Bacillus subtilis to fight against a stress. Bacteria have been exposed to sublethal doses of nanoparticles corresponding to conditions that bacteria may meet in their natural biotopes, the upper layer of soil or the gut microbiome. The analysis of the proteomic data obtained by shotgun mass spectrometry have shown that several metabolic pathways are affected in response to nanoparticles, n-ZnO or n-TiO2, or zinc salt: the methyglyoxal and thiol metabolisms, the oxidative stress and the stringent responses. Nanoparticles being embedded in the agar medium, these impacts are the consequence of a physiological adaptation rather than a physical cell injury. Overall, these results show that nanoparticles, by altering bacterial physiology and especially the ability to resist to a stress, may have profound influences on a “good bacteria”, Bacillus subtilis, in its natural biotope and moreover, on the global equilibrium of this biotope.Due to the physicochemical properties of nanoparticles, the use of nanomaterials increases over time in industrial and medical processes. We herein report the negative impact of nanoparticles, using solid growth conditions mimicking a biofilm, on the ability of  Bacillus subtilis is the upper layer of soil, but it has also been found in the gut microbiome. It is also used to feed broiler chickens or fish to improve growth performance or immunology responses in absence of classical antibiotics stress condition normalized by [F/F0]without stress.The ppGpp content was measured as previously described  using anBacillus subtilis strain, grown on a soft agar LB plate to promote the swarming motion during the formation of biofilm, has been studied by shotgun mass spectrometry. The data are available at the PRIDE repository (data set identifier PXD006444). In order to assess the divergence between the different biological states investigated a global analysis by hierarchical clustering, specifically the abundance data provided by the proteomic study, was performed on 728 proteins. The results displayed in 2) from cells treated with zinc. It was then impossible to separate cells treated with zinc ion (ZnSO4) from cells treated with zinc oxide (n-ZnO), showing that the effects were very similar. The analysis of the proteomic data has shown that several metabolic pathways are modified in presence of at least one nanoparticle.As described by Eymard-Vernain , the pro2O = > an alcohol + phosphate) is significantly increased (at least three fold), in the presence of n-ZnO or ZnSO4 salts and 1.5 fold when n-TiO2  and Crh (catabolite repression HPr-like protein) proteins increased, while those of the HprK (Hpr kinase/phosphorylase) and MgsA proteins decreased. In Bacillus subtilis, the regulation of production and detoxification of methylglyoxal is quite well understood  enzyme, which catalyses the production of inorganic phosphate , BshB1  and BshB2 , was unmodified in the presence of nanoparticles or ZnSO4 , suggesting a potential implication of the Spx and Spx-like main regulators.As previously described , the prelication , we havelleagues  have shoe manner ,38. In fe or the . It alsoat-shock ,42. Spx rulation . Bacillu2), we observe an opposite phenotype. It is remarkable to notice that even in the presence of n-TiO2, which has minimal impact at a macroscopic level  when compared to n-ZnO [spx transcription is stimulated by phosphate starvation [Bacillus subtilis to the nanoparticles in soft agar growth conditions  Abundance ratio of proteins involved in CoA anabolism and iol operon, determined by proteomic analysis compared to the control: in black, ratio of the protein abundance in the presence of n-TiO2/protein abundance in the control growth condition, in grey, in presence of n-ZnO and in white, in presence of ZnSO4. Asterix * indicates significant differences p < 0.05.(a) Abundance ratio of proteins involved in bacillithiol synthesis determined by proteomic analysis compared to the control: in black, ratio of the protein abundance in the presence of n-TiO(TIF)Click here for additional data file.S2 Figiol operon, determined by proteomic analysis compared to the control: in black, ratio of the protein abundance in the presence of n-TiO2/protein abundance in the control growth condition, in grey, in presence of n-ZnO and in white, in presence of ZnSO4. Asterix * indicatse significant differences p < 0.05.(a) Scheme of the inositol metabolism (b) Abundance ratio of proteins coding by the (TIF)Click here for additional data file.


Letter to editor regarding “International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC)” by Singh et al. Critical Care (2020) 24:65First, the presentation of recommendations for POCUS in neonates as evidence-based, rather than as author consensus; second, the inclusion of recommendations for critically ill neonates with older children; and third, the proposal that “these ESPNIC guidelines are developed for use by any neonatologist or paediatric intensivist.” Our intent is not to dissuade readers away from the use of POCUS but to restore balance between the desired recommendations and strength of available evidence and to offer additional suggestions.(i)It is notable that only 2 recommendations achieve Quality of Evidence of A , 4 reach level B , while the remainder is classed as weak evidence. Surprisingly, the authors present strong agreement for all recommendations which creates an impression of greater validation than the evidence supports.(ii)We believe the approach may inadvertently equate neonates to “small children.” Appraisal of cardiovascular physiology in critically ill neonates is challenging due to the complexity of the transitional circulation, unique interplay with neonatal disease and developmental variability of cardiovascular drugs. In addition, the reliability of subjective assessment of heart function or chamber size is questionable. We strongly believe that recommendations for POCUS in neonates be developed separately.(iii)While availability of portable ultrasound machines has expanded, permitting the field to advance, related guidelines are incomplete. Published guidelines articulate the need for a well-defined training structure and guidelines for clinical practice –4. SucceA recent survey indicated that the establishment of hemodynamic programs is a high priority for neonatology leaders, as there is recognition that meticulous hemodynamic data are essential to optimize care . At thisWe read with interest the article by Singh et al. which outlined the role of point-of-care ultrasound (POCUS) in neonatal/pediatric intensive care units . While w We thank the Editor for giving the opportunity to address the concerns and comments by McNamara et al.First, we agree that a comprehensive hemodynamic evaluation involves echocardiographic assessment using many parameters including precise objective measurements [within a patient’s hemodynamic profile [urements . Our pub profile . It refe profile , 9. DeveSecond, we would like to emphasize that these recommendations followed strict methodology consistent with other ESPNIC guidelines and are evidence-based, not expert-consensus guidelines [quality of evidence A” may ultimately impose unnecessary harm. This is similar to the use of echocardiography for diagnosing congenital heart defects (CHD) by a pediatric cardiologist; there is no disagreement that echocardiography is the investigation of choice to diagnose CHD despite the lack of published high-grade evidence.idelines . We agreThird, we agree with McNamara et al. that these guidelines are not for use by any neonatologist. Evidence-based guidelines have been prepared to define the clinical indications where POCUS can be used. The authors would agree that defining specific indications helps to prevent inadvertent use of POCUS in situations where its role is less clear or in settings where an adequate standard of care is lacking. For example, unlike neonatologist performed echocardiography (NPE) cardiac POCUS should not be used as a screening tool for congenital heart defects [for specific clinical indications and by appropriately trained clinicians [ defects . We beliinicians . Furtherinicians , which iThe purpose of guidelines is to guide the implementation of a tool within identified situations or settings where the care of a patient may be improved. The practice of neonatal critical care may be very different in different countries and regions, whether developing countries, American or European NICUs. We believe that with appropriate training, cardiac POCUS can be a useful tool for neonatal and pediatric intensivists to improve standards of care in critically ill children of all ages. Specific to Europe, a relevant proportion of units are mixed pediatric/neonatal critical care, and clinicians are trained to care for both types of patients.There is no doubt that pathophysiologies amenable to POCUS applications bridge the neonatal-pediatric divide. We certainly agree that neonates are not small children, but are there more differences in physiology and physiopathology more than similarities? Many examples point to convergence rather than divergence of applications, demonstrated by the extension of adult lung ultrasound principles in the assessment of neonatal diseases.We are in full agreement that cardiac POCUS, neonatologist performed targeted echocardiography and comprehensive echocardiography by the pediatric cardiologist are ‘the continuum’ of cardiac imaging. Compared to NPE, cardiac POCUS is designed for specific indications only, involves limited imaging and hence, relatively shorter training—allowing utilization of this important skill by more acute physicians in their clinical practice. The neonatal and pediatric intensivists performing both cardiac POCUS and NPE should work in close collaboration with the pediatric cardiologists as recommended in the guidelines (1–4). The consensus reached by the authors in developing our guidelines demonstrate the potential of this important collaboration, which we trust will enhance the care of critically ill newborns and children in the ICU environment. Working together they can share good practice and learn from each other while delivering the best possible care to their patients.


Clinical practice guidelines (CPGs) provide recommendations for practice, but the proliferation of CPGs issued by multiple organisations in recent years has raised concern about their quality. The aim of this study was to systematically appraise CPGs quality for low back pain (LBP) interventions and to explore inter-rater reliability (IRR) between quality appraisers. The time between systematic review search and publication of CPGs was recorded.Electronic databases , guideline organisation databases, websites, and grey literature were searched from January 2016 to January 2020 to identify GPCs on rehabilitative, pharmacological or surgical intervention for LBP management. Four independent reviewers used the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool to evaluate CPGs quality and record the year the CPGs were published and the year the search strategies were conducted.A total of 21 CPGs met the inclusion criteria and were appraised. Seven (33%) were broad in scope and involved surgery, rehabilitation or pharmacological intervention. The score for each AGREE II item was: Editorial Independence , Scope and Purpose , Rigour of Development , Clarity and Presentation , Stakeholder Involvement , and Applicability . The IRR between the assessors was nearly perfect . The median time span was 2 years , however, 38% of the CPGs did not report the coverage dates for systematic searches.We found methodological limitations that affect CPGs quality. In our opinion, a universal database is needed in which guidelines can be registered and recommendations dynamically developed through a living systematic reviews approach to ensure that guidelines are based on updated evidence.1CRD42019127619.REGISTRATION PROSPERO DETAILS: Supplementary information accompanies this paper at 10.1186/s12913-020-05827-w. The worldwide point prevalence of Low Back Pain (LBP) is 9.4%  in 2010 , 7. WhilBut because 1 out of 5 recommendations in clinical guidelines go out of date within 3 years, the validity of recommendations beyond 3 years is potentially questionable . As a geMoreover, existing appraisals of guidelines for LBP do not rely on a comprehensive search of the many possible therapeutic options  for treating acute and chronic LBP . The scoWith this study, we critically appraised only the most recent evidence-based CPGs for LBP interventions by means of the AGREE  II instrument, the gold standard for critical appraisal of guidelines , 23, conThe reporting of this systematic review fulfils the Preferred Reporting Items for Systematic Reviews and Meta-Analyses , 25. No In line with the World Health Organization, we defined a CPG as a document containing “systematically developed evidence-based statements that assist providers, patients, policy makers and other stakeholders to make informed decisions on health care and public health policy” .Inclusion criteria were: (i) the systematic process evaluated the recommendations; (ii) the CPG was focused on rehabilitation, pharmacological or surgical therapeutic intervention for LBP management; (iii) the full text was published in the last 4 years (2016–2020). We used the most up-to-date version and its supplementary documents. No language restrictions were applied. Exclusion criteria were: (i) not primarily focused on LBP, such as national/international guidelines in which LBP was briefly mentioned in the context of a more comprehensive disease evaluation; (ii) not issued by a national or international society ; (iii) declaration of recommendations was based exclusively on consensus statements or systematic reviews or commentary editorials related to published CPGs; (iv) focus on interventions other than therapeutic ; (v) based on population subgroups , specific causes (e.g. spondyloarthritis) or mixed/generic population .We systematically searched the PubMed, Embase, PEDro, and TRIP databases using the adapted terms and keywords derived from the scoping search outlined in the search strategy. We checked guideline organisation databases  and guideline websites . Supplementary Digital Content https://rayyan.qcri.org/) was used to manage screening and selection [Search results were uploaded to Endnote software and duplicates were removed , 28. Twoelection . Reasonshttp://www.agreetrust.org/resource-centre/agree-ii-training-tools/) and participated in two calibration rounds with a sample of four relevant CPGs of varying quality from a previous overview of clinical guidelines for chronic LBP restricted to 2012 [Four independent researchers  appraised each CPG using the AGREE II instrument and recorded with a self-chronometer the time taken for each assessment. The researchers received training in the use of AGREE II. They completed the AGREE II Online Training Tool  and the second global rating item of recommending the guidelines for use in practice, with one of three options . One author (VI) calculated the standardised domain score for each of the six domains as recommended by AGREE II , 32. TheWe used descriptive statistics to summarize the characteristics of CPGs deemed eligible for inclusion. Data are summarized as frequency number (percentage) or median and interquartile range (IQR). We calculated a quality score for each of the six domains of CPGs using the formula presented in the AGREE II User’s Manual . The appThe second global rating item asks whether the appraiser would recommend the guideline for use in practice and to respond with one of three options .P value < 0.05. All tests were two-sided [The first global rating was adopted to formulate the agreement on the overall assessment between the four appraisers measuring the intraclass correlation coefficient (ICC) with 95% confidence interval (CI). The degree of agreement was graded according to Landis and Koch : slight wo-sided . All datThe systematic search retrieved 2502 citations; additional 30 citations were retrieved from the grey literature. A total of 70 CPGs and related documents underwent full-text screening, 25 of which met the inclusion criteria. Four are awaiting assessment Fig. . FinallyTable Overall, the highest rating AGREE II domain was Editorial Independence , followed by Scope and Purpose , Rigour of Development , Clarity and Presentation , Stakeholder Involvement , and Applicability . In the overall guideline assessment, the median of the overall quality item was 42% (IQR 15–67%) and the most frequent recommendation regarding the use of the guideline was “No” . Guidelines appraisal took 42 min on average to complete (95% CI 35–50).Overall, 38.1% of the CPGs did not report the dates of systematic search strategy, whereas less than half (47.6%) reported a median of 2 years (IQR 1–4) from search to publication. Only half provided a search within 1 year after publication  for Domain 5 - Applicability. The overall quality was rated low and the most frequent response for guideline recommendation was “No” (15 out of 21 CPGs).Here we report the results of quality appraisal using AGREE II of the most recent CPGs for LBP interventions (published January 2016 to January 2020) that we retrieved by systematic search of electronic medical databases and guidelines websites. A key finding was the variability in the quality of the CPGs across all six AGREE II domains; the highest average scores (> 60%) were recorded for (Domain 3 - Rigour of Development), the variability in this domain was considerable. A low score for this domain is worrying, as it has been identified as a strong predictor of quality by the AGREE instrument [Our findings are shared by previous appraisals of CPGs for rehabilitation  and othestrument . Regressstrument . The iteThe validity of each recommendation, and of the CPG, is determined by the methodological quality and the transparency of its development and by the “living evidence” on which it is based. As suggested by Garcia et al., waiting more than 3 years to review a guideline is potentially too long, in which case the recommendations may be outdated by the time of guideline publication . This crDomain 2 - Stakeholder Involvement). Guideline developers need to prioritize patient and stakeholder involvement starting from the early stages of CPG development. They should be actively involved as members on guideline panels and their comments and inputs included in the draft guideline [Domain 5 - Applicability), with results similar to other CPGs in rehabilitation [Less than one third of the CPGs in this sample met the AGREE II criterion for participation of patients and their advocate . This may be related to the purpose of AGREE II: the current version makes no distinction between quality of reporting and quality of conduct of a CPG. Despite good reporting, the methodological conduct underlying a guideline can still be weak [Only half of the CPGs in our sample were rated satisfactory for adequacy of the reporting of recommendations and options for management . This could be explained by the focus on LBP, which is the most prevalent musculoskeletal condition for which guidelines are needed in view of the years lived with disability in most countries [. Given the global socioeconomic burden of LBP and the need for care, CPGs must report the presence and management of conflict of interests.We recorded high compliance of the CPGs with the overall aim of the guideline, the clinical question, and the target population , which may partially explain the high overall agreement. Indeed, our team included clinical experts and methodologists with experience in clinical epidemiology, including systematic reviews and CPGs. Even after receiving the same training however, guideline appraisers from different areas may still interpret the items and the scoring system differently . FurtherA possible limitation of our work is linked to characteristics of the AGREE II itself. It focuses on the quality of the development of CPGs, but this is not sufficient to ensure implementation of single clinical recommendations and improvement in health outcomes . While hclincialtrials.gov) and systematic reviews  but for CPGs. In this way, a “living and dynamic” development of recommendations can be better recognized by identifying the most recent literature [At the time of its publication, a CPG can already be outdated and so will not reflect the most recent evidence. Indeed, time can influence its reliability: (a) during the conduction of systematic reviews for the production of the body of the evidence needed during CPG development; (b) between finalization of a CPG and its publication. In order to avoid waste of effort and of resources due to duplication of CPGs or CPGs outdated before their time, we urge for the creation of a universal database in which guidelines can be registered and updated along the lines of registers for RCTs , clinical expertise, and available resources. We call for a universal database in which guidelines can be registered and recommendations dynamically developed through a living systematic reviews approach to ensure that CPGs are based on recent evidence.Additional file 1 Supplementary Digital Content 1. Literature search strategy and list of CPGs appraised with AGREE II.Additional file 2 Supplementary Digital Content 2. Items and domains of the AGREE II instrument.Additional file 3 Supplementary Digital Content 3. Additional Characteristics of included CPGs.


Evidence‐based medicine (EBM), the dominant approach to assessing the effectiveness of clinical and public health interventions, focuses on the results of association studies. EBM+ is a development of EBM that systematically considers mechanistic studies alongside association studies.To explore examples of the importance of mechanistic evidence to coronavirus research.We have reviewed the mechanistic evidence in four major areas that are relevant to the management of COVID‐19.(a) Assessment of combination therapy for MERS highlights the need for systematic assessment of mechanistic evidence. (b) That hypertension is a risk factor for severe disease in the case of SARS‐CoV‐2 suggests that altering hypertension treatment might alleviate disease, but the mechanisms are complex, and it is essential to consider and evaluate multiple mechanistic hypotheses. (c) Confidence that public health interventions will be effective requires a detailed assessment of social and psychological components of the mechanisms of their action, in addition to mechanisms of disease. (d) In particular, if vaccination programmes are to be effective, they must be carefully tailored to the social context; again, mechanistic evidence is crucial. We conclude that coronavirus research is best situated within the EBM+ evaluation framework. Not all association studies are equal, for example, experimental studies such as randomized controlled trials (RCTs) are favoured over observational studies, ceteris paribus. Studies other than association studies tend to be regarded as less useful by EBM. For example, mechanistic reasoning, which appeals to features of the mechanisms by which the intervention is hypothesized to lead to the outcome and to the mechanistic studies that investigate these features, is viewed as inferior to association studies by present‐day EBM.Evidence‐based medicine (EBM) provides the dominant approach to assessing the effectiveness of clinical and some public health interventions. In order to assess whether an intervention A and the putative effect B are correlated  of action as well as the existence of a correlation. Experimental studies such as RCTs are valuable precisely because they can indirectly support the existence of a mechanism (channel C2), by making confounding and bias less likely to corrupt the relationship between the dependent and independent variables. But mechanistic studies also provide evidence of the existence of a mechanism, by confirming or disconfirming specific hypotheses about features of the mechanism complex linking A and B (channels M1 and M2).  Reasoning that proceeds along channels M1, M2, and/or M3 is mechanistic reasoning. Mechanistic reasoning is particularly pertinent when specific hypotheses about key features of the mechanism complex are established (or ruled out) by mechanistic studies , because outbreaks are rapid, limiting the opportunity to conduct high‐quality RCTs. Thus, association studies on their own tend to provide evidence that is too weak to establish causation. When rapid outbreaks are coupled with severe disease, effective interventions need to be identified very quickly. In these circumstances, only by considering mechanistic studies alongside association studies is it possible to build an evidence base that distinguishes those interventions that are effective from those that are ineffective.In the following sections, we provide several examples of the importance of mechanistic evidence to coronavirus research. The assessment of combination therapy for MERS highlights the difficulties that can be encountered when suggesting treatments on the basis of poor mechanistic reasoning Section . That tr2One strategy in seeking interventions for diseases caused by novel viruses is to repurpose existing drugs. This strategy makes much use of evidence from mechanistic studies: evidence that the drug has some action against the novel virus in the laboratory, both in vitro and in vivo in experimental animals, is used to justify the decision to use the treatment clinically. COVID‐19 is no different. For example, the antimalarial drug hydroxychloroquine inhibits SARS‐CoV‐2 replication in vitro,Can this strategy be improved by taking an EBM+ approach? Standard EBM says little about the role mechanistic reasoning can play in attempts to identify effective treatments. As a result, mistakes may be made in how such evidence is handled. On the other hand, EBM+ takes mechanistic studies into account and offers explicit guidance regarding their evaluation. The following analysis of the way repurposing was carried out in response to MERS shows how the EBM+ approach uses mechanistic reasoning to identify effectiveness.combination of an interferon (IFN) and ribavirin has been suggested for treating MERS. The mechanism of action of IFN is fairly well known,As a repurposing strategy, a The problem here is that merely having some evidence from mechanistic studies is not enough to conclude that a mechanism of action exists. Arguably, for a treatment to be put forward for clinical use, the existence of a mechanism linking the treatment and recovery from the disease must be very plausible. However, evidence that a drug inhibits viral replication in vitro is only weak evidence that it will inhibit viral replication in vivo. Evaluating the extent to which mechanistic studies confirm the plausibility of mechanistic hypotheses is something that EBM+ adds to standard EBM.Demonstration of inhibition of viral replication in vitro and in vivo in animals is not enough to conclude that the mechanism is relevant to the clinical outcome in humans for the following reasons. In addition to viral replication, the pathology of MERS may include a mechanism by which the immune system contributes to lung damage, even after viral load is reduced.Of course, it will be no surprise to proponents of EBM that evidence from mechanistic studies may struggle to prove the existence of a relevant mechanism. However, it is not enough merely to note that results are not easily extrapolated from cell cultures or animals to humans, and to apply this scepticism rigidly to all experimental systems. Common marmosets, for example, develop a form of MERS very similar to that in humans, and evidence obtained using these animals is much more relevant to humans than evidence from rhesus macaques.complex of mechanisms by which mycophenolic acid operates should be scrutinized, rather than isolated mechanistic hypotheses. This practice is not always followed, and in this case, a compound made its way into clinical testing that should not have. This is thus another case in which a full evaluation of evidence from mechanistic studies would improve on the current repurposing strategy.Mycophenolic acid was proposed as an intervention for MERS, based on evidence that replication of MERS‐CoV was inhibited in vitro.3Pharmacological risk surveillance is another area in which an evidentially diverse approach to causal evaluation is desirable.Angiotensin converting enzyme 2 (ACE‐2) is the receptor to which SARS‐CoV‐2 binds to enter host cells.The status of H1 and H2 is problematic. There are two separate issues. First, the mechanistic studies from which the evidence is obtained have not been properly evaluated, and neither has the plausibility of either mechanism. The mechanism by which ACE2 protects against lung injury (H2) is fairly well established,Despite the absence of high‐quality clinical trials, we nevertheless have some evidence of possible causal relationships. In this sort of scenario, the EBM+ approach enables evaluation of the plausibility of causality. We might obtain evidence of a correlation between antihypertensive drug therapy and the intensity of COVID‐19 through association studies with lower quality designs, in advance of better ones. Such studies cannot prove causation, because they are subject to biases. However, the EBM+ approach to causal evaluation combines this kind of evidence with  evidence of mechanisms to obtain a better assessment of causality than either strand of evidence provides alone.3.1Ideally, the operation of each feature should have been demonstrated in vitro in different types of relevant cells/tissues/organ, and in vivo in a range of species. When the experimental system differs from the target system , a mechanism that exists in one experimental species and not another is unlikely to be helpful.Such demonstrations should include evidence that the mechanism exists, that enhancing it leads to measurable outcomes, and likewise for inhibiting it or abolishing it.Such demonstrations should involve different ways of doing this , and dose responsiveness should be demonstrated at concentrations that could plausibly occur in vivo.The importance of mechanistic reasoning to conclusions about the effects of antihypertensive drugs depends on the extent to which mechanistic studies shed light on the relevant mechanisms. For mechanistic reasoning to be strong, key features of the mechanism complex should be well established, and this can be achieved by meeting the following conditions:Demonstrating the anatomical location of the mechanism and its relevance. Do strategic lesions cause predictable changes?Demonstrating the time course of the mechanism. Does it change in response to interventions such as upregulation or downregulation?Do genetic polymorphisms,When any changes occur, is dose‐responsiveness maintained?Other criteria that, if fulfilled, would strengthen the mechanistic reasoning further include:Establishing key features of the whole complex of relevant mechanisms through a variety of experimental sources thus makes mechanistic reasoning strong.4Many public health interventions attempt to change or influence human behaviour. For decades, most of this effort has gone into preventing non‐communicable diseases—for example, by preventing smoking, obesity, and alcohol misuse and encouraging physical activity.One important finding from work in non‐communicable diseases, as well as HIV, has been the realization that social and psychological mechanisms are relevant both to aetiology and to the effectiveness of preventive interventions.A major obstacle to effective delivery of public health programmes has been confusion between etiological mechanisms and preventive mechanisms. The default is often to the assumption that if we know the cause, we know how to implement prevention.There are important lessons here for COVID‐19 in the United Kingdom. First, the behavioural mechanisms involved in the aetiology of the disease are the social vectors of transmission. They are complex. They determine vulnerability and risk, as well as the rates at which, and where, the disease will spread. These include mechanisms involving family structures and interaction patterns, occupational behaviour, urban density, housing occupation and overcrowding, workplace and retail environment structures and organization, as well as local social, economic, and cultural variation. However, there is nothing in the public record or the published models of the UK Government that suggests that these well‐known complexities were systematically built into UK models (https://www.gov.uk/government/groups/scientific‐advisory‐group‐for‐emergencies‐sage‐coronavirus‐covid‐19‐response). Furthermore, the predictive models were initially not only based on relatively small amounts of data but also on data from a very different cultural environment to the United Kingdom. The assumption that the cultures were similar enough to allow extrapolation is very tenuous. Above all, they were models of aetiology, not models of prevention, exemplifying the confusion mentioned above.Secondly, the way the population engages with preventive measures is affected by the mechanisms we are describing. So acceptance of the measures introduced by the UK Government, such as closing schools, giving the police new powers, and shutting pubs, restaurants, and many workplaces , will be affected by trust in government and its messaging. Being able to act upon the specific UK Government messaging required, for example, having space to self‐isolate, reliable digital technology and internet access in the home, effective habitual coping skills, feelings of self‐efficacy, and resources such as credit cards or ready access to cash. Behavioural science has had a presence at the table,inter alia of other offers, such as tracing apps and any vaccine, should one become available.Thirdly, one needs to consider mechanisms that affect take‐up of interventions. The use of testing, for example, is based on the assumption that people will avail themselves of the test and understand what the result means. Not everyone will, and different individuals and groups will respond differently to the offer. This response is governed not only by availability, but also by the social and psychological mechanisms in play. The same will be true These mechanisms are not as well understood as we need them to be, and there is an urgent need for programmes of research and evidence synthesis. These mechanisms will also have to be integrated into decision‐making processes in future coronavirus pandemics. The knowledge base, such as it is, is highly Anglo‐American‐centric, and its transferability to other settings is not known. The idea that strategies that have been used in North America and Europe could or should be applied elsewhere is not sound. Likewise, applying strategies that appear to have worked in South Korea, Singapore, or China to the United Kingdom are subject to the same uncertainty. The UK strategy of closing schools assumed that this protects children and families, because schools are potentially infection rich. However, this was premised on the biology of influenza, which thrives in schools, making children vectors of infection.Applied in settings outside the United Kingdom, this strategy is blunter still. School closures have many potential consequences. These include, but are not limited to, increased risks from accidents and injury outside the relative safety of the school, sexual violence to young girls, pressures and demands on parents, including economic costs of staying away from work, living conditions in multiple‐generation households , long‐term educational disadvantages through missing schooling (more likely to damage girls), and pressures on the social fabric to which schools contribute.There are thus two strategies for jurisdictions that seek to establish public health measures to deal with coronavirus pandemics. One is to develop local solutions, building from the ground up, rather than naively importing solutions that may never have been understood properly in the countries that implemented them. The other is to extrapolate interventions that have worked well elsewhere. However, successful extrapolation requires a detailed evaluation of the similarities and differences between the relevant mechanisms in the source and target jurisdictions.5By June 2020, researchers worldwide haddeveloped 149 vaccine candidates against COVID‐19, of which 17 are in clinicalevaluation and 132 in preclinical evaluation. Although the development of an effective vaccine will mark a major step forward, the mere existence of a vaccine will not ensure high uptake.As noted in the “Tailoring Immunization Programmes” guide published by the WHO's Regional Office for Europe, mechanistic studies are crucial in order to understand the psychological, contextual, and social mechanisms that influence vaccination behaviours.Some evidence, for instance, supports a behavioural mechanism known as the “intention‐behaviour gap,”Not all of these mechanisms are equally important, nor do they function in the same way across contexts. Many studies have reported that the prevalence of some mechanisms that inhibit or promote vaccination behaviours differ between and within countries. For example, anti‐vaccine sentiment and its related behaviours appear to be more prevalent in high‐income than in low‐ and middle‐income countries.It follows that identification of the psychological, contextual, and social mechanisms that influence vaccine‐related behaviours is not only important in understanding why vaccination coverage is lower than expected, but is also crucial in developing new effective vaccination programmes. This consideration is even more relevant, when, as in the case of the COVID‐19 outbreak, it may not be possible to carry out large extended trials to test the effects of an intervention, and the limited correlational data available from impact evaluations cannot rule out the risk of bias. Systematically scrutinizing mechanistic studies can help policy makers to develop effective vaccination programmes in at least two different ways.On the one hand, knowing that a mechanism operates in the target context helps policymakers avoid problems of external validity. For example, educational programmes aimed at increasing childhood vaccine uptake were reported to be effective in low‐income countries, where access to vaccination‐related information is difficult and parental knowledge is poor. However, similar programmes that focussed on parents with little knowledge about vaccines in high‐income countries did not show the same effect.On the other hand, identifying psychological, contextual, and social mechanisms can help policymakers to select the factors to target in vaccination programmes Figure . For insIn sum, the explicit and systematic assessment of mechanistic studies is essential for the development of effective vaccination programs in a given context.6how mechanistic studies should be assessed, we refer the reader to Parkkinen et al,We have presented a range of contexts in coronavirus research in which it is beneficial to systematically assess mechanistic studies alongside association studies. The cases we have discussed are illustrative rather than exhaustive. Indeed, we have not touched on assessment of medical devices, for which mechanistic reasoning is clearly essential; for example, the use of less invasive respiratory devicesIn the course of a coronavirus outbreak, it is essential to give neither too little weight nor too much weight to mechanistic reasoning. On the one hand, demanding high‐quality association studies, which usually do not exist in the early stages of an outbreak of a novel virus, can lead to inaction and many lives lost—lives that could be saved by considering the evidence base as a whole, which might warrant the use of particular interventions. On the other hand, advocating interventions solely on the basis of mechanistic reasoning that is of low quality can lead to a proliferation of ineffective interventions or ineffective extrapolations of interventions that are effective elsewhere. Thus, it is vital that mechanistic studies and mechanistic hypotheses are explicitly and systematically evaluated alongside association studies.The relevant mechanism complexes typically involve social and psychological pathways, in addition to biomedical pathways. Social and psychological factors are key to uptake of and adherence to an intervention. Moreover, social behaviours can change radically during an epidemic, partly in response to perceptions about the organism and its effects and partly in response to public health interventions. Only by explicitly articulating and systematically assessing these potential mechanisms can one ensure that coronavirus interventions are effective.The authors declare no conflict of interest.


Introduction: Medical quality indicators (QI) are important tools in the evaluation of medical quality. Their development is subject to specific methodological requirements, which include practical applicability. This is especially true for intensive care medicine with its complex processes and their interactions. This methods paper presents the status quo and shows necessary methodological developments for intensive care QI. For this purpose, a cooperation with the Association of the Scientific Medical Societies’ Institute for Medical Knowledge Management (AWMF-IMWi) was established.Methodology: Review of published German manuals for QI development from guidelines and narrative review of quality indicators with a focus on evidence and consensus-based guideline recommendations. Future methodological adaptations of indicator development for improved operationalization, measurability and pilot testing are presented, and a development process is proposed.Results: The development of intensive care quality indicators in Germany is based on an established process. In the future, additional evaluation criteria (QUALIFY criteria) will be applied to assess the evidence base. In addition, a continuous exchange between the national steering committee of the DIVI responsible for QI development and guideline development groups involved in intensive care medicine is planned.Conclusion: Intensive care quality indicators will have to meet improved methodological requirements in the future by means of an improved development process. Future QI development is intended to improve the structure of the development process, with a focus on scientific evidence and a link to guideline projects. This is intended to achieve the goal of a broad application of QI and to further evaluate its relevance for patient outcome and performance of institutions. The development of intensive care quality indicators (QI) in Germany was initiated by a working group within the German Society for Anaesthesiology and Intensive Care Medicine (DGAI), which aimed to develop evaluation tools for the quality of intensive care. A selection of core processes out of existing Spanish QI seemed to be adequate for this purpose . The selThis contrasts with the development of quality indicators, e.g. from treatment guidelines recommendations, in which the potential for quality improvement has to be determined beforehand (“top-down”) , 5], , , , . In addiIn the following sections, the steps for the development of the next edition of QI, which will be published in 2021, are described and presented for discussion. The evaluation of existing indicators, the development of new indicators including pilot testing, the definition of suitable key figures, and the cooperation in the development process will be addressed.As a first step in the development of the next version of intensive care QI, evaluation criteria were defined, which are based on the QI evaluation instrument QUALIFY . They inimportance for the health care system/potential for improvement,risks of undesirable effects, clarity of definition, evidence- and consensus-based (in guidelines),potential to be influenced by health care providers. These rules differ from the RUMBA system used to date Table 2 . The comAs described in section 2.1, the methodological basis for indicator modification was not rigidly defined. By applying the criteria listed in Table 2 First a review is carried out in the NSPR on the basis of proposals for new indicator topics from the medical societies that are members of the DIVI. Figure 1 Based on the strength of the evidence, the indicator strength will mainly be determined by consensus. This makes sense, since a high level of indicator evidence may still be available if there is an obvious correlation between process fulfilment and outcome (e.g. if no direct studies are possible) .It is desirable that the aspects mentioned in sections 2.3 and 2.4 are pilot tested before a newly developed QI is generally applied. The test focuses on acceptance (by the user) and methodological suitability, including proof of validity, statistical aspects and indicator evidence . The staThe definition of key figures and reference values has so far been based on expert consensus within the NSPR and was based on the existing literature or known indicators. Reference ranges  were determined in a similar way. In the future, determination of indicator key figures and their limits is a central aspect for the development and use of indicators. Two aspects will be essential in this context:collection of valid data to be able to calculate indicators,evaluation of the indicators in relation to the established reference ranges.As mentioned in the previous section, these questions are of particular importance when assessing QI in test phases. As shown in Table 2 In the future, the evaluated indicators should be actively shared with guideline development groups working on intensive care topics Figure 2 . This shThe development and use of quality indicators aims to improve treatment processes and patient outcome. The QI for intensive care medicine of the DIVI meet these requirements. However, as is presented in this paper, there is potential for improvement in the development of the QI in some areas. These relate to the evidence basis of the QI at the patient level and the health care system level and also their definite operationalization to enable broad application. A considerable number of intensive care QI exist worldwide . Their mThe postulated “lack of evidence basis” of QI mentioned in this paper is not intended to discredit the QI developed so far, but to emphasize that the transfer of guideline recommendations into QI is a very complex issue and should therefore be done in a structured and comprehensible way. The following general rule applies: The higher the published evidence for the implementation of a treatment process, the stronger is the evidence for the use of an indicator that evaluates this process. This basically refers to the strength of evidence, especially of guideline recommendations, where this basic principle is based on evaluation criteria from the GRADE system such as inaccuracy, indirectness and inconsistency, as well as others. The evaluation of GL according to the GRADE system cannot be applied directly to QI. However, the described assessment criteria for the transferability of study results into actual treatment recommendations can have an influence on the QI, since GL are the basis of the QI as described, and problems with study safety (=certainty) affect the QI , 29]. I. I29]. IIn Germany, the possibility of standardized data collection, ideally in a digital format, is not available across the country. For this reason, local measurability must currently be considered when developing indicators. The process indicators of the DIVI are well suited for this. However, in order to meet important statistical requirements for a broader application of QI, it is necessary to obtain sufficient data volumes. Here, the opportunities offered by digitalization must be used consistently. In a next step, questions of the statistical evaluability have to be focused on: the question of content validity – that the QI actually measures what it is intended for –, the ability to discriminate between institutions, and the sensitivity to measure change over time, e.g. to detect improvements or failure to improve. Finally, the data have to be consistent enough to evaluate an outcome effect of the indicator in use, since this effect should be as large as possible. The sufficient amount of data can only be collected through the broad implementation of patient data management systems (PDMS) in all ICUs. This would enable low-cost data collection and cross-sectoral data collection on patient-centred outcome parameters , 32]. H. H32]. HWhen a QI is implemented, it is necessary to evaluate whether the chosen indicator is reliable and valid, and whether its measurement can initiate a process of change within an institution or system, and how this is presented. Benefit assessments of QI have to state whether the conclusions drawn from the QI evaluation are reliable enough to prove a change in processes. For the use of QI – at least in intensive care medicine – a positive influence through the use of indicators on patient outcome has not been proven yet. It is also not known if QI can have a negative impact on patient outcome. For example, the application of sedation pauses, as is recommended, might increase the rate of self-extubation, which in itself might pose a risk to the patient. Valid data on this question do not exist. Therefore, a formal risk assessment should be integrated into the QI development process whenever possible. If necessary, an indicator must be withdrawn or amended in such a case.The type of indicator used also plays a role in the benefit assessment. In intensive care, there are some arguments in favor of using process indicators, as they are easy to measure and do not require risk adjustment for disease severity. However, in the literature some indicators are referred to as “process indicators” even if they query a result, e.g. rate of ventilator-associated pneumonia (VAP) as an indicator of appropriate hand hygiene . This woFor the quality dimensions proposed by Donabedian, not only process indicators are considered useful to evaluate a quality problem, but also structure and outcome indicators . In the The following statement by Califf et al. represents an “ideal state” in quality management and quality assurance: “In an ideal clinical world, for every clinical decision there would be an indicator based on a guideline based on evidence from randomized trials” . It is uAWMF: Association of the Scientific Medical SocietiesDIVI: German Interdisciplinary Association for Intensive Care and Emergency MedicineGBA: Federal Joint CommitteeGL: guidelineGRADE: Grading of Recommendations Assessment, Development and EvaluationIQTIG: Institute for Quality Assurance and Transparency in Health CareNSPR: National Steering Committee Peer ReviewNVL: national disease management guidelineQI: quality indicatorQS: quality assuranceVAP: ventilator-associated pneumoniaThe authors declare that they have no competing interests.


Typhoons and associated storm waves in the northwestern Pacific Ocean commonly cause coastal disasters. The possibility remains that an even stronger typhoon than the strongest one observed to date might have occurred before. The development of a method to estimate a maximum intensity of past typhoons over thousands of years is important for paleoclimatology, paleoceanography and disaster prevention. Numerous storm wave boulders exist on reefs in the Ryukyu Islands, Japan, which have been deposited to their present position by the cumulative effects of the past storm waves. These boulders can be used as proxies for the hydrodynamic conditions of the largest waves from past events. Here, we present numerical computations for storm waves and boulder transport with the boulder distribution as a constraint factor to estimate the maximum intensities of storm waves and their causative typhoon events over the past 3500 years. Though the intensities of the maximum estimated waves and associated typhoon events were slightly stronger than those recorded over the past ~70 years in the Ryukyu Islands, our results suggest that no abnormally intense typhoon has struck the Ryukyu Islands in the past 3500 years. The potential impact from tsunamis remains uncertain; however, our results are meteorologically reasonable. Especially, the northwestern Pacific Ocean is one of the most active tropical cyclone areas in the world3, and thus it is necessary to take measures against the impact of intense typhoons in this area. In Japan, records of typhoon measurements have been available since A.D.19514. While measurement records in Japan are relatively long (~70 years) compared to other countries, the record period is still too short for an accurate assessment of long-term risks. It is therefore difficult to exclude the possibility that extremely intense typhoons and consequent wave impacts have been generated in historical and prehistoric times in the northwestern Pacific Ocean. Although historical or archeological records are indeed useful, their availability is sometimes limited depending on both  location and history6. Also, intensities of typhoons are difficult to be estimated from these records. Geological records are crucial to perform the necessary risk assessment of storm surges and waves along the coast over a few hundred to thousand years before the measurement records10. Although there are few previous studies12, the methodology to reconstruct past wave conditions and the causative typhoon intensities from the geological records are still limited.Tropical cyclones and associated storm waves are extreme ocean phenomena that can lead to significant geomorphic changes and serious disasters in the coastal zone15. Here we conducted a field survey and numerical modeling efforts at Kudaka Island, Japan  because the storm boulders accumulate in accordance with the attenuation of the storm waves18. The boulders on the Kudaka Island show a typical distribution of storm boulders so that they are interpreted as stemming from storms16.Goto 20. However, no large historical earthquakes were reported except for some moderately large ones with magnitudes of around 8.022. The 1771 Meiwa earthquake and tsunami that occurred off the Ishigaki Island  was the highest on the southern side of Okinawa Island where Kudaka Island is located. Results showed that Hs and peak wave period (Tp) also become larger as the strength of the typhoon becomes stronger  is the wave with 17 m and 16 sec. Therefore, this wave condition is more likely to be the maximum wave that can satisfy the present boulder distribution at Kudaka Island. Strictly speaking, the actual maximum wave conditions should be slightly smaller than the estimated condition. However, since the difference is sufficiently small (<1 m in wave height and <1 sec in period), the effect may be negligible in the discussion.Among the conditions that can move all marker boulders, the condition with the smallest residual error 13.32 m) is the wave condition with 13 m in H.32 m is s and 14.9 sec in Ts during Typhoon 0704. Using Typhoon 0704 as an example, our simulation showed that the incident waves off Kudaka Island had Hs of 14.97 m and Tp of 15.04 sec. These values are still smaller than the estimated values of maximum waves  is well consistent with the condition with low residual error estimated in the above section . Therefore, we infer that this intensity of typhoon would be the maximum in the past since boulders were emplaced on the reef.Since we independently estimated the wave conditions for arbitrary intensity bins of typhoons, it is also possible to estimate the maximum intensity of the typhoon that hit to the study area in the past. Interestingly, both curves estimated from two independent calculations  in Fig. In this study, we fixed the course of typhoon but one can consider the results might be different if we assume various courses. However, Okinawa Prefecture31 assumed possible maximum typhoon with 870 hPa of the central pressure and 104 knots of the maximum wind speed. Although the assumption of central pressure is appropriate, the difference of maximum wind speed is too large to be ignored. Regarding to the wave condition, our simulation showed that Hs and Tp are 15.85 m and 15.35 sec, respectively, if we assume the model by Okinawa Prefecture31; it is slightly underestimated the calculated maximum wave from this study  in summer has been maintained at 26 °C or more since about 7000 years ago at Kikai Island  was significantly stronger than the most powerful typhoon that hit to the Kudaka Island in the observation record from 1951 (930 hPa). However, Typhoon 6118, which passed to the east of the Ryukyu Islands and hit Honshu (Japan mainland) in 1961, had 145 knots of the maximum wind speed and 888 hPa of central pressure. It is as strong as the estimated typhoon, suggesting that present distribution of boulders at Kudaka Island can be explained if the equivalent size to the Typhoon 6118 pass near the island. The significant advantage of our method is that it can be applied anywhere in the world at places where storm wave boulders are reported. The boulders can be used to evaluate the intensity of tropical cyclones and the corresponding waves.39: typhoons have a certain limit, to which the can be developed physically ). According to Emanuel38, MPI becomes stronger when 1) SST and boundary layer temperature are high, 2) the outflow temperature is low, and 3) the entropy difference on the sea surface is large. Since the boundary temperature and sea surface entropy are deeply related to SST, basically MPI strongly depends on SST. However, it was not unveiled whether the past typhoons before the observation era are within the range of MPI. It is not possible to estimate past MPI accurately without dense and accurate environmental values because it is difficult to calculate typhoon development completely even in current typhoon forecast40. In this sense, our methodology can estimate the maximum intensity of the past typhoons from the geological evidence. Since our result provides a realistic intensity (890 hPa) that is consistent with MPI, the MPI theory is supportable.Our results suggest that the typhoon intensity was not extremely large in the past and there may be a certain physical limit to its development under stable climatic and oceanographic conditions. Meteorologically, there is a theory that typhoons cannot be abnormally large and the maximum intensity is constrained by the local environment18. This sedimentological feature is reasonably explained by high-frequency but similar-size wave events by typhoons rather than low-frequency but different-size wave events (=tsunamis). Even if we assume that a tsunami had occurred in the past and formed the present boulder distribution at Kudaka Island, its size should be as large as the storm wave estimated in this study, which can be regarded as small. If we considering the potential effect of such minor tsunami effect, estimated wave and typhoon intensities in this study might have a chance of slight overestimation. However, the estimated intensities are close to the past ones such as the Typhoon 6118. Hence, we conclude that the estimated wave and typhoon intensities are reasonably valid as maximum.As stated above, we cannot fully exclude the effect of tsunamis unless we perform detail numerical analyses in the future work. However, the boulder distributions are almost identical throughout the entire Ryukyu Islands except for the tsunami-affected southern islands41 was used for the modeling. Secondly, we estimate the intensity of a typhoon that can produces the maximum wave estimated in the first step. For this step, we use topographic data (30 seconds mesh) provided by GEBCO.Numerical simulations of both (1) boulder transport by storm wave and (2) storm wave generation by arbitrary intensity of typhoon are carried out separately. Then, combining these two independent numerical results, the maximum intensities of waves and typhoons that formed present boulder distribution are estimated. The procedure is divided into two steps. Firstly, we estimate the maximum wave that has been affected to Kudaka Island based on the actual boulder distribution as a constraint. The computational domain is the coastal area of Kudaka Island, and the cross-sectional topographic data (5 m mesh) extracted from our multibeam bathymetric results44. Note that this model includes the generation of infragravity waves and surf beat45. Calculation of the boulder movement is simultaneously performed with the wave-field calculation.We conducted coupled calculation using two wave models, BOSZ (Boussinsq Ocean & Surf Zone model) and Delft3D-SWAN in order to express the non-hydrostatic motion in shallow waters and construct the wave and wind fields by the storm. BOSZ is a Boussinesq-type model that handles weakly dispersive waves, wave breaking, run-up on land and recirculation48. These models are commonly based on the Morison’s equation49 so that basic concept is similar. In this study, the equation of motion for boulder movement is based on Imamura et al.13 because the validity of this model was well confirmed by applying it to the 2004 Indian Ocean tsunami50. The external forces acting on the boulder are the fluid force Fm, the friction force at the bottom Fb, and the component of the gravity force Fg along the slope. According to Nandasena et al.51, sliding is the form with the smallest force required for movement. Also, on flat reef, boulder with low height are most likely to be moved by sliding16. Therefore, we assumed that the boulder is moved by sliding. We set the density of the boulder to 2.01, the coefficient of static friction to 0.75, and the coefficient of drag to 2.0 based on Goto et al.16. The coefficient of mass was used 1.67 based on Watanabe et al.27. The empirical dynamic friction proposed by Imamura et al.13 used for the simulation. This dynamic friction includes the effect of the lift force. We assumed that the roughness on the reef is constant for our calculation because the surface rock of the numerical region of boulder movement is composed of the same materials (reef rocks).Some models of boulder movement have been proposed52 and SWAN53. Delft-3D is a program to calculate the water elevation and current field by the shallow water equation. Receiving results from Delft-3D, then SWAN calculates the spectral parameters of the wave field including currents and storm surge; returning back the radiation stresses to Delft-3D.In order to calculate wave field caused by typhoon, we used Delft-3Det al.54. In order to calculate the pressure and wind fields, the path and central pressure of typhoon are input into the parametric model of Holland55. Then, a correction has been incorporated into the method based on Fujii and Mitsuta56 for considering asymmetry of those fields. The maximum wind radius was estimated using the empirical relationship of Quiring et al.57.The typhoon characteristics in the calculation are based on the method of Bricker s (24 cases) and Tp (23 cases) of wave spectrum are schanged independently, and the calculation is performed for 133 cases of initial wave conditions (Table For the simulation using BOSZ, a set of Hns Table . In orde31 conducted storm wave simulation for the generation of hazard map. They assume the typhoon with the central pressure of 870 hPa, with the maximum wind speed of 105 knot, and with a track going north on the west side of Okinawa Island similar to Typhoon 5115. Since the course of the simulation in this study is similar to the assumption by Okinawa prefecture31, it is possible to compare the results. Therefore, as shown as T5115 in Table 31 to evaluate the validity of the damage estimation.For Delft-3D/SWAN modeling, the course of typhoon is fixed as the path of Typhoon 0704, the course of which is considered to induce the largest effect of storm wave to the Kudaka Island. The calculations are performed under the conditions of 15 cases whose central pressure and the maximum wind speed are synchronously changed (Table Supplementary information.Supplementary Table S1.Supplementary Figure S1.Supplementary Figure S2.Supplementary Figure S3.Supplementary Figure S4.Supplementary Figure S5.


Blood, plasma, urine, and feces were collected up to day 25 or until excretion of radioactivity was <1% of the administered dose. In part B, six participants received 500 mg tepotinib orally as a film-coated tablet, followed by an intravenous [14C]-tepotinib tracer dose (53–54 kBq) 4 h later. Blood samples were collected until day 14. In part A, a median of 92.5%  of the [14C]-tepotinib dose was recovered in excreta. Radioactivity was mainly excreted via feces . Urinary excretion was a minor route of elimination . Parent compound was the main constituent in excreta (45% [feces] and 7% [urine] of the radioactive dose). M506 was the only major metabolite. In part B, absolute bioavailability was 72%  after oral administration of 500 mg tablets . In conclusion, tepotinib and its metabolites are mainly excreted via feces; parent drug is the major eliminated constituent. Oral bioavailability of tepotinib is high, supporting the use of the current tablet formulation in clinical trials. Tepotinib was well tolerated in this study with healthy volunteers.Tepotinib (MSC2156119J) is an oral, potent, highly selective MET inhibitor. This open-label, phase I study in healthy volunteers (EudraCT 2013-003226-86) investigated its mass balance (part A) and absolute bioavailability (part B). In part A, six participants received tepotinib orally (498 mg spiked with 2.67 MBq [ The mesenchymal–epithelial transition (MET) factor is a receptor tyrosine kinase with a single high-affinity ligand, hepatocyte growth factor (HGF) . HGF binMET are considered primary tumor-driving alterations in non-small cell lung cancer (NSCLC) -tepotinib was administered orally to evaluate the absorption, distribution, metabolism, and excretion of tepotinib. The availability of [14C]-labeled tepotinib, in conjunction with recent advances in the clinical use of microtracer doses and ultrasensitive bioanalytical methods -tepotinib (five capsules) on day 1. Participants were hospitalized from day 1 to day 16 of the study, and further assessed on days 19, 22, and 25 . Participants fasted for at least 10 h overnight prior to oral tepotinib administration, taken with a high-calorie, high-fat-content breakfast. Blood samples for quantitation of tepotinib and total radioactivity in blood and plasma were taken pre-dose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 34, 48, 60, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 360, 432, and 576 h after dosing. Separate blood samples were taken pre-dose and at 4, 12, 24, 60, 120, and 240 h post-dose for metabolite identification, and at 4, 8, 12, and 24 h post-dose for determination of the unbound fraction of tepotinib in plasma. Pre-dose feces and urine samples were collected on day 1 and day 2, respectively. Urine was collected at 4- to 12-h intervals on day 1 and every 24 h thereafter up to day 16. Feces were collected every 24 h up to day 16. Provision was made to collect further samples up to day 39 if >1% of the administered dose was detectable in the total (urine and feces) excreta per day on two consecutive measurements.In part A of the study, six healthy volunteers received a single oral dose of 498 mg tepotinib spiked with 2.67 MBq [14C]-tepotinib (53–54 kBq) 4 h later to cope with the risk of non-linear PK of the IV tracer dose [14C]-tepotinib administration), 6, 8, 10, 12, 16, 24, 30, 34, 48, 60, 72, 96, 120, 144, 192, 240, and 312 h after oral tepotinib administration. Blood samples for the determination of [14C]-tepotinib were taken at 4 h (pre-IV dose) and 4.05, 4.25, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 16, 20, 28, 34, 38, 52, 64, 76, 100, 124, 144, 192, 240, and 312 h, in relation to the oral tepotinib administration.On day 1 of part B, six healthy volunteers received a single oral dose of 500 mg tepotinib (one tablet), followed by a delayed IV bolus injection of -tepotinib, radiolabeled on one carbon per molecule , was synthesized by Quotient Bioresearch . For part A, tablets were crushed and hard gelatin capsules were prepared to contain approximately 100 mg tepotinib and 0.5 MBq [14C]-tepotinib (~117 μg). For the absolute bioavailability part, a solution for injection was prepared to contain 0.05 MBq [14C]-tepotinib (~11.7 μg) per 1 mL of solution. The definition of the dose of oral [14C]-tepotinib required for determination of mass balance and quantification of tepotinib metabolites was based on preclinical data obtained following oral administration of [14C]-tepotinib to pigmented rats. For dosimetry calculations, the assumption was made that the levels of uptake and retention by respective tissues were the same in man as in experimental animals. Administration of 2.5 MBq  [14C]-tepotinib chosen for part A of this trial was expected to lead to a radiation burden of 0.5 mSv, which is below 1 mSv, as required by the International Commission on Radiological Protection (ICRP) Category IIa. The dosimetry calculation was carried out by the United Kingdom’s Health Protection Agency Centre for Radiation, Chemical and Environmental Hazards.Oral tepotinib  was formulated as 100 mg film-coated tablets. [14C]-tepotinib , used in part B of the trial to determine the absolute oral bioavailability, was in keeping with regulations regarding tracer doses set forth in ICH M3(R2) [The single IV tracer dose of approximately 11.7 μg (in 1 mL) of [H M3(R2) . As thisThe RP2D of tepotinib of 500 mg was chosen to determine PK characteristics at a dose strength that most likely represents the therapeutic dose.2H]-MSC2156119A was added to 20 μL K2-ethylenediaminetetraacetic acid (EDTA) plasma. Tepotinib was extracted by protein precipitation with acetonitrile/water . Samples were centrifuged and 10 μL aliquots of the supernatant were injected onto an Acquity Charged Surface Hybrid™ (CSH) C18 column . Separation was carried out using a mobile phase gradient  with a flow rate of 0.6 mL/min. Detection was performed in the positive ionization mode on an AB Sciex API-4000 triple quadrupole mass spectrometer  with selected reaction monitoring . The lower limit of quantification (LLOQ) was 5.00 ng/mL, and the calibration standard responses were linear over the range between 5.00 and 2500 ng/mL using a weighted (1/x2) linear regression.Bioanalysis of total plasma concentrations of unlabeled tepotinib was performed by Quintiles  using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. In brief, the isotopically labeled internal standard [2H]-MSC2156119A and 100 mM sodium phosphate buffer (pH 7.4) were added to 5 μL of the dialyzed samples and centrifuged. Supernatant (30 μL) was diluted with acetonitrile/water  and centrifuged, and 5–20 μL aliquots were injected onto an XBridge C18 column . Separation was carried out using a mobile phase gradient  with a flow rate of 1.2 mL/min. Mass spectrometric detection of tepotinib and its internal standard was performed as described above. The LLOQ was 0.015 ng/mL in plasma dialysates and 1.00 ng/mL in plasma. Calibration standards between 0.015 and 30.0 ng/mL , and between 1.00 ng/mL and 1000 ng/mL (plasma) were calculated by weighted (1/x2) quadratic regression analysis, respectively.The determination of unbound tepotinib plasma concentrations, following equilibrium dialysis, was performed by Quintiles  using previously qualified LC-MS/MS analytical methods. Plasma (300 μL) was dialyzed against 100 mM sodium phosphate buffer (pH 7.4) in an orbital shaker at 37 °C for 18 h. The deuterated internal standard -tepotinib in plasma samples in part B of the trial was performed by Eckert & Ziegler Vitalea Science  using a validated method that involves isolation of the analyte by ultra-high-performance liquid chromatography (UPLC) fractionation, followed by the quantification of the 14C content in collected fractions using AMS -tepotinib from potentially interfering metabolites or degradants that may have been present in the study samples was carried out using a mobile phase gradient  with a flow rate of 0.75 mL/min. Liquid chromatography fractions corresponding to tepotinib were collected and prepared for AMS measurement, graphitized with a known amount of carrier carbon using a two-step process that involved oxidation to gaseous CO2 followed by reduction to solid, elemental graphite. Samples were then introduced into the BioMICADAS AMS instrument . The LLOQ was 0.0883 pg/mL.The accelerator mass spectrometry (AMS) analysis of -tracer dose. After parallel single oral administration of 500 mg tepotinib in the current phase II tablet formulation, tlag was 0.5 h and tmax was 10 h. Tepotinib concentrations declined in a mono-exponential fashion with an apparent t½ of 28.3 h, similar in range to the t½ values estimated after IV dosing. Geometric mean values for Vz/f and CL/f of 726.0 L and 17.8 L/h, respectively . The grade two TEAEs were abdominal pain and presyncope. All TEAEs had resolved by the end of the study, except for one incidence of grade one arthralgia reported by a subject in part B; however, this was considered to be unrelated to the study medication. Eight TEAEs were judged to be treatment related; diarrhea and abdominal pain were reported in two patients each. There were no withdrawals due to TEAEs and neither deaths, serious adverse events, nor other significant adverse events were reported.14C]-labeled material, as part of a standard mass balance study, is an opportunity to investigate absolute bioavailability in parallel with minimal additional effort -tepotinib to male healthy volunteers, the overall median recovery of the radioactive dose in excreta was 92.5%. For a study to provide appropriate information about the excretion of a compound, the European Medicines Agency recommends that recovery of radioactivity in urine and feces should be at least 90% of the radioactive dose [Following single oral administration of 498 mg tepotinib spiked with 2.67 MBq [ive dose . Therefo14C]-tepotinib in bile-canaliculated rats indeed showed that a predominant fraction of radioactivity is excreted unchanged via the bile. Since tepotinib is known to be a substrate of the drug efflux transporter P-glycoprotein -labeled tepotinib using hepatocytes from multiple species, including humans. The trace amount of M506 and its slow formation rate in hepatocytes likely impeded its detection by LSC. The apparent discrepancy between the prominent appearance of this metabolite in the systemic circulation, and the small fraction excreted may be related to a number of factors. M506 was found to be highly protein-bound, with a low affinity for blood cells. Thus, a low volume of distribution, combined with a low clearance, might explain the relative over-representation of M506 in plasma. Further results from ongoing investigations will provide more information about the PK of this chiral metabolite, and will also contribute to a better understanding of the relevance of enantiomers of M506.M506 was the only major metabolite detected in plasma  , 31, 34.max, in conjunction with the long t½ of tepotinib of 30 h, results in small peak–trough fluctuations at steady-state, and should enable continuous and constant inhibition of the MET receptor with once-daily dosing. Tepotinib has a large volume of distribution, indicating preferential partitioning into tissues, and indeed has been consistently found at higher concentrations in xenograft tumors than in the plasma of mice [In summary, tepotinib has high absolute bioavailability (72%) with low inter-individual variability, providing consistent and predictable dose delivery, and relative insensitivity to factors that can increase variability, such as drug–drug interactions. This contrasts with many small-molecule kinase inhibitors that have poor oral bioavailability and, therefore, also have variable and less predictable PK . Moreove of mice , which fIn this study, a single 500 mg dose of tepotinib was well tolerated by healthy volunteers; although 75% experienced TEAEs, most were mild and resolved rapidly. Tepotinib has also been found to be well tolerated in phase I/Ib and phase II clinical trials in patients with solid tumors, which have further characterized its side-effect profile , 35, 36.½. Thus, its PK profile is considered favorable for once-daily dosing to ensure continuous target inhibition. Hepatic elimination is the major pathway in humans and tepotinib is primarily excreted unchanged via feces, and only to a minor extent via urine. Ten phase I and II metabolites were identified in total (plasma and excreta), with chiral M506 being the only major circulating metabolite that warrants further characterization. The results also indicate that the potential for drug–drug interactions affecting the PK of tepotinib is low, irrespective of whether concomitant medications induce or inhibit drug-metabolizing enzymes.This study has demonstrated that the tablet formulation of tepotinib at the RP2D of 500 mg once daily has high oral bioavailability, supporting its use in phase II studies. Tepotinib exhibits low-to-moderate clearance and a high volume of distribution, resulting in a long plasma t


Newborn screening is a process-based public health service. Newborn screening staff and families alike are essential to maintaining the timeliness of the screening process. Newborn screening education must be accurate and accessible. Past newborn screening conferences have highlighted gaps in best practice and evidence-based guidance on newborn screening education. Sharing successful strategies across programs mitigates the scarcity of resources by cutting costs and reducing the burden of work. These factors illustrate the need for an education framework to guide newborn screening education efforts. The Newborn Screening Education Best Practices Framework responds to these issues by outlining guidance for newborn screening education approaches. Experts in the fields of newborn screening, genetics, and bioethics as well as previous research on best practice guidelines have contributed to the development of this framework. The framework outlines a process for users to evaluate newborn screening education approaches as best practices. This framework reviews best practices using a two-step approach, looking at guiding questions, implementation of the newborn screening issue, and evaluation. The framework helps the user define the characteristics of the newborn screening issue, intended audience, and practical steps to implementation, and then decide whether or not it can be used as a best practice. Newborn screening (NBS) is a public health screening service that determines if babies are at risk for a number of different conditions that may be life-threatening without medical intervention . In the Awareness is an important early step in implementing any public health service. To fully participate in public health programs, consumers must be aware of them ,3. UnlikFor this reason, all staff involved in the NBS process should be well-informed about the role they play, the importance of timeliness, and how they impact the rest of the system. Providers and other staff interacting with families must support learning by communicating effectively and accurately . ProvideFor families, filtering through the abundance of available health information to find direction and make informed decisions can be a daunting task . With meNBS education approaches are highly varied across the US and other countries . An educLooking at all these characteristics of NBS education, a prominent need emerges for a descriptive framework illustrating NBS education best practices. Although there are several education best practice frameworks in the broader public health realm, the distinct context of NBS requires the development of an intentional framework that accounts for the special considerations of the field. With the volume of health education strategies and programs, including individual NBS programs, advocacy groups, training and accreditation programs, and others, a framework can support standardization and streamline guidance and analysis of NBS messaging. Utilizing only effective programs across jurisdictions, programs, and hospitals will maximize funds and resources. The goal of the framework is that programs, hospitals, and other implementers will be able to thoughtfully choose an education best practice that most precisely meets the needs of their community.The NBS Education Best Practices Framework was collaboratively developed with content experts in the NBS field. A workgroup comprised of US state NBS staff as well as experts in health education, ethics, policy, and public health systems all contributed to the development of this framework. The workgroup utilized an iterative process of group discussions, literature review, and writing to draft and further develop the framework presented here. The best practice concepts of broader health fields guided development of the framework ,11,12,13Identify best practices among education approaches;Select a contextually appropriate NBS education approach for implementation;Move through the steps of adapting a best practice aligned with the specific goals and issues in NBS education;Determine if established methods and evidence support practices;Evaluate practices over time; andApply guiding questions and principles for all NBS education programs.The NBS Education Best Practices Framework is primarily a prospective tool to select appropriate, effective approaches prior to implementation, but it is also useful in evaluating past practices to determine their impact or effectiveness. The framework promotes effective education in NBS by helping the user accomplish the following:While anyone involved in the NBS ecosystem may find the framework useful, those responsible for the design and implementation of NBS education programs will benefit most. NBS programmatic and hospital staff can apply the framework when making choices about education strategies, programs, and materials. Though originally designed for implementation in the US NBS system, the general concepts presented in this framework are transferable to NBS programs globally, due to the focus on context.The NBS Education Best Practices Framework reviews best practices using a two-step approach. The first step examines guiding questions integral to NBS and public health education . The ansThe second step looks at practical implementation of an education approach, evaluation of the education approach as a best practice, and provides example considerations . This stBoth the guiding questions and the flowchart have three corresponding levels: 1. What/Why, 2. Who, and 3. When/How are meant to signify checkpoints that guide users through the kinds of questions addressed at each stage of the framework. The levels correspond to stoplight colors to illustrate that users are meant to work though the framework and move towards implementation of a new or existing educational approach. At each level, users are meant to assess whether they have sufficient answers to each set of questions before moving on to the next set of questions within the framework.At the red “1. What/Why” level of the framework, users are asked to clearly define the overall goal of using an NBS education best practice. The changes that need to happen and why they need to happen form the foundation of a program ,8. By spAll education arises from need. A driving factor establishes the need for education, whether it is reactive or proactive. Evidence of the need supports the rationale for the program and matches interventions to resolve problems ,8,9,10. Moving downwards, the yellow “2. Who” level of the framework looks at the characteristics of the target audience for the education. An accurate understanding of the target audience is critical for intentional design and patient-centricity ,9,11. AuMoving to the final, green “3. When/How” section of the framework, this section looks at implementation of the education approach. There are four main components to address: the implementation timeline, funding available, modalities, and whether a new education approach or an existing best practice is most appropriate. Decision-making on timeline, funding, and modality are closely integrated and may happen concurrently. Just as the audience and goal shape the decision-making process, each of these factors helps highlight the best, most practical course of action.Depending on the driving factor of the approach, implementation timelines vary. The timeline determines the funding needed over the duration of the implementation, and, subsequently, what modalities are possible. The key to this step is identifying when the education must meet the goal. Responding to a media story requires a much shorter timeline for implementation compared to educating NBS staff about a change in policy. Similarly, the best practice should consider sustainability over a long period of time or past the availability of grant funding, if relevant. The funds available over the course of the timeline indicate what approaches or strategies are possible. If funds are not available, then plans for implementation cannot move forward. Funding must sustain the program through its duration to achieve intended goals ,8.The modality of the education depends on available funds and resources for distribution and development, as well as the best modality for the target audience. NBS education is often delivered through presentations, webinars, training videos, brochures, or websites, but stakeholders should direct this part of the conversation as they can identify the modalities most likely to reach their communities. Subject matter experts and stakeholder assessments should be engaged to determine which modalities are most effective for the target audience. Education approaches need to apply an appropriate modality, or there is a risk that messages will not reach the intended audience ,8. Some NBS education approaches require occasional updates. New advancements in genetics, metabolics, and precision medicine are frequently introduced. Best practices include established methods for updating the practice as advancements are made.Established outcome measures for the evaluation of an education are another important component . The outJust as stakeholder feedback validates the goal and need, stakeholder feedback validates the plans for the approach itself. Stakeholder and community feedback is a dedicated part of a people-driven program. People-driven programs include budgeting, staff, and processes for addressing feedback throughout the duration of the program ,8,9,10. The education approach must also include the planned metrics for measuring success. Education itself is qualitative, but quantitative and evidence-driven measurements reliably show progress towards education goals. For this reason, establishing metrics in the planning process is essential to demonstrate the specific changes vital to achieving the goal .After the modality, funding, and timeline are determined, the use of an existing best practice is compared with a new program. The quality of the supporting evidence for a best practice is weighed alongside the context of the situation ,8,12,13.Are materials vetted, evidence-based, and current per specialist academies or other trusted organizations?Was the intervention based on a theory or model?Has the intervention and its evaluation been peer reviewed?Have the intervention and outcomes been replicated?The green “3. When/How” level of the flowchart addresses how to weigh the evidence supporting the education approach as a best practice. The strength of the evidence decides whether a new education approach or using an existing best practice is most appropriate. The user must evaluate the evidence supporting a certain practice based on several different criteria. In this framework, there are four fundamental binary questions with a scale used to judge strength. The more substantiated sources in favor of the approach, the stronger the evidence. Strength is judged on a scale of 0–4, with 0 being the weakest evidence and 4 being the strongest. Each question below answered with a “yes” gains a point ,12,13.ASupport from specialist academies or professional organizations is an indication that experts have contributed to the education approach and that the strategies are based on methods considered valid in the field.A model or theory also provides evidence that supports the effectiveness of the education ,13. ModePeer review is another way of demonstrating evidence for an education approach. Peer review of education approaches provides opportunities for experts to validate and support the methods used. Peer reviewed education approaches are described in academic journals ,13.Replication of the education approach with the intended outcome provides evidence for effectiveness. As the result is replicated more and more often, the evidence builds to support the fact that the education approach is meeting its goals ,8,12,13.Finally, during the implementation process, it is important to continually evaluate and collect feedback on the use of the best practice. Even with a robust planning process, unanticipated community reactions or barriers can prevent the education from reaching its intended goals ,8. For tWith increased knowledge sharing and training on effective strategies, NBS programs are currently advancing education efforts. In the US, each state program designs their education approach for a multitude of audiences, including birth center staff, clinicians, program staff, and families . In addiAs these trends in public interest continue, NBS education needs to apply strategies from health education and communication. Proven principles of health education and communication provide a foundation for education that accounts for the many complicated aspects of NBS ,3. TheseAs the field of molecular and genetic testing expands, the capabilities of NBS grow as well. Within the last several years, NBS in the US has expanded to screen infants for categories of diseases not previously screenable, such as lysosomal storage disorders and leukodystrophies. Furthermore, access to the expanded screening capabilities has not been equitable across communities within the US or other countries, so new challenges caused by language and culture may arise as screening capabilities spread. With many new possibilities on the horizon, additional challenges in education are unavoidable. The NBS Education Best Practices Framework will become integral in the coming years to guide and monitor education programs. Because context is so central to the design of the framework, it will be applicable across a wide range of programs, cultures, and audiences. Consistent use of the framework assists education efforts in creating effective NBS education approaches and, ultimately, creates better health outcomes.


Methamphetamine use and harms are rising rapidly. Management of patients with methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU) is challenging, with no clearly established best approach; both psychosocial and pharmacologic interventions have been described. Furthermore, given the diversity of individuals that use methamphetamines, there is a need to assess evidence for treatments for subgroups including youths; gay, bisexual, and other men who have sex with men; individuals with mental health comorbidities; and individuals in correction services. Establishing awareness of the messages regarding treatment from recent clinical practice guidelines (CPG) in the field is also of value.The first study objective will be to establish a greater understanding of the methods, populations, and findings of controlled studies for psychosocial and pharmacologic treatments for MUD and PMU. Investigation of this information can help establish the potential for advanced syntheses of the evidence  to compare therapies for this condition and to identify gaps related to key populations where more primary research is needed. Summarizing the recommendations regarding treatment of MUD/PMU from recent CPGs and systematic reviews will be an important secondary objective.A scoping review will be performed. Using the OVID platform, MEDLINE, Embase, PsycINFO, and relevant Cochrane databases from EBM Reviews will be searched (from databases’ inception onwards). Eligibility criteria will include individuals described as having MUD or PMU, with designs of interest including randomized trials, non-randomized trials, and controlled cohort studies with three or more months of follow-up; systematic reviews and CPGs will also be sought. Two reviewers (with support from automation tools) will independently screen all citations, full-text articles, and chart data. Different approaches to handling and summarizing the data will be implemented for each type of study design. Tables and graphics will be used to map evidence sources and identify evidence gaps.This research will enhance awareness of evidence addressing the effects of psychosocial and pharmacologic interventions for MUD/PMU overall and in sub-populations, both in terms of recent CPGs/reviews and primary studies; inspection of the latter will also help establish the feasibility of future syntheses to compare treatments, such as network meta-analysis.https://osf.io/9wy8p)Open Science Framework ( Staphylococcus aureus), endocarditis , as deemed most interpretable by the research team and dependent upon the quantity of information to be summarized. Per outcome, evidence network diagrams will be prepared to visualize the available evidence base and to consider the potential for NMAs in the context of a full systematic review. Per outcome, median values and ranges of treatment effects for each treatment comparison will be described. A narrative summary will be used to further describe the results from the tables and charts. Organizing data first by outcome will allow identification of (1) comparisons across study design types, (2) contradictory results , and (3) gaps in the evidence for each effect. This will also allow for recognition of which effects have not been evaluated or where evaluation is sparse. It will also identify if an NMA can or should be performed and will highlight covariates which may be considered for exploration using subgroup analyses or meta-regression.Different approaches to charting will be implemented for each type of study design. The approaches to be used are outlined below, and supplements will be used in the review as necessary to present all relevant information for readers.Several past reviews of treatments for MUD/PMU have excluded special populations , did not include comparative cohort studies, and have grouped all forms of stimulant and amphetamine use disorders together. The current review will seek to address these limitations by means of a focused synthesis of treatments specifically for MUD/PMU as well as by incorporating evidence for special populations in order to establish evidence for nuances of treatment. We anticipate certain challenges during study selection with regard to studies involving the treatment of MUD/PMU and other conditions concurrently, and we will work closely with our clinical experts to ensure all relevant evidence is included.In addition to disseminating findings via publication and through the networks of our knowledge users, we will establish a steering committee, consisting of content experts, methodologists, Canadian agency stakeholders/decision-makers , and people with lived experience , for engagement in a prioritization exercise based upon our findings; these groups will participate throughout this research initiative. The prioritization exercise will use an approach that will consist of (i) a webinar to present and discuss findings from the scoping review to be held 1 week after sharing of the final report, (ii) a Delphi survey of team members and knowledge users to establish preliminary perspectives on research priorities based on the study findings that were presented, and (iii) a second webinar of all contributors to discuss results from the survey, with the objective of informing a ranking of priorities with input from all parties. We anticipate the second component to focus upon the need and feasibility for new SR/MAs and CPGs for interventions to treat MUD/PMU, as well as aspects of research of interventions to manage MUD/PMU where future primary research is needed  , 104. A Additional file 1. DSM-5 criteria for Methamphetamine Use DisorderAdditional file 2. PRISMA-P checklist.Additional file 3. Definitions of Psychosocial Interventions and Comparators for MUD/PMU.Additional file 4. Draft Medline Literature Search.Additional file 5. Draft list of data charting components.