Knowledge translation processes are necessary for improving patients' and communities' health outcomes. The aim of this study was to systematically develop evidence-based recommendations for people over 16 years of age who are in risk for or have suffered a lower limb amputation for medical reasons  or trauma (civilian or military trauma) in order to improve function, quality of life, decrease complications and morbidity.Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach we developed a Clinical Practice Guideline (CPG) for lower limb amputees with funding from the Ministry of Health in Colombia and participation of a multidisciplinary group. We included patients' preferences. Based on the scope, purposes and objectives the questions were elaborated with the PECOT strategy. The evidence search was performed for each question in the main databases: Cochrane Library, Embase and PubMed, without time limit or language restriction. Teams were formed with thematic experts and clinical epidemiologists to review the clinical studies, describe the evidence, and evaluate the quality of the body of evidence with the GRADE methodology. The recommendations were made according to the judgments proposed by the GRADE working group. We conducted a stakeholder's dialogue as a mechanism for the external validation of the guideline implementation.The CPG included 43 recommendations related to the diagnosis, surgical treatment, rehabilitation, prescription and adaptation of the prosthesis. They were strong in favor 37.2, weak in favor 53.5, strong against 2.3, Weak against 7.0%. Quality of evidence was high in 0, moderate in 11.6, low in 58.1, and very low 30.2%.In 93% of the recommendations, the quality of the evidence was between low and very low. This is why it was so important to validate and discuss each recommendation with an expanded multidisciplinary group. The research group identified 25 interventions and five milestones to be prioritized in the implementation and in the stakeholder's dialogue participants identified opportunities and barriers for implementation of recommendations.It is necessary to develop a national policy for implementation strategies of CPG recommendations that promotes the necessary arrangements for the provision of services for diagnosis, treatment, and rehabilitation of individuals with amputations. Evidence-based clinical practice guidelines (CPG) are a fundamental tool for reforming medical care and strengthening health systems to achieve better health outcomes for patients and their communities , 2. HoweIn 2008, the Colombian Ministry of Health and Social Protection (MoH), financed the development of the methodological guideline for the development of evidence-based CPG in Colombia, this guideline was updated in the year 2014 . BetweenIn 2013, through a call of the Administrative Department of Science, Technology and Innovation (nowadays Minciencias) and financed by the MoH, we developed the “Clinical Practice Guideline for diagnosis and preoperative, intraoperative and postoperative treatment of the amputee, the prescription of the prosthesis and comprehensive rehabilitation” . An inteOne of the most consistent findings of clinical and health services research is the challenge to translate research evidence into practice . This haThe US National Center for Dissemination Research on Disability defines knowledge transfer as “The collaborative and systematic review, evaluation, identification, aggregation, and practical application of high-quality research on disability and rehabilitation by key stakeholders, in order to improve the lives of people with disabilities” . This deThe aim of this study was to systematically develop evidence-based recommendations for people over 16 years of age who are in risk for or have suffered a lower limb amputation for medical reasons  or trauma (civilian or military trauma) in order to improve function, quality of life, decrease complications and morbidity.National Institute for Health and Clinical Excellence (NICE) and the New Zealand Guidelines Group. The users of the CPG are all the professionals who were involved in the development: surgeons, physiatrists, other professionals in the area of rehabilitation, insurers, health providers and political decision makers.The main guideline developer group consisted of 14 people, including physicians, physiatrists, orthopedists, vascular surgeons, experts in prosthetics, psychiatrists, physiotherapists, occupational therapists, clinical epidemiologists, public health doctors, economists, a documentary librarian, and undergraduate and postgraduate students. A group of professionals from different universities and scientific societies validated the different stages of the process. A focus group of 24 people with amputations of different causes and their relatives were linked to the process in two moments, when the questions were chosen and at the end of the recommendations. The developer group received a training process with different international centers as the McMaster University, the All the professionals who participated in the development made a declaration of interests at the beginning and each year. These are published as supplementary files within the CPG document .The financing entity was the Ministry of Health and Social Protection, none of the people from this entity participated in the group developing the CPG. The Ministry carried out permanent monitoring to guarantee compliance with the methodology and schedules.CPG for lower limb amputees were searched for, and an evaluation of quality was made with the AGREE II Instrument. Six CPG were evaluated independently by two professionals from the group. Only three with a score greater than 60 in the methodological domain were selected, which were used as information during development. .The development of the CPG followed the GRADE  methodology , 11. ForBased on the scope, purposes and objectives of the guideline, the questions were elaborated with the PECOT strategy . Then the developer group and the patients independently rated the importance of each outcome from 1 to 9, according to the GRADE classification . AccordiFor each question, a list of MeSH terms was prepared according to the population, the intervention and the comparison. The evidence search was performed in the main databases: Cochrane Library, Embase and PubMed, and in secondary databases such as Lilacs/Bireme, Current Controlled Trials, TripDatabase and Google Scholar. There was no language restriction. For the selection of the evidence, inclusion criteria were established with respect to the methodological design, the population and the minimum quality characteristics. Systematic reviews and meta-analyses (secondary or aggregative studies), which analyzed primary studies related to the question, were initially sought. Additionally, clinical trials and observational studies were identified.https://www.gradeworkinggroup.org/.The quality of the evidence was evaluated for systematic reviews and meta-analyses with the AMSTAR ; for diaSystematic reviews of clinical trials start with high quality (level 1), while reviews of observational studies start with low quality (level 4). The aspects that can lower the quality of a randomized controlled trial are: Risk of bias, inconsistency of the results, indirect evidence, imprecision of the results and publication bias. Observational studies, although they can lower quality with the aforementioned aspects, also they can increase it if they include some favorable methodological aspects. The three aspects that can increase the quality of are the presence of a large effect size ; evidence of a gradient dose-response relationship and the absence of residual bias or confounding factors –20.The quality of the evidence is related to the confidence that the true effect is close to the estimated effect. Four levels are defined: very low, low, moderate and high . Most ofFollowing the GRADE system, the elaboration of the recommendations does not only take into account the quality of the evidence, but also a series of aspects or judgments based on the following criteria: The priority of the problem, the magnitude of the desirable and undesirable effects, the certainty of the evidence, the values of the interested parties, the balance between desirable and undesirable effects, the resources required, the cost-effectiveness, equity, acceptability and feasibility. With these criteria, a summary table of judgments was created and the direction and strength of the recommendation were defined . The strFive economic evaluations were made during the development of the CPG to assess the cost-effectiveness of five of the interventions and help the guideline development group in the decision-making.In the development of a CPG, it is recommended including the perspective of the patients for the preparation of the recommendations. Thus, people with lower limb amputation were invited to define their priorities in three categories: complications, activities and prosthetic adaptation; using the GRADE methodology. In addition, their preferences of the treatment options in the recommendations with greater uncertainty and with low quality of evidence were evaluated.Between July and November 2014, people with amputation in two institutions that provide health services in two cities of the country were invited. The inclusion criteria were people from 18 to 65 years old, who had a major lower limb amputation of any level and cause and who could attend a meeting with the researchers. Children and upper limb amputees were excluded. A convenience sampling was used, with the people who responded to the call. The objectives of the CPG and their participation, the instruments that were applied and doubts were resolved were explained at the meeting. In the group of 20 patients studied in one of the cities, the preferences of the CPG questions in which there was greater uncertainty at the time of presentation of the evidence synthesis were also evaluated.One search strategy is presented as an example in Forty-three recommendations were made. Nine on the decision of amputation; five on preoperative interventions including: preoperative regional analgesia, cardiovascular reconditioning, psychological support, prophylactic antibiotics, and intraoperative tourniquet use; ten on amputation techniques; ten on the components of the prosthesis, feet, knees, sockets, liners, as well as orthoses for partial amputation and the adaptation of immediate postoperative prostheses. Nine for the post-prosthetic phase, including functioning scales to evaluate the use of prostheses; treatment for neuropathic and phantom limb pain; cardiopulmonary, physical and occupational rehabilitation; ergonomic adaptations and psychosocial interventions. Comprehensive rehabilitation compared to the usual care model was also evaluated and this was a strong recommendation in favor. The synthesis of the quality of the evidence and the strength of the recommendations can be seen in The distribution of the 43 recommendations, according to the quality of the evidence, was: high 0%, moderate 7.5%, low 57.5%, very low 35%. And according to the strength of the recommendations, their distribution was: Strongly in favor 37.2%; weak in favor 53.48%; strong against 2.32%; weak against 6.97%. In updating the prioritized questions, a recommendation changed from Weak in favor to Strong in favor, leaving the distribution as follows: Strong in favor 58.3%, weak in favor 41.6%.As part of the participation of patients in the development of the CPG, they were invited to assess the importance of each outcome of the recommendations . PatientThe results of the first economic evaluation concluded that, after a careful selection of patients and intervention by a multidisciplinary team, limb reconstruction was a dominant strategy compared to primary amputation in the long term .In the second evaluation, the adaptation of an articulated foot was not a cost-effective strategy compared to a SACH foot, in patients with a low level of activity .In the third, in a sample of 113 patients analyzed in a cross-sectional study, the total contact socket was a cost-effective strategy compared to a patellar-tendon-bearing (PTB) type . HoweverIn the fourth economic evaluation, Pregabalin was found to be the strategy with the greatest net benefit, so it can be considered first-line treatment of phantom pain or residual pain in lower limb patients with amputation . GabapenIn the fifth economic evaluation on the cost-effectiveness of prophylactic antibiotics, it was found that this is a dominant strategy and it is unlikely that the uncertainty surrounding the costs and benefits changes the results, the use of this intervention is recommended in Colombia .As a final result of the CPG, the implementation process was described based on planning, implementation activities, monitoring and evaluation. Structure, process and outcome indicators were defined. Structure indicators were the availability of surgical and rehabilitation services. Process indicators were the proportion of patients with prostheses and in a rehabilitation program, according to the recommendations of the guidelines. Outcome indicators were the proportion of patients with reamputation, the proportion of patients adapted to prosthesis, and the proportion of professionals who follow the recommendations of the CPG.This article described the methods and results of the elaboration of an evidence-based CPG for the care of people with lower limb amputations.The elaboration of the CPG started with the formation of a multidisciplinary group that received training in methods form international and national universities and centers. The guideline included 43 recommendations, where nine were about the amputation decision and the level of amputation; five on preoperative interventions; 10 on amputation techniques; 10 on prosthetic components and nine on post-prosthetic rehabilitation. In 93% of the recommendations, the quality of the evidence was between low and very low. This is why it was so important, on a permanent basis, to validate and discuss each recommendation with an expanded multidisciplinary group with experience in treating lower-limb amputees. The socialization was carried out with different actors interested in the care of these patients.This CPG was evaluated by international experts using the AGREE II instrument, with a score of 94/100, and was recommended for its implementation in Colombia. During the development, other CPG were evaluated, in which the scope and purpose domain had scores between 65.3 and 98.6%; in the stakeholder involvement between 54.1 and 97.2%; in the rigor of development between 25.0 and 85.9%; in the domain of clarity of presentation between 62.5 and 95.8; in applicability between 18.8 and 93.8%; and in editorial independence between 14.1 and 7.9% . In addiAlthough there were three CPG that had a score >60 in the methodological domain of the AGREII rating –29, theyThe research group identified 25 interventions and five milestones to be prioritized in the implementation. The milestones included re-amputation, reinterventions due to infectious processes, prosthetic adaptation, return to work and independence in activities of daily living .We conducted a stakeholder's dialogue as a mechanism for the external validation of the Guideline implementation . Fifty-fInsurers must recognize their responsibility in the care, rehabilitation and risk management of their insured population. Extramural actions must be included that allow the decentralization of rehabilitation services.For the stakeholder participants it is important to have an information system for all personnel in charge, and to be able to measure the quality of care and the outcomes in patients. The referral and counter-referral process should be strengthened so that patients residing in rural and dispersed areas can access services in the main cities. In addition, implement a system in which patients are referred to centers where their needs can be effectively responded to. It is important for the country to involve these aspects in medical training and related professions, as well as continuing education for professionals involved in patient care, including evidence-based medicine and CPG training.Several facilitators must be involved to improve patient accessibility such as technological tools, telemedicine and tele-rehabilitation , 33. TheThe most important barriers and facilitators found in a qualitative study made by the research group and that were decisive for the implementation of the CPG for amputees included challenges related to the governance and financial arrangements of the Colombian health systems . For exaThe results of investments in research and training of health personnel to improve the quality of care are not being taken into account in health practice settings and many patients are not receiving the best possible care. This represents a gap between medical advances and clinical practice. Similar findings have been reported around the world in both developed and developing settings, in primary and specialty care .For health professionals in charge of caring for amputees, it is important to emphasize the need for patients to receive the most effective and safe interventions. Patients need to receive this intervention in time to reduce functional limitations and achieve occupational reintegration and social participation for amputees.Rehabilitation services must be comprehensive and available in a place that is close to patients to reduce the possibility of loss in the continuity of care. In the country, travel is paid for by patients and their families and this can be an even greater barrier if they must go to different places for their treatment. Comprehensive rehabilitation must involve mental health aspects to prepare amputees in the phase of acceptance and mourning for the loss of their limb and provide support in rehabilitation. Also, comprehensive rehabilitation must include physiatrist care, physical and occupational therapy, cardiopulmonary rehabilitation, psychology care and very importantly access to the prosthesis and its adaptation. All of the above will make possible for amputees to return to their usual occupation and integrate into society.Professionals must have the necessary training, time and incentives to achieve a change in professional practice.In Colombia, administrative procedures with insurers companies are lengthy and amputee patients must take multiple steps to obtain approval for each of the interventions and devices necessary for their rehabilitation , 37. TheOne limitation of the study is not having the final results of the implementation project to make better analyzes of the situations presented.It is not enough to prepare a CPG of very good quality, to elaborate a comprehensive health care pathway and to assess the barriers and facilitators for recommendations implementation, to improve the healthcare process of people with lower limb amputations in Colombia. It is necessary to develop a national policy that promotes the necessary arrangements for the provision of services as coordination of care amongst different providers, communications between them, continuity of care, package of care, referral systems, shared care, multidisciplinary teams, planning the transition of care from hospital to the community, health information systems development. Financial and governance arrangements and finally implementation strategies targeted at healthcare organizations, at healthcare workers, and in a specific type of practice.All authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.Article financed by the Ministry of Science, Technology and Innovation - Minciencias, under contract 738 of 2017, project called: Efectividad de una estrategia basada en Telesalud para mejorar la implementación de la guía de práctica clínica para el diagnóstico y tratamiento preoperatorio, intraoperatorio y postoperatorio de la persona amputada, la prescripción de la prótesis y la rehabilitación integral en instituciones de salud en Antioquia: un estudio de intervención aleatorizado por conglomerados de hospitales.JP-C is the technical director at Mahavir K-mina, a non-governmental organization that manufactures lower limb exoskeletal prostheses. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To systematically evaluate the guidelines for endometriosis published in the past decade, and to provide reference for the selection of guidelines for endometriosis through quality evaluation and comparison.PubMed database, Embase database, evidence-based medicine clinical practice guidelines (CPG) database and the National Institute for Health and Clinical Excellence in the United Kingdom were searched by computer from December 2012 to December 2020 to retrieve published endometriosis CPG published by professional institutions or organizations. The search languages are English and Portuguese. Two researchers evaluated the quality of included CPG according to appraisal of guidelines for research and evaluation (AGREE II). The evaluation includes 6 areas: scope and purpose, participants, rigor of formulation, clarity of expression, applicability and independence. The recommendation level of CPG is determined by the distribution of standardized scores in the above 6 areas.A total of 8 articles on endometriosis CPG were included, including 5 guidelines and 3 consensuses, covering 5 countries in 2 continents; the publication year was 2013 to 2020. The average standardized scores of the scope and purpose, participants, rigor, clarity, applicability and independence of CPG were 77.1%, 52.8%, 50.5%, 86.8%, 31.3%, and 36.5%, respectively. Among the 8 CPGs, 1 was grade A (recommended), 5 were grade B (recommended after improvement), and 2 were grade C (not recommended). Seven CPG recommendations were based on expert consensus, and one was developed through detailed literature retrieval, analysis and evidence rating evaluation. There was little difference between the guidelines in terms of treatment-related recommendations.The quality of endometriosis CPG released in 2013 to 2020 is quite different, and some CPGs are not ideal in terms of rigor, applicability and independence. The guidelines issued by NICE in 2017 are A-grade recommendations. The standardized scores in various fields are high, and the formation process of CPG is the most standardized, which is worth learning and reference. Women with endometriosis usually have a series of pelvic abdominal pain symptoms, including dysmenorrhea, difficulty in intercourse, large amount of bleeding during menstruation, non-menstrual pelvic pain, ovulation pain, difficulty in urination and chronic fatigue. Endometriosis is also associated with infertility. There is a strong correlation between the severity of the disease and the impact on women’s fertility, due to impaired ovarian function, ovarian endometriosis cysts and subclinical pelvic inflammation, which may reduce the quality of oocytes and reduce the endometrial receptivity to implantation. As a common chronic gynecological disease requiring long-term management, the current guidelines and consensus related to endometriosis have been up to a hundred departments, which brings great difficulties to clinicians “decision-making and patients” informed choice. Therefore, it is very important for both doctors and patients to select high-quality guidelines or consensus as clinical diagnosis and treatment guidance.Endometriosis (endometriosis) refers to the occurrence, growth, infiltration, and repeated bleeding of endometrial tissue outside the uterus, which in turn leads to pain, infertility, nodules or masses. It is a common and frequently-occurring disease in women of childbearing age. In this study, the internationally recognized guideline evaluation tool-appraisal of guidelines for research and evaluation (AGREE II) was used to evaluate the quality of the included CPGs through a comprehensive retrieval of foreign published CPGs specifically for endometriosis, so as to provide further reference for clinicians.Clinical practice guidelines (CPG) are designated and issued by professional academic organizations or departments based on the best evidence and combined with clinical practice to help clinicians and patients make clinical decision-making guidance, including guidelines, consensus, recommendation, etc, which can not only improve the diagnosis and treatment effect, but also make full use of medical resources.http://www.g-i-n.net/), National Institute for Health for Health and Care Excellence website (https://www.nice.org.uk/guidance), National Guideline Clearinghouse (https://guidelines.gov/), Scottish Intercollegiate Guidelines Network (http://www.sign.ac.uk/), Clinical Practice Guidelines Portal website , New Zealand Guidelines Group website , BCGuidelines website , AQuMed Database website (http://www.aezq.de/aezq/publications). In addition, we searched Google Search Engine and checked the references of all the related guidelines to include more potential guidelines. All guidelines were based on previous published studies, thus no ethical approval and patient consent are required.PubMed database, Embase database, evidence-based medicine CPG database, National Institutes of Health and Clinical Medical Optimization were searched online from December 2012 to December 2020 with search terms of “endometriosis,” “guidelines,” “guidance,” “consensus.” We also searched the websites of guideline development organizations: Guidelines International Network Web site , topics, publication years, publication organization, guidelines development methods, evidence level evaluation methods and other basic information.Each included CPG was evaluated by 2 trained personnel for AGREE II. According to the “Instructions for Clinical Guidelines Research and Evaluation System II (Chinese version),” 23 entries in the following 6 fields were evaluated, including scope and purpose (3 entries), stakeholder involvement (3 entries), rigor of development (8 entries), clarity of presentation (3 entries), applicability (4 entries) and editorial independence (2 entries). Finally, a comprehensive evaluation was carried out according to the scores. Two researchers rated each item from 1 (very disagree) to 7 (very agree). Standardized scores in various areas = /(highest possible rating - lowest possible rating) × 100%. The higher the standardized score of a field, the more complete the reporting, reflecting the better the method of developing guidelines in the field. Combined with the scores of each field of the guide, the recommended level of the guide is divided into 3 grades, and grade A is recommended, that is, the standardized scores of the 6 fields are ≥60.00%; grade B is recommended after modification and improvement, that is, the standardized score of the field is <60.0%, and the standardized score of ≥3 fields is ≥30.0%; grade C is not recommended, that is, the number of fields with a standardized score of <30.0% in 6 fields was ≥3. it indicates that the consistency is high and formal experiments can be carried out.Before the formal evaluation, the 2 researchers used AGREE II to perform pre-experimental scoring on the randomly selected 2 guidelines to test the reliability of the results. The scoring results were statistically analyzed by SPSS 20.0 software, and the consistency of the evaluation results was investigated by intra-group correlation coefficient (ICC). When the ICC value is 0.81 to 1.00,A total of 906 relevant literature were obtained through database retrieval. According to the inclusion and exclusion criteria, 8 CPGs were finally included after excluding duplicate articles Fig. .Among the 8 CPGs included in this study, 5 guidelines and 3 consensus. Covering 5 countries of 2 continents; published in 2013 to 2018, with 6 first editions and 2 updated editions; 7 of them were conducted evidence quality rating and recommendation intensity evaluation based on the Grading of Recommendations  method. In addition to the 2016 Portuguese guidelines, the 2017 WES endometriosis classification guidelines, and the 2018 Japanese guidelines, the remaining 5 CPGs are all about the diagnosis, treatment (drugs and surgery), and pain management of endometriosis in the reproductive system. Four articles also cover the treatment of patients with endometriosis and infertility. The 2014ESHRE guideline referred to the primary prevention of endometriosis, while the 2014 German guideline defined the secondary prevention of endometriosis and made recommendations  and 0.91 (0.79–0.96), indicating that the consistency of the evaluation of the 2 researchers was good.The average standardized scores for the scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability and editorial independence of the 8 CPGs included were 1 in grade A (recommendation), 5 in grade B (recommendation after improvement) and 2 in grade C (no recommendation), respectively  and 4 (clarity of presentation) were ≥60%, and the average scores in fields 5 (applicability) and 6  were <30%, indicating that most of the CPGs for endometriosis did not pay enough attention to these 2 fields.Main shortcomings: The average score of field 3 (rigor of development) was 50.5%, because the lack of high-quality and multi-center clinical research data led to the formulation of most CPGs based on clinical experience and consensus of experts; no detailed inclusion and exclusion criteria; there is no clear description of the method for forming recommendations; some CPGs do not even specify the strength and limitations of the evidence. The average score of filed 5 (applicability) was 31.3% because most CPGs did not mention the promotion and impediments to application; economic cost and health budget were not mentioned. The general score of field 6  is not ideal. Although each CPG has a statement of interest conflict, the wording of most guidelines is not clear about the point that the views of sponsors do not affect the content of the guidelines. In particular, Japan’s CPG has barely elaborated on this field. Overall, the progress of endometriosis CPG in the past decade was limited, especially in the recommendation of diagnosis and treatment strategies.The limitations of this study are as follows. The limitations of research tools: there are no primary and secondary divisions in the 6 fields of AGREE II, which leads to the fact that some CPG levels may not be consistent with the actual. In fact, the quality of GDP cannot be evaluated only by the level, which is also clearly pointed out in the use instructions of AGREE II. Language limitation: This study was limited by language, only English and Portuguese CPG were included, and no further study was conducted on CPG in other languages. AGREE II is only an evaluation system, which is subject to the subjective influence of design developers. It is not necessarily suitable for all regions and countries, and it needs to be refined and updated. The 2017 NICE guide has high scores in 6 fields, and is the only CPG published on the basis of literature retrieval and evidence grading assessment. It provides a detailed description of economic and social costs, promotion and impediments, and provides a detailed comparative analysis of drug treatment costs, which is worthy of promotion and reference.In this study, the diagnosis and treatment strategies and methods recommended by the 8 endometriosis CPGs were not significantly different, but in fact, many problems were controversial in the process of CPG production or in the diagnosis and treatment of patients with endometriosis.Conceptualization: Yan Lei.Data curation: Yan Lei, Xin Du.Formal analysis: Yan Lei, Dejun Chen.Funding acquisition: Hongmei Lian.Investigation: Xin Du, Dejun Chen, Yue Gao.Methodology: Yan Lei.Project administration: Yue Gao, Hongmei Lian.Software: Dejun Chen, Hongmei Lian.Supervision: Yue Gao.Validation: Yue Gao.Visualization: Yue Gao.Writing – original draft: Yan Lei.Writing – review & editing: Xin Du, Hongmei Lian.


In times of high demand for scientific evidence for decision-making on COVID-19 mitigation measures, guidelines can be useful for translating scientific evidence into policy and practice. While guidelines are widely used in medical decision-making, they are novel to public health in Germany.Since December 2020, a guideline group has been working on a living, evidence- and consensus-based public health guideline on preventing and controlling SARS-CoV-2 transmission in schools. The group includes scientists across multiple disciplines as well as a broad range of stakeholders, including from the school family. Key features in the development of recommendations included a Cochrane rapid review and the WHO-INTEGRATE evidence-to-decision framework. The development and usefulness of the guideline for decision-making are being evaluated using a multi-method approach.The first version of the guideline containing nine recommendations was published in February 2021. The WHO-INTEGRATE framework facilitated the consideration of factors such as health benefits and harms, feasibility, acceptability and financial constraints. Preliminary findings of the evaluation suggest that under time pressure, developing few essential, consensus-based recommendations while assessing their societal implications is warranted. A shared understanding of evidence and of the purpose and limitations of guidelines is critical. To remain relevant, continuous integration of new evidence and updating of the guideline is necessary.Purpose and limitation of guidelines needs to be clear to ensure engagement and utilization.To remain useful for decision-making, guidelines and the underlying evidence need to be continuously updated.


The present study summarizes the current literature on the presence and the structure of biogenic amorphous silica (BAS) in nature. Based on this review, it is shown that BAS is ubiquitous in nature and exhibits a structure that cannot be differentiated from the structure of synthetic amorphous silica (SAS). The structural similarity of BAS and SAS is further supported by our investigations—in particular, specific surface area (BET) and electron microscope techniques—on oat husk and common horsetail. Many food products containing BAS are considered to be beneficial to health. In the context of the use of SAS in specific applications , this is of particular interest for discussions of the safety of these uses. Synthetic amorphous silica (SAS) can be produced by either a vapor-phase hydrolysis process, yielding pyrogenic (fumed) silica, or by a wet process, yielding hydrated silica . During the manufacturing process of these SAS materials, the primary particles are strongly  bonded or fused to form aggregates . PhysicaSynthetic amorphous silicas can be regarded as nanomaterials (NM)via wear and abrasion) or from biological processes. We should also note the unintended environmental and occupational production of NMs, e.g., via combustion products (automobile engines and wildfires), welding, and other man-made or natural activities.The new nomenclature of NMs led to the impression that these were “novel materials,” whereas it has been overlooked by the general public that some of these NMs have been deliberately produced and/or used either for many decades , centuries , or even millennia . In addition, there are many NMs naturally occurring in the environment originating from natural sources  or amorphous silica .Helpfully, in the “ISO/TR 18401 Nanotechnologies—Plain language explanation of selected terms from the ISO/IEC 80004 series,” the nanostructured amorphous silica found in rice husk is named as an example of a naturally-occurring NM.2) in their body eir body –5.Avena sativa) and common horsetail (Equisetum arvense), their structures are even below 20 nm. This was shown for the latter from as early as 1991  supplied from Blanks GmbH & Co. KG , often used as a herbal tea. Oat husk (A. sativa) was obtained from Bio Bäckerei Spiegelhauer ; usually this is often used for sprinkling proofing baskets in bread making.For our studies, we used samples of the common horsetail  until HCl-concentration <0.05%Centrifugation at 20,000 rpmDrying at 105°C for 16 hCalcination  at 540°C for 4 h—calcined without washingThoroughly washing (employing ultrasonication and centrifuge)Drying at 105°C for 16 h—final sampleFor comparison, samples of the raw materials were dried at 105°C , and washed with water .The common horsetail, as well as the oat husk, were digested with hydrochloric acid at room temperature for several days. Using successive dilution with deionized (DI) water, prolonged sedimentation, and decantation, the resulting greenish (common horsetail) to brown (oat husk) samples were then dried at 105°C overnight and subsequently calcined at 540°C for 4 h. This yielded a white powder which was thoroughly washed with DI water, centrifuged at 20,000 rpm, and finally dried at 105°C overnight.In parallel, comparative samples were prepared for all steps, e.g., without digestion by hydrochloric acid, to ensure that any observed structures are not confounded by the sample preparation process.The scanning electron microscopy (SEM) imaging was done with a Jeol JSM-7600F/Oxford-EDX Aztec and the energy dispersive X-ray (EDX) analysis with Thermo Fisher Scientific Ultradry EDX. The transmission electron microscopy (TEM) analysis was performed with a Jeol 2010F. The quantitative analysis was done with an ICP-OES iCAP 6500 Duo (Thermo Fisher Scientific GmbH). Species preparation took place with a lithium-meta-borate melt.2 with ICP-OES, the samples were calcined at 540°C overnight and a lithium metaborate melt was used in the preparation of the measurements. The SiO2 content was calculated from the data for elemental Si. Values are given about the original biological sample as received  is given in The light microscope picture of untreated common horsetail ((just dried) and show, e.g., stomata with clearly shown subcuticular incorporated silica particles , biological structures still can be seen in the lower magnifications but, on greater magnification, the typical structure of amorphous silica can be identified. A series of SEM micrographs at different magnifications is depicted in 2/g (multipoint) for this horsetail-derived BAS is typical for nanostructured amorphous silica. This measurement corresponds very well with the SEM and TEM pictures, which also reveal a nanostructured biogenic amorphous silica (BAS).The surface area of the final sample was evaluated according to the BET method, the value of 146 mThe SEM-EDX-analysis of the calcined raw material horsetail revealed, besides silicon and oxygen, the presence of Mg, P, S, Cl, K, and a large amount of Ca. This is consistent with the elemental analysis of the raw material described above.2 extraction was shown to be highly effective as well as being rather mild.The SEM-EDX-analysis of the samples, which had been prepared according to the above-described digestion method , only shows the presence of silicon and oxygen. Thus, this method of SiOfinal sample shows in the EDX spectrum the presence of Si and O only; thus, confirming the identity as pure silica. The final sample. The TEM micrographs reveal nanostructured amorphous silica (BAS) consisting of fused primary structures in the range of a few nanometers. To visualize the smallest structures within the BAS derived from the horsetail sample, TEM micrographs have been performed as well as the SEM micrographs. The images were prepared only on the Following the same initial procedure, as was used for the common horsetail, a quantitative analysis of the oat husk raw material was performed in the first stage to get an overview of the composition of the inorganic matter  and washed with DI water, revealed easily identifiable nanoscale structures .2/g is, therefore, an average value of a range of very small and far larger amorphous silica structures.When treated with hydrochloric acid, thus transferring the cations into their corresponding readily soluble chloride salts, and after calcinating and thorough washing, the silica nanostructures can be very clearly seen in In the samples prepared without HCl treatment, nanostructures can already be seen but still seem to be covered by some non-silica material and are difficult to identify clearly. In the fully-treated samples, however, the purified silica reveals unambiguously its nanostructure e.g., , 12.As with the horsetail, TEM images were prepared in addition to SEM pictures to investigate the structure of oat husk-derived BAS in more detail at higher magnifications. Several ATEM-EDX spectra of the final sample revealed that besides silicon and oxygen, only very minor impurities are present, i.e., about 0.06–0.25% (atom) K, up to 0.23% (atom) Al, and up to 0.06% (atom) Ca.2 and its amorphous structure, as well as their nanostructured appearance with similar size ranges in the corresponding primary structures, both BAS and SAS are highly comparable.In terms of the chemical composition of SiO2/g.TEM pictures, as shown below, demonstrate the similarity between BAS and SAS. Thus, it is not possible to easily distinguish between BAS and SAS based on the results obtained by this described analytical methodology. The specific surface area (BET) also shows that the examined BAS substances are NMs with values >100 m2/gPrecipitated SAS: SIPERNAT® 160 BET 170 m2/gPrecipitated SAS: SIPERNAT® 22 BET 180 m2/gFumed SAS: AEROSIL® 200 BET 200 mThe images show clearly a very similar nanostructure compared with the BAS grades described above.As early as 100 years ago, silica was found to occur naturally in the human body . Based o2, presumably both in the particulate and dissolved forms . Robberecht  and amorphous species , 18 and As noted earlier, amorphous silica can be found in the skeletons of algae (diatoms) –26, evenhttp://www.nanomee.de/) in Germany that is tasked “to obtain a detailed understanding of the biomolecule-controlled nano- and microscale processes that enable diatoms to biosynthesize their species-specifically patterned SiO2-based cell walls.”  have been the most extensively studied and the subject of many publications (As for the BAS in grasses, and those in all grains, amorphous silica NMs in rice husk (from ications –53. In tThe ubiquitous occurrence of BAS and its having a very similar nanostructure to SAS is an interesting aspect that needs to be considered and should be taken into account in any discussions about the safety of NMs, especially in the context of the oral uptake of SAS in food, feed, and cosmetic applications.Taken all together, commercial SAS forms are not entirely new NMs with unknown properties, but are well-studied materials that have been in use for decades without changes in their basic physicochemical structure.In this current investigative series performed on oat husk and common horsetail, we have examined the nanostructure of BAS by SEM and TEM analysis and compared them with the nanostructure of commercially available SAS materials. Furthermore, we have also performed BET analysis in both types of natural and SAS products.Scanning electron microscopy is an established method to evaluate the structure of materials down to the nanoscale. In our SEM overview images, it could be shown that the structural analogy between SAS and BAS can be found throughout the whole of the biological sample and not only in isolated locations. Using TEM images, which are suitable to show the structure at even greater magnifications, a direct comparison between BAS and SAS was possible and demonstrated that BAS is structurally very similar to SAS. Thus, the naturally-occurring BAS may even be considered a bio-analog to SAS. This is also confirmed by a comparison of the surface area of both these two amorphous silica types.Based on our findings and the identical chemical composition, there seems no reason to differentiate between naturally-occurring BAS, which is present in many food sources and is perceived beneficial to health, and SAS.The original contributions presented in the study are included in the article/All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.GL, C-PD, KS, TS, and NK were employed by Evonik Operations GmbH.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


One of the most commonly reported COVID-19-related changes to all maternity services has been an increase in the use of digital clinical consultations such as telephone or video calling; however, the ways in which they can be optimally used along maternity care pathways remain unclear. It is imperative that digital service innovations do not further exacerbate  existing inequalities in service access and clinical outcomes. Using a realist approach, this project aims to synthesise the evidence around implementation of digital clinical consultations, seeking to illuminate how they can work to support safe, personalised and appropriate maternity care and to clarify when they might be most appropriately used, for whom, when, and in what contexts?The review will be conducted in four iterative phases, with embedded stakeholder involvement: (1) refining the review focus and generating initial programme theories, (2) exploring and developing the programme theories in light of evidence, (3) testing/refining the programme theories and (4) constructing actionable recommendations. The review will draw on four sources of evidence: (1) published literature (searching nine bibliographic databases), (2) unpublished (grey) literature, including research, audit, evaluation and policy documents , (3) expertise contributed by service user and health professional stakeholder groups (n=20–35) and (4) key informant interviews (n=12). Included papers will consist of any study design, in English and from 2010 onwards. The review will follow the Realist and Meta-narrative Evidence Synthesis Evolving Standards quality procedures and reporting guidance.Ethical approval has been obtained from the University of Nottingham, Faculty of Medicine and Health Sciences Ethics Committee (FMHS 426–1221). Informed consent will be obtained for all key informant interviews. Findings will be disseminated in a range of formats relevant to different audiences.CRD42021288702. A realist synthesis moves beyond effectiveness and acceptability to consider evidence related to implementation .Stakeholder engagement  is embedded at every stage of the review.The focus of a realist review on mechanisms underlying implementation will yield insights that are potentially transferable across geographical and clinical settings.Research on digital communication in healthcare is a fast-evolving field, so it is possible that new evidence may be missed, although this may be mitigated to some extent by the iterative approach to searching within a realist review that will support the identification of relevant evidence, even after the initial searches have taken place.This article sets out a protocol for a realist review to generate a theory-informed and evidence-informed framework to guide best practice in the implementation of digital clinical consultations in maternity care. The project is being undertaken by a UK-based team and is oriented to producing findings that are actionable in the context of the UK’s National Health Service (NHS). Nonetheless, the project will draw on evidence from comparable geographical and health system settings and hence its findings will be of international relevance.Maternity care in England is undergoing a substantive transformation programme whose overall aim is to support services to work across professional and service boundaries to become safer, kinder, more personalised and more family-friendly.6–9One of the most commonly reported covid-related changes to all forms of service provision in maternity care has been an increase in the use of remote/virtual consultations using telephone or video.19Within maternity care, consultations have a wide range of potential purposes depending on the individual circumstances and characteristics of the service user, clinical categorisation of the pregnancy  and stage of the maternity care pathway . Consultations may involve clinical  assessment, monitoring, safeguarding assessments, health promotion, information giving, education or therapeutic support. The interactions need to be organised and implemented within multiprofessional care pathways that seek to promote continuity, personalisation and choice, recognise diversity and ensure safety.The rapid shift to remote or digitally delivered clinical consultations was initially implemented to support pandemic response objectives such as social distancing and service demand management.6Digitally-facilitated clinical communication has a highly diverse nomenclature, including terms such as telehealth, telemedicine, virtual/remote care, video consultations and digital consultation (among many others). In spite of efforts by WHO in 2017 to standardise concepts and terminology, there is no internationally agreed or consistent set of terms, meanings or definitions.consultations that are facilitated through, and/or complemented by, digital technology. To capture this focus, we will use the term ‘Digital Clinical Consultation’—henceforth referred to as ‘DC-CON’.The focus of this project is on maternity care Box 1Digital Clinical Consultation (DC-CON)—Synchronous telephone or video consultations involving direct interaction between a service user and a maternity healthcare professional. It has two-way functionality and can be initiated by either party. It may be linked to, or complemented by, other digital technologies within the maternity care pathways.This definition recognises that the focus is on the consultation itself, but that this might be linked to, or informed by, other digital technologies.This project will investigate digital consultations across the maternity pathway, that is, during pregnancy, the intrapartum period and early postnatal care (up to 10–14 days post-partum).There is a large and rapidly expanding literature associated with DC-CON in maternity care.20 27–33The second DC-CON purpose relates to situations where DC-CON is already the main modality of care .30Overall, existing research on DC-CON in maternity care shows that it can be safe and acceptable in controlled conditions.This project aims to undertake an in-depth and theory-informed investigation of the evidence around implementation of digital clinical consultations. It seeks to illuminate how digital consultations can work to support safe, personalised and appropriate maternity care and to clarify when they might be most appropriately used, for whom, when and in what contexts.Scoping searches of PROSPERO, Medline and the Cochrane Library have not identified any similar reviews currently being undertaken.how particular interventions lead to particular outcomes under particular contexts .58We will undertake a realist synthesis in which patient and public involvement (PPI) and diverse stakeholder participation are embedded at every stage.As applied to our research question, the logic of a realist review proposes that different types of interventions  supply particular resources into a situation that prompt diverse possible reactions and responses  from women and health professionals.70Our proposed realist synthesis will be conducted in four iterative phases (see below). The review will follow the Realist and Meta-narrative Evidence Synthesis Evolving Standards (RAMESES) quality procedures71Each phase of the review potentially draws on three sources of evidence: (1) literature , (2) diverse stakeholder expertise and insights and (3) key informant interviews.This project has been informed by service user involvement from its outset and seeks to follow the National Institute for Health Research (NIHR) UK Standards for Public Involvement in Research.73A maternity research priority setting exercise was undertaken in 2020 by some members of the research team in which a PPI research network played a key role (the Nottingham Maternity Research Network - NMRN).In addition to the COSU-SG, all project phases will also be informed by a health professional stakeholder group (HP-SG). The HP-SG will include between 10 and 20 obstetricians, digital midwives, frontline and managerial midwifery staff from different maternity settings—recruited via social media and through professional networks. Group membership is not bounded and fixed, however, but may evolve as the project progresses to ensure that appropriate expertise and insights are accessed. The purpose of the two stakeholder/PPI groups is to shape, participate in, contribute to and advise the research team on all project phases to ensure that project questions, programme theories and recommendations reflect diverse real-world experiences and are relevant.For both groups of stakeholders, anyone expressing an interest to get involved will first be contacted by the project PI (CE) for an in-depth discussion about the project and their potential contribution and commitment. They will also be sent written information about the study (this information sheet will be reviewed for readability/plain English). It will be stressed that their involvement is entirely voluntary and that they can withdraw at any time. Subsequently, the PPI coapplicant (CS) will contact individuals periodically to offer an opportunity for further discussion, to ask questions and to ensure that they remain happy to contribute. All personal details about stakeholders and records of project meetings/workshops will be securely stored in password-protected files according to a University-approved Data Management Plan.Within this realist review, the overall search approach will follow the only published systematic approach to the ‘realist search’.75The search strategies within each phase will be developed and operationalised by experienced information specialists (AB and MC). The search dates will be restricted to evidence from 2010 to the present to reflect the need for contemporary data. Likewise, inclusion of evidence will be limited to reports and studies in the English language and in high-income settings (Organisation for Economic Co-operation and Development (OECD) countries). The search approach will engage the project advisory group and stakeholders throughout, consulting them where required to provide advice  and help with identifying relevant literature .Data sources for the project may also involve a small number of key informant interviews. Within a realist review, the purpose of these is to provide additional insights to confirm, refute or refine proposed programme theories.Each phase of the review (with its associated search approaches) is described sequentially below, although in practice, there is considerable iteration between them (see 10.1136/bmjopen-2022-062106.supp1Supplementary dataThis phase aims to identify and make explicit (through CMO configurations) an initial set of programme theories that may explain how DC-CON in maternity care can be used to achieve optimal outcomes, for whom and in what contexts? Given the potential variability of modality and use of DC-CON in maternity care, an important part of this process is to focus and prioritise the most important questions and outcomes.Phase 1 involves undertaking some broad background searches to assess the breadth, depth and range of evidence available. The team will then seek to identify key papers (of any study design) on DC-CON implementation that can yield insights into programme theory development. The search is iterative, utilising searches on electronic databases, grey literature sources, suggestions from stakeholders, citation tracking and reference list searching of conceptually rich index papers. This stage will include, but will not be restricted to, maternity care settings as we know from pr-protocol scoping that relevant theories have been developed regarding the implementation of DC-CON in other clinical settings.Phase 1 includes two stakeholder workshops (at the beginning and end) to help generate initial programme theories and to refine the key focus of the review.The aim of phase 2 is to determine whether the initial programme theories are supported by empirical evidence and to analyse this evidence to elaborate, refine, adjust and test the theories. This phase continues the iterative process of literature searching, data extraction and analysis. A core focus is to search for empirical studies that can provide data with which to explore and elaborate the initial programme theories. The search strategy will be iterative, proceeding with carefully formulated searches based on subsets of literature constructed using terms associated with the initial programme theories (CIMO frameworks) and key concepts.Context —postnatal care.Interventions/phenomenon of interest —video-based consultation.A follow-up search might then focus more specifically on the influence of a mechanism  in relation to an outcome . In the first instance, the main focus of the search for evidence will be for literature related directly to maternity settings. However, in a realist review, the focus of analysis is the programme theory (or mechanism of action)—hence, we may also draw on wider literature to seek opportunities for transferable learning. In the example above, we might, therefore, seek evidence related to ‘trust’ in the context of video consultations from other clinical settings such as primary care to confirm or refute our emerging theories.The searches will include systematic reviews and empirical research of any study design, including service evaluation, audit and quality improvement projects. The searches will also include existing policies and practice guidelines surrounding DC-CON in maternity care in the UK. This is because the recommendations set out in policy or practice guidance rest on implicit or explicit theoretical assumptions regarding implementation. Moreover, the inclusion of policy documents will help to ensure that governance issues are considered alongside implementation, so that the review is appropriately contextualised.As in phase 1, search sources will include electronic databases, grey literature and expert stakeholders see  for an i69 7510.1136/bmjopen-2022-062106.supp2Supplementary dataRecords will be imported into EndNote and duplicates were removed. Study screening and selection will be undertaken by two reviewers independently, with recourse to other team members in cases of ambiguity or disagreement. To aid transparency and consistency, once the initial programme theories have been formulated, an ‘inclusion criteria flowchart’ will be constructed in which key concepts are operationalised and against which each potential study can be assessed.82et al,is the evidence provided in this theory area good enough and relevant enough to be included?. These judgements will be articulated and recorded for each study as part of the screening and data extraction process.Records will initially be screened by title and abstract. All seemingly relevant papers will then be examined in full text and reasons for exclusion noted in a table. In line with realist methodology, records will be screened for inclusion based on relevance, rigour and richness.Data will be extracted from the included studies in two ways. First, information about study characteristics will be extracted into a summary table . This will include information on features such as study setting, design, methods, details of intervention modality and technology, participants, outcomes and stage of maternity care pathway. Second, a bespoke data extraction form will be developed based on the initial programme theories, and, as noted above, will include sections in which to note assessments of relevance, richness and rigour. Theory-based data extraction enables the coding and charting of relevant data, so that elements of the theory can become populated to investigate what works, for whom, how and in what contexts. The analytical process involves both deductive and inductive coding. Deductive coding will involve extracting data that appears to be directly related to aspects of the programme theory. Where it is possible to make relevant inferences, the data will also be coded in relation to contexts, mechanisms or outcomes. However, the evidence may also reveal new contexts, mechanisms or outcomes, which will be identified and coded inductively.The data extraction templates and associated analytical process will be developed collaboratively among the core research team and piloted extensively. Once the team feel they have achieved a clear and consistent approach, the remaining data extraction will be undertaken by one reviewer, with a second reviewer checking approximately 20%. The outputs of this stage will be a set of evidence tables. There will be one overarching table representing the key characteristics of all the studies included in the review. There will then be a series of tables organised to represent the different bodies of literature and findings related to each initial programme theory. Thus, each theory area will have its own evidence table.What does this evidence suggest about this aspect of our theory? Does it support it? Does it disprove it? Does it suggest an amendment to it?et alThe process of data analysis will be ongoing and iterative. The evidence will be reviewed within and across the theory areas to explore how it builds on, refutes or provides alternative explanations for the initial CMO configurations. The analytical process will involve asking questions such as: Box 2Juxtaposition of sources of evidence—for example, where evidence about outcomes in one study allows insights into evidence about outcomes in another study.Reconciling of sources of evidence—where results differ in comparable circumstances, these will be examined further to find possible reasons for the different results.Adjudication of sources of evidence—based on methodological strengths or weaknesses.Consolidation of sources of evidence—where outcomes differ in particular contexts, an explanation will be constructed on how and why these outcomes occur differently.Situating sources of evidence—when outcomes are different in particular contexts, a possible explanation will be developed as to why they differ.Our stakeholder groups will continue to be consulted at different points to seek their views and test out new ideas.An important feature of the analysis will be to explore the issue of temporality and sustainability within the evidence. For example, it might be expected that evidence on COVID-19-related DC-CON implementation might include different experiences depending on the stage of the pandemic and the length of time that staff and service users have had to adjust to changes in service delivery models. Likewise, even in non-COVID-related studies, experiences with new technologies vary depending on the length of time since introduction, with many studies focusing on the early stages of implementation rather than exploring how and why technologies become embedded, normalised or sustainable.80 85In this project, we will endeavour to take temporality into account in two ways. The first, relates to evidence that is specifically concerned with changes made during the COVID-19 pandemic. Here, we will ensure that our data extraction template explicitly acknowledges the time period of data collection, extracting and mapping data to the stages of the pandemic and then transparently considering these stages as part of the analysis. Likewise, working with our advisory and stakeholder groups, we will attempt to develop a clearer picture of how digital consultations were initially introduced in different settings and how their use and implementation may have adapted and changed as the pandemic progressed. The second issue relates to the fact that not all of the evidence that we anticipate including in the review will come from the pandemic context. We will endeavour to include temporality as an aspect of our analysis for all the evidence by explicitly considering the stage of implementation of an innovation that is reported and by considering data related to change and adaptation over time (where reported). We plan to draw on concepts from the Dynamic Sustainability FrameworkThe output of phase 2 will be a comprehensive set of evidence tables and refined programme theories linked to associated sets of working papers organised by DC-CON type and purpose in relation to different points in the maternity care pathway.The purpose of this phase is to test and further refine the programme theories. This is done in three interlinked ways.et al,First, as part of an ongoing recursive approach, new literature searches will be undertaken to find, test and empirically explore any new theories identified during the review process.Second, further in-depth consultation/workshops with stakeholders will be undertaken to test and refine proposed theories. Our stakeholder groups will be asked to consider the proposed theories in relation to their own experiences, paying particular attention to clarifying the key mechanisms that are required to produce desired outcomes and to identify the key links between these mechanisms and different contexts. This process will help to identify ‘gaps’ that remain in our understanding and to clarify the essential elements of intervention and context that need to be placed to ensure that the appropriate mechanisms can be activated.Third, as described above, we will undertake a limited number of key informant interviews to test aspects of the programme theories and to evaluate their plausibility, credibility and transferability.58The output of this phase will be a theoretically-grounded explanatory framework for safe, appropriate and acceptable DC-CON in maternity care that can be used to guide intervention development, policy and practice.The purpose of this phase is to generate actionable recommendations from the review. We will do this by holding an online webinar to which a much larger group of stakeholders will be invited. The purpose of this webinar will be to share and ‘sense-check’ the review findings and to solicit suggestions for recommendations, actions and strategies for dissemination. In addition, we will hold further meetings to discuss, develop and finalise recommendations appropriate to a range of constituents  and feasible for implementation in a UK NHS context.Ethical approval for the key informant interviews has been obtained from the University of Nottingham Faculty of Medicine and Health Sciences Research Ethics Committee—reference no. FMHS 426–1221. Formal ethical approval for the stakeholder involvement/consultations is not required; however, the principles of research integrity and informed consent will be followed at all times.Dissemination strategies will be informed through ongoing engagement with our stakeholder groups. Key strategies will include academic papers, conference presentations, development of an online educational resource for health professionals and short papers in ‘practice-focused’ journals.


Dirofilaria immitis nematode infection in a dog imported from Venezuela that had been living for 2 years in Santiago, Chile, where this parasite had not been reported before. Our findings warrant surveillance for all dogs imported to Chile, given that suitable conditions exist for establishing this parasite.We report a case of  Dirofilaria immitis, a species of zoonotic parasitic nematode transmitted by mosquitoes, causes canine dirofilariosis. These nematodes are usually found in countries with temperate and tropical climates and are endemic throughout Europe and in the southeastern regions of Asia and Africa . However, the animal’s condition deteriorated after 1 week (in January 2022). Ultrasound examination showed the presence of a fetus for which no heartbeat was detected. Blood work showed severe anemia, kidney failure, and the presence of microfilariae at the blood smear examination. An echocardiogram examination showed signs compatible with tricuspid valve insufficiency, but no nematodes were observed. A blood transfusion was performed before surgery to remove the uterus, which showed maceration of the fetus. The dog was euthanized days after surgery.https://www.leica-microsystems.com). The average length of 10 microfilariae was 285.6 μm and average width was 6.5 μm  according to the manufacturer’s instructions. We used the DNA as a template for PCR with GoTaq DNA Polymerase  and amplified a section of the mitochondrial cytochrome oxidase I (COI) with the primers COIintF (TGATTGGTGGTTTTGGTAA) and COIintR (ATAAGTACGAGTATCAATATC) (https://dna.macrogen.com). We used the acquired sequences as input in BLAST (http://blast.ncbi.nlm.nih.gov) for comparison. The sequence for the cox1 (OP811228) showed 100% homology with D. immitis entries deposited in GenBank from Spain (accession no. LC107816), Slovenia (accession no. OP494255), Hungary (accession no. KM452920), Thailand (accession no. MW577348), and China (accession no. EU159111). Moreover, the sequence acquired from the 12S rDNA (OP819559) showed 100% homology with GenBank entries identified as D. immitis from French Guiana (accession nos. MT252014), Myanmar (accession nos. OL714336), Thailand (accession no. MW512514), Brazil (accession nos. MZ678855), France (accession nos. MZ435877), and China (accession no. EU182327). Therefore, both sequences confirmed the diagnosis of D. immitis infection.We used 1 mL of a blood sample collected with EDTA from the dog to perform the modified Knott’s test; we measured microfilariae under microscopic examination by using Leica Application Suite 3.4.0 software (Leica Microsystems, s 6.5 μm , which a>448,138 live in Chile (D. immitis infection in dogs arriving in Chile. Little information is available regarding the prevalence of D. immitis infection in Venezuela; an older report indicates a 4%–29% prevalence of D. immitis infection in hunting dogs in Aragua State based on analysis using the modified Knott´s test (The dog was brought into Chile from Venezuela 2 years before the incidental finding of microfilariae in an examination of blood prompted by complications caused by a uterine infection and kidney failure. This finding is relevant because, in recent years, human migration from Venezuela into Chile and other Latin America countries has risen, and the role of pets transported with humans as a reservoir of vector-borne pathogens has not been investigated. More than 6 million people have left Venezuela because of ongoing economic, political, and humanitarian crises (D. immitis nematodes are not endemic in Chile, little knowledge of the infection exists among veterinarians. Massive screening of dogs that arrive in Chile from D. immitis–endemic countries is urgently needed.Unofficial reports from veterinarians in Santiago have mentioned detecting structures resembling adult specimens of nematodes in echocardiograms of some dogs brought into Chile from Venezuela. Autochthonous cases may occur soon in Chile, where mosquitoes capable of acting as vectors are present and suitable climatic conditions for developing the transmission cycle exist. Furthermore, the sizeable population of free-roaming dogs in Chile can act as a reservoir for the parasite. Since


Continuing professional development (CPD) and recency of practice (ROP) standards are components of health practitioner regulation in Australia. The CPD and ROP standards are currently under review, and an evidence base to assist the development of consistent standards is required. Preliminary searching was unable to find a recent systematic review of the literature to provide an evidence base to underpin the standards review.This paper presents the protocol for a systematic review that aims to develop a current evidence base that will support the National Boards to develop more consistent, evidence-based, effective standards that are clear and easy to understand and operationalize.Research questions were developed to support the planned review of CPD and ROP registration standards. Major databases and relevant journals were searched for articles published in English between 2015 and 2021, using key search terms based on previous unpublished reviews of the CPD and ROP registration standards. The quality of the articles retrieved will be assessed using an instrument suitable for use in the development of public policy. The findings will be published in a peer-reviewed journal.In September 2021, our search strategy identified 18,002 studies for the CPD-related research questions after removal of duplicates. Of these, 509 records were screened based on their title, and 66 full-text articles were assessed for eligibility based on their abstract, of which 31 met the inclusion criteria. A further 291 articles were identified as relevant to the ROP research questions. Of these, 87 records were screened based on their title, and 46 full-text articles were assessed for eligibility based on their abstract, of which 8 studies met our inclusion criteria.This protocol outlines the scope and methodology that will be used to conduct a systematic review of evidence for CPD and ROP and inform a review of the standards for regulated health professionals in Australia. Previous research has shown that while CPD improves practitioner knowledge, the link to public safety is unclear. While there has been a greater focus on maintenance of certification and other quality assurance activities over the past 10 years, there remains great variability in CPD requirements across both professions and jurisdictions. ROP was found to be a poorly researched area with most research concentrating on medical practitioners, nurses, and midwives and no clear consensus about the optimal time period after which retraining or an assessment of competence should be introduced. As the CPD and ROP standards are currently under review, it is timely that a review of current evidence be undertaken.DERR1-10.2196/28625 In July 2010, Australia introduced a national scheme for the regulation of health practitioners  for Australian [insert health profession of interest] be as evidence-based and effective as possible in facilitating practitioners to practice safely and competently?More detailed research questions for the systematic review and international benchmarking study are as follows:What research has been conducted since the previous systematic review in 2015 regarding CPD and ROP for the [insert relevant health professions]?How do the current Australian CPD and ROP standards for the [insert relevant health professions] benchmark against regulators in comparable jurisdictions?CPD-specific questions are as follows:Is there evidence to support an optimal quantity of CPD to maintain competence? Does the evidence suggest any benefit or disadvantage in requiring CPD to be completed over a particular period such as 1, 2, or 3 years? Is there a case for these to vary between health professions or to vary within the same health profession depending on differences in the scope of practice, practice division, and practice endorsement?Does the evidence indicate that some types of CPD  are more effective in improving practitioner competence and patient safety?Is there evidence to suggest whether self-directed CPD or mandated CPD is more effective in promoting practitioners’ competence and patient safety? Should some CPD be mandated? Is a mix of mandated and self-directed CPD more effective? If so, is there an optimal ratio of self-directed to mandated CPD?Is there any evidence that CPD that has been accredited or subject to some quality assurance process is more effective in maintaining clinical competency and/or patient safety outcomes? What factors should be taken into consideration in accrediting CPD?Under what circumstances could an exemption from CPD be justified? Is there evidence to suggest that a short gap in CPD  has a negative effect on professional competency, including any specific time frames for this effect to appear?Is there any evidence to suggest a benefit or disadvantage to requiring CPD that is more focused on maintaining a practitioner’s competence in their current scope of practice? What is the evidence on best practice in supporting CPD for practitioners who may wish to change their scope of practice? Is there any evidence to suggest that CPD contributes to other aspects of professional practice?Is CPD more effective when it is based on a practitioner’s assessment or reflection, and peer review or based on curricula to address their learning needs and skills gap, or is CPD more effective when it is based on meeting an externally set requirement that is measured in hours or points?Should practitioners who hold limited registration  be required to undertake CPD?ROP-specific questions are as follows:With regards to skills retention and skills fade, does the period of time vary between different health professions or at different stages of their career ?Is there evidence regarding when competency assessment should be completed?Is there any evidence for the minimum number of hours of practice over a set period of time needed to maintain competency? Does this vary across professions or scope of practice?Studies and reports will be included in the systematic review if they meet the following criteria:The focus of the article or report is on CPD and/or ROP for health professions regulated in AustraliaReviews, original research, reports, and thesesFor research question 4: reviews, original reports or theses that compare different types of CPDPublished from January 1, 2015, onwardWritten in the English languageArticles and reports will be excluded from the review if they are:Focused on health and other professionals not regulated under the National LawFocused on students, interns, or residentsFocused on regulatory standards other than CPD and/or ROPOpinion pieces, newsletters, and conference presentationsPublished before January 1, 2015Not written in the English languageDatabases to be searched for this review are as follows: the Allied and Complementary Medicine Database, MEDLINE, and PsycINFO (using the OVID platform), Better Evidence for Medical Education, CINAHL, the Campbell Collaboration of Systematic Reviews, the Cochrane Database of Systematic Reviews, Database of Abstracts and Reviews of Effects, Education Resources Information Centre, Embase, OTSeeker, Physiotherapy evidence, ProQuest Nursing and Allied Health, International Prospective Register of Systematic Reviews (PROSPERO), ScienceDirect, Web of Science, and Wiley Online Library.Aboriginal Health Worker, the Aboriginal and Islander Health Worker, Academic Medicine, the American Journal of Occupational Therapy, Australian Health Review, Australian Journal of Chiropractic, Australian Occupational Therapy Journal, BMC Medical Education, the British Medical Journal, Chiropractic Journal of Australia, Clinical Teacher, Compendium of Continuing Education in Dentistry, Education Journal of Dental Education, Journal of Alternative and Complementary Medicine, Journal of the American Medical Association, Journal of Chiropractic Education, Journal of Continuing Education in the Health Professions, Journal of Continuing Education in Nursing, Journal of Medical Internet Research, JMIR mHealth and uHealth, Journal of Medical Regulation, Journal of Nursing Regulation, Medical Education, the Medical Journal of Australia, Nurse Education in Practice, Nurse Education Today, Pharmacy Education, Physical Therapy, Prehospital Emergency Care, and Professional Psychology.These will be supplemented by hand searching relevant academic publications including but not limited to the Gray literature will be sourced from the websites for each of the national boards, relevant international health professional regulatory bodies , health professional associations , relevant government departments .Reference lists of articles and reports of interest will be hand searched, and a forward citation search will be conducted using Google Scholar and Web of Science.Databases and other information sources will be searched for literature published between 2015 and 2021 in the English language. The search terms and sources of literature outlined below are based on our experience conducting a systematic review of the evidence for CPD and ROP standards for internal use based on journal articles and gray literature published between 1990 and 2014, and preliminary testing.Medical Subject Headings (MeSH) by the National Library of Medicine will be used to search the databases outlined above, using all relevant root and hierarchical branches related to the terms. MeSH will also be explored to increase the ability to identify relevant publications where there are variations in the way articles are indexed. MeSH is a standardized hierarchically organized vocabulary developed by the National Library of Medicine to index, catalogue, and search biomedical- and health-related information.MeSH terms related to health practitioner groups include “allied health occupations,” “acupuncture,” “chiropractic,” “dentistry,” “medicine,” “emergency medical technicians,” “medicine, traditional,” “midwifery,” “nurse-midwife,” “nursing,” “nursing, advanced practice,” “nursing practical,” “occupational therapists,” “optometry,” “osteopathic physicians,” “osteopathic medicine,” “pharmacy,” “physical therapists,” “physical therapy specialty,” “physicians,” “podiatry,” “psychology, medical,” and “radiologists.”MeSH terms related to the intervention include “competency based education,” “education, continuing,” “education, distance,” “education, medical, continuing,” “education, nursing, continuing,” “education, pharmacy, continuing,” “learning,” “peer review, health care,” “return to work,” “self-assessment,” and “staff development.”MeSH terms related to the outcome include “career mobility,” “competence, clinical,” “competence, professional,” “cultural competence,” “inappropriate prescribing,” “licensure,” “malpractice,” “mandatory programs,” “mandatory reporting,” “patient safety,” “problem behavior,” “professional practice,” “professionalism,” “quality of health care,” “risk management,” and “scope of practice.”Additional search terms related to each health practitioner group include “Aboriginal and Torres Strait Islander health practitioner,” “Aboriginal and Torres Strait health worker,” “Chinese medicine practitioner,” “Chinese herbalist,” “chiropodist,” “medical radiation practitioner,” “nuclear medicine technologist,” “radiographers,” “radiotherapists,” “paramedics,” “physiotherapists,” “new graduate,” “early career,” “mature practitioner,” “mid-career,” “late career,” and “advanced practitioner.”Additional search terms related to the intervention or event of interest include “accreditation,” “competency framework,” “competency standards,” “mentoring,” “objective structured clinical exam,” “on-line learning,” “practice portfolio,” “recency of practice,” “re-entry program,” “reflective practice,” “refresher program,” and “revalidation.”Search terms related to outcomes include “advanced practice,” “authentic learning,” “endorsement,” “extended practice,” “fitness to practice,” “knowledge transfer,” “impaired practice,” “minimum practice hours,” “non-medical prescribing,” “registration standards,” “skills decay,” and “skills fade.”As outlined in the PRISMA-P  guidelines , an illuThe search results will be imported into EndNote Software  [Titles listed in the search results will be checked, and the abstract will be consulted if the title appears relevant to any of the research questions. Articles and reports will be downloaded when the abstract gives the impression of being pertinent to the research questions and checked for inclusion in the review. As noted above, inclusion or exclusion and, where applicable, the reasons for exclusion, will be recorded.A Microsoft Excel (Microsoft Corp) spreadsheet will be used to record bibliographic information about each article or report , the study population , intervention , main findings, study type, National Health and Medical Research Council level of evidence , decisioWhere the full text of the article is assessed as relevant to the research questions, quality appraisal will be conducted by 2 people using the weighted evidence approach developed by the Evidence for Policy and Practice Information and Co-ordinating Centre at the Institute for Education in the University of London .Briefly, this method provides an overall score to be derived for each study by assigning a score  against each of the 3 criteria listed below and summing the scores.The trustworthiness of the results judged by the quality of the study within the accepted norms for the particular research design used in the study The appropriateness of the study design for addressing the systematic review’s research question The appropriateness of the focus of the research for answering the review question (topic relevance)The overall rating is derived by summing the scores assigned for each of the criteria. The overall weight of evidence would therefore be indicated as high , medium , or low (7-9).Two reviewers will independently assess the weight of evidence of the included studies, and their assessment will be recorded on the spreadsheet.Data extraction and quality assessment will be undertaken by the primary reviewer (PM). A second reviewer (SA) will confirm the accuracy of the data. Any disagreements will be resolved through discussion or third-party adjudication. Data extraction by a single reviewer results in considerable time saving and has little impact on the conclusions .As meta-analysis is not feasible for this type of systematic review, the findings will be reported in narrative form with information about the included studies presented in tabular form and published in a peer-reviewed journal. The narrative will draw out the main themes of the systematic review and discuss their implications in the context of health practitioner regulation in Australia.In September 2021, our search strategy identified 18,791 studies through database searching, with an additional 96 records identified through other sources, resulting in 18,002 records after duplicates were removed. Of these, 509 records were screened based on their title, and 17,493 records were excluded. A total of 66 full-text articles were assessed for eligibility based on their abstract, of which 35 full-text articles were excluded because they did not meet the inclusion criteria. A total of 31 studies met the inclusion criteria.Our search strategy identified 278 studies through database searching, with an additional 25 records identified through other sources, resulting in 291 records after duplicates were removed. Of these, 87 records were screened based on their title and 41 records were excluded. Forty-six full-text articles were assessed for eligibility based on their abstract, of which 38 were excluded, leaving 8 studies that met our inclusion criteria.This is the first systematic review completed by Ahpra and the National Boards of the evidence for CPD and ROP standards that covers all health professions regulated by the National Scheme. As such, its focus is wider than that of the recently published protocol for a scoping review of ROP for nurses and midwives .It is anticipated that this systematic review will provide a comprehensive evidence base for CPD and ROP requirements for professions regulated by Ahpra. Previous research has found that even though there is good evidence to show CPD is effective in increasing practitioner knowledge, there is less evidence supporting that CPD changes clinical practice, and even less evidence linking CPD to improved patient safety -10. In 2This protocol has been designed to identify, summarize, and assess the quality of the evidence published to date for CPD and ROP registration standards for selected regulated health professions in Australia. As outlined above, a major strength of the method is that it covers a broad range of health professions. Other strengths include research questions that are designed to support the planned review of CPD and ROP standards in Australia, a comprehensive search strategy with clearly defined inclusion and exclusion criteria, and an appropriate instrument to assess the quality of the evidence for use in the development of public policy.Potential limitations of the method include the following: there are differences in standards for health practitioners in jurisdictions where publications are found and those in Australia; there are likely to be fewer publications focusing on professions with lower numbers of registrants; and, due to the nature of the review, the authors are unable to correct study biases.In conclusion, this protocol describes a detailed method for a systematic review of the evidence for CPD and ROP registration standards for health practitioners. This review will inform a multiprofession review of CPD and ROP standards in Australia. The findings will be of interest to regulators of health practitioners in other jurisdictions and may be used to inform international regulatory standards.


Inflammatory bowel disease (IBD) is characterized by chronic and relapsing inflammation of gastrointestinal tract, with steadily increased incidence and prevalence worldwide. Although the precise pathogenesis remains unclear, gut microbiota, bile acids (BAs), and aberrant immune response play essential roles in the development of IBD. Lately, gut dysbiosis including certain decreased beneficial bacteria and increased pathogens and aberrant BAs metabolism have been reported in IBD. The bacteria inhabited in human gut have critical functions in BA biotransformation. Patients with active IBD have elevated primary and conjugated BAs and decreased secondary BAs, accompanied by the impaired transformation activities (mainly deconjugation and 7α-dehydroxylation) of gut microbiota. Probiotics have exhibited certain positive effects by different mechanisms in the therapy of IBD. This review discussed the effectiveness of probiotics in certain clinical and animal model studies that might involve in gut microbiota-BAs axis. More importantly, the possible mechanisms of probiotics on regulating gut microbiota-BAs axis in IBD were elucidated, which we focused on the elevated gut bacteria containing bile salt hydrolase or BA-inducible enzymes at genus/species level that might participate in the BA biotransformation. Furthermore, beneficial effects exerted by activation of BA-activated receptors on intestinal immunity were also summarized, which might partially explain the protect effects and mechanisms of probiotics on IBD. Therefore, this review will provide new insights into a better understanding of probiotics in the therapy targeting gut microbiota-BAs axis of IBD. Inflammatory bowel disease (IBD), which encompasses mainly two clinical phenotypes, was first described in 1895. The two phenotypes are ulcerative colitis (UC) and Crohn’s disease (CD) . FurtherFor better understanding the probiotics, in the present review, we focused on the certain effects and probable functional roles of probiotics on regulating gut microbiota-BAs axis in IBD and CAC.via its effects on immune cells and epithelial intestinal cells. The processes of BAs synthesis and circulation have been extensively reviewed elsewhere. BAs synthesize in hepatocytes through the classical and alternative pathways. Primary BAs include cholic acid (CA) and chenodeoxycholic acid (CDCA). Subsequently, CA and CDCA conjugate to either glycine (predominantly in humans) or taurine (mainly in mice) to form conjugated BAs. Then, these BAs are released into intestine after a meal, and approximately 95% of them recirculate through enterohepatic circulation in the distal ileum. The remaining about 5% BAs are transported into colon and further metabolized by the colonic microbiota. The bacteria with BSH activity can deconjugate BAs into their unconjugated forms, including CA and CDCA. Afterward, they are converted to secondary BAs, namely, ursodeoxycholic acid (UDCA), lithocholic acid (LCA), and deoxycholic acid (DCA) through the microbiota possessing enzyme action of 7α-dehydroxylation. In addition, iso-BAs are produced by oxidation and epimerization at C3, C7, and C12 positions of hydroxyl by bacteria with hydroxysteroid dehydrogenases (HSDH)  , 16.Crosstalk between BAs and gut microbiota affect metabolic phenotypes, immunological functions, and risk factors for many diseases including diabetes, obesity, non-alcoholic fatty liver disease, IBD, and various cancers . In addiBifidobacterium, Lactobacillus, Bacteroides, Clostridium, and Listeria in BAs deconjugation; Clostridium and Eubacterium in 7α-dehydroxylation; Clostridium, Bacteroides, Escherichia, Eubacterium, Egghertella, Ruminococcu, and Peptostreptococcus in oxidation and epimerization; Fusobacterium, Clostridium, Peptococcus, and Pseudomonas in desulfatation; Lactobacillus, Bacteroides, and Eubacterium in esterification  and IL-10, and elevate Th17 (T helper 17) cells with pro-inflammatory cytokines  –treated macrophages by DCA, LCA, and tauro-LCA was able to inhibit the generation of IL-12 and TNF-α. Simultaneously, it increased the ratio of IL-10/IL-12, indicating the phenotypic transformation of macrophages into anti-inflammatory forms  , 58. Bil, IL-17) . Deficiery forms . Recruitd to gut .reg cells  and NKT cells, ILC, Th1, and Th17 cells . CDCA C. VDR is eg cells . IsoDCA eg cells . Beyond henotype . VDR acteg cells –81. TherBifidobacterium spp. and Lactobacillus spp. Currently, other probiotics, such as Saccharomyces, E. coli, Bacillus spp., Weissella spp., and Enterococci are available in the marketplace  prevented flare-ups of chronic UC by decreasing IL-1β and TNF-α levels, increasing IL-10 expression, and blocking Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Moreover, it elevated fecal Lactobacillus and Bifidobacterium  ameliorated endoscopic findings, clinical symptoms of UC patients, and increased fecal Bifidobacterium (Escherichia coli Nissle 1917 (EcN) by rectum was a well replacement treatment for moderate distal UC  that may involve in modulating gut microbiota-BAs axis are Lactobacillus plantarum, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus acidophilus, Bifidobacterium longum, and Bifidobacterium infantis) plus prednisone therapy could accelerate clinical remission, upregulate the expression of E-cadherin, occludin, and zonulin but did not improve the histopathologic inflammation than prednisone alone group in canine with idiopathic IBD. In addition, the combination therapy increased fecal Bifidobacterium , and exerted an anti-inflammatory effect  lowered macroscopic and microscopic damage, reduced serum cytokine levels, but not dampening M1 macrophages. Of note, fecal Parabacteroides, Clostridium were increased in mice being given VSL#3 than in the TNBS colitis mice  ameliorated decreased body weight and clinical features and simultaneously enhanced fecal Lactobacillus and Bacteroides , claudin-3 and α-catenin1, suppressed Toll-like receptor 4/NF-κB pathway and related pro-inflammatory cytokines. Moreover, it promoted the growth of Lactobacillus and Bifidobacterium in feces -155 and miR-223 expression, and increasing fecal Parabacteroides, Bacillus /DSS-induced CAC. Furthermore, it changed fecal microbiota, which included elevated Blautia and Bifidobacterium at genus level , Cxcl3, Cxcl2 and Cxcl1, increased the abundance of Lactobacillus, Bifidobacterium in the stool  from the National Natural Science Foundation of China, the Key Project of Science and Technology Pillar Program of Tianjin (20YFZCSY00020).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.