Opisthorchis viverrini and 2,661 to have CCA [Cholangiocarcinoma (CCA) continues to occur with an exceptionally high incidence in the northeast of Thailand, where it causes high levels of morbidity and mortality in the affected individuals and a high socioeconomic burden on their families ,2. It hahave CCA .O. viverrini [O. viverrini is classified as a type 1 carcinogen [In northeast Thailand, the popular cultural tradition of villagers eating raw or partially cooked freshwater cyprinid fish leads to a high prevalence of infection with the liver fluke iverrini ,5. O. vircinogen  that is rcinogen –10.O. viverrini-associated CCA have been identified, including coinfection with Helicobacter [O. viverrini are considered a significant risk factor for developing CCA [Despite taking anthelmintics to treat infections, periductal fibrosis remains. This may trigger malfunctions of the biliary system and is a risk factor for CCA, particularly when associated with such cofactors as nitrite-rich diets, smoking, and alcohol consumption ,12. Rececobacter  and diabcobacter . In addiping CCA ,10,15.Public health sectors have been campaigning continuously for the prevention and control of liver fluke since 1950, starting with a small, local effort based on education ,17. The O. viverrini [Nevertheless, the prevalence of liver fluke still reaches high levels in the northeast, although this was found to vary greatly between areas; for example, in Khon Kaen Province it ranged from 2% to 70%, and it was particularly high in the areas close to water sources (up to 40%) . In a saiverrini . The totiverrini .To date, the control programs have all focused only on primary prevention, and none have been extended to secondary and tertiary care. Between 93 and 318 cases of CCA per 100,000 people per year have been reported from Khon Kaen in northeast Thailand , with thO. viverrini-associated-CCA-free population because there is no guarantee that those who were infected with the liver fluke in the past will not develop CCA in the future [If conventional strategies are implemented that passively tackle the problem without new, proactive approaches, and if health professionals, both at the clinical and fundamental medical research levels, are not given the opportunity to expand their expertise or be equipped with the latest technology, then the rural communities of northeast Thailand will continue to suffer from this fatal disease for an extended period of time. This is because CCA is a cancer that has a slow progression; it is classified under the category of cancers associated with inflammation . Assumine future .During its early stages, CCA produces either nonspecific or no symptoms, so that a clinically significant picture only emerges during late stage disease ,29. ThisThe Khon Kaen University in northeast Thailand—a region with very high incidences of opisthorchiasis and opisthorchiasis-induced cholangiocarcinoma—has created the “Cholangiocarcinoma Screening and Care Program” (CASCAP), in collaboration with the National Health Security Office (NHSO) and the Ministry of Public Health. These organizations have launched a policy to improve the diagnosis and treatment of CCA patients systematically and evenly throughout the northeast of Thailand. This commences with the people who are at risk of developing CCA and those people who already have CCA, so that both groups can receive appropriate treatment from state public health professionals.The aim of the strategy is to provide long-term screening with follow-up to 150,000 members of the at-risk population (approximately 20 million in Thailand) in order to diagnose precancerous changes to the biliary tract and liver, such as periductal fibrosis and fatty liver, as well as early stage CCA that is accessible by curative treatment . An exteScreening will be carried out both by members of the medical faculty in the Departments of Radiology and Surgery at Khon Kaen University, as well as at local primary, secondary, and tertiary hospitals and clinics, after appropriate training by CASCAP members. Subjects falling within the risk group will be actively enrolled from local communities or, if an individual suspects CCA, he or she can apply for an ultrasound examination. At-risk patients with pathology will be referred for additional consultation or a repeat ultrasound after six months; at-risk patients without pathology will be asked to do a repeat ultrasound after 12 months . To dateThis public health intervention will be performed according to the principles of Good Clinical Practice—chapter two of the International Council for Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, and national laws and regulations about clinical studies. CASCAP was approved by the Khon Kaen University Ethics Committee for Human Research on February 9, 2013 (HE551404).O. viverrini eggs in stools [At present, a standard method for detecting disorders of the biliary system is the use of ultrasonography ,37. Ultrn stools ,38. ReceThis method requires expensive equipment as well as experienced staff. As the effectiveness of diagnosis may be problematic, depending mainly on the skills of the evaluators, it is essential to accelerate the mobilization of radio-diagnostic training to general physicians in public hospitals. Teleradiology is another way to help solve this problem, by substantially expanding the service areas. This requires the purchase of ultrasonography equipment with a satisfactory capacity for the diagnosis and the storage of digital information. It also enables and relies on the establishment and growth of an internet network for consultation by expert radiologists. A preliminary screening system conducted by suitably trained health professionals is an essential prerequisite for program optimization. This can be implemented by determining concrete criteria that are necessary for identifying those people deemed to be at risk of developing CCA. Based on epidemiological data, people with a history of eating raw or partially cooked fish products, who are or have been infected with liver flukes, who have family members dying of liver cancer, or who are 40 years old or older, are most likely to have CCA and fall within the risk group ,35.O. viverrini or have CCA have an as yet unrealized potential for the rapid screening of people at risk in endemic areas. The most widely studied tumor markers are carcinoembryonic antigen (CEA) and cancer antigen (CA) 19–9. Both CEA and CA 19–9 can be elevated in cholangiocarcinoma [In addition to ultrasound screening, predictive biochemical risk markers for use in detecting patients infected with arcinoma –41. Howearcinoma ,43.Recently, Yongvanit et al. reviewed the genetic progression and molecular changes in the carcinogenic pathway of liver fluke-associated CCA aimed at assessing patients at risk of developing CCA. This review also discussed the possibility of chemoprevention as a secondary prevention method to reduce the incidence of CCA and summarized  the resuA network for administering and managing CCA has been developed. This involves the integration of curative and palliative treatment focusing on reducing the rates of mortality and morbidity from surgery, with survival rate and quality of life as the key indicators. There will be four regional hospitals participating in the project: Khon Kaen Regional Hospital, Udon Thani Regional Hospital, Sunprasitthiprasong Hospital, and Maharat Nakhonratchasima Hospital. These super-tertiary hospitals will liaise with the super-tertiary Khon Kaen University Srinagarind Hospital, as the host institution, to implement activities such as the following:Developing the capabilities of surgeons, anesthesiologists, nurses handling instruments in operating theaters, nurses in the intensive care unit (ICU), and other relevant professionals involved in curative intent, palliative resection, and bypass.Developing procedures for preparing patients for surgery and palliative treatment, covering the following: (1) developing expertise in percutaneous transhepatic biliary drainage (PTBD), (2) developing expertise in the endoscopic implantation of a biliary stent, and (3) developing a method for monitoring and evaluating the therapy provided to the patients afflicted with CCA for curative intent, palliative resection, and bypass.All of these super-tertiary hospitals are of international standard in terms of personnel, diagnostic and clinical equipment, and procedures. All will collaborate to form a network. When this cooperation has been developed, networking will be extended to other hospitals. For example, Udon Thani Regional Hospital will expand the network in the upper northeast of Thailand, Khon Kaen Regional Hospital has an existing network with hospitals in the central northeast, and Sunprasitthiprasong Hospital and Maharat Nakhonratchasima Hospital will build a network with general hospitals in the lower northeast. The network will eventually cover the entire northeast of Thailand. The CCA therapy network hierarchy is detailed in The following is a list of expected outcomes and dissemination mechanisms for the transfer of information: (1) develop guidelines for screening among the at-risk population; (2) develop guidelines for early diagnosis, pre-operative preparation, curative therapy, and palliative therapy based mainly on the quality of life; (3) establish CCA therapy networks in 20 provinces across the northeast, with the five large hospitals providing core support as hosts; (4) develop a system for effectively monitoring and evaluating the screening and therapy programs of the patients to ensure the continuous development of the service system; (5) develop the ability to increasingly detect more patients at the early stage of CCA development; (6) improve outcomes of treatment of the cases—complete cure, a longer life, and a better quality of life; and (7) achieve the goals of the National Health Policy for CCA management.As noted above, surgery is the only effective curative treatment for CCA, with major liver resection being necessary for intrahepatic CCA and either major resection or bilio-enteric reconstruction for perihilar CCA. It is thus critical to empower surgeons in all aspects of disease management. This can be done by education, forming the right attitude toward this disease, motivation, and building morale. Training to increase knowledge of new techniques for liver surgery, web-based networking to support both clinical and inspirational aspects, and encouraging young surgeons to actively participate in addressing the burden caused by this problem are all important.The hospital networking system is hierarchical, with the five super-tertiary hospitals providing the final diagnosis and treatment for patients referred from the primary screening program. The volume of patients arriving, now that the diagnosis of early stage cancer is possible, is increasing so that additional staffs are required and must be trained. Each of the super-tertiary hospitals involved in CASCAP has the capability to train surgeons and nurses in the techniques required for liver resection, post-resection care, and follow-up. This can be made a priority in these institutions.New surgical guidelines alone are not sufficient to increase the cure rate of this disease. Currently, the diagnosis of cholangiocarcinoma needs to be confirmed by the results of a pathology test. This approach also provides doctors with guidelines for appropriate treatment procedures, namely chemotherapy alone or combined with radiotherapy. In order to extend the joint support line at this point, there must be an increase in the number of trained pathologists available. Additionally, clinical trials should be implemented and accelerated in order to obtain more empirical evidence on the chemotherapy regimens for an improved response against the cancer, at a cost that is feasible for the direct medical reimbursement scheme of the Ministry of Public Health in Thailand. It is widely accepted that for cancer treatment, more than one pharmaceutical product, each related to a different mechanism of action, should be applied, with the aim of achieving synergistic effects. These clinical practice guidelines need to incorporate aspects of pathology, oncology, and radiology. The Thai government recently earmarked 430 million baht (approximately US$12 million) for CASCAP over the next five years.Because the progress of CCA can be tremendously diverse among patients, in terms of gross- and histopathological-type, and in-depth studies have shown that the activation of genes can also vary greatly, it is difficult to identify a specific tumor marker for CCA. This is unlike certain other cancers, such as hepatocellular carcinoma that has alpha-fetoprotein (AFP) and prostate cancer that has the tumor-specific prostate marker (PSA), to name a couple. Consequently, researchers at the Liver Fluke and Cholangiocarcinoma Research Center of Khon Kaen University are continuing their efforts to discover new tumor markers that are highly effective in assisting with the diagnosis of CCA. This development is based on a variety of scientific methods; for example, the patterns of protein or gene expression in CCA tissues, or the production of monoclonal antibodies that are specific for CCA. High throughput approaches to identify biomarkers for CCA have recently been reviewed . One wayAs the science of cancer therapy is developing rapidly, it is necessary to conduct targeted therapy research to add more alternative treatments and more effective treatment methods. Targeted cancer therapy is based on the use of certain drugs or substances that can inhibit the growth and spread of cancer cells by interfering with molecular functions that are specific to the growth and spread of these cells ,47. WhenO. viverrini infection by determining species-specific antigens in the urine [O. viverrini in urine (urine OV-ES assay) provide an alternative means for the diagnosis of human opisthorchiasis and facilitate the prevention and control of opisthorchiasis. The next step is to initiate the practical application of this method as soon as possible so that primary health care units or district hospitals can detect infected patients and treat them with praziquantel immediately. This should increase the effectiveness of opisthorchiasis control.One recent advance in this direction has been the development of a new method for detecting he urine . The easAlso of critical importance is an understanding of the socioeconomic aspects of CCA at the community level. Which socioeconomic groups are most commonly affected, what burden on the family and community is caused by the search for medical help and through the morbidity and mortality due to CCA, and what measures have been put into place at the community and government levels to alleviate these problems? The huge database collected by CASCAP can help in answering the first two questions and aid in developing policies for the third .O. viverrini infection and CCA.Of equal importance is an understanding of the effectiveness of the current control and prevention programs, including education via CASCAP and as part of the regional public health and school-based programs. This information will be needed in order to develop new, integrated measures to control The elimination of opisthorchiasis and CCA from northeast Thailand, no matter how effective the policy and strategies are, cannot be accomplished effectively without the collaboration of workforces from all sectors, especially the Thailand Ministry of Public Health and NHSO, as the directly responsible bodies. Advanced study centers affiliated with a university as the main coordinating organization will be established to conduct specific research and to pass on knowledge to operational health professionals in the region. A specific requirement is that the public should be well aware of this problem and that they should be willing to cooperate with the medical authorities. Most importantly, it is imperative that willingness, sincerity, and determination to solve this problem are at the forefront of this enterprise. As such, liver fluke infection and cholangiocarcinoma could disappear as major health problems from the northeast and, in due course, from Thailand and neighboring countries.


Strategic noise mapping provides important information for noise impact assessment and noise abatement. However, producing reliable strategic noise mapping in a dynamic, complex working environment is difficult. This study proposes the implementation of the random walk approach as a new stochastic technique to simulate noise mapping and to predict the noise exposure level in a workplace. A stochastic simulation framework and software, namely RW-eNMS, were developed to facilitate the random walk approach in noise mapping prediction. This framework considers the randomness and complexity of machinery operation and noise emission levels. Also, it assesses the impact of noise on the workers and the surrounding environment. For data validation, three case studies were conducted to check the accuracy of the prediction data and to determine the efficiency and effectiveness of this approach. The results showed high accuracy of prediction results together with a majority of absolute differences of less than 2 dBA; also, the predicted noise doses were mostly in the range of measurement. Therefore, the random walk approach was effective in dealing with environmental noises. It could predict strategic noise mapping to facilitate noise monitoring and noise control in the workplaces. Noise pollution has become a global issue over the past half century because chronic noise exposure induces hearing loss and tinnitus in some individuals and affects their quality of life –3. It inIn current industrial practice, two-dimensional noise mapping is plotted for the workplace and used as information for preparing initial noise monitoring reports. Authorities use the noise map to identify high-noise area for conducting personal noise exposure measurements. However, the development of strategic noise mapping needs to be concerned with workplaces because current industrial practice is inaccurate and unreliable. Authorities lack concern about the utilisation of strategic noise mapping in working environments. Also, there are no standardised procedures or guidelines for developing strategic noise maps in the workplace. Undeniably, occupational noise exposure problems are increasing dramatically every year. Thousands of workers from different industries are exposed to noise levels above the threshold limits , 26. PreIn particular, field measurement is used in construction activities by selecting several critical locations, measuring the noise levels, and comparing them to the permissible levels for further preventive actions. This method is used only with existing construction activities, but it is not possible to obtain actual noise levels during the planning process, before construction activity starts . Two typIn fact, noise levels could be reduced by executing a strategic noise management during the planning process , 44. ThiThe present study introduced the use of the random walk approach for the prediction of strategic noise mapping and personal noise exposure in the workplace. Development of a new stochastic simulation framework and procedures to predict strategic noise mapping were discussed. Simulation algorithms and software interfaces were successfully programmed using the MATLAB. This approach considered the randomness of activities as well as the spatial and temporal distribution of noise levels. Interestingly, this approach was able to predict strategic noise mapping from moving machines and to simulate random movement of workers in working area for noise exposure prediction. Three case studies were conducted for data validation by comparing the prediction and measurement data. The simple prediction chart technique was used to compare the results of this approach. Most importantly, this paper revealed the accuracy, efficiency, and effectiveness of the proposed approach to enhancing current noise prediction methods.Strategic noise mapping is defined as noise maps generated by noise sources used for noise exposure assessment . The EU x and y coordinates for the location of machines, the background noise, the sound power of machines and estimating the location of the combinations of noise levels. Then, the following computational steps are used to calculate the noise levels in a mapping area:Using a computer to program the prediction framework could speed up the calculation process and plot a better visual contour map. The accuracy and precision of computational procedures are important. Asensio  pointed rik from the machine location k to the specified location i. Then, Eq  of the machine at location k.Eq  calculatThen, Eq  calculat surface , where Wi as shown in Eq , in dBA, at specified location i can be calculated from Eq .In Eq , {rk} ix and y axes. By considering the PDF in Eq   x and y In the present study, a new concept was developed by using the random walk approach with stochastic modelling to simulate the noise circumstances in a dynamic working environment. The random walk approach was applied to simulate the random movement of machines and workers in the mapping area. Mapping area: site layout, width and depth of mapping area, background noise, and working periodsBarriers: location, width, and depth of barriersStationary machines: location of noise sources, noise emission levels (Lw), and probabilities of duty cyclesMoving machines: location, width and depth of subarea, number of moving machines, noise emission levels (Lw), and probabilities of duty cyclesGroup workers: location, width, and depth of subareaThe stochastic simulation framework was established by using the random walk approach to predict a strategic noise map, as shown in X and Y coordinates vectors and a 1-meter interval between two grid points was assumed. For example, a 100 m × 70 m  mapping area with a 1-meter interval between grid points would yield a vector matrix with a size of 101 × 71. The grid points in X and Y were important for further application, where they were used to predict the noise levels for every grid point in the mapping area before plotting the noise contour. On the basis of the BS5228-1:2009 [m, n, and p represent the total number of stationary machines, moving machines, and workers in the prediction, respectively.In the initial process, the dimensions of the mapping area were used to mesh the grid points in 8-1:2009 , it was attenuation and Lreflection) due to barriers. The final step in this looping process was the conversion of the SPL into pressure and the accumulation of stationary and moving machine pressures. Looping continued until all machines were taken into the process.After completion of the initial process, the random walk simulation started the walk step from 0 to 1. A looping process on the stationary machines and moving machines was carried out to predict the SPLs on the whole mapping area. The difference in this process between stationary machines and moving machines was their positions, where stationary machines were always in a fixed position and the moving machines were always changing position randomly. The random walk approach was used to simulate new positions for moving machines with random directions and random displacements. The new random positions for every moving machine needed to be limited to their subareas as defined from the input. Furthermore, the next process was the summation of stationary and moving machine pressures to predict the overall SPL and plot a noise map for the current simulation step where the noise contour was plotted by using the linear interpolation method between the nodes. Meanwhile, the random walk approach could be applied to the prediction of personal noise exposure levels. Another looping process was carried out to predict a new position for every worker in the simulation. The noise levels were automatically obtained from the predicted SPL in that particular position and noise data was stored for predicting noise exposure levels at the end of the simulation process. Also, the noise mapping data or SPL in the current simulation step was saved. It was an iterative process, and the simulation step was increased by adding one to every new step.The last part of this framework was to calculate the LAeq for every receiving point. Thus, the LAeq was used to predict the noise map and represented the final result for this simulation process. Also, the personal noise exposure levels, including the noise doses and the time-weighted average (TWA) sound levels, could be predicted based on the working periods as defined from the input. A statistical analysis was applied in this part to compute the standard deviation, the maximum and minimum noise levels, and other noise parameters for each receiving points. The SPLs, histogram, PDF, and CDF were analysed and plotted in more detail. The PDF revealed the density of a continuous noise level distribution by considering machine duty cycles and random positions. Similarly, the CDF showed the probability distribution in multivariate random noise levels from the simulation. On the basis of the CDF, the L50 (noise level exceeded for 50% of the time), L10 (noise level exceeded for 10% of the time), and L90 (noise level exceeded for 90% of the time) could be predicted. Those are important parameters for noise monitoring. In addition, the environmental standard from DOE were incorporated to check the permissible noise level in different receiving land use categories and to assess community annoyance responses . Lastly,To increase prediction performance, MATLAB , powerfuThis section discusses the results of the case studies and compares the measurement and prediction data. It is of crucial importance to validate the accuracy of prediction data and unveil the efficiency and effectiveness of the random walk approach in noise mapping prediction. Three case studies were carried out at an oil palm mill and two construction sites in southern Malaysia. Figs An oil palm mill was selected for measurement, and the objectives of this case study were to obtain noise data for validation, plot an area noise map, and measure personal noise exposure levels from different working areas. In addition, the RW-eNMS was used to simulate a noise map. On the basis of the predicted noise map, it could obtain prediction data from the map to compare with the measurement data. The simulation of noise mapping in the oil palm mill was repeated with different simulation steps, for instance, 100, 250, 500, 750, 1,000, 1,250, and 1,500 steps. Also, every simulation step was repeated three times to obtain more prediction data with similar simulation steps for validation. The reason simulation was stopped at 1,500 steps because the simulation result had reached the steady absolute difference value. A total of 882 prediction data points were predicted in this case study. During the working day, 46 workers were exposed to noise in this oil palm mill. Hearing protection was provided to all workers, but it was observed that they did not wear it regularly. Personal noise exposure measurement was carried out in three critical subareas, as shown in the palm mill layout, namely, Group 1, Group 2, and Group 3. Most of the working activities were implemented in these subareas. Further, the dosimeter was used to measure the LAeq and noise dose percentage. The measurement was repeated four times for every subarea, and the duration of measurement was 30 minutes. Theoretically, the random walk approach assumes that workers are randomly moving and working in a subarea only, without considering that the worker moves outside the boundaries. It needed to be ensured that the measurements were conducted inside the boundary of the subarea with random movement. Hence, the average results of 1,500 simulation steps were compared with the average measurement results, as shown in The previous case study discussed the implementation of the random walk approach in the prediction of area noise map with a majority of stationary machines and personal noise exposure in a workplace. In this section, this approach is applied to predicting a noise map for earth-moving machines. In fact, random movement and the duration of work for earth-moving machines are unpredictable; so, area noise mapping methods cannot be used to obtain data for validation. Therefore, the measurements were carried out by assuming a boundary for the mapping area where the earth-moving machines were operating only inside the boundary. In other words, the measurement locations had to be around the activity, considering that no other external noise sources affected the final results. Several measurement points were selected to measure the LAeq with a duration of 15 minutes. There was a limited period for measurement because construction activity varies continuously. A short designated duration for measurement can be applied to activities with limited working period . The bacBy the same token, several noise maps with different simulation steps were simulated by using the RW-eNMS. The earth-moving machine was randomly moving under the subarea boundary constraints. After the simulation process was finished, the LAeq at the yellow dot locations were recorded, and were used to validate the measurement data at the same locations. The correlation and absolute difference graphs for both case studies were plotted for Figs In this section, the accuracy of the stochastic simulation framework compared with the prediction results of the simple prediction charts technique is discussed . The priApplying the concept of the random walk approach allowed simulation of random movement of machinery and workers to reflect the actual circumstances. This approach considered the randomness of machine emission level and duty cycles, such as "Off", "Idle", and "Full" power operating cycles. Also, the complex interaction of daily working activities was taken into consideration, including concurrent and nonconcurrent activities. Interestingly, this approach was able to predict a noise map for moving machines and occupational noise exposure levels. The results of the three case studies showed that the proposed approach was effective in predicting occupational noise levels with high accuracy and yielded small absolute difference compared with the noise levels from actual measurements. The majority of absolute differences were less than 2 dBA for 1,500 simulation steps, and the prediction accuracy increased with the increments in simulation steps. In particular, noise prediction for moving machines needed more simulation steps in the prediction process to ensure that all moving machines had possibly passed through the bounded area, so the final results could be more precise and rational. In the interim, the prediction of noise exposure levels was in the range of measurement results. Indeed, it could not represent the actual circumstances in the workplace because workers were not necessarily working for the entire period in that particular area. Theoretically, the prediction indicated the risk of noise exposure for the entire period of stay in that particular area. Noise prevention is needed if the noise exposure level is over the permissible level .The proposed approach requires the development of strategic noise mapping in order to obtain machine emission levels and mapping dimensions. Machine emission levels can be easily obtained from the measurements by applying the British Standards BS EN ISO 3744:2010  and BS IComputers accelerated the noise mapping calculation and predicted the noise maps within a short time. Yet there are some factors that might have affected the speed of calculations in this simulation framework, such as grid refinement, number of machines, number of barriers, and the simulation steps. Higher resolution of grid data slows down the simulation process due to handling large data calculation in every simulation step. The study assumed a 1-meter interval between grid points, which was enough to handle the current noise mapping prediction with tolerable simulation speed and smooth contour lines. However, if the dimensions of the mapping area are small, then the adjustment of a smaller interval grid point is needed. This is due to the effect of size of grid refinement on data accuracy and quality of the result . LikewisIn addition, implementation of the proposed approach is important to the future development of noise mapping in the workplace. Strategic noise maps are a useful managerial tool for presenting information on current noise circumstances that can be used to predict the noise levels for future scenarios . ManagemThe stochastic simulation framework was successfully implemented to predict strategic noise maps and personal noise exposure levels. The present study advanced the use of the stochastic technique in noise prediction and increased the quality of noise mapping in workplaces. This framework considered the complex interaction and randomness of noise emission from machinery. The random walk approach was facilitated to simulate the random movement of machinery and workers. Data validation for the study found high accuracy of prediction results and fast production of strategic noise mapping compared with conventional field measurement methods. Hence, simulation software could be used as a managerial tool during the planning process, where it could assist in noise control and monitoring. Eventually, this technique should be widely used in current industrial practice to provide sustainable workplaces with moderate noise levels. Increasing the awareness of workers about noise problems can be done by disseminating information on strategic noise mapping and noise risk zones to the working area.


In this study, clustering was performed using a bitmap representation of HIV reverse transcriptase and protease sequences, to produce an unsupervised classification of HIV sequences. The classification will aid our understanding of the interactions between mutations and drug resistance. 10,229 HIV genomic sequences from the protease and reverse transcriptase regions of the pol gene and antiretroviral resistant related mutations represented in an 82-dimensional binary vector space were analyzed.A new cluster representation was proposed using an image inspired by microarray data, such that the rows in the image represented the protein sequences from the genotype data and the columns represented presence or absence of mutations in each protein position.The visualization of the clusters showed that some mutations frequently occur together and are probably related to an epistatic phenomenon.We described a methodology based on the application of a pattern recognition algorithm using binary data to suggest clusters of mutations that can easily be discriminated by cluster viewing schemes. The human immunodeficiency virus (HIV) shows extensive genetic variability that helps the selection of drug resistance mutations in response to antiretroviral therapy. Hence, it is important to understand the relationship between HIV genotype and phenotype  to increase the probability of treatment success.http://algoritmo.aids.gov.br/).To infer antiretroviral resistance, look-up tables ,2 and ruIn Brazil, patients who fail on antiretroviral therapy receive genotype tests for antiretroviral resistance throughout a network of laboratories . This coOne possible way to answer these questions is to apply clustering algorithms on reverse transcriptase and protease sequences, to obtain clusters containing sequences that are similar. This similarity among the sequences may reveal some of the relationships among the mutations related to antiretroviral resistance.Nonetheless, extraction of a simple and compact representation of the dataset is complex because of the number and size of sequences. The clusters thus generated may provide a representation that contributes to the understanding of the classification and the relationships between mutations.In the present study, a pipeline , where n is the number of patterns . The timFigure The scripts created for data clustering (step 3) and cluster representation (steps 4 and 5) are available at http://www.ime.usp.br/~mcintho/.In the present study, 10,229 reverse transcriptase and protease sequences from HIV subtype B, 801 from subtype F and 424 from subtype C, were obtained from the national database. These samples were taken in accordance with the ethics standards of the Ethics Committee of the Federal University of São Paulo and with the Helsinki Declaration of 1975, revised in 1983. All biological samples were obtained in full accordance with signed informed consent forms (process number in research ethics committee 1433/09).The Brazilian Guidelines for Resistance Testing allowed only one genotype testing for each patient at the time the sequences were generated; therefore, duplication of the sequences from the same patient was not expected.To simplify the representation and comparison of the reverse transcriptase andprotease sequences, bitmap mapping was used. In this technique, if a sequence hadthe same amino acid as the wild-type sequence, it was replaced with the value zeroand when the sequence had a different amino acid, it was replaced by the value1, as previously described  represented the binary sequences featured as rows and the amino acid positions as columns: 44 columns for protease and 38 columns for reverse transcriptase. The sequences were grouped according to clusters and separated by blue lines. When a sequence had the value of 1 in an amino acid position, it would be represented by a black pixel, and when it had a value of 0, it would be represented by a white pixel. Six images were created for each value of k, combining the proteins and subtypes.The black and white pixels were useful for distinguishing the clusters, accentuating differences among them and describing them, as well as for summarizing the information within the sequences and clusters. They also helped to view the amino acid positions that represented and characterized the clusters.To provide more details about the clusters, histograms were plotted for each cluster, for protease and reverse transcriptase, showing the percentage of sequences in the cluster with mutations in each position. Each bar in the histogram represented an amino acid position and the percentage of sequences in the cluster with a mutation at that position.To compare the clusters with the look-up table used to interpret the genotypic resistance from the Brazilian algorithm for resistance interpretation, another image was generated. The HIVDAG software  was usedTo represent the three possible results, red, yellow and green were used for resistance, intermediate resistance and susceptibility, respectively. Thus, as in the binary figure, the rows featured the protein sequences and the columns were the predictions for drug resistance given by the look-up table for that sequence.In these colored images, vertical lines presenting a dominant color in each cluster indicated that the sequences in that cluster have the same drug resistance prediction. Clusters that showed red, yellow or green vertical lines in different positions indicated that there was some correspondence between the prediction of the look-up table and the K-means clusters.For distinct k values, the sequences were distributed in different clusters; black and white images were created for each combination of subtype, k value and protein. Figures K-medoids have been used in a previous study  for clusTo characterize the clusters, the histograms shown in Figures To compare the clusters with the predictions of drug resistance given by the rules in the Brazilian look-up table, colored images were created. The images from the protease clusters  and cluThus, the clusters suggested that mutations in codons 10, 54, 82 and 90, or in codons 30 and 88, in the protease are related and frequently occur together. In addition, mutations in codons 67, 70 and 219, or in codons 41, 67 and 210 in the reverse transcriptase frequently occur together. These patterns were also reported in previous studies ,16,23,25In this work, a new approach to analyzing HIV mutation data was presented. Current classification schemes are based on rule-based systems and look-up tables that comprise data from scientific studies. The proposed framework is based on a bitmap representation that extracts information from protease and reverse transcriptase sequences and provides information on the interactions among mutations.A new visualization scheme inspired by microarray data analysis was proposed to better understand the clusters in the HIV domains. The images produced were useful for viewing and comparing the clusters with binary vectors and large volumes of data. In our study, the black and white figures indicated the occurrence and absence of mutations in sequences in each cluster, respectively, thus highlighting the differences between the clusters.To represent the genetic variability of the virus in a different way from previous works, a large number of sequences and protein positions were used, along with three different HIV-1 subtypes. In the analysis, sequences were clustered, and the clusters were characterized according to the mutation patterns that they represented. The clusters were compared with those clusters revealed by previously published studies, and with the current knowledge of mutation patterns.Along with the large number of sequences and protein positions, the application of a binary representation for the sequences helped to define a simple measure of similarity. The choice of K-means as the algorithm for mutation pattern searching rendered the method suitable for larger data sets because of its time complexity. The use of the binary image also allowed the analysis of large data sets, as the information in the data is visualized more easily, as is the characterization of the clusters and the mutation patterns.K-means obtained clusters with similar sequences representing different mutation profiles, and the clusters showed that some mutations frequently occur together, which are important for defining the clusters and that are present in a large number of the sequences. These positions need to be taken into consideration when inferring drug resistance, because they affect a large number of patients.Some interesting insights came from this clustering result. Notably, mutations in protease codons only produced clusters among non-B strains. Furthermore, as described previously, mutations at codons 89 and 90 in the protease do not cluster together , suggestPathways for resistance mutations are the pathways that viruses select for resistance mutations and this is closely related to cross-resistance. TAM 1 and TAM 2 are well-defined distinct pathways for resistance, but we speculate that these are merely initiating pathways because we observed clusters for the reverse transcriptase with between three and six TAMs, thus augmenting levels of resistance and cross resistance Table . InteresOne interesting outcome from this cluster representation is their alleged relationships with previous exposure to specific antiretrovirals. In this sense, timing or the number of drug exposures, as well as the use of specific drugs, would suggest a specific selection of a cluster of mutations and imply possible resistance/cross resistance. The negative predictive value of a genotype result is low, meaning that the absence of a specific mutation or group of mutations does not mean that this mutation is not present in a minority population and is not present because of the selective pressure of current antiretrovirals being used. Therefore, the history of antiretroviral exposure and the projected profile of mutations can result in a more reliable future salvage therapy regimen.Furthermore, protease inhibitors are designed according to the structure of the proteins; therefore, the clusters may help in designing future drugs for resistant strains.In addition to antiretroviral resistance, understanding the mutation patterns is also useful in collaborative efforts to study of immune escape pathways and vaccine research. However, the HIV mutation patterns can confound the determination of the immune escape mechanisms  that areOur future work will include further validation of the clusters in the HIV domains and updating the current knowledge concerning mutations. We will also evaluate a recent approach to pattern recognition known as biclustering ,41 for t


Local and national governments have implemented sector-specific policies to support economic development through innovation, entrepreneurship and knowledge exchange. Supported by the Welsh Government through the European Regional Development Fund, The Life Science Exchange® project was created with the aim to increase interaction between stakeholders, to develop more effective knowledge exchange mechanisms, and to stimulate the formation and maintenance of long-term collaborative relationships within the Welsh life sciences ecosystem. The Life Science Exchange allowed participants to interact with other stakeholder communities , exchange perspectives and discover new opportunities.Six sub-sector focus groups comprising over 200 senior stakeholders from academia, industry, the Welsh Government and National Health Service were established. Over 18 months, each focus group provided input to inform healthcare innovation policy and knowledge mapping exercises of their respective sub-sectors. Collaborative projects identified during the focus groups and stakeholder engagement were further developed through sandpit events and bespoke support.Each sub-sector focus group produced a report outlining the significant strengths and opportunities in their respective areas of focus, made recommendations to overcome any ‘system failures’, and identified the stakeholder groups which needed to take action. A second outcome was a stakeholder-driven knowledge mapping exercise for each area of focus. Finally, the sandpit events and bespoke support resulted in participants generating more than £1.66 million in grant funding and inward investment. This article outlines four separate outcomes from the Life Science Exchange programme.The Life Science Exchange process has resulted in a multitude of collaborations, projects, inward investment opportunities and special interest group formations, in addition to securing over ten times its own costs in funding for Wales. The Life Science Exchange model is a simple and straightforward mechanism for a regional or national government to adapt and implement in order to improve innovation, skills, networks and knowledge exchange. Following the creation of the National Assembly for Wales in 1998, the devolved Welsh Government (WG) has instituted a string of innovation initiatives in an attempt to invigorate the Welsh knowledge-based economy .have met with varying levels of success, and, interestingly, the most prominent approaches have been, on the whole, less successful in Wales” [Many strategies exist for carrying out knowledge exchange within the life science (LS) sector, yet there is a lack of real-world application and evaluation of these interventions in the context of academic engagement and commercialisation . Interven Wales” . Successn Wales” .In March 2012, the WG launched ‘Science for Wales’ , which sIn September 2012, Swansea University Medical School, in partnership with Cardiff University School of Medicine and MediWales , was tasked by the WG to lead a knowledge exchange project (KEP) for the Welsh Life Sciences and Health Grand Challenge priority area called The Life Science Exchange® (or LSX). The aim of the KEP was to increase interaction, develop more effective knowledge exchange mechanisms, and stimulate the formation and maintenance of long-term collaborative relationships between industry and academia.The LSX was created as a process, not an organisation. The vision was to create a mechanism which could continuously network all the stakeholders in Wales’ complex LS ecosystem, in a way that allowed all to be involved. The objective was to allow participants to interact with other stakeholder communities , exchanging perspectives, and then to support them by thinking about how Wales could improve its performance. To provide focus, the work was streamed into groups representing six of Wales’ specialist areas , which were selected to encompass the 12 LS areas prioritised in ‘Science for Wales’ policy.The LSX project was designed with a goal of having real world impact by supporting knowledge exchange, policy development and collaborative projects. The aims of this article are to articulate the methodologies used by the LSX project, provide case studies of collaborative projects identified and facilitated, and suggest how these methodologies could be applied to other sectoral or regional innovation systems.In line with best practice for knowledge management projects , the LSXThe LSX team comprised four staff members who provided overall project administration. Beyond planning, organising and documenting the focus groups and sandpit events, the team provided bespoke support to LSX members, including answering general inquiries regarding the Welsh LS sector, making introductions, identifying potential funding streams for collaborative projects, assisting with grant applications and mapping of the sector.Given the aims, participant profiles and number of participants as well as the relatively informal manner in which discussions were held in these sessions, they were not ‘focus groups’ as understood in qualitative research. However, using the term ‘focus groups’ during and after the project allowed both participants and non-participants to quickly understand the activities that were being undertaken. After the end of the LSX project, some of these groups continued to meet and were more properly referred to as ‘special interest groups’.For each of the six specialist areas, a focus group was established which aimed to include participants from academia, industry, the WG, industrial networks and NHS Wales. The project was funded with £181,553, of which a majority  was used to support the staff organising the network communications and events over the 18-month project. Once the staff were recruited, they organised the branding, communications and organisation of the first focus groups to be held. The project team adopted an open and inclusive recruitment process for the groups. The LSX was widely publicised across the sector through established networks , MediWales, NHS Health Boards), as well as by using phone calls, e-mails, face-to-face meetings, social media (e.g. LinkedIn and Twitter), leaflets and other networking events. Additionally, the project team engaged in sector research early into the project to target individuals and organisations. The aim of this was to give all the major sector stakeholders a fair chance to feed into the process and to create groups that covered the interests of their specialist area as broadly as possible.Each partner institution chaired two focus groups on a quarterly basis. The purpose of the focus groups was to act as the primary information gathering mechanism for the project – primarily for developing policy recommendations, performing a knowledge mapping exercise and to promote collaborative working across the sector. Members of the group were invited to regular, facilitated discussions which captured stakeholder perspectives on the strengths, weaknesses and opportunities for growth across the LS sector. As well as taking this broad approach, specific focus groups also identified areas that were unique to their field of interest.Focus group attendance ranged from 10 to 40 stakeholders, depending on the subsector, time of year, availability of the individuals, and geographic location of the meeting. The focus groups were audio-recorded and transcribed, which provided a meticulous and robust capturing method whilst allowing the project team to focus on the discussions , ChathamAs the groups developed, the members were encouraged to consider which interventions might be put in place to counteract sector weaknesses and capitalise on existing strengths. An outcome of each focus group session was a detailed record of the main conclusions that had been agreed upon. These were used to inform the final summary and subsector reports which were produced and circulated to WG’s Departments of Economy, Science and Transport and of Health and Social Services to consider for action.For example, towards the end of the project, the Regenerative Medicine focus group had the objective to critically consider a strength, weakness, opportunity and threat (SWOT) analysis of the regenerative medicine landscape within Wales in order to produce a final recommendation for future development of this sector across the academic, clinical and commercial Welsh research landscape. A one-day focus group was organized in Cardiff, bringing together representatives from across the academic, clinical and commercial regenerative medicine settings. To position thinking in a wider United Kingdom context, initial presentations from Innovate UK (formerly the Technology Strategy Board) and Cell Therapy Catapult were received. This was followed by a comprehensive update of the findings from previous LSX Regenerative Medicine focus groups to that point in the form of a SWOT analysis. Break out groups then considered, in detail, shortfalls, problems and solutions to stimulate the regenerative medicine sector in Wales. Feedback was collected and outputs produced for feedback to the LW KEP management board.The project team and stakeholders instigated a knowledge mapping exercise of their respective specialty areas similar to the process described by Ebener et al. . The proScoping: The knowledge mapping exercise began by identifying potential data sources. The project partners provided the LSX project team access to a range of existing networks and also knowledge bases of the sector. These included academic centres and NHS research and development centres, as well as Welsh government and industrial contacts. The project team then cross referenced these sources.Data collection: Information was gathered from the data sources identified during scoping.Validation: Verification checks were made by team members to ensure the information supplied was accurate.Collation: The mapping was collated by both the LSX project team and MediWales and presented in both visual and database formats suitable for searching by keyword.Gap analysis and review: The mapping was reviewed by all the focus groups and also peer examined by other academic, NHS, industrial networks and WG Expertise Wales. Any gaps identified were addressed to ensure the final mapping was reflective of the sector.Knowledge mapping was performed to provide a comprehensive visual map and database of expertise and facilities across academia, NHS and industry relevant to each sub-sector within Wales. The mapping was undertaken using a five-step process:The databases contained the names, affiliated institution, contact information, web-link and a short description of the individual/group expertise which could be probed by keyword. Academic researcher and medical team data was gathered from institute websites and email contact with departmental leaders. Industry data was compiled from MediWales’ Picture of Health , online The LSX engaged in a series of half-day sandpit events which came about in response to opportunities raised through the focus groups. Sandpits were originally designed by the United Kingdom Research Councils as a residential interactive workshop over 5 days involving 20–30 participants with a multidisciplinary mix of participants to drive lateral thinking and radical approaches to address research challenges . The proOne example of the sandpit approach was focused on the objective of ‘developing approaches to address unmet needs in the area of managing chronic illness in ageing’ within the Medical Technology group. This event was a collaborative opportunity for leading academics, medical practitioners, service managers and industry representatives in Wales to consider which chronic diseases were not met within the NHS, where expertise may exist in Wales and whether participants in the sandpit were collaboratively equipped to enable a technology to manage a met condition better or address an unmet disease. The purpose of the first part of the sandpit was to familiarise the group with the participants on the day, their interests and background, and to define a list of 10–12 illnesses that cannot be cured but can be managed. The sandpit participants, in multidisciplinary groups, then examined this list to consider the expertise, experience and interests of the group to explore the opportunities to create collaborative proposal(s) for future work. The final part of the sandpit was looking at scoping initial collaborative ideas to address the objective of the event and presenting them. The 40 participants were drawn from across academia, industry and the NHS in Wales and worked together in small multi-disciplinary teams to maximise shared experience and knowledge with the aim of generating creative solutions to known issues through partnership working. By the end of the day the participants explored their interests in collaborating with a number of different groups/individuals with the outcome of championing a single idea in a multi-disciplinary group for onward funding proposal preparation and work. This sandpit led to the preparation of funding proposals as an output.The LSX project was able to support the Welsh LS sector by a range of mechanisms. These activities resulted in a variety of outcomes for the sector, including detailed policy recommendation reports delivered to the WG, a codified mapping exercise of the LS sector in Wales, and a range of collaborative projects.A global overview of the opportunities identified in the focus groups have been categorised into seven major themes – each opportunity represented by a mark in Table There was a recognised need for the discussions instigated by the LSX to continue into the future. A number of organisations expressed the desire to maintain the momentum of their respective focus groups as special interest groups.The need for an accessible, cost-effective, up-to-date source of sector-specific information relating to funding, regulation, international trade and market intelligence has been consistently expressed by the stakeholder focus groups. This represents a significant and ongoing opportunity to provide Welsh LS organisations with a valuable resource offered in addition to what is (and is not) available.The vital role that the Welsh NHS plays in providing access to clinical expertise, facilities and, ultimately, as a customer was widely expressed. While the relationship between the NHS, academia and industry in Wales is considered to be a significant national strength, there was an expressed need to improve the evaluation and adoption of new Welsh innovations when they can demonstrate the opportunity for improved patient outcomes and cost savings. Furthermore, academics and industry expressed a strong desire for NHS Wales to increase its level of engagement and receive clinical access for research and development.A key driver for future success is the ability to attract and retain highly skilled individuals. Whilst the higher education sector can focus on the development of training and, where feasible, accredited education in key skills, retention requires growing industrial small and medium enterprise clusters to provide sustainable employment opportunities across Wales. An all-Wales LS skills group consisting of key academics has organised discussions on delivering apprenticeships, continuous professional development and degree-level training in close collaboration with WG, NHS Wales and LS industry.Stakeholders felt that significant strengths in Wales’ LS research activity have been demonstrated across the entire Welsh LS sector. They recommended that, in order to build upon these strengths, further support through provision of facilities and resources was required to close specific gaps in research capacity.The focus groups also made a strong case for ongoing support for international trade and promotion. Most LS sector products occupy global markets and numerous Welsh companies sell the majority of their products outside of Wales. To support this activity, focus groups requested continued or additional support to attend trade shows and conferences.A second outcome was a stakeholder-driven knowledge mapping exercise for each area of focus. Many examples of duplication of activity as well as underutilisation of resources were identified. In some instances, businesses were paying to utilise resources outside of Wales due to a lack of awareness of resources existing locally..).The outputs of the knowledge mapping exercises for each focus group were represented in various formats, including a database of key figures, lists of key organisations, process diagrams, organisational charts and maps. For example, the eHealth focus group produced a database outlining key individuals in WG, learned societies, industry, academic departments, and research facilities. This database included institution and/or department names, named individuals, websites and contact details which were publicly available. The eHealth group also created a set of PowerPoint slides containing organisational charts of academic, WG, NHS Wales and third sector organisations. Similarly, the Regenerative Medicine focus group produced a database containing academic, commercial and NHS Wales networks and facilities. As the group was research-focused, they also created an organisational chart of regenerative medicine research by technology type , Abertawe Bro Morgannwg University Health Board (ABMUHB)£772,208: WG, Health Technology and Telehealth Fund AliveCore, ABMUHB£50,000: Welsh Government Academic Expertise For Business Digital Health Conference£40,000: Betsi Cadwallder SBRI SymlConnectAlthough funded with only £181,553, the LSX project was able to secure over £1.66 million pounds of project funding for its participants through the sandpit events and bespoke support:Beyond quantitative financial outputs, a range of case studies have been provided below in order to describe the types of outcomes the LSX was able to accomplish beyond the focus groups and knowledge mapping. Such outcomes included the piloting of new procurement mechanisms, securing grant funding for a commercial clinical trial, establishment of new special interest groups, and the formation of an all-Wales LS Skills Group, among others.One of the projects the eHealth group identified was the 3-year SBRI, funded by Innovate UK, which aims to boost the research and development industry, increase commercialisation of new technologies and create jobs and wealth. A project to improve ABMUHB, in partnership with Swansea University, has received £800,000 funding towards their £950,000 project to support health services in Swansea, Bridgend and Neath Port Talbot through the better use of patient records and data.2) and WG.The SBRI project came about following discussions in an eHealth focus group, which was led by a member who had prior experience of undertaking SBRIs outside of Wales. Also at that meeting was the manager from the eHealth Industries Centre in Swansea University, who subsequently identified the SBRI opportunity and engaged with ABMUHB. ABMUHB identified a challenge and were extremely receptive and supportive of the SBRI process. The eHealth group then discussed the opportunity and many attended the two events hosted by LSX with eHealth Industries Innovation Centre  provide a faster more streamlined service to their customers, (2) to create new business opportunities, and (3) to deliver a complete clinical trials service and to support their customers’ needs through a strong referral network. Following this launch, the Members will work together to deliver on a commitment to provide a more integrated streamlined service, saving customers time and money, and delivering the highest quality of service. The Group will work together to extend each organizations visibility on the world stage through promotion at international events, press coverage and online. Each individual organisation will act as a referral point to all of the members of the Group.This ‘sub-sector’ approach is now being rolled out to create a medical technology and diagnostics special interest group led by MediWales.Within a diagnostics focus group, skills for the sector were identified as an area where development was required. The LSX project team subsequently met with representatives from Cogent, the Sector Skills Council for Life Science, as well as WG’s Department for Education and Skills and Department of Economy, Science and Transport. There was a level of involvement from the Sector Skills Council for Science, Engineering and Manufacturing Technologies, University of South Wales and the Regional Learning Partnership.An all-Wales LS skills group organised discussions on delivering apprenticeships, continuing professional development and degree-level training in close collaboration with WG, NHS Wales and the LS industrial sector. The group, now chaired by a representative from Swansea University Medical School, has been recognised by the WG for its proposed work on the LS skills agenda and aims to represent the needs of the growing sector in this arena.The LSX project delivered extensive engagement with the Welsh LS sector in order to provide authentic insight into the strengths, challenges and opportunities for Wales. The significant contribution made by representatives from the Welsh LS academic, industrial and clinical organisations has culminated in the final reports of the LSX project.Detailed conclusions have been made by each of the sector focus groups, with a number of common and unique themes across all of them. Based on the varying outputs of recommendations by each focus group, it is clear that each of the specialties has different needs. The stakeholders in the Neuroscience Group appeared to be more active in earlier stage research and development and recognised opportunities in enhancing Wales’ neuroscience research capacity. Those that have more of an industrial base  focused their attention on NHS engagement, procurement and technology adoption. All of the summarised opportunities found in Table The detailed reports have been supplied to the WG’s LS Sector Team to inform policy and strategy; however, it is unclear just how effective these recommendations will be until future policy is implemented. They were also made available to key stakeholders by the WG upon request. These recommendations provide the best opportunity for the sub-sector groups to progress their work as they provide the unified view of the current state of the Welsh LS sector and how it should be improved in their areas of speciality. In current discussions with stakeholders, these recommendations are being used to inform research and funding applications, especially in the establishment of new special interest groups, growing a skilled and trained workforce, and enhanced research capacity (i.e. equipment and facilities).The value of the exercise is difficult to quantify, though recipients of the mapping have utilised it to inform new academic- and industry-based knowledge sources of their own. It could be stated that the exercise provided a clearer sector picture of a diverse range of mapping and knowledge already in existence and therefore gave organisations who received it an up to date and accurate ‘snapshot’ of the LS sector in Wales for others to build on. In a fast moving sector this was as much as could be expected as the accuracy and completeness of any mapping exercise lessens as time passes.The knowledge mapping exercises were supplied to the WG’s LS Sector Team to inform policy and strategy. The maps were developed to cover four constituent areas, those being academia, industry, NHS and Government . These maps were then focused further on the theme  to provide a snapshot of subsectors of LS in Wales. They were made available to NISCHR, LSX participants, LS Hub Wales and key stakeholders by the WG upon request. MediWales has since utilised the mapping to inform their ‘Picture of Health’  interactHowever successful, a major drawback of the LSX was the short 18-month time frame and limited budget to carry out its operations. The timeline and budget was solely based on the project obtaining funds from the end of the European Regional Development Fund structural funds programme running from 2007 to 2014. Following the end of the project, further actions were required to ensure its legacy was exploited. The subsector focus groups were able to codify their detailed reports and mapping exercises by the end of the project. However, without the project staff to organise the network after the report submissions, there was very little that could be done by the LSX support staff to ensure the policy recommendations were addressed by the WG. Furthermore, it was difficult to resource collaborative projects identified towards the end of the project, as there was a risk of leaving them without support. If LSE had been funded for a longer period of time or refunded after the initial period, the project could have had more impact on the LS sectoral policy in Wales. As a recommendation, sustainability and/or continuity planning should be performed at the beginning of projects such as the LSX in order to ensure that value in the personnel, networks and project(s) are not lost between funding rounds.The LSX was focused on supporting the LS sector in Wales in a subsector approach. Notwithstanding this, the framework could be applied to a very wide range of other (sub)sectors and/or regions. Simply setting up a knowledge exchange mechanism similar to the LSX would not necessarily result in successful or similar outcomes – each sector and region has its own particularities that would need to be considered. For example, although two other KEPs were funded by the WG concurrently to the LSX, they did not follow the same governance and methods. Instead of holding focus groups, the Materials and Advanced Engineering Knowledge Exchange Strategy KEP determine the sector’s barriers and opportunities compared to 30 companies outside Wales. Through these methods, this KEP was able to secure two Knowledge Transfer Partnerships valued at £129,000, placed about £500,000 in collaborative grant applications and created a range of Masters-level studentships with industry. The Low Carbon Energy and Environment Network for Wales KEP used a mixture of workshops, surveys and research to report on the major barriers and opportunities for the low carbon energy and environment sector in Wales; yet it is unclear how successful their model was in producing collaborative projects.The implementation of a successful knowledge exchange programme requires a number of factors to be in place. First and foremost, a relatively active sectoral innovation system is needed to ensure enough stakeholders can contribute to the process. Secondly, project leaders need to have relatively established networks in place to ensure effective and timely recruitment. Thirdly, dedicated staff and an event budget are needed to ensure the network is able to communicate, meet regularly and synthesise their knowledge. Finally, in order for meaningful and innovative collaborative projects to be supported beyond the conception stage, robust funding mechanisms are required (e.g. Innovate UK or the United Kingdom Research Councils).The output of the LSX is a valuable body of intelligence that represents the collective expertise of a wide range of expert contributors. This work should serve to inform future policy and planning across the sector and will help to align support activities with the needs of companies, universities and healthcare providers. Specific, actionable recommendations have been provided in the detailed reports provided by the LSX to the WG. Ultimately, this work should be used to improve innovation, health and wealth in Wales, as well as influence the design and implementation of knowledge exchange mechanisms in other geographies and sectors.There was a recognised need for the discussions instigated by the LSX to continue into the future. In some cases, specific challenges and opportunities need to be crystallised into detailed proposals with specific objectives, deliverables, budgets and time-scales. A number of organisations have expressed the desire to maintain the momentum of their respective focus groups as special interest groups operating under the LSX brand or unique branding .The LSX process succeeded in bringing together hundreds of stakeholders in a sub-sectoral approach to the Welsh National Innovation System. This has resulted in a multitude of collaborations, projects, inward investment opportunities, and special interest group formations, in addition to leveraging over ten times its funding for Wales. Processes such as the LSX can be considered exemplars of best practice for knowledge exchange for other sectoral systems of innovation. The LSX model is a simple and straightforward mechanism for any regional government to adapt and implement with the hopes of improving innovation, skills, networks and knowledge exchange.


Despite the implementation of various initiatives to address low enrollment in voluntary micro health insurance (MHI) schemes in sub-Saharan Africa, the problem of low enrollment remains unresolved. The lack of process evaluations of such interventions makes it difficult to ascertain whether their poor results are because of design failures or implementation weaknesses.In this paper, we describe a process evaluation protocol aimed at opening the ‘black box’ to evaluate the implementation processes of the Redesigned Community Health Fund (CHF) program in the Dodoma region of Tanzania.The study employs a cross-sectional mixed methods design and is being carried out 3 years after the launch of the Redesigned CHF program. The study is grounded in a conceptual framework which rests on the Diffusion of Innovation Theory and the Implementation Fidelity Framework. The study utilizes a mixture of quantitative and qualitative data collection tools , and aligns the evaluation to the Theory of Intervention developed by our team. Quantitative data will be used to measure program adoption, implementation fidelity, and their moderating factors. Qualitative data will be used to explore the responses of stakeholders to the intervention, contextual factors, and moderators of adoption, implementation fidelity, and sustainability.This protocol describes a systematic process evaluation in relation to the implementation of a reformed MHI. We trust that the theoretical approaches and methodologies described in our protocol may be useful to inform the design of future process evaluations focused on the assessment of complex interventions, such as MHI schemes. There is a growing body of evidence from resource-limited countries on the potential of micro health insurance (MHI) schemes to advance progress toward Universal Health Coverage, thanks to improved access to care and reduced out-of-pocket spending –9. The cAcross SSA settings, there have been efforts to overcome the problem of low enrollment –23. HoweThe Community Health Fund (CHF) model in Tanzania represents a form of district-based MHI scheme. CHFs are voluntary prepayment schemes whereby households pay flat-rate contributions set by each district based on the community's ability to pay. Premiums range from US$3 to US$18 , and theLike other MHI schemes, CHFs have repeatedly been found to attain penetration rates which rarely exceed 10% , 17. LitTo address low enrollment in CHF, multiple interventions have been implemented across districts. These initiatives have received support from various stakeholders, ranging from international donors (such as the Swiss Agency for Development and Cooperation (SDC) and Deutsche Gesellschaft für Internationale Zusammenarbeit (GIZ) to nongovernmental organizations ), as well as various local cooperative unions , 30. TheThere has been a limited effect of the aforementioned initiatives on enrollment , 21, 31.Literature attests to the importance of comprehensive evaluation studies that explicitly link implementation processes to program outcomes –34. ThisIt follows that process evaluations offer potential to describe the mechanisms through which a given intervention produces certain outcomes, documenting both expected and unexpected effects. In particular, process evaluation focusing on a Fidelity of Implementation (FOI) approach, that is, evaluations focused on ascertaining whether a given program has been implemented as intended, provide additional explanations in relation to the intervention outcomes, as it has been demonstrated that FOI mediates outcomes , 34. FOIIn this paper, we describe a process evaluation protocol aimed at evaluating the implementation of the Redesigned CHF in the Dodoma region of Tanzania. Our study follows the implementation of the scheme for its first 3 years. Specifically, our study examines the extent of adoption (including the stakeholders’ response to the intervention) and FOI as well as the factors that influence the two, in the light of the scheme sustainability.2 with a population of 2,083,588 people  and the Micro Insurance Academy (MIA), aims at enhancing enrollment by strengthening structures and creating new motivation for people to join the scheme. Vodacom Tanzania supports the Internet and communication services for the data management system.The intervention builds on the results of a situational analysis of the former (standard) CHF program which revealed structural problems . The majTo address the problems listed above, the Health Promotion and System Strengthening (HPSS) project developed the Redesigned CHF program which includes: 1) a comprehensive re-organization of the CHF structures to clearly distinguish the purchaser (CHF) from the provider  function; 2) installation of an Insurance Management Information System (IMIS) to empower the CHF with a comprehensive data management system that includes membership enrollment through mobile phone technology, contribution management, claim processing and payment, as well as member feedback collection; 3) a close-to-client enrollment strategy, which relies on enrollment officers (EOs) recruited at the village level; 4) active community sensitization and mobilization campaigns on CHF; and 5) review of the CHF benefit package, expanding the range of services to include hospitalization and portability of cards within the region. To participate in the Redesigned CHF program, the seven districts of the Dodoma region signed an agreement with HPSS project and adopted the CHF Standard Operation Procedures (SOP) manual.The Redesigned CHF operations are implemented at four levels and comprise the community members (level one), village implementation teams (level two), district implementation teams (level three), and regional-level actors (level four). Village implementers (Village executive officers (VEOs) and EOs) work directly with the community either to handle enrollments or to mobilize people to enroll in the scheme. The district council with its CHF board, CHF management team, and CHF officers has the full responsibility for implementing the scheme in the area of its jurisdiction. Technical backstopping to the districts is provided by regional-level actors through the HPSS project regional advisory board (RAB). Chaired by the regional administrative secretary, the RAB has members from central government, the regional secretariat, representatives of each of the districts, and other stakeholders with a stake in Redesigned CHF, such as SDC and NHIF. Political leaders at all levels are expected to motivate people to join the scheme.This study relies on a conceptual framework  that is The Diffusion of Innovations Theory addresses the complexity of getting innovations diffused into a community. It distinguishes four phases – dissemination, adoption, implementation, and sustainability – as crucial steps to the adequate diffusion of innovations , 44, 45.The FOI Framework  providesIn our conceptual framework, we use constructs from the two theories above to understand the implementation processes of the Redesigned CHF program. We combined the two theories as we aim to be comprehensive in identifying both the issues related to the adoption of the program and to its actual functioning as a health insurance scheme. This study defines the implementation process as a continuum from adoption through FOI to sustainability of the program processes.In our study, we define adoption as the degree to which the intervention is integrated in the beneficiary organization structures and is practiced by them as the best course of action available to improve enrollment in CHF. In the course of understanding adoption, the study also attempts to understand whether there is rejection (active or passive) to the intervention. We define implementation as the way the Redesigned CHF program is delivered in the beneficiary districts.We define FOI as the extent to which the program under observation (including its contents and processes) is implemented as designed . Although other components may vary (be modified), past research recommends that core components be implemented in fidelity, as greater FOI of core components is associated with better program outcomes . We recoTo conduct this process evaluation, we rely on the following sequential steps: 1) identification of the essential intervention's components and the development of a comprehensive Theory of Intervention (TOI), 2) definition of the study design, 3) identification of a sampling strategy and data gathering procedures, 4) data analysis, 5) interpretation and integration of the results in the light of the conceptual framework, the TOI, and the study design.Developing a TOI represents the first essential step in the conduct of a process evaluation study . The TOIOur TOI is outlined to show how the activities nested within the Redesigned CHF are expected to induce change in a series of intermediate outcomes, ultimately leading to an increase in enrollment rates in CHF. This study employs a cross-sectional, convergent parallel mixed methods design . The croThe quantitative component measures the extent of program adoption, FOI, and sustainability of the intervention processes. The qualitative component is set to explore reasons behind adoption and FOI, the reactions of the stakeholders to the intervention and the contextual factors that affect the program's implementation.Data will be collected from the four different levels of implementation and sources of information. Respondents include community members, village-level teams , district-level actors (such as CHF management team members), and regional level actors .Supplementary File outlines the single tools to be used in relation to the specific research questions and the evaluation domain (variables and their definitions) they refer to. To increase validity and reliability, we developed data collection tools following recommendation from literature . The different data collection tools are described in detail hereafter. The two strands of data will be collected concurrently by two different research teams in a parallel manner.The study will use several data collection tools for each level of data collection. In line with our mixed methods design, these include structured questionnaires, semi-structured open-ended interview guides to facilitate focus group discussions (FGDs) and in-depth interviews (IDIs), and the checklists for document review. terature , yet adjQuestionnaires will be administered to district and village implementation teams to capture their sociodemographic characteristics, knowledge on CHF, adoption of the Redesigned CHF, FOI of Redesigned CHF operations, and sustainability of the operations. We aim to capture respondents’ knowledge on the CHF scheme. We focus on their knowledge of CHF benefits, enrollment criteria, and differences between the old (standard) CHF and the Redesigned CHF.To measure the way the teams adopt the Redesigned CHF, questions will focus on the functionality of Redesigned CHF structures and the usability of the guidelines in daily routines. FOI questions capture adherence to or departures from the CHF-SOP and the moderating factors. Sustainability questions focus on actions that are vital to sustain CHF operations. The questionnaire is composed of yes/no, Likert scale 1–5, and open-ended questions. We have developed two distinct questionnaires, to reflect the specific roles of the implementation teams being interviewed, that is, the district-level questionnaire and the village-level questionnaire.Participants from the district level involve a census of implementers as per CHF-SOP manual, that is, from each of the districts, at least 10 members of the CHF implementation team. We use a multistage cluster sampling technique to select village-level participants. We include all of the geographic divisions of the seven districts (i.e. 28 divisions), as we aim to describe what happens across all parts of the concerned district. Each of the geographic divisions has an average of six wards and we will randomly select at least three wards per division and thereafter at least two villages from the selected wards. We divide the villages into two clusters based on the presence of a health facility, as we also wish to find out if there are differences in the implementation results between the two clusters. We will randomly select an equal number of villages from the clusters and include all the VEOs and EOs as study participants. We aim at selecting at least 20 villages from each of the districts to reach a sample size adequate for statistical analyses.We use Cochran's formula for categorical data  to deterFGDs will be conducted with community members (those enrolled and not enrolled in the CHF) in order to explore their perceptions and reactions to the program. Community members as ultimate beneficiaries of the scheme are included as participants because of their central role in the scheme. The group dynamics presented by FGDs allow in-depth understanding about a particular issue that cannot be obtained through personal interviews or a questionnaire. We will use semi-structured guides to collect information.FGDs will be performed in only three districts selected purposively depending on percentage increase (speed) of CHF enrollment , and relative to the baseline values for the 3 years of program implementation. From the selected districts, we will select villages from the entire geographic division by first selecting three wards depending on enrollment speed and thereafter two villages from each ward depending on the presence of a health facility and the distance from the ward headquarters. The aim is to record reactions from diverse groups of community members.We plan to carry out FGDs until we reach redundancy and saturation , 59, butWe plan to conduct in-depth qualitative interviews with a wide range of key informants drawn from various levels of Redesigned CHF implementation. The key informants who occupy specific functions  in Redesigned CHF implementation will participate in the study by virtue of their positions, whereas others will be selected based on their expected knowledge about the scheme.We use IDIs as a tool to obtain detailed information from the participants. The interview questions aim at understanding the experience of implementing the scheme. We use semi-structured interview guides to collect information. We plan to carry out at least 12 interviews with regional level stakeholders and at least 36 interviews with district stakeholders. Participants from the districts will only come from three districts as in the FGDs.We will use a checklist to collect information related to documentation of the implementation of the program. The checklist will be used to extract data from existing CHF documents and other permanent written products of the program.The documents and permanent products set to be the source of data include program reports, day-to-day communications about the program as documented in the files , CHF policy documents, bylaws, strategic and operational plans, documentaries, and meeting minutes. In addition, the checklist will collect some secondary data from the IMIS-database.The checklist will independently collect verifiable data to be triangulated with data from other tools. The checklist will be semi-quantitative  and will extract a mixture of data that is set to provide insights on implementation of the Redesigned CHF and its documentation.Data from the questionnaires will be analyzed using standard statistical procedures. We quantify our dependent and independent variables because our interest is to respectively measure the extent of adoption, FOI, and sustainability, and find out what factors moderate adoption, FOI, and sustainability.Dependent variables. Guided by our conceptual framework and parallel to the work of Proctor et al.  adoption intensity, that is, the presence and functioning of the Redesigned CHF structures; 2) adoption rate, that is, the proportion of community members who join the scheme per year; and 3) degree of adoption, that is, the cumulative number of members enrolled in the Redesigned CHF.FOI is measured as adherence to the program model as originally stipulated in the CHF-SOP and related program operational documents, such as training manuals, supervision guidelines, and movement plans. We will measure both structural and process fidelity. The former measures the way various structures have been institutionalized, while the latter measures the various processes related to the Redesigned CHF.The proportion of procedures implemented as intended or modified is measured by the sum of scores of the responses to a set of questions representing a defined function as per TOI. We describe FOI per function and use it to calculate the overall FOI for a given implementation team. We will measure sustainability by a sum of scores of sustainability questions whereas sum scores of a set of satisfaction questions will measure stakeholders’ satisfaction.Independent variables. The independent variables are the participants’ background variables and moderating factors. The background variables are age (years), sex , types of jobs , duration of work (months), and level of education and knowledge on CHF. We measure knowledge on CHF as sum scores of correct responses to the knowledge questions.Supplementary File.We determine and measure the influence of moderating factors by the proportion they are mentioned by participants as moderators of implementation of the scheme. Included in our study as moderating factors are program characteristics, stakeholders’ responsiveness (such as degree of involvement and motivation), strategies used to facilitate program delivery, organizational factors, and contextual factors. They will be assessed by sum of scores of the responses to a set of questions representing a respective factor as detailed in Analysis of qualitative data will be carried out by two independent researchers on the original transcripts and document-review extracts. Analysis will utilize the framework method  assistedGiven the mixed methods nature of our study, we aim at integrating findings from across the data sets. Since in our case, quantitative and qualitative findings hold equal weight and are used to explore different aspects of the same phenomena, we aim at investigating where the findings converge, offer complimentary information, or appear to contradict each other. Integration here allows us to develop a composite, holistic, and cross-validated picture of the reality based on the results from both quantitative and qualitative data sets. Integration takes place after completion of data analysis and entails identifying similarities and differences, merging the results and discussing the meaning of the integrated results.The study will be conducted within a framework of the HPSS project in Tanzania . The stuThe protocol is under implementation. The entire timeline for completion of this study is 24 months and it is implemented in two stages. The theoretical stage  is estimated to take 9 months whereas the empirical stage  is estimated to take 15 months. Early field engagement began in July 2014 in order to develop and agree with implementing partners on a TOI, which could serve as the basis for the development of the protocol presented in this manuscript. Data collection was completed in early 2015. Data analysis will not have begun at the time of submission of this manuscript.The lack of process evaluations of MHI interventions set to increase enrollments makes it difficult to identify and understand the contextual factors responsible for the success or failure of such initiatives. Our study aims to fill this knowledge gap by assessing the implementation of the Redesigned CHF. This is done with the dual objective of understanding the effect of the intervention and of shedding light on which elements contribute to the success or failure in implementing MHI interventions set to address low enrollments.Our work situates itself within a context of fostering assessment of implementation just as much as the assessment of impacts of the interventions. This is important because process evaluation helps to determine the strength or weakness in implementation that could help to differentiate implementation failure and design failure when determining the impact of a given intervention , 45, 47.We integrate multiple schools of thought and perspectives in methodological and analytical choices in order to conduct a robust assessment of the implementation of the scheme. Our approach of using mixed methods corroborates the work of Peters et al. , which dThe study shall explore the challenges of implementing a complex intervention by looking at policy makers, frontline policy implementers, and consumer perspectives. While relevant from a conceptual point of view, this study will not explicitly explore the role of the funding agencies and the donor agencies in shaping the intervention content. The role of funding agencies and donors will be explored exclusively as a function of the environment, more specifically as a contextual factor influencing implementation processes. Looking at a scheme's implementation from multiple viewpoints helps to understand both the implementation processes and the reactions of the stakeholders, which are critical in explaining the implementation results , 47, 64.Successful implementation research requires good collaboration . Our resAlong with the strengths of our study protocol, we need to acknowledge some of its obvious limitations. In the first place, as mentioned above, we will not explicitly focus on exploring and understanding the role of the funding agencies in shaping the intervention content. It needs to be noted that our choice stems from the pragmatic need to narrow the focus to our process evaluation but may inevitably influence interpretation of its findings, since it may limit our ability to contextualize them in the light of all relevant elements. Second, the implementation of this study protocol may be influenced by factors such as field operational difficulties, cooperation from the implementing organization, and the researcher–participant relationship. There is the risk, albeit small, that these factors will influence what information we manage to successfully collect and thus, what interpretation and policy recommendations will follow from our research. Third, we must acknowledge the impossibility of conducting a prospective process evaluation, which relies on longitudinal data collection methods, given that our study team will gather data only a few years after the official launch of the Redesigned CHF. The impossibility of conducting longitudinal data collection motivated us to adopt a mixed method approach, relying on multiple data sources in order to recognize and incorporate multiple view points and to triangulate emerging interpretation at multiple levels. In addition, to strengthen our emerging interpretation and provide further contextualization of the findings, we will link the preliminary findings of the process evaluation with information on enrollment rates derived from the program. Unfortunately, however, we do not have access to information on the community health status, thus we cannot use this element to contextualize our findings. Fourth, our study is prone to recall bias as we intend to collect information concerning events that occurred in the past.In conclusion, the proposed research is intended to contribute to the understanding of the implementation processes of the Redesigned CHF program and helps to place the results of the intervention in context. In addition, evaluation studies like this help to differentiate implementation failure from design failure of a given intervention, which could not be identified by the impact of evaluation studies. The theoretical approaches and methodologies described in our protocol may be useful in informing the design of future process evaluations focused on the assessment of complex interventions.Click here for additional data file.