Bacterial infections caused by antibiotic-resistant isolates have become a major health problem in recent years, since they are very difficult to treat, leading to an increase in morbidity and mortality. Nitrofurantoin is a broad-spectrum bactericidal antibiotic that, through a complex mode of action which is not completely understood, affects both Gram-negative and Gram-positive bacteria. Nitrofurantoin has been used successfully for a long time for the prophylaxis and treatment of acute lower urinary tract infections in adults, children and pregnant women, but the increased emergence of antibiotic resistance has made nitrofurantoin a suitable candidate for the treatment of infections caused by multidrug-resistant pathogens. Here, we review the mechanism of action, antimicrobial spectrum, pharmacology and safety profile of nitrofurantoin. We also investigate the therapeutic use of nitrofurantoin, including recent data which highlight its role in the management of community urinary tract infection, especially in cases of multidrug-resistant isolates, in which oral active antimicrobials are limited resources nowadays. Nitrofurantoin, a chemotherapeutic compound of the nitrofuran family, was introduced into clinical practice in 1952. Nitrofurantoin is a synthetic antimicrobial derived from furan by the addition of a nitro group and a side chain containing hydantoin . NitrofuThe exact mode of action of nitrofurantoin is not completely understood, though it is mainly known to inhibit a number of bacterial enzymes that participate in bacterial carbohydrate metabolism at three points in the Krebs cycle  as well in vitro susceptibility includes the majority of Escherichia coli, Citrobacter species, group B streptococci, enterococci, Staphylococcus aureus, S. epidermidis, Klebsiella pneumoniae and Enterobacter species [Nitrofurantoin spectrum of  species . Thus, i species .Nowadays, in Spain, the compound is marketed as both an oral suspension and tablets. The bioavailability is about 90% and the urinary excretion is 40% .Nitrofurantoin is well absorbed from the gastrointestinal tract with the most absorption occurring in the proximal small bowel. There are many factors which affect bioavailability, but studies have shown that the amount of drug absorbed and the duration of therapeutic urinary concentrations are substantially increased if nitrofurantoin is taken with food . ParticlNitrofurantoin is excreted almost exclusively in the urine and bile. Urinary excretion results from glomerular filtration, tubular secretion and tubular reabsorption. Tubular reabsorption of nitrofurantoin is pH dependent. Thus, manipulating the urinary pH permits preferential concentration of nitrofurantoin into the upper or lower urinary tract . NitrofuThe excretion of the drug is directly related to creatinine clearance . In the in vitro. Nitrofurantoin can alter a number of laboratory test results. Thus, there may be elevation of the urinary creatinine value. Also, the urine glucose determination using Benedict´s qualitative reagent may yield a false-positive result. Serum levels of glucose, bilirubin, alkaline phosphatase and blood urea nitrogen may be spuriously elevated. Also, patients should be warned that the color of the urine may be altered (brown) [It has been suggested that antacid therapy would increase the ionization of nitrofurantoin, resulting in decreased absorption. Also, nitrofurantoin is a potent inhibitor of primary adenine diphosphate-induced platelet aggregation  (brown) .Nitrofurantoin is, overall, a relatively safe drug. The overall experience after more than three decades of extensive use shows a very low reported side-effect incidence of less than 0.001 per cent based on total courses of therapy ,13,14. HGastrointestinal disturbances  are the most common side effects. They usually develop during the first week of therapy and efforts have been made to reduce their frequency by altering the nitrofurantoin crystal size, thus modifying the absorption. Skin eruption, consisting of macular, maculopapular or urticarial lesions, are the second most common side effect of nitrofurantoin. Hemolytic anemia in patients with red blood cells deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD) is a well-documented hematologic complication of nitrofurantoin therapy . A serioThe incidence of these side effects is difficult to ascertain, and they are probably on the same order of magnitude (or less) than severe antibiotic associated diarrhoea caused by beta-lactam drugs or fluoroquinolones, or severe skin eruptions caused by trimethoprim/sulfamethoxazole .et al. [While medical literature generally defines nitrofurantoin as an antibiotic that is safe for use during the first trimester of pregnancy, new concerns about a possible association between congenital malformations following exposure to nitrofurantoin during the first trimester of pregnancy have recently surfaced. During the last decade, several studies have suggested an increased risk of enophthalmia, cardiovascular malformations, oral cleft, and scull anomalies ,18. Howeet al.  support et al. . Moreoveet al. . HoweverThe conventional dosage of nitrofurantoin for an established urinary tract infection is 50 mg or 100 mg four times a day and it started being prescribed both in adults and children for the treatment of acute symptomatic urinary tract infections, also for the treatment of recurrent urinary tract infections and finally for the prophylaxis of recurrent urinary tract infections .Another of its main indications is that of bacteriuria of pregnancy, which occurs in approximately 7 to 10 per cent of all pregnant women . NitrofuDuration of nitrofurantoin therapy has always remained controversial. Lumbiganon and co-workers sought to find out if the dosing schedule of nitrofurantoin could be decreased from the traditional seven days of treatment to one day to increase compliance, while retaining its efficacy in the treatment of asymptomatic bacteriuria in pregnant women . AlthougAlso, a decrease in the number of doses per day has always been desirable. Recent data indicate that nitrofurantoin three times per day, instead of four, either in adults or in children, could be effective in the management of UTIs, increasing adherence to nitrofurantoin treatment and sparing the use of other antibiotics .et al. [Recent data suggest nitrofurantoin as the first drug of choice for treating uncomplicated UTI in women. Nitrofurantoin has been recently compared to trimethoprim/sulfamethoxazole and proved equally effective. Moreover, it was less likely to cause a rash while having similar rates for any adverse event. Based on these findings nitrofurantoin should probably be considered the first drug of choice for treating uncomplicated UTI in women . Also, Get al.  reportedet al. . Finallyet al. .Nowadays, nitrofurantoin is a synthetic nitrofuran antimicrobial agent that has been used for more than 50 years. It still has a role and continues to be prescribed, particularly in the ambulatory setting for uncomplicated UTIs, especially in its macro-crystalline formulation. In recent years, there has been a new interest in “rediscovering” new applications for older antibiotics due to changes in pathogen distribution and resistance. Regarding nitrofurantoin, it has been suggested for the treatment of UTI caused by multiresistant strains.i.e., catheter-associated bacteria). It is one of the few non-ampicillin derivatives that is active against enterococci. Nitrofurantoin is active against both vancomycin-sensitive enterococci (VSE) and VRE. It is the preferred oral antibiotic for nosocomial VSE or VRE catheter-associated bacteriuria [In this sense, nitrofurantoin is being used increasingly at present to treat vancomycin-resistant enterococci (VRE) nosocomial urinary tract infections  [et al. [E. coli in the urine (>105 CFU/mm3). Microbiological success was defined as a sterile control urine culture and it was achieved in 51 out of 75 patients (68%). Also, Chen et al. conclude that nitrofurantoin may be an alternative in the treatment of ESBL-producing E. coli-related lower UTI [Also, the progressive increase of extended-spectrum b-lactamase (ESBL) producing enteric bacteria in recent years has called for a re-evaluation of current antibiotic therapy for these infections. The rate of resistance to nitrofurantoin in recent surveys in the USA and Canada was 1.1% among 1,142 isolates of isolates . Very si in 2005 . Howeverurantoin . Also, Eospitals  and in Iospitals . In K. p< 0.001) . These r [et al.  who studower UTI ,44,45. E. coli non-ESBL is excellent. In a recent study, the susceptibility for E. coli was 99.5%. High susceptibility of E. coli clinical isolates to nitrofurantoin (2.3% resistance rate), compared to trimethoprim/sulfamethoxazole (29%) or ciprofloxacin (24.2%) was recently confirmed [E. coli, such as Klebsiella spp. (69.2%) or Enterobacter spp. (63%). There is no activity against Proteus spp. or P. aeruginosa [E. coli is the most common pathogen, typically being isolated from approximately 80% of outpatients with acute uncomplicated cystitis across the various regions of the world [E. coli therefore determine the empiric antibiotic treatment. The range of pathogens associated with acute uncomplicated pyelonephritis is similar to that seen in acute uncomplicated cystitis [Nevertheless, activity against onfirmed . Howeverruginosa . Nowadayruginosa . In uncohe world ,50,51. Icystitis . The moscystitis . The reset al. [Finally, Slekoveck et al.  state thNitrofurantoin has been used for a long time, but the emergence of antibiotic resistance and the decline in newly developed antibiotics has increased interest in the treatment of bacterial UTI with this antibiotic. Pharmacology limitations, such as four doses per day needed, may be soon something of the past. Not only has resistance to nitrofurantoin remained virtually unchanged since its discovery but also its safety profile have made it the antimicrobial of choice in the prophylaxis and treatment of lower UTI in adults for many years. In this new microbiological era characterized by multi-drug resistant pathogens, nitrofurantoin’s role is crucial.


Lifestyle is an important aspect in maintaining good health in older adults, and home health care (HHC) workers can play an important role in promoting a healthy lifestyle. However, there is limited evidence in the literature regarding how to develop an effective training programme to improve the physical activity level and fruit and vegetable consumption of older adults within a HHC setting. The aim of this paper is to describe how Intervention Mapping (IM) was used to develop a training programme to promote preventive activities of HHC workers relating to the physical activity and fruit and vegetable intake of older adults living at home.IM, a systematic theory and evidence-based approach was used to develop, implement and evaluate the training programme. This entailed a literature search, a survey, semi-structured interviews and consultation with HHC workers and various field experts, and a pilot training session.The determinants associated with the provision of preventive activities were identified, and an overview was created of those objectives, matching methods and practical applications that could influence these determinants. The performance objectives for the HHC workers were early detection and monitoring, promoting a healthy lifestyle, informing colleagues, continuing allocated preventive activities and referring to other experts and facilities. Findings were translated into a comprehensive training programme for HHC workers focused on motivating older adults to adopt and maintain a healthier lifestyle.IM was a useful tool in the development of a theory-based training programme to promote preventive activities by HHC workers relating to fruit and vegetable intake and physical activity of older adults. Lifestyle is a key factor in good health; this is also true for older adults . SufficiHome health care (HHC) could prove an important setting for interventions here. HHC in the Netherlands is a form of nursing care provided at home, comparable to nursing practices at home in e.g. France and Germany. This care can be given, for example, to clients with chronic illnesses, clients with a handicap or to older adults to support ADL. Nurses conduct more simple care tasks, e.g., washing clients, or more complex medical nursing tasks, e.g., setting insulin dosages, depending on their level of nursing education. HHC workers are a valuable channel for providing preventive activities because they are in frequent contact with their clients and can therefore observe changes and developments in the clients’ behaviour, but evidence on the effectiveness of these activities lacks. Another advantage is that they observe their clients in an environment that is safe for the clients: their own homes. Furthermore, a relationship of trust often forms between HHC worker and client, which makes it easier for the HHC worker to raise the subject of lifestyle.Interventions in the HHC context show promising results, for example positively affect health and functional status for a diversity of interventions provided at home –31, 43 aThe provision of preventive activities by HHC workers is low and could therefore be improved (unpublished manuscript submitted for publication). In order to achieve this, it is first necessary to describe the different preventive activities that HHC workers can execute to promote physical activity and healthy eating. These activities can be divided into six areas: early detection and monitoring, informing, promoting, continuation, referring and recording. Early detection and monitoring means detecting health risks such as inactivity or the risk of obesity. Informing means discussing the advantages of healthy and disadvantages of unhealthy behaviour with the client. Promoting entails motivating the client to be more physically active and to eat more healthily. Continuation means continuing to provide the activities that colleagues have been providing or to follow up with new activities. Referring entails informing clients about opportunities in the area if extra help is needed to change their behaviour. The last area, recording, means registering the health of clients in their health records. All these preventive activities are executed in the context of the individual client, meaning that the HHC worker always is sensitive to the individual needs of the client and inquires what the client can and cannot do by himself. For example, when it concerns dietary habits, the clients’ needs and wishes are mapped, as well as who is doing the shopping and who prepares the meals. As HHC workers have not previously perceived lifestyle prevention to be among their duties, they consequently do not provide it. Intervention is therefore necessary to encourage them to provide such preventive activities.There is limited evidence in the literature regarding how to develop an effective training programme, specific within a HHC setting, to improve the physical activity level and fruit and vegetable consumption of older adults. Intervention Mapping (IM) was therefore used for the process of developing a training programme , 6. As IIM was used to develop this training programme , 6. It cBelow we first describe the most important groups of that are involved: The HHC clients as the target group, and the HHC workers as the channel. In the subsequent steps of Intervention Mapping, information needs to be gathered systematically from different types of sources, using different methods. These methods  are next described below. The Medical Ethical Committee of the University Medical Center Groningen evaluated the study protocol and considered it was not necessary to file it for ethical approval.The training was developed for HHC workers within an HHC organization in a deprived, rural area of the Netherlands. This deprived area entails many inhabitants with a low socioeconomic position (SEP), with more unhealthy behaviours, more chronic diseases and a lower life expectancy compared to other regions of the Netherlands. The target group, clients of the HHC workers, were community-dwelling, dependent older adults who receive home care. Clients with various health problems of differing severity were taken into account, with the exception of those with mental diseases such as dementia and those who receive palliative care.The HHC workers with whom and for whom the training will be developed worked in the selected areas and included nursing aides and registered nurses who provide care at home for the clients the most. These HHC workers provide their clients with basic and medical and nursing care. Their common task also includes prevention, which can mean detecting emerging problems such as pressure ulcers, malnutrition, obesity, falling, problems with medication use, depression and incontinence .A first means of gathering information to develop the training programme is a literature search. This was conducted in EBSCOhost and ScienceDirect to find relevant information from other studies that could be integrated into the training. Various combinations of the keywords lifestyle, physical activity, exercise, fruit, vegetables, diet, preventive care, preventive activities, prevention, health promotion, psychosocial determinant, nurse, homecare, elderly, older adults, intervention, programme and training were used. The search began in 2011, and updates were carried out until June of that year. Only articles written in English were taken into account.Furthermore, while following IM, suitable theoretical methods and practical applications were chosen that could influence the relevant determinants. A theory-based method is a technique or process used to influence the determinants of behaviour. Applications are techniques that use theory-based methods in a way that suit the intervention population and context , 6. In aSecond, a survey was conducted in one of the work areas of the HHC workers to generate an overview of the enabling determinants and barriers that might be associated with the provision of preventive activities. The analyses of this survey showed that social support, social pressure, role modelling and knowledge were associated with the performance of preventive activities. These potentially modifiable factors have been taken into account when developing the training programme. Forty-six HHC workers, not included in this study, response 40 %, used a self-report questionnaire to rate whether they conducted twenty-eight types of preventive activities relating to physical activity and healthy eating. They were also asked about what motivated them to provide these preventive activities. More information can be found in the study of Walters, Dijkstra, de Winter and Reijneveld (unpublished manuscript submitted for publication).Third and prior to the development of the training, semi-structured interviews and meetings were held with local field experts to gather information about which tasks undertaken by the HHC workers related to prevention together with the possible determinants that could influence them. These experts were district managers of the HHC organization, a medical officer, a senior staff member of the community, a sports consultant, a manager of a social work foundation and a general practitioner. In addition, five semi-structured interviews were conducted with HHC workers to discover what motivated them to engage in preventive activities and what could be possible barriers for them not to perform these activities. This information was used to further tailor the training programme to the HHC workers. Verbal consent was obtained for all interviews.A final way for input for the training development was a pilot study. A pilot training was set up to pre-test several aspects of it. This pilot training was evaluated and minor modifications were made to the training protocol.The I-change model  explainsIn this paragraph, the results of the six steps of Intervention Mapping are presented.The purpose of this step was to analyse the problem faced by the target group, older adults. The problem of an unhealthy lifestyle accounts for our target group, older adults living in a rural part of the Netherlands, the region of Groningen. Approximately 60 % of older adults (65+) in the province of Groningen are overweight and 37 % do not meet the Dutch physical activity recommendation . In addition, approximately 67 % do not meet the recommended intake of vegetables (200 g a day) and 50 % do not meet the recommended two pieces of fruit a day . These nAction is therefore needed to change the unhealthy behaviour patterns of these older adults in region of Groningen and encourage them to adopt a healthier lifestyle. The study focused on the HHC workers providing preventive activities to promote a healthy lifestyle. It seems that, despite their potential influence, the HHC workers do not make full use of this opportunity. The literature tells us that only half of all nurse practitioners provide preventive counselling on physical activity on most days of the week, and only a third of physicians discuss nutrition or diet with their patients , 15. FurThere could be several explanations for the behaviour of the HHC workers. Psychosocial factors, such as level of knowledge, could have an effect on their behaviour, and work-related factors, such as the work culture within the organization and facilities such as a reporting tool, could also be associated with the provision of preventive activities. These factors will be further elucidated in step 2.In this step, specific determinants that could change the target behaviour were defined, and the programme goal and corresponding objectives formulated. This overall goal was divided into five separate performance objectives and translated into change objectives based on the needs assessment, literature search, survey and interviews with HHC workers and experts in the field  believed that the following were important determinants for the provision of preventive activities: the HHC worker’s level of knowledge, the quality of the relationship between the HHC worker and the client, the HHC worker having only a limited focus on health and a limited focus on health within the area. An important determinant that arose in the interviews with the HHC workers and was also found in the literature was a lack of client interest in changing their behaviour , 27. TheIn addition, the survey showed that the determinants social support, social pressure and modelling were associated with whether HHC workers provide preventive activities relating to physical activity and healthy eating. This accounted for the total provision of preventive activities but also for specific activities such as informing the client, promoting a healthy lifestyle and continuation and recording of activities.awarenessknowledgeself-efficacyattitudeskillssocial influence.Once the above performance objectives and relevant determinants had been defined the following psychosocial determinants were selected that could be influenced or considered a preconditioning factor. Additional determinants from the I-change model that might influence whether the HHC worker provides prevention activities, such as attitude, self-efficacy and awareness, were also included. This yielded the following determinants that could be influenced . The health-related behaviour-checklist and registration tool were developed to support the HHC worker in providing preventive activities. The checklist concerns a list of various preventive activities the HHC worker can perform, whereas the registration tool is used as a monitoring tool for the HHC worker to register the agreements reached with the HHC client. In addition, various situations in which client behaviour seemed difficult to change were discussed. It was important that the HHC workers learned how to determine the clients’ personal goals in order to motivate them to change their behaviour.The second training session was about practising motivating the client to adopt a healthier lifestyle. During this training session their experiences, both successes and failures, were discussed and were taken into account to further develop their knowledge and skills. The HHC workers were trained in how to converse with clients about their lifestyle and how to do this in a supportive way using motivational interviewing and persuasive communication. They also learned how to determine which stage of change the client was in and therefore adapt the motivational preventive activities to this specific stage.The third training session focused on motivating the client to continue with a healthier lifestyle, even after a relapse. The HHC workers also learned how to give and receive feedback to and from colleagues and supervisors so that preventive activities can be discussed in work meetings. The HHC workers also discussed how to continue providing preventive activities and how to deal with barriers to this. See Table The materials developed for the three training sessions consisted of a lifestyle checklist, registration tool and training booklet. The HHC workers can use the lifestyle checklist as a communication tool for addressing lifestyle with the client, and the registration tool to ensure continuity and as an aid in monitoring the preventive activities they have allocated. These tools are added to the client’s health file. The training booklet contains practical assignments that the HHC workers carry out during the training as well as the theory on communication with clients and how to overcome barriers clients may encounter when attempting to change their lifestyle.In addition to the training programme, the HHC workers and their supervisors attended work meetings every 6 weeks. The topic of prevention was on the agenda at these meetings, and the HHC workers could discuss the preventive activities they provided and address any barriers they faced. Their colleagues and supervisor could offer any advice or share any experiences. These meetings also meant that the HHC workers received feedback and thus felt supported in the provision of preventive activities, which encouraged them to keep up the good work.The adoption and implementation of this training programme was kept in mind to ensure that it could be applied to the field of study and in future to a different field or community adoption of the program is crucial for example for the creation of support and ownership of the workers for the training. According to Rogers , the ratDuring the training programme, several important aspects became apparent that need to be taken into consideration. For example, it was important to involve the HHC workers in the programme adoption and implementation phase. This was achieved by discussing any ideas and recommendations that the HHC workers might have during the training sessions and taking them into account when developing the adoption and implementation plan. For example, the HHC workers indicated the way how they wanted to register the provided preventive activities and thus gave input for the registration tool. This ensured that the training programme was optimally tailored to the HHC workers and based on their own input. Moreover, involving the HHC workers in this process seemed to motivate them more to make a contribution and start providing prevention activities themselves. To ensure the full involvement and commitment of the HHC organization and allegiance of the intervention implementation, meetings were held with the management staff of the organization about the provision of prevention and the training. To further reinforce the implementation, supervisors discuss the provision of prevention with the HHC workers.An inventory was also made of barriers, facilitators and ideas for the implementation suggested by the HHC workers, training instructors and management team of the HHC organization. It is very important that the supervisor of the HHC workers pays regular attention to the programme and the topic of lifestyle. This together with the assurance of continuity can be a standard item on the agenda of work meetings.For the evaluation of the training programme, a longitudinal study with a quasi-experimental design will be carried out that will measure any changes in the behaviour of the HHC workers and their clients. The training development process will also be evaluated. This will show us how effective the training programme has been, and whether changes need to be made or the programme discontinued should the effects prove counterproductive. In this longitudinal study we aim to include two hundred HHC workers and three hundred HHC clients. A comparison will be made between two groups, a trained HHC worker group, and their HHC clients, and an untrained HHC worker group, and their HHC clients. Intermediate and final outcomes will be measured both at the level of the HHC workers and of their clients. The HHC workers will evaluate the programme at the end of each training session, both in a discussion and on an evaluation form. In addition, the training instructors, supervisors of the HHC workers, the management team of the home health care organization and the project management group will evaluate the training at evaluation meetings, in which they consider the value of each part of the training. This information can be used to adjust the training during and after the implementation of the programme.The HHC workers and their clients will also evaluate the effect of the training programme at three time points in time: before the programme begins (baseline) and 6 and 12 months after the baseline measurement. The HHC workers and clients will fill in a questionnaire that asks them about the preventive activities they have provided or received. In addition, the level of physical activity and dietary pattern of the clients and satisfaction of the received preventive activities will be measured by questionnaire at these three points in order to determine changes in behaviour and satisfaction with the received training. The information obtained will be used to evaluate the training programme and decide whether changes need to be made and whether the programme as a whole should be continued. A control group will be added to the study to create a quasi-experimental design.The aim of this article was to describe the use of IM to develop a training programme to promote preventive activities by HHC workers relating to the physical activity and fruit and vegetable intake of older adults living at home. We presented the methods used and the results of Intervention Mapping steps and how information was gathered to build the program. IM was chosen because it has been widely used by several researchers, although not used in a HHC setting and community-living older adults, who found it to be a fitting, useful, systematic and practical framework , 26, 33.IM proved to be a helpful tool in developing a training programme tailored to the needs of the target population, in this case HHC workers. The training programme was based on theory, matching methods and practical applications. IM facilitated the identification of those determinants that needed to be influenced to ensure behavioural change. The use of IM during the process of intervention development also created the opportunity to adjust the training programme during the implementation phase. Using IM in the development of a training programme meant that it was systematically developed, theory-driven and based on the available evidence. Interventions developed on the basis of the theory are often more effective when they target determinants of behaviour and behaviour change . In the Other studies describing the development of a training programme also reported that IM was a helpful, beneficial or valuable tool , 46, 50.Although IM is a valuable tool, it nevertheless has certain constraints that should be mentioned here. As IM is so broad and thorough, it makes training development a long and time-consuming process. While defining the multiple IM steps, constraints such as lack of information became apparent, for example information about the intensity and frequency of a training programme and how to implement and adopt it. In addition, the programme addressed a selection of risk behaviours, physical activity and dietary pattern, instead of multiple risk behaviours such as smoking or alcohol misuse. It is not yet clear which strategy works best. IM was selected for the development of the training programme, but there are other frameworks for developing behavioural interventions. It is therefore recommended that more extensive studies be conducted that take into account the aforementioned points.This study has several strengths. Multiple methods were used, such as a survey of HHC workers, interviews with field experts and a pilot training session in the development of the training programme. This was to make sure that sufficient information was available at the start of the programme development. As the stakeholders were involved, the training programme could be tailored to the HHC workers and thus ensure relatively smooth implementation in the organization.In addition to the strengths, it is important to note some limitations to the training development. One of the tools used was a survey to specify which determinants needed to be influenced. This survey had a relatively low response rate (40 %), which could have biased the outcome of certain determinants associated with the provision of preventive activities. In order to limit the risk of bias, a wide range of methods were used to identify which determinants needed to be influenced, and the I-change model, which also takes into account the particular determinants, was applied. A further limitation was the lack of a pilot for the second training session and therefore the lack of feedback on this session. Nevertheless, each session was evaluated so that the upcoming sessions could be improved.Future studies should focus on specifying which determinants should be influenced by the intervention. This is one of the most important steps of IM because it serves as a main hook for the intervention. It is therefore essential to use multiple sources to reveal which determinants need to be addressed in order to influence the behaviour. The training programme should be sufficiently generalizable for HHC workers within another HHC context, given that this involves similar duties and a similar rural area. Organizations are consequently encouraged to adjust this training programme to their specific setting before implementing it. However, the next step is to implement and evaluate this training programme. The benefits of providing the training and meetings for HHC workers are inherent to the expectation that it will contribute to lowering the problems among HHC clients. Further research is necessary to determine whether this training programme can also be applied to other roles in the care sector, to other contexts, at home or abroad. Sufficient financial resources are needed to implement a comprehensive programme, and those resources are not always available. Further studies are also needed to enhance the provision of preventive activities by HHC workers so that they are actively involved in promoting physical activity and healthy eating. Finally, HHC organizations should further review how to maintain the knowledge and skills of HHC workers, for example in a refresher course as well as the implemental aspects within the organization.Although extensive and time-consuming, we found IM to be a useful tool in the development of a theory-based training programme to stimulate HHC workers to provide preventive activities relating to the fruit and vegetable intake and physical activity of older adults with a low social economic position. Our next step is to evaluate the effectiveness of the training in a longitudinal study with a quasi-experimental design.


A new smart concrete aggregate design as a candidate for applications in structural health monitoring (SHM) of critical elements in civil infrastructure is proposed. The cement-based stress/strain sensor was developed by utilizing the stress/strain sensing properties of a magnetic microwire embedded in cement-based composite (MMCC). This is a contact-less type sensor that measures variations of magnetic properties resulting from stress variations. Sensors made of these materials can be designed to satisfy the specific demand for an economic way to monitor concrete infrastructure health. For this purpose, we embedded a thin magnetic microwire in the core of a cement-based cylinder, which was inserted into the concrete specimen under study as an extra aggregate. The experimental results show that the embedded MMCC sensor is capable of measuring internal compressive stress around the range of 1–30 MPa. Two stress sensing properties of the embedded sensor under uniaxial compression were studied: the peak amplitude and peak position of magnetic switching field. The sensitivity values for the amplitude and position within the measured range were 5 mV/MPa and 2.5 μs/MPa, respectively. For such purpose, monitoring with the use of low-cost distributed sensors could be an alternative. An effective monitoring action can not only keep under control an increasing number of concrete infrastructures with only a minimal increase in effort, but will also reduce  the cost of inspection while offering a higher level of reliability. With respect to inspections, especially in-depth ones, monitoring would not require traffic interruptions. The main goal of applying low-cost distributed sensors is the reduction of maintenance costs by using currently available wireless technologies .Traditional state-of-the-art non-destructive evaluation (NDE) techniques with attached sensors have some insuperable disadvantages: the necessity of external connections, small coverage area, complicated signal processing, and quite strong local mechanical distortions introduced by the sensor elements. Much progress in concrete science is expected in the near future with the adaptation of new knowledge generated by the quickly growing field of micro/nanotechnology. However, because nano-sensors have extremely small dimensions, their exploration and fabrication require access to sophisticated and sometimes expensive technology . To simpCompressive strength is the most common performance measure for concrete. Tests are usually carried out in the laboratory by loading cubic or cylindrical samples in a compression testing machine until failure . UltrasoVarious techniques have been applied to detect the internal stress/strain in concrete structures. Strain gauges, which are basically adhered to the outer surface of a specimen, are capable of measuring pressure, force and tension, converting the units into measurable electrical resistance at low cost. The value and distribution of strain inside a concrete specimen under axial loading are not equal to those obtained at a point on the surface of the specimen. Information on different cement-based sensors embedded as simple aggregates to obtain data on the internal mechanical stress in different parts of the structure is necessary for a better understanding of the behaviour of this heterogeneous material. Large concrete structures tested by surface strain gauges require more complex analysis that includes observing time-history records for damage location and long-time durability predictions . CurrentMost commonly, the positioning of the mechanical stress/strain sensors in reinforced concrete elements is determined by attaching sensors to the reinforcement. However, the degree of reinforcement in massive concrete elements is relatively low, and reinforcement is mostly concentrated in near-surface areas.All the sensing techniques that rely on magnetic, piezoelectric, and optical approaches have their own specific merits and disadvantages. However, large-scale applications in civil structures require the development of innovative distributed sensors that are able to fulfil most of the following requirements: accuracy, robustness, price, immunity to magnetic interference, easy positioning, simplicity of operation, surface bonding between the sensor and the cement structure, and remote operation. To satisfy this need, magnetic sensors based on cement-based composites with embedded magnetic microwires were developed.Amorphous magnetic microwires have attracted much attention due to their tiny dimensions (around 1–100 μm in diameter), enabling the possibility of tailoring their magnetic and mechanical properties by a specific method of fabrication, appropriate treatments, and simplified measurement . These mThe domain structure of amorphous microwires with positive magnetostriction consists of one single axial domain in the inner part of the microwire, which is surrounded by a radial domain structure just below the surface , as illuGlass-coated ferromagnetic microwires exhibit unusual and interesting magnetic properties such as magnetic bistability and giant magneto-impedance effect . The mags and −Ms) [The change of magnetization takes place when an axial magnetic field H is gradually increased in the opposite direction from the stable state (i), the magnetization remains close to the stable state, and then the magnetization reverses its orientation within the core at the critical or switching field H*, as only one Barkhausen jump from the magnetic wall formed at the end of the microwire, to finally reach another stable state in (iv). The static magnetization of such microwires has just two values (+Mand −Ms) , and theBecause the magnetic properties of amorphous glass-coated microwires are determined by the magnetoelastic interaction of the magnetic moment with the mechanical stresses, the switching field is very sensitive to the applied mechanical stress ,15. Due Apart from the magnetoelastic contribution to the switching field, there exists another contribution that arises from the structural relaxation of amorphous microwires. This contribution is sensitive not only to temperature, but also to the frequency of the exciting magnetic field. Hence, by setting the excitation frequency, one can choose to measure either the temperature or the applied mechanical stress . The strOn other hand, the results of a study of giant magneto-impedance effect on the glass fiber-reinforced composites containing continuous magnetic microwires have revealed that they are very promising for applications in structural health monitoring and stress sensing .etc.The dynamics of domain wall propagation can be very effectively modified by the different anisotropies introduced into the microwire by a magnetic field , mechaniDue to their complex anisotropy distribution, microwires have very fast domain wall propagation with the domain wall velocities of up to 18,000 km/s , which gThis leads us to the idea of using microwires in the construction of a miniaturized multifunctional sensor for structural health monitoring purposes. Consisting of a single microwire embedded in cement-based composite, this sensor can measure the state of the internal stress of concrete by means of electromagnetic induction. Its versatility comes from its simple and cheap method of preparation, efficiency , insulaIn the current paper, a new design of smart concrete aggregate as a candidate for applications in structural health monitoring of critical elements in civil infrastructure is presented. The smart concrete aggregate is a cement-based stress/strain sensor which has been developed by utilizing the stress/strain sensing property of an embedded magnetic microwire in cement-based composite (MMCC).2.2.1.The MMCC sensors were made of magnetic microwires embedded in cement-based composite. The use of magnetic microwires allows creating a built-in stress/strain sensor inside the material without affecting its mechanical behaviour.2.1.1.75B9Si12C4 (magnestostriction constant of λs ≈ +30 × 10−6), fabricated according to the Taylor-Ulitovsky method [The study has been performed on glass-coated amorphous microwires with a nominal composition of Fey method .−). The composition of the Pyrex-like glass coating can be specified with a high percentage of zirconia (ZrO2), which enhances its resistance to alkali in cement composites [The microwire length was 60 mm. In an alkaline concentrated environment, such as concrete (pH > 13 in most cases), the glass-coating of the microwire can provide moderate protection against metallic core deterioration by hydroxide ions  and induced (V2) voltage signal. Therefore, the time at which the maximum (t+) or minimum (t−) induced signal takes place fixes the voltage peaks (V+* and V−*) of the excitation signal at which the domain wall propagation occurs. The corresponding switching fields H*+ and H*− can be easily determined from the value of the current through the excitation coil that creates the magnetic field. The switching field H*+ can be estimated from the sharp peak voltage (maximum) position, as shown in As described above, the pick-up coil is able to detect the motion of a magnetic domain wall represented as an induced voltage peak see  when theThe sensor can be influenced by the local metallic materials, or the surrounding magnetic fields, such as in reinforced concrete. It is possible to remove stray magnetic fields resulting from both the Earth's magnetic field and the surrounding metallic materials. In such case, the switching field must be measured in both directions of the applied excitation magnetic field.+ is measured when the excitation magnetic field increases, and H*− when the excitation magnetic field decreases. Finally, the switching field immune to parasitic magnetic fields, H*, is proportional to the difference of two components [Thus a reverse magnetic field H*mponents :(1)H*=Hmponents . As a re2.2.Several concrete cubic specimens (15 cm of side) were fabricated with Portland cement. The fine aggregate was natural sand, and the coarse aggregate presented a maximum radius of 12 mm. The mix proportions are shown in In this work, the measurements were carried out with embedded windings around the mortar cylinder to allow taking measurements at any depth and with the greatest possible stability. However, the primary and secondary windings of the MMCC sensor may be replaced by windings outside the concrete specimen if the microwire is located near the surface of the structure.Compressive strength tests were done on cubic and prismatic specimens of concrete and mortar, respectively, by using a compression machine (3000 kN) supplied by Proeti S.A. . The sam3.3.1.The values of compressive strength obtained in mortar and concrete specimens without sensor were 44 MPa and 33 MPa, respectively. The compressive strength of concrete is used to determine the rupture load limit of concrete and to establish the upper limit of cyclic load for concrete with sensor, in this case, 75% of the compressive strength.3.2.The as-quenched microwires showed rather sharp voltage peaks induced in the pick-up coil, which were associated with the fast magnetization switching in magnetically bistable microwires. The shape of the voltage from the pick-up coil changes under tensile stress application ,20.Based on the performance of the embedded MMCC sensor , is shown in The concrete specimen contains voids and micro-cracks in the initial state . Stress For the concrete specimen with sensor, no cracks appeared during the application of successive loading, which was applied only up to 75% of the rupture limit. Finally, when the specimen was tested until failure, macro-cracks progressively extended after 28 MPa; when the load reached about 33 MPa, the materials fails completely. However, the sensor integrity and sensing characteristics were maintained after the breaking of the specimen .4.A non-destructive testing method for the determination of the mechanical resistance of concrete is presented, consisting of the stress sensitivity of the magnetization reversal of a ferromagnetic microwire. The proposed MMCC sensor was designed to study the possibility of contact-less measurement of compressive stress in a cement-based composite by using an embedded amorphous magnetic microwire. Two stress sensing properties of the switching field value of the embedded sensor under uniaxial compression were selected: peak amplitude and peak position. The sensitivity values of the amplitude and position within the application range were 5 mV/MPa and 2.5 μs/MPa, respectively. The peak amplitude allows greater precision and measurement range. The MMCC sensor under uniaxial compression shows a precise and repeatable sensing ability for compressive stress. The experimental results indicate that it is possible to obtain a signal from a microwire embedded in a concrete structure and thus to determine its internal stresses. Hence, it is possible to estimate the structural health of concrete. Their versatility and also its possible integration without physical contact make these sensors suitable and useful for several applications in field of the embedded sensors.Knowledge about fatigue is very important both from an economic point of view and from the aspect of structural safety. Examples of concrete structures that are exposed to cyclic loading that causes fatigue are roads, bridges, wind power plants, and so on. The sensors described in this paper may provide enhanced diagnostics and damage progression prediction capabilities, as well as new capabilities for concrete structural health monitoring.


The long average incubation time from HIV infection to AIDS makes it difficult to estimate the recent tendencies of HIV from AIDS incidence data. The objective of this study was to investigate the effects of three temporal components in AIDS incidence in the state of Rio de Janeiro, Brazil - age, period, and cohort.Age-specific AIDS incidence rates per 100,000 from Rio de Janeiro (Brazil) were calculated for both sexes using five-year age classes from 1985 to 2009 based on reported data from the Notifiable Disease Information System of the Brazilian Ministry of Health and from census population counts. Multivariate negative binomial models were used to analyze the risk of AIDS by age, period, and birth cohort.From 1985 to 2009, AIDS incidence initially increased with age in each birth cohort and then decreased . High peaks in the rates in each birth cohort were detected in 1995–1999 for males and in 2000–2004 for females. Multivariate analysis showed the maximum risk of AIDS in the 30–34 age group and 1958–1962 birth cohort.Age, birth cohort, and period effects all may have influenced the AIDS incidence rates over the period investigated. From 1985 to 1999, comparison of the tendencies (by age) of the period with the birth cohort revealed opposing tendencies in individuals older than 29 years and in the youngest age groups (0 to 14 years). From 2000 to 2009, a strong age effect can be observed in both sexes. Consistent changes in period tendency curves suggest the occurrence of period effects. A reduction in the intensity of the risk of AIDS can be observed after 2000–2004. The past three decades have seen great biomedical and behavioral advances in preventing, diagnosing, and treating human immunodeficiency virus (HIV) infection ,2. The tAt the start of the AIDS epidemic, most of those who became infected with HIV were homosexual males and users of injected drugs. Although this pattern has changed over time, several regions and countries do not fit the overall global trend of AIDS. There is evidence of a resurgence of HIV in several high-income countries among men who have sex with men . In EastAccording to a study carried out in the United States, the proportion of women with AIDS increased significantly between 1982 and 1986 from 12% to 26%. The authors agree that this trend may prove to be a good marker for following trends in heterosexual transmission . In 1995The advances of interventions in last decades have significantly reduced perinatal transmission of AIDS . DespiteThe number of annual AIDS-related deaths worldwide is steadily decreasing from the peak of 2.1 million (1.9 million–2.3 million) in 2004 to an estimated 1.8 million (1.6 million–2.1 million) in 2009. This decline reflects the increased availability of antiretroviral therapy, as well as care and support to people living with HIV, particularly in middle- and low-income countries .Since the AIDS epidemic began in Brazil, 608,230 cases have been reported (January 1980 - June 2011), of which 65.4% occurred in males and 34.6% in females. These percentages have been changing over time, with the differences between genders narrowing . In the Fitting the global trend, most of the people that became infected with HIV in Brazil in the beginning of AIDS epidemic were homosexual males, injecting drug users, and hemophiliacs. This pattern has changed since 1993, when more cases of AIDS were attributed to heterosexual rather than homosexual transmission. From 1995 until 2007, the share of injecting drug use as the exposure category in the occurrence of new AIDS cases declined from 27.5% to around 10% among adult males and 21.9% to just over 4% among adult females. With the implementation in 1988 of HIV blood-screening tests, HIV transmission through blood transfusion and blood products began to decline, and today HIV transmission resulting from contaminated blood products and blood transfusions can be considered practically non-existent .Over time, the Brazilian population has gone through a transition process of the AIDS epidemic, which changed from the first pattern rooted among active homosexual men to a new one, which increasingly affects women . AlthougSince the introduction of antiretroviral therapy in Brazil, the AIDS mortality rate significantly declined, from 9.6 annual deaths per 100,000 inhabitants in 1996 to 6.1 in 2008 . The numThe objective of this study was to investigate the effects of three temporal components in AIDS incidence in the state of Rio de Janeiro – age, period, and cohort – with the aim of shedding light on the observed trends in recent years.Information of reported cases of AIDS of residents of Rio de Janeiro by sex, age, and year of diagnosis recorded over the 25-year period from January 1, 1985 to December 31, 2009 was obtained from the Notifiable Disease Information System (SINAN/DATASUS) of the Brazilian Ministry of Health. Population data from the Brazilian censuses of 1980, 1991, 2000, and 2010 and estimates for between-census years, stratified by age and sex, were used to calculate the incidence rates. AIDS incidence for each calendar year of the study was obtained by summing all notified cases of residents and dividing by the person-year for the respective year. Incidence rates per 100,000 inhabitants were calculated for both sexes using five-year age classes to investigate trends by period and by birth cohort. Period and birth cohort of five calendar years were considered; the central year was used as label: 1987 (1985–89), 1992 (1990–94), 1997 (1995–99), 2002 (2000–04), and 2007 (2005–09) were middle-points of periods; 1925 1923–27), 1930 (1928–32), 1935 (1933–37), 1940 (1938–42), 1945 (1943–47), 1950 (1948–52), 1955 (1953–57), 1960 (1958–62), 1965 (1963–67), 1970 (1968–72), 1975 (1973–77), 1980 (1978–82), 1985 (1983–87), 1990 (1988–92), 1995 (1993–97), and 2000 (1998–2002) were middle-points of birth cohorts. Period and birth-cohort effects also were investigated graphically using curves constructed separately for each sex -22. Mult–27, 1930Model specifications:cases) = α + β1 * sex + β2 * age-group + β3 * period + log (population)1st model: log (μcases) = α + β1 * sex + β2 * birth-cohort + β3 * period + log (population)2nd model: log .Table Figure Figure Figure Table This study revealed that gender, age, birth cohort, and period effects are important factors for explaining AIDS incidence rates in Brazil.The risk of AIDS in men, adjusted by age and period, was approximately two times greater than in women. Comparing the incidence rates of AIDS among sexes, it was found that although males show higher rates than females, women had the greatest increase during the period investigated. The largest differences occurred in older individuals aged 60–64 years and in young individuals aged 10–19 years. For example, for individuals aged 10–14, while in males the incidence increased 4.36 times from 1987 (1985–89) to 2007 (2005–09), in females it increased 34 times in the same period. The greatest difference occurred in the 60-64-year-old age group. In this age group, while male incidence increased 5.4 times from 1987 (1985–89) to 2007 (2005–09), in women it increased 51.5 times over the same period. The results of a study that covered the Brazilian population of a northeastern state from 1985 to 1998 also detected that incidence rates showed an annual growth that was higher in females than in males. The relative risk of the disease was about 1.2 for men, 1.3 for women, and 1.22 for both .Looking at each calendar year curve Figure , one canIncreasing trends of AIDS by age (adjusted by period and sex) were observed in individuals between 10–14 and 30–34 years old. In the other age groups, a decreasing trend of AIDS risk by age was observed Figure A. VerdecFrom 1985 to 1999, comparing the tendencies (by age) of the period curves Figure , oppositSince the cohort effect may result from lifetime experiences of the individuals born at a given point in time that have influence on the disease, the variability of past exposures in successive generations (birth cohorts) can distort the apparent associations between age and disease incidence observed at any given point in time. The health status of an individual at a point in time may be partially dependent on past exposures, such as behavioral changes that occur over time that may affect the health status of individuals . For exaIn the last two periods analyzed (2000–04 and 2005–09), shown in Figure The recurrent changes in tendencies over time shown by the cohort curves plotted for the entire study period, 1985–2009  of time that affects the entire population (or a significant segment of the population), such as new interventions which can produce changes independently of age and cohort . In the There is an intrinsic mathematical relationship amongst cohort, period, and age  . One canPeriod effects associated with incidence rates tend to be more prominent for diseases for which the cumulative effects of previous exposures are relatively unimportant, such as infectious diseases . AIDS isAn important limitation of this study for the interpretation of AIDS incidence trends is the deficiency in the coverage of the epidemiologic surveillance system. The data in this study exclude not only individuals who are infected and asymptomatic but also underreporting cases. Studies on underreporting in Brazil conducted over the last decade suggest underreporting rates from 15% to 43.3% ,31. A reAnother factor that can cause subregistration, especially in the most recent years analyzed, is related to the missing data due to registration delay, i.e., cases of AIDS that have not been registered in the system, despite having been diagnosed .Although this study focuses only on patients who developed AIDS and not in asymptomatic HIV-infected individuals, it is important to consider for the estimates of HIV-infected that the HIV incubation period, which was already long in the beginning of the epidemic, has been further increased by the introduction of combination antiretroviral treatment .Recent decades have witnessed great biomedical and behavioral advances in preventing, diagnosing, and treating HIV. A transformation has been noted between 1981 when AIDS was a rapidly fatal condition to the present remarkable prolonged survival pattern. However, much remains to be done on the long road to eradication of HIV disease. Preventive health politics, like health education, must continue to play key roles in reducing AIDS risk and the impact of the epidemic on affected individuals, integrating combinations of biomedical, behavioral, and structural interventions.Age, birth cohort, and period effects all may have influenced the AIDS incidence rates over the period investigated. From 1985 to 1999, comparison of the tendencies (by age) of the period with the birth cohort revealed opposing tendencies in individuals older than 29 years and in the youngest age groups (aged 0 to 14). From 2000 to 2009, a strong age effect can be observed in both sexes. Consistent changes in period tendency curves suggest the occurrence of period effects. A reduction in the intensity of the risk of AIDS can be observed after 2000–2004.The author declares that she has no competing interests.


Antibiotic resistance continues to spread even as society is experiencing a market failure of new antibiotic research and development (R&D). Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Scientific solutions to rekindle R&D include finding new screening strategies to identify novel antibiotic scaffolds and transforming the way we think about treating infections, such that the goal is to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction. Future economic strategies are likely to focus on ‘push’ incentives offered by public-private partnerships as well as increasing pricing by focusing development on areas of high unmet need. Such strategies can also help protect new antibiotics from overuse after marketing. Regulatory reform is needed to re-establish feasible and meaningful traditional antibiotic pathways, to create novel limited-use pathways that focus on highly resistant infections, and to harmonize regulatory standards across nations. We need new antibiotics with which to treat our patients. But we also need to protect those new antibiotics from misuse when they become available. If we want to break the cycle of resistance and change the current landscape, disruptive approaches that challenge long-standing dogma will be needed. It is difficult for modern physicians to appreciate the impact that the sudden availability of antibiotics had on the practice of medicine in the 1930s and 1940s . Then, sIndeed, the absolute reductions in mortality afforded by antibiotics are virtually unparalleled in the annals of medical pharmacotherapy. Conservative estimates of the absolute reductions in death mediated by antibiotic therapy include 25% for community-acquired pneumonia (CAP), 30% for nosocomial pneumonia, 75% for endocarditis, and 60% for meningeal or cerebral infections . Even cePerhaps it is not surprising that the availability of such powerful weapons against disease quickly led to hubris. As early as 1948, one expert expressed ‘optimism’ that ‘bacterial diseases have been brought under control’ . By 1962Nor is recognition of the threat of antibiotic resistance new, despite our failure to act effectively to confront the threat. Fifty years ago, a gathering of legends held a symposium focusing on the lack of new antibiotics that could deal with rising rates of resistant pathogens . Indeed,Sadly, it has not been, and we have not learned from our past. We expose our environment to more than 15 million kilograms of antibiotics every year in the US alone . This stThere are three primary causes of the antibiotic market failure, each of which interacts with, and exacerbates, the others Figure .More than 140 antibiotics have been developed for use in humans over the past 80 years ,19. ScieThese scientific complexities are further compounded for discovery of antibacterial agents targeting Gram-negative bacilli because of the unique biology of the Gram-negative cellular structure . The lipMultiple economic factors make antibiotics less attractive for investment in R&D than other classes of drugs. For example, antibiotics are short-course therapies that cure their target diseases. Companies can make more money selling drugs that are taken every day for the rest of a patient’s life . Also, prices for antibiotics are typically not competitive with other drugs that have a high impact on morbidity and mortality . Small market sizes are further exacerbated by the appropriate principles of antibiotic stewardship, which lead thought leaders to advise judicious use when new antibiotics become available, such that sales of new antibiotics typically under-perform relative to expectations, particularly during the first years after market entry.As a result of these and other market forces, a recent sophisticated study from the London School of Economics estimated that, at discovery, the net present value (NPV) of a new parenteral antibacterial agent was minus $50 million . The NPVFor more than a decade, a shift in thinking at the FDA, particularly in the Office of Antimicrobials, has resulted in increasingly infeasible trial design requirements to enable new antibiotics to get approved for use in humans ,17,21,22Clear clinical trial guidances took many years to be released for trials of new antibiotics. When such guidances were released, they generally created trial conduct standards that were infeasible, nonsensical, or both ,24. SomeOther specific examples of unreasonable and damaging elements to new trial standards included banning any pre-study antibiotics from being administered to patients who were going to be enrolled in antibiotic clinical trials; this eliminated the possibility of enrolling any patients who were seriously ill. At the same time, studies were required to administer multiple days of intravenous therapy in hospital for diseases such as pneumonia, urinary tract infections, and intra-abdominal infections; this eliminated the possibility of enrolling any patients who were not seriously ill. Thus, there were few patients left to enroll.New requirements that patients be considered evaluable for efficacy only if an etiologic bacterium was identified resulted in doubling or tripling of sample sizes for pneumonia studies. Non-inferiority margins shrunk because of arbitrary mathematical manipulations that were used to ‘discount’ the best guess of antibiotic treatment effect sizes for various diseases, further driving up sample sizes ,25.The cumulative effect of this ‘lost decade’ of debate, discussion, and deliberation was a substantial exacerbation of the risk, cost, and time it took to develop new antibiotics, just at the time when scientific challenges and other economic realities were having the same effect. The net result of these three converging forces, which fed off of one another, was a marked decrease in the number of companies, and number and experience of scientific experts, working in this space.Given the above barriers, what solutions can be implemented to relieve the obstructions and rekindle antibiotic R&D in industry?Two broad methods may be useful to change the pool of antibiotics that can be discovered and developed . The firA second scientific approach is, rather than modifying the substrate of the screen, to modify the screening methodology to make the screening conditions more physiology relevant . TraditiAcinetobacter baumannii with a novel experimental antibiotic that blocks the rate-limiting step of lipopolysaccharide biosynthesis did not kill the bacteria but rendered them incapable of causing disease in mice [An even more transformative approach is to fundamentally change the way we think of disease, and to begin to try to treat infections by disarming pathogens or blunting excessive host response, rather than by trying to kill microbes . Clinica in mice . Targeti in mice .Finally, direct targeting of the host, rather than the microbe, should also exert minimal selective pressure and can allow the host to minimize damage caused by invading microbes even if organisms are present . Direct Economic incentives are needed to rekindle the antibiotic R&D pipeline. Some help has already been provided to companies via passage into law of the Generating Antibiotic Incentives Now (GAIN) component of the FDA Safety and Innovation Act in 2012. The most direct economic support for antibacterial agents provided by GAIN is a maximum of 5-year extension of Hatch-Waxman ‘data exclusivity’, which helps prevent generic copies of drugs from reaching the market . It is iMuch of the previous attention on economic incentives has focused on ‘pull’ mechanisms, which are effective after a drug reaches approval ,20,32,33One effective means of distributing push economic incentives is to increase emphasis on public-private partnerships (PPPs) to rekindle the antibiotic R&D pipeline. Space limits preclude a thorough discussion of PPP structures and functions, but previous literature on these points is available ,22,34. EAn advantage of the PPP mechanism, which requires both a vigorous private industry and strong and focused support from government, is the ability to ensure that R&D efforts are aligned with unmet need. Traditional drug development programs in industry have focused on the largest markets, such as skin infections and CAP, since they are perceived to bring the largest return on investment and to be the easiest trials to complete. Thus, a plethora of new treatments for bacterial skin infections have become available in the last decade, even though there is little unmet need for such therapies. Even worse, when broad-spectrum antibiotics that can be used to treat lethal Gram-negative infections are developed to treat skin infections or even pneumococcal pneumonia, the drugs are wasted post-marketing on such diseases when numerous other, more narrow-spectrum therapies would suffice. Thus, we need to begin to align drug development with unmet need, to ensure that the drugs we need to save lives are being developed, and also to protect those drugs from overuse post-approval.A. baumannii infections could be priced well in excess of $10,000 per treatment course, and perhaps as much as $30,000 per treatment course, while still easily meeting standard cost-effective metrics [Ironically, the rise of highly resistant Gram-negative bacterial infections has created a new opportunity for an economic incentive: pricing. Pricing is the one ‘pull’ incentive that is likely to be highly effective at stimulating new industry R&D in the antibacterial space. If a new antibiotic is developed to treat lethal infections caused by resistant bacteria with limited to no alternative therapy, a marked pricing premium can be charged. As a result, a large market can result even if the number of cases is relatively small. For example, economic modeling indicates that a pathogen-specific therapy to treat carbapenem-resistant  metrics . Such a Three fundamental elements of reform regarding regulatory standards for new antibiotic development are needed. First, traditional non-inferiority designs must be feasible and relevant. The European Medicines Agency (EMA) has released recent guidances that meet these objectives and set logical, reasonable, and achievable standards for such studies ,37. In cSecond, we need to focus on facilitating development of antibiotics that meet high-impact, unmet need. Several ideas have been forwarded for new regulatory paradigms that would facilitate focusing on unmet need, including the Limited Population Antibacterial Drug (LPAD) pathway proposed by the Infectious Diseases Society of America , and theBut sponsors too need to recognize the shifting landscape. It is no longer true that older, traditional entry indications, such as skin infections and CAP, are the least risky and least expensive ways to develop drugs. Crowded entry indications have become commodities markets, with numerous competitor antibiotics already available, driving down pricing and creating (appropriately) a minimal risk tolerance threshold at the regulatory level. Trials focused instead on highly resistant bacterial pathogens for which limited available therapy exists may well be less expensive and shorter to conduct and can be used to support premium pricing, as discussed above. Such a situation is favorable for our patients, as it supports focus on true unmet need, and also helps prevent misuse and overuse post-marketing, as discussed above. Feasibility of such studies will increase over time as rapid molecular diagnostic tests become available to support their conduct .Third, there must be harmonization between US and European regulators and ideally regulators in other parts of the world as well. The FDA exists in a very different political and legal climate than other national regulatory agencies, and it is true that congressional or public advocacy pressure has been instrumental in causing the FDA to become hyper-defensive in its recent approach to antibiotic pathways ,23. NeveScientific thought leaders must be prepared to help explain complex scientific and clinical concepts to the public and to political leaders in order to help bring a more reasoned, patient-centric, and clinically relevant approach to antibiotic development in the US, which ultimately will support trans-national harmonization of standards.While the primary focus of this article is on facilitating new antibacterial development, we must stop making the same mistake over and over again with respect to misuse and overuse of antibiotics. Resistance will occur to all new antibiotics developed. Thus, as we facilitate new antibiotic development, we must re-emphasize our core responsibility as physicians and members of our communities to help preserve and protect the precious, limited, and exhaustible resource of antibiotics. Summaries of novel, disruptive approaches to enhancing infection prevention, disinfection, and decontamination; use of rapid diagnostics to enhance stewardship; and other improvements in antibiotic stewardship have been recently published ,13,34.The struggle with microbes will not end with new antibiotic availability. Indeed, it will never end. We bear great responsibility to protect the ‘awesome power’ of antibiotics that our forebears in medicine bestowed upon us. To prescribe a powerful new antibiotic is easy. To protect it is hard. But if we want to break the cycle and stop repeating the same mistakes of the past over and over, we must learn how to not use and abuse new antibiotics.Highly accomplished clinician-scientists who experienced the before and after of the availability of antibiotics described their effect as being ‘almost beyond belief’  and ‘an Antibiotic resistance in the ICU, edited by Steven Opal. Other articles in this series can be found at http://ccforum.com/series/antibioticresistance.This article is part of a series on CAP: Community-acquired pneumonia; EMA: European Medicines Agency; FDA: US Food and Drug Administration; GAIN: Generating Antibiotic Incentives Now; LPAD: Limited Population Antibacterial Drug; NPV: Net present value; PPP: Public-private partnership; R&D: Research and development.Within the last year, BS’s employer has received consulting fees on his behalf from GlaxoSmithKline , Meiji Seika Pharma Co., Ltd , Cardeas Pharma , Affinium Pharmaceuticals , aRigen Pharmaceuticals , and Synthetic Biologics  and grants or contracts for basic science or clinical research from Cubist , Pfizer , and Bristol-Myers Squibb Company .


Current studies showed that detection of c-Met status in tumor is critical in Met-targeted therapy. However not all patients are suitable for tissue sample collection. It is important to discover novel surrogate markers to detect c-Met status. In the study, soluble c-Met (s-Met) in plasma from 146 Chinese lung cancer patients and 40 disease-free volunteers was measured by enzyme-linked immunosorbent. In parallel, expression of c-Met in those tumors was also assessed by immunohistochemistry. Results showed that, in 146 lung cancer patients, 93 were c-Met expression positive and 74 of 93 were overexpressed. In c-Met-overexpressed patients, plasma s-Met was significantly increased. And further studies showed that plasma s-Met linearly correlated with c-Met expression in tumor. After tumor was removed in Met-overexpressed patients via resection, plasma s-Met significantly decreased to basal level. In addition, plasma s-Met showed to be poorly correlated with tumor size in Met-overexpressed patients. These results demonstrated that plasma s-Met is a sensitive and reliable marker to detect c-Met overexpression in lung cancers, and it is independent of tumor volume. Met gene amplification. Furthermore, Met gene amplification also was found to be an additional mechanism of acquired EGFR-TKI resistance. Amplified Met results in overexpression and overactivation of c-Met and consequently triggers the activation of Her3 which activates downstream signal transducer molecules, such as Akt and Erk, independent of EGFR kinase activity [ Met gene amplification was detected in 22% of acquired EGFR-TKI resistant non-small cell lung cancers, and, compared with patients unexposed to EGFR kinase inhibitor, Gefitinib or Tarceva treatment was more likely to select Met gene amplification (21% versus 3%) [c-Met is the cell surface receptor for hepatocyte growth factor (HGF) . HGF-indactivity . In clinα/β heterodimer at cell surface. The 140 KD β chain of the complex can be proteolytically cleaved by cells constitutively and released to the surrounding environments [Soluble Met (s-Met) is generated via c-Met ectodomain shedding. c-Met is initially synthesized as a single-chain intracellular precursor and subsequently undergoes proteolytic processing at different stages during intracellular trafficking , leadingronments . s-Met wronments , and a sronments , 10.Here, we aimed to employ plasma s-Met as a sensitive biomarker to monitor c-Met status in lung cancer tumors and explored the sensitivity and specificity of plasma s-Met in diagnosis.Plasma and tumor tissues were obtained from 146 Chinese patients with lung cancer in Fourth Hospital of Hebei Medical University from 2007 to 2012. In parallel, 40 disease-free volunteers were recruited and plasma was collected for reference. In lung cancer patients, 14 were small cell lung cancer (SCLC) and 132 were non-small cell lung cancer (NSCLC). And 47 NSCLC patients received tumor resection; 31 NSCLC patients were diagnosed as EGFR mutation and received EGFR-TKI treatment (erlotinib). The male-to-female ratio was 1 : 1.32, and the median age was 59 years (range from 42 to 83 years). The World Health Organization Classification of Tumor was used to determine histological classification . TNM claThe tumor tissues were obtained via surgical resection or biopsy. After being fixed in 10% formalin overnight, the tissue fragments were dehydrated by ethanol and embedded in paraffin blocks. The blood was collected before/after treatment, and plasma was separated via centrifugation at 4°C.μL of plasma diluent was added into the well precoated with capture antibody and incubated at room temperature for 2 h. Then the medium was removed and the wells were washed with PBST buffer. 100 μL of detection antibody was added and incubated at room temperature for 2 h. The detection antibody was removed and wells were washed with PBST buffer. 100 μL of substrate reagent  was added and incubated at room temperature for 20 min. Then 50 μL of 5 M H2SO4 was added to stop reaction; the density of solution in wells was read at OD450 nm/570 nm, respectively. The concentration of s-Met was calculated using standard curve following the suggestion of manufacturer.The concentration of soluble Met in plasma was quantitated using human soluble c-Met quantitative ELISA kit (Invitrogen) which was described in previous study . Brieflyμm thickness. Immunohistochemical study was performed using the streptavidin-biotin complex method and TechMate 1000 automated staining system . Antibody against to c-Met (Roche) was used to detect the expression of c-Met in tumor tissues. The results of staining were evaluated by two independent pathologists who were blind to the clinical data and the difference in interpretation was resolved by consensual agreement. The staining of c-Met in tissues was quantitated using two scoring systems, respectively: (1) the intensity scores: IHC 0 indicated no appreciable staining in the tumor cells; IHC 1+ indicates faint/barely appreciable partial membrane staining in >10% of tumor cells; IHC 2+ indicates weak to moderate staining of entire membrane in >10% of tumor cells; IHC 3+ indicates strong staining of entire membrane in >10% of tumor cells and (2) H scores: H score indicates 0 × (% tumor cells with IHC 0) + 1 × (% tumor cells with IHC 1+) + 2 × (% tumor cells with IHC 2+) + 3 × (% tumor cells with IHC 3+). These scoring systems were also used in previous study [Paraffin-embedded tissue blocks were sectioned with 4 us study .The tumor sizes were assessed using total lengths (TL), which were calculated by summing the lengths of maximum horizontal diameter in major lesions (at most 5 lesions/person). The maximum horizontal diameter of lesion was determined by CT scan.t-test and paired t-test analysis were used to examine the relationships between groups. Each P value was corrected by Bonferroni's method for multiple testing. Prism 5.0 software (GraphPad Software Inc.) was used for statistical analysis. And P values less than 0.05 were considered significant.Chi-square P < 0.05). However, plasma s-Met in patients with weak c-Met expression (IHC 1+) had no significant difference compared with disease-free donors or Met-negative patients (P > 0.05).Expression of c-Met in tumor tissues from 146 lung cancer patients was detected and scored by IHC . Resultspatients    . Then H P < 0.05). In Met-negative patients, removal of tumor did not significantly affect the s-Met level (P > 0.05). Furthermore, slight decrease of plasma s-Met was observed in Met-slight patients, but there was no significant difference (P = 0.113). The above results demonstrated that overexpression of c-Met in tumor leads to the significant increase of plasma s-Met in blood.The above results demonstrated that there was basal level of plasma s-Met in disease-free donors, suggesting that, besides tumor, normal tissues also could secret s-Met into blood. In order to confirm whether the increased plasma s-Met in Met-overexpressed patient was from tumor, plasma s-Met in 47 patients who received tumor resection was remeasured 14–20 days after surgery. In those patients, 23 were c-Met-negative, 6 were c-Met IHC 1+, and 18 were c-Met IHC 2+/3+. As shown in In disease-free subgroup, the upper 95% CI of plasma s-Met was 888.7 ng/mL , which mP > 0.05) compared with c-Met-negative or weakly expressed patients. In order to further evaluate the correlation of plasma s-Met and tumor size, plasma s-Met concentrations were pooled and plotted against tumor sizes, and calculated results are presented in Figures Multiple preclinical studies demonstrated that plasma s-Met directly correlated with tumor size in xenograft mice . In ordePlasma s-Met was generated by shedding of c-Met ectodomain, which was regulated through broadly distributed signaling pathways including those of EGF, G-protein coupled receptors, and integrins as well as intracellular pathways activated by phorbol myristate acetate , 13. PreAlthough multiple preclinical studies demonstrated that plasma s-Met correlated well with tumor volumes in mice bearing Met-positive xenograft tumor and Fu et al. also reported that plasma s-Met associated with tumor size in NSCLC , 10, in  Met gene amplification may be considered as a prognostic marker [ Met gene amplification was a sensitive and independent predictor [ Met gene amplification was an important mechanism which acquired resistance in EGFR-targeted therapy. Because plasma s-Met was easily measured, it could be used to detect dynamic changes of c-Met in tumor.Overexpression of c-Met has been documented as a prognostic marker in non-small cell lung cancers, which associated with poorer outcome of NSCLC . Althougc marker , howeverredictor . Thus deIn conclusion, plasma s-Met would function as a prognostic marker in lung cancers; it correlated well with c-Met expression in tumor but did not associate with tumor size. Plasma s-Met over than 888.7 ng/mL could specifically predict the c-Met overexpression in lung cancer.


There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries.Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1‐year‐period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic.The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0–9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty‐nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin.Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons, Ltd.Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries. © 2015 The Authors.  Studies on antibiotic use in Europe have shown an increase in the total volume of outpatient antibiotic sales and reimbursements between 1997 and 2009.The current study was designed to measure and understand the variation in antibiotic utilization across specific databases as part of ‘Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium’ (PROTECT).The analyses were conducted in patient populations from the following databases: (i) the Clinical Practice Research Datalink (CPRD) from the UK; (ii) The Health Improvement Network (THIN) from the UK; (iii) the ‘Base de datos para la Investigación Farmacoepidemiologica en Atencion Primaria’ (BIFAP) — a Spanish computerized database of medical records of primary care; (iv) the Bavarian Association of Statutory Health Insurance Physicians (‘Kassenärztliche Vereinigung Bayerns’ [KVB]) database (henceforth referred to as the Bavarian Claims Database); (v) the Dutch Mondriaan Netherlands Primary Care Research Database (NPCRD); (vi) the Dutch Mondriaan Almere Healthcare group (AHC) database; and (vii) the Danish national registries.The two UK general practice databases, CPRD and THIN, collect and archive the electronic medical records of more than 5 and 3 million active patients, respectively, covering over 8% of the UK population Table .5, 6, 15The source population in all five countries included all individuals with access to primary health care.As primary care is free at the point of delivery, it has almost universal coverage in the UK, Denmark, the Netherlands, Germany and Spain. Primary care physicians are gatekeepers to specialist care and are usually the first healthcare contact for all non‐emergency care. After registration, a general practice becomes the typical source of care. In most European countries, the choice of general practice is dependent on geographical proximity to the primary address of an individual.The study population in every database was composed of all available patients of all ages with an active registration status during the study period of 1 January 2004 to 31 December 2009. In the Dutch Mondriaan AHC and the Bavarian Claims Database, the last available year of data collection was 2008. The remaining databases ended data collection in December 2009. Valid data collection started a year after the date when a practice became up to research quality standard or the date when a patient enrolled into a practice or the date that a practice was enrolled into the database, whichever came last. The follow‐up time of patients was censored on the date a patient died, the date a patient was transferred out of the practice, the end of the database's data collection or the date that the practice left the database, whichever came first.Exposure was defined as a recorded prescription for an antibiotic agent listed in chapter 5 of the British National Formulary or therapeutic subgroup J01 of the Anatomical Therapeutic Chemical (ATC) Classification System. In the Danish, Bavarian and Mondriaan AHC databases, exposure was defined as the dispensing of an antibiotic agent to a registered individual. Prescriptions for topical antibiotics were excluded. Antibiotic agents were grouped in seven categories: tetracyclines, penicillins, cephalosporins, macrolides, aminoglycosides, quinolones and other antibiotics (sulphonamides and other combinations). To assess the point prevalence of antibiotic use, duration of exposure was calculated by dividing the total quantity of prescribed or dispensed antibiotics by the numeric daily dosage prescribed or dispensed. The mode (BIFAP only) or median duration of exposure to all antibiotic agents was imputed when information on the total quantity or the prescribed daily dosage was missing. The total number of patients registered in every database was based on the total active annual patient population at mid‐year from 2004 to 2009.Annual 1‐year‐period prevalence was calculated by dividing the number of patients being prescribed an antibiotic in the study period of interest (numerator) by the number of patients available in every database at mid‐year (denominator). Antibiotic users were defined as patients with at least one recorded antibiotic prescription or dispensation. Crude prevalence rates and prevalence rates standardized by age and sex were calculated to account for potential differences in the age–sex distribution of the different populations across databases and over time. We applied direct standardization according to the 2008 European population standard.Point prevalence was assessed in the CPRD, BIFAP, DKMA and both Mondriaan databases on the 1st of March, June, September and December from 2004 to 2009 to take seasonal variations into account. For this analysis, antibiotic use was defined as having received a prescription/dispensation for an antibiotic agent before or on the 1st of March, June, September and December that lasted until or after the 1st of the same month.The highest crude prevalence of antibiotic use was observed in the BIFAP, DKMA, CPRD and THIN databases, with an average annual prevalence of 30 users per 100 patients in the Spanish and Danish databases and 29 users per 100 patients in the UK databases . The seasonal difference in the number of prescriptions was more pronounced in BIFAP than in other databases, with an average increase of 42% in the proportion of patients who were prescribed an antibiotic in December and March compared with June and September  received more than five prescriptions per year  to 31 (Spain) users per 100 patients, with the exception of the Netherlands. The lowest average annual prevalence was observed in the Dutch Mondriaan NPCRD database: 16 users per 100 patients. There were similar patterns of antibiotic use across all databases with regard to gender, age and seasonality. Across all databases, most patients received only one prescription in any given year. National preferences for types of antibiotics prescribed, after penicillin, strongly differed per country.Our results are similar to studies using sales and reimbursement data to compare rates of antibiotic use in Europe. When limited to the five countries that we included in our study, the European Surveillance of Antimicrobial Consumption (ESAC) project found the lowest antibiotic prescription rate in the Netherlands, followed by Germany. Danish and UK prescription rates were similar, and Spanish prescription rates were among the highest.Our main findings show that the prevalence of antibiotic use in five European countries is very similar, with the exception of the Netherlands. The prevalence of antibiotic use in the Netherlands is not only lower compared with the prevalence in other countries, but most individuals that received an antibiotic agent only received a single antibiotic prescription in any given year (81%), which suggests that the prescribing behaviour of physicians is highly effective. Whilst we did not set out this descriptive study to find the best‐case scenario of antibiotic use, we believe that research using Dutch electronic health records could produce reliable estimates of the most conservative absolute estimates of adverse events associated with the use of antibiotics, including hepatic injuries and antibiotic resistance.Whilst variability in the overall prevalence of antibiotic use was minimal across the UK, Spain, Denmark and Germany, there were differences in the recorded clinical indications for use and the intensity of use and clear differences in preferences for antibiotic classes between the countries. In studies investigating antibiotic‐induced injuries, the absence of recorded indications would restrict effective stratification by indication. Moreover, differences in preferences for individual antibiotic classes likely indicate significant differences in the composition of comparison groups.The implications for future pharmacoepidemiological research on antibiotics are twofold:To our knowledge, this is the first study to measure and compare the prevalence of antibiotic use as recorded on a patient level in different European healthcare databases with access to primary care data. The primary strength of this study was the inclusion of the entire source population in every database. DKMA data (Denmark) represent complete quantitative national figures. Comparisons with national statistical data have shown that the CPRD, THIN and Mondriaan NPCRD databases are generalizable to the UK and Dutch populations, respectively.All seven partners used a single protocol and shared code lists to identify different types of antibiotic agents and underlying diagnoses. For some databases, dispensing records rather than prescription data were used, which may have affected the measured differences in prevalence of antibiotic use between the databases. For example, a small proportion of the dispensing data may have included antibiotic prescriptions prescribed by health care providers other than the regular primary care physicians, such as prescriptions received from dentists for emergency dental care. Different coding systems to measure prescriptions in every database  could also have caused some variability in the inclusion of some combinations of antibiotic agents.We were not be able to detect patients who were prescribed or dispensed antibiotic agents outside primary care . The differences between the UK databases were very small. The differences in the Dutch data could be explained by the fact that the Mondriaan AHC data were collected in a single city (Almere) with a relatively young population, whereas the Mondriaan NPCRD comprises a national sample of GPs.As healthcare databases are increasingly being used to conduct drug utilization studies and pharmacoepidemiological investigations, including studies that link the use of antibiotics to several health‐related outcomes, we believe that our results contribute quantitatively to the true understanding of the use of antibiotic agents in primary care in different EU countries.Key PointsDespite heterogeneity between seven European electronic health care databases in structure, terminology, underlying healthcare systems and data capture, we found relatively stable and similar yearly prevalence rates of crude and standardized antibiotic use between 2004 and 2009, with the exception of the Netherlands.There were clear differences in preference for antibiotic classes, recorded clinical indications for use and intensity of use between the five European countries in this study, which has implications for comparative studies investigating antibiotic‐induced injuries.The low prevalence rate of antibiotic use in the Netherlands in combination with the low intensity of use suggests that Dutch electronic health records could produce reliable estimates of the most conservative absolute estimates of adverse events associated with the use of antibiotics.A. B., R. S. and R. R. belong to EFPIA  member companies in the IMI JU and costs related to their part in the research were carried by the respective company as in‐kind contribution under the IMI JU scheme. The views expressed are those of the authors only and not of their respective institution or company. None of the results presented in the current manuscript were published elsewhere.http://www.encepp.eu/encepp/studiesDatabase.jsp). CPRD ISAC approval for the study was obtained in October 2011 (11_019A_2). We maintained a blinding procedure until the final results from both CPRD and BIFAP were submitted to the coordinating centre at Utrecht University.The protocol was approved by the Spanish Agency for Medical products (AEMPS) to be performed in the BIFAP database as part of the PROTECT project and was registered in the ENCePP electronic register of studies (Supporting info itemClick here for additional data file.