Research on collaboration in primary care focuses on specific diseases or types of collaboration. We investigate the effects of such collaboration by bringing together the results of scientific studies.We conducted a systematic literature review of PubMed, CINAHL, Cochrane and EMBASE. The review was restricted to publications that test outcomes of multidisciplinary collaboration in primary care in high-income countries. A conceptual model is used to structure the analysis.p < .05). By contrast, a higher proportion of significant results were found in studies that report on clinical outcomes.Fifty-one studies comply with the selection criteria about collaboration in primary care. Approximately half of the 139 outcomes in these studies is non-significant. Studies among older patients, in particular, report non-significant outcomes (This review shows a large diversity in the types of collaboration in primary care; and also thus a large proportion of outcomes do not seem to be positively affected by collaboration. Both the characteristics of the structure of the collaboration and the collaboration processes themselves affect the outcomes. More research is necessary to understand the mechanism behind the success of collaboration, especially on the exact nature of collaboration and the context in which collaboration takes place. Many countries stimulate collaboration between different disciplines in primary care and between primary care and other sectors . There iEarlier research on collaboration does not always show these benefits , 6, 7. MThere are often two main problems with studies on collaboration in primary health care that can lead to ambiguous results. The first problem is that most studies focus on one specific diagnosis or group of patients. This makes their results difficult to compare and as a result does not provide reliable evidence on how far general conclusions can be drawn from their outcomes. In addition, it also creates the risk of new and probably unnecessary separate ‘silos’ where people operate in isolation, such as care professionals organized and collaborating around one specific condition  and thusThe second problem is that the actual collaboration, meaning the form and the activities carried out in collaboration, is poorly described. As a result, no replication, evidence synthesis and implementation in different situations can be carried out . TherefoThis review tries to overcome these problems by bringing together the studies on collaboration regardless of all their different patient populations, collaboration characteristics and activities. By doing so, and by identifying similarities between studies, a new light is shed on the outcomes of collaboration. To our knowledge, earlier reviews have never taken this approach. This conceptual model is based on the structure, process and outcomes model of Donabedian  and is aA Systematic Literature Review was performed to select and analyse scientific publications on collaboration in primary care. PubMed, CINAHL, Cochrane Library and EMBASE were searched for relevant studies in July 2014. We developed a Boolean search strategy for PubMed incorporating potential synonyms. The elements of our research question determined the search terms (MeSH). This search strategy was fine-tuned for the other databases. We searched under the four categories: (1) Multidisciplinary, (2) Collaboration, (3) Primary Health Care and (4) Outcomes. The search strategy was executed by combining all the terms within one type of search term to search for synonyms within (1), (2), (3) and (4)) together with a Boolean ‘OR’ operator. The four sets of terms were joined together with the ‘AND’ operator. All search terms for the electronic databases are available as a supplement.Language: English, Spanish, German and Dutch, as these are the languages we understand.Countries: 68 member states of the World Health Organization that fall into the category of high income countries in 2011.Methods: Only studies with quantitative data as primary outcomes had to be defined in quantitative measures. This makes it possible to compare the primary outcomes and judge them on their significance.Object of study: Does it describe an intervention with activities carried out in collaboration in primary care? Some form of communication between the disciplines involved in the care provided had to be part of the collaboration, while studies about the training of undergraduates within schools or universities were excluded.The article describes outcomes for patients, primary health care professionals or organizations. Studies that only reported on costs without reference to other outcomes were excluded, since this was not the main focus of our paper.The inclusion criteria are:p < 0.05) which means the agreement is substantial. The few disagreements were resolved by discussion. In two cases, the full text of the publications was read by a third reviewer in order to resolve the disagreements that could not be solved by discussion.The literature identified was dominated by case studies that did not report quantitative data and analysis and were therefore excluded. The same applies to studies where there is a main focus on another subject other than collaboration. We also excluded 12 reviews which were relevant studies but which had already been retrieved in our own search. This indicated that our search strategy was valid. Eventually 51 studies remained after duplicates were eliminated and studies were excluded based on title, abstract and full text.We used the criteria of Cochrane Collaborations Effective Practice and Organization of Care (EPOC)  to assesThe studies found show similarities. These similarities were structured by the structure, process and outcomes model of Donabedian . This moz-test. It is used to determine whether the difference between two proportions is significant.We conducted the analyses in two steps. First, the studies were coded and mapped according to the elements of our conceptual model: structure, process and outcomes see . Here, tN = 22) [N = 8) [N = 7) [N = 18) [N = 5) [The largest share of studies in this review was conducted in the USA (N = 22) , 20–40,  [N = 8) –48 and t [N = 7) –55. Five [N = 7) –60, two  [N = 7) , 62, and [N = 7) , New Zea [N = 7) , France  [N = 7) , Spain [ [N = 7) , Israel  [N = 7) , Austral [N = 7)  and Puer [N = 7) . The lar[N = 18) , 69 and  [N = 5) , 48, 61.Care coordination by a case manager is the third most frequently found activity, occurring in 13 studies. A GP/physician was involved in the collaboration in the majority of the interventions. Most (60%) of the interventions are medium or large collaborations involving four or more different disciplines rather than small collaborations. Interventions that included two or three different collaborating disciplines use individual care plans more frequently. However, interventions where four or more different disciplines are involved more frequently collaborate through multidisciplinary meetings. A relatively large share of interventions, occurring in 18 papers, focused on an older patient population.The majority of these interventions work with individual care plans. Studies about other age categories, some non-specific, describe interventions more frequently with multidisciplinary meetings.The interventions are often targeted at patients with chronic, or multiple chronic, conditions (19 studies), or at patients with mental, or multiple mental illnesses (10 studies). Eight studies tested interventions that use individual care plans for patients with one or more chronic conditions. The studies describe not only interventions involving collaborations within primary care itself, but also half of them (25 studies) involve interventions between primary care and one or more other sectors such as mental health or secondary care. Interventions about collaborations within primary care mostly use individual care plans. However, interventions involving collaboration with different sectors such as mental health or secondary care are more frequently carried out through multidisciplinary meetings.The structure and process characteristics of the interventions are related to the outcome parameters used in the studies in One hundred and thirty-nine different outcomes were reported in the 51 studies. Taking these 139 outcomes as the unit of analysis provides an opportunity to estimate what evidence is present to suggest a successful collaboration and to what extent the structures and processes of the collaborations are related to success. Of the studies in this review, 16 studies did not show any significant outcomes. z-tests. When tested there was no significant difference between interventions with or without a physician involved in the collaboration. Neither did we find that medium or large interventions, in terms of number of disciplines involved, coincide more often with positive and statistically significant effects for each type of outcome. In the case of smaller collaborations, the only category that was most likely to be significant is the proportion of clinical outcomes. However, these specific outcomes were not tested because of the small number. When comparing non-specific age groups to older people, there is a significant difference in the outcomes. Non-specific age groups more often show a positive significant outcome (p < .05). It is only for the outcome category ‘use of health services’ that a higher proportion of positive and significant outcomes was reported for interventions targeted at older people. There is no significant difference in outcomes between the patients’ conditions. The last column of When looking at the collaborative activities, that is the type of collaboration process, care coordination interventions have the highest proportion of significant effects on the four different outcomes. In general, if interventions report using multidisciplinary meetings, they show relatively more outcomes and significant outcomes in those outcomes related to a professional. Individual care plans most often report positive outcomes on clinical outcomes.The objective of this study was to perform a review of scientific papers that present empirical results about multidisciplinary collaborations in primary health care and their effect on patients’ and professionals’ outcomes. We believe this review is the first in which empirical studies on collaboration in primary care and its outcomes, and not limited to specific patient groups or diseases or the type of collaboration, are compared and analysed.The studies found in this review reported on the structure and outcomes. However, the processes were often poorly described and monitored. As a consequence, it remains difficult to investigate the expectation that processes could be as important as structures for outcomes of primary care collaborations. However, of the process activities, the three most reported and clearly described activities were extracted from the studies and tested in this review. Because of a small number of studies and outcomes, the three components of the conceptual model could not be tested simultaneously.Most of the 51 studies analysed focused primarily on the outcomes for patients. A few studies reported outcomes for professionals. The underlying reason for this might be that outcomes for patients are considered to be the most important and therefore these are the most researched. However, it remains relevant to investigate too if collaborations that show better outcomes for professionals also lead to better care for patients. In future research this aspect should be taken into account.not supported by the collaborations reported in the studies and analysed in this review. We believe there are possible reasons why the results of collaboration in our review are disappointing:Collaboration is not leading to better outcomes, at least not all types of collaboration interventions lead to better outcomes;The intervention involved in the collaboration was not implemented properly in some of the studies. For instance, a protocol was introduced but not all professionals adhered to it.The research project was not able to identify the effect on outcome.The 51 papers and the 139 outcomes reported in this review show that collaboration in primary care equally does, and does not, result in positive and significant outcomes. The proportion of significant outcomes in the 51 papers is lower than 50%. We believe this is a significant insight given the common belief that collaboration in primary care will generally result in greater efficiency-including cost efficiency, greater professional satisfaction due to task enrichment and better health outcomes for patients. We find that this is All three reasons are plausible given our results. It might be that some interventions are less successful, for instance for older people. Also, the idea of the collaboration may not sometimes have been implemented properly. However, the last reason seems the most plausible in our review. First, the quality of the studies might result in a bias towards the opportunity to find significant outcomes. By using the EPOC tool, the risk of bias in the studies was screened out, leading to exclusion of studies of very low quality (26 based on full text). However, there remained 21 studies of low quality included in this review. This low quality could have influenced the results and could lead to them becoming less significant. Second, the sensitivity of the outcomes we measured limits the opportunity to find significant outcomes. Some outcomes are harder to improve by investing in collaboration than others. Studies that do show an improvement mostly concern clinical outcomes. This is probably related to the fact that collaborations which focused on specific diseases have better conditions to show clinical outcomes. In general, the clinical effects in one specific patient group can be better quantified and are more easily achieved in a shorter time. Finally, the follow-up in the measurements might be too short a period of time for outcomes to be realized. The studies in this review varied in their period of measurement from three months to four years. We did not account for this as it was beyond the scope of this review. However, the review of Kruis  showed tThe large number of studies in this review that address the involvement of primary care physicians reflect perhaps the dominant and crucial position that physicians have in many health care systems. Some characteristics of the structure of collaborations show higher positive significant outcomes, such as the involvement of a physician in the collaboration compared to no involvement of a physician (not significant). The paper of Poulton  showed tIt is suspected that collaborating between sectors can have more language or payment barriers . This isWhen it comes to the process of collaboration, it appears most beneficial to implement some form of care coordination, especially when trying to improve clinical and patient-related outcomes. However, the difference in outcomes between the activities is small. Collaborations that include multidisciplinary meetings more often than the other activities show a higher proportion of significant outcomes for professionals. This may indicate that these meetings help professionals simply get to know each other and thus stimulate team building .Interventions to improve collaboration show a large variation in the structure of the collaboration, the actual collaboration process that is improved and in the implementation of the interventions. However, grouping the interventions by their characteristics of structure and process reveals significant patterns.Nevertheless, the results may be subject to both a publication and study selection bias. Publication bias may occur as studies will be more likely to get published when the outcomes show an effect. This could overestimate the proportion of significant outcomes. At the same time, we find that 16 of the 51 studies in this review did not report any positive significant effect. Study selection bias occurs as this review is limited to studies using quantitative data from high-income countries. As a result, general conclusions should not be applied to other, middle- or low-income countries. Our selection of databases in health care could also have resulted in a study selection bias. Still, these databases are the most common and suitable to retrieve studies on collaborations and outcomes in health care. This was reflected by the fact that all relevant studies incorporated in previous reviews were also found in our search strategy and in the databases we used. Moreover, the selection process included a selection on outcomes, which excluded some studies such as those on costs alone.The study selection was first undertaken on title and later on abstract and on full text. The selection on title might have excluded studies with a title giving no clue about the objective of the study. However, when in doubt the study's abstract was screened.N = 139), instead of focusing on the number of studies (N = 51). Still, this number is too small for multivariate analysis. Therefore, it is not possible to draw causal inferences on the effect of the type of study and the outcomes involved. To overcome problems with multiple testing, a two-proportion z-test is used. By reducing the analysis to separate structures and activities, the variation is made as small as possible, and comparisons are made on the level of these separate elements. For example, the three most reported activities were chosen for the analysis. Unfortunately, the intensity and quality of these actions could not be taken into account because of a poor description.Our data set is essentially cross-sectional and the numbers involved are rather small. We tried to overcome this shortcoming by testing on the number of outcomes (Much research on collaboration has been carried out, often focusing on small parts of a collaboration , 74, 75.Until now collaboration in many studies does not live up to its expectations with less than 50% of the outcomes positive and significant. However, this might be the problem of the quality of the studies, the expectation riding on some outcomes and the follow-up time;A higher proportion of significant results of collaboration was found in studies that report on clinical outcomes;Many studies suggest collaboration for older people is unsuccessful.In conclusion we argue that:The important implications for daily practice are that implementation of a collaboration resulting in outcomes takes time and effort, especially in the long run. It is important to monitor the process and special attention is required for older patients.


The deleterious changes in environmental conditions such as water stress bring physiological and biochemical changes in plants, which results in crop loss. Thus, combating water stress is important for crop improvement to manage the needs of growing population. Utilization of hydroponics system in growing plants is questionable to some researchers, as it does not represent an actual field condition. However, trying to address a complex problem like water stress we have to utilize a simpler growing condition like the hydroponics system wherein every input given to the plants can be controlled. With the advent of high-throughput technologies, it is still challenging to address all levels of the genetic machinery whether a gene, protein, metabolite, and promoter. Thus, using a system of reduced complexity like hydroponics can certainly direct us toward the right candidates, if not completely help us to resolve the issue. Water deficiency has a profound impact on ecological and agricultural systems and is a limiting factor in the initial phase of plant growth and establishment  and metabolite data   a phytoalexin that has high estrogenic activity and is known for the antioxidant activity was one of the major novel findings of this study. Coumestrol, has also been shown to be a UV stress indicator and also plays a role in plant-microbe interactions . Various physiological parameters were monitored to gain insight of the response to water stress. In roots, an 11% decrease in total water content (%TWC) from 3 to 5 h of dehydration was observed while a 10% decrease in leaves %TWC from 2 to 5 h was observed (data not shown). This observation is in accordance with the similar trends seen in experiments performed in soil (Harb et al., Our dataset has shown that hydroponics system validates itself to be comparable to field conditions as proposed by soil. We agree with the difference in nature of the complexity of field conditions and growth chambers. However, the use of hydroponics in growing plants to understand the molecular mechanism of plant response to water stress is a valid option. Because imposing water stress is less complex and eliminates combinatorial effects brought by heat and other environmental factors, commonly experience in field-grown plants. Based on our findings, we able to hypothesize about the putative role of coumestrol as another stress biomarker in the leguminous crop like soybeans.de novo biosynthesis of amino acids during water stress, and this constitutes a potential drought tolerance strategy in soybean. Also, identification of the novel metabolite coumestrol could be another biological marker for understanding and making drought/water stress tolerant crop plants. Validation of these hypotheses needs further experimentation.In light of comparative findings of hydroponics system and soil directs that observations be alike. Also, it greatly minimized the effect of abiotic stresses other than water stress as conditions like temperature, relative humidity, and the light regime were constant. Soybean plants were subjected to a rapid and uniform water deficit stress by removing the plants from the hydroponics solution using the pots. With the use of hydroponics, we have also shown that there is a flow of nitrogen into amino acid metabolism and PT and PR designed the study and planned the experiment. PT and RR performed the experiments. VS and QS helped in the analysis. PT wrote the manuscript. All authors have read and approved the manuscript.This work is supported by the National Institute of Food and Agriculture, U.S. Department of Agriculture, under award numbers 2008-35100-04519 and 2008-35100-05969. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture.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.


Saccharomyces cerevisiae is one of the oldest and most frequently used microorganisms in biotechnology with successful applications in the production of both bulk and fine chemicals. Yet, yeast researchers are faced with the challenge to further its transition from the old workhorse to a modern cell factory, fulfilling the requirements for next generation bioprocesses. Many of the principles and tools that are applied for this development originate from the field of synthetic biology and the engineered strains will indeed be synthetic organisms. We provide an overview of the most important aspects of this transition and highlight achievements in recent years as well as trends in which yeast currently lags behind. These aspects include: the enhancement of the substrate spectrum of yeast, with the focus on the efficient utilization of renewable feedstocks, the enhancement of the product spectrum through generation of independent circuits for the maintenance of redox balances and biosynthesis of common carbon building blocks, the requirement for accurate pathway control with improved genome editing and through orthogonal promoters, and improvement of the tolerance of yeast for specific stress conditions. The causative genetic elements for the required traits of the future yeast cell factories will be assembled into genetic modules for fast transfer between strains. These developments will benefit from progress in bio-computational methods, which allow for the integration of different kinds of data sets and algorithms, and from rapid advancement in genome editing, which will enable multiplexed targeted integration of whole heterologous pathways. The overall goal will be to provide a collection of modules and circuits that work independently and can be combined at will, depending on the individual conditions, and will result in an optimal synthetic host for a given production process.The yeast  The development of economically feasible and sustainable biotechnological processes as alternatives to oil based chemistry is one of the major goals of biobased economy. The success of this strategy will require efficient, robust and versatile cell factories but the improvement of currently used strains towards such platforms is hindered by the limitations of conventional methods for strain improvement. Synthetic biology is expected to provide means for engineering cell factories in a more efficient and controllable way.Synthetic biology is regarded as the engineering discipline by which novel organisms can be constructed by assembling parts, devices and modules into systems. Proponents such as the iGEM  foundation aim at a high level of standardization and foster the definition of a framework of rules for the conceptualization, design and manufacture of biological systems with predictable properties. A more practical, problem driven approach, however, sees synthetic biology as the field that makes use of advanced tools of genetic engineering, genomics and systems biology in order to programme and control a biological device and create new behaviour previously not found in that system. In contrast to the former approach, this description does not draw a clear line to other sciences; the designation of a strain as simply genetically engineered or synthetic seems rather arbitrary. Because of the complexity of biological systems, each problem is seen as unique and the occurrence of unpredictable effects of genetic modifications is expected, making attempts for standardization a futile effort. Irrespective of the ongoing debate about its definition , 2, therSaccharomyces cerevisiae is the most intensively studied unicellular eukaryote and one of the main industrial microorganisms used in the production of biochemicals. Apart from traditional applications in alcohol fermentations, baking processes and bio-ethanol production, S. cerevisiae is being used for the production of many industrially relevant biochemicals and for heterologous expression of proteins [The yeast proteins . The potproteins , and theproteins , 6.S. cerevisiae and optimize it for the desired product and required bioprocess conditions. Many examples for this strategy exist, but species-specific traits often hinder the development of hosts with high productivity and yields close to theoretical limits. Nevertheless, S. cerevisiae is the host of choice in many cases, due to the vast array of tools for genetic engineering and to the immense range of knowledge about all aspects of yeast biology. In this review, we will highlight recent achievements in engineering S. cerevisiae for biotechnological processes, with focus on advanced synthetic biology tools for genome editing, pathway control and for the analysis and transfer of industrially relevant traits. Moreover, we will discuss further developments that will be required to establish S. cerevisiae as one of the chassis in synthetic biology and as a platform for future cell factories. Finally, we will present an approach whereby both aforementioned strategies for strain development can be combined in a synergistic manner, to obtain a platform strain that can be individually adapted according to the requirements of a specific process.There are two basic strategies for developing a production host for a biotechnological process. In the first, a suitable host can be selected from a large number of species based on its performance regarding parameters such as product yield, productivity, and tolerance to the product or other environmental stressors . In many cases, targeted optimization of such a host is not possible because the tools for genetic analysis and engineering in that species are not available, leaving only evolutionary optimization or random mutagenesis to produce optimized strains. The second possible strategy is to start with a well-known species such as S. cerevisiae. The use of Cre recombinase or other recombination based approaches, like the 50:50 method [delitti perfetti, leaving no foreign DNA in the yeast genome. Although such techniques are currently an important tool for synthetic biology, they are relatively time consuming and therefore not suitable for the introduction of whole heterologous metabolic pathways or deletions of several genes in a reasonably short time. In the last few years, new approaches like Zinc finger nucleases [Traditional DNA editing techniques, such as transformation and deletion of genes by homologous recombination, have been readily feasible for many years in 0 method , allow fucleases , Yeast Oucleases , transcrucleases  and the ucleases , 12 haveucleases . Similarucleases , 14. HenS. cerevisiae by simultaneous transformation of a recipient strain with several different integration cassettes. One successful strategy used up to four cassettes, with each one containing two genes under the control of the bidirectional GAL1/10 promoter and a phleomycin resistance marker, and with targeted chromosomal δ sites of transposons. An alternative approach, the DNA assembler technique, is based on the in vivo recombination of overlapping DNA sequences. All genes of a pathway together with a marker were amplified by PCR with extension primers that resulted in overlapping sequences at the 3′-end of one gene and the 5′-end of the next one. The 5′-end of the first and the 3′-end of the last cassette bore sequences homologous to sequences in the chromosomal δ sites. For both strategies, pathways with up to eight genes were successfully assembled in one round of transformation [Other approaches make use of the high recombination efficiency of ormation , 16. Theormation . The ratloxP sites, allowing for random deletion of genes upon expression of Cre recombinase and on screening for viable strains with improved characteristics for a selectable trait. Furthermore, one of the three stop codons will be eliminated from the genome in this project. In the future, an orthogonal codon could be used for the targeted incorporation of an alternative amino acid, thereby altering protein properties. Such a recoded genome will also enable the development of efficient biocontainment strategies as the free codon can be used to engineer orthogonal auxotrophies in cell factories to minimize risk in the case of accidental release and allow for processes to be carried out in open bioreactors [The currently most ambitious project in yeast synthetic biology is the complete de novo synthesis of all 16 chromosomes, Sc2.0. In this effort, all nonessential genes will be flanked by reactors , 19. Altreactors , the conreactors . It is treactors . HoweverOne of the central aims of synthetic biology is to apply classical engineering principles to the development of strains. This includes the concept of orthogonality that requires a biological system to be divisible into modules that are independent from each other and can therefore be engineered individually, without consideration of other modules and with predictable outcome Figure . In contS. cerevisiae, the majority of promoters that are used for control of expression are endogenous promoters that respond to the concentration and type of the carbon source [MET15), to metal ions (CUP1) or to antibiotics, like the well-established tetR/tetO system [S. cerevisiae. The advantage of these systems is that the ligand binding domain can be mutated to bind, with high specificity, a number of different, although structurally related, ligands. Starting from one TF, such mutations would result in a series of variants with identical binding but different activation domains. Most such approaches in yeast, however, use the binding domain of the GAL4 TF. For this reason, although these engineered systems work independently of galactose induction, they interfere with genes of this regulon and activate their transcription upon induction. To obtain modules that can be controlled orthogonally, foreign binding mechanisms will have to be used. As noted in the previous section, genome editing tools can be used, not only for targeted modifications of DNA, but also for the control of gene expression. For example, the TAL effector can be designed to bind to any specific DNA sequence with high specificity; it has already been demonstrated to work as a repressor of a constitutive promoter in yeast [Approaches in this field that go beyond theoretical considerations include the synthetic yeast strain with an orthogonal codon on the DNA level (see above), the engineering of aminoacyl-tRNA synthetases , riboregn source . BesidesO system , but, siO system , the retO system , and theO system , which hin yeast . A CRISPin yeast . If the Biotechnological processes often require strains that are tolerant to one or several stress conditions from a broad spectrum, like extreme pH, high temperature, osmotic pressure, shearing forces, organic acids and toxic substances. Most of these properties are complex traits, encoded by several genes Figure , left. Bknown factors can influence the resulting phenotype [hidden factors [These complex genetics techniques use the advantages of next generation sequencing capabilities to greatly increase the number of segregants that can be tested, but also produce more data that cannot be interpreted with traditional computational tools. To infer causative relationships between loci/genes and complex traits, novel data integration models are applied. While it is a common practice to apply conventional statistical testing on SNP polymorphisms for QTL discovery, it has been observed that a larger number of additional henotype –37. Exis factors , e.g. ce factors , Bayesia factors  and mult factors , exploit factors , with thThe aforementioned methods enable integration of data on mutations, environmental conditions , 44 and S. cerevisiae is specialized for the utilization of glucose, fructose and its disaccharide sucrose. In the emerging era of bioeconomy, however, microbial cell factories will have to efficiently utilize more sustainable, cheaper and generally available carbon sources, especially lignocellulose [S. cerevisiae cannot directly utilize cellulose and therefore pretreatment is required to release glucose (see below).The second most abundant monosaccharide in plant biomass is xylose, but the rate of xylose metabolism in currently used laboratory and industrial yeast strains is too slow to be of use in a biotechnological process, especially because of too low xylitol dehydrogenase (XDH) activity [XDH1 [The metabolism of ellulose , 48 , but development in this field has until now brought only limited success, although with promising predictions for the future . TherefoS. cerevisiae on fast fermentation of sugars is the basis for its use in the production of alcoholic beverages and biofuel and in the baking industry. At the same time, aerobic ethanol fermentation  is one of the main obstacles to obtaining high yields in processes aimed at producing bulk products other than ethanol. Indeed, sustainable and cost-effective production of many commercially important metabolites cannot be achieved in S. cerevisiae as long as most of the carbon source is converted to ethanol. Hence, a stable conversion of S. cerevisiae physiology to respiration in the presence of high sugar levels, allowing efficient use of the substrate, is an important prerequisite for its use in high yield production processes.The specialization of S. cerevisiae focus mainly on a reduction of the normally high glycolytic flux, because it is assumed that the degree of fermentative activity is a function of the rate of glucose catabolism [Most attempts to eliminate the Crabtree effect in tabolism , 58. A ptabolism . On the tabolism  or lactatabolism . Hence, Synthetic biology approaches have resulted in recombinant yeast strains for the production of metabolites that are not normally produced by this species Figure , right. Orthogonality, although theoretically worthwhile, is difficult to achieve in biological systems. Nevertheless, it should be seen as one of the goals of synthetic biology in order to design modules for the supply of intermediate metabolites and cofactors with general applicability in metabolic engineering that are independent of the overall pathway which they serve. Examples would be circuits for regenerating redox cofactors or efficient modules for providing central building blocks such as 2-carbon (acetyl-CoA), four carbon , and six carbon (citrate) metabolites that can be of use in engineering many different pathways. Such readily available circuits would considerably facilitate metabolic engineering and enable faster expansion of the product spectrum of yeast.Several genetic modules –75 show S. cerevisiae and so-called non-conventional species will be diminished, since we can envision that some cell factories could make use of S. cerevisiae only as a chassis, whereas the specific biotechnologically relevant traits will come from a number of different organisms.Improved substrate spectrum, enhanced product spectrum and increased stress tolerance and robustness are the main demands for the future cell factories that will be used in biorefineries Figure . As descS. cerevisiae will most probably also play a role as a chassis for synthetic biology and for the next generation of production hosts in biotechnology. The well-developed toolbox for the analysis of yeast, both on the single gene level and in -omics and systems biology techniques, is an important advantage of this organism. Combination of the recent developments in the fields of synthetic biology with polygenic trait analysis provides a means to engineer traits for increased stress tolerance and robustness, improved substrate spectrum, and enhanced product spectrum. However, synthetic biology research in yeast lags behind that in other organisms, especially E. coli. Indeed, there are only few efforts to standardize engineering and to improve the collection of biological parts for yeast are only limited. To establish S. cerevisiae as a promising candidate as a chassis in synthetic biology and future biotechnology, research will have to catch up in several areas, such as the development of orthogonal parts for expression control and genome editing. These are not only aspects of academic relevance but also prerequisites for the rapid and predictable engineering of readily controllable synthetic hosts.New technologies for the analysis of whole genomes and for large scale DNA editing have the potential to revolutionize biotechnology. The engineering of production strains will no longer be restricted by the length or complexity of a pathway and the use of computational and -omics tools will enable more accurate prediction and prevention of undesirable side effects in the design phase. Due to its current importance in biotechnology and its immense knowledge base,


Background: Mass gatherings including a large number of people makes the planning and management of the event a difficult task. Kumbh Mela is one such, internationally famous religious mass gathering. It creates the substantial challenge of creating a temporary city in which millions of people can stay for a defined period of time. The arrangements need to allow this very large number of people to reside with proper human waste disposal, medical services, adequate supplies of food and clean water, transportation etc.Methods: We report a case study of Maha Kumbh, 2013 which focuses on the management and planning that went into the preparation of Kumbh Mela and understanding its water, sanitation and hygiene conditions. It was an observational cross-sectional study, the field work was done for 13 days, from 21 January to 2 February 2013.Results: Our findings suggest that the Mela committee and all other agencies involved in Mela management proved to be successful in supervising the event and making it convenient, efficient and safe. Health care services and water sanitation and hygiene conditions were found to be satisfactory. BhuleBhatke Kendra (Center for helping people who got separated from their families) had the major task of finding missing people and helping them to meet their families. Some of the shortfalls identified were that drainage was a major problem and some fire incidents were reported. Therefore, improvement in drainage facilities and reduction in fire incidents are essential to making Mela cleaner and safer. The number of persons per toilet was high and there were no separate toilets for males and females. Special facilities and separate toilets for men and women will improve their stay in Mela.Conclusion: Inculcation of modern methods and technologies are likely to help in supporting crowd management and improving water, sanitation and hygiene conditions in the continuously expanding KumbhMela, in the coming years. The World Health Organization (WHO) defines a mass gatheringas a “gathering of more than a specified number of persons at a definite location for a specific purpose for a defined period of time”. The number of persons may be as few as 1000, but the available literature suggests that gatherings exceeding 25,000 persons are considered to be a mass gathering.Kumbha means a pitcher and Mela means fair in Sanskrit. The KumbhMela is the biggest and the most important periodic mass gathering in India. It is a mass Hindu pilgrimage of faith in which Hindus from all over the world gather to have a dip in a sacred riverThe name Kumbh Mela comes from Hindi, and originally from Sanskrit. We did a case study of MahaKumbhMela, 2013 which aims to examine the details of the management and planning of the event and to understand the water, sanitation and hygiene conditions of KumbhMela. We outline the overall management, which will help others to derive useful methods that can be adopted and replicated by the other states and the countries when organizing similar mass events. It might help to identify innovative methods to provide better water, sanitation and hygiene conditions to a mass gathering. The study provides a framework for similar research on future mass gathering events in India.In order to have complete understanding of the planning, management and understanding of water, sanitation and hygiene situations in KumbhMela 2013, field work was done for 13 days, from 21 January to 2 February 2013. Permission for conducting this study was obtained beforehand from all the concerned authorities and government officials who were involved in the Mela organization and management.These steps were followed during the field work:Interaction with the concerned authorities for understanding overall scenario of Kumbh: Interaction took place with different doctors, municipal authorities, Disaster Relief force, fire service personnel to understand the overall scenario of Mela and to do social and resource mapping. The interaction was open ended with a focus on the measures which were applied by these authorities for organizing and managing the KumbhMela.Transect walk (Observation), Social and Resource Mapping: In this, the resources available for managing Mela were visited and observed. These included services such as health care centers, fire station, and water and sewage facilities. It was used to verify the claims of the different authorities providing services during the Mela. It used observation to map out the important available resources in the KumbhMela.Water, Sanitation and Hygiene (WASH) survey: To find out the status on water sanitation and hygiene conditions, a study was done in the Akharas/Santhas of KumbhMela. Akhara/Santhas is a Sanskrit word which denotes a place of practice with facilities for boarding, lodging,education and sports for a particular group of people. Akharas/Santhas were the places where the devotees temporarily stayed during the Mela. The water, sanitation and hygiene conditions of these Akharas are particularly important. In total, five Akharas/Santhas were randomly selected from each of the sectors. There were 11 sectors included in the study, which resulted in the sample size of 55 Akharas/Santhas. A close-ended questionnaire was used to interview each of the Akharas/Santhas. The questionnaire consisted of small set of questions, such as source of drinking water, water storage practices, defecation and hygiene practices in the Akharas/Santhas. The questionnaire was completed either by interacting with sadhus and people living there during the study or by observation of the researcher. The information regarding number of person and toilets in each of the Akharas/Santhas was obtained from those who were in charge of these Akharas/Santhas. Data analyses were done using Microsoft Excel and SPSS (version 20).Health Care interventionsDuring the interaction with the Zonal Officer Health Department (ZOHD), we were informed that health care services became operational in mid November 2012, when approximately 250 doctors, including specialists and AYUSH  doctors were deputed in the Mela area. Ten Sector hospitals had been constructed in the Mela area, each of which comprised of a general outpatient department (OPD) and 20 bedded inpatient unit. The hospitals were open for 24 hours every day throughout the duration of the Mela. Four MBBS (Bachelor of Medicine and Bachelor of Surgery) doctors were deputed in each sector hospital, with two doctors working in 8 hour shifts and two working in 12 hour shifts. In addition, nursing staff and one ambulance were also deputed for each sector hospital. The doctors arrived from the new Primary Health Centers in the other area of Allahabad and were assigned to Mela for two months. Each sector hospital had a pharmacy and medicines, which were provided free of charge. The daily OPD load was approximately 250-300 patients in each sector hospital. There were also 22 First Aid centers that had been set up by the health department in 12 sectors. Each first aid center had one AYUSH doctor, one pharmacist and a 2-bed inpatient unit. There were two infectious disease hospitals in the Mela area, with 20 beds in each. The focus of this healthcare delivery system was the central hospital in sector 2, where patients could be seen by a range of specialists, including Orthopedics, Medicine, Surgery, Eye, Skin and Obstetrics. There was a 100-bed inpatient unit and a 2-bed Intensive Care Unit. Diagnostic facilities such as X-ray, ultrasound, ECG (ElectroCardioGram) and a laboratory were also available. The additional directorate for health that supervised the entire healthcare delivery system was at the Mela field office, in Sector No. 2. More than70 ambulances and some river ambulances were deployed for transferring patients who needed specialized care from the First Aid Centers or Sector Hospitals to Central Hospital or Swaroop Rani Medical College. Safe passages had been constructed in the Mela area for the running of emergency vehicles during any emergency periods.It was also noted that, in case of any mass casualty incident, 100 beds were reserved for the Mela in Swaroop Rani Medical College. No major health outbreaks occurred in the Mela area but the health department is ready to tackle any such outbreak by having a proper surveillance system in place. Illnesses such as fever, cold and cough were the most reported from the sector hospitals.In addition to above facilities, the main focus areas of the health department were hospitals to provide health care to prevent vectors migrating from Allahabad city to the Mela area, the use of DDT (DichloroDiphenylTrichloroethane) spraying, fogging etc. to prevent vector breeding in the Mela area, and the provision and maintenance of sanitation facilities to all the Akharas/ Santhas and general public in the Mela area. The health department also looked after water quality in all their 22 circles, by conducting random orthotolidine tests twice every day.Water and Sewage interventionsUnsafe water is the main cause of many water-borne diseases in mass gatherings like MahaKumbhMela. To prevent these diseases, water was another major focus area where the Government of Uttar Pradesh provided input. We were informed by those in-charge of the Uttar Pradesh Jal (water) Board, Sector 4, that the Jal board provides a running water supply for 24 hours every day, with a 550 km network of pipelines connecting all the Akharas/Santhas, hospitals, police and fire stations. A total of 42 high pressure pumps had been set up for this purpose. An average of 45 liters of water was provided per person per day. With the mission to provide safe and clean drinking water for the devotees, water quality was tested by Jal board, through an orthotolidine test of the supply water from 6 random sites. The Tata group of companies also worked with the Uttar Pradesh Jal Board to provide safe and clean drinking water to the devotees in KumbhMela. The Uttar Pradesh Jal Board was also responsible for sewage disposal in the Mela area. The board had constructed retention pools for sewage collection in the Mela area, so that sewage did not pollute the Sangam area.Bhule Bhatke Kendra (Center for helping people who got separated from their families)The Kendra (center) is meant for those who get separated from their families during the mass gathering. At the KumbhMela, the kendra is marked by balloons with the words “BhuleBhatke Kendra”. Those in-charges of BhuleBhatke Kendra, Sector No. 4, informed us that there were 6 BhuleBhatke Kendra in the Mela area, as well as one camp where anybody who got lost was looked after. The devotees who got separated from their family members could come to kendra and report the incident. The Kendra then made a public announcement and displayed the picture of the missing person on their display panels. All information regarding the missing person was uploaded on their website which could be accessed by anyone. We were informed that 1560 missing persons were successfully located.Fire stationsFire incidents were frequent in the KumbhMela because of the cottages that were constructed with plastic sheets, inadequate temporary shelters, the use of LPG (Liquid Petroleum Gas) cylinders, and unplanned electrical lines near dwelling areas. The Fire Station Officer in the Mela area informed us that the department had set up 36 fire stations in the Mela area. They had 46 fire tenders with 422 firemen deployed in the Mela area. He added that the department has motorcycle mounted firemen with back pack fire extinguishers to provide emergency services to areas that could not be accessed by the fire tenders. The department also had an ambulance that could be used to transfer people from the incident site to the hospitals. They provided information on 18 major incidents of fire reported in the Mela. (See table 1)Disaster Response TeamTo mitigate the risk of any kind of major incident, the Government of Uttar Pradesh deployed a National Disaster Response Team in the KumbhMela. The National Disaster Relief Force team had been deployed to aid in search and rescue operations, if necessary. The team had specialized diving equipment and experienced personnel for such operations and was available throughout the course of the KumbhMela. The battalion comprised of navy and paramilitary forces, who had been given one month’s special training before being sent to NDRF . Other paramilitary forces were also deployed in the Mela area.WASH interventionsWater and sanitation facilities were maintained by the Mela Committee. All the Akharas was provided with toilets depending upon the number of people staying in each Akharas. We observed that every Santha/Akhara was provided toilets from Mela committee and sweepers were also allotted for each Santha/Akhara.WASH SurveyIn all the Akharas, water for drinking and other uses was the water supply provided by the Uttar Pradesh Jal board (table2). Buckets were used to store the water in these Akharas and all water containers were also clean. Similarly, all the Akharas had latrines which were used by both males and females. All Akharas had a garbage pit for waste disposal. Our findings were consistent with earlier observation and claims of the Uttar Pradesh Jal Board. However, drainage was a major problem in 45% of Akharas. We found that 42% of Akhara/Sanstha had 11-15 persons per toilet and 30% of Akharas/Sansthas had more than 15 persons per toilet (figure 1).Our study shows that there was high quality planning and administration in the KumbhMela 2013. Mela committee and all other agencies involved in Mela management were successful in the supervision of the event and in making it convenient, efficient and safe. Health care services and water sanitation and hygiene conditions were found to be satisfactory. Our findings are consistent with the claims made by the Uttar Pradesh Jal board and previous studies done on KumbhMela. One of these studies stated that after seeing the top quality arrangements of KumbhMela, the world witnessed the administration of Mela with awe and surprise; and considered the planning and management of KumbhMela as one of the wonders of modern day management.Some shortfalls were that drainage was found to be a major problem and some fire incidents were reported, which needs serious attention from the Mela organizers. Improvement in drainage facilities and reduction in fire incidents are basic but essential tasks to make Mela cleaner and safer. A higher number of persons per toilet than would be preferred were found and there were no separate toilets for males and females. Special facilities and separate toilets for men and women would improve their stay in the Mela, and will help to improve the public health conditions and increase the effective use of toilet facilities provided. Inculcation of modern methods and technologies can help in supporting the crowd management and improving water, sanitation and hygiene conditions in the continuously expanding KumbhMela, in the coming years. For example, Kumbh could be improved with strategies from Hajj. In the past few years in Hajj, different kinds of sensor devices, scanners, trackers of footsteps, modern medical and emergency related services and many other innovative technologies were found to improve its management.Despite the shortfalls, one must appreciate that the government has done a great work in managing this unique event. Additionally, it has adopted some of the best practices that have captured the attention of many researchers, governments, and international research firms, not only in India but around the world. The management of KumbhMela provides an example to follow for mass gathering events inside and outside India, showing how a mass event can be well organized with utmost safety security and cleanliness. Further research is needed on KumbhMela to bring into focus the strengths and weaknesses of this large event for its further improvement.The authors have declared that no competing interests exist.


Despite the increasing popularity of the theory of change (ToC) approach, little is known about the extent to which ToC has been used in the design and evaluation of public health interventions. This review aims to determine how ToCs have been developed and used in the development and evaluation of public health interventions globally.We searched for papers reporting the use of “theory of change” in the development or evaluation of public health interventions in databases of peer-reviewed journal articles such as Scopus, Pubmed, PsychInfo, grey literature databases, Google and websites of development funders. We included papers of any date, language or study design. Both abstracts and full text papers were double screened. Data were extracted and narratively and quantitatively summarised.A total of 62 papers were included in the review. Forty-nine (79 %) described the development of ToC, 18 (29 %) described the use of ToC in the development of the intervention and 49 (79 %) described the use of ToC in the evaluation of the intervention. Although a large number of papers were included in the review, their descriptions of the ToC development and use in intervention design and evaluation lacked detail.The use of the ToC approach is widespread in the public health literature. Clear reporting of the ToC process and outputs is important to strengthen the body of literature on practical application of ToC in order to develop our understanding of the benefits and advantages of using ToC. We also propose a checklist for reporting on the use of ToC to ensure transparent reporting and recommend that our checklist is used and refined by authors reporting the ToC approach.The online version of this article (doi:10.1186/s13012-016-0422-6) contains supplementary material, which is available to authorized users. Most public health interventions are inherently complex, with multiple interacting components, delivered at multiple levels. This complexity makes them difficult to evaluate using traditional experimental designs. Public health interventions often rely on ongoing quality improvement based on the implementation experience. Therefore, they may not reach the level of stability required to conduct evaluations such as randomised controlled trials (RCTs) . Some reTheory-driven evaluation is a collection of evaluation methods which emphasise the importance of understanding how and why a programme works in order to evaluate it , 5. By plong-term outcome and then maps the required process of change and the short- and medium-term outcomes required to achieve this [assumptions about what needs to be in place for the ToC to occur are made explicit as well as the contextual factors which influence the ToC. Additional elements of a ToC can include beneficiaries, research evidence supporting the ToC, actors in the context, sphere of influence, strategic choices and interventions, timelines and indicators [ToC was developed by Weiss and others  within teve this . During dicators . These edicators .The ToC is usually developed in consultation with stakeholders through workshops or interviews although the participation of stakeholders can vary substantially in practice . For exaToC is distinct from sociological or psychological theories which describe why change occurs although these may be used to inform the ToC . For exaToC differs from other theory-driven approaches to evaluation despite similar origins. For example, although logic models outline the inputs, processes, outputs and outcomes of a programme in a similar manner to ToC, they can be rigid and do not make explicit the causal pathways through which change happens in the way that ToC does . SimilarToC has been used widely in the development sector for programme development and evaluation by funders such as the UK’s Department for International Development, Comic Relief, Grand Challenges Canada and the Gates Foundation , 19. HowThe lack of a systematic review means that there is no clear idea of how the ToC has been used and reported in the peer-reviewed and grey literature in relation to public health interventions. Given the increasing popularity of the ToC approach, understanding how it is has been used and described previously allows future users of the approach to learn from the work of others and build upon it. It also helps to move towards a more consistent way of using the ToC approach.How are ToCs for public health interventions developed and refined? development of an intervention; implementation of the intervention; development of indicators for measurement; evaluation of the intervention, including statistical approaches; and conceptualisation/evaluation of the influence of context.How is the ToC approach used in theIn this review, we sought to review both peer-reviewed and grey literature to determine how ToCs have been developed and used in the development and evaluation of public health interventions globally. Specifically, we sought to answer the following questions:The authors developed a protocol for this review which was agreed prior to the commencement of the study. This is available in Web Additional file The inclusion and exclusion criteria are listed in Table We required papers to specifically mention that they used “theory of change” and excluded those who did not for the following reasons. Firstly, as described above, there are a range of overlapping definitions for ToC and other programme evaluation methods. Given the often minimal amount of detail provided about the programme theory in papers, and especially in abstracts, it would be difficult to enforce a standard criteria for ToC against which papers could be evaluated for inclusion. Secondly, piloting the initial broad search strategy  returned more than 20,000 hits in only three databases. By refining the criteria to specify ToC by name, we were able to thoroughly explore literature which explicitly self-identified using ToC.As the focus of this review was on public health interventions, we excluded papers in which the long-term outcome of the ToC was a change within an individual rather than change in the population. For example, a ToC describing how cognitive behavioural therapy may impact on an individual’s cognitive processes and behaviour would be a change within the individual. However, if the focus of the ToC was on how a cognitive behavioural therapy intervention impacted the prevalence of depression would be change in the population. We excluded reviews and methodological or advocacy papers unless they included an example of how a ToC was developed or how ToC was used in the design, evaluation and/or implementation of a public health intervention. We did not limit the inclusion by date, language, study design or type of publication.The database searches were conducted between the 16th November and the 4th December 2013 by EB. The main search term used was “theory of change”. Where the database allowed, we limited this to health or healthcare and to humans. We searched databases of peer-reviewed journal articles . An example of a search string used for PyschInfo was “theory of change” AND . We also searched grey literature databases  and the first 50 pages of a Google search. The websites of Comic Relief, DFID, Grand Challenges Canada, The Bill and Melinda Gates Foundation, HIVOS, World Vision, the Robert Wood Johnson foundation, Actknowledge and the Theory of Change Community were also searched. In addition, we contacted experts in the field and sent requests for papers to two existing global mailing lists for evaluators: MandENEWS and Pelican.Following the search of databases of peer-reviewed journal articles, the titles and abstracts of the search results from peer-reviewed papers were exported into Endnote  where duFollowing the grey literature search as described above, all potentially relevant results were saved into Evernote . These wAny differences between authors’ opinions were resolved via discussion throughout the review process.The data from the papers were extracted by the first author (EB) onto a data extraction form. This included information on authors, publication dates, the type of interventions and outcomes, the development of ToC, the use of ToC in the design, implementation and evaluation of the intervention and the influence of context. The data collection form also included key principles of theory-driven evaluation proposed by Coryn et al. . These iDescriptive statistics were calculated using STATA 13 . The papIn total, 566 abstracts were screened, resulting in 200 full text peer-reviewed articles which were assessed for eligibility. An additional 65 records were identified from the grey literature search and screened for eligibility. A total of 62 papers were included , 26–82. The publication dates of the papers range between 1999 and 2013, with a steady increase in papers over time  of the papers developed their ToCs prospectively and 19.4 % (n = 12) retrospectively. The remainder either developed their ToC during project replanning (n = 3.5 %) or did not specify when they developed their ToC .Forty-nine papers (79 %) included some information on the ToC development process. Forty-three percent , diagrams  or both . In one case, a table was used. Table The resultant ToCs were described using narrative summaries n = 15, 3.1 %, diaEighteen papers (29 %) described the use of ToC in the development of a public health intervention. The majority of these reported that they used the ToC as a framework for the intervention , 43, 70 Forty-nine papers (79 %) describe the use of ToC in the evaluation of the intervention. This includes the development of indicators, the overall evaluation design and data analysis.The development of indicators used in the ToC was described in 28 papers. The indicators were often developed from the short-, medium- or long-term outcomes described in the ToC , 81, 84.The majority of papers (62.9 %) reported formulating their evaluation questions around the ToC. However, the papers varied in the amount of detail they provided on this process. A common description was that the ToC was used to provide a framework for the evaluation , 81, 82.The data collection and analysis methods used varied greatly across papers. Data collected for the evaluation included routinely collected data , 44, cusFew papers explicitly explored the influence of context of the intervention in relation to ToC. Although some ToCs mentioned context, particularly those with a realist evaluation focus, there was little description of how context affected the interpretation of the evaluation. There were some exceptions , 64, 72.Few papers reported on the identification of breakdowns and side effects, effectiveness or efficacy and causal explanation as described by Coryn et al. . Only foIn this systematic review, we provide an overview of how ToCs have been developed and used to develop and evaluate public health interventions. As expected, there is variation in how ToCs are developed and used in evaluation although the papers report very little detail about the ToC process.We have shown that the ToC approach has been in use since at least 1999 with 62 papers found in peer-reviewed journals and grey literature. This was significantly more than expected, given that Coryn et al.  found onIn this review, many papers provided little detail in relation to the process of ToC development and how the ToC was used to design the intervention or conduct the evaluation. For example, Bonner  describeIn contrast, other papers provided extensive detail on the ToC development process. For example, Hernandez and Hodges  describeA range of methods were used to develop ToCs. The methods ranged from participatory methods which encourage stakeholder participation and ownership of the ToC such as workshops and working groups, to more evaluator focused approaches such as programme observation and review of programme documentation. Although the reason for the choice of methods was rarely made explicit by the authors, these methods were presumably chosen based on the purpose, depth and level of stakeholder buy-in the ToC required. For example, the examples of the development of systems of care for children and adolescents with mental and behavioural disorders viewed stakeholder participation as very important and therefore held a series of workshops with multiple stakeholders from different government departments, service providers, families and service users , 50, 61.The lack of detail in most of the examples in this review makes it difficult to assess the thoroughness of ToC development. In many cases, the ToC seems to have been developed superficially and then used in a cursory way during evaluation. Similarly, where diagrams or narrative summaries of ToCs are presented in the papers, very little detail is included. Most authors present the long-term outcomes, sequence of change, beneficiaries and context. However, very few make their assumptions explicit although Vogel identifies these as a core part of ToC . Where Tn = 2). Given the popularity of ToC as a monitoring and evaluation tool by international development agencies such as the Department for International Development, UK, [A surprising finding of the review was the paucity of papers that describe the use of ToC for use during the implementation of the intervention (ent, UK, , we had ToC theorists such as Connell and Kubisch  emphasisMost papers failed to explicitly discuss the results of the ToC in relation to unexpected outcomes, direction of causation and mediation of effects. This is similar to the conclusions drawn by Coryn et al. who report that programme theory was not used in any meaningful way to develop evaluation questions or plan and conduct and interpret the analysis .It is interesting to note that no studies used ToC alongside RCTs as a method to unpack the programme theory underpinning the intervention. As we have noted previously, ToC holds much potential for this as RCTs alone are no longer considered adequate for the evaluation of complex health interventions .Detailed reporting of the ToC process is particularly important as definitions of ToC differ considerably . Many paTwo limitations to this review are the lack of double data extraction and the inability to effectively measure the quality of the included papers. We did extract data on a checklist of ToC components proposed by Vogel  and prinWe suggest that authors planning to report on ToC to guide the development or evaluation of public health interventions provide more detail on the ToC process to readers. In particular, it is important to make the ToC used explicit and this is usually easier in diagrammatic form. Complex ToCs can be simplified in a summary diagram with detailed ToCs provided as web appendices. This will help the reader to understand the authors’ expected pathways of change and judge their validity. In addition, it is imperative that authors describe in detail how the ToC was developed and used. This is particularly important as there is no single way to develop or use a ToC. Making the process explicit helps readers judge the credibility of the ToC and strengthen the literature in this field.We have therefore developed a checklist based on this review and the work of Coryn et al.  and VogeThe ToC approach is widespread in the public health literature. Clear reporting of the ToC process and outputs is important to improve to allow the readers a thorough understanding of the work and allows them to judge the validity of the approach. We recommend that our proposed checklist is used and refined by authors reporting the ToC approach.


It has been an interesting endeavor for us to contribute as the guest editors for this special issue. At the same time, it was a daunting task for us editors to go through each of the papers thoroughly and select only the ones which we thought were unique and matched the scope of this special edition of the journal.According to Nobel Laureate Richard Smalley (1996 Noble in Chemistry), water is the second, next to energy, among the humanity's top ten problems in the next 50 years. Water, one of the most important factors required for life to sustain on planet Earth, requires proper attention in terms of uses as well as treatments. The challenge for scientists and engineers working in the field of water is that they encounter new problems with every passing day, where the effective use of new techniques, such as tracers and modelling simulation, is becoming inevitable. The purpose of this special issue is to define the emerging water problems and possible technical solutions to the arising problems. We were interested in articles that explore various water research domains with relevant techniques and integrate in a single text the subject matter that deals with the concurrent “Emerging Water Quality Issues.” We, in principle, wanted to emphasize on topics like (i) emerging water problems in developing countries, (ii) emerging pollutants in water environment, (iii) health-related issues of water environment, (iv) water analysis tools and techniques, (v) flood-related issues, (vi) public involvement and participation, and so forth.This special issue is comprised of topics dealing with the subject mentioned above and intended for the students, professionals, and researchers working on various aspects of water quality issues. The issue seeks its impact from its diverse topic coverage revealing situations of different contemporary issues, such as drinking water treatment, microbial contamination in fresh water system as well as in sewage water, metal contamination in sediment using isotope tracers, using low cost adsorbent like rice husk, and projections of climate change in Tibetan Plateau. Various case studies have been discussed to present a cutting edge scenario of the problem, perspective, and challenges of emerging water quality issues in the present context of climate change and significant human interventions.− were present at relatively higher levels and should be remediated. The microbial levels were found to be least in the bottled water and highest in pots. This study could be used to devise better solutions for treatment and supply of drinking water in the urban areas of Myanmar.To mention a few highlights of the findings reported in the issues are as follows: H. Sakai et al. have conducted a survey of the quality of the source water and drinking water in urban areas of Myanmar; for this study two urban areas were selected and the drinking water samples were collected from a variety of sources like public pots, nonpiped taps, piped taps, and bottled waters. The overall water quality of the samples was found to be good while As and F− in the water, research in the field of microcystin is limited and its effects were not properly understood. Moreover, the study has been carried out in the third largest lake of China, Lake Taihu, which is a unique opportunity to study the effects of this pollutant in a lake ecosystem.H. Sakai et al. also conducted a study on the occurrence and distribution of microcystins in Lake Taihu, China. Microcystin is an emerging pollutant and very toxic in nature; it is reported to be carcinogenic in animals including humans. Microcystin levels correlated with COD, chlorophyll-a, and turbidity. This study is important because, unlike traditional pollutants like As or FZ. Hao et al. have checked the effectiveness of 22 different global climate models (GCMs) provided by the IPCC to predict the climate change pattern in the Tibetan Plateau. Tibetan Plateau is a very large area and almost all the models which were reviewed for their climate predicting abilities had limitations in predicting the precipitation (which was overestimated) and temperature (which was underestimated). It has been suggested that both the temperature as well as the precipitation levels in the Tibetan Plateau will increase in the next 90 years. Barring a few models, resolution of most of the climate predicting models were low and further work needs to be done in order to improve the accuracy of these models. Based on the studied models, the authors have predicted three possible scenarios of future climate in the Tibetan Plateau, A1B, A2, and B1. In A2 scenario, the greatest increase in precipitation was observed while in the least increase in precipitation was observed in the A1B scenario. This study is important, because it tests the effectiveness of different established GCMs to predict the changes in the climate of a large geographical area. The inputs from this study can be used for further improvement and development of the climate predicting models.Vedat et al. tested the effectiveness of a hybrid membrane system in removing natural organic matter (NOM); ultrafiltration membranes fortified with powdered activated carbon (PAC) were found to remove NOM more effectively than unfortified UF and microfiltration (MF) membranes. This technique also required less amount of energy as the pressure required for separation of NOM in PAC-UF was lesser than that required in MF and UF membranes. However, the problem with using PAC activated filters was the clogging of the filter pores by the deposited PAC, called membrane fouling.2+, Cd2+, and Cr2+ ions in sorption experiments. The bagasse and rice husk were phosphorylated after pretreatment with NaOH to increase their sorption capacity; it was found that these two waste materials could remove the heavy metals more effectively than commercially available ion exchange resins like Dowax. Modified rice husk took lesser time (about 20 minutes) to reach 92% removal of Pb2+, while Dowax took 90 minutes to reach the same efficiency. This study is important because it highlights the effectiveness of easily available crop waste like bagasse and rice husk in removal of heavy metals.S. Rungrodnimitchai reported a cost effective method of heavy metal remediation using raw materials widely available in their geographical locality using bagasse and rice husk to effectively sequester PbA study to determine the effects of nutrient inputs on strophic state and environmental quality of coastal ecosystem has been also included. Both TRIX (Trophic Index) and the AZCI  systems were used to assess the seasonal change in the trophic levels of the Gulf of California. In summer, an oligotrophic condition prevailed due to absence of sewage disposal into the Gulf of Mexico, while in winter there was an increase in the nutrient load of the water in the Gulf, which leads to a mesotrophic condition. Temperature variation between summer and winter in the region is high and water temperature itself varies by ~12°C between summer and winter. This difference would play an important role in the growth of phytoplanktons in the Gulf of California which also affects the overall quality and DO of the water.It is evident but worth mentioning that all the papers have been prepared by individuals who are experts in their field. Honest effort has been made to check the scientific validity, depth of study, and justification of each chapter through several iterations. We, the editor, publisher, and hard-working water professionals, have put together a comprehensive reference work with a belief that this issue will be of immense use for present and future colleagues who teach, study, research, and/or practice in this particular field.Manish KumarManish KumarGurmeet SinghGurmeet SinghTushara ChamindaTushara ChamindaPham Van QuanPham Van QuanKeisuke KurodaKeisuke Kuroda


Gastrinoma is most commonly located in the gastrinoma triangle  or in the adjacent lymph nodes. Due to the low mortality rate, it is often misdiagnosed as other diseases with similar clinical characteristics, such as a solid pseudopapillary tumor of the pancreas (SPTP). Therefore, the current study reports a rare case of gastrinoma located in the tail of the pancreas of a female patient under medical examination, who exhibited no clinical symptoms. The tumor, which was located in the body and tail of the pancreas, was successfully resected and the spleen was preserved. The outcome of surgery combined with the postoperative pathological examination resulted in the patient being misdiagnosed with a SPTP. During the consequent six-year follow-up period, low-density liver lesions and an intractable peptic ulcer gradually appeared. Finally, the patient diagnosis was confirmed as a malignant pancreatic neuroendocrine carcinoma with liver metastases. On June 1, 2011, a liver transplant was successfully performed and the patient has maintained a good overall condition. The underlying clinical and pathological factors that may have resulted in misdiagnosis are investigated in the present study. Through providing our preliminary clinical experiences and lessons, the aim of the present study was to focus the attention of clinicians on this type of cancer in order to improve its diagnosis and treatment. Gastrinoma is a type of neuroendocrine tumor with an incidence of approximately one to three cases per year for every 1,000,000 individuals  and a fiOn December 15, 2006, a 39-year-old female was admitted to the Anhui Provincial Hospital  following the observation of a pancreatic body and a tail lesion in an annual periodic health examination. The patient had not experienced any discomfort and was hemodynamically stable. A benign abdominal examination was conducted and all of the blood and biochemical parameters were within their respective reference ranges. The family and personal medical histories were unremarkable. Written informed consent was obtained from the patient for publication of the present study and any accompanying images. Enhanced computed tomography (CT) revealed a cystic mass in the pancreatic body and tail . ConsideThe current study presents a rare case of a female patient with malignant pancreatic neuroendocrine carcinoma with liver metastases, who was initially misdiagnosed with SPTP. The potential underlying clinical and pathological factors that may have led to misdiagnosis are analyzed and listed in the present study.First, the majority of gastrinomas are located in the gastrinoma triangle (comprising of the duodenum and the pancreas) or in the adjacent lymph nodes , whereasSecondly, it is known that gastrohelcosis and diarrhea are common first signs of a gastrinoma, particularly in non-functioning cases, while SPTP are generally characterized in young females with no clinical symptoms prior to the onset of the illness, negative tumor markers and without a history of peptic ulcers . CombineThirdly, pathological assessment is the most reliable diagnostic basis and considered to be the gold standard. However, it is worth noting that the characteristics of hematoxylin and eosin (H&E) staining with gastrinoma and solid pseudopapillary tumors are similar and may be confused, even when specific typical immunohistochemical indicators, such as Syn or CgA , are obsFinally and most significantly, a monism, rather than pluralism, approach is required to diagnose the disease. The patient in the present case experienced intractable recurrent peptic ulcers and multiple low-density liver lesions developed continuously during the postoperative follow-up period. If clinicians are able to connect these novel conditions with previous surgical history, it may allow a correct revised diagnosis to be obtained promptly following surgery.Therefore, a serious misdiagnosis emphasizes the requirement for a more accurate differential diagnosis of such a rare case of a disease without a typical clinical manifestation. The aim of the present study was to focus the attention of clinicians on this disease in order to improve its diagnosis and treatment to a certain extent.In conclusion, pancreatic gastrinoma should be carefully differentiated from SPTP during diagnosis. Immunostaining of E-cadherin and β-catenin may be necessary to aid with the differential diagnosis.