Background: There are numerous guidelines developed for bone health. Yet, it is unclear whether the differences in guideline development methods explain the variability in the recommendations for vitamin D and calcium intake. The objective of this systematic review was to collate and compare recommendations for vitamin D and calcium across bone health guidelines, assess the methods used to form the recommendations, and explore which methodological factors were associated with these guideline recommendations. Methods: We searched MEDLINE, EMBASE, CINAHL, and other databases indexing guidelines to identify records in English between 2009 and 2019. Guidelines or policy statements on bone health or osteoporosis prevention for generally healthy adults aged ≥40 years were eligible for inclusion. Two reviewers independently extracted recommendations on daily vitamin D and calcium intake, supplement use, serum 25 hydroxyvitamin D [25(OH)D] level, and sunlight exposure; assessed guideline development methods against 25 recommended criteria in the World Health Organization (WHO) handbook for guideline development; and, identified types identified types of evidence underpinning the recommendations. Results: we included 47 eligible guidelines from 733 records: 74% of the guidelines provided vitamin D (200~600–4000 IU/day) and 70% provided calcium (600–1200 mg/day) recommendations, 96% and 88% recommended vitamin D and calcium supplements, respectively, and 70% recommended a specific 25(OH)D concentration. On average, each guideline met 10 (95% CI: 9–12) of the total of 25 methodological criteria for guideline development recommended by the WHO Handbook. There was uncertainty in the association between the methodological criteria and the proportion of guidelines that provided recommendations on daily vitamin D or calcium. Various types of evidence, including previous bone guidelines, nutrient reference reports, systematic reviews, observational studies, and perspectives/editorials were used to underpin the recommendations. Conclusions: There is considerable variability in vitamin D and calcium recommendations and in guideline development methods in bone health guidelines. Effort is required to strengthen the methodological rigor of guideline development and utilize the best available evidence to underpin nutrition recommendations in evidence-based guidelines on bone health.  Due to global aging, the prevalence and incidence of osteoporosis and fractures continue to rise in both developed and developing countries . The socVitamin D and calcium are two essential nutrients for normal bone growth and bone maintenance. Calcium plays a crucial role in skeletal mineralization, supporting bone strength and muscle contraction. Vitamin D facilitates calcium absorption via its active hormonal form, 1,25-dihydroxycholecalciferol , working together with the parathyroid hormone to maintain calcium homeostasis ,7,8,9. TIn public health and clinical guidelines on bone health, vitamin D and calcium recommendations constitute an important, non-pharmacological strategy for bone maintenance and the prevention of osteoporosis and fractures. However, specific recommendations vary in the guidelines from different countries and even differ among organizations within a country. This is partially due to the conflicting evidence seen in the effectiveness of vitamin D and calcium supplements on bone mineral density ,12 and fLike other health conditions, bone health guidelines are ubiquitous in the healthcare system. Many national and international bodies have established similar standards to develop evidence-based guidelines ,21,22,23The objective of this study was to collate and compare recommendations for vitamin D and calcium across bone health guidelines globally, use the guideline development methods recommended by the WHO to appraise the quality of the methods used to develop guideline recommendations, and identify methodological factors that might affect the recommendations of vitamin D and calcium intakes, dietary and supplemental intakes, serum level of 25(OH)D, and sunlight exposure. We registered this systematic review in PROSPERO (registration number: CRD42019126452) in March 2019 and published a peer-reviewed protocol .Working with an experienced academic librarian, we searched for bone health guidelines or policy statements in the following electronic databases: MEDLINE (via OVID), EMBASE (via OVID), CINAHL (via EBSCO), Practice-Based Evidence in Nutrition, National Guideline Clearinghouse , NICE, and Guidelines International Network (GIN) in March 2019. The search period was restricted from 1 January 2009 to 28 February 2019. For other databases, the searches were based on a single keyword or a combination of vitamin D , bone, osteoporosis, guideline/policy, and recommendation as search terms. The search strategy used to retrieve the guidelines in MEDLINE, EMBASE, and CINAHL as well as the other databases indexing guidelines mentioned above are described in the Details of the inclusion and exclusion criteria were published in our protocol . To qualOne reviewer (ZD) screened the titles and abstracts of all the retrieved records. The full text of potentially eligible guidelines or policy statements was further assessed and finalized among three reviewers  based on reading the full text thoroughly and the eligibility criteria noted above. Data on guideline characteristics, vitamin D and calcium recommendations, and evidence cited to support the recommendations were extracted . For botTo ensure consistency in the extraction of the recommendations, which comprised of both quantitative  and qualitative  information, we adopted the criteria proposed by Woolf and colleagues . We firsUsing a content analysis approach, two reviewers (ZD and SM or LB) independently appraised each guideline according to a set of 25 criteria, adopted from the 2014 WHO handbook for guideline development  that areFor each guideline, we rated whether each of the recommended WHO methodological criteria were applied  using thAll data extraction and method assessments of the guideline development processes were captured and stored using the Research Electronic Data Capture, an electronic data capture tool hosted at the University of Sydney . The datDescriptive summary statistics, using frequencies and percentages, were used to summarize guideline characteristics and the recommendations made for the daily recommended intake of vitamin D , calcium (mg/day), and the recommended level of serum 25(OH)D (1 ng/mL = 2.5 nmol/L). We also recoded some of the recommendations into the dietary recommendations made for either vitamin D/calcium-rich food (Yes/No), supplement recommendations made for either vitamin D/calcium supplements (Yes/No), and sunlight exposure recommendation (Yes/No). For the types of evidence supporting the recommendations, we combined three groups of guidelines ) into one category. For assessing guideline development methods, we calculated the mean  of the WHO methodological criteria met for each guideline and the proportion (95% CI) of guidelines that fulfilled each of the criteria. We examined the association between each of the WHO methodological criteria and the forming recommendations of daily intake for vitamin D and calcium to investigate whether the variability in the quality of the guideline methods could potentially explain the variations in the recommendations. Because of the small sample of the guidelines, we combined different types of recommendations into a binary variable, i.e., vitamin D or calcium recommendation made (or not made). We calculated the risk difference (RD) between a guideline process that had met or not met a WHO guideline development criterion and the recommendations made on vitamin D/calcium . We used a confidence level of 99% to calculate the confidence intervals for these differences (rather than 95%) to facilitate greater caution in our interpretation of the results, due to the number of associations examined. We calculated Fisher’s exact P-value because there were a small number of guidelines. p-value (<0.05) is considered statistically significant. All analyses were performed using SAS (version 9.4) or Stata version 16 . The forThis study was supported by the Australian National Health and Medical Research Council (NHMRC) project grant (APP1139997), which aims to strengthen the evidence foundation for public health guidelines. The NHMRC is one of the two major government funding agencies that allocates competitive research funding at Australian universities. The funding source played no role in the conceptualization, design, analytical methods, data interpretation, reporting of the manuscript, and publication decisions.After the removal of 160 duplicates from the 733 records identified from different databases, 573 records remained. A further 456 records were removed after screening the title or abstract and 117 records underwent full-text screening, from which 47 eligible guidelines were included . Supplemn = 12) were for women only. Based on the World Bank Gross National Income per capita [n = 35) were developed in countries at middle-upper or high-income levels; a majority of the guidelines originated in Europe  and North America . A medical or academic society produced most of the guidelines  and 62% (n = 29) did not disclose a funding source. Among the 47 guidelines, 65% were published between 2009 and 2014 . Most gur capita , 81% (n n = 19) recommended getting vitamin D from dietary sources, 96% of the guidelines (n = 45) recommended taking vitamin D supplements, and 26% of the guidelines (n = 12) recommended getting vitamin D from outdoor sunlight to maintain bone health. Notably, one guideline may recommend getting vitamin D from different sources; therefore, the percentages of the different types of sources do not add up to 100. Furthermore, 33 guidelines (70%) recommended serum concentration for 25(OH)D, ranging from 25 to 75~250 nmol/L  and used words such as “optimal”, “sufficient”, “adequate”, “ideal”, “desirable”, “sustained”, “required”, and “minimal” for the recommended level. The daily intake recommendations on vitamin D or calcium vary considerably in the guidelines. For vitamin D, most guidelines 37, 79%) provided a daily intake recommendation ranging from 200~600 IU to 4000 IU per day . Among t, 79% proFor calcium, 35 guidelines (74%) provided daily recommended intake, ranging from 600 to 1300 mg . Among tn = 8) of the guidelines recommended having a nutritionally balanced diet to maintain bone health or prevent osteoporosis. Regarding the recommendations on a whole foods diet, only 17%  of the 25 WHO methodological criteria were met per guideline. Four criteria that were met by more than 70% of the guidelines were: “Priority of the problem stated: Is the problem a burden of disease?” (83%), “Disclosure of conflicts of interest” obtained (74%), “Are recommendations explicitly linked to evidence?” (74%), and “Discipline representation” of the guideline development group (70%) . The leap = 0.02) and between “guidelines that had undergone an external review” and recommendations made for daily intake of calcium , we cannot rule out whether these results were found by chance, due to the small sample size and wide confidence intervals. There was no clear evidence of an association between the WHO methodological criteria being met and making recommendations for daily intake of vitamin D or calcium . The CIsPrevious bone health guidelines were cited the most to support the recommendations, except for those on sunlight exposure (commentary) and supplemental calcium (systematic reviews of RCTs) . For exaIn this systematic review of 47 evidence-based bone health guidelines around the world, we found that the range of the recommended daily intake and supplementation of vitamin D, calcium, and serum level of 25(OH)D varied substantially; most of the guidelines recommended taking supplements for bone health and the prevention of osteoporosis. Overall, the methodological quality of these guidelines is low, with, on average, only 10 out of 25 of the WHO methodological criteria for guideline development being met. Particularly concerning criteria included, lack of diversity of representation in the guideline development group, little description of the management of conflict of interest (COI), limited use of systematic review methods to synthesize evidence, lack of consideration in health equity and acceptability to meet target users’ needs, and there was a paucity of external review of the guidelines. With a small sample of bone health guidelines, although we could not find clear evidence of the associations between the WHO methodological criteria and variabilities of the recommendations on daily intake of vitamin D or calcium, we found that the primary source of evidence underpinning most recommendations was previously published guidelines. The substantial variability in the recommended levels of vitamin D (200~600–4000 IU/day) and calcium (600–1300 mg/day), particularly vitamin D, and a lack of systematic reviews as supporting evidence, raises concerns about vitamin D and calcium supplementation recommended by these evidence-based bone health guidelines. As a comparison, the WHO nutrient requirement intake (NRI) for vitamin D is 200 IU/day for adults aged 19–50 years, 400 IU/day for those aged 51–65 years, 600 IU/day for those aged 65+ years, 1000 mg/day for 19–65 years/menopause, and 1300 mg/day for 65 years+/post menopause . The US Moreover, current findings on the effectiveness of vitamin D and calcium supplementation on bone mineral density and on fracture prevention are inconsistent. Several systematic reviews of RCTs have suggested no beneficial effect of vitamin D supplementation on the prevention of total fractures or hip fractures ,13,45,46With a sample of 47 guidelines and the width of confidence intervals from our results, we were not able to establish whether any of the guideline processes were associated with the recommendations made on daily intake of vitamin D or calcium, nor the variation of the recommended levels. However, the top 10 guidelines that met at least 16 of the 25 WHO methodological criteria  for guidAlthough most guidelines disclosed authors’ COI, only 15% described a procedure to manage it. Disclosure alone does not prevent bias associated with COI; hence, any identified COI must be eliminated or managed ,51 to reWe also found that many bone health guidelines used previous bone guidelines to support their recommendations. A similar finding was reported in a review of national dietary guidelines in support of dietary recommendations . The higThis review has several strengths. We adopted a comprehensive search strategy to identify global bone health guidelines and policy statements related to vitamin D and calcium recommendations among generally healthy adults aged 40 years and above. Our research questions, search strategy, and planned methods were developed a priori and published in a peer-reviewed journal . Two revThis review also has limitations. We primarily relied on what was documented in the published guidelines. This may limit our ability, for criteria marked as “Unclear”, to fully determine whether a process was not implemented or simply not mentioned. Secondly, certain aspects of the development processes were deemed missing if guideline development standards other than the WHO methodological criteria were used. Thirdly, although we assessed whether systematic review methods were adopted to identify and evaluate evidence for each guideline, we did not evaluate whether an original systematic review was conducted or whether previous guidelines were the primary source of evidence. Also, we did not assess the methodological rigor of previous guidelines that were used as a primary source of evidence. Including English only publications has limited our sample size and regional coverage, resulting in a higher portion of guidelines from English-speaking countries. In conclusion, we found that recommendations on vitamin D and calcium vary substantially in a set of 47 evidence-based bone health guidelines across different countries/regions in the world; variability exists in guideline development methods and in the types of evidence underpinning the recommendations. From the public health’s perspective, these substantial variations in the bone health guidelines could affect clinicians’ prescribing decisions regarding vitamin D/calcium supplemental intake levels for their patients to prevent osteoporosis. Hence, our review points to the importance of adhering to the standard evidence-based guideline development methods to formulate rigorous recommendations.In summary, our findings suggest that future guideline groups should document efforts to utilize the best available evidence to substantiate nutritional recommendations, implement procedures to eliminate or manage potential conflicts of interest, and address health equity and acceptability in formulating guideline recommendations. This review provides a benchmark of methods and processes used to develop public health guideline recommendations, against which future studies can be compared.


The Evidence Integration Triangle involved engaging stakeholders in the 12 month FFC-AL-EIT activities including identifying community specific goals, supporting the staff implementing the intervention, and intervening when champions or staff were not engaged in intervention activities. Ongoing participation of the stakeholder team occurred through monthly meetings. Evaluation of implementation was based on the Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM) Model. Reach was based on 85 of 90 communities participating and 794 residents recruited. Effectiveness was supported based on less functional decline and more function focused care performed by residents. Adoption was based on evidence that monthly meetings were held, 77% of settings engaged as, or more than expected, and caregivers increased the amount of function focused care provided. The intervention was implemented as intended, knowledge was received, and environments and policies supporting function focused care were maintained. The Evidence Integration Triangle is an effective implementation approach for assisted living.


We looked at existing recommendations for preventing unintentional injuries in children under five years of age, and we attempted to identify the main sources used as evidence for formulating these recommendations.We conducted a literature search up to the 18th October 2019 by using key terms and manual search in selected sources. We summarized the recommendations and source of the evidence in tables for each of five areas of unintentional injuries: road traffic injuries, drowning, poisoning, thermal injuries, falls.In 2008, the World Health Organization (WHO) published a comprehensive report with strategies for child injury prevention for the European region. More recently, the WHO published several guidance documents focused on one area such as drowning, usually with a global focus. The PrevInfad workgroup (Spanish Association of Primary Care Pediatrics) updated their document on road safety in April 2019, providing recommendations and a summary of the existing evidence. Preventive strategies for injuries in childhood are mainly based on surveillance data and the identification of risk factors. The key strategies for preventing unintentional injuries are a combination of environmental and behaviour modification, that can be achieved through engineering, enforcement and education. Consequently, for this kind of strategies, it is important to evaluate the effectiveness of both the intervention itself, and the way the intervention is advised to parents and caretakers so that there is good compliance of the recommendation. The World Health Organization (WHO) European Region is developing a new pocket book for primary health care for children and adolescents in Europe. This article is part of a series of reviews, which aim to summarize the existing recommendations and the most recent evidence on preventive interventions applied to children under five years of age to inform the WHO editorial group to make recommendations for health promotion in primary health care. In this article, we looked at existing recommendations for preventing unintentional injuries in children under five years of age, and we attempted to identify the main sources used as evidence for formulating these recommendations.An injury is ‘the physical damage that occurs when the human body is suddenly subjected to amounts of energy that exceed the physiological threshold or is deprived of vital elements such as oxygen’ . ‘The enUnintentional injuries cause death and long-term disabilities in many children in the WHO European Region. Already in 1958, the WHO European Region Office recognized injuries as ‘the leading cause of childhood death in Europe’ . Among cHowever, injuries are an important preventable cause of premature death. In 2015, the Royal Society for the Prevention of Accidents in England estimated that unintentional injuries constitute between 60 to 65% of preventable deaths among children under five years of age, and more than 85% of preventable hospital admissions among children under nine years of age . Prevention of unintentional injuries in children is a broad area comprising preventive measures for traffic injuries, drowning, poisoning, burns, falls, etc. Summarising all the existing recommendations and conducting a search to identify all the systematic reviews and other relevant studies for each of the areas included in prevention of unintentional injuries in childhood is beyond the scope of this document. Therefore, we used a different approach for this topic compared to the rest of the preventive interventions we have summarized in the other articles of this supplement . We have selected five areas of unintentional injuries that we estimated to be the most relevant as for prevalence and severity, following the classification usually used by the WHO: 1) road traffic injuries; 2) drowning; 3) poisoning; 4) thermal injuries; 5) falls. For each of the selected area, we report existing recommendations given by selected guidelines or institutions and provide illustrative systematic reviews and other relevant studies that the guidelines used in formulating their recommendations.We conducted the search up to the 18th of October 2019, by manual search and by using the search terms: ‘road traffic accident’ OR ‘unintentional injuries’ OR ‘pedestrian’ OR ‘child restraint device’ OR ‘helmet’ OR ‘drowning’ OR ‘poisoning’ OR ‘intoxication’ OR ‘burn’ OR ‘thermal’ OR ‘scald’ OR ‘fall’ within child health OR ‘accident prevention’. We searched the same sources as for the other articles of this supplement, those are: the WHO, the US Preventive Services Task Force (USPSTF), PrevInfad, the Royal College of Paediatrics and Child Health (RCPCH), the Centers of Disease Control and Prevention (CDC), the National Institute for Health and Care Excellence (NICE), and the Cochrane library. We contacted field experts for additional references such as reports from meetings. For the sources of the evidence, we report systematic reviews and trials we deemed relevant, cited as references for supporting the identified strategies, as well as those identified by directly searching in the Cochrane library. In most cases, the documents reporting the strategies and recommendations present a broader and more extensive list of references; some documents summarised the main findings. The list we provide is therefore not exhaustive but attempts to be rigorous and methodical.We summarise the recommendations and source of the evidence in tables for each of the five selected areas.Evidence indicates that a range of different approaches can prevent or reduce the impact of injuries, commonly referred as the 3 Es: 1) Engineering, for modifying products and modifying the environment to make home safer; 2) Enforcement, through laws, regulations and standards; and 3) Education and skills development, including emergency health care [Randomized controlled trials that compare injuries or deaths between children exposed and unexposed to a preventive strategy or measure are most of the times not feasible and unethical. Most of the data come from surveillance data, and retrospective analysis, that identify risk factors and risk patterns, which assist in the development of strategies to reduce the risk. Consequently, due to the nature of the topic and the lack of supportive evidence, some recommendations are characterized as ‘good practice recommendations.’ Those are ‘overarching principles derived not from scientific evidence but from common sense and established international agreements on ethics and human rights’ .In this document, we summarize recommendations and sources of evidence by type of injury. However, the evidence supporting approaches that work for prevention goes beyond this. On the one hand there is a need to understand which preventive interventions work for preventing unintentional injuries, for example whether installing fencing around a pool will prevent drowning. On the other hand, there is a need to understand by which means it is most effective to put the preventive intervention into practice. That is, how to make families to install fencing around their pool. The PrevInfad and the RCPCH groups assessed the evidence around these aspects on a structured way in their respective documents on road safety and book chapter , 5.In 2008, the WHO estimated that road traffic injuries were the leading cause of fatal injuries in children and a leading cause of traumatic head and extremity injuries with consequent long-term disability throughout the WHO European Region . The SusSeveral publications on road traffic safety are available from the WHO, ‘which have been developed jointly by multiple partner agencies of the UN Road Safety Collaboration, or in some cases by individual partner agencies’ . Other rPrevInfad has recently updated their recommendation (April 2019) and provided a comprehensive document summarising the existing evidence around measures for preventing traffic injuries in children . The PreThe USPSTF have decided not to update their 2007 recommendations. ‘Based on the currently available evidence, the USPSTF believes the potential impact of a new USPSTF recommendation on counselling for proper use of motor vehicle occupant restraints and avoidance of alcohol use to prevent injury is limited’ . TherefoIn 2010, NICE published three guidance documents on how to prevent unintentional injuries in children under 15 years of age. One of them addressed unintentional injuries on the road .EuroSafe, the European Association for Injury Prevention and Safety Promotion, was created with the mission ‘to prevent home and leisure accidents by working in partnership with industry, governments, research institutes and health and safety practitioners to help reduce the greatest risks’ . In 2006Aware of the importance of the topic and the need of updating evidence-based recommendations, the WHO has very recently made a call ‘to review literature on new evidence on selected road traffic injury risk factors and interventions’ . The WHOWe summarize in Table Drowning is ‘the process of experiencing respiratory impairment from submersion/immersion in liquid’ . In 2008The 2008 WHO European report on child injury includes strategies for the prevention of drowning . More rePrevInfad recommendations date from 2011; the Group is currently updating this chapter . Under tOne of the three NICE guides published in 2010 recommends some actions to be taken for preventing drowning in children .We identified one Cochrane systematic review, published in 1998, that assessed the pool fencing for preventing drowning in children. The rest of the evidence comes mainly from national, state or provincial health data collection systems, national databases on drowning information, and surveys. The 2017 global WHO guide provides a broad bibliography.We summarize in Table Poisoning refers to ‘an injury sustained due to exposure to a substance that causes cellular injury or death’ . The expPoisoning is the third leading cause of unintentional injury death in the European Region, as estimated by the WHO in 2008 . Non-fatThe 2008 WHO European report on child injury classified their recommendations and key strategies to prevent poisoning as effective, promising, insufficient evidence, or ineffective . Four keOther sources and information can be found in the WHO website . The IPCAs mentioned for drowning, PrevInfad recommendations date from 2011 . Under tA Cochrane systematic review determined the effect of modifications to the home environment on the reduction of injuries due to environmental hazards . The revWe summarize in Table A thermal injury is ‘an injury to the skin and other organic tissue caused by thermal trauma’ . ThermalThe 2008 WHO European report on child injury give recommendations for preventing thermal injuries, with a focus to the European region. The same year, the WHO published a global report known as the ‘Burn plan’ . In 2011A 2010 NICE guidance document on prevention strategies for unintentional strategies recommend some actions to be taken for preventing thermal injuries in children .The Cochrane systematic review that looked at the effect of modifications to the home environment on the reduction of injuries due to environmental hazards included some interventions related with thermal injuries . AnotherWe summarize in Table A fall is defined as ‘an event that results in a person coming to rest inadvertently on the ground or floor or other lower level’ . Falls oOne of the three NICE documents published in 2010 on prevention strategies for unintentional strategies recommend some actions to be taken for preventing falls in children .We summarize in Table In 2008, the World Health Organization (WHO) published a comprehensive report with strategies for child injury prevention for the European region. More recently, the WHO published several guidance documents focused on one area such as drowning, usually with a global focus.The PrevInfad workgroup (Spanish Association of Primary Care Pediatrics) updated their document on road safety in April 2019, providing recommendations and a summary of the existing evidence. They are currently working on updating the document on home safety, which includes prevention of drowning, poisoning, thermal injuries and falls.The key strategies for preventing unintentional injuries are a combination of environmental and behaviour modification, that can be achieved through engineering, enforcement and education. Consequently, for this kind of strategies, it is important to evaluate the effectiveness of both the intervention itself, and the way the intervention is advised to parents and caretakers so that there is good compliance of the recommendation.Preventive strategies for injuries in childhood are mainly based on surveillance data and the identification of risk factors.


Nephritis is a recognised complication of IgA vasculitis  contributing to 1–2% of all chronic kidney disease (CKD) stage 5. Improved understanding may reduce irreversible damage in IgAV nephritis (IgAV-N).The aim of this study was to perform a comprehensive systematic literature review to identify promising clinical and pre-clinical urine biomarkers in children with IgAV-N that could predict the presence of nephritis and/or determine its severity.p < 0.05) and area under the curve (AUC) values.A systematic literature review was performed using four search engines and a predefined search term strategy. Promising biomarkers were divided in terms of clinical or pre-clinical and ability to predict the presence of nephritis or determine its severity. Results were described using statistical significance (n = 761), children with IgAV-N (n = 1236) and children with IgAV without nephritis . Fifty-one percent were male, median age 7.9 years. The clinical markers, 24-h protein quantity and urine protein:creatinine ratio, were deemed acceptable for assessing severity of nephritis (AUC < 0.8). Urinary albumin concentration  performed well (AUC 0.81–0.98). The most promising pre-clinical urinary biomarkers in predicting presence of nephritis were as follows: kidney injury molecule-1 (KIM-1) (AUC 0.93), monocyte chemotactic protein-1 (MCP-1) (AUC 0.83), N-acetyl-β-glucosaminidase (NAG) (0.76–0.96), and angiotensinogen (AGT) (AUC not available). Urinary KIM-1, MCP-1, and NAG appeared to correlate with disease severity.One hundred twenty-one studies were identified; 13 were eligible. A total of 2446 paediatric patients were included: healthy controls (Longitudinal studies are needed to assess whether pre-clinical biomarkers enhance standard of care in IgAV-N. Immunoglobulin A (IgA) vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is the most common form of vasculitis in children, with an estimated incidence of 20.4 cases/100,000 childhood population . The proThe primary aim of this study was to perform a comprehensive systematic literature review to identify promising clinical and pre-clinical urine biomarkers in children with IgAV that can either predict the presence of nephritis and/or determine its severity.The inclusion criteria were paediatric participants (<18 years) of any sex and ethnicity, with a diagnosis of IgAV-N. A diagnosis of IgAV-N included any of the following: abnormal urinalysis; haematuria and/or a high urinary protein concentration within 6 months of the onset of rash; and/or a reduced estimated glomerular filtration rate (eGFR) in participants who had met the clinical diagnosis of IgAV . The excThe intervention of interest was biomarker assay evaluation in a urine sample.The study aimed to compare: (i) urine biomarkers that may determine the presence of nephritis in children with IgAV-N compared to children with IgAV and no nephritis (IgAV-noN) and/or healthy paediatric controls and (ii) urine biomarkers that may determine the severity of nephritis in children with IgAV-N.The outcome of interest was the identification of clinical or pre-clinical biomarkers that are able to determine the presence of nephritis as defined by each individual study and/or the severity defined in terms of the International Study of Kidney Disease in Children (ISKDC) classification histological grade or extent of proteinuria .n > 5) that were all accessible in full text through the University of Liverpool, with at least an English abstract. Secondary data and animal studies were excluded, as well as papers with an original publication date before October 2000, allowing for a 20-year inclusion period. The reference lists of relevant literature were hand-searched to identify any additional eligible studies.Using predefined methodology, this systematic review evaluated the current available literature. Four online databases, PubMed, Web of Science, Medline, and Scopus, were used with the following terms: (((((((((neonat*) OR (adolescen*)) OR (infan*)) OR (child*)) OR (pediatric*)) OR (paediatric*)) AND ((((((immunoglobulin A vasculitis) OR (IgA Vasculitis)) OR (IgAV)) OR (Henoch Sch*nlein purpura)) OR (Henoch-Sch*nlein purpura)) OR (HSP))) AND (((((((nephritis) OR ) OR (kidney injur*)) OR ) OR (kidney damage)) OR (ckd)) OR (chronic kidney disease))) AND (urin*)) AND (biomarker*). The studies included were meta-analyses, randomised control trials (RCTs), cohort studies, case-control studies, cross-sectional studies and case series . Where full English transcripts were unavailable, data was extracted from the English abstract.p-values < 0.05 and a confidence interval which does not overlap 0 will be considered significant. As it was expected that the studies revealed would be heterogeneous, a meta-analysis was not conducted.The “Appraisal tool for Cross-Sectional Studies” (AXIS) tool was used, which comprises 20 questions to appraise and compare the quality of the literature . Pre-cliEthical approval was not necessary for the performance of this review, as per the National Health Service Research Authority, as it involved secondary review of existing literature.The search took place in September 2020 and yielded 121 papers. A total of 65 duplicates were removed leaving 56 titles eligible for abstract screening. Of these, 26 papers were eligible for full text review. After full text review, 11 were included in the systematic review. A second, independent reviewer (AT) repeated the search, at a time point 1 month later, to identify papers and determined whether the studies met the inclusion criteria; 128 papers were retrieved and after deduplication, two additional papers were identified that met the inclusion criteria, producing a total of 13 papers , 761 healthy paediatric controls  and 449 children with IgAV-noN . The publication dates spanned from 2011–2020 , 17, 27 The quality appraisal produced a good median AXIS score of 16/20 range 14–17). One study was excluded from the quality assessment as it was not available in full text in English and there was insufficient detail in the abstract [. One stuA total of 23 urine biomarkers were discovered that had been reported to be associated with IgAV-N; 20 were pre-clinical and 3 considered clinical biomarkers (Table (i)n = 694) compared to healthy controls . In a second paper, the urine Malb concentration was significantly increased in the IgAV-N group (n = 37) compared to both healthy controls and the IgAV-noN cohorts (p < 0.05) and the control group (n = 37) was not significantly different to the IgAV-noN patients  [Presence of nephritis: As expected, the 24h-UPRO was significantly increased in children with biopsy-proven IgAV-N ( > 0.05) .(ii)p < 0.01). The AUC value was 0.77 for 24h-UPRO as a biomarker in distinguishing histology grades IIb, IIIa and IIIb. UPCR was also evaluated when assessing the severity of nephritis producing an AUC value of 0.73 [n = 45, p < 0.05), with excellent AUC values for histological comparison  [Severity of nephritis: Importantly, differences could be seen within the IgAV-N cohort when comparing histological grades I and IIa versus IIb, IIIa and IIIb  .(i)n = 37) compared to both healthy controls (n = 37) and IgAV-noN  [n = 66) compared to children with IgAV-noN  [Presence of nephritis: One paper found that urine β2-MG was significantly increased in IgAV-N patients ( < 0.05) . Qin et  < 0.05) .(ii)n = 45) compared urinary β2-MG with the histological grades, grouped according to the ISKDC classification [p < 0.05) with no statistical difference between the histological classifications [p = 0.89) [Severity of nephritis: Another paper  .(i)n = 29) when compared to the controls (p < 0.005) but there was no significant difference between IgAV-noN (n = 18) and IgAV-N (n = 11). Urinary KIM-1 concentrations decreased over time in IgAV-N and IgAV-noN [n = 32) compared to IgAV-noN  and healthy controls . The AUC for KIM-1 in predicting nephritis was outstanding at 0.93  [Presence of nephritis: This was reported as a potential biomarker in two studies. Dyga et al. found that KIM-1 was statistically significantly increased acutely in all IgAV patients (IgAV-noN . Zhang e < 0.05) .(ii)r = 0.671, p < 0.01) [Severity of nephritis: A positive correlation between urinary KIM-1 levels and histological grade or total urine protein was found ( < 0.01) . Another < 0.01) .(i)n = 57) compared to healthy controls (n = 25) or IgAV-noN  [n = 126) compared to healthy controls  and IgAV-noN . Urine MCP-1 concentrations increased in parallel with the degree of urinary protein concentration [Presence of nephritis: This was found to correlate with IgAV-N in two studies, reporting 447 children. Fuentes et al. reported a statistically significantly increased urinary MCP-1/Cr concentration in the IgAV-N cohort ( < 0.01) . Wang etntration .(ii)p < 0.01) [Severity of nephritis: One paper found that the AUC for MCP-1 predicting nephritis was excellent  .(i)n = 32) compared to IgAV-noN . There was no difference between IgAV-noN (n = 27) and healthy controls (n = 16). The AUC for urinary NAG in distinguishing patients with nephritis was excellent  [Presence of nephritis: Zhang et al. also found increased urinary NAG concentration in IgAV-N ( < 0.01) .(ii)n = 45). The concentrations correlated with increasing histological grade (p < 0.05) and the AUC in predicting the histological grades were excellent for grade I vs. II (AUC 0.84 95% CI 0.67–1.00), outstanding for grade I vs. III (AUC 0.96 95% CI 0.89–1.00); and acceptable for grade II vs. III (AUC 0.76 95% CI 0.59–0.93) [Severity of nephritis: An and Xia evaluated urinary NAG in biopsy-proven IgAV-N (59–0.93) .(i)n = 14), IgAV-noN (n = 28) and healthy controls (n = 23). UAGT/Cr was significantly increased in IgAV-N compared to healthy controls and IgAV-noN (p < 0.05). This paper was unavailable in full text in English so limited data was extracted from the abstract only [n = 13) compared to both IgAV-noN (n = 51) and IgAV-N with only haematuria . This finding remained even during the convalescent phase where UAGT concentrations remained increased in the IgAV-N with a high urinary protein concentration compared to the IgAV-noN (p < 0.01) and the IgAV-N with haematuria (p < 0.01). The difference in concentration during the convalescent phase between the IgAV-noN and IgAV-N with haematuria was not significant [Presence of nephritis: Ma et al. compared IgAV-N (act only . Mao et nificant .(ii)Severity of nephritis: No studies assessed UAGT to determine the severity of nephritis.This systematic review aimed to identify current clinical and potential pre-clinical urine biomarkers associated with the presence of nephritis and its severity in children with IgAV-N. Using a predetermined systematic evaluation, we have reported a cohort of 2446 children, including 1685 children with IgAV, using data from 13 papers. These data identified 23 potential biomarkers described in the literature including the clinical biomarker of urinary protein concentration and 5 pre-clinical urine biomarkers that had been evaluated by more than one study. Of these pre-clinical biomarkers, 4 demonstrated promising association with IgAV nephritis: KIM-1, MCP-1, NAG and UAGT , 22, 24.The clinical biomarker that performed best at assessing the severity of nephritis was urinary albumin concentration with excellent AUC values (AUC 0.81–0.98) in determining the grade of histological inflammation in IgAV-N. The pre-clinical biomarkers, KIM-1, MCP-1, NAG and UAGT, demonstrate promise for their association with either the presence or severity of nephritis, and their relative advantages and disadvantages are summarised in Table In addition to highlighting promising biomarkers, this study provides insight into key biological pathways in IgAV-N. The fact that many of the most promising biomarkers arise as a result of tubulointerstitial inflammation is an extremely interesting finding as IgAV-N is traditionally considered solely a glomerulonephritis. Examples of these markers are KIM-1 and NAG. KIM-1 is a type 1 transmembrane protein that is absent in the normal kidney, upregulated in tubular injury and not expressed in other organs . It is aNephritis is the main long-term complication of IgAV and there is currently no way to predict and identify which children may get irreversible kidney damage from the outset, thus all children are committed to a period of at least 6 months of monitoring. A better understanding of the underlying biology represented by urine biomarkers may allow identification of children who are at low or high risk of disease progression allowing monitoring stratification from the outset. Further studies are required to demonstrate whether pre-clinical markers are superior to current clinical biomarkers in terms of their ability to earlier detect nephritis or predict severity.Limitations of this study include some studies being small and the heterogeneous nature of the papers regarding descriptive statistics, definition of nephritis, and type of sampling, methodologies, outcomes and data presentation made comparisons challenging. This review has identified the need for standardisation of biomarker evaluation in this disease to allow systematic comparison in the future. Some papers had missing data and one was only available in abstract form in English. The majority of these studies were cross sectional in design, so future longitudinal studies are needed to evaluate how the biomarkers change with the course of disease. Finally, most of the papers included in our review were from China and the relevance of ethnic variation of the expression of urinary biomarkers is currently unknown.Overall, this study suggests that there are promising urine biomarkers for IgAV-N and some of these also originate from the tubulointerstitial region suggesting a pathophysiological role. In order to assess their true potential as adjuncts to clinical practice, long-term evaluation of these urine biomarkers is needed.


Parental preconception exposures to built and natural outdoor environments could influence pregnancy and birth outcomes either directly, or via a range of health-related behaviours and conditions. However, there is no existing review summarising the evidence linking natural and built characteristics, such as air and noise pollution, walkability, greenness with pregnancy and birth outcomes. Therefore, the planned scoping review aims to collate and map the published literature on parental preconception exposures to built and natural outdoor environments and adverse pregnancy and birth outcomes. We will search electronic databases  to identify studies for inclusion. Studies will be included if they empirically assess the relationship between maternal and paternal preconception exposures to physical natural and built environment features that occur outdoors in the residential neighbourhood and adverse pregnancy and birth outcomes. Two reviewers will independently screen titles and abstracts, and then the full text. Data extraction and assessment of study quality will be performed by one researcher and checked by a second researcher. Results will be summarised in a narrative synthesis, with additional summaries presented as tables and figures. The scoping review will be disseminated via a peer-reviewed publication, at academic conferences, and published on a website. Adverse pregnancy and birth outcomes are an ongoing health challenge globally. They also have lifelong consequences, with small and preterm infants having an increased risk of hypertension , type 2 Built and natural outdoor environments are important, yet underappreciated, avenues to intervene to improve pregnancy and birth outcomes at the population level. Considerable evidence shows that environmental characteristics near the home  are associated with health-related outcomes in both children and adults ,12,13,14Preconception is a critical window of susceptibility ,24,25. EOutdoor built and natural environments therefore, could well play a role in preconception health. There is a small but growing body of evidence demonstrating that maternal preconception exposure to environmental toxins–including air pollutants that commonly occur in residential neighbourhoods -adversely affects pregnancy and birth outcomes ,35. TherBeyond air pollutants, other aspects of the built and natural environment could also play an important role in preconception health. We know these outdoor environments are associated with health-related behaviours and conditions, such as physical activity, sedentary behaviour, diet, obesity, mental health, stress, smoking, and alcohol consumption. For instance, neighbourhoods with highly connected streets, high population density and a variety of destinations are associated with higher levels of physical activity and less sedentary behaviour  and obesThese same behaviours and conditions, which are in part determined by built and natural outdoor environments, also contribute to preconception health and to pregnancy and birth outcomes. For instance, the preconception diet for mothers predicts risk of gestational diabetes , preeclaWe know less about the impact of paternal preconception behaviours and health on birth outcomes . Most evIn summary, parental preconception exposures to built and natural outdoor environments could influence pregnancy and birth outcomes either directly, or via a range of health-related behaviours and conditions. A clear understanding of these relationships would enable us to identify modifiable environmental and behavioural risk factors that could improve the lifelong health of mothers, fathers, and infants. Yet the existing evidence is sparse and scattered, with a necessary first step being a coherent and systematic appraisal of what evidence exists and key evidence gaps. This is a task that is best suited to a systematic scoping review , which a(1)Identify and characterise the existing scientific evidence on relationships between maternal and paternal outdoor residential neighbourhood environments in the preconception period and adverse pregnancy and birth outcomes.(2)Identify evidence gaps and publish a narrative summary of the review and evidence map.Since there are no existing scoping or systematic reviews on parental preconception exposures to outdoor natural and built environments, we will conduct a scoping review that aims to:Previous versions of the protocol are registered in Zenodo. Version 1 was the initial protocol. We modified this prior to submission of this manuscript (Version 2). This manuscript represents the current version of the protocol. Any future modifications to this protocol will be similarly documented (including date and description of change), registered in Zenodo and reported in the final review paper.We will identify relevant peer-reviewed published literature by searching the following databases: PubMed, Embase, CINAHL and Scopus. The search terms will cover three topics: (1) the outdoor neighbourhood environment, (2) the preconception period, and (3) adverse pregnancy and birth outcomes. The specific search strings for each database and the initial number of hits are provided in Eligibility for inclusion is based on the Populations, Exposures, Comparators, and Outcomes PECO statement . To be iPreconception exposures: Given the variation in definition of the preconception period ,33, we wObjectively assessed physical outdoor environment features: We will restrict exposures to the physical characteristics of the outdoor environment. These will include environmental pollutants most commonly associated with residential neighbourhoods , weather/climate, and built and natural environmental features. We will focus only on the residential neighbourhood. We will include multiple definitions of residential neighbourhoods  at any scale.Objective and quantitative measurement of the environment.Peer reviewed, full text publications in the English language (acknowledging that this may result in English language bias).Additional inclusion criteria are:Search results will be imported into Covidence where the screening/selection process will be managed . DuplicaThe number of studies evaluated at each step will be recorded. Any modifications to the search or protocol will be included as amendments to the registered protocol.Data shown in Two researchers will independently extract the data from the included full text studies into the form. Inconsistencies will be discussed and if no agreement is reached, a third reviewer will decide. During data extraction, study quality will be assessed for each included study using the relevant Joanna Briggs Institute critical appraisal checklist ,81. As is appropriate for a scoping review, we will systematically map the existing evidence on parental preconception exposures to the natural and built environment, and we will visualise the evidence using charts, tables and maps. We will also provide a narrative summary of the results. Gaps and trends in the evidence will be discussed with reference to study quality. The synthesis will be grouped by exposures, outcomes, and study regions.This will be the first synthesis of evidence on parental preconception exposures to the broad range of natural and built environment features that we are exposed to in the course of our everyday lives. The findings from this review will be an important step towards helping to identify modifiable environmental and behavioural risk factors that could improve pregnancy and birth outcomes, as well as the lifelong health of mothers, fathers and infants. It will aid researchers by identifying key evidence gaps and important targets for future research and be of interest to stakeholders involved in urban environmental planning and design. The results will also be of practical use to primary care practitioners, who may use the findings to enhance evidence-based preconception patient education. Furthermore, these results will be applicable to clinicians’ assessments of women during the preconception period, as they may be better equipped to conduct an evidence-informed patient assessment related to environmental determinants of health. The review will be submitted for publication in a peer-reviewed journal and result summaries  will be published online. The scoping review does not require ethics approval since it consists of collecting and review publicly available documents.


This is the 24th in the ongoing series of articles describing the GRADE approach for assessing the certainty of a body of evidence in systematic reviews and health technology assessments and how to move from evidence to recommendations in guidelines.Guideline developers and authors of systematic reviews and other evidence syntheses use randomized controlled studies (RCTs) and non-randomized studies of interventions (NRSI) as sources of evidence for questions about health interventions. RCTs with low risk of bias are the most trustworthy source of evidence for estimating relative effects of interventions because of protection against confounding and other biases. However, in several instances, NRSI can still provide valuable information as complementary, sequential, or replacement evidence for RCTs.In this article we offer guidance on the decision regarding when to search for and include either or both types of studies in systematic reviews to inform health recommendations.This work aims to help methodologists in review teams, technology assessors, guideline panelists, and anyone conducting evidence syntheses using GRADE. This explains the advisability of incorporating evidence from NRSI in systematic reviews when they provide complementary, sequential, or replacement evidence to RCTs ,7.If RCTs alone may be unable to answer a PICO question  an evidence review team faces the following issues: (a) When to search and include both types of study designs? (b) What are the optimal methods to synthesize information from both type of studies, including the decisions about pooling data from different study designs? (c) How should authors present results in evidence profiles and summary of findings tables? and (d) When both RCTs and NRSI contribute to the evidence synthesis, what is the possible influence on certainty of the evidence? Interpretation issues may be particularly challenging when RCTs and NRSI show differences in the direction or magnitude of effects, as well as in other individual GRADE domains. This 24th article in the ongoing GRADE series in the Journal of Clinical Epidemiology represents the GRADE Working Group guidance assessing the first question: that is, when is it appropriate to search for and include NRSI in addition to RCTs during the evidence synthesis process.2This guidance is based on previous published work ,6,8, scoevidence synthesis as any systematic review, rapid review, health technology assessment or any other method aiming to summarize the evidence with the highest certainty available for a specific question about the effects of an intervention For this guidance, we define 33.1Guideline developers and authors of systematic reviews may have reasons to search for and include NRSI from the outset — this is, other than for assessing relative effects of interventions — irrespective of the availability of RCTs . Current reference managers and filters can make this sorting process feasible,15. At tThis process requires a review team with the appropriate content and methodological expertise, with a protocol describing precise methods for the optimal use of RCTs and NRSI. Although screening and reviewing NRSI are more time consuming than for RCTs 3.2After completing the sorting process and data extraction and risk of bias evaluation of available RCTs, authors should use the GRADE methodology to assess each RCT. Importantly, this assessment should always be made considering each outcome to rate the certainty of the body of evidence , as quantitative analyses , or a combination of both. In a recent survey we asked authors of systematic reviews about their preferences when facing a research question that could be informed by RCTs and NRSI; 17.5% preferred combining RCTs and NRSI into a single pooled estimate , while a majority reported their findings separately for the two types of study designs — either in sub-groups, in separate meta-analyses, or in narrative tables When crafting health recommendations, guideline development groups or panelists must decide if using the two bodies of evidence would leave them with higher certainty in the evidence than if they would use only 1 of the bodies of evidence, considering each GRADE domain affected and the implications on the final recommendation per outcome.5Until now, we have assessed the integration of both bodies of evidence in GRADE irrespective of which risk of bias assessment tool had been used. Several tools to assess risk of bias in NRSI exist  A useful contribution of the ROBINS-I tool, within the framework of developing a systematic review, is the conceptualization and consideration of a “target trial” , which prompts authors assessing a clinical question about an intervention to ask, how a study that answers this question would be conducted by a randomized controlled experiment, regardless of the feasibility to do it. The target trial, in terms of the integration of NRSI with RCTs, facilitates the comparison between RCT and NRSI because they are placed on a common metric allowing the investigator to evaluate bias in the NRSI compared to the target trial.The main difference between RCTs and NRSI results from randomization that protects essentially against imbalances in prognostic factors 6Including both RCTs and NRSI in a single systematic review or health guideline has generated controversy and diverse opinions Practitioners, coverage decision makers, health policymakers, and other stakeholders often face challenging health questions for their decisions and recommendations. These questions require evidence syntheses that strive for the highest certainty of evidence, whether this comes from high certainty RCTs or from NRSI that further complement (e.g. when indirect or imprecise) or replace the body of evidence from RCTs .In this article, we provide guidance for authors interested in maximizing the amount of informative evidence in health syntheses from different study designs. In subsequent work, we will address the issue of using both RCTs and NRSI in systematic reviews using GRADE, including the question of whether or not to pool them, and if they can be pooled, what conditions should be fulfilled. Meanwhile, further research is needed to address the distribution of GRADE certainty of evidence levels in systematic reviews that includes RCTs and NRSI, or which GRADE domains prove to have serious limitations when review authors consider both bodies of evidence.7•The GRADE approach supports authors in deciding whether to search for and integrate NRSI with RCT in evidence syntheses about health interventions.•high certainty evidence for critical and important outcomes, we suggest not screening, nor using NRSI for an evidence synthesis.If authors identify RCTs that prove to have •moderate certainty of evidence from RCTs, it is unlikely that NRSI will supply higher certainty than moderate. NRSI will be classified as high or moderate only when authors can show reasons for rating up . However, NRSI may serve as complementary or sequential evidence when the reason to downgrade RCTs to moderate is due to indirectness.With •low certainty evidence from RCTs for critical or important outcomes, in particular undesirable health outcomes, searching for relevant NRSI may allow drawing conclusions with more confidence if they have information suggesting well-done NRSI are available When authors anticipate or identify •very low certainty evidence from RCTs for critical or important outcomes, in particular undesirable health outcomes, they should also search for relevant NRSI When authors anticipate or identify •Survey Slides and case studies presented at GRADE meetings in Washington, D.C., U.S. (2016), Seoul, South Korea (2016), Rome, Italy (2017), and Hamilton, Canada (2017).•Article first draft on 31-May-2017.•Reviewed by Holger Schunemann, Gordon Guyatt, and Jan Brozek on 27-July-2017.•Presented as part of CC's Ph.D. Thesis on 28-September-2017•Presented in Bogota, Colombia on April 2018.•Revised September, October, November, and December 2018•Revised September 2019•Revised December 2019 after calls•Revisions by CC until June 2020•Revised by HJS June 2020; January 2021•Approved by GGG, March 2021Carlos CuelloConceptualization and writing of original draftCarlos A. Cuello-Garcia; Gordon Guyatt; Holger J. SchünemannWriting, review, editing, final approvalCarlos A. Cuello-Garcia; Nancy Santesso; Rebecca L. Morgan; Jos Verbeek; Kris Thayer; Mohammed T. Ansari; Joerg Meerpohl; Lukas Schwingshackl; Srinivasa Vittal Katikireddi; Jan L. Brozek; Barnaby Reeves; Mohammad H. Murad; Maicon Falavigna; Reem Mustafa; Deborah L. Regidor; Paul Elias Alexander; Paul Garner; Elie A. Akl; Gordon Guyatt; Holger J. SchünemannCCG, NS, RLM, JV and HJS have received funding from the Methods Innovation Fund from Cochrane for the development of this guidance.SVK acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2) and the Scottish Government Chief Scientist Office (SPHSU17).Part of this work has been presented in scientific conferences and at GRADE working group meetings and Cochrane symposia.We are thankful to all Cochrane, G.I.N., and GRADE members for their support and advice throughout this project, as well all McMaster graduate students, faculty, and staff.The Cochrane Methods Innovation grant, the National Toxicology Program in the U.S., and the McMaster GRADE centre also provided support for this project.


A training plan, or an exercise prescription, is the point where we translate sport and exercise science into practice. As in medicine, good practice requires writing a training plan or prescribing an exercise programme based on the best current scientific evidence. A key issue, however, is that a training plan or exercise prescription is typically a mix of many interacting interventions  that additionally change over time due to periodisation or tapering. Thus, it is virtually impossible to base a complex long-term training plan fully on scientific evidence. We, therefore, speak of evidence-informed training plans and exercise prescriptions to highlight that only some of the underlying decisions are made using an evidence-based decision approach. Another challenge is that the adaptation to a given, e.g. endurance or resistance training programme is often highly variable. Until biomarkers for trainability are identified, we must therefore continue to test athletes, clients, or patients, and monitor training variables via a training log to determine whether an individual sufficiently responds to a training intervention or else re-plan. Based on these ideas, we propose a subjective, pragmatic six-step approach that details how to write a training plan or exercise prescription that is partially based on scientific evidence. Finally, we advocate an athlete, client and patient-centered approach whereby an individual’s needs and abilities are the main consideration behind all decision-making. This implies that sometimes the most effective form of training is eschewed if the athlete, client or patient has other wishes. Physicians, physiotherapists, lifestyle and sports coaches, as well as fitness trainers all have one thing in common: they prescribe interventions to change the human body. The aims of physicians are to prevent, treat or ideally cure diseases by prescribing medical treatments. In contrast, sports coaches and fitness trainers aim to improve athletic performance, fitness and/or health by writing training plans or prescribing exercise often combined with nutritional recommendations. In doing so, physicians and sport practitioners can choose from a myriad of possible interventions including resistance or endurance exercise training, a Mediterranean, vegan or protein-rich diet or, in the case of medicine, drugs or surgery. But how can one select those interventions that most likely to achieve the desired treatment effects or adaptations in an individual?For many years, practitioners simply followed their opinion or the opinion of experts published in books or on the internet plus perhaps information from some random scientific papers. For example, “experts” have recommended that endurance can be best improved by training at the lactate threshold or that sets with 8–12 repetition maximum are “optimal” for muscle hypertrophy, despite a paucity of research supporting these beliefs. In medicine, however, the advent of evidence-based medicine has changed medical decision-making , the one without the ginseng developed severe shortness of breath, while the one who took the ginseng breathed evenly and smoothly” [“moothly” .Whilst this intervention study provided evidence for beneficial effects of ginseng, the evidence is low quality: the breathing measurement is subjective, the subjects probably differed at baseline, there was only one subject per group and the researcher probably had a conflict of interest as he seemed enthusiastic about ginseng. This highlights that scientific evidence is not automatically a truth but needs to be interpreted critically. Over time, scientists learned to design more robust intervention experiments as researchers improved scientific methods and reduced bias, and other sources of error.Since Ben Cao Tu Jing’s historical experiment, researchers have used many study types to investigate the effect of a given medical treatment or exercise on an outcome. The most important difference is the use of observational studies, where the investigator just observes the effect of a treatment but does not control the treatment, versus experimental studies where the experimenter administers the treatment or the intervention. A key step forward was the advent of randomized control trials (RCTs) with additional control measures such as blinding and placebos as advocated by Archie Cochrane, who deemed these designs a superior alternative to observational studies and anecdotal opinions .the conscientious, explicit, and judicious use of the current best evidence in making decisions about the care of individual patients” [“atients” .So how has the refinement of studies that test the effectiveness of an intervention led to “evidence-based practice”? The actual term “evidence-based medicine”, or more broadly “evidence-based practice”, was first used in the 1990s by researchers at McMaster University and has been especially linked to David Sackett who, from 1994 to 1999, led the Centre for evidence-based Medicine at the University of Oxford. In a review titled “Evidence based medicine: what it is and what it isn’t,” Sackett and colleagues define evidence-based medicine as …conscientious, explicit, and judicious use” mean that we do not necessarily need to do exactly what the evidence says; rather, we have the option to make alternative, subjective decisions if we feel that there is a good reason to do so.By that definition, David Sackett and colleagues instruct evidence-based practitioners to do two things: First, gather all of the currently available scientific evidence of sufficient quality and second, interpret and apply that evidence. Importantly, the terms, “Several issues must be considered when judging the available evidence. First, not all scientific data is of equal quality. Single pieces of evidence include subjective “expert” opinion, case reports and series, non-randomised control trials, and randomised control trials. On the path towards becoming an evidence-based practitioner, we must, therefore, develop the skill of critically interpreting scientific evidence. To aid this, e.g. Greenhalgh has published book “How to read a paper” .current best evidence for an intervention decision as there may be dozens of observational or experimental studies in relation to a single intervention such as the use of aspirin for treating headaches. This demand has led to systematic reviews and meta-analyses as two new publication types that support evidence-based practice as they aim to synthesize the current best evidence for treatment decisions. These forms of evidence also comprise the tip of the so-called evidence pyramid .Evidence-based medicine has now become the gold standard in medical decision-making, i.e. in deciding how to treat a patient. That said, evidence-based medicine is not without issues, as summarized by Greenhalgh et al. . One sucp values < 0.05 used for accept-or-reject-hypothesis conclusions), which has been termed “dichotomania”. The issue is that we should never conclude ‘no difference’ or ‘no relationship’ in an intervention simply because a p value is above a given threshold of “statistical significance” [p values simply indicate how probable an effect is and should be considered just one of several decision-making criterions. It can be argued that magnitude-based statistics such as effect sizes and confidence intervals are potentially more valuable for deciding whether, e.g. the adaptation to a training intervention is likely more than just measurement variability and biologically meaningful [A second problem is that statistical analyses often employed in the applied sciences are inherently flawed from a decision-making standpoint. A primary problem here is the focus on null hypothesis statistical testing ” [the ACSM’s new Position Stand contains all the flaws that were pervasive in their previous Position Stand” [In 2002, the American College of Sports Medicine published a position stand on resistance training for novice, intermediate and advanced exercisers. The position stand makes specific recommendations about how many repetitions, sets and intensities are necessary to trigger certain adaptations . This pof data)” . This nen Stand” . In summIn summary, these three examples show that there are sometimes issues with the evidence base for current training recommendations. This does not always imply that these training recommendations are ineffective or that future training recommendations must all be based on near-perfect evidence, as such evidence does often not exist. To us, the “lesson learned” is to honestly state the quality of the evidence and to avoid exaggerating evidence claims.In this section, we will now discuss how to apply evidence-based practice to writing a training plan or exercise prescription. When writing a training plan or prescribing exercise, trainers or coaches interact with athletes, clients or patients. In line with the concept of patient-centred care , we advoExercise training interventions typically include a mix of many different exercises (e.g. 10 exercises for different muscles in a resistance training plan), with variable exercise intensities and durations . In addition, these interventions change over time due to periodization or tapering, and are combined with other interventions such as nutrition (e.g. a protein-rich diet or carbohydrate loading). Whilst it is possible to base some training plan decisions on the current best scientific evidence, it is virtually impossible in a complex, months-lasting training plan to base every decision on scientific evidence. Also, there will probably be no studies comparing the planned, complex intervention mix to a matched control intervention. For example, assume we aim to train a natural, female bodybuilder for 20 weeks, with 20 resistance exercises, nutritional and supplement recommendations, with a bulking and cutting period. Whilst we can easily find answers to questions such as “What are the general guidelines for maximizing muscle hypertrophy?” with scientific evidence , 45, we For this reason, we use the terms evidence-informed training plan or evidence-informed exercise prescription to highlight that only some of the underlying decisions were made with an evidence-based approach, whilst other decisions are based on personal experience. So how can we write an evidence-informed training plan or exercise prescription? Fig. 2max of 60 ml/min/kg , a pace of 4 m/s at 2.5 mmol/L lactate [2 [Step 1 and 2 define the overall goal and break it down into smaller factors or goals. For example, if the overall goal in step 1 was a sub 3 h marathon in April 2021, then the sub-goals could be a V̇O lactate  and a BMctate [2  at the tctate [2  or the tIn an evidence-informed approach, some decisions should be based on the best available evidence. How to do this is proposed in the green box in Fig. 2max [In the yellow box in Fig. 2max , or to tFinally, note that the six-step plan is a subjective approach to planning training or prescribing exercise and that there are no studies investigating whether this approach as an intervention works better than alternative approaches.In summary, training plans and exercise prescriptions are typically a complex mix of interventions where realistically only some of the underlying decisions can be based on the best, current scientific evidence whilst the remaining decisions are based on unsystematic evidence or experience resulting from practice, academic courses or coaching qualifications.In this current opinion article, we have suggested a pragmatic six-step strategy detailing how an evidence-informed training plan or exercise prescription could be written. This six-step training plan strategy is a subjective proposal not based on direct research. It also has not been compared to other ways of planning training or prescribing exercise. An added complication is that training responses to a given training programme can vary greatly and hence practitioners need to integrate a personalization strategy to identify non-/poor responders early on. Until biomarkers for trainability are identified, the only way to identify a non-/poor responder is to test and to monitor key training variables to see whether an athlete, client or patient responds to the training intervention. This is, of course, current practice. Moreover, we advocate an athlete, client or patient-centred approach which means following the athlete’s, clients or patient’s wishes even if there are more effective interventions. The trainer’s/coaches’ role is to ensure that the athlete, client or patient can make informed decisions.Finally, training plans and exercise prescriptions are the points where sport and exercise science knowledge is translated into sport and exercise practice. In our view, methods of how to plan training or prescribe exercise and how to base some of the decisions on scientific evidence should be taught as part of sport and exercise science degrees in the same way as evidence-based, patient-centred and personalized/precision medicine is taught to medical students.