A framework was developed to characterize the antimicrobial use/antimicrobial resistance complex in livestock systems in Indonesia, Vietnam, and Thailand. Farm profitability, disease prevention, and mortality rate reduction were identified as drivers toward antimicrobial use in livestock systems. It revealed that antimicrobial use was high in all sectors studied, and that routine preventative use was of particular importance to broiler production systems. Misleading feed labeling was identified as a hurdle to the collection of accurate antimicrobial use data, with farmers being unaware of the antimicrobials contained in some commercial feed. Economic analysis found that the cost of antimicrobials was low relative to other farm inputs, and that farm profitability was precariously balanced. High disease and poor prices were identified as potential drivers toward economic loss. The research indicates that antimicrobial use in small-scale poultry production systems improves feed conversion ratios and overall productivity. However, data were limited to quantify adequately these potential gains and their impacts on the food supply. During the study, all countries embraced and implemented policies on better management of antimicrobial use in livestock and surveillance of antimicrobial resistance. Future policies need to consider farm-level economics and livestock food supply issues when developing further antimicrobial use interventions in the region. There has been a continual increase in the human population from 2.5 billion in 1960 to 7.53 billion in 2017 with growth projected to reach 10 billion by 2050. Much of the future population expansion is predicted to be in low income and middle income countries (LMICs) .The increasing demand for animal source proteins has been met through a global shift toward more intensive livestock production systems with a focus on the monogastric species (predominantly pigs and poultry). These systems rely heavily on the availability of cheap feed grains and oilseed cake, which are in limited supply in some LMICs. This raises doubts over the economic sustainability of such a food system approach. Highly integrated and intensive production systems require antimicrobials to ensure animal health and maintain productivity and profitability. Thus, alongside this intensification of livestock production, there has been an accompanying increase in antimicrobial consumption and a consequential increase in antimicrobial resistance (AMR) .The global concerns over AMR are well documented with Lord O’Neill estimating a potential human mortality in the region of 10 million by 2050 with an accompanying economic burden of 100 trillion USD . AMR hasThe zoonotic pathways for the spread of resistance from organisms existing within animal populations to those of significance to human health are well recognized and known to result from the use of antimicrobials in livestock. Consequently, antimicrobial use in food-producing animals is considered to present a risk to human health . While tA call has been made to create an intergovernmental panel for AMR  and, morAMR and the livestock and aquatic species should be viewed as an antimicrobial use/AMR complex due to its multi-dimensional nature with influence on: food production and productivity, pathogen management, AMR change, and environmental and human health impacts. Interpretation of AMR findings requires a more complete understanding of the inputs to the system, antimicrobial use, and antimicrobial residues in the environment and animal products. This challenge starts with basic building blocks with a focus on areas of likely highest risk. Surveillance, research, and interventions must all be designed to be applicable to the context of the specific situation in each country .In South-East Asia, a large number of antimicrobials are used in the livestock sector, and studies suggest that AMR may be widely prevalent . Weak orThe framework has three phases to explore the antimicrobial use/AMR complex in livestock systems. First, a detailed literature review identified existing knowledge and defined the major questions on the costs and benefits of antimicrobial use. Second, detailed case studies were undertaken to address some of these knowledge gaps described. In the final phase, a detailed analysis and discussion about the case study and literature review results was presented.The application of the framework has allowed the development of informed policy suggestions and identified information gaps and priority areas for future research, which this paper summarizes. An exploration of the economic importance as of antimicrobials through the case studies has identified the challenges, and potential negative consequences, of policy to reduce use on small commercial livestock systems. As previously outlined, it is essential that AMR is addressed from a One Health perspective and such farmers’ livelihoods need to be considered, in parallel with the human and animal health concerns from antimicrobial use in livestock. Thus, the framework highlights the importance of collecting accurate farm productivity data and undertaking economic assessments in any interventions to reduce antimicrobial use in LMICs.Pork is an economical and sustainable protein source . Pigs arDetailed case studies in Vietnam and Thailand addressed the antimicrobial use/AMR complex in the pig sectors. There were many parallels between the production systems on the case study farms in these countries where the housing and management systems are similar but with marked differences in the scale of production. Overall, the farms observed in Thailand were on a much larger scale and were more likely to be part of an integrated supply chain than those in Vietnam. Additionally, pig production was of a greater economic significance to the individual households interviewed in Thailand when compared with Vietnam. An overview of the production systems from the case studies are shown in Globally, broiler production is undergoing a process of intensification with the increasing dominance of integrated supply chains . BroilerThere is an ongoing transition across Asia from traditional open housing systems to modern closed and automated systems. This transition has been somewhat accelerated due to the outbreaks of Highly Pathogenic Avian Influenza (HPAI) in the early 2000s ,45. The Aquaculture production systems are of growing importance, as global demand for fish continues to rise . This inAs in many other LMICs, there is currently no requirement for a prescription for the use of antimicrobials in animals or humans in any of the case study countries . HoweverStricter legislation on antimicrobial use may be seen as a positive step in the global fight against AMR, which, to be truly effective, requires the development of enforcement capacity. For example, despite a more extensive infrastructure and tighter control over antimicrobial use in Thailand, researchers have described black market and illegal use of antimicrobials in livestock ,59, whilIn Indonesia and Vietnam, antimicrobial use surveillance in animals are either absent or restricted to small surveys or national estimates such as the data presented in the OIE report on global antimicrobial use . The accIndonesia has an established animal health surveillance system as the ‘integrated animal health information system,’ which is referred to as iSIKHNAS. This is a farmer-based reporting system for disease, animal population, and animal treatments . The sysThe focus of the case studies in Thailand and Vietnam was the small-medium commercial pig sector. The literature review highlighted this sector as having relatively high antimicrobial use in comparison to backyard or large integrated production systems ,32,66. IIn Asian LMICs, antimicrobials are freely available over the counter for use in both humans and animals ,68. Thern = 11 in All of the pig producers in the case studies in Thailand and Vietnam identified that there was an economic advantage to the use of antimicrobials in pigs. The most frequently volunteered justifications were that antimicrobials improved farm profitability, reduced mortality, and improved pig productivity . InfluenThe case studies also sought to collect quantitative data on antimicrobial use by indication, formulation, and active ingredient . The penThe collection of these antimicrobial use data presented some challenges. First, some of the commercially mixed feed on farms did not include information on the ingredients or antimicrobial content on the feed labels. Therefore, in-feed antimicrobial use may be under reported. Second, the bin collection method used in the Vietnamese case study proved to be an inefficient method of collecting quantitative antimicrobial use data. There was poor understanding of the methodology by many participants and, consequently, few farms retained antimicrobial packaging for the full six-week study period.The focus of the case study in Indonesia was the small-medium commercial broiler sector. The literature review identified that the Indonesian broiler sector relies heavily on antimicrobials for routine disease prevention programs . In addin = 419) of respondents identified that an improvement in productivity and growth was a motivation toward antimicrobial use. The majority of farmers (44%) considered that advice from veterinarians or para-veterinarians would drive antimicrobial use and 88% identified that veterinarians played an important role in monitoring the prudent use of antimicrobials. Equally, the dominant opinion was that the government (85%) and farmers (80%) played an important role in monitoring antimicrobial use in broilers in Indonesia. The behavioral influences behind antimicrobial use are shown in The influences behind antimicrobial use behaviors in the small-medium broiler sector in Indonesia identified that the active presence of disease, increasing mortality rates, and an aspiration to prevent disease were major drivers of antimicrobial use on the case study farms. In addition, in spite of a ban on the use of antimicrobials for growth promotion, 27%  of broiler farmers were able to correctly define AMR. The most frequent definition was that AMR is ‘resistance to drugs.’ However, some offered a more general description that AMR ‘caused treatment to be ineffective’. However, 56% of farmers identified that AMR was a major challenge in human medicine and an equal number felt that antimicrobial use in broilers might affect the health of consumers.The case study sought to describe baseline knowledge of farmers on the issue of AMR. In an open response question, only 45%  in order to refine the generic recommendation of ‘reduction in antimicrobial use’ toward a set of guidelines on how to reduce antimicrobial use with minimal impact on livestock production, profitability, and livelihoods and maximum impact on AMR management and general pathogen control .The ability to undertake more detailed economic analyses was limited by the lack of detailed on-farm production and cost data. In these small-to-medium scale enterprises, farmers do not routinely collect any such data, which reflects the relative costs of data collection and the benefits gained from such activities in small production units. The project was able to provide initial estimates of the importance of antimicrobial costs to the economic viability of these small-to-medium scale production systems.The economic analysis in Vietnam used the data from those farms who had sows in 36 rather than the 40 farms in the entire survey. The management and economic landscape of farms that specialized in fattening (three of the 40) was very different to those who managed a farrowing to fattening production system. In addition, a recent decline in price led to some of these fattening farms not purchasing weaners for fattening in the previous 12 months. One farm produced 900 fatteners and was regarded as an outlier in this study.The gross margin analysis, difference between output and variable costs, indicates that returns have been poor during the time of this survey with two out of the three scenarios indicating losses to the farmer. The result supports the perceptions of the study team and enumerators that the pig sector was facing a difficult economic environment during this time.Medicines and antimicrobials were only 2% of costs in the pig production system, which is an important result when considering policies on pricing as a way to manage antimicrobial use. As expected, feed was the most significant cost and, therefore, the input of greatest concern by farmers. The low cost of antimicrobials could well mean that farmers are not in a conscious process of searching for optimal antimicrobial use around a classic production function of output. Rather the use, as shown in the behavioral aspects, is in response to a mix of managing impacts of disease and health issues that support production. It is, likely, best described as a risk management strategy in an uncertain environment. While the internal farm costs are relatively low with current pricing, the potential externalities of poor on farm antimicrobial use leading to AMR risks to humans is not properly accounted for in the price. Further work is required to estimate the product development costs, the effects of AMR on future pig production and disease control, or the present and future effects on human health.With regard to the survey of pig farmers in Thailand, nine out of the 11 farmers surveyed had large herds. The data showed that they were selling an average of 334 pigs, probably fatteners, which would provide a weekly gross income of $60,000 USD. Investing in medicines and, more specifically, antimicrobials turned out to be a very minor cost. Investing $2.03 USD to maintain an asset of $180 USD, most farmers regarded the value of a fattener as good value for money even if the actual benefits are unclear. Likewise, a preventive medication of $2.07 to have potential health benefits to their breeding sows may seem to be a good investment.Farmers were also requested to list the antimicrobials used, the active ingredients, cost per pack, and which pig age group they were used on. Once again, these data were very difficult to recall and some farmers could not, or would not, provide estimates. While routine antimicrobials could be estimated, it was not possible to estimate what antimicrobials were actually given as disease treatments. The antimicrobials were listed but farmers found it difficult to allocate costs to pigs in a cycle or year, so another measure was developed to show the relative importance of antimicrobials to the farming system. The conclusion is that, once again, antimicrobials are a very small cost to the farmer. For every kilogram of pig on the farm at the time of the survey, the farmers on average expect to spend, or at least identified costs of, $0.06/kg live weight on antimicrobials.Gross margin data and antimicrobial costs per cycle were not able to be estimated from the survey data. The economic analysis, therefore, considered some alternative measures. First, a more simplified analysis that assesses whether or not there are differences in medicine costs between farmers’ performance index  × liveability [%])/FCR × 10) results in their last broiler cycle. The study identified the possibility that the higher the performance index is, the lower the use of medicines are. The farmers with the highest performance index (highest 25% of farmers) invest, on average, Indonesian Rupiah350/bird (US$0.02/bird) on medicines. The range for the other farmers is between IDR390 and IDR405/bird. While this may be a small difference in costs per bird when extrapolated over the whole flock, it may be significant.The survey collected information concerning the number of days that antimicrobials were used on the most recent batch of broilers. This may be used as a proxy for antimicrobial usage on the farm. It may be that, the more days that antimicrobials are used, the more antimicrobials are actually used. Although this does not provide insights into the reasons for use or even the types of antimicrobials used, it still may provide useful information concerning the extent of use. The analysis showed that, with regard to farm size, there is a slight difference between smaller farms and the larger farms with respect to the number of days that antimicrobials are used. The larger farms may tend to use less antimicrobials than the smaller farms.Another useful measure is the correlation between the average performance index and the number of days that antimicrobials are used. There may be a positive relationship between antimicrobials and the index. The more days that antimicrobials are used, the higher the performance index is. The context of these results is that antimicrobial use in this system tends to be a preventative measure with advice from the contract company to use antimicrobials if bad (hot or cold) weather is expected and fear of respiratory disease. In addition, farmers, particularly independent producers, often give antimicrobials on the day the one-day old chick arrives since this is a critical point in the production process. There are often doubts about the strength of the newly arrived bird to survive the transition from the hatchery to the farm.The small commercial livestock sector runs on tight profit margins and producers are highly susceptible to changes in market prices. This economic vulnerability has been shown through the Vietnamese pig industry since the sector has experienced a turbulent economic scene since early 2017 with falling pig prices from an oversupply of pork and a cessation of exports to China. As a consequence, it has been estimated that around 30% of smaller pig farms have gone out as a business in Vietnam ,82. WithKeeping detailed farm records on livestock production can enable farmers to identify which areas of their business may benefit from additional investment and where losses may be occurring. These data are also required to present to financial lenders for proof of reinvestment potentials on the farm . HoweverFarm profitability, disease prevention, and reducing mortality rates were identified as drivers towards antimicrobial use in livestock systems. In broiler systems in Indonesia, the use of antimicrobials in feed were identified as a method of compensating for the significant disease burden seen in open housing systems . While tThe use of medicated feed to prevent disease is a frequent practice in global livestock systems . This beThe use of antimicrobials for disease prevention is a contentious issue and there is increasing pressure to discontinue this practice internationally ,8,88. ThThe easy availability of antimicrobials over the counter and from a range of sources results in antimicrobial costs remaining consistently low throughout Asia . The stuA ban on antimicrobial growth promoters in Denmark was shown to increase the need for antimicrobials for therapeutic indications in the years following the ban . This waThere is a grey area around prophylactic and growth promoting antimicrobial use whereby studies have shown that producers may use antimicrobials for growth promotional effects, but justify this practice as being for disease prophylaxis ,94. DangThe case study results identified the frequent use of the HP-CIA classes in all livestock groups. There has been increasing international pressure to reduce or discontinue the use of HP-CIA classes in livestock ,8. EfforRestricting access to antimicrobials by removing over-the-counter sales has been identified as a potential route to better antimicrobial use in animals in such countries ,8. HowevDiscussions with pharmacists and drug sellers in Asia have highlighted indiscriminate antimicrobial sales and raised concerns over poor knowledge on AMR and responsible antimicrobial use ,102,103.At present, there is no easy route through which the sale of antimicrobials through retail outlets and pharmacies can be monitored . This prPoor awareness of AMR concerns by veterinarians have been identified as a challenge for reducing and optimizing antimicrobial use in LMICs ,85. ThusThe case studies present data from a small number of small-scale commercial pig and broiler farms in each country. A convenience sampling method was implemented by in-country collaborators and, as such, there is a potential for selection bias . Thus, tThe bin collection methodology implemented in the Vietnamese case study presented a number of limitations. The farmer was requested to retain all antimicrobial packaging over a six-week period. However, these data were missing for the majority of farms and the farms that did collect packaging frequently collected packaging from non-antimicrobial packaging and did not retain feed labels. Redding et al. (2014) found parallel issues with a lack of understanding by farmers on what constituted an antimicrobial with farmers retaining non-antimicrobial products and disposing of antimicrobial packaging in dairy farms in South America . In addiThere were issues with collecting a complete set of data from some of the case study farms particularly concerning productivity and economic parameters. Gaps in farm data on productivity and economic costs are a familiar theme across livestock production systems in South East Asia, which limits the scope for conducting detailed analyses into productivity, the financial implications of disease, and the economics of antimicrobial use. Consequently, many of the economic and productivity results reported in the case study are not complete. This issue identifies a hurdle for assessing the effects of any interventions or management changes introduced on farms to reduce antimicrobial use, since, presently, most farms do not collect sufficient productivity data to assess whether such interventions are economically viable.A review of the literature and in-country discussions identified priority livestock sectors, understanding of antimicrobial use and AMR within these sectors, private and public research programs, and the extent of policy support. Pigs and poultry were identified to be the livestock sectors of most economic and social importance across the countries . These sThe small-medium commercial broiler sector in Indonesia,The small-medium commercial pig sector in Vietnam,The small-medium commercial pig sector and the larger integrated broiler sector in Thailand.Quantitative data relating to the economics of antimicrobials, farm productivity, and farm-level antimicrobial use were collected alongside qualitative information on farmer attitudes to AMR, responsibility, and drivers for antimicrobial use through a face-to-face questionnaire in each country. The questionnaire was designed based on a previous questionnaire study on the drivers into antimicrobial use in the UK pig industry and on information gained from previous Knowledge Attitudes and Practices (KAP) surveys undertaken in the South East Asian region by the FAO . In addiOverall ethical approval was granted by the University of Liverpool Veterinary Science Research Ethics Committee, which also required proof of local (country-level) ethical acceptability (Reference number VREC640). In Thailand, the ethical review committee of the department of Health Sciencesfrom Chulalongkorn University granted ethical approval. Since the study did not involve the collection of samples from animals or humans, the research collaborators and local government in Indonesia and Vietnam did not require a specific ethical review. Therefore, documentation mitigating the need for a detailed ethical review was provided from the government livestock departments in each country  in Indonesia and National Institute for Veterinary Research (NIVR) in Vietnam). An overview of the key findings from the framework development to characterize the antimicrobial use/AMR complex in Indonesia, Thailand, and Vietnam and the implications of these conclusions for policy development are presented in A national scheme to promote responsible antimicrobial use in livestock may be a route through which veterinarians and industry stakeholders could be united. This could have an end goal of producing antimicrobial prescribing guidelines for key livestock sectors and advice on alternative methods to prevent disease. Similarly, an independent initiative in the UK has been led by the Responsible Use of Antimicrobials in Animals Alliance (RUMA), which have produced guidelines to support producers in ensuring that antimicrobial use is prudent on livestock farms . FurtherSalmonella species have been found to be highly prevalent in pigs, chickens, and their products in the Thailand and the Cambodian border provinces [Country-level actions on antimicrobial use should be undertaken with close communications with neighbouring countries as well as at the wider international level. AMR does not respect country borders, which is of particular importance in the South East Asian region where many countries share common borders and have permanent land crossings for importation and exportation. For example, multidrug-resistant rovinces .Salmonella species have been found to be highly prevalent in pigs, chickens, and their products in the Thailand and the Cambodian border provinces [Country-level actions on antimicrobial use should be undertaken with close communications with neighbouring countries as well as at the wider international level. AMR does not respect country borders, which is of particular importance in the South East Asian region where many countries share common borders and have permanent land crossings for importation and exportation. For example, multidrug-resistant rovinces .In the case study countries, engaging the private sector in policy development and the implementation of the AMR action plan presents a number of challenges. First, there is strong competition between companies in livestock production. Second, there are great concerns by the private sector over the potential economic effects of reducing antimicrobial use and, third, there seems to be little incentive to reduce antimicrobial use in the present climate ,115. HowWhile collecting national farm-level antimicrobial data is likely to be a future aspiration, there is still hope to encourage production companies and farmers, through producer organizations, to improve farm recording of key productivity parameters.


The objective of this study is to describe variations in the healthcare resource utilization (HRU) among individuals with Angelman syndrome (AS) over the first 12 years of life. Data for this study were drawn from the AS Natural History study (ASNHS), which is an observational study on the developmental progress, behavior, and medical morbidity of individuals with AS conducted over eight years. Caregiver-reported information on hospitalization, surgery, and medication utilization was used to assess HRU. Repeated measures mixed effect models were used to assess the relationship between age and probability of hospitalization, surgery, and prescription medication utilization.Mean age at study enrollment was 6 years of age and both sexes were equally represented. The mean number of visits per participant was three. Results from this study suggest that individuals with AS have a high HRU burden. Hospitalization and surgery burden were highest in the first year of life. Use of medications for seizures and sleep disturbance increased over time.The study highlights the significant healthcare burden among individuals with AS. Future studies that estimate cost and caregiver burden associated with AS are needed to assess the lifelong economic impact of AS on families and healthcare system. Angelman syndrome (AS) is a rare, neurodevelopmental condition characterized by severe impairment in behavior, motor function, sleep, and cognition. There are no approved treatments for AS and the current goal is management of comorbidities and symptoms . AS has There is limited information on the healthcare burden of individuals with AS and how it varies with age. In a study of 34 individuals with a mean age of 21.6 years, [While the above studies have established the significant healthcare burden for individuals with AS, there are no published data on how this burden changes with age. The primary aim of this study is to describe how healthcare resource utilization (HRU) varies with age in the pediatric population with AS in the United States (US). By documenting the HRU among children with AS, we will begin to characterize the unmet needs for this population, which may help determine how resources should be allocated for the management of this chronic condition.ClinicalTrials.gov Identifier: NCT00296764). Individuals with AS were recruited at six study sites across the United States. Inclusion criteria included a molecular or clinical diagnosis of AS, and age between 1 day and 60 years. A total of 311 individuals were enrolled in the ASNHS. For the purpose of this analysis, only 302 individuals with molecularly confirmed AS and no concomitant medical condition  were included.The ASNHS gathered longitudinal data on the developmental progress, behavior, and medical morbidity of individuals with AS from 2006 to 2014 . The stuAt the baseline visit and at each annual follow-up visit, data were collected through interviews with the caregiver who was present at the visit about the participant’s previous and current medical history and developmental progress since birth. With respect to HRU, the dates of, and indications for, any hospitalization or surgery, and length of stay (LOS) were recorded. Information was also collected on the use of prescription and non-prescription medications, including the reasons for using each medication and the duration of use.The date of event  and date of birth were used to calculate the age at time of event, if age was not directly reported. If the event date was completely missing, the date of visit at which the event was reported was used to calculate the age at time of event, provided that no more than one annually scheduled visit was missing immediately prior to the visit reporting the event. If there was more than one missing annual visit immediately prior to the visit reporting the event, then age at time of event was considered missing and not included in the analysis. As we could not determine whether a given surgery was performed in an outpatient or inpatient setting, hospitalization and surgery data were not considered mutually exclusive. In addition, length of stay (LOS) was defined as the number of nights in a hospital, with a minimum of one overnight stay in the hospital. Finally, analyses were restricted to individuals 12 years of age or younger due to small sample sizes for older age groups.Descriptive statistics of the resource utilization in the sample are presented by age. For continuous variables, the mean and standard deviation (SD) are presented. For categorical variables, frequencies and related percentages are presented. To analyze how healthcare utilization changes with age, a mixed model for repeated binary measurements was used. Separate models were fitted to estimate the probability of hospitalization, surgery, and prescription medication utilization. Models included fixed effects for intercept, age, molecular genotype, and genotype-by-age interaction, and random effects for intercept and slope. Molecular genotype was defined as a binary measure where individuals with a deletion genotype were categorized together and individuals with non-deletion etiology were categorized otherwise, as the reference category. Molecular etiology was added as a covariate since previous studies suggested that individuals with deletion genotype generally have a more severe course –9. All sTable Table Table AS is a rare condition with an estimated prevalence of 1 in 12,000 to 1 in 20,000 in the US . The mosThe ASNHS is a large-scale longitudinal study of individuals with AS in the US designed to improve knowledge of the condition and investigate associated morbidity across ages. Individuals in the analyzable sample were younger than 12 years with a mean age of six years and equal sex distribution. On average, we had three years of data for each individual. Our analyses suggest an overall high HRU in this population especially among younger children between 0 and 1 years of age. Hospitalization, surgeries and use of prescription medications to manage various symptoms were common. Our data suggests that younger children, often in the first year of life, tended to experience more surgeries, hospitalizations, and longer hospital stays than older children. The use of prescription medications increased with age in this cohort and by age six almost 80% of children were using at least one medication.Our analyses support the heterogeneity of the condition. It appears that the various symptoms were managed through a combination of hospital-based interventions and prescription medications. Seizures are one of the most common symptoms associated with AS , and antMedications to treat sleep disturbance were the other common category. Sleep difficulties may manifest as increased sleep latency, decreased total sleep time, abnormal sleep-wake cycle, and frequent nocturnal awakening . Some stIndividuals with AS may have behavioral issues, such as hyperactivity, impulsivity, and aggressive behaviors . We obseThis study has several limitations. The population was skewed towards individuals younger than five years old and the mean number of data points per individual was only three. The ASNHS study did not record any information on use of outpatient care . While not as costly as hospitalization, outpatient care tends to be one of the largest volume drivers of healthcare burden. We were unable to determine whether the reported surgeries were performed in an outpatient or an inpatient setting. Since the data used in these analyses were collected via caregiver  interviews, the HRU was likely underreported due to recall failure and should be considered a minimum estimate, particularly true for medication use. In addition, we are using the event dates to create longitudinal history of healthcare utilization and misreporting is likely to be higher for medication use and as such the medication results should be interpreted in the light of these limitations. Replication of the findings in this study using claims data or administrative sources will help to corroborate these results.In summary, this is the first study to describe how the HRU varies with age in children with AS. We have shown overall high HRU use as well as different types of HRU, to manage a constellation of heterogeneous symptoms and co-morbidities. The high healthcare burden for these individuals and their families can be demonstrated by the high hospitalization and surgery rates, especially in the first year of life. We also described how the use of medications increased with age, especially for conditions such as seizures, sleep disturbance, and behavioral issues. Future studies are required to provide a holistic view on the HRU use in both children and adults and evaluate the overall impact on caregivers and the healthcare system.


Advances in Optofluidics”, collects 9 review articles that update the latest progress of the optofluidics in a broad range of topics, such as droplets, light manipulation, display, refractometry, microcavities and tunable lenses.Optofluidics grew up from the early attempts to integrate optics with microfluidics to exert the benefits of both. Over the last decade, it has made steady progress from the passive interaction of light and liquid media such as liquid waveguides, optical sensors and liquid tunable lenses to the active interaction of photons and liquids such as lasers, particle manipulations and photoreactions. This special issue of Micromachines, entitled “One of the core parts of optofluidics is to use liquids as the optical media. Two review articles cover this topic. Yang et al. discussed how to use inhomogeneous liquids to form refractive interfaces for light focusing, or to generate gradient refractive index profiles for advanced effects such as self-imaging, discrete diffraction and optical cloaking . In the Another core part of optofluidics is to use light to measure the change in the liquid media. This special issue has two review articles in this topic. Jian et al. reviewed the recent work on optofluidic refractometry and elaborated different sensing mechanisms/structures and the performance enhancement . In addiDroplet microfluidics aims to discretely manipulate tiny volume of fluids. The use of light enables the droplet sensing and manipulation. In this special issue, El Abed reviewed recent developed methods for real-time analysis of droplet size and size distribution, for active merging of microdroplets using light, or for optical probing . Huang eOptofluidic microcavities confine both liquid and light in a tiny space and significantly enhance their interaction, especially the active interaction of photons and liquid media. Along this line, Feng et al. summarized the recent advances in the liquid microlasers and their biochemical sensing applications . This reOptofluidics is often based on a microchip. In fact, it can also utilize other supporting structures with air channels, for instance, microstructured optical fibers. Shao et al. reviewed the recent progress in this interesting and useful topic and discussed various sensing applications .Optofluidic display has become a hot topic in recently years thanks to the brilliant idea and the bright market prospect. As an expert of this field, Shui et al. elaborated the working principles and device structures of three types of reflective displays, and summarized the optofluidic behavior and the controlling factors . DisplayCertainly, there are some overlaps among these review articles. For instance, the review of optical sensors may partially cover the optical structures, and the application discussions of microcavities and droplets have to involve optical sensors. In view of the completeness of each individual review article, such an overlap is inevitable. Fortunately, the overlap is minor because each article has its own focal interests, which are different from those of the other articles.I would like to thank all the authors for their great contributions to this special issue. Sincere appreciation also goes to all the reviewers for their efforts and visions to ensure the quality of review articles.


Primary care (PC) is the foundation of the Kenyan health care system, providing comprehensive care, health promotion and managing all illnesses across the lifecycle. In the private sector in Nairobi, PC is principally offered by the general practitioners, also known as family doctors (FDs). The majority have no postgraduate training. Little is known about how patients perceive their capability.To assess patients’ perceptions of the scope of practice of FDs working in private sector PC clinics in Nairobi and their awareness of the new category of family physicians (FPs) and the discipline of family medicine.Private sector PC clinics in Nairobi.A descriptive survey using a structured, self-administered questionnaire. Simple random sampling was used to recruit 162 patient participants.Of the participants, 30% knew the difference between FPs and FDs. There was a high to moderate confidence that FDs could treat common illnesses; provide lifestyle advice; family planning (66%) and childhood immunisations (64%). In adolescents and adults, low confidence was expressed in their ability to manage tuberculosis (58%), human immunodeficiency virus (55%) and cancer (33%). In the elderly, there was low confidence in their ability to manage depression (55%), anxiety (57%), urinary incontinence (57%) and diabetes (59%). There was low confidence in their ability to provide antenatal care (55%) and Pap smears (42%).Patients did not perceive that FDs could offer fully comprehensive PC services. These perceptions may be addressed by defining the expected package of care, designing a system that encourages the utilisation of PC and employing FPs. According to a 2008 WHO report:Forty years after the Alma-Ata Declaration that launched the primary health care (PHC) movement and which committed the World Health Organization (WHO) to tackle ‘politically, socially and economically unacceptable’ health inequities,2… it is necessary to invest in and renew the commitment to primary health care not only to promote health equity in developing countries, but also help to address the Millennium Development Goals, and now Sustainable Development Goals, at a population level.3 The WHO further subdivides PHC into four main areas, that together, ensure a strong PHC system: universal health coverage, policy, leadership and governance, and primary care (PC).4 Health systems that effectively implement PHC achieve better results in comparison to those that focus more on a biomedical and hospital-based approach.5Primary health care has been defined as the sum of all elements of a health system meant to address basic health needs, including preventive care.6Primary care is defined as the first contact with the health system and needs to be as accessible as possible. Primary care is characterised as being long-term and patient-centred; that is, both comprehensive and coordinated with other levels of care in the context of both family and community.7In European countries, most reforms aim to create health care systems with efficiently organised PC services as their foundation. In the Netherlands and the United Kingdom, general practitioners (GPs) function as the PC providers and gatekeepers to the health system.9 Sub-Saharan Africa countries face many challenges with regards to the accessibility and affordability of high-quality PC. Whilst the WHO encourages the promotion of comprehensive PC, it is still an emerging concept in SSA.10Primary care delivery in sub-Saharan Africa (SSA) has delivered selected programmes for diseases such as human immunodeficiency virus (HIV), tuberculosis (TB) and malaria, but has been criticised for not being comprehensive and being poorly resourced in terms of equipment, medications and delivered by low-level and poorly trained health care workers.11 This was achieved through increased staffing, provision of essential commodities, elimination of cash payments and introduction of free maternal services.11 Two-thirds of all consultations in PC now occur in the public health care sector and health equity has improved.11 Clinical officers (mid-level clinicians) and GPs are the main PC providers in both the private and public sector. Doctors are essential contributors to strengthening the PHC system in both the public and private sectors.12A sustained focus on and attention to PC in the public sector in Kenya has resulted in a doubling of utilisation over a 10-year period.5 Most studies have focused on hospital-based care in the public sector.13Little is known in Kenya about the performance of PC, particularly in terms of access, comprehensiveness, continuity, coordination, people-centeredness and quality of care. Health information systems struggle to collect, analyse, interpret and use data for improvement.14 Primary care in the private sector is provided mainly by GPs, hereafter referred to as family doctors (FDs), most of whom have not received postgraduate training in family medicine (FM).Nairobi, the capital city of Kenya, is home to approximately 3 million people and is the largest city in Kenya.Family medicine trains doctors to work in PC and the broader district health services, but in Kenya is still in its nascent stage with no more than 100 registered family physicians (FPs). In contrast, the number of GPs total around 3400. As FPs, with four years of postgraduate training, enter the health system, there may be a mismatch between their more comprehensive competencies and public expectations of the scope of PC practice based on untrained FDs. Little is known about how the patients view the competence of the existing FDs in private practice, the range of services that they offer and whether they are aware of the new discipline of FM and how this could further benefit services.A pilot study carried out in Nairobi demonstrated a higher recognition of the term ‘family doctor’, amongst patients attending a PC clinic, which led to the use of this term in this study. However, there was less understanding of what FDs do, what conditions they could treat or procedures they could perform. There is very little research on the services offered by the FDs in the private sector in PC in Kenya and even less from the patient’s perspective. Understanding the current perceptions of patients regarding the scope of services offered by the FDs in Kenya, is a crucial step in promoting, marketing and planning the delivery of PC services.This study aimed to assess patient’s perceptions of the scope of practice of FDs working in private sector PC clinics in Nairobi and their awareness of the new category of FPs and the discipline of FM.This was a cross-sectional descriptive survey using a structured self-administered questionnaire.15The Kenyan health system consists of three main categories of service providers: public, private non-profit and private for-profit organisations. The government operates 41% of health facilities in the public sector, whilst the private for-profit sector operates 43% of health facilities and is becoming more prominent. Private clinics of varying complexity exist in most major urban centres.There were 13 PC clinics associated with the tertiary care private hospital within the city of Nairobi at the time of the study. These clinics were run by FDs and offered health promotion, preventive and curative services to all age groups. The staff in each clinic included a FD, registered nurse, laboratory technician and pharmacist. On an average, 35 patients were seen at these clinics per day. Almost all of them were covered by private medical insurance.A non-stratified Fisher’s sample size calculation was based on: an expected proportion of 50%, as there was no previous data to estimate the expected proportions across multiple variables, a margin of error of 5% and a study population of 280 which was the sum of the daily average number of patients seen in the eight selected facilities. This resulted in a minimum sample size of 162 participants.The study included eight clinics with the highest workload, of which three clinics were located in the centre of Nairobi and five in the broader metropolitan area.The proportion of the sample selected from each clinic was based on the proportion of the total workload (average daily headcount) seen in each clinic in the study. In each clinic, simple random sampling was used to recruit the participants. The study population consisted of adult patients (18 years and above) attending the clinics. Those who were too sick or those who could not provide their own consent were excluded from the study.Data were collected using a structured self-administered questionnaire. The questionnaire was developed by the researcher, based on the common conditions seen in the Nairobi context and services usually provided by PC. As there was no defined package of care for the PC services offered in the private sector, items were generated by G.M. (an experienced FP) and M.M. (head of the FM department) and the content and construct of the questionnaire was further validated by a FD and a medical psychologist, all of whom had research expertise and work experience in PC. The questionnaire was piloted in a PC clinic also associated with the same tertiary care hospital to assess its acceptability, feasibility and ease of understanding in the study population. This clinic did not form part of the main study. The feedback from the pilot was used to adjust the final questionnaire.14All the patients attending the clinic spoke English and consultations and treatment at all the chosen clinics were conducted in English, hence the choice of language. Literacy level in Nairobi is measured at 85%.The questionnaire captured information on demographics and patients’ perceptions of whether FDs could offer clinical services for different age groups, acute and chronic conditions, disease prevention and health promotion.As a secondary objective, patients were also asked about their awareness of FM and the new cadre of FPs. Patient perception was defined as patient’s awareness of the conditions, preventive health care services and life style advice that the FD could treat or carry out.Data were captured in MS Excel, checked for errors or omissions and then analysed in Strata version 12. All variables were categorical and were analysed descriptively using frequencies and percentages. The patients’ perception as to whether the FD could offer a service was categorised into high (≥ 80%), moderate (60% – 79%) and low (< 60%).The study was approved by the tertiary care hospital’s Research and Ethics Committee (research protocol no. 2014/REC-50(v3)) and by the National Commission for Science, Technology and Innovation (permit no. NACOSTI/P/15/1304/5166).The socio-demographic characteristics of the 162 participants are presented in Most respondents had heard of the terms FP, FD and FM . In all,Most respondents believed that FDs were able to treat people across the lifecycle, although the perception was slightly less for small babies and the elderly . Table 2In children below 12 years, patients expressed high confidence in the FDs’ ability to treat diarrhoea and upper respiratory tract infection; moderate confidence in their ability to manage lower respiratory tract infections, asthma, ear and eye infections, and low confidence to treat dermatological problems.In adolescents, there was a high level of confidence that FDs were able to treat cough, malaria, diarrhoea, headache, upper respiratory tract infections and injuries. There was moderate confidence in the treatment of skin diseases, diabetes, sexually transmitted infections (STIs) and asthma. There was a low level of confidence for the treatment of HIV, TB and cancer.In adults, there was a high level of confidence that a FD could treat common conditions such as cough, malaria, diarrhoea, headache, upper respiratory tract infections and injuries; a moderate level of confidence was expressed regarding the treatment of chronic conditions such as diabetes, high blood pressure, asthma as well as STIs. There was low confidence expressed in their ability to treat HIV, TB, chest pain, cancer and thyroid disease.Regarding the elderly, patients had moderate level of confidence that FDs could treat joint pains and/or stiffness, injuries from falls, high blood pressure, sleep problems, asthma and skin diseases, but low level of confidence in treating depression, anxiety, urinary incontinence, diabetes and thyroid problems.The patients had moderate confidence that the FD could offer services like childhood immunisation, adult vaccination and family planning and low levels of confidence in antenatal care, cervical cancer screening and circumcision .Regarding lifestyle issues, patient’s had moderate confidence that a FD could advise on obesity and weight loss, on nutrition in general, behaviour change counselling for tobacco smoking and alcohol and low level of confidence was expressed regarding end-of-life issues .This study showed that patients had limited expectations of the services offered by FDs in the private sector PC in Nairobi. They had confidence in the FDs’ ability to treat common minor illnesses and non-communicable diseases, as well as underlying risky behaviours such as tobacco smoking and harmful alcohol use. They were not fully convinced by the FDs’ ability to treat communicable diseases, emergencies, pregnant women, skin conditions, cancer or to provide preventive care such as cervical cancer screening and immunisations. They also lacked confidence in the FDs’ ability to treat small babies and the elderly.16Whilst our study showed positive confidence in FDs’ abilities to treat common illnesses, there were gaps that indicated the need for more awareness on the role of FDs, as well as empowerment of the FDs to reduce them. Studies elsewhere concur that the ability of FDs to treat common conditions and to counsel patients on lifestyle issues are important in saving patients’ time, cost and in preventing disease. However, their results also showed gaps in the patient’s perception of what FDs could deliver in this context compared to what would be expected elsewhere.17The patients’ perceptions of the scope of practice may have been influenced, not only by the capability of the FDs, but also by the private medical system itself, which does not automatically offer all the PC services. Medical insurance may enable direct access to general specialists such as paediatricians and obstetricians for common illnesses or routine antenatal care that could be competently provided by FDs in PC. Patients may also prefer care offered by a specialist with regards to non-communicable diseases and specialists may resist their business being taken over by PC. This emphasises the need for the FDs and the specialists to work together not only to maximise efficiency of care but also for the benefit of the patient.19 A study by Starfield et al. showed that ‘the supply of PC physicians was significantly associated with lower all-cause mortality, whereas a greater supply of speciality physicians was associated with higher mortality’.6 However, in a system with untrained FDs, a lack of trust in their capabilities might drive patients to consult hospital specialists.19There may not be an incentive for PC to act as a gatekeeper to the health system in the private sector, whilst in the public sector; gatekeeping is needed to make the system more efficient and equitable. Health systems that allow patients to directly access specialist care may be less efficient in the use of resources, cause more harm and patients can be less satisfied.20 In the public sector in Kenya, antenatal services, delivery, postnatal care and childhood immunisations are all provided free of cost. In addition, private insurance does not usually fully cover costs related to these areas of health need. Hence, there is fairly high usage of these services from the public health facilities which may explain our findings whereby patient’s expressed low confidence in FDs’ ability to manage women’s health.The lack of confidence in FDs’ ability to manage children could be explained by the fact that specialist paediatric care is initiated in all private hospitals immediately from the time of birth. The general tendency is for the parents to continue with this care from a paediatrician along with childhood immunisation. A study also confirmed the tendency by FDs in private practice to refer patients to the public sector for immunisation because of the high costs involved, thereby diminishing their role in this important activity.A similar situation exists with regard to care for HIV, TB and STIs. Care is provided free for these conditions in the public sector; hence, most patients are managed in this setting. Family doctors, therefore, may become deskilled in managing these conditions. In addition, patients can also access care from infectious disease specialists in the private sector and bypass PC.Emergency care is usually provided at emergency centres within the hospital environment. This could have contributed to the low perception about FDs treating emergencies such as chest pain.22 Not surprisingly, therefore, the perception in this study is similar to others that FDs were not very capable at end-of-life counselling and cancer care.24 FM and palliative care have been intimately linked in many health systems.Cancer treatment is typically within the domain of the oncologist, although shared care with a FD is recommended to bring a more holistic and family-orientated approach.26The perception that FDs were less capable at managing the elderly could be because of the complexity of multi-morbidity in the elderly, and the challenges of multiple cognitive, medical and social issues. Also, reliance on specialist care, along with a gap in the training of the FDs in elderly care could have contributed to this perception. In addition, the number of elderly patients seen in PC in Nairobi are few, as most of them reside in their rural homes. In this study, only two of the respondents were above the age of 60 years. Although caring for the elderly in PC can be fulfilling and rewarding, it is also complex, difficult, heart breaking and time-consuming, more so with the addition of geriatric mental disorders.Although the scope of practice of FDs in the private sector may be shaped by the private health system itself, there may also be issues with the capability of FDs. Doctors with a basic medical degree often have gaps in their undergraduate training that reflects the tertiary hospital teaching setting. Care of common conditions seen in general practice may be omitted, particularly skin, eye, ear and nose problems, which are sub-specialities in the tertiary hospital environment.Tertiary hospital training may also reduce exposure to undifferentiated problems, psychosocial issues and the health needs of the community. Hence, graduates may not be well prepared for PC.10 Family physicians are also trained to support the development of comprehensive PC that is equitable, accessible, continuous, patient-centred and holistic.10 The number of FPs in the health system of Kenya is still very low, therefore, it was not surprising to find that patients were not fully aware of this new cadre of specialists.Postgraduate training in FM is a recent initiative in Kenya, and there are now five training programmes (four in the public sector and one in the private sector). Postgraduate training in FM prepares doctors to become FPs with a more comprehensive set of competencies for PC and district hospital settings.Patients’ perceptions on the scope of practice may be shaped, not only by their experience, but also by shared beliefs in their families or communities on the services offered by the PC clinics. This may be based on past or other experiences of the health system, media stories or other factors. This may merit further studies.Because of the absence of a defined package of care, some diseases or services may not have been fully captured in the questionnaire. It is likely that the patients attending the eight clinics shared similar socio-economic and demographic characteristics to patients seen in the other PC clinics of the same hospital. Hence, the findings could be generalised to include patients attending all the PC clinics associated with this particular private tertiary care hospital, but cannot be generalised to other private and public health facilities.The FDs need to upgrade their skills for the management of different conditions, which will help them to improve the care provision. This will positively affect patient’s perceptions regarding their capabilities in handling various conditions and performing certain procedures.With the development of FM in Kenya, the FDs could be promoted to FPs after 4 years of postgraduate training. The FPs would bring a more consistent and comprehensive set of competencies to the practice. Patients, however, are not yet aware of the new speciality and might not change their perceptions or behaviour easily in a system that incentivises access to specialists. If patients have low expectations of PC, then the tendency to bypass clinics for anything but minor illness will be high.The beliefs of patient’s in this study are consistent with this type of health-seeking behaviour, which may change over time as the patients become more aware of the scope and services provided by the FPs.The health system provision would need to be changed and reorganised if highly trained and competent FPs are to be placed in the PC clinics in order for the patients to fully benefit.Here the managed care organisations might encourage patients to access specialist care through FPs because it is more cost-effective, accessible, comprehensive and patient-centred.Patients’ lack of confidence in a comprehensive PC service could also be addressed by clearly defining the expected package of care and ensuring that patients’ expectations and health-seeking behaviour are modified through effective communication strategies. The findings of the study may have been different if it had been carried out in the rural setting where access to specialist care is more difficult. Patients’ ideas could also be further explored in qualitative studies.Patients did not perceive that FDs could offer a fully comprehensive PC service and were not very clear about the difference between a FD and a FP.They believed that FDs could handle common illnesses, common chronic conditions and counsel on lifestyle change. They were less convinced that FDs could offer care for communicable diseases, such as HIV and TB, to pregnant women, small babies, the elderly, manage skin problems and offer some forms of prevention such as immunisations and cervical cancer screening. Perceptions may be addressed by defining the expected package of care, designing a system that encourages utilisation of PC and ensuring that care is offered by competent generalists. One way of ensuring this is to employ FPs in the PC clinics.


Haemophiliacs are hereditary coagulopathies whose basic anomaly consists of the quantitative or qualitative alteration of one or more plasma proteins in the coagulation system. The objective of this review is to analyse all risk factors, predispositions and alterations to the oral-maxillofacial district in patients with haemophilia. The broader assessment also includes the psychological aspects that could affect the treatment and maintenance of oral conditions. The study takes into consideration all the works in the literature in the last 10 years. Works that present oral, dental and psychological changes in haemophilia patients have been combined. A total of 16 studies were analysed carefully evaluating and explaining all the alterations and risk factors that this disease provides. The aim of the review is to report all the anomalies reported in the literature for these patients, and to direct and update the clinician in the treatment of haemophilia patients.  Haemophilia is a disease of genetic origin due to a defect in blood coagulation. It occurs only in the male sex, while women are healthy carriers: this is because it inherits in recessive mode through the X chromosome. Under normal conditions, in the event of leakage from the blood vessels, the blood forms a clot that prevents bleeding. This process involves the chain activation of several plasma proteins. In haemophilia, two of these proteins produced by the liver (factor VIII and factor IX) are deficient or present a functional defect ,2. The gThis review is registered at PROSPERO with ID number 122731. PROSPERO is an international database of prospectively registered systematic reviews in health and social care, welfare, public health, education, crime, justice, and international development where there is a health-related outcome. Is there a correlation between haemophilia and oral and dental alterations? Is their main pathology a risk factor for oral diseases?Is there a correlation between haemophilia and psychological conditions?The following focus question was developed according to the population, intervention, comparison, and outcome (PICO) study design: The search strategy incorporated examinations of electronic databases supplemented by hand searches. A search of four electronic databases, including Ovid MEDLINE, PubMed, and Dentistry, Oral Sciences and Psychology Source, for relevant studies published in the English language from January 2009 to January 2019 was carried out. The search was limited to English language articles. A hand search of the reference lists in the articles retrieved was carried out to source additional relevant publications and to improve the sensitivity of the search. OR Dental) AND Alterations) OR Defect) AND Haemophilia + Dental Haemophilia. OR Alterations) AND Haemophilia + Psychological Haemophilia.The keywords used in the search of the selected electronic databases included the following: The keywords were selected to collect and to record as much relevant data as possible without relying on electronic means alone to refine the search results.Two independent reviewers (G.C. and A.S.H.), analysed the obtained papers in order to select inclusion and exclusion criteria as follows. A complete independent dual revision was performed.The review included studies on humans published in the English language. Letters, editorials, case reports, and PhD theses were excluded. The review included all human Radomized Controlled Trials (RCTs), prospective and retrospective studies and clinical trials, cohort studies, case–control studies, and case series studies, animal studies and literature review published between January 2009 and January 2019, on haemophilia and dental, oral and psychological alterations.Haemophiliacs are hereditary coagulopathies whose basic anomaly consists of the quantitative or qualitative alteration of one or more plasma proteins in the coagulation system. The entities’ most frequent nosological diseases are represented by: haemophilia A, haemophilia B and the angioemophilia of von Willebrand. Haemophilia A is the most frequent pathology with an incidence estimated at 1:20,000–100,000 male births per year, of which 30% of cases are without familiarity (largely attributable to new mutations). It is a hereditary recessive coagulopathy linked to the X chromosome, in which the male is ill and has variously reduced plasma levels, while the female is usually a healthy carrier. The haemostatic defect derives from the lack of factor VIII to which follows a reduced generation of thrombin through the way intrinsic coagulation. The severity of the clinical picture is related to the degree of deficiency: a normal haemostasis requires a residual activity of> 25%; the majority of patients have levels below 5% and have spontaneous symptoms and complications. The symptomatology is represented by spontaneous haemorrhages or in relation to minor traumas . In 15% of severe haemophiliacs, antibodies of the IgG class (anti-factor VIII inhibitors) appear to decrease the efficacy of substitution therapy and make treatment difficult. Haemophilia B consists of factor IX deficiency and von Willebrand angioemophilia in a joint protein defect plasma of the coagulation cascade and vascular wall; the clinical picture is superimposable and requires replacement therapy with blood products. Based on the severity of the coagulant factor deficiency, we distinguish three different degrees of haemophilia: the severe form, in which an extremely reduced or absent activity of the coagulant factor (less than 1%) can be demonstrated; the moderate form, in which the plasma levels of factor VIII are between 1% and 5% of normal; and the mild form, in which the plasma levels of factor VIII are between 5% and 40%. There is a close correlation between the severity of bleeding symptoms and factor VIII activity levels. The disease in its severe form is characterized by massive haemorrhages, deaths, hemartri and bleeding disproportionate to trauma. In the case of trauma, in fact, the subject can also be at risk of a cerebral haemorrhage but more widespread are the muscular ones, which can cause serious difficulties in movement, and gastrointestinal haemorrhages , bleeding in cavities, haemorrhages of the gold-pharynx, the hemoftoe, epistaxis, hematuria, spinal hematomas. The moderate form is associated with haemorrhagic diathesis which does not lead, if not infrequently, to severe or haemorrhagic bleeding. In cases of mild form, although there may be bleeding after dental avulsions, trauma or after surgery, they are light and never have the character of copious haemorrhages. As for factor IX, this is essential for a prompt conversion of prothrombin into thrombin in native systems, but not in those employing tissue thromboplastin. Clinical manifestations are similar in both forms and only through laboratory tests, or by knowing family history, can we distinguish the two types. For the diagnosis of haemophilia, in the first place, blood analysis is performed to measure the partial thromboplastin time (PTT), which is more prolonged than normal. Confirmation and typing of haemophilia  is then supported by the deficient plasma protein assay. The treatment consists in the substitution therapy, that is in the administration of the missing factor  intravenously. The main complication of substitution therapy is the appearance, in the blood of the recipients, of antibodies directed against the factor VIII or IX, called “inhibitors”, which neutralize the effect, and which can make treatment difficult. Patients with mild haemophilia are usually treated with the missing factor concentrate only in case of surgery or after an accident or major injury. However, patients with mild haemophilia can face serious problems, especially because they cannot immediately recognize the signs and symptoms of haemorrhage. This would result in disabling consequences: untreated haemorrhage involves an aggravating pain due to the state of distension to which the surrounding tissues are subjected. In the long run, an articulation affected by a haemorrhage can become arthritic, resulting in chronic pain and disability [There are different systemic pathologies, and in particular genetic pathologies that have correlations with oral health. The most striking cases of oral abnormalities are represented by chromosomal pathologies. An example is the Down syndrome, where the patients present anomalies in the oral, hard and soft tissues and teeth. In these pathologies some teeth may be missing, or present anomalies of number or form. Other systemic diseases that show oral and maxillofacial district abnormalities are Gorlin–Golz syndrome, Stevens–Johnson syndrome and Lyell’s syndrome. Kawasaki syndrome also has muco-cutaneous changes and lifonodes. Dental abnormalities are present in Unverricht–Lundborg disease and in juvenile idiopathic arthritis ,10,11. ASurely patients suffering from systemic and genetic diseases have feedback from a psychological point of view. It is possible in some pathologies to highlight proper deficits of a cognitive type. These are associated with organic abnormalities of the patients. As mentioned in the previous paragraph, for example, cognitive impairment is evident in the Down syndrome and in Unverricht–Lundborg disease ,12. CognDentistry and psychology are closely related. This correlation covers different aspects. Suffice it to say that the term “odontophobia” was coined to describe the fear of the dentist, of dental care or of the dental environment . This paCorrelation between oral, dental alterations and haemophiliaPsychological condition of haemophilic patientsThe full text of all studies of possible relevance was obtained for assessment against the following inclusion criteria:Articles published prior to 1 January 2009Studies involving patients with other specific diseasesNot enough information supporting this reviewNo access to the title and abstractThe applied exclusion criteria for studies were as follows:After a careful analysis of the literature, all the titles of the articles were screened by the authors to eliminate all the non-useful results, case reports and non-English publications. Therefore, the researches were not selected on the basis of data obtained from abstract screening. The last phase involves an analysis of the full text and assesses the eligibility of each study, based on the inclusion and exclusion criteria.The data were independently extracted from studies in the form of variables, according to the aims and themes of the present review, as listed onwards.Data were collected from the included articles and arranged in the following fields :Assessment of risk of bias was undertaken by two authors during data extraction process. For the included studies, this was conducted using the Cochrane Collaboration’s two-part tool for assessing risk of bias ,33. An oAs shown by the studies analysed, there are correlations between haemophilia patients and oral health disorders. Furthermore, there are important correlations between haemophilia patients and psychological conditions. We will broadly evaluate all the various aspects of these correlations later on.Article review and data extraction were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram . The iniAfter the selection of the studies all the different aspects regarding the oral anomalies and the cognitive-psychological anomalies were evaluated .Dental Caries.Gengivitis/parodontitis.DMFT.Hemarthrosis.Bleeding.Pain.Psychological issues.Sexual Dysfunction and psychological issues.Summarizing the risk of bias for each study, most of the studies were classified as unclear risk. More studies were considered as having low risk of bias. Not all the studies analysed in this review of the literature carry useful information to verify the variance of the samples examined. A statistical analysis of variance cannot be performed between studies, but only within other works that present sufficient information to perform statistical calculations. In accordance with the evaluation and the findings of the works, some works present a risk of low bias , other works instead present a risk of bias not clear.The current review includes studies written in English only, which could introduce a publication bias. There were various degrees of heterogeneity in each study design, case selection, and treatment provided among studies.Dental care tends to be more conservative than in the past and above all thanks to advances in medicine in research it is possible to treat patients suffering from systemic diseases in safety. In this article we wanted to consider all the alterations or risk factor present in the field of oral health in patients affected by various forms of haemophilia. Also considering the psychological aspect, related to care or not. Patients with haemophilia live in a psychological condition of fear, due to what may occur following a trauma or a laceration of the skin or mucous membranes, and therefore the risk of bleeding. Complicating the situation, as evidenced by the articles taken into consideration, is the fact that their susceptibility to pain has increased. Von Willebrand disease, Haemophilia A and Haemophilia B account for 95–97% of all coagulation deficiencies for this reason the topic is current and has a good spread. There is a prevalence of oral diseases in haemophiliacs. The main oral diseases affecting these patients are the same of the rest of population: dental caries and periodontitis or gingivitis. A common alteration in these patients is hemarthras of the temporomandibular joint . AccordiThere were several limitations present in the current review. This study aims to highlight how this disease may represent a risk factor for oral diseases, and in parallel these patients can develop psychological problems if not properly supported. Much is present in the literature regarding these correlations, but unfortunately there are not many works to support the hemocoagulation pathologies.In this paper we have extensively debated the psychological conditions of these patients since their childhood. Unfortunately, this is a disabling pathology that tends to be present in the patients’ daily life. It is undoubtedly a risk factor for the onset of oral diseases, as highlighted during the discussion, these patients, as children, fear the bleeding caused by tooth brushing. This fear, a fear of bleeding that can also be complicated, often leads them to avoid these prophylaxis manoeuvres. Surely this leads to an aggravation of their condition compared to healthy patients. On the other hand, it must be considered that access to dental care by these patients is much more complex, as there are important medico-legal responsibilities in dealing with these patients. Often, colleagues are intimidated by this type of disease and tend to avoid treatments or send them to facilities where waiting times are much longer. We have certainly understood that it is possible to perform surgical practices on these patients by evaluating both systemic and collaborative conditions. however, it is necessary to carry out the appropriate protocols for each patient. As can be seen from some articles taken into account in our review, these patients often have a worsening of oral health conditions, not so much related to their systemic conditions, but due to their difficult management and, from a clinical point of view, and bureaucratic difficulties. Surely the path of research that we started with our team, will move in producing a guideline to the surgical treatment in the dental field of these patients. A guideline that can be used and consulted by all clinicians, so as to be able to treat these patients in a more secure and predictable way. Important support of this work regarding the psychological aspect of these patients, as already highlighted above, is essential during a dental treatment, especially if the patients are still in childhood.


Regular breakfast consumption has the potential to prevent the prevalence of NCDs and to improve the nutritional profile of diets. Given consumers’ interest in improving their diets, food suppliers are interested in introducing new cereal products making different health claims to capture consumers’ attention. The purpose of this study is threefold: first, it aims to understand whether UK food suppliers are working to increase the availability of breakfast cereals with healthy and nutritious attributes; second, it explores which companies are leading the launch of these products; and third, it assesses to what extent health and nutrition claims made by breakfast cereals have an impact on their market success. The study employs an assembled database combining data from Mintel Global New Products Database (GNPD) and Kantar Worldpanel Dataset (KWDS) for the UK. A hazard-based duration model was used to analyse the success of the new products launched in the UK market in 2011 following them up to 2015. Our results reveal that UK suppliers broadened the number of breakfast cereals on offer in the period 2000 to 2018, with a particular focus on multigrain cereals, porridge and granola. Health and nutrition claims were added to 27% of these products. Although consumers welcome healthy alternatives such as muesli, the impact of positional claims on the success of newly developed breakfast cereals is claim-specific. No clear pattern regarding the impact of health and nutrition claims is identified. However, other elements such as celiac-friendly ingredients and UK origin do have a positive impact on the success of breakfast cereals. Diet quality has been reported to be an important risk factor for non-communicative chronic diseases  ,2. Poor-Gaal  and ReevIn terms of firm competition, the breakfast cereal market displays common characteristics with fast-moving consumer goods, which compete intensively to introduce new products . RaubitsNew breakfast cereals are introduced following consideration of several positional claims trying to attract consumers. For instance, products may contain a high level of fibre and protein content, added vitamins and other nutrients, such as calcium and iron, less sugar and additional multigrain ingredients. Positional claims are strategic in food marketing because, in many cases, food choices are made at the point of purchase . Claims Previous studies have observed the positive impact of health claims on consumers’ evaluations of food ,24. MoreTo what extent are UK food suppliers working to increase the availability of breakfast cereals with healthy and nutritious attributes?What are the companies that are leading the launching of these products? Which is the role of private labels?What claims are particularly important for the market success of newly developed breakfast cereals?Several studies have audited the prevalence of health claims in different EU and non-EU countries and analysed their impact on healthy diets ,27. OtheThe results reveal that manufacturers and retailers are actively working on the introduction of new options with health and nutritional claims. Some of these claims do affect the success of the new product in the market, but no clear pattern can be identified.The structure of the paper is as follows: it begins with the empirical section, which describes the data and methods. The following section presents a description of the introduction of new products in the UK breakfast cereals sector and the results of the survival analysis, considering the uptake of newly developed breakfast cereals. The final section provides the discussion and conclusions.The first part of this study employs the Mintel Global New Products Database (GNPD) to present and provide an overview of the introduction of new breakfast cereals launched in the UK between January2000 and September 2019 . The dataset contains information on 2262 new breakfast cereals launched in different types of retail stores between January 2000 and September 2019 by 282 manufacturing or retailing companies using 700 different brands.The products are classified into two categories, cold and hot cereals, and into 12 subcategories, as follows: corn cereals, granola, muesli, multigrain cereals, oat-based cereals, porridge, quinoa cereals, rice cereals, rye cereals, spelt cereals, wheat cereals and other. The database also contains information on the type of label , introduction price, and type of packaging. The fact that the dataset also provides information about the positioning claims of each product was particularly important for this study; 96 different claims were found in the dataset for breakfast cereals. This is important because such claims convey information to consumers about the product. For the analysis, these claims were classified into five groups: convenience , demographic , health and nutrition , safety , sustainable  and others . See The second part of the study employs an assembled database combining data from GNPD and the Kantar Worldpanel Dataset (KWDS) for the UK. GNPD data were used to gather information on which new breakfast cereals were launched in the UK market in 2011. KWDS includes weekly records of all foods and beverages that were taken home from supermarkets and similar stores by UK households during the period 2013 to 2015. The breakfast cereals products observed in the GNPD database were identified in KWDS to follow its sales in UK retail and trace their durability in the market.t, as follows:T is a continuous random variable, T can also be expressed as the hazard function, which is the rate of occurrence of the event. In our case, the event means failing or disappearing from the market, and this is expressed as follows:In order to respond to the first and second research questions—exploring the trend in the introduction of breakfast cereals and identifying the leading suppliers—this research employs descriptive statistics . To assess the influence of product claims on consumer acceptance, this study uses hazard-based duration models, which provide an explanation on the length of time that launched breakfast cereal products survived in the market. Duration models are based on the survivor function, which in our case is the probability of the product still being available in the market up to a specific time t), In order to estimate the hazard function, different models can be used depending on the shape of the hazard and the features of the explanatory variables included in the model. A Cox’s proportional hazards model  was estiDue to the highly concentrated breakfast cereals market, companies invest in research and development in order to differentiate their products and increase their market share. It is important to note that 96% of the newly launched products make a positional claim on the packaging. Health and nutrition claims represent 27% of all the claims on the newly introduced breakfast cereals for the period January 2000 to September 2019. The most frequent health claim for the period January 2000 to September 2019 is identifying the product as wholegrain. A total of 40% of the newly introduced products—1043 products—claim to be wholegrain. The claim emphasising a high presence of fibre is the second most frequent, with 37% of the newly launched products carrying this claim—970 new products. Products claiming to be fortified with vitamins and minerals and those declaring they have low or reduced levels of sodium comprise around 20%—549 and 491 products. Claims regarding allergens, such as low/no/reduced allergen or gluten-free are also important; these are made by 17% (446 products) and 16% (427 products) of the new products, respectively. Claims of containing less fat are carried by 12% of the newly developed breakfast cereals (303 products). Finally, the remaining health and nutritional claims are made by less than 10% of the new products. First, we undertook a descriptive analysis of the success of the new breakfast cereals see . Table 4Second, we examined the factors influencing the success of the newly developed breakfast cereal products in the UK market using a duration model. p < 0.10. The remaining launch strategies considered were not significant and were removed from the model. We can observe that the rate of failure of products launched with new packaging compared to other launch types (ceteris paribus) is 44% lower. The second and third variables considered were the type of company introducing the product (private company launching branded products or retailer launching private labels) and the introduction price. However, the t values were found to be non-significant for our model and they were, therefore, removed for the final estimation. Next, the origin of the product (UK or not) was considered, and interestingly this variable resulted in significant reduction of the probability of failure. However, its hazard ratio was minimal.The first variable considered in this analysis was the launch type . The estimation revealed that the only launch strategy with a significant impact on the probability of the success of new breakfast cereals is the introduction of new packaging with a The impact of the type of breakfast cereal  on the uptake of the product was also considered. The only category that was found to be significant was muesli, with a 76% lower chance of failure than other categories (ceteris paribus).Considering the relevance of the ingredients listed on the product packaging , only the wheat and rye results were significant and were, therefore, retained in the final model. We can observe from Regarding the utility of including claims, we can observe that the probability of failure for products not including claims is higher than for those making claims. In particular, not listing any claim on the cereal package increases the risk of failure 9.58 times compared to products that do include claims (ceteris paribus). When considering the different claims associated with the newly introduced breakfast cereals, only ten claims had a significant result and were, therefore, included in the final estimation. Half of the significant claims are health- and nutrition-related claims, three are sustainability claims, there is one safety claim and, finally, one convenience claim. The impact that the different claim groups have on the uptake of the products can be either positive or negative, depending on the claim. It is important to highlight that all claims with a positive impact appear to have a very small hazard ratio. This means that its effect is significant but very small; this is the case for products stating to have added calcium and making low/no/reduced glycaemic index health claims. Another claim with a small but positive impact on the success of new breakfast cereals is all-natural products, which we consider as a safety claim, but it can also have some health implications. Sustainability claims, such as ethical animal and organic, also increase the probability of success of new breakfast cereals. Other health and nutritional claims, such as improving the brain and nervous system, with low/no/reduced lactose and prebiotic, increase the probability of failure by 5.9, 8.2 and 10.5 times, respectively, compared with products not labelled with these claims. Finally, being an environmentally friendly product and being instant reduce the probability of success of breakfast cereals 3.174 and 3.969 times, respectively.Interactions between subcategories and claims were considered in the analysis; the results were non-significant, and these variables were eliminated from the final estimation.The present study first explores whether food suppliers  are working to increase the range of breakfast cereals they offer and whether these new products are labelled with health and nutritional claims. Second, it identifies which suppliers are leading this process, and third it assesses to what extent health and nutrition claims made by breakfast cereals have an impact on their market success.An increasing number of new breakfast cereals were introduced into the UK market during the period 2000 to 2015, with a clear reduction in the number of new products from 2016 to 2018. Our results show that 96% of the newly developed breakfast cereals launched from 2000 to 2019 do include positional claims. Therefore, we can state that manufacturers and retailers include health and other information to differentiate their products effectively and, as indicated by previous research , potentiAmong the positional claims, we identified health and nutrition, sustainability, convenience and demographic attributes. The most common are demographic claims, which are included in 77% of all new breakfast cereals. It is essential to note that being suitable for vegetarians comprises 66% of the products with demographic claims. Moreover, if we also include products informing customers about the absence of animal ingredients or reporting to be suitable for vegans, this encompasses 97% of all the new products making demographic claims. Taking into account that a reduction in the use of animal ingredients is an important aspect of achieving a rich and healthy diet, we can state that, by including these claims, suppliers are, in a way, assisting consumers to not only make ethical and sustainable choices but also healthier ones.The second most numerous claims are health- and nutrition-related, present in 27% of the new breakfast cereals. Although we identified 51 different claims for this group, the most frequent are those reporting that the product is wholegrain, which appears in 40% of the products making health claims. Informing customers about the high level of fibre in the new product is also a very common claim. These two claims are particularly important in improving the nutrition levels of Western diets and they can explain the higher consumption of high-fibre cereals per person compared to other breakfast cereals reported in the introduction section. Health claims reporting the absence of allergens have also become increasingly frequent since 2014. These claims can have a positive impact on the section of the population suffering from food allergies and food intolerances that require them to avoid specific ingredients in their diets. Adverse reactions to foods have been reported to represent a key health-issue in Western societies . It is aOur results demonstrate that the breakfast cereal industry in the UK follows the diversification model defined by . A smallIn line with previous research on the success of newly developed products, our results support the suggestion that a limited proportion of newly launched products succeed in the market in the mid- to long-term. We found that less than 40% of the newly introduced breakfast cereals succeeded in the UK market in the medium–long term. This result highlights the complexity of finding a good new product development strategy and explains why this activity is mainly concentrated among big companies that can afford the economic implications of failing in the food market, and who can also undertake broader market research strategies to capture consumers’ needs.Regarding the impact of health and nutritional claims on the success of newly developed breakfast cereals for the UK market, there is no clear pattern. Our Cox regression results clearly show that placing claims informing consumers about the benefits of the newly developed breakfast cereals on the packaging does positively influence the success of these products in the market. That is, when consumers are informed about what they can get from a newly developed product in comparison to other options, they are more likely to purchase it. This result is in line with . The estWe also found that the ingredients listed on the product packaging have an impact on the uptake of the products. Our results show that using wheat as an ingredient reduces the level of success of the newly developed breakfast cereals, while including rye as an ingredient increases its success. This result may be related to the increase in the incidence of celiac disease and the negative information reported on social media about gluten and wheat as a cause of obesity and other health problems . Our resInteractions between subcategories and claims were considered in the analysis, but the results were non-significant and were, therefore, eliminated from the final estimation. The lack of significance found in these interactions may be due to the sample size. The products introduced over one year might offer limited variability within the different categories and claims.Taking these results together, we can suggest that manufacturers and retailers are assuming a proactive and important role in research and development to capture consumers’ needs and, therefore, help consumers to move towards healthier and better diets. Positional claims carried by food products need to be very clear on the potential benefits and risks of the products in order to be of real help to consumers in their food-purchasing decisions. Future research can consider a longer time period and the nutritional value associated with the newly introduced products.