical education journals and visited the websites of leading medical schools around the world and also collected national documents of undergraduate medical education programmes. Next, expert panels were held to generate a preliminary draft of the framework of the undergraduate medical education programme on the basis of context evaluation and literature review results. The preliminary draft was converted to the final version of the programme during a participatory process. Meetings were conducted with faculty members from different departments, medical school administration and students’ representatives in both basic and clinical sciences phases, as well as with the recent graduates, to receive their input. Finally, expert judgment was considered to determine the feasibility of the proposed model and adjustments were made to improve it. Overall, 170 faculty members and administrators participated in the input evaluation phase. We also asked three experts for their comments from abroad. We involved students considerably during the planning phase: 18 students in committees and subcommittees, 35 students in panels and some others in workshops.In September 2011, School of Medicine implemented the revised undergraduate medical education programme with extensive changes on the basis of input evaluation results. The process evaluation started from scratch when the new programme was launched. Information was regularly collected through diverse methods. For instance, online questionnaires were administered and focus groups were conducted after each interdisciplinary organ-system block in order to receive the students’ viewpoints. We also reviewed the course syllabi to make sure all classes and sessions were held as planned   with the basic science phase, and 56.12 % of the students strongly agreed or agreed  that they achieved the vertically integrated theme outcomes. The DREEM questionnaire scores, student grade point averages, the failure rates, and National Comprehensive Basic Science Exam results did not differ significantly between the traditional and renewed curriculum (all By employing unique features of the CIPP evaluation model, we succeeded in convincing stakeholders of the need for major changes in the undergraduate medical education programme. We were also successful in creating a sense of ownership of the new programme in our stakeholders. We achieved some success in reassuring students, faculty members and administrators during the programme installation about the programme progress by continuous process evaluation and initial product evaluation, communicating successes and challenges with the stakeholders and using evaluation results for improvement. However, proving the effectiveness of the programme demands the passage of time. We also found that maintaining stakeholders’ collaboration and enthusiasm was a difficult task. Hence, establishing a reward system for compensating faculty participation and overload teaching might be beneficial.The aim of this evaluation study was to utilize the CIPP evaluation model to assist decision-makers to initiate, develop, establish, and evaluate a revised undergraduate medical education programme in one medical school in Iran. This is the first study applying all four interrelated components of the CIPP evaluation model in a longitudinal work throughout the renewal cycle of an undergraduate medical education programme. The results of this study showed that the components of the CIPP evaluation model could successfully address all steps of the reform even when the new programme is still being developed. We took advantage of context and input evaluation before, as well as process and product evaluation after the implementation of the new programme. Context evaluation identified the weaknesses and strengths of the traditional programme and the needs of the learners and the community which, in turn, directed the rest of the renewal process. Input evaluation resulted in formulating a new programme tailored to our context and was helpful in saving precious resources. Process evaluation enabled us to improve the weaknesses early on in the reform installation. Product evaluation examined the extent of the initial achievements in the outcomes in basic science phase.Few studies have applied the CIPP evaluation model longitudinally to the evaluation of medical education programmes. Steinert et al.  conducteThe CIPP evaluation model was also helpful in managing the stakeholders’ reactions through the reform process. We found it challenging to initiate and sustain major reforms in the undergraduate medical education programme in a large and old medical school with a history of success. Therefore, we conducted a comprehensive context evaluation with triangulation of the evaluation sources and methods. The context evaluation revealed the problems of the traditional programme deeply and broadly, which was very helpful to convince decision-makers and faculty members about the need for broad changes in the programme. Triangulating the evaluation data has been mentioned in the literature on medical education reform as an important factor to create the need for change as well , 28.Once the need for change was confirmed, the prevailing reaction of the stakeholders was that our medical school is different and models of the undergraduate medical education programme reform are not necessarily suitable to our context. The steps taken during the input evaluation phase along with extensive stakeholder engagement were effective strategies to design an educationally sound undergraduate medical education programme that was readily adaptable to our situation and more importantly was accepted by the programme stakeholders .Ongoing process evaluation and formative product evaluation with the use of qualitative methods enabled us to explore stakeholders’ reactions systematically during the implementation of the revised programme. For example, the first cohort of students was confused about the details of the reform and concerned about the success and continuation of the programme Table . AdditioApplying the CIPP evaluation model is a time-consuming and demanding task which needs full administrative support and leadership stability. We faced the challenge of four changes in medical school dean during the reform process. However, the behaviour of all the administrators was supportive and we dealt with this instability successfully by creating a shared responsibility for the reform process between different groups of stakeholders. We also found that gathering evaluation data from different sources, and combining and timely reporting of these triangulated data, were difficult tasks that needed administrative support and expertise. We tried to overcome these challenges by involving our medical students in graduate courses in the evaluation process. We also assigned some parts of the evaluation practice to a volunteered group of medical students. We intend to involve the course directors in gathering evaluation data directly from students in the near future. Although these strategies were helpful, medical schools that may consider using this model should prioritize the evaluation questions carefully in order to manage the evaluation burden. Another weakness of the CIPP evaluation model was its focus on evaluating the predetermined plan and product. Therefore, some important questions such as the extent and nature of unintended outcomes of the programme might have remained unanswered in our study. Beyond the limitations of the CIPP evaluation model, our study mainly focused on the basic sciences phase of the undergraduate medical education programme during the process and product evaluations. We need to continue the project to examine the extent of outcome achievement, especially in the clinical phase.The CIPP evaluation model has the potential to guide policy makers and other stakeholders to systematically collect evaluation data at each stage of reform in an undergraduate medical education programme in order to make informed decisions. Moreover, this model seems useful in managing the change process in terms of stakeholders’ reactions. The use of this evaluation model in other programmes in the context of medical education should be further studied.