Cardiac risk stratification is related to the risk of the occurrence of events induced by exercise. Despite the existence of several protocols to calculate risk stratification, studies indicating that there is similarity between these protocols are still unknown.To evaluate the agreement between the existing protocols on cardiac risk rating in cardiac patients.The records of 50 patients from a cardiac rehabilitation program were analyzed, from which the following information was extracted: age, sex, weight, height, clinical diagnosis, medical history, risk factors, associated diseases, and the results from the most recent laboratory and complementary tests performed. This information was used for risk stratification of the patients in the protocols of the American College of Sports Medicine, the Brazilian Society of Cardiology, the American Heart Association, the protocol designed by Frederic J. Pashkow, the American Association of Cardiovascular and Pulmonary Rehabilitation, the Société Française de Cardiologie, and the Sociedad Española de Cardiología. Descriptive statistics were used to characterize the sample and the analysis of agreement between the protocols was calculated using the Kappa coefficient. Differences were considered with a significance level of 5%.Of the 21 analyses of agreement, 12 were considered significant between the protocols used for risk classification, with nine classified as moderate and three as low. No agreements were classified as excellent. Different proportions were observed in each risk category, with significant differences between the protocols for all risk categories.The agreements between the protocols were considered low and moderate and the risk proportions differed between protocols. Studies indicating similarity between cardiac risk stratification protocols are important in clinical practice.Most protocols for cardiac risk stratification present low or moderate agreements.The protocols have shown good applicability to most patients.,Cardiovascular diseases (CVD) are the leading cause of death in most countries, including Brazil, accounting for about 20% of all deaths in individuals over 30 years of age,The central idea for CR is to perform exercise, the prescription of wich should be made on an individual basis in order to provide beneficial effects and safety during performanceIn a literature review conducted by our group,The criteria for stratification consider factors associated with an increased risk of morbidity and mortality during physical exercise, and based on these criteria, the individual is usually classified as low, moderate, or high riskHowever, the existence of multiple risk stratification protocols may hamper the selection of the most suitable to be used during the CR process. A search in the literature found no studies evaluating the similarity between the risk stratification protocols, demonstrating gaps in the literature that raise the following questions: Would an individual be classified in the same risk level in different protocols? Are there agreements between the risk ratings used in the protocols? If so, which ones can be considered similar and which differ? This information may contribute to researchers and clinicians who act in CR programs, giving safer direction for adopted behaviors and exercise prescription with cardiac patients and even identifying differences between specific protocols.One of the few studies that compared protocols was carried out by Paul-Labrador et al.In this context, the aim of this study was to evaluate the level of agreement between existing protocols on the cardiac risk score in heart disease. It was hypothesized that despite the differences between the protocols, there would be agreement between them regarding the prediction of the risk of developing complications during exercise.This is a descriptive/analytical cohort study, transversal, with a restropective characteristic, developed from data drawn from 50 medical records of individuals seen in an outpatient exercise program for patients with cardiovascular disorders, between April and May 2014, with no restrictions concerning age or gender.These patients received information about the objectives and procedures of the study and signed a consent form authorizing the use of their data. All procedures were approved by the Research Ethics Committee of Universidade Estadual Paulista Júlio de Mesquita Filho (UNESP), Presidente Prudente, SP, Brazil, under protocol number 792.373 of 05/09/14.The patient records were analyzed and the following information extracted: age, gender, weight, height, clinical diagnosis for which the patient was referred to the heart disease unit, medical history, risk factors (RF) for the development of CVD, associated diseases, and the results of recent laboratory tests and complementary tests related to the evaluation of the cardiovascular system . This information was tabulated and subsequently used for risk stratification of patients using the different protocols evaluated in this study. A single evaluator performed all data collection.rd editionThe characterization was based on information regarding age, weight, height, and clinical diagnosis. Body mass index (BMI) was calculated from weight and height using the formula: body weight (kg)/heightThe main clinical diagnosis was considered as the diagnosis that led to referral to the unit. Patients with coronary artery disease (CAD) were divided into groups according to the procedure performed: coronary artery bypass grafting (CABG), angioplasty with stent placement, CABG and stent, or conservative treatment. Patients with heart failure (HF) were also subdivided according to the New York Heart Association (NYHA) Functional ClassificationThe following information was extracted from the medical records: the presence and number of cardiopulmonary arrests, number of days of hospitalization, complications during hospital stay or after performing an invasive procedure, and current complications.2 15.The information contained in the medical records was analyzed for the presence of the following risk factors (RF): sex/age (men over the age of 45 years and women over 55), family history (considering the presence of CVD in first-degree relatives), hypertension, dyslipidemia, and smoking. For the obesity risk factor, the value obtained in the calculation of BMI was used, considering patients obese with a BMI≥30 kg/mAssociated diseases were considered as any musculoskeletal, neurological, pulmonary, or metabolic dysfunction, with the data obtained from the medical records.The most recent exams recorded in the medical records were analyzed, regardless of the results contained in these exams. Blood glucose, triglycerides, total cholesterol, HDL-cholesterol, and LDL-cholesterol were obtained from the laboratory records. Only complementary tests that assessed the cardiovascular system were used. The results for patients who had undergone Holter monitoring were classified according to Lown and WolfFor risk stratification, we used the following protocols described in the study of Silva et al.The guidelines of the ACSMUnlike previous guidelines, AHAThe guidelines of the AACVPRThe FSC protocol,,,-The protocols are aimed at the participation of individuals in exercise programs and/or CR and covers patients diagnosed with coronary artery disease, particularly post-acute myocardial infarction, although they are expandable to all CVDData normality was tested by the Shapiro-Wilk test. To characterize the sample, descriptive statistics were used, with the results presented as mean, standard deviation, absolute and relative values. Comparison of risk ratios  between the protocols was performed by applying the chi-square tests. To analyze the agreement among the protocols, the Kappa index was used. The agreement was considered weak for k values below 0.40, moderate for values between 0.40 and 0.75, and excellent for k values greater than 0.75. Differences were considered significant if p<0.05. The software used was SPSS version 15.0.The agreement between risk classifications obtained from the protocols can be seen in The agreement table also shows that the ACSM protocol had no agreement with any of the analyzed protocols and that the AHA protocol presented agreement only with the FSC and SSC, though the agreement was low. Low agreement was also observed between the BSC and SSC protocols, and the highest agreement was found between the BSC protocol and the Pashkow protocol.This study aimed to evaluate the level of agreement between existing risk stratification protocols in individuals who regularly attended a CR program. According to the results observed in this study, there were only 12 agreements between the evaluated protocols, which were classified as low or moderate, without any agreement considered excellent. Different proportions in each category of risk stratification were observed among the evaluated protocols, this ratio being less accurate between the AHA and ACSM.,This is the first study to evaluate the existence of agreements between protocols developed to stratify the risk of individuals in exercise programs and CR. Different proportions in each category of risk stratification were observed in the majority of the evaluated protocols. In the ACSM protocol, 90% of patients were classified as high risk in contrast to the AHA, which ranked only 6.4% of these patients in the same risk category. One of the reasons for this discrepancy is the fact that the ACSM protocol is the only one that uses the presence of cardiovascular, metabolic or pulmonary disease as criteria for classifying the individual as high riskDepending on the stratification criteria adopted by the protocols, not all were able to stratify all individuals in the sample. In the BSC, FSC, SSC, and Pashkow protocols, it was not possible to stratify three patients who did not have complementary tests or information that allowed allocation into one of the stratification criteria. In the AACVPR protocol, only one of these three patients was stratified, because although the patient had no complementary test, their clinical condition satisfied one of the stratification criteria of this protocol.In the AHA protocol, three patients could not be stratified. Two patients had complementary tests, but basic conditions  did not meet any of the criteria for determining the risk class, and one patient had no complementary tests to determine the risk class, although the underlying disease was among the criteria.,,,-The above data highlight the importance of complementary tests in the risk stratification process of these patients. Complementary tests related to the evaluation of the cardiovascular system were present in 94% of the analyzed records. Among the patients with complementary tests, only one had not undergone the ergometric test or echocardiography, which are examinations used as stratification criteria for the majority of protocolsRegarding the agreement between the protocols, it was observed that the risk classification of the ACSM protocol did not agree with any of the other protocols used, which is related to the fact that this protocol uses the clinical history of the patient as the criterion for stratifying, without the use of complementary tests.Due to the low number of similarities in the risk ranges between the AHA protocol and other protocols, this protocol did not agree with four of the six guidelines and the two agreements that were found, with the protocols of the FSC and the SSC, were classified as low according to the Kappa coefficient (K<0.40).The FSC and Pashkow were the protocols that obtained the highest number of moderate agreements (each with four protocols) with other protocols. The highest agreement was observed between the BSC and Pashkow protocols (K=0.74) and it was close to the value considered as excellent (K>0.75). These protocols have similarities regarding the criteria for risk classification that may explain, at least in part, the agreement found. In addition, the criteria use the most prevalent examinations in the study sample.,,,-The majority of protocols examined in this study are based on the findings of complementary tests for cardiac risk classification,,-Echocardiographic data are also used by six of the seven protocols, and ejection fraction is a reference in five protocols,,-Some factors that contributed to the disagreements between the protocols were: i) a number of the protocolsThis study has some limitations that should be pointed out. The fact that some records contained incomplete medical history without some details necessary to some protocols, such as the presence of complications during hospitalization, reinfarction, and the occurrence of cardiac arrest, may have produced errors in the stratification of patients in some protocols AACVPR21. It iThe results of this study do not allow us to determine the best protocol to be used, however it can be stated that the ACSM protocol is the most suitable for patients who have no complementary tests. All of the other protocols can be used in patients who have complementary tests, however according to the tests they have and the patient's clinical history, some protocols may be more suitable for assessing the risk of cardiac events during exercise.The SSC protocolThe AHA protocolThe majority of the evaluated protocols presented low or moderate agreement. However, despite their limitations, all protocols showed good applicability for the cardiac risk assessment of the majority of the patients, which is important for professionals acting in the CR area.Based on the findings of the present, it can be concluded that the agreements between cardiac risk classification protocols in cardiac patients undergoing a CR program were considered low to moderate. Furthermore, the risk ratios differed between protocols according to each category of risk stratification.


Now 30 years old, the chronic mild stress (CMS) model of depression has been used in >1300 published studies, with a year-on-year increase rising to >200 papers in 2015. Data from a survey of users show that while a variety of names are in use (chronic mild/unpredictable/varied stress), these describe essentially the same procedure. This paper provides an update on the validity and reliability of the CMS model, and reviews recent data on the neurobiological basis of CMS effects and the mechanisms of antidepressant action: the volume of this research may be unique in providing a comprehensive account of antidepressant action within a single model. Also discussed is the use of CMS in drug discovery, with particular reference to hippocampal and extra-hippocampal targets. The high translational potential of the CMS model means that the neurobiological mechanisms described may be of particular relevance to human depression and mechanisms of clinical antidepressant action. The chrThis paper presents a historical overview of the CMS model, considers some areas of controversy, and reviews recent research in three major areas of application: neurobiological processes mediating the effects of chronic stress, cellular and systemic mechanisms of antidepressant action, and antidepressant drug discovery. The focus of the review is on the specific contributions of CMS research, rather than an integration of CMS studies with the wider literature. The aim, in taking this approach, was to explore how comprehensive a story this single model provides.2The origin of the CMS model was in series of studies by Katz and colleagues, published in the early 1980s, in which rats were exposed sequentially to a variety of severe stressors. Most of these studies assessed the effects of stress using changes in open field behaviour, which were reported to be reversed specifically by chronic treatment with antidepressant drugs, but not by non-antidepressants e.g. . HoweverIn addition to making hedonic measures the primary focus of the model, a second change to the procedure described by Katz and colleagues was that the severity of the stressors employed was greatly reduced. This change was made for ethical reasons, and in the context of the Animals (Scientific Procedures) Act (1986) that had very recently tightened the framework for animal research in the UK, placing an emphasis on minimizing stress wherever possible. Consequently, the CMS regime as initially developed did not include any of the severely stressful elements used by Katz and colleagues, such as intense footshock, cold water immersion, or prolonged (48 h) food and water deprivation. The birth of the CMS procedure was in a lab meeting in 1986 where those present brainstormed the problems that might arise if animals were curated by a thoroughly incompetent technician: water bottles might leak into the bedding; it might not be noticed that food and water supplies needed replenishment; the light-dark cycle in the animal house, and the lights themselves, might malfunction; housing conditions might change unpredictably; the environment might be noisy; and so on. All of the ideas generated were then implemented in a combination that was unremitting (no stress-free periods) and continuous over many weeks (the chronic element of CMS). For licensing purposes under the 1986 Act, all of the individual micro-stressors were considered to be ‘mild’ but the overall procedure was given a ‘moderately stressful’ banding. The first publication using the CMS procedure reported that rats exposed chronically (5–9 weeks) to CMS, and tested weekly, showed a reduced consumption of, and preference for, weak solutions of saccharin or sucrose, which developed over the course of several weeks exposure, and that the decreased sucrose preference was restored by 2–4 weeks of treatment with a tricyclic antidepressant .Over the next few years, this observation was extended to other typical and atypical antidepressants e.g. , and the3From those beginnings, there has been an exponential growth in the number of laboratories and publications using the CMS procedure, amounting, in 2015 alone, to 230 publications from 180 labs in more than 30 countries . From thWith the exception of two studies in fish, the 230 papers published in 2015 all concerned studies in rats or mice. In order to gain an overview of the scientific focus of CMS studies, these 230 papers were classified, on the basis of the abstract, into three categories: Neuroscience, where the paper included direct measures of brain structure, function or constituents; Other, which comprised studies of stress effects on behaviour or on physiological systems other than the brain, including tests of putative antidepressant agents; and Traditional medicine, which included any publication with a focus on plant-derived or other natural products as well as procedures such as acupuncture, irrespective of the other content of the paper . 4Although in this paper the model under discussion is referred to generically as CMS, the literature reviewed covers a range of ostensibly different procedures with the common feature that they involve chronic administration of a variety of different stressors. An accompanying paper  describeThe question of predictability is easily addressed by interrogating the survey responses with respect to whether the micro-stressors making up the stress regime were presented in a fixed order from week to week, or randomly.  The survey received a total of 71 responses, with a roughly equal representation of rat and mouse labs. The majority of labs (75%) employed random presentation, with a marginally greater usage with mice than with rats . The question of severity is more recondite, because the relative severity of different stress procedures is uncertain in the absence of comparative physiological data. To address this issue, the different micro-stressors included in CMS-type studies were each rated for severity, on a 5-point scale, using an expert consensus procedure described in the accompanying paper , and theWe may conclude from this analysis that the name by which the stress regime is described contains almost no information. With a single modest exception (presentation order in rats) the use, or non-use, of the terms Mild and Unpredictable has no discernible relationship to the content of these stress schedules. The content of the schedules is highly variable, but not in a manner that is reflected in the names by which they are described. Therefore, the differently designated procedures have been treated as equivalent for the purposes of this review.5The validity of animal models of psychiatric disorders is usually assessed using a multidimensional approach in which a model is evaluated in respect of its predictive validity (performance in the test predicts performance in the condition being modelled), face validity , and construct validity . In relation to animal models of depression, predictive validity refers primarily to specific and selective responsiveness to (drug and non-drug) antidepressants; face validity is assessed by comparison to DSM (now DSM-V) symptom checklists, with particular reference to core symptoms of depression; and construct validity is based on an argument for similarity of psychological constructs, such as responsiveness to rewarding events, or if they are known, the underlying neurobiological mechanisms. These principles were first proposed in relation to animal models of depression  and the Regarding its predictive validity, the CMS model was shown in early research to respond to chronic, but not acute, administration of a wide range of established antidepressant drugs (and to electroconvulsive shock), but not to drugs that are clinically ineffective as antidepressants , diagnoses that are almost unchanged in DSM-V . The effBroadly speaking, theories of depression have either a psychological or a neurobiological basis  model of depression is considered by many to be the animal model of depression that has the greatest validity and translational potential, but it has often been criticized for a perceived lack of reliability. Indeed, the view that the procedure is unreliable is widely accepted, and features prominently in reviews of animal models of depression see . The stuResponses were returned by 71 (42%) of the recipients, followed by further correspondence with some of them. Most of the respondents (n = 53: 75%) reported that the CMS procedure worked reliably in their hands. Of the others, 15 (21%) reported that the procedure was usually reliable, though not always (n = 9: 13%) or not for all measures (n = 6: 8%). Only three respondents (4%) reported being unable to reproduce the characteristic effects of CMS, two of whom may be using an insufficient duration of CMS exposure. The study has the obvious limitation that it was not possible to include laboratories that may have worked with the CMS model but not published their data. However, the overwhelming message from a large sample is that the CMS model does appear to be generally reliable within laboratories and robust across laboratories. Consequently, it appears that the many published statements to the effect that the procedure is unreliable are incorrect.A series of analyses compared the 75% of ‘reliable’ labs with the 25% of ‘less reliable’ labs on a range of experimenter, subject, stress and outcome variables. Few if any significant differences between these two samples were identified, possibly because of the small size and diversity of the ‘less reliable’ sample. Consequently, the study did not succeed in identifying the critical features of the CMS procedure that result in a less effective implementation in a minority of laboratories. However, from an overview of the survey responses and the published literature, it appears that success with using the model depends on an interplay between (i) individual differences in susceptibility to stress, both within and between animal populations, (ii) the overall severity of the micro-stressors applied, which need to be sufficiently intense to evoke a physiological stress response and sufficiently variable to prevent habituation to their repeated presentation, and (iii) good laboratory practices, which are particularly important when the sucrose test is used as the main outcome measure. The evidence underpinning these conclusions is presented in the accompanying paper .7Of all the factors that have been studied in relation to the reliability of the CMS model, individual differences have received the greatest attention. Individual differences in susceptibility to CMS have been studied in relation to strain differences, ‘personality’ characteristics, genomic manipulations and natural variation.The best characterized strain difference is between the more resilient C57BL/6 and more susceptible BALB/c mouse strains . IncreasGenomic manipulations have been reported that increase both susceptibility and resilience to CMS. For example, a knockout of the cannabinoid CB1 receptor increased susceptibility to CMS , consistThere is increasing interest in examining neurochemical differences between subgroups of susceptible and resilient rats  and miceBecause CMS-susceptible and CMS-resilient animals are identified post hoc, it can be difficult to determine whether differences between these populations, and between these subgroups and non-stressed animals, represent trait-like individual differences that could play a causal role in the differential behavioural response, or consequences of CMS exposure. For some findings, the neurochemical differences appear consequential to CMS. For example, 8As described above, there has been extensive research on the physiological changes seen in the brains of rats and mice subjected to CMS, and a comprehensive review of this literature described how the effects of CMS on numerous neurochemical systems closely parallel the neurochemical abnormalities described in the brains of depressed patients . But whaThe major stress-responsive system is the hypothalamus-pituitary-adrenal (HPA) axis. The critical role of this system in the effects of CMS is demonstrated by experiments showing that the development of a depressive phenotype during exposure to CMS  is blocked by the glucocorticoid receptor antagonist mifepristone , the corThe systemic mechanisms by which CMS-induced HPA activation results in behavioural impairments are also now reasonably well understood. The critical factor is that HPA activity is held in check by negative feedback systems operating through forebrain structures, with the primary feedback at the level of the hippocampus . HoweverWhile the hippocampus is the brain area that is most sensitive to the neurotoxic effects of stress, prolonged exposure to stress or high levels of glucocorticoids can also cause damage in many other brain regions, particularly the prefrontal cortex (PFC) , which, The amygdala is the point of entry through which stress stimulates the HPA axis. In contrast to the negative feedback of the HPA axis that operates primarily through the hippocampus , a positive feedback system operates through the amygdala, such that activation of the amygdala by stress stimulates the HPA axis, which in turn further stimulates the amygdala, the system being held in check by the hippocampus . ConsequIt is evident that CMS influences multiple brain systems, and that the mesolimbic dopamine system, which has been most closely associated with the anhedonic effects of CMS, is affected by CMS via a very indirect route . This is perhaps relevant to the observation that decreases in sucrose intake may be more limited e.g.  or more 9Any analysis of antidepressant action must start with the observation that the canonical action of antidepressants, to increase transmission at monoaminergic synapses by blocking the reuptake of 5HT and NA, is indeed the basis of their clinical action. While many alternative mechanisms have been proposed in recent years, this basic observation was established many years ago by the classic clinical observations of Delgado and colleagues that, following successful antidepressant treatment of depression, the effect in patients treated with specific 5HT reuptake inhibitors (SSRIs) is reversed by a dietary intervention that decreases transmission at 5HT synapses , while tAs outlined above, and elsewhere , CMS hasThe mechanisms by which the primary effect of antidepressant drugs, increased transmission at monoaminergic synapses, gives rise to behavioural changes that may emanate from distant brain areas is now reasonably well understood, and mirrors in large part the picture described above. In brief, antidepressants reverse the neurotoxic effects of stress. As summarized in A critical role of adult hippocampal neurogenesis was first described in the classic study of Perhaps more important than neurogenesis for the early stages of recovery from CMS is the effect of synaptogenesis. Antidepressants, both monoamine uptake inhibitors and MAO-A inhibitors, restore the atrophied dendritic tree of hippocampal neurons in animals subjected to CMS . This efWorking back towards the synapse, the expression of BDNF, VEGF, and other neurotrophins, is controlled by the nuclear transcription factor CREB. The expression of CREB in the hippocampus is increased by chronic, but not acute administration of antidepressants of all classes . In an iWith the exception of neurogenesis, which is specific to the hippocampus, a similar story is developing in the PFC. For example, CMS has been shown to decrease glial cell proliferation in the PFC, which was reinstated by chronic antidepressant treatment . The expThe importance of the PFC as a target for antidepressant action is highlighted by the effectiveness of deep brain stimulation of the ventromedial PFC in treatment resistant depression , togetheThe ketamine story has heightened interest in glutamatergic synapses in the PFC as a potential extra-hippocampal and non-monoaminergic target for antidepressant action. Antidepressant-like effects of NMDA antagonists were described in early CMS studies , and mor10The CMS model was originally developed as a platform for investigating neurobiological mechanisms, as discussed in the two preceding sections, rather than as a drug discovery vehicle, for which it is ill-suited by virtue of the long duration and labour-intensive nature of CMS experiments. Nevertheless, use of the CMS model has been widely adopted within drug discovery and development programmes. Analysis of publications retrieved in the PubMed search , Fig. 2 The major driver of the search for novel antidepressants has been the failure over many years to achieve significant improvements in efficacy, delay of onset, or proportion of depressed patients responding to treatment, prompting a search for drugs acting other than by potentiating transmission at monoaminergic synapses. The growing evidence that antidepressants act by repairing a damaged hippocampus provided an alternative starting point, leading to many new approaches aimed at achieving the same end by different means. These include drugs that act as HPA antagonists (to decrease the threat to the hippocampus by dampening the response to stress), neuroprotective agents (to protect the hippocampus against glucocorticoid-induced neurotoxicity), or promoters of neurogenesis and synaptogenesis (to repair the damage). As discussed earlier in this review, and elsewhere , stress-Of particular significance, most of the interventions listed in One final point worth making is that the chronic time-course of CMS experiments makes it possible to distinguish between anxiolytic and antidepressant drugs. Anxiolytics act by dampening activation of the amygdala , and con11After a slightly rocky start, the CMS model has become firmly established as an indispensable experimental tool for studying the neurobiological basis of depression. Recent research has added further to the validity of the model, and early concerns about its reliability appear to have largely receded. The model has made substantial contributions to our understanding of the neurobiological consequences of chronic stress and the reversal and repair of those effects by chronic antidepressant treatment. It is also evident that the CMS model has become established as a valuable component of antidepressant drug discovery and development programmes. Of course, there is much more to say about these problems: the aim of this review was identify some specific contributions of CMS research, not to present a comprehensive account of the neurobiology of depression and antidepressant action see , and cer


Advances from pharmacogenetics (PGx) have not been implemented into health care to the expected extent. One gap that will be addressed in this study is a lack of reporting on clinical validity and clinical utility of PGx-tests. A systematic review of current reporting in scientific literature was conducted on publications addressing PGx in the context of statins and muscle toxicity. Eighty-nine publications were included and information was selected on reported measures of effect, arguments, and accompanying conclusions. Most authors report associations to quantify the relationship between a genetic variation an outcome, such as adverse drug responses. Conclusions on the implementation of a PGx-test are generally based on these associations, without explicit mention of other measures relevant to evaluate the test's clinical validity and clinical utility. To gain insight in the clinical impact and select useful tests, additional outcomes are needed to estimate the clinical validity and utility, such as cost-effectiveness. Health care professionals, scientists, and policy makers have recognized the potential of precision medicine to optimize therapeutic outcomes. Appropriate therapeutic choices could be made by prospectively identifying patients through pharmacogenetic (PGx) tests. A PGx test can identify patients at high risk of treatment failure, for example due to drug toxicity or inferior treatment efficacy. However, predictive biomarkers are not used to the expected extent in health care practice Teng, . NumerouSeveral initiatives exist to translate knowledge on PGx to the broader clinical practice  independently extracted data following a predefined template of relevant topics. The topics included in this template are summarized in Table From the extracted data two researchers (MJ and TR) independently analyzed the following items: 1) measures of effect; (2) arguments used for or against eligibility; and (3) implementation advice. In the data on measures of effect and arguments for eligibility we specifically analyzed: parameters for potential clinical validity, clinical validity, and clinical utility  and arguments about eligibility (item 2) it was evaluated if the implementation advice was inconclusive.In the next analysis step, the consistency within publications was analyzed between the three items. For example, when a publication reported In total 132 publications were identified in the search, of which 89 were included for review (Supplementary Table n = 45), the ratio of positive outcomes reported compared to the total number of studies was the largest with 35 studies that reported a positive outcome. In the review publications, a ratio of 21 to 36 was found.The reviewed publications included 45 original studies , 36 reviews, and eight expert opinions . A range of statins was studied in the publications  clinical validity. However, none of these papers gave a positive implementation advice: three gave inconclusive advice, and one did not give an implementation advice.Some authors commented on the research and translation process in a more general manner. These comments suggest general steps for research and translation, which apply to ensure evidence-based guidelines for PGx for statins, such as (Needham and Mastaglia, “It is essential to first establish a valid association between a genetic variant and a drug response, which has been done for some genetic variations and muscle toxicity as reviewed above, and to then demonstrate a clinically significant outcome that results in improved patient management.”While many scientific publications describe promising PGx results, implementation appears to lag behind. Our results suggest an explanation can be found in the type of evidence reported in literature, because solely associations are often reported. Other types of evidence are needed for implementation, including guideline development and coverage decisions. To review arguments for the eligibility of PGx testing and what evidence is used to substantiate this, 89 scientific publications were evaluated on PGx for statins in cardiovascular disease. In 64 of the 89 publications, positive findings were reported on the research aims. Only in nine of these 64 publications a positive implementation advice was given. As multiple authors also discuss (Ong et al., Though our study is limited to published research and is inherently influenced by publication bias, it is a unique approach to reviewing scientific publications. The broad review of arguments in publications on the topic of PGx for statins, enabled a clear identification of the gap between scientific efforts and evidence needs for implementation. The call for reporting on a level of clinical utility finds resonance in other publications that discuss the gap between reported measures and necessary measures for implementation (Voora and Ginsburg, The context in which a test should take place and be piloted remains unclear in research suggestions from current publications. The timing of a PGx test influences the impact of the test greatly, for example there are significant differences between pre-emptively testing for a broad panel or targeted testing at first prescription. One of the few international initiatives on translation of PGx information into practice—CPIC—only offers information on dosing advice (Ramsey et al., A bridge is needed between the necessary and highly relevant work from basic science to relevant implementation research for clinical practice. Only through following the steps from clinical validity to clinical utility in a well-defined health care context Box , scientiResults from PGx studies on statins for cardiovascular disease are often summarized as associations between the genotype and phenotype: from effective drug levels to ADRs. For the next steps in translation, evidence is needed on clinical validity and clinical utility through implementation studies. It needs to be clearly defined what drug is studied, what the target population is, and when they should be tested. To support this contextual thinking, experts from health technology assessment could be included in early phases of research. This will offer opportunities to make recommendations on the steps from clinical validity to clinical utility, and for example include recommendation to study cost per QALY. Furthermore, to have an incentive for fundamental researchers to think about these steps, journals and peer reviewers can easily ask for measures that can directly be derived from measures for association. As Tonk et al.  describeMJ contributed to the analysis and interpretation of data, drafting the work and revising it critically. TR, WR, and MC contributed to the conception of the work, analysis and interpretation of data, and revising the work critically. TF, MW contributed to the analysis and interpretation of data, and revising the work critically. EH contributed to the conception of the work, and the data analysis. All authors approved the version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Central Asian countries of Uzbekistan, Turkmenistan, Kazakhstan, Tajikistan and Kyrgyzstan are tied together with similar histories and genetic heritage. Historically, these countries formed from nomadic populations along the Silk Road with common cultures, religions, and languages. They also have similar health patterns and life expectancies  which are near to the global average life expectancy. 1Since World War II, Central Asian countries have demonstrated a rapid increase in life expectancy, although there is still a large gap between genders. 5Overall, these countries have had little research collaboration despite sharing similar geographic locations environments, and migration patterns. Central Asian scientific productivity was determined by examining the publication rates for the five Central Asian countries . Every c6The publication numbers presented in 6The scientific disciplines of these publications are similar across these countries. The majority are in physics, chemistry, mathematics, and to a lesser extent, agriculture. There is a paucity of publications in medicine, public health, and social sciences. Clearly, it is important to boost the scientific culture of these countries, especially in the little represented areas.Despite the rates of publications being low, there has been a significant increase since 1993, as shown in 6The general conclusion is that rates of scientific productivity are relatively low in Central Asia and that focus has been almost exclusively on the “hard sciences” with little global health and behavioral research. However, we are seeing a rise in scientific productivity as well as an interest in international collaboration.Our mission is to build capacity to improve scientific productivity in Central Asian countries. We hope to double the number of publications coming from the region in the next five years through building a global network of scientists, fostering research training, and providing access to broadband connectivity for scientific communication and the sharing of knowledge.The first element required to improve scientific productivity is to provide networking for the universities in this region. This will lead to the free flow of ideas within and across borders. Secondly, it it is necessary to build a system that will provide training in research. This will be accomplished by creating programs and bolstering classroom research training by creating a Central Asian Supercourse. Finally a human scientific network in these countries will enable people to learn from each other within their countries, the region, and with the world.The implementation of fiber optic networking for universities in the region will facilitate collaboration between investigators at multiple institutions and will improve research capacity. Launched in January 2009, the Central Asian Research and Education Network (CAREN) is a high-capacity regional research and education network that provides high-speed internet for universities and research centers. The CAREN project, which evolved from the Silk Project funded by the European Commission (EC), is nearing completion. The goal of this project is to improve research collaboration within the region and worldwide. This fiber optic backbone provides the superhighway for research and training programs. 7To date, CAREN has networked over one-million users in more than 200 universities and facilitates joint regional and global projects. The user communities for CAREN include: distance learning, environmental studies, seismology, telemedicine, and textile research. The CAREN project will next link Central Asia and Europe to connect researchers across the world, increasing the collaboration and fostering development. 4Supercourse is a unique combination of a human network and a digital network containing state of the art content about global health and prevention The Supercourse model is very simple. The Central Asian Scientific Supercourse team has built a global network of over 50,000 primarily academic faculty members from 174 countries. The network contains 4855 PowerPoint lectures including: 77 from Nobel Prize laureates, 300 from IOM/NAS members, several lectures from the past two directors of the NIH and CDC, and the US Surgeon general. On average, each of the authors in the Supercourse has published 100 articles. 8These lectures can be distributed to faculty across the world, and can be used to compile cohesive lectures and presentations from disparate sources. For example, and educator using Supercourse might select five slides from Peter Bennett, an expert on diabetes, eight from their own lectures, and ten from scientists in Europe. Through the Supercourse, teachers are empowered by having access to current, state-of-the-art lecture material.There are 31 different languages represented in the Supercourse, with over 200 lectures in Russian, and several in Uzbek and Turkmen. The Central Asian Journal of Global Health (cajgh.pitt.edu) is a product of extensive scientific networking and capacity of the Supercourse Project.Scientists from Central Asia are already participating in the Supercourse. Over 60 faculty members from the region are involved (200 accessing the site within the past 12 months), with most of the lectures from within the region coming from Kazakhstan. In addition, all of the medical schools in the region are connected with the Supercourse and to each other via CAREN.Supercourse is a two-way street on which scientists in Central Asia and around the globe share their knowledge. We have already seen the benefits of this exchange through the 46 outstanding lectures prepared by participating faculty. These lectures were of interest to the world as they received 913 page views from outside the region, primarily from Europe and the U.S.http://www.pitt.edu/~super1/faculty/centralasia.htm. Its growth will be monitored as it becomes connected to the CAREN network.Clearly, there is an interest in building research capacity as well as in sharing knowledge within the region. The Central Asian Supercourse facilitates network fulfills this need. The origins of the Central Asian Supercourse can be found at: The field of “Mobile Global Health” represents the applications of cellular telephone technology to global health and prevention. It is expected that the number of cell phones will be equal to the number of people on earth in the next five years, which means that the vast majority of the global population will be accessible via cell phone. There are especially exciting implications for this trend in Central Asia, where cell phone use is already rising as shown in 10Furthermore, Supercourse developer Eric Marler has been capturing all the phone applications pertaining to science. The Central Asian countries of Uzbekistan, Turkmenistan, Kazakhstan, Tajikistan and Kyrgyzstan are primed for an increase in scientific productivity, measured by anticipated increase in peer reviewed scientific publications. Since the use of cellular/mobile devices is increasing in Central Asia, we support establishing a new field called “Mobile Global Health”. With the help of the CAREN project and our Central Asian Supercourse Team, the region will be able to utilize computer and human networks in order to share scientific research and reach out to each other and around the world.


Due to the limited safety data available at the time that a new medication is first marketed, it is essential to continue the collection and monitoring of safety data about adverse drug reactions (ADRs) during the medication’s life cycle. This activity, known as pharmacovigilance (PV), is performed worldwide by the pharmaceutical industry as well as by regulatory agencies. In 2012, the Israeli Ministry of Health (MOH) established a Pharmacovigilance and Drug Information Department. The Department is tasked with identifying, monitoring, and initiating activities aimed at minimizing risks associated with medication utilization. To enable this, the MOH has devised procedures for PV and promoted extensive legislation in this area that require marketing authorization holders (MAHs) and medical institutions in Israel to report ADRs and new safety information to the MOH. A computerized database was created to support the reporting process. The objective of this article is to characterize the PV tools and activities implemented in Israel.Since September 2014, The Israeli Pharmacovigilance and Drug Information Department receives ICSRs at a central computerized database developed for this purpose. The data were analyzed by Department personnel and ICSRs were characterized according to their seriousness, source, categories of drugs involved, and the reporting format. Additionally, the Department reviewed signals detected from ADR reports and from other sources and assessed the resulting regulatory actions.An analysis of the Individual Case Safety Reports (ICSRs) submitted to the MOH’s ADRs central database reveals that during the review period, a total of 16,409 ICSRs were received by the Department and 850 signals were identified, resulting in the following PV activities: inquiry and enhanced follow-up , prescriber’s and patient’s leaflets updates , recall of products/batches , alerts for health care professionals . Eighty five (10%) of the signals required a comprehensive investigation involving external specialist and 1 (0.1%) resulted in initiation of epidemiologic study. Additionally, in 2015 the Department incorporated comprehensive framework for risk minimization of marketed medicinal products, also known as risk management plans (RMPs).As practiced by other health authorities, the Israeli MOH effectively implemented various PV tools to ensure the safety of the Israeli health consumer. At time of approval of a new medication, the information available about the product’s safety is based primarily on clinical trials. As such, the information is limited by many factors such as the trial’s sample size, duration of follow-up, as well as exclusion criteria. Generally, even the largest trials consist only of thousands of patients while real world utilization of a medication may involve millions of patients. Thus it is essential to routinely monitor and update medications’ safety profiles throughout their life cycle in order to ensure an optimal benefit to risk balance. Pharmacovigilance (PV) is defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems . Among tIn 1968, the WHO established its Programme for International Drug Monitoring in response to the notorious thalidomide catastrophe, which was detected in 1961. The program provides a forum for WHO member states to collaborate in the monitoring of drug safety, and notably, the identification and analysis of new adverse reaction signals from data submitted to the WHO global individual case safety report (ICSR) database by member countries . WHO’s dPharmacovigilance activities in Europe are overseen by the European Medicines Agency (EMA) as well as at states level. Each of the 28 member states in the EMA, operates a national PV system which collects and analyzes its findings locally and reports them centrally. The EMA also supports and coordinates the European PV system and consults on the safe and effective use of drugs. Pharmacovigilance information is gathered from various sources and stakeholders, including regulatory agencies, industry, healthcare professionals, as well as from consumers. At the EMA, the reports are assessed by the PV Risk Assessment Committee. This committee is responsible for evaluating and monitoring safety issues for human medicinal products and is composed of experts from regulatory authorities in member states, experts in medicine safety, healthcare professionals, and patient representatives .The EMA’s reporting system for suspected cases of adverse reactions is the EudraVigilance. The EudraVigilance database includes reports of suspected adverse reactions to medicines from medical practice and from clinical trials. This system is not fully accessible by the general public and has different levels of access for different stakeholders .The US Food and Drug Administration (FDA) Division of Pharmacovigilance assesses safety issues and detects signals for all marketed medicinal products in US. The FDA uses a variety of PV tools including post-marketing reports of adverse events, published scientific literature, and preclinical/clinical data to provide a comprehensive evaluation that leads to regulatory actions as well as safety communications concerning marketed products. The reports are maintained in the FDA Adverse Event Reporting System (FAERS). This database is designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biologic products .Israel established a Pharmacovigilance and Drug Information Department within the Pharmaceutical Division of the MOH in 2012. Prior to this, reports on safety issues related to the use of medications were dealt with by various departments within the Pharmaceutical Division and not managed centrally. The Department was created in response to a series of multiple adverse events reported to the Ministry, highlighted by intense media and social media coverage; this was commonly referred to as the “levothyroxine (Eltroxin) event”. Upon establishment of the Department its manager underwent extensive training at the WHO’s center in Uppsala, Sweden. The Department also adopted the main principles of PV as practiced by the FDA and EMA.The Pharmacovigilance and Drug Information Department is composed of pharmacists and clinical pharmacists who work in collaboration with the Clinical Pharmacology Department at Asaf Harofeh Medical Center in Israel. The department’s main functions include ADR and signal management, submission of safety evaluations of medicinal products to other departments within the MOH, implementation of risk minimization plans and communicating drug safety issues to healthcare professionals and to the public.In February 2011, the composition of the levothyroxine product, Eltroxin, which has been registered and marketed in Israel since 1981, was changed. Upon introduction of the new formulation in Israel, health care professionals began receiving reports of adverse events which were mostly related to hormonal imbalance  and a few involving allergic reactions. Since, the health care professionals were not aware of the change in the formulation, the adverse events were not attributed to the formulation of the medication. At the time, there was no requirement for medical institutions/health care providers to report suspected ADR to the MOH, therefore only some of the events were reported to the MOH. After additional investigation the ministry decided to take measures and instructed the MAH to raise awareness of health care providers and patients about the change and the need of close monitoring.In the aftermath of the event, an investigation revealed that a similar change in formulation took place in Denmark in 2006 and in New Zealand in 2007. These changes also resulted in hundreds of reports of adverse events. Gaps in transferring this important PV information by the MAH to the Israeli Ministry of Health prevented preemptive measures that should have been taken by the Ministry.In January 2012 an inquiry committee appointed by the Ministry’s Director General, published its report . By thenPrior to establishing legislation on PV, the Ministry of Health followed procedures that were published in 2012 and were updated in February 2013. However these procedures were only aimed at the MAHs and excluded the obligation of health institutions to report the Ministry. In June 2013, the Israeli Parliament (“Knesset”) amended the Pharmacists Regulations  1986, and anchored the obligations of all MAHs, health maintenance organizations (HMOs), and hospitals in Israel to report ADRs, or any new safety information relating to medications used in Israel to the MOH. This also included a requirement for the reporting to be done by a designated appointed person, also known as Qualified Person Responsible for Pharmacovigilance (QPPV), and for the organization to operate a drug safety monitoring system. As per the regulation, the QPPV has to be a pharmacist or a physician holding an Israeli license to practice, with practical experience of at least 2 years in his/her profession. This individual needs to be appointed by the organization and approved by the MOH. For situations involving medical gases, a practical engineer may also be appointed to this position.Subsequently, In October 2013, the Pharmacovigilance and Drug Information Department published an updated version of the procedure for reporting adverse events and new safety information . The updIn accordance with the aforementioned legislation, each of the 4 Israeli HMOs appointed a QPPV whose responsibility is to receive and collect reports from health care professionals within the institution and submit them to the MOH’s Pharmacovigilance and Drug Information Department. Clalit health services , which serves more than 4 million citizens , is the Since September 2014, The Israeli Pharmacovigilance and Drug Information Department receives ICSRs at a central computerized database developed for this purpose. The data were analyzed by Department personnel and ICSRs were characterized according to their seriousness, reporting source, categories of drugs involved, and the reporting format. Additionally, the Department reviewed signals detected from ADR reports and from other sources and assessed the resulting regulatory actions.Individual case safety reports are received by the Department from health care professionals, patients, and from the MAH. Between September 2014 and August 2016, 16,500 reports were entered into the PV central database. Of these reports, 94.3%were submitted by pharmaceutical companies (MAH and importers), 5.5% were submitted by health care professionals from medical institutions, and only 0.2% of the reports have been submitted by patients and the general public. In addition to the electronic reports received in the database, health care professionals also reported adverse events via mail or by phone and patients reported them as complaints or questions via the drug information call center or ADRs patients’ Forum, a web-based service offered by the PV department to the public (more than 130 per year). 40% of the ADR reports in the database, were defined as serious, 59% defined as non-serious, and for the other 1% seriousness was not specified.Individual case safety reports can be submitted to the Pharmacovigilance and Drug Information Department by sending a standard International Conference on Harmonization (ICH) E2B format, an electronic format facilitated by the ICH for transmission of ADR reports. This method of transmission is currently used mainly by the industry . Additionally the Department developed a designated electronic form allowing for an online reporting of ADRs by the general public, health care professionals as well as from QPPVs at various MAH/importers who do not have ICH E2B reporting system . The forOver the course of the assessment period, 50% of the reports were submitted via the online government form and 50% were submitted via E2B format. We performed an analysis of the ICSRs in our database according to Anatomical Therapeutic Chemical (ATC) classification – a classification of the suspected drug or active substance, according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties . The mosDuring the assessment period, the top 10 ATC-3 medication groups, which account for 68% of all ADRs reported to the department were immunosuppressant drugs (L04A), antineoplastic agents (L01X), parathyroid hormones and analogues (H05A), antithrombotic agents (B01A), blood glucose lowering drugs , hypothalamic hormones (H01C), direct acting antivirals (J05A), hormonal contraceptives for systemic use (G03A), immunostimulant drugs (L03A), and all other therapeutic products (V03A). The latter medication group consists of antidotes, iron chelating agents, drugs for hypercalcemia, hyperkalemia and hyperphosphatemia, detoxifying agents, tissue adhesives, drugs for embolization, medical gases, nalfurafine, diazoxide, cobicistat and ethanol. Figure Signal detection is often based on a review of ICSRs. In the Pharmacovigilance and Drug Information Department, pharmacists and clinical pharmacists, specializing in PV, perform a case by case assessment to detect signals.Additional sources for signals are reports of medication misuse and/or quality concerns arising from medical staff, industry-operated patient support programs, observational studies, clinical trials, ADRs patients’ forum, scientific literature, periodic safety reports/periodic benefit risk evaluation reports (a document submitted by the MAH to regulatory agencies), and safety communications from other health authorities (whose websites are monitored on daily basis). In order to confirm a signal, it is cross referenced with various sources of data. This process of signal detection, evaluation and prioritization takes into consideration factors such as frequency of the ADR, its severity, impact on public health, and the feasibility of counteract measures.Additional factors taken into consideration include signals that involve serious, unexpected ADR, with reasonable causal association to the suspected drug, or a new aspect of a known association involving new product or new formulation. Moreover, the Department prioritizes signals derived from ADR reports that can indicate national safety issues such as a local quality concern and unusual frequency of a known ADR. Another important resource used by the Department to evaluate ADRs, signals, and other safety issues is an independent experts advisory committee appointed by the MOH for this purpose. Comparable committees exist at other regulatory agencies such as the FDA and EMA. The advisory committee consists of representatives from a variety of health disciplines, including clinical pharmacologists, pharmacists, and other specialists.In addition, Israel has signed agreements with several leading medicines agencies, such as Swissmedic and the FDA. These memorandums of understanding include PV data sharing. Overall, when needed, the Department communicates safety dilemmas with other regulatory agencies, mainly the EMA, FDA and Swissmedic. Following an internal assessment process and additional consultation with other regulatory agencies (if needed), the Department concludes whether the evidence is sufficient to support a safety concern to the public and determines what steps should be taken to manage and minimize this potential risk.Since 2014 until the end of 2016, 850 signals have been identified from all sources. Following evaluations that took into account the impact on public health and the feasibility of counteract measures, it was determined that 430 signals required inquiry or follow-up and 420 of the signals required additional regulatory actions. Forty percent of the signals originated from ADR reports.n = 850).Among the PV activities initiated following the signal detection were: initiating leaflets and label updates, informing health care providers and the public regarding safety concerns, and in special cases –withdrawing a drug from the market, recalls or inventory holds of specific products or batches. Figure In addition to the described activities, as of 2015 the Pharmacovigilance and Drug Information Department takes proactive risk management process to minimize potential risks associated with the use of medications by implementing risk minimization plans (RMPs) with the MAHs. RMPs are key regulatory tool for characterization, assessment, mitigation, and minimization of risks associated with use of a medicinal products. A procedure that sets the guidelines for submitting RMPs to the Pharmaceutical Division was published in March 2016. Since 2015 to date, 30 RMPs were implemented in Israel.In 2014 the Department received 11 reports in a period of 10 days regarding urticaria, which presented as intense itchy skin rash, and developed during or minutes to hours after the infusion of a specific batch of an immunoglobulin product. In the prescribing information, urticaria is listed as an uncommon adverse reaction of immunoglobulin products. An investigation was initiated which revealed no quality issues that may have caused the above ADR. Nevertheless, due to the unexplained unusual frequency of these serious drug events, the Department decided to hold the marketing of this batch. Following this hold, there were no additional reports.Three spontaneous reports of death associated with intramuscular administration of benzathine benzylpenicillin (penicillin G benzathine) had been received by the Department during a period of 9 months (2014–2015). The 3 cases involved elderly female patients aged 91, 77 and 70 years with underlying cardiac disease but in stable clinical condition. The patients were treated for erysipelas, with monthly intramuscular injections of the benzathine benzylpenicillin diluted with lidocaine. In each of the cases, shortly after the intramuscular injection of Benzathine benzylpenicillin, the patient lost consciousness with respiratory and cardiac arrest. After a thorough investigation among the 4 HMOs, 3 more cases of severe adverse reactions to benzathine benzylpenicillin during occurring within the last 3 years were identified; one of which was fatal. The benzathine benzylpenicillin was imported from different manufacturers and was from different batches. Chemical analysis of the suspected products revealed no quality issues. In all cases the benzathine benzylpenicillin was diluted with a small amount of lidocaine 1% in order to minimize the pain associated with the injection but the amount of lidocaine injected could not explain this adverse reaction. In each case, the drug was administered for at least several months prior to the event and therefore an evaluation performed by the PV expert advisory committee concluded that anaphylaxis was not a reasonable explanation for the events. It should be noted that the product leaflet contains strict administration instructions for the drug. Specifically, it states that the drug may only be administered by deep intramuscular injection and that intravenous administration of penicillin G benzathine has been associated with cardiopulmonary arrest and death. After considering the available data, it was determined that a possible explanation of the events might have been cardiopulmonary arrest due to embolism after inadvertent intravascular injection. Considering the benefit to risk evaluation, the MOH decided that the risk outweighs the benefit when administering this agent for most indications. In 2015, the MOH issued a communication regarding the restriction of using benzathine benzylpenicillin for a limited number of infections such as syphilis, where other alternative therapies are not suitable .In June of 2016, the FDA issued a communication that emphasized the existing warning about acute kidney injury with the sodium glucose transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin, which are used for treatment of diabetes mellitus . A questFulvestrant is indicated for the treatment of breast cancer. Due to a structural similarity between fulvestrant and estradiol, fulvestrant may interfere with antibody-based estradiol assays and may result in falsely increased levels of estradiol. Following a report on an unnecessary surgical procedure performed in a patient who was treated with fulvestrant which resulted in falsely elevated estradiol levels, the MOH ordered the company to issue a communication letter to health care professionals regarding this cross reactivity. The letter emphasized the importance of informing the laboratory performing the estradiol immunoassay about the treatment with fulvestrant and viewing the results of the estradiol levels in correlation with the clinical status of the patient. The product leaflets will be updated accordingly.In July 2014, the Department received 3 reports of infection with Pantoea in children treated with total parenteral nutrition (TPN) prepared by the largest compounding pharmacy in Israel. After a special request that was made to the medical institutions for similar reports regarding pantoea infections in TPN users, additional 8 validated cases were received. The MOH with the compounding pharmacy collected the suspected batches and initiated a comprehensive investigation including examination of manufacturing process, equipment, and the sterility of each component. Medical institutions were instructed to switch patients to alternative products and to report adverse events related to TPN treatment. This crisis was managed by multidisciplinary team from various professions, expertise, and institutions. Following corrective activities, the compounding pharmacy resumed its routine manufacturing. Since this crisis, as a preventive measure, the MOH instructed the preparation centers to check sterility of samples from each prepared batch.The MOH receives numerous reports of hemorrhagic events involving new oral anticoagulants (NOACs). Many of these events are serious and some are partially preventable. Because of these reports and in light of safety communications issued by some regulatory agencies, in 2014 the Department decided to initiate a risk minimization plan in collaboration with MAHs of NOAC products. The plan included prescriber guides, patient cards, and education plans for health care professionals. These educational materials were designed to emphasize the most important safety information, contraindications, main risk factors for bleeding, recommendations for conversion from vitamin K antagonists, recommendations for dosing adjustments, and more. The plans were implemented successfully in Israel in 2015.Following the Eltroxin incident, the MOH supported the registration of additional levothyroxine products in order to provide therapeutic alternatives to patients with hypothyroidism in Israel. Two new products were registered in 2013. Since then, a few clusters of ADR reports for levothyroxine products were received by the Department. One of these clusters was received in 2014 and involved the alteration of the external packaging information of a specific product. As a response to that cluster, the Department initiated an inquiry, involving the MAH and the Institute for Standardization and Control of Pharmaceuticals of the MOH. The inquiry did not reveal any quality issues, changes in the formulation, or deviation from specifications. According to the MAH there has been no a change in the manufacturing site or the manufacturing process. It seems that the change in the information on the packaging triggered the ADR reports. Prior to its registration, the product was marketed in Israel with a US label and after its registration, it was marketed with a Canadian label. After completing the investigation, a communication was issued to health care providers informing them about the inquiry findings and the differences in labeling that were due to different labeling requirement of the 2 regulatory authorities.In 2015 a second cluster of ADR reports including chest pain, gastrointestinal complaints, headache, and general “bad feeling” was received concerning a specific batch of levothyroxine. The Department initiated a new inquiry. Samples from new packages and used packages from different batches were examined by the Institute for Standardization and Control of Pharmaceuticals of the MOH. This inquiry also did not reveal any quality problem, changes in the formulation, or deviations from specifications. Following a clinical consultation with the advisory committee, no causal association was found between the medication and the complaints. No further action was required.In 2016, a MAH of levothyroxine announced a change in the external packaging for marketing reasons. As a preventive measure, a communication about the change was issued to health care professionals and patients. The communication stressed the fact that no other change was made. Nevertheless, since this communication another cluster of ADR reports was received. The Department continues to monitor and evaluate these reports and will take actions as needed.The Pharmacovigilance and Drug Information Department was established with a mindset for optimal use of national resources for effective identification, communication, and minimization of risk. This is manifested in the form of initial and ongoing robust education and training program for the Department’s personnel, establishing a legal framework for reporting, managing and communicating safety and risk data, benchmarking its activities to international standards, and creating partnerships and close collaborations with leading medicines agencies and the academy. These activities were supported by an extensive information technology infrastructure as well as by creating a network of experts in the field, advising on ongoing and emerging risks.Unfortunately, only a minority of ADRs are reported to regulatory agencies. ADR reporting behavior varies between countries but, in general, it is believed that approximately 5–10% of all adverse reactions are actually reported , 16. OneAs noted earlier, the Department developed an electronic form allowing for an online reporting of ADRs. The form is available on the MOH website. In the near future, the Department plans to implement a new version of the online reporting form with a simplified adapted version for patients and health care professional in order to facilitate reporting.In order to optimize the process of signal detection from high volume data, various statistical methods have been developed for routine monitoring of big data for signal detections. The MOH devotes resources to update the PV system and develop online forms to enable such quantitative signal detection. For example, implementation of the MedRA medical coding dictionary in the new version of the electronic reporting form will allow a quick and efficient identification, evaluation and analysis of ADR reports. However, it is important to point out that currently such decision support capacity is not aimed at replacing clinical judgment of PV experts.Future attempts will be aimed at gathering safety information from non-conventional sources of data such as social media, apps, and real world evidence derived from patients and patients groups. While this may be challenging, it will assist in bridging the gap in real time reporting and enable the MOH to capture the broad picture while utilizing big data for the purpose of PV.The Israeli Pharmacovigilance and Drug Information Department is tasked with identifying, monitoring, and minimizing adverse outcomes associated with the use of medical products. The PV approaches described in this article have been implemented successfully in Israel. The main strategies for risk minimization are publication of safety alerts, updates of prescriber’s and patient leaflets and development and approval of additional risk minimization plans. Efforts are ongoing to update the surveillance system and to improve the online forms to enable more effective ADR reporting and signal detection. The Department will continue its collaboration with international regulatory agencies to promote the health of the Israeli public.


Optimization of production medium is required to maximize the metabolite yield. This can be achieved by using a wide range of techniques from classical “one-factor-at-a-time” to modern statistical and mathematical techniques, viz. artificial neural network (ANN), genetic algorithm (GA) etc. Every technique comes with its own advantages and disadvantages, and despite drawbacks some techniques are applied to obtain best results. Use of various optimization techniques in combination also provides the desirable results. In this article an attempt has been made to review the currently used media optimization techniques applied during fermentation process of metabolite production. Comparative analysis of the merits and demerits of various conventional as well as modern optimization techniques have been done and logical selection basis for the designing of fermentation medium has been given in the present review. Overall, this review will provide the rationale for the selection of suitable optimization technique for media designing employed during the fermentation process of metabolite production. Fermentation technology is widely used for the production of various economically important compounds which have applications in the energy production, pharmaceutical, chemical and food industry. Although, fermentation processes are used from generations, the need for sustainable production of products, meet the market requirements in a cost effective manner has put forward a challenging demand. For any fermentation based product, the most important thing is the availability of fermented product equal to that of market demand. Various microorganisms have been reported to produce an array of primary and secondary metabolites, but in a very low quantity. In order to meet the market demand, several high yielding techniques have been discovered in the past, and successfully implemented in various processes, like production of primary or secondary metabolites, biotransformation, oil extraction etc.  and the appropriate medium components  must be identified and optimized accordingly. Further, by optimizing the above said parameters, maximum product concentration could be achieved  components of the fermentation media, followed by detailed description of statistical/mathematical optimization techniques. Also, the advantages and disadvantages associated with the above methods along with the future directions in the fermentation media design and optimization have been discussed in detail.Fermented products that are used in our daily life are either primary or secondary metabolites produced during the trophophase and idiophase of the microbial growth, respectively. High productivity titer is the pre-requisite for the industrial production of any type of metabolite. The production of specific metabolites in high titer could be possible by maintaining proper control and regulation at different levels via transport and metabolism of extra-cellular nutrients, precursor formation and accumulation of intermediates  production by different strains. In order to enhance the productivity of the metabolites , researchers investigated the nutritional requirements for the production of secondary metabolites and found that the nutritional requirements were varying from strain to strain  experiments, only one factor or variable is varied at a time while keeping other variables constant. The concentrations of the selected medium components were then changed over a desired range. Because of its ease and convenience, the OFAT has been the most preferred choice among the researchers for designing the medium composition and used in the initial stages in diverse fields  for the media optimization in fermentation process can overcome the limitations of classical OFAT method and can be a powerful tool for the optimization of metabolite production. Fisher  proposedDOE is a series of experiments which are strategically planned and executed to obtain a larger amount of information about the effect of more than one parameter at a time on the output, i.e., product yield. Most DOE procedures allow the preliminary screening of 2–10 medium factors in a limited number of experiments. In this method, several medium factors or components are compared simultaneously and the effects are observed and ranked based on the results. Once the response variables are determined and ranked, statistical performance parameters are generated from the subsequent analysis. Due to the requirement of higher number of experiments, OFAT is laborious, time consuming process, and extremely tedious for a large number of variables, whereas DOE requires fewer experiments, lesser time, and lesser material to obtain the same amount of information , is a two-level design, which is very useful for economically detecting the main effects and assuming all the other interactions are negligible when comparing the some important major effects, i.e., when there are no interactions, the observed effect of a factor can be superior or under estimated by other factors  and low (L). Each horizontal row represents a trial and each vertical column represents the either of two levels (high or low) of each independent and dummy variables in all the trials. Usually, the classical experiments help in the selection of independent and dummy variables. The effect of each variable is determined by the following equation:All the components present in the medium do not contribute in the metabolite production. Hence, it is utmost important that the non-contributing factors, should be eliminated from the study as early as possible. In 1946, R.L. Plackett and J.P. Burman published their work entitled “X1) of the concentration effect is the square root of the variance (√ Veff). The significance level of the effect of each variable is determined by student's t-test: tx1 = Ex1/SE. The variables with confidence levels greater than 90–95% will be considered to influence the metabolite production significantly.Experimental error is estimated by calculating the variance among the dummy variables as follows: VStreptomyces sp, we have used PBD to identify the most effective components in the media and reported soybean meal, calcium carbonate, and potassium phosphate can significantly increase the antibiotic production  (nb − 1)] followed by the selection of standard orthogonal array . At the end of the experiment, the factors are assigned to appropriate columns. Unlike PBD, it analyses the main effect and two factor interactions. However, higher order interactions are assumed as negligible. Noise, i.e., uncontrolled variables of experiments is taken as focal point for the analysis. Uncontrolled variables (noises) generally cause the loss of the quality. This effect of noise can be removed by employing the Taguchi methodology ; center points, where experimental runs having the median values of each factor used in the factorial design. This point is often replicated in order to improve the precision of the experiment; star points, experimental runs identical to the center points except for one factor, which will take on values both below and above the median of the two factorial levels. The numbers of star points are double the number of factors used in the design. On the basis of set of experiments and the level of factors, CCD are of three types: Circumcentered CCD (CCC), Inscribed CCD (CCI) and Face centered CCD (CCF)  was first described by Box and Wilson . NowadayF) Table .The Box-Behnken design is an alternate to CCD, it is independent of quadratic design, which does not contain an embedded factorial or fractional factorial design  and require 3 levels of each factor. The designs have limited capability for orthogonal blocking compared to the central composite designs.Some of the frequently used fermentation media optimization design techniques in the last 25 years have been summarized in Table Alealigenes xylosoxydans and found 1.4-folds production enhancement. Shih et al. , where the neural network is trained by giving it input and output experimental data. Unsupervised (Self-organization) in which output unit is trained to respond against clusters of pattern within the input. Different from the supervised, there is no prior set of groups into which the patterns are to be classified; rather the system must develop its own representation of the input stimuli. Reinforcement where learning may be considered as an intermediate form of the above two classes of learning. The learning system categorized its action as good or bad based on the environmental response and accordingly adjusts its parameters. Generally, the parameter adjustment is continued until the attainment of an equilibrium state.An artificial neural network (ANN) is a mathematical or computational model that is influenced by the structural and/or functional aspects of the biological neural networks. Neural networks are typically applied in the estimation and multi-step prediction problems, but can also be used as controllers directly or as an adjuster of any process parameter for a conventional controller. ANN mimics the learning ability of the brain Bhagat, , and conANNs have been widely applied with great success for system designing, modeling, optimization and control mainly due to its capacity to learn filter noisy signals and generalize information through a systematic training procedure  higher yield in optimized media in comparison to the normal production medium (yield 110 mg/l). One of the major advantages of GA is, it can handle a large amounts of data with no new guessing at each experiment, as the direction is automatically set. Hence, GA is the best method for solving complex optimization problems.A trained mathematical model serves as a fitness function in the determination of optimum concentration of the medium components using GA. GA mimics the process of mutation and is based upon the principle “survival of the fittest”. This algorithm is based on the biological process of evolution, i.e., natural selection  simplex method is another statistical technique, which has been found to be helpful in reducing the expenses of classical optimizations and gives satisfactory results. NM simplex method is based on a real-parameter black-box optimization method and works well with irregular objective functions. The “term” simplex denotes a regular-sided figure in Streptomyces sindenensis under submerged fermentation conditions is one of the best example, where the above combination has been used  formed during the biosynthesis of that metabolite which in turn will be helpful during the selection of carbon, nitrogen or salt solution which can also act as an inducer for the production of desired metabolites.Candida tropicalis, and reported that under aerobic conditions xylitol is the end product that acts as a substrate for ethanol production by anaerobic cultivation. Likewise, Huang et al. .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Since its inception in 2012, the British Neurosurgical Trainee Research Collaborative (BNTRC) has established itself as a robust example of a trainee-led research collaborative. This article summarises the work of the collaborative over its first 5 years of existence, outlining the structure, its research projects, impact and future directions. Multi-centre research can limit bias and can increase the external validity of study results. The British Neurosurgical Trainee Research Collaborative (BNTRC) was founded in 2012, with the aim of encouraging high-quality, multi-centre research and fostering a culture of collaboration. This includes engaging different units, increasing the accessibility of research for neurosurgical trainees and consultants and, ultimately, improving care and outcomes for neurosurgical patients. It was established as an initiative of the British Neurosurgical Trainee Association (BNTA) with the strong support of the Society of British Neurological Surgeons (SBNS) .The BNTRC was inspired by the successes of the West Midlands Research Collaborative (WMRC), a regional general surgical research collaborative established 4 years prior. The WMRC had demonstrated significant success in implementing a trainee-led collaborative, including funding and running a randomised clinical trial that recruited to its target ahead of schedule .The inaugural meeting was held at the Royal College of Surgeons of England (RCS) on 19 October 2012, with trainees from 13 of the 18 training programmes in the UK and Ireland in attendance and representatives from the BNTA and SBNS. Several projects were proposed by the attending trainees and a decision was made to pursue three projects , a steering committee (five to six members) and local collaborators at each unit , 2. The Protocols for each study are written by the study leads with input from the steering committee and are published  prior to study commencement. Each local lead is responsible for gaining relevant regulatory approvals  and ensuring robust data collection. Once the data collection period is complete, the study leads and steering committee are responsible for data cleansing and analysis.http://www.orioncloud.org) and Castor Electronic Data Capture (http://www.castoredc.com). Each have their advantages and disadvantages, and the best platform for each project must be individually chosen.A key aspect of each study is the data management strategy. This includes finding robust platforms for data collection. The BNTRC has explored a number of strategies, from the simple method of combining anonymised data on Microsoft Excel to robust online platforms for data entry such as the Outcomes Registry Intervention and Operation Network , with several new projects in the pipeline  are distributed more widely, including to the SBNS and European Association of Neurosurgical Societies (EANS).A BNTRC website was also developed to act as a resource for trainees and interested parties to learn more about the collaborative. It contains a wealth of information on the structure of the group, its constitution and the range of BNTRC projects. It is an important route for communication from interested doctors and medical students. Regular communications are also sent out via the BNTRC Twitter account (@BNTRC), which acts as an important social media resource for the collaborative. The group has an active account with over 650 followers and 9600 impressions over a 3-month period (Feb-Apr 2017). It is a useful means to communicate news and progress reports about BNTRC projects.The most important stakeholders in collaborative research are patients, who stand to benefit through the comprehensive, high-quality investigation of clinically relevant questions. Over the last 5 years, the projects completed by the BNTRC have demonstrated the ability to benefit patients, in terms of identifying practices associated with improved outcomes. For example, the National CSDH audit identified that practices associated with unfavourable outcomes included lack of post-operative drain, use of post-operative bed rest and single burr-hole drainage .Neurosurgical trainees also stand to benefit from involvement with the BNTRC. Trainees get the opportunity to be involved in the development and execution of robustly designed research protocols, skills that are vital in inculcating a generation of academically equipped neurosurgical consultants of the future. We also hope to contribute positively to the high-calibre research output of the UK neurosurgical community, which has produced many recent landmark clinical trials, including the STICH trials, RESCUEicp and STASH , 18, 19.From a national perspective, the BNTRC is viewed as one of the flagship specialty surgery research collaboratives, both in terms of the extent of its research activities and output so far , 20. ImpAs the first of its kind in the global neurosurgical community, the BNTRC has played a pivotal role in setting an example to trainee neurosurgeons around the world. The collaborative has served as an inspiration and has provided support to a number of other collaboratives, including the Canadian Neurosurgical Research Collaborative (CNRC) , the DutOver the last 5 years, the collaborative has faced a number of challenges. We have addressed some of these in this section, which, along with a previously published ‘how to’ guide , should At inception, the biggest challenges include selling the model to trainees, consultants and supporting professional bodies. The BNTRC has been fortunate in having the unwavering support of the SBNS and the SBNS academic committee. Examples of successful trainee research collaboratives, such as the WMRC, were instrumental in convincing the trainee community of the potential of the collaborative research model.The choice and success of the first project is also crucial to convincing all the stakeholders of the potential of the collaborative. It is prudent to pick a simple, non-controversial research question, with an observational study design that will serve as a conduit for establishing the multi-centre network. The study should have a relatively short timescale, with clearly established author and collaborator policies, rewarding all collaborators for their involvement.Each project also requires dedicated and motivated project leads and steering committee members, who are willing to drive the project forwards. Key challenges for the committee include developing a watertight protocol, obtaining ethical approvals and assembling the team of collaborators at each centre. In the UK, approvals are facilitated by having separate approval processes for ‘audit’ projects, which are less stringent than the ethical approval process for research projects. Data collection platforms also require careful thought, taking into account ease of use, financial considerations and security of the platform. As outlined above, the BNTRC has used a number of different platforms and we feel this flexibility has educated the group about the pros and cons of each, allowing us to tailor the choice of platform based on the particular needs of future projects.Although the BNTRC established their constitution 3 years into its existence, we would advocate new groups establish a constitution at inception, outlining transparent policies for authorship, leadership and choice of new projects.www.ideal-collaboration.net) [In addition to completing and continuing to expand the current portfolio of projects, there are several challenges that lie ahead. First and foremost is sustaining enthusiasm and interest in collaborative research, and this can only be achieved by ensuring that the collaborative projects are relevant to our specialty. Enhancing our relationship with the SBNS and each of the subspecialty groups  will facilitate this. Second, maintaining the highest standards when conducting audit and research will be critical. Following relevant guidance, such as the IDEAL framework, will be helpful in that respect. The IDEAL framework describes the research stages from first-in-human to evaluation in randomised trials (ion.net) . Third, ion.net) .In the 5 years since its inception in 2012, the BNTRC has come a long way. There are significant challenges that lie ahead in sustaining and expanding upon this early success, with much of it depending on the sustained enthusiasm of future generations of UK neurosurgical trainees.