Alcohol and substance use results in significant human and economic cost globally and is associated with economic costs of £21 billion and £15billion within the UK, respectively, and trends for use are not improving. Pharmacological interventions are well researched, but relapse rates across interventions for substance and alcohol use disorders are as high as 60–90%. Physical activity may offer an alternative or adjunct approach to reducing rates of alcohol and substance use that is associated with few adverse side effects, is easily accessible, and is potentially cost-effective. Through psychological, behavioural, and physiological mechanisms, physical activity may offer benefits in the prevention, reduction, and treatment of alcohol and substance use across the lifespan. Whilst physical activity is widely advocated as offering benefit, no systematic review exists of physical activity  and its effects on all levels of alcohol and substance use across all ages to help inform policymakers, service providers, and commissioners.Reduce the risk of progression to alcohol and/or substance use (PREVENTION)Support individuals to reduce alcohol and/or substance use for harm reduction (REDUCTION), andPromote abstinence and relapse prevention during and after treatment for an alcohol and/or substance use disorder (TREATMENT).The objectives of this mixed methods systematic review are to describe and evaluate the quantitative and qualitative research obtained by a diverse search strategy on the impact of physical activity and its potential to:With the input of key stakeholders, we aim to assess how what we know can be translated into policy and practice. Quantitative, qualitative, service evaluations, and economic analyses will be brought together in a final narrative synthesis that will describe the potential benefits of physical activity for whom, in what conditions, and in what form.This review will provide details of what is known about physical activity and the prevention, reduction, and treatment of alcohol and/or substance use. The synthesised findings will be disseminated to policymakers, service providers, and commissioners in the UK.CRD42017079322.PROSPERO number: The online version of this article (10.1186/s13643-018-0674-0) contains supplementary material, which is available to authorized users. Alcohol and substance use is common: globally, 5.9% and 1% of deaths are attributable to alcohol and illicit drug use, respectively , and alcPharmacological interventions for alcohol and substance use disorders have been well researched and reported on for the management of withdrawal, dependence, and relapse prevention. The Cochrane Drug and Alcohol Group has published 11 and 30 reviews of pharmacological interventions for alcohol and substance use, respectively, whilst psychosocial interventions  are less well reported, with six and eight published reviews, respectively. Preventive interventions only have five reviews for alcohol use, and three reviews for substance use . Due to Physical activity  and heaProspective studies indicate that sports participation in adolescents and young people is associated with an increase in alcohol use but decrease in illicit drug use . HoweverIn contrast, a rigorous study in Finland tracked 1870 twin pairs from 16 to 27 years of age and concluded that low levels of physical activity increased the risk of both alcohol and illicit drug use ) then imported into EndNote. Using a structured and piloted data extraction form, we will extract relevant outcome data, study characteristics, and participant characteristics from each included paper. Data will be extracted by one reviewer and checked by another.Exported citations from traditional databases will be entered and de-duplicated into EndNote X8 . Grey literature results will be manually entered or, where available, captured through a browser-based citation management plug-in (such as Zotero [https://rayyan.qcri.org/)). Two initial subsets of 500 results will be screened by two reviewers and inclusion and exclusion discrepancies discussed following each in order to ensure good agreement between reviewers. Following this, a set of 1000 will be completed and discussed before the remaining results being screened independently by two reviewers. This will help ensure reliable and consistent screening. Full texts will be obtained for studies appearing to meet the criteria above and screened by two reviewers (each paper reviewed by one member of the team and checked by another). Disagreements are resolved through discussion and a third reviewer (AT). RK will be consulted in relation to uncertainty over economic evaluations arising from the two independent reviewers.Two waves of study selection will be undertaken. Titles and abstracts will be screened by two reviewers independently and disagreements resolved by discussion or, where necessary, a third reviewer , we will conduct a meta-analysis to estimate the overall effect and consistency of the intervention effect across studies. As the population and setting of studies are likely to be different, we will use a random-effects model to obtain the summary result as an estimate of the average intervention effect rather than the common effect estimated from a fixed effects model . Where pWe will not combine data from non-randomised trials which used different study designs, or data from randomised trials and non-randomised trials, in a meta-analysis, as the estimated intervention effects from different study designs can be influenced by different sources of bias and/or increased heterogeneity . In thosThe qualitative synthesis aims to describe qualitative data relating to the acceptability, feasibility, mechanisms, mediators, and moderators of physical activity in relation to alcohol and/or substance use. Data on the development, design, methods, and the populations involved will be extracted from qualitative studies using a bespoke data extraction form. The complete “findings” or “results” sections of the qualitative study reports will be exported into NVivo 10 . Each section will then be read and re-read by two reviewers, in conjunction with the data extraction form, to enable the reviewers to familiarise themselves with the study findings in the context of the study population, setting, and methods. Adopting a thematic analysis approach, reviewers will code and identify emergent themes and concepts independently (extracting associated quotes). The reviewers will come together to consolidate the findings into one summary of overarching themes. Associated quotes will be presented to support the identified themes. The review team will then draw out implications of the themes for policy and practice.Service evaluations will be considered separately from the academic literature, and through a thematic synthesis approach will be summarised to help understand contextual and implementation issues surrounding the delivery of PA for alcohol and/or substance use. It will also be used, where possible, to contextualise data from the academic literature within the UK context to aid with the final narrative synthesis.The review of resource use, costs, relative effectiveness and cost-effectiveness will include a descriptive summary of the (economic) study questions, methods, and results, culminating in a narrative synthesis. Since the purpose of our review is to provide clear and concise information on the existing economic evidence base, we will also consider partial economic evaluations. These may include cost comparisons, as well as studies with an exclusive focus on relative benefits, i.e. studies that discuss willingness to pay or preference-based outcome measures. Summary tables will not be limited to description of economic outcomes alone and will include all relevant information integral to the economic study. We will extract detail on analytic methods, study perspective, price year, country, currency, and time horizon with further extraction fields informed by section headings within the CHEERS  checklisThe analysis of the quantitative , qualitative , service evaluation , and economic  data will be integrated to develop a narrative synthesis. This will be summarised for dissemination to PPI groups and key stakeholders and used as a basis for generating critical input to help understand the implications of the findings for different groups.We will present dichotomous data as risk ratios with their associated 95% confidence intervals (CI).For continuous data, we will calculate the mean differences (MD) for outcomes measured by the same scale or the standardised mean differences (SMD) for outcomes measured by different scales and present both with a 95% CI.If outcomes were collected at multiple time points, we will attempt to present a summary effect over all time points. If this is not possible, we will choose one time point that is the most appropriate one and report the corresponding summary effect at that time point.Cluster randomised trials are susceptible to unit-of-analysis errors if the analysis was performed at the level of the individual without accounting for the clustering in the data. If the clustering effect has been accounted for in the analysis, the estimated intervention effect will be obtained from the reported summary data. If the clustering effect has not been accounted for, we will conduct an approximate analysis using the intra-cluster correlation coefficient (ICC), as suggested in the current guidelines . If the If a study did not provide the summary data of the intervention effects, we will contact the study authors on one occasion to request these data. Where individual-level data are missing due to participant dropout, we will conduct available case analyses and record any issues of missing data in the ‘Risk of bias’ table. If standard error is available but standard deviations are not reported in a study, we will estimate the standard deviation from the reported standard error and the sample size. We will calculate the effect estimate and its standard deviation if these are not reported, but the 95% CI is reported.I2) [2). We interpret the level of heterogeneity as follows: the heterogeneity is not important if I2 is lower than 40%; there is moderate heterogeneity if I2 is between 30 and 50%; and there is substantial or considerable heterogeneity if I2 is greater than 50% [We will assess statistical heterogeneity by inspection of forest plots, and by formal statistical tests of homogeneity (Chi-squared), measures of inconsistency (I2) , and betthan 50% . If subsWe will examine the possibility of publication bias and other small study effects using funnel plots of the intervention effect estimates against the inverse of their standard errors and test funnel plot asymmetry using Egger’s method  when theWe will conduct a sensitivity analysis based on quality indicators thought to be significant by the review team. Studies thought to be at high risk of bias due to specific quality indicators (e.g. lack of randomisation) will be removed to ascertain their effect on the estimated overall effect. We also intend to conduct a sensitivity analysis using fixed-effect models.The quality of evidence will be assessed using domains of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)  guidelinWe will explore generalisability at the study level and on the level of the aggregated evidence.We will collect the following data from each study: details of the intervention, fidelity of the intervention and adherence to it (this includes who delivers the intervention), rationale supporting the choice of outcome measures, and setting in which the study was conducted . Depending on the type of available data, we will analyse them using subgroup analyses, meta-regression, or contextualise it through narrative synthesis.We will establish advisory groups: consisting of academics, service providers, and service users. These groups will offer varying perspectives on pertinent issues arising and will provide input into different aspects of the review.The academic group will be asked to provide a critical voice on the interpretation of findings, to ensure no aspect has been overlooked, and to aid in establishing networks for finding data and disseminating results.The service provider group will offer insight into the UK context in which alcohol and substance use exists, what the commissioning landscape looks like, current and future reach and structure of services and interventions, contextualise findings to the current UK climate, and to aid in dissemination and implementation of results.The service user group will offer input into what outcomes we should be searching for, approaches to promote physical activity  would be most acceptable to people; and in what other ways could support services  be set up to maximise the reach and effectiveness for promoting physical activity for the prevention, reduction, and treatment of alcohol and substance use.To maximise the impact of stakeholder, public, and patient involvement, we will develop a user-friendly synthesis of the findings and nature of interventions and their apparent strengths and weaknesses working with the advisory groups. Once a user-friendly synthesis has been generated, it will be disseminated to key stakeholder groups and individuals and their feedback and input will be used to gain further insights into what the evidence suggests and where any gaps may exist. Specifically, people will represent different stages of addiction, including those who are occasional users at risk of progressing to regular users of alcohol and/or substance use, non-treatment seekers who wish to minimise harm, and those currently receiving treatment or who are in recovery. This synthesis will then be disseminated to key stakeholder groups and individuals and used as the basis for several group and individual meetings to gain further input into what the evidence suggests and where any gaps may exist.Upon completion of the review, we will develop a summary of key findings of the review of literature, a summary of the PPI assessment of the findings, and issues associated with service development and delivery highlighted by policy makers and service managers. We will present the findings at relevant academic conferences and a website that will be established to summarise the findings and implications, with links to access a final report. We intend also to organise a one-day conference to which key stakeholders, advisory board members, and any interested party will be invited. In addition to a final report, we anticipate submitting articles for publication in peer-reviewed open access journals.We will also disseminate the findings by phone or Skype to Directors of Public Health  and managers of organisations across the UK who do or could involve physically active interventions to gain a further insight into the issues associated with securing the necessary resources.The scope and methods for this review have been strongly influenced by both service provider and user perspectives throughout the development of the application and this protocol. The review will generate important and timely information to inform the provision of services for alcohol and substance use. Through the continued engagement with stakeholders, the information produced will have relevance across a variety of settings in addressing the prevention, reduction, and treatment of alcohol and/or substance use throughout the UK. A wide variety of dissemination plans will ensure the information is accessed by the most relevant services, as well as aiding to direct future research efforts.The size and scope of the review, whilst challenging, will ensure that the information brought together in this review will be as encompassing as possible and will provide all the necessary information about what we know about what works, for who, when, where, and how in an accessible and appropriate way. Information generated from this review will have the potential to directly impact on provision in several domains and address (where possible) issues of acceptability, feasibility, implementation, and cost-effectiveness.


Escherichia coli, microbiological indicators of faecal contamination at the sea. The same faecal contamination can be considered as the main cause of pollution phenomenon under current Italian and European regulations for the bathing waters . The main objective of the study is to verify, taking into the account the anthropic pressures acting on the coastal zone, the efficiency of the Apulian regional monitoring plan currently in force for the assessment of bathing waters quality, with a view to a hypothetical reduction of sample collection points.Geostatistic analysis was applied to the dataset from multi-year monitoring, in the Apulian marine-coastal zone , on the presence and abundance of intestinal Enterococci and  The Italian coastline stretches for more than 8000 Km, making it the European country with the highest number of bathing waters, 5518 , of which 4866 are marine-coastal bathing waters and 652 are inland bathing waters (rivers and lakes). The national coastline is highly anthropized, featuring intensive urbanization  and extensive settlements (13%). Under Italian law, bathing waters management and monitoring is regulated by the Government Decree n. 116/2008 in compliancy with European Directive 2006/7/CE establishing the objectives of bathing quality management [At national level and in compliancy with the above Directive, the Italian Government Decree 116/2008 is aimed at safeguarding human health from risks that may derive from bathing in poor quality waters also by means of environment protection and enhancement. To such purpose, the decree establishes how to monitor, classify, manage and diffuse information on the quality of bathing waters. Under the new regulation, the criteria for the definition and classification of bathing waters are essentially based on the concepts of forecasting and evaluating health risks, with less emphasis on temporary bathing suitability conditions.Legionella, Vibrio, Shigella). The majority of these pathogens are due to particular microorganisms  deriving from the gastrointestinal tract of humans or warm-blooded animals, as a consequence of faecal contamination of the water environment. The concentration of these pathogens highly depends on the efficiency of waste water collection and treatment systems as well as from the self-purification ability of the receiving water bodies, often favoured by natural factors such as the presence of current [A few human pathogens can be ascribed to autochthon microorganisms from a water environment  be present in the water every time pathogen microorganisms are present; (ii) have a life-span similar to the life-span of pathogen microorganisms; (iii) have a resistance to depuration and disinfection treatments similar to the resistance shown by pathogen microorganisms; (iv) its characteristics should not change over time.Escherichia coli (EC). They are the most widely-used faecal indicator bacteria [Enterococcus , suggested that site-specific conditions at each beach determine which indicator or indicators best predict health risk. Confirming what just stated, Molina et al. [Establishing the best bacteriological indicator system for water quality monitoring has historically been a significant issue which already occupied a great deal of time of the American Public Health Association committees in the 1930s and continued to feed a debate through the 80s, with interesting results . The maibacteria , which hbacteria  highligha et al.  identifiConsequently, the use of organisms as “indicators” does not allow a direct estimate of the presence of a given pathogen microorganism in the water environment, yet it allows to forecast the probability of its presence, therefore verifying the quality of bathing water. The Italian Government. Decree n. 116 issued on 30 May 2008 and its subsequent amendments established the IE and EC concentration limits to allow bathing at 200 CFU/100 mL and 500 CFU/100 mL, respectively. The subsequent classification is based on a quality evaluation obtained by means of a statistical calculation . Such evaluation is carried out every year at the end of the bathing season based on the data available for that season and compared with three previous seasons. It distinguishes four quality categories based on the microbiological indicators’ density, as shown in Test frequency may vary, based on the pollution type and significance, in compliancy with the terms indicated in They concluded that the method to gauge compliance was statistically unreliable due to failure of the log-normality assumption at many beaches. More recently, this assumption was investigated by Haggarty et al.  for the Scientists have always tried to study and comprehend the dynamics of natural and man-induced phenomena, such as costal water pollution, so to be able to predict and control them. These phenomena come in a wide and variegated range: from the simplest, showing in space and characterised by a single variable, to the most complex ones, ruled by a great number of mutually interacting variables that can be defined in space as well as in time .Studying such complex natural phenomena has required the development of specific mathematical and statistical instruments for both field monitoring and data analysis. A continuous and real-time field monitoring allows not only to assess water environment quality, but also to prevent its deterioration, since it allows collecting data at large time and space scales. In the last 30 years, several video system techniques, based on image processing, have been developed in order to extract from images different information e.g., ,17. At tOn account of its widespread use, suitability for the data and error calculations, one form of kriging, i.e., Indicator Kriging (IK), is used to process data in this research. The Indicator Kriging (IK) technique allows evaluating the probability of exceeding the established limits at interpolation points. For some sites, sampling areas grouping procedures were also studied, testing a reduction of monitoring points to verify whether such reduction, with its significant political and environmental effects, may interfere with the interpolation activity previously analysed.The application of geostatistic analysis aims at the spatial or temporal characterisation of data and information as well as at their modelling and estimate ,23. BesiThe spatial, temporal or spatial-temporal characterisation of a phenomenon is the first step in a geostatistic study. It essentially consists in highlighting, in terms of quality and quantity, the phenomenon variability, specifying its typology in relation to the presence of any spatial-temporal anisotropies and variables ,25.Once the phenomenon characterisation has been completed, variables can be spatially reconstructed by estimate. This stage consists in the spatial reconstruction of a variable, starting from a limited number of measures of the same variable . If needEstimating a variable is most commonly done as part of spatial data processing. It aims at constructing thematic maps, i.e., geo-referenced maps of a portion of a geographic area, showing the spatial-temporal trend of an interesting variable by means of a suitable representation method .The method used for estimations under this study is the Indicator Kriging (IK), a linear indicator that can be applied to data characterised by non-Gaussian distribution, similar to ordinary Kriging but with the input of a threshold value .It does not use its own values of the variable to be estimated, but rather it makes use of new variable indicators to obtain a prediction on the values. Unlike ordinary Kriging, the IK is a type of non-parametrical interpolation and can estimate a value at an unknown point by means of the aggregate distribution function reconstructed using the thresholds.N observations available as D ⊂ R2, then for each x ⊂ D, taken a value of the searched field characteristic as threshold z, the following indicator function can be defined:If we name the region that contains all z(x) for any location x0 within the examined area D, given the N available observations.The objective of this approach is to provide a prediction of the regionalized variable x0, determined based on the indicator values , which depend on the selected cutoff value z, is defined by the formula:The estimated value in point z(x) for the cutoff value kz in point x0:n is the conditioning caused by the proximity of other values at point x0.This value may be presented as the value of the cumulative distribution function of the regionalized variable z(x) for any location within the examined area, at the cutoff value kz, will be:The conditional cumulative distribution function of the regionalized variable An accurate description of the IK and its comparison with other estimation methods are respectively well discussed in Journel ,31 and Gz(x) takes specific values, limited by any given cutoff values, which is extremely important in practical use, e.g., to evaluate the impact of contaminants on water quality. In this case, geostatistical analysis can be useful both for definition of bathing water profile and the evaluation of effects due to “short term pollution” and “abnormal situations”. The application of IK can provide useful elements to identify the extent of the area being affected by pollution, as well as to estimate whether the pollutant load may represent a health risk. Therefore, it is a valid instrument to formulate and evaluate the effectiveness of environmental management measures.Indicator kriging allows the preparation of maps of the probability with which the regionalized variable This work was carried out with the objective of studying and analysing the phenomenon of marine water pollution deriving from faecal contamination at local scale, using as study area a region in Southern Italy, Puglia, with the aim of detecting any critical areas along its coastline.The regional coastline of Puglia stretches close to 1000 km , ranking third in length at national level after only Sardinia and Sicily. The geomorphology of the Apulian coastline varies as we move along the coast, featuring sandy beaches, river mouths as well as rocky cliffs. Such a natural coastal variety is emphasised by the effects of anthropic development , which impact on the marine-coastal ecosystem.http://www.arpa.puglia.it/web/guest/balneazione) and refer to monitoring activities carried out at a monthly frequency between April and September each year along the Apulian coastal zone. In compliance with national and European regulations, 674 different bathing waters have been identified in the region, according to the water basins, hydrological and morphological characteristics and the anthropic pressures along the coastline. Each of bathing waters is monitored in pursuance of Government Decree 116/2008, which establishes the rules for such activity in Italy. The data used for this study were provided by the Regional Agency for Environmental Prevention and Protection (ARPA Puglia), responsible for bathing water control on behalf of the Puglia Region-Department of Health, in compliancy with the national Government Decree 116/2008. The data were collected from the “Bathing Waters Monitoring Bulletin” issued by ARPA Puglia for the years 2010, 2011, 2012, 2013 and 2014 . The microbiological parameters measured are expressed in Colony Forming Units per 100 mL of water (CFU/100 mL). The total number of records available for this study was 18,360.The distribution of EC and IE data showed the prevalence of null values and a small number of records over the threshold values established under the regulation in force for bathing suitability The GIS processing of EC and IE Colony Forming Units analytical results was performed after categorization of data according to fixed intervals see The geostatic technique used for prediction under this study is the Indicator Kriging (IK), a linear interpolation similar to ordinary Kriging with the input of a threshold value. This technique provides a value for the probability that the threshold established is overcome at interpolation points. The spatial distribution of threshold overcoming probability was achieved taking into account the values shown in the variograms of The probability values observed were mapped in The municipalities of Molfetta, Bisceglie and Bari are the biggest concerns, since they show a high threshold overcoming probability from contamination for both microbiological indicators. The software used also provides an estimate of error probability (in the form of error variance). Such estimate can be utilised for a direct evaluation of prediction reliability. As shown in A range of thematic maps were also developed in order to establish the correlation between the results obtained and the point or diffused anthropic pressures. 2. The information on the territorial extension of Apulian coastal municipalities was obtained from the Apulian Territorial Information System website (SIT Puglia), while data on the number of inhabitants were collected from the 2011 population census dataset published by the Italian National Institute of Statistics (Istat). Looking at The last analysis was carried out based on the coastal population density in terms of inhabitants/kmAs established under the current Italian regulation, in some cases contiguous bathing waters within the same water basins can be grouped into a unique bathing water, if under the same anthropic pressure and health risks. Thus, a purely qualitative grouping procedure was simulated, grouping contiguous bathing waters maintaining the highest measured values of contamination for the widest areas. For the purpose of this work, the analysis was carried out at different scales, taking into account two specific areas along the Apulian coastline, featuring a critical but different extent of pollution from IE faecal contamination, i.e., the sea coastal areas under the municipal territories of Molfetta and Bari.The grouping procedure simulation was carried out by halving the number of bathing waters in the municipality of Molfetta from eight to four Upon completing the grouping procedure simulation, the IK spatial interpolation method was applied, using data exclusively related to IE concentration. Such process produced the same typology of results above described, with very similar probability values but with significant variation in terms of minimum error probability, with consequent impact on prediction reliability. This analysis shows, in the case of the Apulian coastal area under study, that a grouping procedure and therefore a reduction in the actual number of related monitoring points may determine a higher error probability in the evaluation of water quality. The spatial scale used in this type of evaluation can significantly impact on the final result, too.This research confirmed the IK as a good tool for spatial interpolation of environmental data, ordered on the basis of the bathing water denomination, the bathing area code, the municipal belonging, the position and Gauss-Boaga geographical coordinates and, mainly, the numerical values of the microbiological contamination detected along the Apulian coasts.The study highlights the potential correlation between waste water discharge into inland water bodies and the quality of Apulian coastal waters. Discharge systems carrying waste waters to the sea through a river can contribute to an increased faecal contamination risk along the coast, although some biological constrains have to be considered . The overlapping between the contamination maps and the coastal inhabitants’ one underlines that population density alone can be one of the most important factors affecting the bathing waters pollution from faecal contamination. So, the importance of the anthropic pressures assessment was highlighted, since strictly related to the results obtained.Moreover, data processing qualitatively showed that grouping Apulian bathing waters and therefore reducing monitoring points determine a not appropriate evaluation, with a significant increase of the minimum error probability, of bathing water quality, demonstrating the congruity of the actual monitoring plan implemented by the regional agency ARPA Puglia. It is necessary to consider also spatial scaling as a factor that may considerably modify final results in the sampling point optimisation process.This study indicates the possibility to process historical data to obtain worthwhile information for the assessment of water monitoring plans, as well as for studying pollution phenomena at relevant spatial scale. The methodology discussed turned out to be useful to the concerned authorities for the planning of environmental impact mitigation measures, as well as for the improvement of sectorial regulations.


As populations increase in size, and as total hip arthroplasty is increasingly performed in younger patients, the burden on healthcare systems grows. Implant survivorship beyond two decades is becoming an imperative. Unfortunately, many hip implants have been introduced—often as minor modifications of a successful design—only to fail catastrophically. Joint registries pioneered by the Scandinavian countries are powerful tools with which to compare implants in the long-term, but detection of underperforming implants sooner remains difficult because registries generally have focused on the endpoint of revision, rather than on signs of failure that may be evident earlier on. By the time it is apparent that an implant does not have acceptable long-term survival, many thousands, if not tens of thousands, have been implanted.Radiostereometric Analysis (RSA) has been shown to be adept at detecting implants that are prone to early failure long before the evidence was apparent from longitudinal studies or registry data . HoweverA consensus is required on how new implants, or new designs of existing implants, are introduced in to clinical use. In the UK, the National Institute for Health and Care Excellence, in response to the widespread use of poorly performing implants, recommended that surgeons only implant total hip replacements that had solid long-term data, with a minimum survival of 95% at 10 years . This apThis system should also incorporate laboratory-based testing, and limited clinical release in groups with careful early- and long-term followup to continue in the original cohort. The authors of the current study should be commended for their examination of a new prosthesis. The study is a worthy example of how to: (1) Properly investigate a novel prosthesis, (2) confirm that the results of a clinical RSA trial of the same implant are useful, and (3) provide strong guidance on likely long-term outcome regarding fixation. The strength of this paper is based on its adherence to the consensus guidelines for the use of RSA in orthopaedics . FurtherWhile the current study should be commended, there are still some potential concerns. The system is expensive and arduous for the implant companies and it does not encourage engagement by orthopaedic surgeons unless they are attached to large research centers with the infrastructure to perform the necessary investigation.The Beyond Compliance system was developed in the UK in response to the NICE guidelines . The sysHopefully, by developing and maintaining a structured, cost-effective, and accessible method of device evaluation, we can avoid repeating the mistakes of the past.


Many indices have been proposed for cardiovascular risk stratification from electrocardiogram signal processing, still with limited use in clinical practice. We created a system integrating the clinical definition of cardiac risk subdomains from ECGs and the use of diverse signal processing techniques. Three subdomains were defined from the joint analysis of the technical and clinical viewpoints. One subdomain was devoted to demographic and clinical data. The other two subdomains were intended to obtain widely defined risk indices from ECG monitoring: a simple-domain (heart rate turbulence (HRT)), and a complex-domain (heart rate variability (HRV)). Data provided by the three subdomains allowed for the generation of alerts with different intensity and nature, as well as for the grouping and scrutinization of patients according to the established processing and risk-thresholding criteria. The implemented system was tested by connecting data from real-world in-hospital electronic health records and ECG monitoring by considering standards for syntactic (HL7 messages) and semantic interoperability (archetypes based on CEN/ISO EN13606 and SNOMED-CT). The system was able to provide risk indices and to generate alerts in the health records to support decision-making. Overall, the system allows for the agile interaction of research and clinical practice in the Holter-ECG-based cardiac risk domain. Sudden cardiac death (SCD) can be defined as a natural death with cardiac origin. It is given this denomination when no prior fatal condition has been observed, and either (a) it takes place in less than one hour from the observation of the first detected symptoms, or (b) it happens in the next 24 h of having seen the person alive ,2,3. SCDOn the other hand, clinical decision support systems (CDSSs) have been widely studied in recent decades ,6,7,8. IHowever, there is a separate evolution among the Electronic Health Record (EHR) and the CDSS due to the lack of maintainability and interoperability between CDSS components in EHRs, and the lack of EHR semantics that capture the highly structured patient data needed in computerized guideline execution and CDSSs . This meOur long-term objective is to create an advanced intelligent and interoperable system for supporting the cardiac risk stratification from ECG monitoring and EHR data for SDC, capable of integrating both research and clinical practice from multiple hospitals collaborating in this domain. This is a complex task, which requires advances in quite different fields, including ECG-advanced signal processing, the design of centralized intelligent engines, interoperability considerations, and precise medical descriptions for this wide, complex, and intensely studied domain .In this work, we generated the technical and clinical domain descriptors, together with the interoperability elements, necessary to create a system in which a cardiovascular risk model can grow with clinical practice. For this purpose, three subdomains have been created. First, a patient data summary that represents the data that can be extracted from the EHR or even from the Hospital Information System (HIS), and that can be potentially useful for risk stratification, is included. Second, a low-complexity subdomain is given based on the heart rate turbulence (HRT), and provides us with a reduced set of risk indices derived from the ECG in Holter recordings from simple signal processing and with simple risk rules defined in the literature . Third, The proposed SCD Risk Stratification System based on the HRT and HRV indices from ECG monitoring for Clinical Decision Support (CDS) can be used by different EHRs, thanks to the use of SNOMED-CT, CEN/ISO EN13606, and HL7 standards. Our system (1) supports the use of clinical standards for CDS, (2) supports the scientific assessment and improvement of HRT and HRV knowledge within their domains by developing a structured database, paving the way toward a progressive domain expansion, and (3) provides technological support for implementing SCD risk stratification in clinical practice (see Current SCD risk stratification techniques can be divided into three groups : (a) invThere is no consensus about the best convenience on signal processing algorithms and their adjustment in SCD risk stratification from ECG monitoring . HereinaHRT has been pointed out as a promising, strong, and noninvasive index CRS after acute myocardial infarction . The terHRV measures the temporal dispersion of series of consecutive beats. The short-term and the long-term HRV are associated with the heart rate control by the autonomic nervous system and with the complex auto-regulation cardiovascular mechanisms, respectively . Many otAccording to the Institute of Electrical and Electronics Engineers (IEEE), interoperability is defined as the capacity of several systems or elements to share and use information. Two types of interoperability can be defined, namely, syntactic  and semaThe HL7 standard provides a comprehensive framework for the sharing of electronic health information supporting clinical practice . It alloThe CEN/ISO EN13606 Standard aims to achieve the semantic interoperability by using a dual model architecture. The main advantage of the dual model architecture. The main advantage of the dual model is that knowledge (archetypes) is upgraded when it changes, whereas the reference model (information) remains unaltered . A referhttp://openehr.org/ckm/). The collection contains a set of reviewed and validated archetypes, and is constantly growing. This repository has 513 active archetypes in August 2017, which are in various stages of development , and includes clinical and administrative archetypes developed by a large number of clinical and computer experts at an international level.The most relevant international resource repository is the openEHR Clinical Knowledge Manager (CKM), promoted by the openEHR Foundation  and Clinical Terms Version 3 . SNOMED-Our research group has been working for the last several years on the standardization of the cardiac domain from the EHR to provide CRS. Given that this is an extremely wide knowledge domain, our focus is on the indices measuring repolarization heterogeneity and autonomous nervous system control from long-term ECG signal processing. To this aim, we first built an ontology based on the conceptual model of SNOMED-CT for CRS using ECG-derived parameters in the HRT domain . Two praWe found two main drawbacks in these practical implementations. First, the HRT template based on the ontology did not achieve semantic interoperability in the EHR, because it was created with no clinical standard to model the clinical domain. Second, the implementation of the HRT form in different clinical systems was very difficult to reach, since changes in commercial systems require political consensus. For the former, a CRS archetype was subsequently built, following the CEN/ISO EN13606 standard, to achieve the interoperability among heterogeneous clinical systems . A simplFor the latter, we propose in this work an interoperable web-based CDSS that uses archetypes and clinical terminologies. We used the standard HL7 v.2.6 to achieve syntactic interoperability, and CEN/ISO EN13606 to achieve semantic interoperability.In this section, we describe the implementation of a risk system based on ECG monitoring (RSEM) for making the interoperability (collection and exchange) of EHR, HRT, and HRV data provided by different health entities. The recommendation in  suggestsOur system integrates several parameters and measurements from EHR and Holter, all of which are potential indices of SCD, hence allowing for the creation of increasingly improved risk indices. The process is the following: first, a set of non-Holter variables with prognostic interest are extracted from the EHR ; second, the Holter recording is analyzed and additional indices are automatically obtained ; third, a risk scale is built for all of them.It is important to note the paradoxical state of art of risk stratification from Holter measurements . On the to create a system, external to the EHR and HIS, that is interoperable with them, thanks to its design following clinical standards;to cover a significant part of the CRS domain from ECG-derived indices measured in Holter recordings, namely, patient summary data, HRT, and HRV subdomains;to be able to grow by including other cardiac risk subdomains;to allow us to perform signal processing;to generate alerts related to the CRS domain, with different levels, and to feed them back into the EHR.According to previous considerations, the specifications for this work are the following:One of the long-term requirements of the RSEM is to model the CRS domain and to describe all the related concepts and data logged on the EHR. For this purpose, an advantageous approach can be given by establishing the required standards starting from the patient data, HRT, and HRV subdomains. This way, if we define the interoperability requirements for these subdomains, these requirements will be readily extended to other SCD risk subdomains, so that other hospitals can integrate and share the existing subdomains descriptions, as well as their use and integration in clinical practice. Since clinical and demographics variables can be also identified as risk factors related to CSR, they are included in our RSEM system.The availability of the clinical data in the EHR for an SCD risk stratification system is naturally provided by the semantic and the syntactic interoperability. Specifically and described previously, in this work, we considered (1) the standard HL7 for communication purposes; (2) the standard CEN/ISO EN13606 for the archetypes construction; and (3) SNOMED-CT for binding archetypes and the ontology and thus obtaining semantic interoperability.To achieve the semantic standardization of clinical data from the EHR for providing with CRS, clinician expertise was required. Given that CRS is an extremely wide knowledge domain, our focus was on those indices measuring repolarization heterogeneity and autonomous nervous system control form long-term ECG signal processing. To this aim, clinicians suggested using ECG-derived indices on the HRT domain as a first approximation due to its concise guidelines. This simple subdomain was then completed with a more complex subdomain of SCD, given by HRV indices. Toward that end, several archetypes were developed.Apart from the construction of a clinical structured database, interoperability among different healthcare systems is also pursued by exporting clinical data as extracts in xml format . These eClinicians in our group defined the subdomain elements (nodes and constraints) needed for achieving a good knowledge representation from a clinical viewpoint. Main archetypes for defining CRS domain are shown in general factors. The green color identifies the archetypes from the CKM, which requires specialization in order to be used in the CRS domain. The requirements were established with the clinical expert (author AGA). The archetype that models the information of the diagnosis was specialized to reflect the set of pathologies that can influence the HRT or the HRV. Fifteen pathologies were identified: asthma, cerebral damage, depression, diabetes mellitus, myocardial dysfunction, chronic kidney disease, chronic obstructive pulmonary disease, hypothyroidism, myocardial infarction, heart failure, stroke, peripheral neuropathology, Parkinson’s syndrome, overweight, and tetraplegia. The drug archetype also needed to be specialized only to consider drug families by pharmacological activity. A total of 44 families were identified as relevant to the CRS domain. The archetype selected for modeling the information about procedures was also specialized. We considered 5 procedures as relevant: cardiac transplantation, coronary revascularization surgery, cardiac resynchronization, pacemaker implantation, and implantable cardioverter defibrillator implantation. Finally, the blue color is used to identify new archetypes: LVEF and patient summary, which compiles with all of the described archetypes related to demographic and clinical information.(1) The Patient Summary Subdomain. The description of the patient summary subdomain is shown in (2) The HRT Subdomain. It compiles the information of 24 h Holter recordings in order to infer the CRS in terms of HRT indices, and TS and TO values. The inferred category was also considered as an element in the HRT archetype. We defined and built two more archetypes to model this subdomain  The HRV Subdomain. Because of its complexity, the HRV subdomain has not been previously standardized in the literature. Toward that end, we first describe the archetypes related to HRV measures according to  , duration , the number of NN intervals, a free text field for comments, and the possibility of extending the archetype with other archetypes that complete the information of previous elements. The archetype power spectral density for the calculation of the power spectral density is used only with the spectral methods to collect information on the method used to calculate the power spectral density. It facilitates with a slot the power to embody the archetype of cardiac signal processing.The definition of these subdomains, together with a basic implementation, are the key contributions of the present work, as they have been raised from the interaction of Holter signal processing experts and clinical experts, following the guidelines when present or their surrogates otherwise ,34.Data were assembled from a clinical trial performed in UHVA. The ongoing study aims to evaluate the CRS of a patient population hospitalized for congestive heart failure. A set of variables were taken for each patient, namely, demographic and clinical variables at hospital release, ECG, and echocardiographic variables, and Holter analysis including HRT and HRV measurements.us beats . EvaluatNormal values of these indices were obtained from  for HRT Data from patient summary and EHR were connected with RSEM by using HL7, archetypes, and SNOMED-CT, as described in The RSEM provided with (1) SCD risk stratification based on HRT and HRV indices and (2) alerts appearing in the EHR to support decision-making. The RSEM was able to exchange in real time information with full meaning between an actual EHR and the proposed RSEM, and to functionally provide the user with a CDS system for CRS.Demographic and cardiac data from the patient is recorded in the EHR, as shown in A CRS request is made in the EHR by a clinician. This generates an OMG HL7 message , which is sent from the EHR to the RSEM following the structure of the patient summary and the HRT and HRV archetypes. This message starts with a header identified by the segment MSH, followed by segments PID (patient identification) and PV1 (patient visit). OBR describes the observation request, and OBX is the observation/result. This segment contains the information related to tobacco or alcohol, among others  of the ST–T complex occurring on a beat-by-beat basis ,42,43. THolter-Based Risk Literature. Many techniques for Holter-based SCD risk stratification have been proposed to date Similar Sications  by buildications  discusseications  for a liIn the case of the cardiac domain, several studies can be found. For example, authors in  used an Limitations. Though our focus was not to define new cardiac risk indices, our system allows one to readily include and check new indices that can emerge in the clinical and technical literature. In other words, our target is to contribute to the actual use (or discarding if this is the case) of the existing risk indices. We did not propose here a complete and final system working and connecting several hospitals at this moment, as this will be a developmental project. However, the domain definition in terms compatible with the computational/algorithmic requirements and with the EHR standards turned out to be a complex research work that needed to be addressed separately. For security purposes, we worked with fully anonymized patient data, though VPN-based solutions could also be considered.Close cooperation with cardiologists was assessed to define the chosen cardiac risk subdomains. In the long term, the system will allow one to not only include other indices but also work on a large scale of a number of patients. Achieving multicentric connectivity in different hospitals will represent an increase in the scale of collected data. This approach paves the way toward intelligent systems that will take advantage of the current state of knowledge and advances on machine learning models and big data systems so that the CRS in large patient databases can be analyzed.


During the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Guéckédou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community’s communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted. The largest and most complex Ebola virus outbreak in history started in Guinea in December 2013 and spread rapidly to neighboring countries in March 2014 [In August 2014, the World Health Organization (WHO) convened an advisory panel that unanimously concluded it would be acceptable to assess potential unregistered interventions that had shown promising results in preclinical laboratory and animal phases but had not been fully evaluated in phase I or II trials in humans . MédecinWith the recruitment of the first patient in the Guéckédou ETC on December 17, 2014, the JIKI trial became the first phase II study on EVD ever implemented by a research team in collaboration with an international nongovernmental organization. This unique situation was complicated by the international humanitarian crisis associated with the uncontrolled Ebola virus epidemic and a vulnerable resource-poor setting of rural Guinea.This paper is a systematic assessment of the JIKI trial implementation in the field at the Guéckédou ETC, the first center involved in the study. It does not address the prefield aspects . As all authors of the present paper were involved in the trial, the assessment may be subjective. Our goal is to offer the scientific and clinical research communities critical feedback into the issues and challenges of this unique situation in order to highlight potential problems in future EVD outbreaks.We will discuss the issues surrounding the implementation of the JIKI trial in the field in order to address the interaction between Good Clinical Research Practices  and the Communities from Forested Guinea were known to mistrust government and Western humanitarian aid agencies, which led to serious security incidents . EVD wasTo ensure the community involvement in the trial, local leaders, including women’s organizations, youth groups, religious leaders, and village elders, were invited by the research partners to participate in a Community Advisory Board (CAB). This was headed by the regional coordinator of the fight against Ebola and specifically created to counsel and support the trial implementation. During the preparation phase, the CAB discussed the trial protocol and the communication strategy for the community. Following their recommendations, the focus for communication was put on providing correct and comprehensive information to patients, their families, and all 350 MSF staff members, most of whom originated from Guéckédou prefecture, rather than informing entire communities. Anthropologists and key national staff collaborated to develop the form and content of the messages, which was tested on various members of the staff to ensure correct translation into local languages, sensitivity to local culture, and ease of understanding.At the same time, a mobile health promotion team addressed rumors in the communities, countered misconceptions, and answered questions on the trial. They also relayed community responses to the trial team to modify the messages to patients and their families. For example, when a rumor arose that 4 EVD survivors treated with favipiravir became “crazy” after returning to their villages, a combined MSF and INSERM team visited the villages and discussed the issue with the families and the local health authorities.However, the interventions were limited by the rapid geographical expansion of the epidemic. It was not possible to ensure that all villages in the ETC catchment area were included in the communications. Patients referred from prefectures outside Guéckédou would not have heard any information about the trial.Research with human subjects must ensure that 3 basic ethical principles are followed: respect for persons, beneficence, and justice , 14, 15.Pregnant women were another particularly vulnerable group. Since no human studies of favipiravir in pregnancy had ever been performed and embryonic teratogenicity was reported in mice, no insurance company would cover the risk for pregnancy; thus, pregnant women had to be excluded from the JIKI trial. Pregnant women, however, had a higher case-fatality rate compared to nonpregnant women. The vast majority of pregnancies in EVD patients resulted in miscarriage or intrauterine death, and the few babies born died in a few days , 21.To avoid denying pregnant women access to a potentially beneficial investigational product, MSF accepted responsibility and liability for the emergency use of favipiravir in this group. A protocol for monitored emergency use, including informed consent and rigorous data collection, was submitted for approval to the appropriate ethics committees. Pregnancy testing was introduced for all women of childbearing age admitted in the ETC.Nonetheless, a time complication occurred, as the emergency-use protocol for pregnant women was still under ethics review when the trial started. This did not, however, have any practical impact, because no pregnant women were admitted in the ETC during the trial period.The trial’s standard operational procedures (SOPs) had to be incorporated into the MSF Ebola virus case management protocol without creating any negative impact on patient care or adding extra risks for the staff. To ensure compatibility with the routine management protocols already in place, the research team wrote the SOPs on site with MSF medical staff. Feasibility and organizational changes were evaluated before implementation to ensure smooth integration of the trial into clinical activities.After trial initiation, the first challenge was related to the study endpoint, which was survival to day 14. Some patients met MSF’s discharge criteria (negative PCR results after 3 days without symptoms) before day 14 but still needed monitoring. Thus, a rehabilitation zone was built so that these patients could move more freely but still remain under surveillance of clinical staff.The second challenge was the follow-up tests for the trial participants. Routine clinical procedures called for PCR testing at admission and at the end of symptoms, with no blood collection between these 2 samples. However, the trial protocol demanded extra sampling at day 2 and day 4, which increased risks for patients and staff. In practice, the additional venous sampling was considered acceptable as it included follow-up biochemical tests, which were beneficial to patient care. Patients were informed of the increased number of blood draws at the time of informed consent. The volume of each blood collection was limited to a minimum. The diagnostic laboratory adapted its organization to the new requirements, including new schedules and the incorporation of biochemical testing. The clinical staff was trained to use the biochemistry results in EVD practice. There were, however, some limitations related to these new procedures. Adding new tests at the laboratory led to some unexpected difficulties. The platform, Abaxis Piccolo Xpress analyzer, was sensitive to heat, and the laboratory did not have a cooling system. Disinfection of the machine was also a challenge, as the chlorine solution normally used harmed the electronic components.The third challenge was the need for early initiation of treatment. As the antiviral medication was expected to be more effective the earlier in the course of the disease it was started, it was crucial to include patients in the trial as soon as possible. Treatment initiation, however, could only be done after the laboratory confirmed EVD and informed consent was obtained. This required important changes in the staff shifts to ensure that inclusion could be done as late as 1:00 AM. Moreover, the samples for PCR testing had to reach the diagnostic lab before 6:00 PM, due to the long process of decontaminating samples and performing the necessary tests. Consequently, some patients arriving late in the evening, mostly those transferred from other prefectures, had to wait almost 24 hours before inclusion.Closely related to the principle of respect for the dignity of participants, an informed consent had to be obtained from all patients before their inclusion in the trial . During Some patients could not decide for themselves without extensive family consultation. In addition, there were no clear legal or traditional rules for ethically obtaining proxy consent for the inclusion of children or impaired persons who arrived at the ETC without guardians.Several actions were taken to try to ensure a freely given and culturally adapted informed consent. Firstly, a multidisciplinary team of medical, health-promotion, psychosocial, anthropological, and research personnel translated the informed consent into comprehensive and culturally sensitive local languages. Secondly, oral consent was preferred over signed consent because of cultural acceptability; according to the local psychosocial team, signing a document while hospitalized was considered as signing a legal will. Therefore, informed oral consent was signed off by 2 witnesses or by the guardian in the case of minors.Finally, the Guéckédou CAB was consulted regarding unaccompanied children and advised to seek special authorization from national authorities. The national coordinator of the fight against Ebola was contacted and accepted the responsibility for the inclusion of unaccompanied minor children in the trial.However, despite efforts to explain the protocol in local languages, it was difficult to assess the amount of information understood by each patient, due to language and cultural barriers and the clinical status of patients.In order to assure that the benefits continuously outweighed the potential risks associated with the investigational drug, strict pharmacovigilance of favipiravir was crucial, as no safety data were available for the high doses used in the trial. However, due to the severity of EVD and limited availability of clinical facilities, distinguishing potential adverse effects of the favipiravir treatment from the signs and symptoms of EVD was challenging.During and after administration of favipiravir, the patients were closely monitored for any adverse signs or symptoms not corresponding to typical EVD symptoms, with a focus on those adverse events previously described in clinical studies with favipiravir for the treatment of influenza infection. Biochemical tests were used to observe possible liver and kidney damage. However, at the individual patient level, the interpretation of the causes of deterioration was still difficult, because some signs and symptoms, such as diarrhea, vomiting, or dizziness, could be related to either EVD or favipiravir.Additionally, mortality data were sent to the Data Safety Monitoring Board (DSMB) on a daily basis. The protocol included rules that allowed for stopping the trial if interim analysis, planned after every 20 patients, showed that on-trial mortality did not trend lower than pretrial mortality.The quality of the data collection is related to clinical staff qualifications as well as quality of the recording system. Therefore, medical personnel were trained on specific data-collection methods. What proved to be more challenging was handling these data. Due to the infection-control restrictions in the ETC, paper-recorded patient data could not leave the high-risk zone. To address this problem, case report forms and routine patient documents were scanned inside the high-risk zone, and the data were sent electronically to both the medical and research databases. Compared to the pretrial practice of verbal transmission of patient data between the high- and low-risk zones, this new procedure resulted in fewer transcription mistakes and less time for the staff in the high-risk zone.The context of the trial, with high social, media, and political pressure, threatened the confidentiality of the study data. The trial was an open-label, single-arm study. After the trial was launched, most EVD-confirmed patients admitted into the ETC received favipiravir treatment. This was known by the staff and easy to grasp for the local communities. As the primary study outcome was mortality, confidentiality in regards to individual patient outcome and the potential efficacy of the favipiravir treatment was difficult to keep undisclosed to the outside world. In an attempt to limit the spread of rumors in the local community, regular meetings with the staff were held to explain the need for prudent interpretation of the observed outcomes and the importance of confidentiality regarding patients and trial results. The ETC teams and CAB were the first to be informed of interim and final results.In February 2014, the trial DSMB and Scientific Advisory Board recommended that the results of the first interim analysis should be shared with the international scientific community. These results suggested good tolerance of the drug and the importance of baseline viral load as a key stratification factor in further final analysis, but they did not demonstrate the effectiveness of the drug. However, the research team could not control the interpretation of these interim results by the media and political leaders. Rumors circulated in the national and international media about favipiravir efficacy. With decreasing EVD incidence rates in Forested Guinea, it became obvious that the initial estimation of the patient cohort size would not be met. National authorities strongly urged the trial leaders to publicly announce the results before the trial completion in order to make the drug available in other Guinean ETCs.Both MSF and INSERM had little experience in the unique collaboration between a humanitarian organization and a typical life-science research institute.The trial agreement stipulated that INSERM was responsible for compliance with the trial protocol and the quality of data collection and analysis, while MSF was responsible for patient management. Communication channels were improved when MSF appointed a research coordinator to coordinate trial preparation and patient care and to ensure full integration of the research and clinical teams.Additional trial staff, financed by INSERM, were recruited with the same working contracts as MSF national staff and trained together with the other ETC staff in the trial SOPs. This process created a strong team spirit and a feeling of ownership of the project and avoided dividing the staff into 2 groups with different management and working conditions.Field logistics were provided by MSF, while INSERM was responsible for official communications about the trial with the media and the authorities.Implementing a phase II clinical trial during a devastating epidemic in a research-illiterate environment was full of challenges. Success required cultural sensitivity to build trust within communities and among patients, inclusion criteria based on equity and a risk/benefit assessment, close collaboration between research and clinical teams, and flexibility to adapt trial procedures to field constraints. The main pitfalls were related to protocol compliance: the technical lab problems after the introduction of new tests and the contradiction between study endpoint and clinical discharge criteria. Confidentiality of trial data was not fully controlled and required continuous surveillance.In a context of fear and mistrust of international actors, community engagement was essential to ensure the appropriate implementation and progression of the trial. A pretrial initiative to inform and involve community leaders; the development of thoughtful, culturally appropriate messages; and a consensual community strategy were essential aspects of this engagement that should not be neglected in any Ebola virus trial.Scientists have argued for –25 and aIn conclusion, the JIKI trial illustrated how an international research team collaborated both with a humanitarian medical organization and local researchers to improve scientific knowledge, create innovative partnerships, promote local capacity building in research, and help EVD patients. Our observations are context specific but may be useful to understand the complexity and challenges of establishing research activities during future international medical emergencies.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.


The 1st International Caparica Conference in Antibiotic Resistance, was held in Caparica, Portugal in January 26–28, 2015. This very successful meeting attracted nearly 110 attendees, from 32 countries and involved a total of over 70 oral presentations, 16 shotguns presentations and 27 posters. The results and insights from this meeting are being made accessible to the general scientific community by this special dedicated issue of the Frontiers in Microbiology Research Topic.Antimicrobial resistance within populations of different infectious agents is a worldwide public health threat. Already the available treatment options for common infections in some settings are becoming ineffective. There are now reports of bacterial resistance to all antibiotic classes used in either human or veterinary medicine, and in several cases, of an association between antibiotic use and the development of clinical resistance. To counter this emergent problem, the World Health Organization has appealed for urgent and concerted action by governments, health professionals, industry, civil society and patients to slow down the spread of drug resistance, limit its impact today and preserve medical advances for future generations.The present Research Topic brings together a group of leading researchers from all over the world who have described different aspects of antimicrobial resistance patterns found in diverse ecosystems. The articles in this topic seek to address this question, including the epidemiology of resistance in animal and zoonotic pathogens, mobile elements containing resistance genes, the omics of antimicrobial resistance, emerging antimicrobial resistance mechanisms, control of resistant infections, establishing antimicrobial use and resistance surveillance systems, and alternatives strategies to overcome the problem of antimicrobial resistance worldwide.http://www.ic2ar2017.com).We want to thank the reviewers for their many thoughtful and insightful comments, and the authors for their high-quality contributions. In closing, we would like to encourage all those who have not yet had a chance to participate in a “Caparica Meeting” and remind all to participate in the 2nd edition of the International Caparica Conference in Antibiotic Resistance that will be held in Caparica on 12–15th June 2017 (All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


In the late 1970s, he showed that suicide was three times as common in prisoners as in the general population, that it was most common in those with sentences longer than 18 months and that the greatest risk was in the first few weeks in custody.Topp always felt deeply that the prison medical services were often unfairly maligned. He knew that the antiquated estate and restrictive budget did nothing to enhance the practice of modern medicine; yet, he felt that on the whole prisoners were given good care within these constraints. He found the hospital officers of the Prison Medical Service to be generally excellent but felt that many were denied opportunities to achieve the nursing qualifications they desired. Much criticism, he felt, would have been spared if training had been far better resourced and achievement suitably rewarded. Nevertheless, his view was that although the service was not superficially attractive, for those prepared to put effort and interest into it, there could be considerable work satisfaction – something he enjoyed himself despite much frustration.Dudleigh Oscar Topp, always known as John, was born on 11 September 1924 in Hove, the son of a bank manager. A practising Roman Catholic, he was educated at the Xaverian College in Brighton and attended King's College London, from where he went to Charing Cross Hospital Medical School, qualifying in 1949. After house posts at Oldchurch Hospital, Romford, he served as a captain in the Royal Army Medical Corps in Northern Ireland. He joined the Prison Medical Service in 1953 at Wakefield prison and later became Senior Medical Officer at Brixton prison, from where he was promoted to Principal Medical Officer to serve regionally and centrally, administrating various aspects of the prison medical services.He retired on medical advice in 1984 but remained actively interested in prison affairs and wrote books on the history of the Prison Medical Service. His particular regret was that the Prison Medical Association, which he founded towards the end of his career with the object of promoting the highest standards of medical care in English prisons, did not survive his retirement. However, he lived to learn of the inception of an Academy of Prison Medicine which naturally had his full approval.Living latterly in Weymouth, where he had the close companionship of two local retired hospital chief officers, he became the founder president of the Pickering Society, a nationwide group of retired hospital prison staff of all categories. It was named after a respected director of prison medical services under whom most of them had served.Soon after qualifying, John married his childhood sweetheart Joyce Stoner, a nurse from Brighton. They had four daughters, three of whom trained as nurses at the Westminster Hospital, where two of them met and married doctors. There are now eight grandchildren and five great-grandchildren. Tragically, Joyce died in 1975 of carcinoma of the stomach, following which he married her friend Peggy Lange, then a Principal Nursing Officer in Sunderland.


Among linguistic-cognitive failures, the retelling of stories and lexicaldisorders occur from the onset of AD. Recent studies have discussed whetherlexical failures in AD patients include naming actions.The aims of this study were to verify naming and reformulation of actiondifficulties in AD patients and their relationship with the retelling ofstories. Our main questions were: Are there two linguistic abilitiesimpaired in the early stages of AD? Is there some correlation between thecapacity of naming actions and the retelling of stories?We assessed 28 elderly participants: 17 with probable AD and 11 controlsubjects, with schooling ≥4 years. The textual reading comprehensionwas measured using four stories with descriptive and narrative textualstructure. The lexical production was verified by 17 actions on video,assessed by the participants' first and second verbal emissions.The results showed that the retelling of stories is a task that discriminatespatients with AD from healthy individuals. The naming and reformulation ofactions tasks did not show significant differences among the patients andtheir controls. A positive correlation was found between the difficulties inretelling stories and the reformulation of the naming of actions.These results confirm previous findings that show the preservation of namingactions in patients with AD, which involve familiar actions, and that theretelling of short stories is an instrument that discriminates patients withAD from healthy elders. Results also suggest that the difficulties inretelling are related a breakdown in reformulating information, perhapsstemming from mechanisms of decreased memory work. These studies show that the retelling of storiesis an accurate procedure to discriminate the disease.5 On the other hand, lexical difficulties, verified through thenaming of pictures, have been said to be due to flaws in the lexical access or tosemantic memory flaws. As the studies about linguistics disturbances in patients with ADhave focused on these two activities separately, little is known about how these lexicaldifficulties interfere in the retelling of stories.The cognitive functions of language and memory are compromised in the initial stages ofAlzheimer’s disease (AD). Among the language tasks that are impaired in the initialstages of AD are the understanding of textual reading and lexical production. Thedifficulties in understanding textual reading in these patients are known to beattributed to cognitive flaws, such as those involving episodic memory, short termmemory (working memory) and attention, found early in the disease. Reportsfrom6 Labov and Waletzky7 present a structural model fornarratives. These are composed of five parts called macrocategories. The narrativestarts with the orientation and situation macro category, informing thereader where, when, who and the situation (what); moving on tocomplication, that presents a series of events. Subsequently, thecomplication macrocategory introduces an event (following anaction) and a problem, which will be solved or ended by the resolutionmacrocategory. Between complication and resolution lies the evaluation macrocategorythat compares narrative units within the same structure. The resolution macrocategoryends the actions, while some narratives have one more macrocategory, theconclusion of the story offering a summary of what happened.The understanding of contextual reading demands a variety of abilities from the languagebeholder, such as codification of text information, ability to retain the ideas read,search of textual coherence and narrative reproduction. Different models have beenproposed in order to understand how people comprehend a text, taking into considerationthe constructive process the reader performs during textual comprehension.3 Within theperspective of the model,7 thedescriptions are texts with a predominance of the first macrostructure, thesituation/orientation component. In a study by Gély-Nargeot, Ska andTouchon,3 not only the patientswith AD but also those without dementia presented a better performance when thestructure was of a narrative. These authors also verified that more detailed versions,that is, more redundant, improve the comprehension of patients with AD. On the otherhand, the results have shown that remembering, not only the main idea but also thedetails, decreases with the severity of the dementia, although in spite of this overallworsening, the main ideas are retained for longer than the details. The worsening ofdementia, thus, besides impacting the story recall in patients with dementia, led themto remembering the main idea of the text over and above the details.9No studies were found verifying whether one of these macrocategories hamperscomprehension of stories for patients with AD. Nevertheless, studies on patients with ADhave shown that the kind of textual structure may facilitate comprehension, as evidencedin the comparative study between patients with AD and elderly patients without dementia,in which the participants have to retell 4 stories, 2 narrative and 2descriptive.10 focused on the participation of short term memory(working memory) and long term memory (episodic memory) for textual comprehension. Dueto the limited capacity of the short term memory, it is important to select themacrostructures of the text, that is, identify the main idea and discard themicrostructures (details).12 Comprehension is performed in cycles,sent to the episodic memory, to build a base text. On the other hand,13 the relationship between cause andconsequence of the events are emphasized in the text. According to this model, thecomprehension of the narrative is stored in the long term memory (semantic memory) as anetwork, and the nodes of this net (sentences in the text) are interconnected by thecausative relations.14 Under thismodel, the possibility of creating inferences, based on the four criteria of casualrelation is important. Furthermore, the same model assumes that comprehension is basedon the possibility of solving problems, and is not concerned about memory.Two models have proposed that text comprehension is a complex activity, with theparticipation of cognitive functions. Kintsch and van DijkRetelling a story is not reproducing it word by word. Memory mechanisms retain the plotor the script and a variety of significant units of the story. The latter are calledpropositions. Each proposition is formed by an argument and a predicate. The argumentcorresponds to an action (verb) and the predicate may be who performs the action,suffers its consequences, etc. The nucleus of the narrative information is, thus, basedon the actions and it is possible that the retelling of stories is related to thepatient’s capacity of naming these actions.16 Some neuroimagingstudies (PET and RMf) however, show mixed representations that do not support thisantero-posterior dissociation.17Tyler, Russell, Fadili Cappa18 alsofound an extensive area of semantic processing that extends from the inferior frontalcortex up to the temporal lobe of the same side, with no grammatical classdifferentiation of words.Studies on the lexical difficulties of patients with AD have shown dissociation in theflaws in naming actions and objects. From the neuroanatomic point of view, there isevidence that various areas are responsible for the processing of these two wordclasses. While common and proper nouns are processed by posterior and temporal regions,verbs are represented in frontal circuits.19 has shown that both groups were worse in naming compared totheir controls in both classes, while patients with FTD were significantly better atnaming objects compared to patients with AD. Overall, maintaining the ability to nameactions with difficulties in naming objects is explained by the anatomical organization,since in the early stages of AD the posterior areas responsible for naming objects aremore affected than the anterior ones, responsible for naming actions.Comparing the task of naming of actions and objects performed by patients with AD versuspatients with front temporal dementia (FTD),23 This pattern is explained through the semanticcharacteristics of the verbs. Verbs are more complex, less imaginable and moreabstract.Another study group found the opposite pattern where verbs were more affected thannouns.This work intends to fill a gap in the literature concerning the linguistic difficultiesof patients with AD, studying the same group of participants for the capacity ofretelling a story, naming verbs and retelling with naming production (reformulationtask). Based on previous studies, patients with AD are expected to perform worse on bothtasks than their controls. Given the action is an extremely important feature to theinformation units of a narrative, one expects to find a correlation between theretelling tasks and naming of actions.24 and theNINCDS-ADRDA for probable AD,25 aswell as the Clinical Dementia Rating scale – CDR.26 The Mini Mental State Examination (MMSE) was alsoapplied,28 and patients with scores between 24 and 27 wereincluded in the group of mild AD, whereas patients with scores between 12 and 24were included in the moderate group. Cognitively normal individuals were selectedfrom within the community and only those with scores greater than 27 on the MMSEwere selected. All subjects were submitted to the GDS-1530 scale,and those with scores lower than 10 were included in this study. Other criteria forinclusion were: schooling greater than four years, lack of history of anypsychiatric or neurological disease, and visual or hearing impairment withoutcorrection. Twenty-eight aged native speakers of Brazilian-Portuguese participated in this study. Patients fulfilled the DSM-IV criteria fordementiaTwo experimental tasks were selected for this study: a reading comprehension taskand a verb naming task.7  were calculated fordemographic data, MMSE, verb naming and data and text scores .TheKruskall-Wallis test was used for comparison of the three groups. Spearman’s rhocorrelation coefficients were calculated for correlations between MMSE, textscores and verb naming and reformulation data. The statistical analysis wascarried out by the Statistical Package for the Social Sciences for Windows (SPSS11).Descriptive statistics of naming action and reformulation tasks of AD patientsand their controls are shown in To study text recall, we obtained six different scores: one score thatcorresponded to the mean recall of the four texts; one score of the story bestrecalled by each subject, and four individual scores that express the recall ofeach text. Significant correlations were found between MMSE and all six text recall measures. No correlation was foundbetween MMSE and naming or reformulation tasks .As shown in Our results showed that the retelling of stories is a task that discriminatespatients with AD from healthy elders. In all the measurements obtained, the ADpatients remembered significantly fewer propositions than their controls. Thisdifference was found even among patients with mild AD and healthy elders. Among theelders with moderate AD and those with mild AD, only one story did not yield asignificant difference. The results also show that even in very short stories,cognitive impairment measured by MMSE, is associated with the difficulty of commonretelling in the elderly. Therefore, further studies involving a greater populationof patients with AD could describe different levels of abilities according to mentaldecline, improving the communicative diagnosis of these patients.As this text is a set of inter-related meanings, some results can evidence a degreeof semantic influence. Our work did not evidence a major preservation of thenarrative structure over the descriptive. Perhaps due to the control of the size ofthe sentences and the fact that the descriptive text was short and having thequalities of a teacher that could be summarized in one topic only, “the teacher wasgood”. The information became redundant, making memorization easy. On the otherhand, factors related to the familiarity of the story could explain the goodperformance of the moderate AD patients compared to the mild AD, in the story thatended in complication. This story was about a domestic dog and its general meaningwas frequently retold by the patients with moderate AD.21The naming of actions and their reformulation did not present any difficulties forour patients with AD. These two tasks did not inter relate with the scores on theMMSE. In relation to the correlation between the tasks of naming and textualretelling, only the reformulation task showed a positive correlation with the besttold story by the participants. These results indicate the preservation of thenaming of actions in patients with AD, at least for fairly familiar actions and whena wide aspect of conventional answers is considered . Is it possible that patients with AD use more genericverbs as a strategy to compensate for the semantic impairment?The correlation between the reformulation task and three scores of story retellingindicates that one of the processes involved in the difficulty in retelling forpatients with AD is the process of reformulating textual information. Uponretelling, the individual looks for words associated to the meanings of the storyand then reformulates it seeking to maintain the same meaning. This process likelyinvolves mechanisms of working memory, which is very impaired in the early stages ofAD.This work has shown that the retelling of stories, even short ones, is compromised inpatients with mild and moderate AD. The same does not hold however with tasks ofnaming and reformulation of actions. On the other hand, retelling of texts linked tothe reformulation task, indicating that among the difficulties these patientsencounter in retelling texts, flaws occur in reformulating the information of a textwhich is heard or read.From a clinical point of view, the retelling of short stories seems to be aninstrument able to discriminate patients with AD from healthy elders. Future studiesshould establish performance levels according to the severity of the disease,enriching the diagnosis and body of knowledge on the communicative capacity of thispatient group.