The electrochemical measurements prove these composites with MnO2 definitely offer better supercapacitive performance of the MgCo2O4 electrode material. The nanowall structure provides more active sites and charge transfer during the Faradic reaction. The MgCo2O4@MnO2 nanowall shows an excellent electrochemical performance (852.5 F g−1 at 1 A g−1). The asymmetric supercapacitor is composed of the MgCo2O4@MnO2 nanowall and the activated carbon (AC). The energy densities of the asymmetric supercapacitor device can keep up 67.2 Wh·kg−1 at 5760.0 W·kg−1. The MgCo2O4@MnO2 nanowall shows excellent supercapacitive performance and has a great potential for more research and application in the asymmetric supercapacitor devices field.Design and fabrication of a hierarchical core/shell MgCo Some new energy storage devices enter the field of view of researchers, such as fuel cells, Li-ion batteries and electrochemical capacitors7. The novel energy storage device is typically environmentally friendly, reusable and high conversion efficiency10. Right now, the interest in electrochemical capacitors  is growing worldwide. Supercapacitors are used in electric vehicles, computer memory system audio equipment and intermittent power supply systems13. The high energy storage device is mainly composed of electrodes and electrolyte17. The researches of the materials are significant for the development of supercapacitors23.With the increase of environmental pollution and the growing energy consumption, the research on new energy and energy storage device is very urgent25. The AB2O4 is a typical ternary oxide, has been widely researched as a high-rate anode material for supercapacitors27. The transition metal oxides were deemed to be excellent as the electrode materials for reaction pseudocapacitance. The transition metal element provides more potential charge transfer transitions28. The ligand-to-metal charge-transfer transition can easily occur in the high oxidation transition metal oxides31. These materials usually have excellent electrochemical performance which has the AB2O4 spinel with two transition metal elements and one of the elements is cobalt39. The cobalt-based oxides with AB2O4 spinel structure are widely used in the field of supercapacitors, such as NiCo2O440, ZnCo2O420, CuCo2O441 are better electrode materials for supercapacitors. The MgCo2O4  has a theoretic specific capacitance (3122 F g−1)43. This stable structure of MgCo2O4 will lead to a new research field. MnO2  as one of the supercapacitor electrode materials has been extensively investigated. MnO2-based nanocomposites can be used in aqueous electrolytes, which can meet the requirements of the test conditions46. A feasible attractive design is to grow MnO2 nanostructures on MgCo2O4 nanosheets by two steps of hydrothermal to get the MgCo2O4@MnO2 core/shell structure.The special crystal structure of the spinel-type oxides gathers enthusiasm for research in recent years. The ordered microstructure of the spinel-type oxides provides the stable electrochemical performance2O4 nanowall arrays (MCNA) and the hierarchical core/shell MgCo2O4@MnO2 nanowall arrays (MCMNA) have fabricated in the series of the processes. The as-prepared MgCo2O4 nanowall arrays are using a hydrothermal reaction. The nanowall (on the MgCo2O4@MnO2) was prepared using the second mild step of the hydrothermal reaction. The pore volume of the MgCo2O4@MnO2 is 0.69 cm3·g−1 and the surface area is 140.04 m2·g−1. The typical nanowall thickness is about 100 nm, the microstructure of the nanosheets are regular and dense. These nanostructures of the MCMNA-2 provide the rich reactive compared with MCNA, MCMNA-1 and MCMNA-3. The MCMNA-2 sample shows a prominent property at 1 A g−1 that the specific capacity is 852.5 F g−1 and it shows the excellent cycle stability after 2000 cycles. Table −1 at 5760.0 W·kg−1.Herein, the MgCo2O4@MnO2 nanowall arrays (MCMNA) on Ni-foam were prepared via two steps of hydrothermal reaction. The fabrication procedure of the MCMNA electrode is schematic illustrating in Fig. 2O4 nanowall arrays (MCNA) layer on Ni-foam. The MnO2 sheets are grown on the ordered MCNA in the second hydrothermal reaction.The core/shell MgCo2O4@MnO2 core/shell nanowall arrays was characterized by XRD. The typical XRD patterns (from 20° to 80°) of the hierarchical core/shell MgCo2O4@MnO2 nanowall arrays is shown in Fig. 2O4 phase (PDF card No. 02-1073), which are (220), (311), (222), (400), (422), (511), (440), (620) and (444), respectively. Other reflection peaks (marked with a diamond sign) which are correspond to the PDF card (No. 80–1098) characteristic peaks of MnO2. The diffraction peaks (low and wide) of the hierarchical core/shell MgCo2O4@MnO2 nanowall arrays show a low crystallinity, indicating that the crystallite has a small size.In order to analyze the composition and crystal phase details, the hierarchical MgCo2O4 nanowall arrays (MCNA). The SEM images of MgCo2O4@MnO2 nanowall arrays (MCMNA)  are shown in Fig. 2O4 nanowall arrays is about 20 nm. It is found that the MCNA are vertically grown on the surface of the Ni-foam skeleton and interconnected with each other. The new micro/nanostructure of the MCNA can provide a high-rate reaction surface for electrolytes and the electrodes. The SEM images in Fig. 2O4@MnO2 nanowall arrays on Ni-foam which with the second hydrothermal with 120 °C for 2 h (MCMNA-1). The SEM images on low magnification . There are many regular nanowall grown on Ni-foam which are shown in low magnification SEM images  are shown in Fig. 2 shell structure continued to change  analyses. The TEM and the HRTEM images of the MCNA and MCMNA-2 are shown in Fig. 2 nanosheets. Figure 2O4, respectively. The lattice spacing of 0.67 nm  corresponds to the characteristic bands of an oxygen atom (with a hydroxyl group).X-ray spectroscopy photoelectron (XPS) is the typical quantitative spectroscopic science method for identifying the valence states of the elements in the core/shell MgCo1/2 Fig.  energy l2O4@MnO2 nanowall. The isothermal plots of N2 adsorption/desorption for the hierarchical core/shell MgCo2O4@MnO2 nanowall arrays with a clear hysteresis loop show the pours nanostructure. In Fig. 2O4@MnO2 nanowall arrays. The BET surface area of the hierarchical core/shell MgCo2O4@MnO2 nanowall arrays is about 140.04 m2·g−1 and the pore volume is 0.69 cm3·g−1. The average pore size computed using by BJH model of 31 nm, and most pore sizes range from 10 to 40 nm, and. This hierarchical core/shell MgCo2O4@MnO2 nanowall arrays has a large pore volume and a high reaction area which is beneficial to the high-rate charge/discharge reactions.Fig. −1) are shown in Fig. The electrochemical performances of the MCNA, MCMNA-1, MCMNA-2 and MCMNA-3 were tested as the work electrodes in KOH (2 M) aqueous. The Fig. −1 at 0.5 V. The discharge time of the electrodes determined the discharge capacity at the same current densities. The discharge curves of the MCMNA-1, MCMNA-2, and MCMNA-3 show longer discharge time than that of the MCNA.As shown in Fig. 2 nanowall (as the shell) provides the added capacitance. In the Fig. 2 composite process is an important factor on the specific capacitance, MCMNA-2 has a high electrochemical property in these four electrodes.These results obviously indicate the MnO−1 under window potential of 0–0.7 V. Every typical CV curves in Fig. In Fig. −1, respectively. In Fig. 48:Cs (F g−1) is the specific capacitance; Δt (s) is the discharge time; I (A) is the current of discharge reaction; ΔV (V) is voltage; m (g) is the electrode mass.Figure −1. The MCMNA-2 sample exhibits excellent performances with specific capacity of 852.5 F g−1, 837.7 F g−1, 824.7 F g−1, 788.0 F g−1, 762.7 F g−1, 735.0 F g−1, 656.7 F g−1 and 573.3 F g−1, respectively.In Fig. 2 nanosheets provide richer redox reactions in the discharge process.The specific capacitance of the MCMNA-2 and MCNA at different current densities is displayed in Fig. −2 to 105 Hz. In the electrochemical test system, the Faradic impedance of the KOH-MCMNA interface is composed of the charge transfer resistance and the joint electrical resistance. The EIS curve consists of a semicircle and a straight line in high and low frequency regions, respectively. As shown in Fig. W0) with before. The solution resistance (Rs) before 2000 cycles is 1.01 Ω and after 2000 cycles is 1.04 Ω. The curves of high frequency shows the excellent electrochemical stability of MCMNA-2. The low frequency show the capacitance resistance was increased with the 2000 cycling. On the whole, the EIS test results further confirm MCMNA-2 electrode has a stable cycle stability.The electrochemical performance of the MCMNA-2 has been further confirmed by Nyquist plots of the electrochemical impedance spectrum (EIS). In Fig. In the cause of the future electrochemical property test of MCMNA-2, the asymmetric supercapacitor (ASC) devices are assembled. The structure illustration of MCMNA-2//AC is shown in Fig. Figure −1 scan rate. Figure A series of tests were performed on the MCMNA-2//AC ASC device to choose the potential window at 40 mV s−1 (0–1.6 V). The oxidation and reduction peaks in Fig. Figure −1 under window potential of 0–1.6 V. The charge and discharge curves shows a platform region which indicated the characteristic of the Faradaic pseudocapacitance. As shown in these curves, the discharge time and the specific capacities decrease as the current density increase.Figure 49:ΔQ (C); is the charge stored (expressed in coulombs); Es is the energy density (Wh·kg−1); Ps is the power density (W·kg−1); Cs is the specific capacitance (F g−1).The energy and the power densities was vary with current, as shown in Fig. −1 is 93.1 Wh·kg−1. The energy densities keeping up at 67.2 Wh·kg−1 at 5760.0 W·kg−1. The excellent electrochemical property of MCMNA-2//AC ASC via GCD tests and the data indexed in Fig. −1), 89.3 (at 1152.0 W·kg−1), 80.6 (at 1728.0 W·kg−1), 75.0 (at 2880.0 W·kg−1), 71.3 (at 4320.0 W·kg−1) and 67.2 Wh·kg−1 (5760.0 W·kg−1) at 0.2, 0.4, 0.6, 1, 1.5 and 2 A g−1, respectively 50, the MgCo2O4 cuboidal microcrystals of 24 Wh·kg‒1(at 252 W·kg‒1)34, MgCo2O4@PPy/NF//AC of 33 Wh·kg‒1 51, SiCF/MgCo2O4//SiCF of 41 Wh·kg‒1(at 465 W·kg‒1)52, mAC//MnCo2O4 is 3 Wh·kg−1 (at 6805. W·kg‒1)12 . The nanostructure of the core/shell MgCo2O4@MnO2 nanowall arrays is regular and dense which provides a high specific area . These materials which composite MnO2 have better electrochemical properties from the result of electrochemical measurements. The MgCo2O4@MnO2 nanowall shows an excellent electrochemical performance (852.5 F g−1 at 1 A g−1). The asymmetric supercapacitors are mainly assembled by the MgCo2O4@MnO2 nanowall and the activated carbon. The energy densities of MCMNA-2//AC device can keep up 67.2 Wh·kg−1 at 5760.0 W·kg−1. The MgCo2O4@MnO2 nanowall arrays on Ni-foam show excellent supercapacitive performance, which have great potential for more research and application in the asymmetric supercapacitors.The hierarchical core/shell MgCoThe process of fabrication of the Mg-Co precursor/Ni-foam is shown in Supplementary Information (Page S1).2O4 nanowall arrays and the MgCo2O4@MnO2 core/shell nanowall arrays are MCNA and MCMNA, respectively. These abbreviations will use in this paper.The abbreviations of the MgCoMCNA: The dry Mg-Co precursor/Ni-foam was calcined at 350 °C for 2 h with a ramping rate of 5 °C/min.4) were dissolved into 50 mL deionized water. The Mg-Co precursor/Ni-foam and the KMnO4 solution transferred into a 100 mL Teflon lined autoclave was sealed and maintained at 120 °C for 2 h (MCMNA-1), 4 h (MCMNA-2) and 6 h (MCMNA-3), respectively.MCMNA-1, MCMNA-2 and MCMNA-3: In the second hydrothermal process, 2.5 mmol of potassium permanganate .Supplementary Info


Medical librarians lack professional development opportunities in the critical appraisal of biomedical evidence. An update to our professional development opportunities could support our efforts to teach critical appraisal of biomedical evidence during evidence-based medicine or information literacy instruction. If we enhance our understanding of latent influences on evidence quality—such as changes to Food and Drug Administration regulations, predatory or deceptive publishing practices, and clinical trial study designs—we can improve our value to medical education and hospital systems. Understanding health care in the United States requires a sustained effort, as it is always changing. As the US health care system undergoes changes, whether it be a new law or medical treatment breakthrough, it behooves medical librarians to understand the process by which these changes occur. New policies and legislation, such as the 21st Century Cures Act (Cures Act), open up opportunities for medical librarians to develop a richer knowledgebase. Physician groups forming to combat medical distrust or unnecessary medical recommendations  indicate the need for trusted analysis of biomedical literature. If we enhance our understanding of the step-by-step processes necessary to implement changes in the health care system, we can better predict the emergence of user information needs .To further appreciate the information needs of our patrons and improve our delivery of biomedical information and education, we could benefit from an expansion in our professional development offerings. I propose that we introduce content into our professional development opportunities about the interplay between such areas as medical education curriculum design, clinical trial study designs, the history of Food and Drug Administration (FDA) policies , and scholarly publishing . These areas all play an integral part in constructing medical recommendations. With a better understanding of these influences that bear upon the evidence leading to medical recommendations, we could update our knowledgebase and deliver more interesting, pragmatic evidence-based medicine (EBM) or information literacy instructional sessions.relevance to their current curriculum and testing schedule. Without being engaged in clinical experiences, students lack adequate understanding of the clinical context in which to place the material that we deliver.When and how we introduce the above topics are important considerations. During medical school, academic medical librarians face the challenge of overcoming relevancy and context gaps when delivering EBM content . For medHowever, some medical schools are shifting to a more integrated curriculum, in which basic science and clinical science are taught together in all three to four years. If this trend continues, our algorithm of a clinical scenario—question → PICO → search → retrieve → basic appraisal—may allay relevancy and context gaps, allowing us to focus more fully upon appraisal instruction. Advancing our appraisal instruction is an opportunity to place the biomedical literature into such a context where we elucidate some of the influences  that weigh upon the quality of the evidence.To help our learners build an understanding of these influences on the evidence obtained through these information resources, we have to have a better understanding of the relationships among clinical trials, regulatory policies, and scholarly publishing. Imagine an update to our delivery of EBM or information literacy sessions, where we progress through more nuanced discussions about the fact that a surrogate end point “that is not itself a direct measurement of clinical benefit” can be used as proof-of-concept for a therapy and that it is possible that evidence of benefit for “breakthrough therapies” now “means data…other than randomized clinical trials” . We couland information literacy education. In other words, they help support a type of belongingness to and immersion into health care culture.Or imagine sessions where rather than simply showing students how to search for evidence related to mammography screening outcomes, we introduce some conflicting peer-reviewed recommendations leading to the controversy surrounding appropriate mammography screening ages and ask learners to debate this controversy by further identifying the literature that supports either side. We may suddenly improve how engaging our sessions are for learners, whether they are in science or medicine curricula, because we place learners in positions where they can leverage more of their natural critical thinking strengths to engage the material and the clinical context. We allow learners not only to search and appraise evidence, but also to engage with the material and participate in conversations around the material. These types of exercises and discussions would help deliver more comprehensive EBM If academic medical librarians do open EBM sessions by sharing how low-quality evidence can lead to poor or tragic patient outcomes , we wilIn private practice, providers are met with challenges to their information literacy . We need to ensure that we prepare medical learners to think critically about evidence that is presented to them. Medical librarians in the nonacademic health care setting can reinforce what we introduce in medical school by illustrating to clinical teams that there are many influences that have the potential to undermine a medical recommendation and that we are here to help ensure that they receive the information support to ensure they are making informed medical decisions. In essence, we are augmenting information literacy training and increasing our value to the organization in a timely manner as hospital librarians face shifts in staffing . CoupleTo illustrate, let me offer an example of how aforementioned changes in my own knowledgebase have influenced my practice. In December 2016, Congress passed the Cures Act. The FDA states that the Cures Act will “accelerate” the introduction of new therapy options to the market, as there are “patients who need them faster and more efficiently” . The CurThe Atlantic about the trend of physicians making medical recommendations based on poor evidence  at their own risk” [I find it humbling that my awareness of the Cures Act came via an article in evidence . This arevidence . In The wn risk” . The FDAwn risk” , 12, 13)What is novel now is that the Cures Act seems to signal an acceptance of medical recommendations with lower evidence standards that do not produce improvements in patient outcomes. Anecdotally, when I asked some faculty colleagues about the Cures Act, no one had heard of it. This has led to many discussions with faculty on the range of medical recommendations with dubious evidence to support them. In the classroom, only one student had heard of the Cures Act but did not know any details.Therefore, I introduced the Cures Act, medical recommendations with dubious evidence, and medical reversals in an introductory EBM session and witnessed a significant increase in student interest. As a result, librarians at our institution continue to update learners, staff, and faculty on predatory publishing  and work diligently to discuss the conflicts of interest that can occur on trusted pre-appraised evidence platforms or in guideline authorship. Our learners’ overall interest in gaining a better understanding of how medical recommendations are constructed has extended to residents and some expert clinicians, and has generated more education sessions led by librarians on these topics.We do not want a generation of physicians practicing medicine without understanding how the evidence on which they are basing their decisions may misrepresent true clinical benefit to patients. Training students on the minutia of the human body , as occurs in medical school, can introduce reductionist thinking, which reduces complex patient scenarios to a single molecule or pathway that causes illness. Similarly, in our practice as medical librarians, we often ask learners to reduce a complex scenario to a single question and further into a simple search.Although we already offer some basic appraisal strategies, I am arguing that an update to our knowledgebase can help us better empower our learners. Holistic learning about the health care system and scholarly culture that I am proposing—for example, knowing that the passage of the Cures Act further reduced funding for preventive medicine and allowed lower evidence thresholds for new therapies to be signed into law—can help medical librarians better adjust to information literacy challenges that health care professionals face.With this knowledge, we may be better able to anticipate information requests from our patrons or at least augment our current delivery of EBM or information literacy sessions. We have an opportunity to showcase information resources with a more precise framework that could help learners better assess the benefits and flaws of the informational materials that we teach them how to access. While complications in the US health care system are myriad, how we frame these complex challenges through the lens of industry, government, and evidence standards in classrooms or clinic settings may help allay anxieties that can arise due to limitations that are present in sources of evidence. We should encourage learners’ natural critical thinking strengths and offer a more substantial supportive role to help them reinforce their ability to see more sides of the ever-changing story of the health care system.


It is fit for purpose from an industry perspective and was used by pharmaceutical company Roche to develop a framework for internal assessment of evidence required for market access and coverage/reimbursement (“access evidence”).Evidence requirements and assessment methods access differ between health technology assessment (HTA) agencies. The HTA Core Model® domains and rolled-out in selected development teams in 2017. Five months after full implementation, the impact of tools was assessed in an internal survey.Tools were developed to systematically scope, assess, plan, and summarize access evidence generation. The tools were based mainly on the first four HTA Core ModelSystematic access evidence generation started with the Access Evidence Questionnaire, to scope evidence requirements and identify evidence gaps. Findings were summarized in the Access Evidence Metric, which assessed the alignment of available/planned evidence against HTA bodies’ requirements and developed scope mitigation strategies. The Access Evidence Plan was then used to plan and document  evidence generation. Once generated, evidence was summarized in the Access Evidence Dossier. A survey of twenty-seven Roche employees involved in evidence generation showed that the tools made discussions around access strategies and evidence more efficient and transparent.® provided a useful framework around which to optimize internal evidence generation and assessment. The benefits of using a standardized HTA approach in industry mirror those expected from implementing the HTA Core Model® in HTA agencies.The HTA Core Model Making novel healthcare technologies available is a complex process that requires careful assessment of the technology from the perspective of various stakeholders in healthcare, for example, patients, providers, manufacturers, and payers –3. In a Access evidence is usually generated by manufacturers to be assessed and appraised in HTA, which in turn informs coverage and reimbursement decisions ;6. There® (“the model”) was developed by the European Network for Health Technology Assessment [EUnetHTA] .In 2013, pharmaceutical company F. Hoffmann-La Roche (Roche) set up a joint project with EUnetHTA to evaluate if and how the model could support standardized assessment of market access evidence in industry . The HTA Core Modeleholders . Roche a®  was developed to scope access evidence requirements and identify evidence gaps. Based on HTA Core Modelinterest . For allThe Access Evidence Metric (AEM) was developed to summarize findings from the AEQ and assess the alignment between the available/planned evidence and the evidence required to achieve the desired benefit rating by a payer or HTA agency . For eacFor each domain considered in the AEQ , the available/planned evidence was classified to be in “full alignment,” “partial alignment,” or “lack of alignment” with the required evidence. Where misalignments were identified, the discrepancy between requirements and available/planned evidence is described. In addition, the importance of each domain for assessing benefit and value and for achieving the desired benefit rating was classified as “essential,” “important,” or “unimportant.” The available/planned evidence was considered fully aligned overall with evidence requirements only if full alignment was achieved in all essential and important domains. Following this overall assessment, potential market access risks could be identified, enabling the development of strategies to overcome misalignments and assess their likely impact. Finally, the AEM was updated with outcomes from access evidence planning (see the third AEx tool).The Access Evidence Plan (AEP) was developed to plan and document access evidence generation. Completion of the tool took the form of a workshop, during which all relevant functions and teams provided structured input to the planning of  evidence generation. In the AEP, access evidence needs and gaps, as identified in the AEM, were discussed to develop mitigation strategies as well as their risks and trade-offs. Upon finalization of the AEP, the AEM was updated accordingly.® for Rapid REA and focused on the first four domains (The Access Evidence Dossier (AED) was developed to provide a global evidence summary by integrating evidence from all sources. Accompanied by comprehensive internal guidance, the AED served the basis for global value guidance and HTA submissions. The structure of the AED closely followed that of the HTA Core Model domains . Upon coThe first AEx tool to be completed was the AEQ, which informed the AEM . The AEMThe lifecycle of AEx tools generally began once an indication has been identified for the drug under development. Tools were updated regularly and reflected important development milestones such as the design of pivotal studies or major changes in strategy or external circumstances. Initiation of work on the AED was scheduled approximately 9 months before regulatory submission for marketing authorization at the European Union (EU) level. The AED was updated after initial completion to accommodate new or changed data as well as feedback and requests from payers and HTA bodies.The remit of AEx tools comprised all drugs developed by Roche during research and early development as well as during late stage confirmatory development and commercialization and across all development phases, from before phase 1 clinical trials to product launch and management of its lifecycle  in each market. Notably, AEx tools were designed to complement and support, not to replace, existing processes for strategic planning, evidence generation and submission preparation. AEx tools were developed for evidence assessments in the United States and key Roche markets in the EU  but can also accommodate assessments for other countries.The tools and guidance on their use were rolled out across several product development teams throughout the company. In addition, procedures establishing responsibilities for and timing of AEx tools completion and updates over the product lifecycle were implemented. Simultaneously, an online platform was developed on which to store the AEx tools for ready access by affiliates and development teams.Implementation of the AEx tools and the standardized evidence assessment process at Roche began in January 2017 in selected product teams. Teams volunteered for participation and were selected by the lead investigator to reflect a range of different disease areas. By July 2017, twelve teams across the portfolio used the tools and followed the newly established process. By December 2017, the tools and process were implemented for thirty drugs/indications, all in the countries for which AEx tools had been developed. The tools were integrated into templates and processes for decision governance bodies. In addition, AEx tools were made available on the online platform to all involved global and affiliate teams and stakeholders.In a survey of users and cross-functional stakeholders, the impact of AEx tools was assessed and areas for improvement were identified. A total of twenty-two interviews were conducted with twenty-seven Roche employees involved in development and use of the AEx tools. Most interviews were individual interviews, while four interviews were conducted as group interviews with an entire team. In group interviews, responses were collected separately for each interviewee as interviewees did not necessarily agree on all items. Of the interviewees, most (43 percent) came from pharmaceutical development functions, followed by participants from commercial functions (27 percent) and affiliates (20 percent), while the remainder were from research and early development (10 percent).Overall, the AEx tools and processes were considered to provide the expected value, that is, more transparency and clarity for decision makers and affiliates around access evidence planning and generation, alignments on market access strategies, and more efficient discussions around evidence generation. All interviewees reported that the overall process for generating evidence was working well and achieved the aims of access evidence generation, especially as it fostered alignment across teams with regard to evidence requirements, gaps, planning, and documentation . Two-thiAn area of improvement was the length of the AED , in particular given its partial overlap with other submission documents. It was suggested to integrate into the AED the possibility to link to other documents, to further reduce duplication of work. Seventy percent of interviewees thought that the communication on the purpose of access evidence generation and the tools worked well. Thirty percent suggested that more communication would be helpful to increase internal understanding and commitment to the access evidence process.®. For implementation in AEx tools, HTA Core Model® domains were adapted to specific Roche requirements to increase their applicability and usability. Compared with the model, domains in the AEx tools were shorter and more targeted, with elements considered redundant or less relevant from an industry perspective left out or combined, respectively. A similar approach to adapting the HTA Core Model® by reducing domains and re-shuffling assessment elements was chosen by HTA agencies, for example, in the development of an HTA framework in Lombardy (® to specific institutional requirements, mirroring the experience at Roche (The present study reports on the development and implementation of a standardized approach to assess evidence generation in a large pharmaceutical company. Several tools for scoping, assessing, planning, and summarizing evidence were developed and built into the product development lifecycle to provide a transparent and clear structure for evidence generation across teams and functions. Development of the AEx tools was informed by an internal assessment of the HTA Core ModelLombardy . These aat Roche ;20.The initial roll-out of the evidence assessment process and AEx tools covered teams in multiple therapeutic areas. Both the process overall and the tools were considered by users and process leaders to work well and add value. Discussions around access evidence, for example, were judged to have become more structured and efficient both within and across teams. Challenges in using the tools were an initial lack of familiarity and partial overlap of the tools with existing process and submission requirements. In addition, more communication around the intention and role of the AEx tools was considered helpful. This feedback was used to inform further development of the tools and the planned company-wide roll-out to ensure efficient implementation and acceptance by internal stakeholders ;22.Developed in response to the absence of a standardized HTA framework in key markets, the AEx tools and the process overall are anticipated to have several benefits for Roche, some of which have already been realized. First, the timely consideration of evidence requirements increases the efficiency of evidence generation within the company. A standardized approach to scoping, assessing, planning, and summarizing evidence, with information and evidence shared in real-time across involved teams, is associated with a lower risk of missing evidence or duplicating work. With coordination costs reduced due to standardized tools and central documentation of evidence and with time saved due to duplicated work avoided, resources can be freed up and used, for example, on accelerating evidence generation or extending the communication with external stakeholders. In addition, a standardized approach used across different disease areas is likely to improve quality control capacities and staff mobility: as there is a common, company-wide access evidence vocabulary, experience with access evidence generation in one area becomes applicable in another.Second, from the perspective of internal stakeholders and decision makers, the transparency of a standardized process to assess access evidence is useful to inform internal product development and investment decisions. Evidence gaps that might affect market access, in addition to costs and development time associated with additional evidence generation, can be identified and documented early on in the drug development lifecycle. Consequently, the transparency of decision making is expected to increase in line with a shared and better understanding of the strategies and status of the available/planned evidence. In addition, evidence needs can be documented systematically while internal expectations and evidence assessments can be compared with assessments and decisions by payers and HTA bodies. Such a comparison is anticipated to provide feedback loops and, thereby, opportunities to improve internal evidence assessment and generation further.#TAg platform, on which AEx tools and evidence are stored. Benefits of this digitized approach are anticipated to include faster evidence generation and sharing with reduced transaction costs as well as more efficient collaboration (Third, the standardized approach, based on the HTA Core Model® and centered on the AEx tools, can support the move toward a digitized, more automated production of HTA evidence within the company. A structured framework can be developed into an online platform to enable collaboration as well as information exchange and storage across teams and functions. From the perspective of Roche, the foundation for collaborative, Web-based evidence generation has been laid by the development and roll-out of the boration .®, which was adapted to the specific requirements of Roche. The tools are currently implemented in several disease areas and contribute to structuring assessments of and discussions around evidence generation. Over the coming years, the tools will be refined further and implemented throughout the company.In conclusion, a systematic approach and a set of tools designed for scoping, assessing, planning, and summarizing access evidence for submission to payers and HTA agencies were implemented at Roche. The tools were developed based on an assessment of the HTA Core Model® framework, throughout product development inside a pharmaceutical company. Similar to the benefits that can be derived from standardization of HTA requirements across settings, a standardized approach to assessing evidence and its generation within a company is likely to be associated with efficiency gains and improved decision making and contributes to providing relevant evidence for demonstrating value.These results show that it is possible to implement a standardized process for access evidence assessment, based on the HTA Core Model


Preventing Chronic Disease has a mission to enhance communication between researchers, public health professionals, and policy makers to integrate research and practice experience with a goal of improved population health. As a result, those involved in dissemination and implementation (DI) science — a growing field of study that examines the process by which scientific evidence is adopted, implemented, and sustained in typical community or clinical settings — have submitted and published their rigorous and relevant work in the journal with a high degree of success. Over the previous 2 years, the journal also added a new article type — Implementation Evaluation — to facilitate submission of articles that examine the implementation of evidence-based public health interventions in community and clinical settings. In an effort to continue the focus on DI, we wrote this commentary with the following objectives: 1) to provide a brief DI description, 2) to demonstrate the shared systems–based focus of DI science and public health practice, and 3) to highlight pathways to move public health–focused DI science forward. We reflect on our own learnings and by doing so hope to motivate more public health researchers and practitioners to engage in DI research.DI research emerged — by name — over the past 25 years , but itsKurt Lewin founded the field of action research ,8. He anArchie Cochrane — the inspiration for the thriving Cochrane collaborative  and the Diffusion of Innovations from the first edition in 1962 through the fifth and final edition in 2003  — that Rogers proposed are still foundational across the primary theoretical approaches being applied in DI research –16. In aIn case you think that these issues are not as relevant today as they were three-quarters of a century ago, the promulgation of evidence, the lack of relevance of evidence, and the time and capacity needed for public health professionals to adapt and implement new interventions has resulted in a considerable evidence–practice gap . CochranThe more recent emergence of the DI field can be traced back to the early 1990s and the energy focused on developing a myriad of DI models to address the evidence–practice gap ,24–26. TMost DI researchers use a process model, though few characterize the specific steps taken at each phase of a DI project . HoweverDiffusion of Innovations as our example of an explanatory model  of why a systems change occurred to allow for replication within and across public health settings . It is tSystems-based, collaborative processes for DI ideally engage practice partners that contribute across the life course of any one project and often across multiple projects ,41,42. Tinformed decision making  identification of priority areas or needs within a system , 2) matching of available evidence to the identified need (community action plans), 3) piloting or implementing strategies, 4) evaluating outcomes, and 5) deciding if a strategy should be sustained, adapted, or abandoned. Within this iterative learning process, numerous things need to be considered, and much is related to how we define evidence and evidence-based practice. Beginning with evidence-based practice, evidence is both used and produced by public health professionals . Kohatsun making –53. Thisn making .Evaluation of the application of evidence-based principles and processes in the context of real-world systems is key in the iterative learning process. Often, the focus of evaluation is to provide evidence that the contribution of one or a few factors make a difference among a set of predetermined outcomes while holding all other factors constant. A systems-based approach acknowledges that in public health practice, all factors, even  those that are not being measured, are dynamic rather than static and influence the context of the evaluation. In other words, evaluations of programs, practices, and policies in the field of health and well-being are complex. The introduction of complex systems science provides an opportunity to consider an approach to evaluation that optimizes the context, does not attempt to control variables that cannot be controlled, and may be helpful in evolving the field of evaluation and pragmatic DI research to become more responsive to the needs of practitioners and decision makers ,56.Systems-based approaches, by nature, cannot be completed without representation from the system that is intended to change . This apThroughout this article we have highlighted the sustained relevance of the work of some of the giants in our field, provided descriptions of the importance of explanatory, process, and outcome models, and outlined the common systems-focused basis for DI science and EBPH. Here, and in the Building and sustaining opportunities for DI science in public health practice requires a combined emphasis on developing individual and team-based skills and capabilities as well as organizational capacity ,58. IndiPhysical Activity and Public Health Course for Practitioners, has shown positive benefits in building capacity to design, implement, and evaluate interventions (As the field of DI science continues to mature, there is increasing urgency and need for new and expanded approaches for building DI research and practice capacity . Becauseventions .Given that the field of DI research is relatively young, many gaps exist in the science . Some ofIn summary, a rich body of research knowledge is not moving into the hands of practitioners and policy makers as quickly and efficiently as needed. The DI approaches outlined here can begin to speed up this translation. In doing so, we will more effectively apply EBPH approaches that will use resources more efficiently, account for dollars spent, and increase impact. We encourage public health professionals — in their day-to-day work — to generate evidence that is relevant and describes how best to implement new evidence-based strategies, report on the reasons why those strategies worked, and track the effect of those strategies on implementation and population health.


Background: Shigella remains the primary cause of diarrhoea in paediatric patients worldwide and accounts for up to 40,000 deaths per year. Current guidelines for the treatment of shigellosis are based on data which are over a decade old. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for shigellosis in children is necessary, taking into account susceptibility patterns, cost and the risk of adverse events.Methods: A systematic review of the current published literature on the treatment of shigella dysentery was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).Results: The initial search produced 131 results, of which nine studies met the inclusion criteria. The quality of the studies was assessed as per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. International guidelines were also reviewed. There is a lack of current research regarding the clinical treatment of shigellosis in paediatric and adult patients, despite rising antimicrobial resistance worldwide. In particular, there is a lack of studies assessing the non-susceptibility of community-acquired strains, with almost all published research pertaining to microbiological data from hospital-based settings.Discussion: Current WHO guidelines support the use of fluoroquinolones (first-line), β-lactams (second-line) and cephalosporins (second-line) which accords with currently available evidence and other international guidelines, and there is no strong evidence for changing this guidance. Azithromycin is appropriate as a second-line therapy in regions where the rate of non-susceptibility of ciprofloxacin is known to be high, and research suggests that, from a cardiac point of view, azithromycin is safer than other macrolide antibiotics. Cefixime is also a reasonable alternative, although its use must be weighed against the risk of dissemination of extended-spectrum β-lactamase-producing organisms. S. dysenteriae, S. flexneri, S. boydii and S. sonnei  with multiple serotypes. Of the estimated 165 million shigella diarrhoeal episodes every year, 99% of cases occur in low- and middle-income countries (LMIC), mainly (69%) in children [Shigella is a Gram-negative, non-motile bacillus belonging to the enterobacteriacae family of which four species exist: children .S. boydii and S. sonnei usually cause a relatively mild illness (watery or bloody diarrhoea only), S. flexneri and S. dysenteriae are chiefly responsible for endemic and epidemic shigellosis, respectively, in developing countries, with high transmission rates and significant case fatality. S. dysenteriae  is capable of causing a more severe and prolonged illness owing to the production of a potent cytotoxin (Shiga) which is associated with the development of haemolytic-uraemic syndrome [Because of overcrowding and poor sanitation, shigellosis occurs predominantly in LMIC. Infants, non-breast fed or malnourished children and adults >50 years have a more severe illness and a greater risk of death . Acquiresyndrome .S. sonnei is the predominant species worldwide, S. flexneri is more prominent in low-income settings in Africa and Asia [S. sonnei predominates in higher-income settings [The species distribution of shigella infection varies globally. While and Asia  while thsettings . Transmisettings . Once inThe resultant infectious diarrhoea causes a loss of water and electrolytes with a clinical picture of abdominal cramping, fever, and bloody/mucoid stools. Stool microscopy – a cheap, rapid and simple diagnostic test – demonstrates numerous polymorphonuclear cells on methylene blue stain; however, microbiological culture is required to differentiate between shigella and other causes of colitis . MultiplWith effective antibiotic therapy, clinical improvement occurs within 48 h, resulting in a decreased risk of serious complications and death, shorter duration of symptoms, and the elimination of shigella from the stool. This results in diminished transmission of infection by decreasing the duration of faecal carriage from approximately 4 weeks to 3 days, conferring significant public health benefits . CurrentCurrent guidelines are therefore based on evidence which is increasingly outdated. In view of changing patterns of resistance to antimicrobials worldwide, this systematic review was undertaken to evaluate the current international literature on the treatment of shigellosis in children.A systematic search for systematic reviews, meta-analyses, multi-centre studies and randomised controlled trials of antibiotic therapy was undertaken using the MeSH search terms ‘Shigella’, ‘dysentery’, ‘antibiotics’ and ‘antimicrobials’. The databases EMBASE, Cochrane database of systematic review and Pubmed were searched. To ensure accurate and up-to-date information on antimicrobial non-susceptibility patterns, the search was limited to trials in humans published since 2005. Inclusion and exclusion criteria are listed in Table Initially, the search was restricted to studies in the paediatric population but published research in this age group was limited and the search was, therefore, expanded to include all ages. International clinical practice guidelines were also reviewed, including the Infectious Diseases Society of America (IDSA), BMJ Clinical Evidence, the American Academy of Pediatrics and Therapeutic Guidelines .The initial search produced 131 results . One, a multi-centre study, evaluated 600,000 cases of shigella diarrhoea in six Asian countries. Two papers were based on data collated from a multi-centre randomised trial in Vietnam.Four papers were classified as high-quality evidence, three as moderate-quality evidence and the two papers based on data investigating a multi-centre trial in Vietnam were classified as low-quality evidence.Two systematic reviews exclusively assessed paediatric antimicrobial response, while the remainder included adults and children in their population. The papers based on a multi-centre trial in Vietnam investigated clinical outcomes in children < 16 years.A systematic review in 2013  used CHEAnother systematic review in 2010  assessedvs 3.6% in adults (95% CI 2.2–5.3%).A third systematic review  assessedThe same authors conducted a review which compared resistance to third-generation cephalosporins  between 1999 and 2012 : it founS. flexneri isolates in China , Pakistan  and Vietnam  [Assessing the Asia region independently, a 2006 multi-centre study (of 2927 shigella isolates in children and adults) in Bangladesh, China, Pakistan, Indonesia, Thailand and Vietnam documented ciprofloxacin-resistant In view of the research above documenting increasing resistance to ciprofloxacin and ceftriaxone, the international literature was reviewed for alternative antimicrobials that might be used for shigella dysentery. Previously effective agents  have been removed from the WHO guidelines on dysentery because of extensive resistance, a decision which continues to be supported in view of the evidence above.A 2010 Cochrane review [in vitro gentamicin resistance in the Asia–Africa region which reached 32.4% (95% CI 17.87–48.91%) in 2005–2007. Resistance to gentamicin, kanamycin and amikacin was higher in children than in adults. The 2010 Cochrane review outlined above further supported the ineffectiveness of aminoglycosides which tend to have poor absorption when administered orally, further limiting their usefulness.A 2013 systematic review  which asvs ciprofloxacin for shigellosis in Vietnamese children between 2006 and 2008 [vs 11% for ciprofloxacin, p = 0.72), with gatifloxacin showing similar efficacy in the treatment of paediatric dysentery [Gatifloxacin, a fourth-generation fluoroquinolone, was investigated as an alternative therapy in a multi-centre randomised trial assessing the efficacy of gatifloxacin and 2008 . No supeysentery .vs ciprofloxacin in children have been published. In the late 1990s, azithromycin was found to be as effective as ciprofloxacin in adults in Kenya and Bangladesh [S. flexneri and all were reported to be sensitive in vitro to ciprofloxacin, nalidixic acid and cefuroxime, while 98% were sensitive to azithromycin. By 2010/2011 in Dhaka, Bangladesh, in vitro susceptibilities to ciprofloxacin, pevmecillinam, azithromycin and ceftriaxone were 65, 50, 74 and 95%, respectively [Azithromycin, a macrolide antibiotic, is listed as an alternative second-line therapy for adults in current WHO guidelines as well as in most international guidelines (for both paediatric and adult patients). To date, no trials comparing the efficacy of azithromycin ngladesh . In Tanzectively .Cefixime is an oral third-generation cephalosporin which inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs), inhibiting cell wall synthesis. It is widely distributed throughout the body and reaches therapeutic concentration levels in most tissues and body fluids, with a time to peak serum concentration of 2–6 h and a half-life of 3–4 h . CefiximNo other antimicrobial agents were investigated in the research which met this review’s inclusion criteria.Four evidence-based international guidelines were reviewed (listed in order of most recently updated): the Infectious Diseases Society of America (IDSA) , TherapeOf note, comparison of international guidelines reveals differing dosage ranges for ciprofloxacin, from 12.5 mg/kg  to 20 mgA 2010 systematic review of 1748 paediatric and adult patients [torsades de pointes (TdP), a potentially fatal polymorphic ventricular tachyarrhythmia which may present as sudden death (owing to ventricular tachycardia), syncope, palpitations, seizures or asymptomatically if the duration is short and it terminates spontaneously [Previous case reports of fluoroquinolones and macrolides have been associated with prolongation of the QT interval . Indepenaneously . Of noteaneously .Existing evidence suggests that the individual risk of cardiac arrhythmias secondary to these antimicrobials is minimal; yet, when combined with a genetic propensity to poor metabolism of CYP3A4-inducing medications and co-administration with other CYP potentiators, the risk may be magnified. How this might affect clinical practice, however, remains unclear. Another important risk factor to consider is the possibility of acute renal failure in the setting of severe dehydration secondary to shigellosis which could result in decreased clearance and enhanced toxic effects, increasing prolongation of the QT interval in a clinical setting.p < 0.0001) as well as of death from any cause . However, the risk was found to be most pronounced in patients with a high baseline risk of cardiovascular disease, and there was evidence of confounding by factors associated with both azithromycin use and risk of cardiovascular disease – namely a history of smoking, high body mass index, poor diet and low physical activity. At present, published case reports of an increased risk of sudden cardiac deaths in patients taking azithromycin are limited to adults [As discussed, the predominantly reported risk of macrolide-associated TdP is the co-administration of other CYP3A4 inhibitors, resulting in increased drug toxicity. However, azithromycin has been identified as distinguishable from other macrolides as a group in terms of its cardiac toxicity as it minimally inhibits CYP3A4, resulting in a lack of appreciable interaction with other CYP3A4 substrates, and is classified as one of the safer macrolide antibiotics from a cardiac perspective . In receo adults .As with macrolides, there is interclass variability in the QT prolongation effect of fluoroquinolones. Ciprofloxacin’s inhibition of CYP1A2 has been described as ‘relatively inconsequential’  and the In 2013, the FDA issued a communiqué to specifically address the risk of peripheral neuropathy (PN) for all oral fluoroquinolones , mainly Co-administration of macrolides or quinolones with other QT-prolonging agents could present a clinical problem, yet nearly all data examining the risk are for adults (often with pre-existing cardiac risks), and genetic differences between populations may limit interpretation. Azithromycin is a weak antimalarial that has been used in combination with several other anti-malarials or co-administered to treat non-malarial infections. Current evidence evaluating the cardiac risk of azithromycin co-adminsitered with chloroquine , artesunS. sonnei and S. boydii strains containing a single class 2 integron, while S. flexneri and S. dysenteriae carry a class 1 integron, often in combination with a class 2 integron which increases the propensity of dissemination of MDR strains of shigella) [Evidence suggests that antibiotic resistance is an increasing challenge in the therapeutic management of shigellosis, as recognised by the WHO prioritising ciprofloxacin-resistant shigella as a target of current international focus on antimicrobial resistance . There ahigella) . This unS. sonnei isolates in the USA, Vietnam and elsewhere [The primary target of fluoroquinolones is the DNA gyrase, a type II topoisomerase essential for DNA replication and transcription. Mutations in the gyrA gene have been shown to increase the MICs of fluoroquinolones for shigella spp. and other enterobacteriaceae, while plasmid-mediated quinolone resistance genes can also be acquired . Of conclsewhere , and patlsewhere . CiproflCephalosporin resistance is also of concern, arising from the production of plasmid-mediated β-lactamase . ResistaShigella, a Gram-negative enterobacteriaceae, is responsible for 165 million diarrhoeal episodes each year, 99% of which occur in LMIC, and 69% in the paediatric population. With effective antibiotic therapy, there is clinical improvement within 48 h, diminishing the risk of mortality and decreasing transmission by eliminating shigella from the stool. The WHO 2005 Guidelines for the Control of Shigellosis, Including Epidemics due to Shigella Dysenteriae Type 1 listed the fluoroquinolone ciprofloxacin  as first-line treatment for shigellosis in children, and (more expensive and less available) pivmecillinam (amdinocillin pivoxil) and  ceftriaxone were listed as second-line therapy when local strains were known to be resistant to ciprofloxacin. The macrolide azithromycin was listed as a second-line therapy for adults.in vitro studies which do not necessarily correspond with clinical outcomes, and studies of clinical efficacy do not evaluate individual drugs.There is a lack of current research on the clinical treatment of shigellosis in paediatric or adult patients, despite rising antimicrobial non-susceptibility rates worldwide. In particular, there is a lack of research assessing the non-susceptibility of community-acquired strains; almost all published research pertains to microbiological data from hospital-based settings. Research investigating non-susceptibility of community-acquired shigellosis is urgently required. A large proportion of the current evidence is based on in vitro susceptibility; however, reports of azithromycin-resistant strains are increasing. In areas where ciprofloxacin-resistance is evident, azithromycin is an appropriate second-line alternative therapy owing to its oral administration and affordability. Safety concerns (the risk of polyneuropathy in ciprofloxacin use and prolonged QT syndrome secondary to azithromycin) are based mainly on retrospective studies in adults and results cannot necessarily be extrapolated to the paediatric population, although care should be taken when co-administering with other CYP450 inducing medications.A number of international guidelines currently list azithromycin as a first- and second-line therapy for shigellosis in children. While there are no published trials comparing the efficacy of azithromycin with that of ciprofloxacin for shigellosis in children, previous trials in adults have demonstrated similar efficacy and higher in vitro non-susceptibility studies need to be correlated with clinical outcomes. Further randomised controlled trials adhering to CONSORT guidelines are required to guide future treatment options for shigellosis, especially in populations at risk of high case fatality . The efficacy of oral cephalosporins (cefixime) for shigellosis should be a priority for research as it is affordable and easily administered compared with (the currently recommended) parenteral ceftriaxone. Specifically, a large randomised controlled trial in children in the Asia–Africa region should compare the efficacy of ciprofloxacin, azithromycin and cefixime as the first-line treatment of shigellosis in children, including the assessment of MICs in relation to treatment outcomes and addressing the risks of exacerbating resistance in other intestinal bacteria, especially ESBL-producing enterobacteriaceae.Prior research has investigated the antibiotics currently recommended by WHO together rather than assessing individual therapies. Research investigating non-susceptibility of ahigellosis – particularly community-acquired strains – is urgently required, and In conclusion, current WHO guidelines supporting the use of fluoroquinolones (first-line), β-lactams (second-line) and cephalosporins (second-line) accord with currently available evidence and other international guidelines, and there is no strong evidence to change this guidance. Azithromycin may be considered as an appropriate second-line therapy in regions with known high rates of ciprofloxacin non-susceptibility. Cefixime is also a reasonable alternative, although its use must be balanced against the risk of increasing antimicrobial resistance and the spread of ESBL.Phoebe C. M. Williams, MBBS (Hons.), received her medical degree from The University of Sydney and a Masters in Global Health Science from The University of Oxford. She is a paediatric registrar and dual trainee in Infectious Diseases at Sydney Children’s Hospital, Australia. She is a DPhil candidate through The University of Oxford, with her research focusing on antimicrobial resistance in paediatric patients.James A. Berkley FRCPCH, MD is a professor of Paediatric Infectious Diseases at The University of Oxford based at the KEMRI-Welcome Trust Research Programme in Kilifi, Kenya. He is the principal investigator of the CHAIN network with a research focus on serious infection and survival in highly vulnerable groups of infants and children.This work was supported by The World Health Organization, The Nuffield Department of Medicine (University of Oxford), The General Sir John Monash Foundation, The Wellcome Trust and the Bill and Melinda Gates Foundation.No potential conflict of interest was reported by the authors.


The field of eating disorders has notable problems of definition. For this year’s Editorial we were stimulated to focus on this because it is both the year of pre-release of the 11th Edition of the International Classification of Diseases (ICD-11)  or more Despite lack of definitional clarity, people with unremitting anorexia nervosa have very poor outcomes , 6 and t2) which are cross-sectional [Clear definitions are very important. They are the reason the DSM-III in 1980 was universally popular to the point that copies had to be chained to desks to prevent their theft by students in the hospitals where we (PH and ST) then worked. The understanding of aetiology, prognosis and the relationships between disorders rests on precise diagnosis, and valid and reliable diagnostic systems are necessary for meaningful communication between clinicians and researchers . Let’s eectional . Howeverectional . Second,ectional . The numectional . In sum,As a trainee psychiatrist I (PH) recall a common question in our examinations was “The specialist approach to assessment of a person with treatment resistant disorder X”. The answer always began with first, review the diagnostic formulation. Only after establishing that that the formulation is accurate, and the person has been offered and received all appropriate first line evidence based therapy is the term “treatment resistant” to be applied. Then the specialist will discuss second and third line therapies, including those often with higher risk, e.g., clozapine for schizophrenia or irreversible monoamine oxidase inhibitors for major depression. Finally, the “do no harm” or “comfort always” time honoured approach of clinical medicine – supportive care – may be offered.However, we are reluctant to use the term “treatment resistant” in our field. It is perceived understandably as pejorative and blaming of the individual and those who care for them. It may seem to imply that as we have evidence based therapies, it’s the person’s fault if they “drop out”, do not engage or otherwise are unresponsive. On the other hand, they may have not engaged because of poor health literacy on the part of the health care practitioner  who has Finally, it must be acknowledged that categorical systems are problematic in mental health where clinical features are often dimensional and boundaries are by necessity somewhat arbitrarily imposed. In consequence, diagnostic schemes such as the ICD-11  and may The criteria we propose are based on (1) clinically significant functional impact i.e. impoverished and poor quality of life, with unrelenting symptoms, i.e. sustained dietary restriction leading to a persistent underweight state with weight/shape overvaluation and other eating disorder cognitions (2) duration of several years (minimum three) of anorexia nervosa, and (3) exposure to at least two evidence based treatments delivered by an appropriate clinician or treatment facility together with a diagnostic assessment and formulation that incorporates an assessment of the person’s eating disorder health literacy with an assessment of the person’s stage of change.In conclusion, the Journal of Eating Disorders encourages submissions on any aspect of improving and testing current classifications and definitions in any domain relevant to the field, and including the neurosciences, in the spirit of the Research Domain Criteria approach . We look


In his recent review for the Journal of Cardiovascular Development and Disease, Cirillo offers a concept for “cardiac memory” based on the notion that the ventricular cone can be unwrapped to show a myocardial band extending from the pulmonary to the aortic root. The concept of the myocardial band was itself developed by Torrent Guasp, and has subsequently been championed by Buckberg. Neither Torrent Guasp, when formulating his initial concept, nor Buckberg in his subsequent endorsements, have validated the results of dissection using histological or other techniques that would reveal the boundaries of the alleged band. In contrast, there is a wealth of evidence showing that such boundaries do not exist and that the cardiomyocytes are packed together within the walls of the ventricular cone in the form of a three-dimensional mesh. The evidence demonstrating the manner of packing of the cardiomyocytes within the ventricular walls was summarised in another recent review published in the journal. It is disappointing that Cirillo chose to ignore the wealth of evidence disproving the concept on which he bases his entire review. Only by recognising the existence of this evidence can we truly understand ventricular function correctly, as envisaged by Cirillo. When summing up, in his recent review , the memIn his acknowledgements, Cirillo comments “We cannot fail to be grateful to all the scientists, cited and not cited, who have worked for centuries on the structure and function of the heart”. It is, however, those who have not been cited who have provided evidence, as opposed to speculation, “to understand it correctly”. It is particularly disturbing that Cirillo should conclude that Pettigrew  providedAs we emphasised in our review, there are multiple anatomic investigations, carried out by means of dissection, histology, and more recently by techniques such as computed tomography and diffusion tensor magnetic resonance imaging, which confirm the opinion of Streeter that the ventricular walls are arranged in the form of a three-dimensional myocardial mesh. Cirillo himself comments on the value of the newer techniques, arguing that “Thanks to the more widespread use of these two techniques, an increasing number of literature dealt with the study of cardiac layers structure and function in normal and diseased heart.” He fails to appreciate, again as emphasized in our own review,  that theIt is also disturbing that Cirillo begins his review by suggesting that cardiac looping provides the basis for the subsequent formation of the alleged band. As was shown by the recent study of Captur and colleagues, formation of the compact components of the ventricular walls is a late event during cardiac development.  As yet, When considering ventricular mural architecture, as Cirillo summarized, we need “to understand it correctly”. This must surely be achieved when the understanding is based on evidence as opposed to speculation. Such evidence is singularly lacking from the extensive review of Cirillo. In producing his review, it is would have been difficult for him to avoid the numerous publications demonstrating, on the base of anatomic evidence, that the ventricular cone is not arranged in the fashion proposed by Torrent Guasp. In addition to the review published in this journal , my coll


Neck pain (NP) is a very common musculoskeletal condition with potential for a high burden in disability and length of disorder. Clinical practice guidelines (CPG) give recommendations to clinicians for providing optimal care for patients however best practice recommendations are often contradictory. The purpose for this review was to conduct a SR of CPGs to assess the management recommendations for NP .Standard SR methodology was employed including a grey literature search . Medline, Cinahl, Embase, ILC, Cochrane, Central, and Lilacs were searched from 1995-to March 2018. Two raters evaluated all citations and a third rater resolved any disagreements. The AGREE II was used to assess risk of bias of each CPG. Data was extracted and included CPG purpose, type of NP problem and clinical recommendations. The AGREE II critical appraisal tool was used to assess risk of bias of each CPG.From 640 articles, 241 were available for screening. A total of 46 guidelines were selected. CPG’s were categorized by the NP population  and type of clinical aim . Each clinical NP population had a large overlap of clinical aims presented. The CPGs were directed to a variety of clinicians that included physicians, physiotherapists and chiropractors. Results suggest heterogeneity in CPG recommendations within each clinical aim. CPG characteristics accounting for these differences are outlined.The majority of CPGs were developed for general NP that focused on treatment recommendations, with fewer number aimed at recommendations for diagnosis, prognosis, and outcomes. Heterogeneity of recommendations within the categories were noted as were potential factors associated with these differences, including CPG quality as assessed by the AGREE II.The online version of this article (10.1186/s12891-019-2441-3) contains supplementary material, which is available to authorized users. Neck pain (NP) is the most common musculoskeletal pathology second only to low back pain . It is tIn efforts to decrease the amount of practice variation for NP, many guidelines have been developed to improve efficiency and effectiveness. Clinical practice guidelines (CPGs) are defined by the Institute of Medicine as “recommendations that intend to optimize patient care that are informed by systematic review (SR) of the evidence with an assessment of harms and benefits of alternative care options” . They arTo date, no previous research has systematically summarized and appraised all relevant CPG’s for the management of NP. The purpose of this SR was not only to summarize the existing evidence regarding all CPGs regarding NP but also to provide a “panoramic view” of the CPG literature with an appraisal of the methodological quality. In the context of NP, an SR is ideal to provide the evaluation of the evidence from many different clinical settings, professions that treat NP and different countries where guidelines are developed. NP’s widespread frequency and reoccurrence can cause differentiating levels of pain and disability, highlighting the need for a global summary of findings.This SR was an update of an existing review that was updated for CPG’s only . A searcCPG’s focusing on any form of management of neck pain were eligible. CPGs are defined as systematically developed statements to assist practitioners and patient decisions for specific clinical circumstance; they can be developed by local, regional, national or international groups or affiliated governmental organizations . ConsensCitations identified within the search were uploaded into a SR software (DistillerSR) and screening using a standardized form for eligibility. SR and CPGs were eligible but narrative reviews, commentaries, editorials were excluded. Two independent raters screened the articles at titles and abstract and full text with conflicts resolved between the screeners. If the screeners were unable to resolve conflicts, a senior investigator made the final decision for eligibility.The following criteria were used to include CPGs: 1) All CPGs that included recommendations 2) English language; 3) Diagnosis of non-malignant NP that included adult (> 18 years of age) populations; 4) NP defined as pain from the occiput to upper thoracic spine  and can include upper regions of the torso or shoulder area; 5) General musculoskeletal or chronic pain guidelines that could potentially include NP populations; Articles were excluded if they met the following criteria: 1) narrative reviews or articles that only contain consensus statements or algorithms; 2) included children (< 18 years of age); 3) trauma associated with fracture or head injury; 4) definite or possible long tract neurological signs (i.e. myelopathies); 5) NP caused by other pathological entities ; 6) headache not of cervical origin but associated with the neck (i.e. migraine headache).Appraisal of the eligible guidelines was conducted using the Appraisal of Guidelines for Research and Evaluation version II (AGREE II). It is the most commonly used guideline appraisal tool  that incTwo to four independent researchers appraised all included guidelines. Each investigator was trained using the web tutorials provided on the AGREEPLUS website in addition to individual one on one sessions with a senior researcher. Discussions were held between the investigators with regards to overall guideline quality. Final grading was determined using the AGREE II scoring system for each domain as a %. The overall guideline quality scores were based out of 7 with recommendations for use in practice had three options .One researcher extracted guideline data and a second checked the data. Extracted elements were organized in tabular format and included demographic information , aim of CPG recommendations  and specific recommendations grouped according to the CPG intent of diagnosis, prognosis, interventions and imaging.Recommendations from each of the guidelines were organized via tables to facilitate comparison between them based upon their intention. They were divided into those that 1) recommended specific course of action 2) recommended against a specific course of action 3) did not note any course of action  4) explicitly noted that there was no evidence to support of refute the recommendation.Our search yielded 3082 citations from our databases and 20 from other grey literature sources for a total of 3102  and in contrast physiotherapists and chiropractors were the primary leads in CPG’s for the whiplash, NP and headache guidelines (N = 28).The majority of guidelines originated from Australia, Canada, United States and the UK 93%) . Guidelines scored poorly in domain-5 (applicability), domain-6  and domain-3 (rigor of development). With the exception of five, guidelines did not adequately describe facilitators and barriers to their application, give recommendations on how to be put into practice and outline the potential resource implications of applying the recommendations given [The overall quality of the included guidelines varied greatly  headache. Sandirini  recommenTwo guidelines outlined intervention for cervicogenic headache , 62. BryTwo CPG’s outlined imaging guidelines for headaches , 30  , 35, 70 Four out of five of the guidelines main objectives were for early diagnosis and presentation of Cervical Arterial Dysfunction , 34, 35.None of the guidelines detailed prognostic factor associated with poor prognosis. Rather, risk factors were outlined for Cervical Arterial Dysfunction. Rushton  indicateHarrigan  was the Harrigan  recommenThis review of 46 CPG’s found substantial limitations in AGREE II scores pertaining to mechanical NP. In addition, significant heterogeneity was presented in regard to their recommendations. Previous reviews for NP guidelines have concluded that guidelines were overall poor quality and lacked methodological consistency , 8. Our It was surprising to note the significant heterogeneity that was found for the definitions of NP, whiplash and headache in terms of both durations (acuity) and severity of classification. Due to the lack of appropriate classification standards regarding neck pain the interpretation of their findings as a group must be taken with caution. Although many standardized definitions do exist for diagnosis  many guidelines have not interpreted and collected evidence based upon these differing definitions. This could also be a reason for the large amount of heterogeneity found in the recommendations for diagnosis, prognostic factors, interventions and imaging. In addition, guidelines failed to identify subgroups likely to benefit from interventions. Newer guidelines were better than older ones however no standardized subgrouping method was presented. Finally, few guidelines mentioned dosing of interventions. Dosing is key component to understanding the effectiveness of interventions and should be included for future research of neck pain trials .Overall, many of the recommendations for interventions have not changed over time for each of the difference NP disorders considered. Active exercise, manipulation and mobilization are recommended by almost every guideline as the main treatment for NP. Throughout the years the number of trials related to NP have increased and the evidence base has grown substantially. However, no overall changes in recommendations have been observed. The interventional guidelines have also followed this trend. If anything, some recommendations have been weakened with the emergence of evidence showing lacking efficacy among treatment modalities, such as was the case with implantable intrathecal infusion systems.When grading the evidence throughout the publications, many had few “grade A” recommendations and used low quality evidence and consensus to determine their recommendations. Although the amount of evidence may have increased it appears the quality of these that the guidelines are based upon has not.While many guidelines intertwine recommendations for NP with other areas of pain (such as the lower back), it may be difficult and time-consuming for clinicians to extract the relevant information that could be implemented in their own practice. This review resolves this by filtering the pertinent information from each guideline and summarizing key similarities and differences in simple charts. Furthermore, a clinician who independently reads one of the guidelines included in this systematic review would not have a basis of comparison with regards to methodology and compilation of evidence, facing the risk of blindly accepting recommendations without having assessment of quality. This review provided a detailed assessment and comparison for clinicians that are based upon explicit and transparent observations between all available literatures. The use of the widely recognized AGREE II instrument not only provides an objective way of evaluating the quality of guidelines, but also standardizes the assigned scores. Ideally, anyone can view each domain’s criteria and know precisely why the guideline in question received the score that it did. Also, guidelines were reviewed by at least two and up to four investigators, reducing potential deviations due to personal subjectivity. Most guidelines were scored very similarly between investigators, suggesting high inter-rater reliability.It is evident that the classification of NP varied greatly by guideline  obtained the views of patients when developing recommendations , 54, 56.Most clinical guidelines included within this review did not identify or discuss factors that may facilitate or create barriers for their dissemination and adoption nor have authors given recommendations on how to implement them into clinical practice. These guidelines have translated complex evidence into pragmatic recommendations that are simplified to enhance practice patterns or to be so generic in format that the clinician has no clear direction. In our judgement the majority of guideline developers did not seem to explicitly state how their recommendations would be translated into policy or practice even though these were likely discussed and considered during the development process. This may reflect either a lack of knowledge on how to promote adaptation and implementation or that they felt this was beyond the scope of the guideline developmental process. Determinants are factors that obstruct or enable changes in target professional behaviours or the healthcare delivery process . IncreasAlthough many clinical trials are conducted yearly pertaining to mechanical NP, the recommended treatments have not changed much in the past decade. This raises doubts about continuous resource allocation to the testing of the same treatment modalities, when the outcomes are reinforcing the same doubt that guidelines have on the efficacy of many of these treatments.Most guidelines related to mechanical NP are of poor quality as assessed by the AGREE II but those published from 2012 are rated of higher quality in all domains. Despite an increase in the evidence base, treatment recommendations have not changed significantly over time in their recommendations for interventions used to manage NP.Additional file 1:Appendix A Search terms used within MEDLINE and all search engines for all areas in the overview of reviews across different clinical areas for the management of NP (DOCX 50 kb)Additional file 2:Appendix B PRISMA Flow diagram (DOCX 68 kb)Additional file 3:Appendix C Demographics table for all guidelines reviewed (DOCX 17 kb)Additional file 4:Appendix D Combined table for all AGREE scores for all guidelines reviewed (DOCX 21 kb)Additional file 5:Appendix E Combined table for diagnostic recommendations  for general neck pain and whiplash guidelines. (DOCX 17 kb)Additional file 6:Appendix F Combined table for prognostics factors for general neck pain and whiplash guidelines (DOCX 20 kb)Additional file 7:Appendix G Combined table for psychological prognostic factors for neck pain and whiplash guidelines (DOCX 19 kb)Additional file 8:Appendix H Combined table for interventional/treatment recommendations for general neck pain and whiplash guidelines (DOCX 30 kb)Additional file 9:Appendix I Imaging. Combined table for imaging recommendations for all guidelines (DOCX 17 kb)Additional file 10:Appendix J Combined table for diagnostic recommendations among interventional focused guidelines (DOCX 14 kb)Additional file 11:Appendix K Combined table for all invasive techniques recommended by interventional and non-interventional focused guidelines (DOCX 20 kb)Additional file 12:Appendix L Combined table for VAI risk factors and testing procedures (DOCX 14 kb)


The application of cranial osteopathic manipulative medicine (OMM) is always controversial in the literature. Primary respiration related to the movement of spheno-basilar synchondrosis in the adult goes against the knowledge of complete ossification that occurs at this articulation after the pubertal phase. The idea that the operator's hands can communicate with the meninges is difficult to accept. The anatomy shows us that the fascial system involves the meninges and that from the microcellular point of view there are no layers that divide one tissue from another. The backing of new sciences, such as quantum physics, suggest that cranial palpation allows the osteopath to come into contact with the meninges. Recent scientific evidence shows that meningeal afferents can affect extracranial areas and that the pericranial musculature itself is able to influence these afferents. The article highlights some reflections in support of cranial osteopathy, based on scientific information that could help the osteopath to improve clinical work. In the scientific landscape, the approach with the cranial osteopathic manipulative medicine (OMM) is much debated . At presMetanalytic reviews forget which are the foundations of evidence-based medicine, that is, the fusion of the operator's clinical experience, the patient's experience and experimental research: "External clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether external evidence applies to individual patients at all, if, how it should be integrated into a clinical decision" . The synThe sutures consist of extracellular matrix, proteoglycans, collagen fibres and water; the synarthrosis with interdigitations, for example, the occipitoparietal, have a modulus of elasticity and absorption of mechanical stresses are greater Figure  4]..4].The sutures play different mechanical roles, including cushioning the extracranial tensions towards the skull and those intracranial towards the outside, thanks to the presence of cranial meninges . We knowTo give an example of the myofascial presence above the bone tissue of the skull, the occipitofrontalis muscle has a very large tendinous arch below the galea capitis, which connects the muscular occipital body with the frontal one . This muThe cranial osteopathic manipulative medicine is not always positively shared by the scientific world, but it cannot even be rejected by scholars and scientists since non-knowledge does not preclude the end of knowledge. The article discussed an orientation of the current literature that goes against the scientific nature of the osteopathic manipulative medicine (OMM), showing, however, that there are further reflections that are able to be made in support of osteopathic cranial therapy.References