Policy development by partnership is difficult, however, ‘Reducing Harm, Supporting Recovery- A health led response to drug and alcohol use in Ireland 2017-2025’ hailed a new era. This policy was based on an agreed philosophy and core values across a 21-member partnership and has stated a common commitment to a health-led response.To drive strategy development, a cross-discipline committee with an independent Chair was created by the Minister. Members came from statutory, voluntary, community, research and service-user organisations. A consensus-based, partnership approach was taken to developing the policy and the action plan. Over 18 months of debate, a public consultation, focus groups, evidence reviews and an external expert review were conducted. Evidence was reviewed by the committee and following a very robust debate, a set of priority actions and responsible organisations were established.Nineteen meetings were held. Epidemiological indicators illustrated that cannabis use, young people, chronic opiate use, mortality and geography were a priority. Almost 3000 individuals/organisations responded to the public consultation and themes arising were, supply-reduction, prevention, treatment, rehabilitation and research. The evidence review found that evidence was weak or lacking. The focus groups addressed priorities in supply, education, prevention, continuum of care, evidence and best practice. Finally, the expert review examined structures. Significant contentious debate arose around the initial terms of reference and the authority of a member to agree to an action on behalf of a ministry. While not all members were fully satisfied with the strategy, all welcomed the commitment to the health-led approach. An implementation committee was established, a tender for the first medically supervised injecting facility was issued and a sub-committee to explore decriminalisation was formed.A key recommendation from the process was to ensure that all voices had an equal opportunity to be heard and to ensure that priority actions identified from the wider sources of evidence were not lost during the extended process. The breath of the partnership aided this. While we have succeeded in developing a sound strategy, success will depend on continuing support from the partnership and appropriate resourcing from the ministries. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is responsible for monitoring the drug situation in the EU member states plus Turkey and Norway. In their recent paper on developments in national drug strategies, they highlighted a gradual change in national drug strategies, with new strategies emerging with a broader focus covering other substances and to a lesser extent other addictions . The EMCWithin Ireland, ‘Reducing Harm, Supporting Recovery- A health led response to drug and alcohol use in Ireland 2017-2025’ was hailed as a new era in Irish drug policy  and the .…attention should be given to: encouragement of social life and of hobbies and sports; improvement in length of education and end achievement; provision of jobs; and discouragement of cigarette smoking and of frequent drinking.…Here then is a challenge: for parents, for the clergy, for teachers, for social workers, health educators, publicans, and government – and, not least, for the young people themselves. .These changes in national political philosophical underpinnings can be traced back to early challenges in the then current philosophies and policies of the 1980s. This is evident in the original 1980s treatment outcome studies which reported that in a follow-up study in 1984 of 88 people who used heroin in 1982, 74 (84%) participants were tracked, and of these, 69 (93%) had attempted to give up heroin, primarily through detoxification programmes . HoweverThe need for a consensus-based partnership approach to economic and social policy development in Ireland was first introduced in 1987 and was reflected in the sentiments expressed by the Prime Minister who called for greater social inclusion and a new focus on equality .The aim of this paper is to present the Irish policy development process and to show how three decades after the work of Dean , a wide,To drive the strategy development, the Minister of State with responsibility for drug strategy formed a cross-discipline committee with 21 official members and an independent chair. The Minister invited members from all relevant statutory, voluntary, community, research, and service user organisations. These included senior decision-making civil servant members from each ministry, relevant senior members or chair persons from agencies or networks working with people who use drugs and finally senior independent researchers. Each organisation was invited to propose a relevant representative who had the authority to speak on behalf of the organisation. When the representative could not attend due to a diary commitment, a reserve representative was sent in their place. Positions within organisations and ministries were selected rather than individuals. All organisations who were invited accepted. Some further specific organisations were not invited to the main strategy committee but were invited as part of specific working groups. An example of one such group was the International Nurses Society for Addictions. Members were not remunerated for their time but rather were released from their place of normal work to attend and prepare for the meetings. The committee was fully supported by the Department of Health’s Drug Policy Unit (DPU). A full list of the partnership committee is provided in Table A set of concise terms of reference were developed and agreed following wide ranging debate. Over 18 months, a public consultation, focused or working groups, evidence reviews and an external expert review were conducted. The working groups and the public consultation enabled the partnership to access the views of additional organisations and the general public. National data from the EMCDDA’s five key epidemiological indicators  were preAll evidence resulting from the various methods was reviewed by the committee. Sections of draft strategy was prepared by the drugs policy unit. These were presented to the full committee and following strong and often difficult debate, independently chaired, sections of strategy were rewritten, debated upon again and finally agreed often by consensus rather than by unanimity. This difficult but transparent process was repeated over the 19 meetings and a final set of priority actions and responsible organisations was established. Some key findings, tensions and resolutions in the process are provided in the following.National data from the EMCDDA’s five key epidemiological indicators  on generThe Department of Health opened a public consultation on the development of the proposed new national drug strategy. Almost 3000 individuals/organisation responded to the public consultation and overarching themes arising were supply-reduction, prevention, treatment, rehabilitation and research. Further details on the consultation methods and results are available .To allow for a wider group who would ultimately be responsible for delivering the services of the strategy to contribute in key areas, four focused working groups were established and chaired by the chair of the main steering committee. Each member of the particular group was asked to prepare their responses to a set of questions in advance. The time in the group was then used to obtain consensus and a single position paper identifying priorities and practical recommendations was prepared by each group. This paper then went to the main committee for consideration and ultimately for inclusion in the final action plan. Questions posed were the relevance of the current strategy, the identification of gaps from their organisational or professional perspective and an indication of how they thought this gap could be addressed. The four working groups covered the topics of supply reduction, education and prevention, continuum of care and finally evidence and best practice. Full details of the position papers are available from Drugs Policy Unit . All recAn external expert review panel with invitees from the EMCDDA and elsewhere were asked to review existing drug strategy structures and consult with key structure personnel. Following this review, the structure in Fig. Finally, a tender to conduct a review of evidence reviews was issued. Topics to be addressed were prevention, harm reduction and treatment and recovery. Reviews were based upon high-quality systematic reviews published since 2010. Authors reviewed 90 systematic reviews, which themselves included over 1700 primary research studies. Evidence was classified as category A: evidence suggests these intervention approaches may be effective; category B: evidence suggests these interventions approaches are not likely to be effective/may be harmful and category C: evidence is inconclusive or lacking on this intervention approach , The lack of agreement on this aspect of the terms of reference can be clearly seen in the tone of the minutes and in the range of partners objecting, but it did not prevent the partnership making progress. The final resolution came in June 2016 in an email from the DPU 7 months after the inaugural meeting. It was interesting to note that while the Chair was waiting for a ministerial response, the terms of reference item was not on the agenda, nor was it on the agenda for the meeting in July 2016 following the ministerial decision and the decision of the ministers was accepted by the partners. The July meeting also had international external experts in attendance and partners respected both the visitors and the new ministers as there was still much work to be accomplished. However, partners were encouraged as the final wording of the item in the terms of reference did take into account concerns about linking strategies and the need to include alcohol. This can be seen in the final wording of the term of reference point 2 which stated:Facilitate increased use of school buildings, where feasible, for afterschool care and out of hours use to support local communities.’ , 8, p28), p288], Additional challenges and lessons learned arose when non-statutory and statutory partners had opposing suggestions for actions. One example was the suggestion that as school buildings within disadvantaged communities were a possible community resource in terms of meeting rooms or space for youth activities, it was proposed that the Department of Education and Skills (DES) open these buildings for the community use after school. However, as this was a major change in operational procedures for the schools, this could not be agreed by the partner representative in attendance. A more senior representative was requested to attend the subsequent meeting by letter of invitation from the Chair. This finally resulted in Action 1.2.7 of the strategy which states that the DES will,We can see within the wording of this action where a compromise position was adopted and accepted by both partners to enable the process to move forward.A further challenge and a lesson learned during the evidence gathering stage of the process was to ensure that priorities identified in the epidemiological evidence, public consultation, evidence reviews, focus groups and expert review were not lost or omitted during the drafting stage of the policy development process. This is where the wide partnership role had its greatest impact and was of greatest benefit. As certain aspects of the background evidence were of a more pertinent interest to some groups than others, these groups could highlight, advocate for and keep track of their particular priority. Examples of this can be seen in the language of the policy and in the addiction nursing aspect of the policy. Throughout the drafting of the policy, the service user organisation representative could highlight any inadvertently stigmatising language. Similarly when the Irish Chair of the local chapter of the International Nurses Society on Addictions (IntNSA) was invited to participate in the focus group on the continuum of care, they could highlight the need for methadone prescribing by nurses to be explored within the new strategy and this recommendation was carried through from the focus group findings to the final draft of the strategy.While not all members were fully satisfied with the strategy, the action plan was finalised and all partners welcomed the clear commitment to the health-led approach. Partnership was clearly articulated as one of the six values underpinning the strategy. The values were compassion, respect, equity, inclusion, partnership and evidence-informed. Actions within the strategy spanned five goals and these were promote and protect health and well-being; minimise the harms caused by the use and misuse of substances and promote rehabilitation and recovery; address the harms of drug markets and reduce access to drugs for harmful use; support participation of individuals, families and communities; and develop sound and comprehensive evidence-informed policies and actions. An implementation committee was established with many of the original committee members. This is chaired by the Minister and meets biannually to monitor progress on actions and to discuss barriers to implementation. A further operational subcommittee meets on a monthly basis to enable obstacles and barriers at the local service level to be addressed in a timely manner. Perhaps one important mistake in the development of these implementation committees was a lack of detail in the terms of reference, specifically with decisions on membership, succession planning, responsibility for and scope of agenda setting and monitoring of shorter term actions and outcomes from meetings. As indicated in the strategy action plan, a tender for the first medically supervised injecting facility was issued and a sub-committee to explore decriminalisation was formed.Using a genuine and committed partnership approach, where all voices at the table were heard, we succeeded in developing a sound strategy. While recognising that the partnership approach to policy development in Ireland is not novel, generalising a similar approach across jurisdictions could be initiated or piloted in the first instance. The independently chaired wide partnership approach with an agreed action plan based on trust, compromise and consensus to policy development is recommended. Success however depends on continuing support within the partnership and ongoing resourcing from the ministries. Early evidence of successful outcomes from the policy are not yet available, but annual monitoring reports of the action plan are scheduled and these will highlight barriers and enablers of progress and importantly the process of implementation.


Public health interventions and health technologies are commonly described as ‘complex’, as they involve multiple interacting components and outcomes, and their effects are largely influenced by contextual interactions and system-level processes. Systematic reviewers and guideline developers evaluating the effects of these complex interventions and technologies report difficulties in using existing methods and frameworks, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE). As part of a special series of papers on implications of complexity in the WHO guideline development, this paper serves as a primer on how to consider sources of complexity when using the GRADE approach to rate certainty of evidence. Relevant sources of complexity in systematic reviews, health technology assessments and guidelines of public health are outlined and mapped onto the reported difficulties in rating the estimates of the effect of these interventions. Recommendations on how to address these difficulties are further outlined, and the need for an integrated use of GRADE from the beginning of the review or guideline development is emphasised. The content of this paper is informed by the existing GRADE guidance, an ongoing research project on considering sources of complexity when applying the GRADE approach to rate certainty of evidence in systematic reviews and the review authors’ own experiences with using GRADE. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is an internationally prominent system for rating certainty of the evidence in systematic reviews estimating intervention effects.Researchers conducting systematic reviews on public health and health system interventions report difficulties in using the GRADE approach.Applying a ‘complexity perspective’ can help identify aspects of using the GRADE approach that require particular consideration when rating certainty in the estimates from systematic reviews estimating the effects of global health interventions.These aspects include: sources of complexity when framing the review questions, such as important dimensions of context and implementation and other potential mediators and moderators of effect; a choice of thresholds or ranges for certainty of evidence ratings that matches the needs of intended users of the review; assessment of evidence from non-randomised study designs; the criteria within each GRADE domain for rating certainty of evidence and coherence of evidence across the hypothesised causal pathway of the intervention.This primer can help systematic reviewers, health technology assessors and guideline developers better assess evidence relating to complex interventions and systems, which could enhance the use of such evidence in global health policy and practice decisions.Systematic reviews that estimate the effects of interventions can have a significant influence on subsequent decisions to either implement or disinvest in an intervention. In biomedicine, there are established methods for synthesising and rating certainty in the effects of medications and other single-component interventions.5 6WHO is the leading institution for producing evidence-informed guidelines at a global level. WHO recommendations for practice and policy are underpinned by systematic reviews of evidence on the effects of interventions and health technologies and aim to follow a transparent and evidence-based process.9Recently, there has been increased attention to evaluating effects of complex health interventions implemented within complex systems.Using a complexity perspective in systematic reviews of the effects of interventions can facilitate the more nuanced conceptualisation and assessment of interventions ultimately needed for health decision making.et al,et alet alBox 1Context and Implementation of Complex Interventions framework63Guidance on the integrated assessment of complex health technologies: the INTEGRATE-HTA model64Intervention Complexity Assessment Tool for Systematic Reviews65Preferred Reporting Items for Complex Interventions for Systematic Reviews and Meta-analyses66Template for Intervention Description and Replication tool6 67In planning and undertaking systematic reviews, a ‘complex systems perspective’ necessarily entails broadening the scope of a review to include evidence on how the wider system changes when the intervention, such as a complex technology, is introduced. This may involve collecting qualitative evidence on social norms and the dynamics of social networks to describe the broader system impact of the intervention. Not all sources of complexity are relevant to every systematic review and HTA. Researchers should take a pragmatic approach that focuses on the key aspects of interventions, their causal pathways and the levels of target relevant to the specific aims of the review and users’ needs. There is a growing body of literature and guidance, which can be helpful in deciding on the important sources of complexity to consider in systematic reviews, HTAs and guidelines, including approaches described in earlier papers in this series, by Booth Box 2The Grading of Recommendations Assessment, Development and Evaluation (GRADE) process starts with an initial certainty rating based on the design of studies included in the body of evidence: if the body of evidence contributing to an outcome consists of randomised controlled trials, certainty is initially rated as ‘high’, whereas a body of evidence consisting of observational or non-randomised studies (NRSs) is initially rated as ‘low’.The assessing team then uses five domains for potential downgrading of the initial certainty rating: study limitations, indirectness, inconsistency, imprecision and publication bias.Next, the team assesses three further domains for potential upgrading of the initial certainty rating: magnitude of the effect, dose–response relationship in the effect and counteracting plausible residual bias or confounding.Evidence Profiles and Summary of Findings tables are used to summarise the effect estimates and the certainty ratings for those estimates for each main outcome in the assessment.The GRADE ratings are further used as one of the criteria in the Evidence to Decision frameworks to inform recommendations about implementing interventions in practice, where high-certainty evidence is more likely to result in a strong recommendation compared with low-certainty evidence.68The GRADE Working Group has taken a leading role in developing guidance and methods for using research evidence to inform healthcare recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) offers an explicit and transparent system for rating certainty in the body of evidence underpinning conclusions in a systematic review, an HTA or a guideline . In GRAD17Despite its wide uptake in biomedicine, systematic reviewers and guideline developers report difficulties applying GRADE in reviews of broader health technologies, health system and public health interventions.2 3 9 21 22estimating the effects of complex interventions and technologies in global health.As part of the overall series intended to stimulate thinking about how methods for reviewing and assessing evidence in guideline development can be enhanced to take account of complexity, this paper clarifies how a complexity perspective may be applied when using the GRADE approach to rate certainty of evidence. The GRADE Working Group is actively working to advance the GRADE methodology for different applications, including for diagnostic tests, prognostic studies and qualitative evidence.GRADE Guidance for Complex Interventions, involving five key studies that follow an established methodology on developing guidance for health research.et al, forthcoming). In Study 4, we conducted an online modified-Delphi process to explore areas of agreement and disagreement among 116 stakeholders about the importance of specific domains and criteria for rating certainty in systematic reviews of complex interventions . In Study 5, we held a 3-day consensus meeting to discuss proposals for the content of the new GRADE guidance for complex interventions with 28 stakeholders, purposively invited from the Delphi process, representing a range of subject areas . All studies were approved by the Departmental Research Ethics Committee at the Department of Social Policy and Intervention, University of Oxford (SPI_C1A_16_009). This project draws suggestions from several sources–including the existing GRADE guidelines and conceptual papers, previous work considering complexity in systematic reviews, HTAs and guideline development and consultation with relevant stakeholders–to advise how to apply the GRADE approach using a complexity perspective in the context of global health.This paper is largely informed by an ongoing, mixed-methods research project, Several aspects of using GRADE require particular consideration when using a complexity perspective in systematic reviews and HTAs on the effects of interventions in global health see . Particuet al, 2019et al, 2019Box 3et al (2016) developed a system-based logic model taking into account:von Philipsborn Beverage choices and diet-related health and non-health outcomesPhysiological and psychological mechanisms linking sugar-sweetened beverages with health outcomes at an individual levelInterventions aimed at policy (macro) and settings (meso) and interpersonal and intrapersonal factors (micro level)Determinants of diet-related outcomes and related interventionsThis logic model was used to guide data extraction, analysis and interpretation.Tools used for data collection:Template for Intervention Description and Replication framework to extract and report relevant data related to the intervention6Context and Implementation of Complex Interventions framework for contextual data63Internal and external sources of heterogeneity were predefined at multiple levels, such as at policy or setting level:With or without behavioural cointerventionsTargeted at: sugar-sweetened beverages, sugar-sweetened milk, beverages with non-nutritive sweeteners or beverages without added sweetenersImplemented in high-income, middle-income or low-income countriesTargeted at the general population or at disadvantaged populationsThe certainty ratings at the final stage of the review are inextricably linked to the purpose and key questions established at the beginning of each complex intervention review. Similar to the approach described in Petticrew A frequent challenge for authors of intervention reviews in global health arises from posing broad review questions on bundles of conceptually similar interventions  aiming to estimate the effects of deworming interventions on the developmental health and well-being outcomes of children in LMICs.34Logic models may be particularly helpful in depicting intervention components and identifying potential effect modifiers.The GRADE Working Group conceptualises ‘certainty of evidence’ as confidence that the true effect of an intervention lies on one side of a specified threshold or within a chosen range see .38 In ge38all potential contexts of application. Rating certainty in the non-null effect would inform the broad global readership about the general direction (positive or negative) of an intervention effect. The task will then be left for the end-users of the evidence at the local level to further contextualise the evidence and set the corresponding thresholds informing implementation of the intervention depending on their specific circumstances. Importantly, contextualising the evidence usually involves a broad range of considerations and decisions not solely driven by evidence of intervention effectiveness.15The non-null effect is likely the simplest and most feasible threshold for rating certainty on the effects of public health interventions. Since these intervention effects may vary depending on implementation factors, context and settings, it may be very challenging for a review group to define specific magnitudes of effect for various outcomes that are practically important for The choice of the thresholds or ranges will have implications for how the domains of the GRADE approach are applied in a given review or guideline. For example, the criteria of imprecision and inconsistency are only marginally relevant when assessing certainty in the non-null effect (as long as there is consistency in the direction of effect across studies), but are highly relevant when assessing certainty in a specified magnitude of effect. It is therefore critical for systematic reviewers and guideline developers to make their choice explicit and to carry it through into rating the evidence Interventions examined in global health reviews often vary in how they are implemented in different contexts and in outcome measures used across settings.32 502 and its p value), rather than using only a single statistical measure of heterogeneity.50Judgements of inconsistency in the magnitude or direction of effects should correspond with the chosen threshold or range that the review team adopts for rating certainty of evidence. For example, if the review team chooses the null effect as a threshold for rating certainty in the estimate of effect, then judging inconsistency in the direction of effect  would be a relevant approach to follow. In this case, variation in point estimates and statistically significant heterogeneity may not warrant downgrading for inconsistency if the effects across studies are consistently in the same direction with respect to the null effect.et al, forthcoming).Judgements for imprecision are contingent on reviewers’ chosen thresholds for rating certainty. If the chosen threshold is the null effect, then imprecision will not be a concern to warrant downgrading evidence unless the confidence or prediction interval includes the null effect, in which case the evidence is either (1) imprecise  or (2) precise and the intervention does not have an effect relative to the comparator.Many of the reported challenges of judging indirectness can be addressed by specifying appropriate review questions. Important differences in the PICO elements beyond what is expected and specified in the review may weaken inferences regarding the directness of evidence. As outlined in the original GRADE guidance on indirectness, “it is however rare and usually unnecessary, for the intended populations and interventions to be identical to those in the studies, and evidence should be downgraded only if the differences are considered sufficient to make a difference in the outcome likely”.52Another potential challenge relates to incompleteness of available evidence with regard to the review question. As questions for the global health audience might necessarily be broad , the available evidence might not address all elements in the PICO framework . If authors suspect major differences in effect across the locations, rather than downgrading all evidence for indirectness, an alternative approach is to split the question to be able to provide direct evidence for a subset of conditions . In this case, authors may report a lack of evidence for the remaining subset of conditions  or extrapolate based on available data. In the latter case, however, reviewers may need to downgrade evidence for indirectness. Again, it is highly recommended that reviewers think about the factors that may modify intervention effects at the beginning of the review process, when scoping the review and formulating specific questions.Many evaluations of global health interventions are published as reports, working papers or programme evaluations. If review authors suspect that eligible studies are likely published in this format (rather than in indexed scientific literature), a comprehensive multicomponent search that includes grey literature and contacting of experts is critical. In addition, authors should assess whether a substantial number of studies are sponsored by any vested industries  or run by researchers with a potential ‘allegiance bias’ to warrant downgrading for publication bias.53upgrading evidence of complex interventions should follow the guidance of the GRADE Working Group,The criteria for Based on our project findings, we suggest several areas of future work. Many interventions and complex technologies may have long and variable causal pathways. Our consultation with stakeholders suggests a strong interest in developing a robust domain for an approach to rating certainty that is based on the ‘coherence of the causal pathway’ or ‘chain of evidence’.59Second, several stakeholders are interested in more systematically examining whether there are specific NRS designs that are consistently sufficiently robust to start as ‘moderate’ rather than ‘low’ certainty in the traditional GRADE approach. Such an approach would allow for a ‘quick and dirty’ sorting of study designs, where stronger NRS designs would start off as ‘moderate’ certainty and weaker designs as ‘low’ certainty. Advantages would be a quicker and more user-friendly distinction between different levels of certainty, which is likely to be applicable by many Cochrane and non-Cochrane systematic reviewers; the initial rating could then be refined by risk of bias assessments, but would be less dependent on the use of a very sophisticated risk of bias tool, such as the ROBINS-I tool. The significant challenge, however, relates to which study designs and associated features merit starting in one category versus the other.This primer provides a concise discussion of how to incorporate a complexity perspective when applying the GRADE approach in systematic reviews estimating the effects of interventions in global health. Key considerations include: sources of complexity when framing the review questions, such as important dimensions of context and implementation and other potential mediators and moderators of effect; a choice of a threshold or a range that matches the needs of intended users of their review, assessment of evidence from NRS designs and the criteria within each GRADE domain for rating certainty see . SuggestThere is wide interest in finding ways to assess which interventions are effective and, equally, which ones are relevant and appropriate in diverse contexts. Using a complexity perspective can contribute to this. This discussion on considering the ‘complexity perspective’ in GRADE ratings provides a primer for systematic reviewers, authors of HTA and guideline developers to better assess evidence relating to complex interventions and systems, which could ultimately enhance the use of such evidence in global health policy and practice decisions.


Bladder cancer (BC) has become a major worldwide public health issue, especially non-muscle-invasive bladder cancer (NMIBC). A flood of related clinical practice guidelines (CPGs) have emerged; however, the quality and recommendations of the guidelines are controversial. We aimed to appraise the quality of the CPGs for NMIBC within the past 5 years and compare the similarities and differences between recommendations for therapies.A systematic search to identify CPGs for NMIBC was performed using electronic databases , guideline development organizations, and professional societies from January 12, 2014 to January 12, 2019. The Appraisal of Guidelines Research & Evaluation (AGREE) II instrument was used to evaluate the quality of the guidelines. Intraclass correlation coefficient (ICC) analysis was performed to assess the overall agreement among reviewers.Nine CPGs were included. The overall agreement among reviewers was excellent. The interquartile range (IQR) of scores for each domain were as follows: scope and purpose 69.44% ; stakeholder involvement 41.67% ; rigour of development 48.96% ; clarity and presentation 80.56% ; applicability 34.38%  and editorial independence 70.83% . The NICE, AUA, EAU and CRHA/CPAM clinical practice guidelines consistently scored well in most domains.It was generally accepted that the transurethral resection of bladder tumour (TURBT) and intravesical chemotherapy should be performed in the management of bladder cancer. The application of chemotherapy was highly controversial in high risk NMIBC. The courses of BCG maintenance were similar and included 3 years of therapy at full maintenance doses.The quality of NMIBC guidelines within the past 5 years varied, especially regarding stakeholders, rigour and applicability. Despite many similarities, the recommendations had some inconsistencies in the details. Bladder cancer (BC), the 10th most common form of cancer worldwide, has become a major global public health issue . Timely To optimize patient health care, the use of unnecessary medical intervention should be minimized, and cost-effectiveness should be improved. Clinical practice guidelines (CPGs) for NMIBC drafted by many national and international organizations have therefore been developed.According to the Institute of Medicine (IOM), a trustworthy CPG is to “be developed via a transparent process by a group of multidisciplinary experts (including patient representatives) screened for minimal potential bias and conflicts of interest, and supported by a systematic review (SR) of the evidence” .Given the standardization of the evidence-based medicine paradigm and concerns about the quality of care and increasing healthcare costs, the flood of CPGs for NMIBC has been accompanied by growing concerns about the variations in guideline recommendations and quality.There has been considerable debate regarding the management of NMIBC, the clinical course of which is variable and complicated. Significant consensus exists in the majority of areas despite some variations in NMIBC guidelines .To our knowledge, the quality of NMIBC guidelines has not yet been systematically searched and appraised. Therefore, to assist clinicians and patients in the field to make decisions about appropriate healthcare for specific clinical circumstances, we have thoroughly reviewed NMIBC guidelines published within the past 5 years, evaluated the quality of NMIBC guidelines, summarized the management of NMIBC and identified the discrepancies and consistencies.An exhaustive search  was performed in the PubMed, Embase, and Web of Science databases using a combination of text-free terms and their corresponding MeSH terms, as well as four major Chinese academic databases. The search strategy on PubMed is outlined in Additional file We also searched the websites of guideline development organizations and professional societies. A list of the websites with potential NMIBC guidelines are outlined in Additional file All guidelines related to NMIBC published in English or Chinese were included. A document was considered a guideline if it met the following criteria: (1) Explicit recommendations on the management of NMIBC have been provided. Only the CPGs including recommendations of transurethral resection of bladder tumour (TURBT) and intravesical therapy were included. (2) Evidence-based guidelines. To determine whether the guidelines were evidence-based, we investigated whether they reported a search strategy, literature quality or data extraction that classified the level of evidence (LOE) and graded the strength of recommendation (SOR). (3) Only the recent updated version was included. Single-author overviews, consensus statements, translations of CPGs and adapted CPGs were excluded.Four reviewers  from different backgrounds, consisting of urologists and methodologists, with extensive experience in evaluating CPGs independently evaluated the eligible guidelines using the AGREE II instrument. AGREE II consists of 23 key items organized within 6 domains  [Each domain identified a unique dimension of guideline quality rated on a 7-point scale scored from 1 (strongly disagree) to 7 (strongly agree). We summarized the domain scores individually and scaled the total of that domain, calculated by the following formula: / × 100% .Two reviewers  independently extracted the details of the guidelines pertaining to the CPG characteristics, such as target disease, guideline developers, LOE and SOR of guidelines, and the related recommendations. The records of the two reviewers were compared, and any disagreement was resolved based on the evaluation of a third reviewer (F.H.).Whereas various grading systems have been used to evaluate the LOE and SOR in different guidelines, for the convenience of statistics, we discussed and reached a consensus on a composite grading system generated in Additional file We conducted a textual descriptive synthesis to analyse the scope, content, and consistency of the included recommendations related to the management of NMIBC. The synthesis was divided into the following sections and items: (1) TURBT and re-TURBT; (2) immediate postoperative instillation of intravesical chemotherapy; (3) measures to optimize chemotherapy administration; (4) induction and maintenance intravesical chemotherapy or immunotherapy; (5) side effects of and contraindication for Bacille Calmette-Guérin (BCG). Only recommendations with any assigned grade could be extracted.A descriptive statistical analysis was performed by calculating each domain score and scaled domain score. The data for each AGREE II domain were provided as medians and interquartile ranges (IQRs).Agreement among four reviewers was tested with intraclass correlation coefficient (ICC) with a 95% confidence interval (CI) for each domain. According to the scale proposed by Fleiss, the degree of agreement between 0.00 and 0.40 was deemed poor, 0.41 to 0.75 was fair to good, and 0.75 to 1.00 was excellent [The flow chart in Fig. The ICC values for appraisal of the identified guidelines ranged from 0.81 to 0.97, indicating a good agreement among appraisers. The overall quality of the included CPGs was moderate, with the domain ‘clarity of presentation’ receiving the highest score, and the domain ‘applicability’ receiving the lowest score Table .Table 2Guidelines for this domain received a median score of 69.44% with the IQR ranging from 35.42 to 85.42%. The highest score in this domain was 86.11%, as the guideline clearly defined its scope and global objectives and specifically defined the related clinical field and target populations [The guidelines appraised received the second lowest scores for stakeholder involvement . Six guidelines (66.67%) scored lower than 50% for domain ‘stakeholder involvement’ , 13, 15.The median score for the domain ‘rigour of development’ was 48.96% with an IQR ranging from 27.08 to 65.63%. Five guidelines (55.56%) scored lower than 50% , 13, 15,The domain ‘clarity of presentation’ received the median score of 80.56% (IQR: 66.67–93.06%), with all guidelines scoring > 60%, as the most relevant recommendations in all guidelines could be easily found with explicit SOR and LOE.The domain ‘applicability’ received the lowest median score . In general, there was little information regarding potential organizational barriers, cost implications, and tools for application, except for the NICE guideline  and variThe greatest range of scores was observed in the domain ‘editorial independence’ . Although all the guidelines disclosed their conflicts of interest (COI), the quality of disclosure was not ideal. They gave minimal information about ways in which any COI were managed in either tabular or narrative form. A complete summary of the process for identifying, managing and reporting COI during guideline development was only presented in one of the guidelines .Of the 9 guidelines, one guideline did not present the LOE underpinning the recommendations , and theA total of 177 recommendations on the management of NMIBC were extracted for statistics (Additional file To demonstrate differences between the identified guidelines, the key recommendations for the management of NMIBC were extracted and summarized Tables , 8 and 9The rigour of development could be an important domain for measuring the credibility of guidelines. The most effective CPGs should incorporate the current best evidence and place it in the context of local settings. Failure to use SRs to support their recommendations or to make explicit links between the supporting evidence and the recommendation still existed in some guidelines.If recommendations were made, the strength is linked directly to the consideration of benefit and harm. Research for intervention safety should be conducted and safety outcomes should be set as key outcomes to balance benefit and harm. A transparent process for reaching consensus is vital for guideline validity, and it is also necessary to record details of all processes by which evidence was appraised and how recommendations were formulated.Consumers are broadly defined as recipients of health care who provide a layperson’s perspective and can help in reaching consensus regarding the appropriate rating, presenting recommendations in ways that are understandable to patients and respectful of their needs and acting as a safeguard against conflicts of interests .For example, a patient might consider that the potential benefits in terms of survival might not be worthwhile in view of the potential important, even life-threatening side effects, of a given treatment. Therefore, it is important to consider patient views and expectations in cancer-related treatment recommendations.BCG instillation has more noticeable side effects than chemotherapy, so the balance between benefit and harm it should be given special attention when making recommendations, especially when attributing the SOR.The score of the applicability domain was disturbingly low, indicating that guideline panels considered the development and implementation of the guidelines as separate activities and did not pay enough attention to the potential facilitators and barriers to the guideline dissemination .To facilitate implementation, guideline panels should consider the publication types and format when reporting the guidelines. Some derivative products were specifically tailored for the target users, including summaries, algorithms and wall charts . Some otFurthermore, disparities in available resources for health care were enormous and shocking. Most included CPGs were developed for situations having full resources so incurring the maximal level of costs, making the applicability of limited utility. Cost-effectiveness analyses were needed for a sensible recommendation especially for developing countries. Economic evaluation should start during scoping of the guidelines. A reliable health economist shall be available to give advice on which questions are likely to require an assessment, and conduct the assessment and then report the results prior to the formulation of recommendations .Although most CPGs recommended TURBT and intravesical therapy, they differed in some details such as indications for re-TURBT and the use of chemotherapy agents and BCG in intermediate and high risk NMIBC.The reasons for offering different recommendations were undoubtedly multifactorial, which might in part be explained by the fact that the guidelines were produced by organizations from different contexts and settings. It could be possible that some discrepancy in guidelines arose through limitations in the current evidence for guideline panels to support their recommendations. In addition, the lack of a transparent process for recommendation formulation resulted in the risk of current evidence having been interpreted differently, because of the different weighting given to certain outcomes during decision making process.Notably, the recommendations were mostly based on low and moderate quality evidence, whereas the SOR results rated strong plus moderate accounted for a higher proportion. The lack of high-quality evidence might have increased the role that the decision-makers’ opinion had to play in framing the recommendations. Apart from the methodology of guideline development, guideline panels need to focus more on the growing body of evidence.Although the recommendations covered most areas for managing NMIBC patients, some issues that need to be resolved for optimizing treatment have been indicated in some guidelines.8 The need for further research was obvious.The first important item was whether the second TURBT should be performed after the intravesical therapy followed by the TURBT and whether intravesical therapy should be offered before pathology reports are available. The ESMO guidelines described re-TURBT as a reasonable option in high-risk NMIBC tumours after intravesical therapy, whereas the grade of the recommendation was rated low at III.Such an acknowledged item was which BCG strain is the safest and most effective option , 12–14. Different drug combinations of BCG, chemotherapeutic agents and interferon have been evaluated in various studies, such as interferon plus BCG , interfeDespite the disappointing results of combination therapy to date, device-assisted therapies have shown some promising data. Several studies have evaluated the efficacy of hyperthermia to improve the penetration of chemotherapy agents into the bladder wall, thus potentially improving outcomes . The useOur study might have some potential limitations. First, various grading systems to rate the LOE and SOR make it difficult to compare LOE and SOR among guidelines. Second, recommendations about BCG relapse and radical cystectomy have not been extracted from guidelines, causing the presentation and synthesis of recommendations on the management of NMIBC to be potentially incomplete.Nonetheless, our present study was reliable and helpful. First, a systematic literature search was conducted for screening eligible CPGs. Second, the reviewers applied AGREE II quality criteria to each CPG and achieved excellent interrater agreement. Furthermore, this is the first attempt to systematically synthesize and appraise CPGs for NMIBC management.The quality of NMIBC guidelines in the past 5 years was moderate. The included guidelines often failed to meet the methodological criteria for ideal development and implementation as described by AGREE II. Notwithstanding many consistencies, the recommendations were sometimes inconsistent in details; to what extent this was attributable to the underlying development process remained unclear.Additional file 1. Search strategy on PubMed. An exhaustive search was performed in the PubMed using a combination of text-free terms and their corresponding MeSH terms. The search strategy on PubMed is outlined in Additional file Additional file 2. A list of the websites with potential NMIBC guidelines. We searched the websites of guideline development organizations and professional societies. A list of the websites with potential NMIBC guidelines are outlined in Additional file Additional file 3. A composite grading system for ranking evidence and recommendations in NMIBC guidelines. Various grading systems have been used to evaluate the LOE and SOR in different guidelines, for the convenience of statistics, we discussed and reached a consensus on a composite grading system generated as a table in Additional file Additional file 4. AGREE II domain score of included CPGs for NMIBC. A bar chart was provided in Additional file Additional file 5. Grading systems used and descriptions of evidence and recommendation in the identified guidelines. The grading systems used and descriptions of evidence and recommendation in the identified CPGs were listed in Additional file Additional file 6. Distribution of the SOR and LOE among the identified guidelines on management of NMIBC. A total of 177 recommendations on the management of NMIBC were extracted for statistics. The distribution of the SOR and LOE among those recommendations was displayed in Additional file Additional file 7. Recommendations of immediate postoperative instillation. To demonstrate differences between the identified guidelines, the key recommendations for the management of NMIBC were extracted and summarized. The recommendations of immediate postoperative instillation were synthesized and presented as a table in Additional file Additional file 8. Recommendations of measures for optimizing chemotherapy administration. The recommendations of measures for optimizing chemotherapy administration were synthesized and presented as a table in Additional file Additional file 9. Recommendations of side effects and contraindication of BCG. The recommendations of side effects and contraindication of BCG were synthesized and presented as a table in Additional file


In the Conclusions subsection of the Abstract, there is an error in the first sentence. The words “seem to” should not be bolded. The correct sentence is: Our data seem to challenge the idea that self-paced exercise is regulated by top-down processing, given that we did not show clear evidence of exercise impairment  in the high cognitive load condition task with respect to the low working memory load condition.


This paper is a response to the growing reference to archaeological evidence by linguists and geneticists interested in the spread of early farmers and pastoralists in southern Africa. It presents two databases. The first contains the archaeological evidence for pastoralism and farming in southern Africa, for the period 550 BC to AD 1050. This is the first time that the seven different types of archaeological evidence that have traditionally been used to identify both spread events are presented together at this scale. This was stimulated by our interest in investigating the antiquity of an early ‘Iron Age package’ relative to the spread of single archaeological traits. The analysis shows that the package appears approximately 700 years after sites containing pottery, cattle and sheep, without agriculture, appear in the drier parts of the sub-continent. It post-dates the appearance of earlier sites with pottery associated with farmers, metal-working and cultivation in the eastern half of the sub-continent. While poor preservation undoubtedly explains the absence of some parts of the package, the analysis suggests that other explanations should be considered. The second database is a quantitative, spatial study of archaeological publications on southern African farming and pastoralism for the period 1950 to 2016, covering the same geographical area and archaeological timeframe. This is presented as a proxy for research-intensive areas in attempt to show the gaps in archaeological fieldwork and knowledge. Archaeologists have long grappled with the identification of past movements of people through the examination of their material culture. Consensus has not been reached on how, why and with whom livestock first spread in southern Africa, but recent genetic analyses, in particular, have freed archaeologists to once again talk of demic diffusion as an explanation for change, particularly for the spread of livestock without agriculture. Genetic evidence for the relatedness of present day Bantu-language speaking Africans across the sub-continent, and the persistence in Namibian Khoesan descendants of the gene that enables adults to digest milk proteins, has allowed geneticists to see migrations , 2, 3 anThere is an increasing reference to archaeological evidence by researchers outside the discipline, but this evidence has not been brought together by archaeologists. Previous research has considered the spatio-temporal spread of single traits , this isWe were concerned about how to label people in the database and maps. Traditionally southern Africanist archaeologists have labelled sites by the subsistence type of their occupants–farmer, herder, hunter-herder, for example. Conventionally, livestock bones and pottery found within a Later Stone Age context (i.e. without iron tools) in the western half of southern Africa are understood to be the remnants of herders (who may or may not be related to autochthonous hunter-gatherers and who spoke languages related to the Khoe language group), whilst pottery  found on the eastern side of southern Africa is interpreted as having an agro-pastoralist origin, and is linked to the movement of Bantu-language speakers. We have retained these conventional labels for ease of comparison with other work, while recognizing that they may be problematic . The detIn summary, the objectives are:To present a spatio-temporal review of multiple archaeological traits that are taken as evidence for farming and pastoralism in southern Africa.To investigate the antiquity of an early ‘Iron Age Package’ relative to the spread of single archaeological traits.To look for patterns that might be missed at a smaller scale of analysis.To present an overview of the coverage and quality of the archaeological data.To investigate whether archaeological classifications have been over-influenced by the modern distribution of linguistic groups.Two geo-referenced databases and a southern African language distribution map are presented. The first database (Database 1) is named the ‘Southern African Database for the appearance of Livestock, Pottery, Metal and Crops’ . The nampastoralist and here we use it very broadly to describe livestock-keepers without agriculture. It thus encompasses all the various terms  that have been used to describe livestock-keepers by southern Africanist archaeologists. We use the term hunter-gatherer to describe LSA sites where no livestock are found.There are multiple ways of being a This is the first database to provide a chronological, geo-referenced list of the material that is commonly used by archaeologists to identify the presence of early farmers and pastoralists in southern Africa. The database contains geo-referenced and radiocarbon-dated archaeological evidence for farmers and pastoralists from 209 sites dating to between 550 BC to AD 1050 in southern Africa. Southern Africa includes all countries which lie to the south of Congo, the Democratic Republic of Congo and Tanzania. The cut-off of 1050 AD is chosen to exclude the Later Iron Age and the increasing socio-political complexity that occurs thereafter. Farmers are traditionally identified in the archaeology when the remains of domestic livestock, crops, iron tools, iron working, diagnostic pottery, daga walls and floors, grain bins, pits and livestock byre floors or enclosures are found. Together these constitute what has been called the ‘Iron Age Package’ or the ‘Chifumbaze complex’ . This arPastoralists are identified by the remains of livestock, pottery type and the geographical location of the site. Sites containing evidence of livestock and/or pottery without agriculture might contain other items of material culture such as stone and bone tools, and/or ostrich eggshell and marine shell beads but we have chosen not to include these in the database. Instead we have focused on recording those items that are common to both farmer and pastoralist sites. For example, grindstones, metals, pits and stone features, when they occur at pastoralist sites, are listed in the database. Traditionally, pastoralists are understood to be non-Bantu-language speakers and ancestral to the Khoe.We collected all available archaeological data relating to farming and pastoralism, by southern African country. All except two sites fell below latitude 10 degrees south. The two outliers, at 8 degrees south, are Benfica in northern Angola and Kalambo Falls in northern Zambia. Benfica, on the coast of northern Angola, stands out as a potentially important site because Huffman , 18 has Database 2 presents a spatio-quantitative study of the numbers of publications on farmer and pastoralist archaeology for the period 1950 to 2016 for the research area .This map presents the distribution of extant southern African languages. It excludes European languages and Afrikaans. Whilst the Bantu language distribution is based on the modern distribution of these languages, the distribution of Khoe languages is based on their precolonial distribution (after ).All maps were created using ArcGIS version 10.5. The base map for Database 1 was compiled using the freely available USGS  Africa Digital Elevation Map.Radiocarbon and the Journal of African History. Other journals publish site specific reports which contain the detail required to understand what a radiocarbon date is associated with. A full list of journals and reports consulted whilst compiling the database are provided in The database was compiled from a combination of site reports, academic publications, radiocarbon laboratory lists and existing databases in print. It expands on previous spatio-temporal databases that focused on single traits in southern Africa . The priA unique site identifier and its location by country.The official site name, the type of site and the subsistence base of its occupants as designated by archaeologists.Uncalibrated radiocarbon date and laboratory number. Direct dates are noted in bold alongside the material dated.Calibrated date ranges. Dates were calibrated using OxCal 4.2 and the southern hemisphere calibration curve ShCal 13. Calibrations are to 1 sigma and reported as calibrated years BC/AD.Average date ranges are given in cases where there is overlap in the calibrated date ranges of multiple dates at a site and/or where a researcher recognizes a single occupation phase which has multiple dates.Good. A direct date.Fair. Sequence of dates with relatively good stratigraphic control/excavator is highly confident of the association between dates and materials.Poor. Single radiocarbon dates or poor stratigraphic control and/or poor correlation between radiocarbon date and associated material and/or excavator notes that the date is unreliable.The radiocarbon dates are given the following rating:Insufficient detail was provided about an archaeological trait and its context.Reports were not accessible.The radiocarbon date is considered an outlier (i.e. very old or very young).A number of archaeological sites were excluded from the database . The criThe sites are grouped temporally into eight 200 year time slices: 1: 551–351 BC; 2: 350–150 BC; 3: 149 BC-AD 51; 4: AD 52–252; 5: AD 253–453; 6: AD 454–654; 7: AD 655–855; 8: AD 856–1056. We are cognizant of the fact that the way in which data are grouped can manipulate patterns. However the information in Database 1 allows the reader to see the finer chronology for the appearance of archaeological traits within each time slice and their overlap. The use of a tight time range is to try to ensure that things that are plotted on the same map are contemporaneous, although the calibration distributions on radiocarbon dates constrain how refined these slices can be.To show the spatio-temporal co-occurrence of archaeological traits at a site, a coding system is used. It represents the 12 combinations of types of archaeological evidence that may be present at archaeological sites across southern Africa. These are simplified for easy visualization; for a detailed description of each of the archaeological traits at a particular site see Code 1: Site with pottery.Code 2: Site with livestock.Code 3: Site with pottery and livestock.Code 4: Site with pottery, livestock and metal artefacts.Code 5: Site with pottery and metal artefacts.Code 6: Site with pottery and metal-working.Code 7: Site with pottery, metal-working and cultivation.Code 8: Site with pottery, metal-working, cultivation and livestock.Code 9: Site with pottery, metal-working and livestock.Code 10: Site with pottery and cultivation.Code i: Site with structures (including pits).Code ii: Site with livestock byres.The following criteria were used to compile the codes:Presence of cultivation: carbonized seeds, seed impressed pottery and/or raised granary structures. Grindstones were not taken as a proxy for cereal cultivation but their presence is noted in the database.Presence of livestock: faunal remains and livestock byres.Presence of metal use: metal artefacts.Presence of metal-working: slag, tuyere and other fragments; bloom, ore, and furnace remains.Presence of structures: daga, floors, post-holes and pits.Presence of byre: phytolith analysis of soil and dung layers.th to 8th centuries AD but we have no way of knowing where in this 400 year period a particular find (e.g. a cattle tooth) fits.For farmer sites, in particular, there is frequently inadequate information on the association between radiocarbon dates and the archaeological finds. This means that it is difficult to determine exactly when a particular item was first introduced at a site. For example a site may be described as having a date range that covers 4Livestock are reported as Minimum Number of Individuals (MNI) represented by (M) in Database 1. When MNI is not available the number of individual specimens (NISP) is given, represented by (N) in Database 1. In cases where livestock are reported without a breakdown with stratigraphy, only the total livestock at the site can be presented.The following online publication databases were accessed (1) Ebsco Host (Academic Search Complete and Africa-Wide Information); (2) ProQuest; (3) Taylor and Francis and (4) Jstor. We searched by country name, the term ‘archaeology’ and one of the following additional search terms: Iron Age, Later Stone Age (LSA), farming communities (early and late), pottery, livestock, herder, hunter-gatherer and hunter-herder.All language categories were searched with the majority being in English; less frequently were, in order, Portuguese, German and French. Rock art research was omitted from the study as our focus was on survey and excavation for occupation sites. Once the results were reviewed, references were identified and included that were missed by the search . These databases of world languages provided the modern day distribution of different language groups. Glottolog and Ethnologue provide a classification for western and eastern Bantu-language speakers. Other reference material was also consulted to validate the map–an overview of Western, West-central and Eastern Bantu languages [The language map was compiled by reference to the online sources: anguages , a classanguages , Westernanguages , and theanguages .The maps Figs –9 S1–S8S8 Figs aIn southern Africa the earliest evidence for sheep and undecorated pottery comes from the western half of the sub-continent. Directly dated sheep bone and associated pottery are found at Leopard’s Cave in Namibia  . This isFurther directly dated decorated pottery is found in the same area in Mozambique (farmer) . BambataThis period sees the appearance of more LSA sites with pottery and sheep in Namibia . The earliest evidence of cattle in southern Africa is directly dated to an LSA site in Botswana, where they are found in association with sheep  . Decoratrd century AD—impressions of bulrush millet in pottery at the site of Silver Leaves, South Africa [Sheep and pottery are found in further LSA context sites, along the western and southern coast of southern Africa . Pottery is found in a variety of contexts. For the first time evidence of metal-working, metals and daga remains are found alongside pottery at farmer sites. This period has the first evidence of crops at a farmer site dating to mid-3h Africa . Farmer th century AD, however, the dating is poor [th century AD, this is their earliest occurrence at farmer sites in South Africa. Further sites appear with metal-working, metal artefacts and pottery in Namibia (occupants unclassified) [rd century AD), although the dating is poor [th century AD [There is the first evidence of cattle, a single tooth, in a farmer context north of the Zambezi . It dates to the end of 4 is poor . During ssified) . Sheep a is poor . Cattle,ntury AD .As well as cattle and caprines appearing at many farmer sites  for the first time, proxy evidence for cattle byres also appears for the first time. Cattle byres are only found at sites from the Limpopo basin southwards. Caprines and pottery predominate at LSA sites in the drier western half of the sub-continent, although cattle do occur . In Zimbabwe, a possibly circular hut floor is recorded, if this is correct it is the earliest example of this type of feature . This isThe Iron Age package is found at many sites in the eastern half of southern Africa during this period. Cattle numbers increase, with many farmer sites having evidence for pottery, metal-working, cultivation and livestock. Caprines and pottery have a continued presence in the drier western half of southern Africa. The spread of farming reaches its most southerly point near the Fish River, South Africa. This is the first time that farmer sites with livestock significantly outnumber LSA sites with livestock (18 LSA to 32 farmer). Farmer sites containing cattle are at a peak.The ratio of farmer sites with livestock to LSA sites with livestock remains almost constant from the proceeding period (16 LSA to 32 farmer). This period sees the continued dominance of cattle, caprines and the Iron Age Package at farmer sites throughout eastern southern Africa and the continued presence of pottery and caprines in LSA contexts in the western half of southern Africa.This paper is a response to evidence of increasing interest from other disciplines in the spread of farming and pastoralism in southern Africa, as evidenced in cross-disciplinary papers , 41, 42.The main contribution of our analysis is to suggest five patterns in the archaeology of this period. New archaeological finds may well change such patterns. Our data highlights the gaps in our evidence.Contrary to prevailing assumptions, our data shows a strong and enduring pastoralist presence in the western half of the subcontinent. Most papers on the spread of pastoralism to South Africa recount the sightings of large herds of cattle by early European mariners visiting the southern shores of Africa and then discuss the absence for evidence for them in the archaeological record. Mapping at this scale reveals that which has been overlooked by archaeologists–the enduring pastoralist presence in the western half of southern Africa, ahead of and during the period of farmer expansion. This pattern is revealed because we chose to group all the various categories of LSA people who are found with domestic animals as pastoralists, rather than following previous research that focused on categorizing people with livestock to distinguish hunter-gatherer-herders from immigrant herders (for a discussion see ).Different types of early pottery, which have been attributed to pastoralists, farmers and hunter-gatherers, appear at the same time at widely dispersed points across southern Africa (cf. ).Crops predated livestock in farmer contexts. Livestock are absent at the earliest farmer sites on the eastern side of southern Africa. This absence of evidence has most commonly been attributed to poor preservation and the ritual disposal of bone , but witth century AD onwards, contemporaneous with the appearance of the Iron Age package at many sites across eastern southern Africa th centurPastoralism arrived in southern Africa ahead of farming: livestock-keeping spread rapidly from present day Namibia across a wide area southwards and eastwards (cf. ).Arthur  draws atWe have made the assumption in presenting this work that the identification of cattle and caprines is valid. Recent debates about the strength of genetic identification versus morphological identification suggest we need to be cautious and that there is need for increased analysis of the ancient DNA of animal bones –53. SimiThe dating of pottery is also problematic. It is still overwhelmingly dated by association with stratigraphic layer at LSA sites, even at those sites where bones within the same stratigraphic layer have shown to be younger (i.e. ).We compiled the Southern African Language map because of a concern that there was inherent bias on the part of researchers to interpret the subsistence base of a site’s occupants based on a site’s geographical position. To explore this we have plotted all of the archaeological sites onto the language map . We wantIn 2004, Smith and Ouzman raised the hypothesis that a body of southern African geometric rock art had a pastoralist authorship , 59. In When we mapped the number of publications on pastoralist and farmer research for the period 1950 to 2016, the bias in our data towards research-rich areas is clear. More research is needed in Angola, Mozambique, large parts of Botswana and South Africa’s interior. Angola is a potentially important route for the spread of pastoralists, farmers and livestock , 17 and This paper is a response to a growing interest in the spread of farming and pastoralism in southern Africa by other disciplines, particularly geneticists, by providing a detailed spatio-temporal overview of the archaeological evidence that is used to interpret the past spread of these groups. Sadr  has streOur key findings are (1) evidence for an enduring pastoralist presence in southern Africa ahead of, and during, the appearance of agro-pastoralists; (2) the early, contemporaneous and widespread appearance of pottery that has conventionally been assigned to different subsistence groups , and (3), the appearance of crop farming ahead of agro-pastoralism at farmer sites. These findings are tentative. Patterns may change as more data becomes available. In particular we draw attention to the bias towards rock shelter excavation in Later Stone Age Archaeology and to the complete absence of direct dates on livestock within farming research.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S4 Fig(TIF)Click here for additional data file.S5 Fig(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(TIF)Click here for additional data file.S8 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.


We report a case of an arteria lusoria causing swallowing difficulties known as dysphagia lusoria. Although the presence of an arteria lusoria is quite common, dysphagia lusoria is relatively rare. Interestingly, our patient also presented with a concurrent aneurysmal dilatation, known as a Kommerell’s diverticulum, at the aortic origin. Complete thrombosis of the artery and flow reversal in the right cervical artery resulting in an asymptomatic subclavian steal syndrome was also seen. No underlying primary pro-thrombotic defects were identified but due to the presence of locally advanced prostate cancer, a paraneoplastic phenomenon was suspected. A 87-year-old man with no apparent medical history was admitted to the geriatric ward due to malaise which had been persisting for several months. He reported anorexia and intermittent dysphagia. A routine chest X-ray was negative and subsequently contrast enhanced CT imaging of the thorax was performed, revealing the presence of a thrombotic arteria lusoria with an aneurysmal dilatation at its aortic origin Figure . The artOf all congenital anomalies of the aortic arch an abberant subclavian artery, also known as an arteria lusoria, is the most common one being present in 0.3–2% of the general population 2. It is 63In our case, surgical treatment options were explored and discussed as our patient presented with clear symptoms of anorexia and intermittent dysphagia. However, due to the presence of significant co-morbidity on one hand and the fact that our patient declined further therapy on the other hand, a fully conservative treatment approach was chosen.Interestingly, we report the first patient who seems to present himself with a total occlusion of the abberant artery, together with an asymptomatic subclavian steal phenomenon. This was quite intriguing from a clinical point-of-view as higher rates of thrombosis at the level of the arteria lusoria have not yet been reported in the current literature. As venous and arterial thrombotic events were identified, other pathophysiological mechanisms were explored through an extensive work-up of the coagulation system which succesfully excluded diffuse intravascular coagulation, factor V Leiden, factor II mutations, anti-phospolipid syndrome, elevated levels of factor VIII, protein C/S deficiency or hyperhomocysteinemia. As subsequent investigations revealed the presence of a locally advanced stage of prostate cancer, we suspected the presence of a paraneoplastic pro-thrombotic state. Disorders of hemostasis are known to be commonplace in patients with prostate cancer through hyper-expression of tissue factor, cancer pro-coagulant, and platelet-activating factor, inducing the release of pro-thrombotic and pro-fibrinolytic substances into the bloodstream . As it wThis case stresses the importance of considering the possible presence of an arteria lusoria in the differential diagnosis of patients with chronic swallowing difficulties, as it can lead to significant morbidity when undiagnosed. CT-based techniques are pivotal as they provide vital information on the presence of aneurysmal formation, thrombi or compression of surrounding structures, as clearly illustrated in this case. The abberant artery can be missed when only endoscopic techniques are used to explore the patient’s complaints, further stressing the importance of radiologic imaging techniques. As higher levels of thombosis at the level of the arteria lusoria have not yet been reported in the current literature, we advise further investigations to exclude complications i.e. dissection of the vessel, underlying coagulation defects or the presence of a paraneoplastic pro-thrombotic state, when thrombosis of the abberant vessel is observed.The authors declare that they have no competing interests.


Dirofilaria: D. immitis and D. repens. We describe here an outbreak of D. immitis and D. repens infection in military working dogs (MWDs) housed in a kennel in the Indre department (centre of France). Out of a total of 17 dogs, 6 (35.2%) tested positive for D. immitis, D. repens or both parasites. Infested dogs were treated and prophylactic measures were implemented for the entire kennel staff. To our knowledge, this is the first documented description of an outbreak of canine cardiopulmonary dirofilariasis in the center of France, unlike in the south of this country, where D. immitis and D. repens dirofilariasis are enzootic. In France, as mosquito vectors expand their territory and new non-native vectors are introduced, it is likely that the distribution area of these two diseases of domestic and wild carnivores will be wider and underestimated.Canine dirofilarioses are nematode infections caused by two species of the genus  Dirofilaria immitis  . On. OnWolba® 96 PCR DNA purification plate, and was then amplified using a BigDye® Terminator v3.1 Cycle Sequencing Kit . The BigDye PCR products were purified on the Sephadex G-50 Superfine gel filtration resin prior to sequencing on the ABI Prism 3130XL. Nucleotide sequences were assembled and corrected using ChromasPro 2.0.0, then aligned against close reference sequences of filarioids species, representative members of Onchocercidae available in GenBank. The alignment was performed using the ClustalW application within BioEdit v.7.2.5 [Samples harbouring a single DNA of filaria were subjected to sequencing analysis. The pan-Nematoda primers named Fwd.18S.631 & Rwd.18S.1825r  were des v.7.2.5 . The max v.7.2.5 , based o v.7.2.5 .D. immitis microfilariae. DNA and Wolbachia complex qPCRs tests as well as the two serological tests gave positive results. Five dogs had mixed infestation with D. immitis and D. repens . Dirofilaria repens DNA was identified in dogs Nos. 2, 10 and 13. Furthermore, both Wolbachia genotypes known to be associated with D. immitis and D. repens were also detected in the same samples. Two samples (Nos. 2 and 13) provided positive results with both serological tests. One dog (No. 7) was positive for both D. immitis and D. repens microfilariae by the Knott test, the PCR test for both Dirofilaria and Wolbachia DNA, and by ELISA; whereas, it was negative by the immunomigration test. Finally, dog No. 8 was positive for D. immitis and D. repens and Wolbachia DNA; and for both serological tests. All samples were free of A. reconditum infection.D. immitis, having 100% identity with D. immitis isolated from foxes in France (Marseille)  and 99.9% with that isolated from dogs in Japan (AB973231). Three D. repens sequences were 100% identical both to each other and to D. repens isolated from humans in Japan  because of a stomach dilation-torsion. The necropsy performed on this dog revealed the presence in the right heart of four females and two males of  immitis . The heaD. immitis, without circulating microfilariae. Occult infestations occur in several situations, including monosexual infestation by male or female worms only, infertility of female worms, low infestation levels and/or destruction of microfilariae due to the host’s immune response [D. immitis was 66.6% (4/6). The detection of occult infections is usually based on adult worm antigen testing [D. immitis and D. repens, the reliability of these tests decreases, due to two main factors: (i) cross-reaction of rapid diagnostic tests between D. immitis and other parasites, including D. repens, and (ii) the immunosuppressive capacity of D. repens over D. immitis microfilariae, which hinders diagnosis based on the detection of blood microfilariae [D. immitis dirofilariasis, according to the protocol recommended by the American Heartworm Society, was effective against D. repens [D. immitis and D. repens showed 100% and 99.3% sensitivity and specificity, respectively. The reliability of the method is not reduced, even in case of occult dirofilariasis possibly accompanied by infestation by other filaroid species like Acanthocheilonema reconditum, leading to false positives following cross-reactions of rapid detection tests for D. immitis antigens [D. repens was observed in 60% (3/5) of Dirofilaria spp. coinfected dogs, of which only 40% (2/5) were positive for D. immitis antigen.It is known that heartworm can occur as an occult infestation, resulting in the presence of at least one mature female  of response . In our  testing . Howeverfilariae . Adultic. repens . The appantigens . This isD. repens is more endemic and spreads more rapidly than D. immitis within northern and eastern Europe [D. repens is widespread, the progression of D. immitis would be hindered, and vice versa [D. immitis have also been reported in western France, they concerned hunting dogs living in kennels near ponds [Aedes (Stegomyia) albopictus, more commonly known as the “tiger mosquito”, has been introduced into metropolitan France from Italy and is now present throughout the south of the country, as well as in regions further north, including the Paris region and the department of Indre since 2017 [D. immitis among A. albopictus populations is associated with an increased risk of infestation of dogs with this parasite [Canine filarial infections have increased significantly in recent years . This trn Europe , 31, 36.ce versa . Outbreaar ponds . In our nce 2017 . This hiparasite . An inteD. immitis and D. repens, resulting from their low host specificity. Human infestation by D. immitis results in a pulmonary form (nodules), the most severe but less frequent form, which is found mainly in southern Europe  [D. immitis are reported in endemic regions, such as Corsica and the Bouches-du-Rhône department [D. repens causes subcutaneous filariasis [A wide range of mammalian hosts, including humans and cats, can be infected by both e, etc.) . In Franpartment , 32. In lariasis , 19.D. repens and D. immitis) in the Rosnay military kennel, with a health risk for military personnel and military dogs in this area. In late 2018, after the detection of several infected dogs in the kennel, the following management measures were implemented: all dogs infected by D. immitis and cases of mixed infection (N = 6), except one that died before the treatment was administered (dog No. 7), received adulticide (melarsomine), combined with larvicide treatment (ivermectin), doxycycline and glucocorticosteroids (prednisone), according to the treatment protocol recommended by the American Heartworm Society [D. repens and D. immitis larvae, as well as Wolbachia complex and the existing susceptible larvae. Moreover, all infected dogs were treated with insecticidal repellent effective against mosquitoes during the period of vector activity (from May to November in mainland France). The aim was to prevent secondary cases and outbreaks, in the presence of competent vectors in the area where the military kennel is located.We report here for the first time, an outbreak of canine dirofilariosis ( Society . During D. immitis and D. repens infection in dogs, using macrocyclic lactones [The epidemiology of dirofilariosis infections is complex and has even been related to the concept of the episystem, represented by the multiple interactions between climate, environment, animals, humans and parasites . As theslactones , in comblactones .


Purpose: To investigate whether a deep learning-assisted contour (DLAC) could provide greater accuracy, inter-observer consistency, and efficiency compared with a manual contour (MC) of the clinical target volume (CTV) for non-small cell lung cancer (NSCLC) receiving postoperative radiotherapy (PORT).Materials and Methods: A deep dilated residual network was used to achieve the effective automatic contour of the CTV. Eleven junior physicians contoured CTVs on 19 patients by using both MC and DLAC methods independently. Compared with the ground truth, the accuracy of the contour was evaluated by using the Dice coefficient and mean distance to agreement (MDTA). The coefficient of variation (CV) and standard distance deviation (SDD) were rendered to measure the inter-observer variability or consistency. The time consumed for each of the two contouring methods was also compared.Results: A total of 418 CTV sets were generated. DLAC improved contour accuracy when compared with MC and was associated with a larger Dice coefficient  and smaller MDTA . The DLAC was also associated with decreased inter-observer variability, with a smaller CV  and SDD . In addition, a value of 35% of time saving was provided by the DLAC .Conclusions: Compared with MC, the DLAC is a promising strategy to obtain superior accuracy, consistency, and efficiency for the PORT-CTV in NSCLC. Accurate delineation of the clinical target volume (CTV) is one of the most crucial aspects of treatment planning in radiotherapy. The quality of this process depends on the expertise of the individual observer and is associated with quality outcomes in lung cancer care –4. HowevComputer-aided tools can potentially improve contour accuracy and reduce variation. Recently, deep learning methods have been increasingly involved in the field of radiotherapy –19. Our With regard to lung cancer, deep learning-related published data have predominantly focused on organs at risk (OAR) or gross tumor contouring , 20, 21 In this study, we established a robust deep learning algorithm to segment the CTV for non-small cell lung cancer (NSCLC) receiving PORT and determined if the assistance of deep learning could provide greater accuracy, inter-observer consistency, and contouring efficiency than those of manual delineation.We selected 250 pN2-NSCLC patients who received PORT in our department between 2012 and 2016 to build the deep learning model, with 200 patients randomly assigned to a training set and 50 to the validation set. We then selected 19 patients treated between 2016 and 2018 in our department as the test cohort to generate the automatic delineation of the CTV. All patients were simulated in the supine position with both arms raised above the head. The thickness of all scanned slices was 5 mm, and all computed tomography (CT) images were transferred using the Digital Imaging and Communications in Medicine (DICOM) format. The CT data were acquired on a Somatom Definition AS 40  or on Brilliance CT Big Bore  systems.We introduced a robust deep learning algorithm based on ResNet-101 to segment the CTV for PORT patients, which has been proven to provide high performance in CTV delineation . An end-Three senior radiation oncologists  also contoured the CTV in accordance with the protocol of a randomized phase III trial of the PORT study primarily investigated by our institute (NCT00880971) while blinded to the others' work on the same set of PORT images. The majority voting was used to generate the ground truth (GT).Eleven junior radiation oncologists (working experience ≤ 5 years) from 11 institutions with various volumes of radiation oncology departments  with the GT as a reference , 23–25. J represents the CTV contoured by each junior physician, and VGT represents the ground truth CTV created by the three senior physicians. A value of 1 indicates a perfect concordance between two contours. MDTA is the mean distance between the surfaces of both volumes, with a value of 0 representing perfect agreement. Both Dice coefficient and MDTA were generated in MIM software .where VThe inter-observer consistency was assessed using both volume and spatial metrics. The coefficient of variation (CV) was defined as the standard deviation (SD) divided by the mean CTV volume of all observers for each patient contoured with each delineation method, where a larger CV indicates greater variability or lower consistency. For the spatial metrics, the standard distance deviation (SDD) was used to measure the dispersion of the centroid distribution of CTVs contoured by the 11 junior radiation oncologists, which represents the standard deviation of the distance of each point from the mean center :Xi, Yi, and Zi represent the coordinates of the centroids of the CTVs created by the junior radiation oncologists and can be obtained from the MIM. Xc, Yc, and Zc represent the coordinates of the mean center of a set of centroids of CTVs for each patient delineated by the 11 junior radiation oncologists using one specific contour method. The unit of SDD is cm and a larger SDD indicates a greater systematic shift across all of the radiation oncologists.where t-test or Mann–Whitney U-test were used to compare the variables between two contouring methods. These analyses were all performed in SPSS version 19.0 . All tests were two sided, and p ≤ 0.05 was considered to be indicative of statistical significance.The continuous variables were presented as the mean ± SD or median (interquartile range), which depended on the normality of the data. Correspondingly, the General characteristics of the patients in the test cohort are demonstrated in p = 0.43). As for juniors' contour, a total of 418 unique CTV sets were generated, with 209 sets (19 × 11 = 209) for the MC and DLAC, respectively. The volume measures for each junior radiation oncologist with DLAC and MC are shown in p = 0.49). As shown in p < 0.001). Similarly, the DLAC also presented a smaller MDTA per individual CTV set than that of the MC performed by the junior radiation oncologists , as shown in Using GT contours as the reference, the Dice coefficient of each junior radiation oncologist for the DLAC and MC is graphed in p < 0.001; p < 0.001), which led to a 35% decrease in the SDD (For volume metrics of inter-observer variability, the DLAC introduced a remarkably lower CV than that of the MC (mean ± SD: 0.129 ± 0.040 vs. 0.183 ± 0.043;  the SDD .p < 0.001; Accurate delineation of the CTV is one of the most crucial aspects of treatment planning in radiation therapy, whereas the quality of CTV delineation largely depends on the academic expertise of the individual physician. In our country, with a shortage of facilities and workforce, there is inevitably a great disparity in clinical expertise across physicians from different areas . The intFor pN2 NSCLC patients receiving a complete resection, the role of PORT is still open to debate. Notwithstanding the paucity of randomized data, a majority of evidence suggests that selected high-risk patients could benefit from PORT in terms of both local control and OS –33. For Regarding the automatic segmentation of a target specifically for lung cancer, we noted that all of the published studies assessed the contour accuracy of the gross tumor on the basis of MR or PET, with the reported Dice coefficient ranging from 0.71 to 0.93 –18. To tInter-observer variability in the CTV contour has been considered to be the decisive source of uncertainty in radiotherapy treatment planning , 36. SucAnother important issue in target delineation is time consumption. With a prophylactic intent of radiation, the contouring time for PORT depends mainly on three factors: visualization of the boundary of the target, anatomical knowledge of the lymph node regions, and comprehension of the regions with a high-risk of failure. When comparing the DLAC directly with the MC, it should be equally easy to visually distinguish the high-contrast edges, whereas the latter two factors may be better contemplated through the DLAC. The most evident advantage of the DLAC is that it directly offers a possible delineation solution, and the physician only needs to edit the contour rather than to manually contour by slice. In our study, employment of DLAC achieved a 35% reduction of the time consumption for the CTV contour, leading to a considerable improvement in working efficiency.We acknowledge several limitations in our study. First, the patients enrolled for model establishment were treated over a certain time span, during which there might be certain changes throughout the process of the treatment planning. For instance, several anatomical protocols for the mediastinal lymph node region have been proposed within the recent decade, such as the IASLC lymph node map, Japan consensus, and Michigan atlas –43, whicThe DLAC is a promising strategy offering superior accuracy, consistency, and time saving for PORT-CTV delineation, which leads to higher quality and efficiency of radiotherapy for NSCLC after complete resection. These results indicate that deep learning-based automatic segmentation is promising for assisting CTV delineation, particularly for junior physicians from low patient volume institutions.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.NB, JW, ZZ, and JD contributed conception and design of the study. NB, JW, and ZZ independently contoured the CTVs to generate the ground truth. NB and JW organized the database and performed the statistical analysis and wrote the first draft of the manuscript. NB, JW, TZ, and XC wrote sections of the manuscript. XC, WX, JM, and JD established the deep learning segmentation model. KX, LWu, and QF collected the original data of the study patients. LWa, YL, and ZZ treated and selected the study patients. All authors contributed to manuscript revision, read, and approved the submitted version.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.


Falls in hospitals and care homes are a major issue of international concern. Falls cost the US $34 billion a year, with injurious falls being particularly life-limiting and costly. Shock-absorbing flooring decreases the stiffness of the ground surface to reduce the impact of a fall. There is a growing body of evidence on flooring for fall-related injury prevention, however no systematic review exists to inform practice. We systematically reviewed the evidence on the clinical and cost-effectiveness of shock-absorbing flooring use for fall-related injury prevention in care settings. We searched six databases, clinical trial registries, conference proceedings, theses/dissertations, websites, reference lists, conducted forward citation searches, and liaised with experts in the field. We conducted study selection, data collection, and critical appraisal independently in duplicate. We evaluated the influence of shock-absorbing flooring on fall-related injuries, falls, and staff work-related injuries. We adopted a mixed methods approach considering evidence from randomised, non-randomised, economic, qualitative, and implementation studies. We assessed and reported the quality of outcomes using the GRADE approach and Summary of Findings Tables. This review, conducted over the course of 2019, summarises the certainty of the evidence on whether and which shock-absorbing floors influence injuries from falls, the chance of someone falling over, and work-related injuries in staff (e.g. from manoeuvring equipment across softer floors). Our findings are applicable to health and social care professionals, buildings and facilities managers, carers, older adults, architects, and designers. Funded by National Institute for Health Research, Health Technology Assessment (ref 17/148/11); registered in PROSPERO (CRD42019118834).