Mental health disorders contribute significantly to the global burden of disease and lead to extensive strain on health systems. The integration of mental health workers into primary care has been proposed as one possible solution, but evidence of clinical and cost effectiveness of this approach is unclear. We reviewed the clinical and cost effectiveness of mental health workers colocated within primary care practices.Systematic literature review.We searched the Medline, Embase, PsycINFO, Healthcare Management Information Consortium (HMIC) and Global Health databases.All quantitative studies published before July 2019 were eligible for the review; participants of any age and gender were included. Studies did not need to report a certain outcome measure or comparator in order to be eligible.Data were extracted using a standardised table; however, pooled analysis proved unfeasible. Studies were assessed for risk of bias using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool and the Cochrane collaboration’s tool for assessing risk of bias in randomised trials.Fifteen studies from four countries were included. Mental health worker integration was associated with mental health benefits to varied populations, including minority groups and those with comorbid chronic diseases. Furthermore, the interventions were correlated with high patient satisfaction and increases in specialist mental health referrals among minority populations. However, there was insufficient evidence to suggest clinical outcomes were significantly different from usual general practitioner care.While there appear to be some benefits associated with mental health worker integration in primary care practices, we found insufficient evidence to conclude that an onsite primary care mental health worker is significantly more clinically or cost effective when compared with usual general practitioner care. There should therefore be an increased emphasis on generating new evidence from clinical trials to better understand the benefits and effectiveness of mental health workers colocated within primary care practices. This review’s inclusion of a broad range of population types enables it to be more representative of the general practice setting the review is focused on.This review’s inclusion of multiple different types of mental health worker can reduce the potential for the type of mental health worker being a confounding factor in whether significant outcome changes were identified.Non-English language studies were not included in this review; therefore, relevant evidence from non-English studies may have been missed.This study could have included a broader literature search that removed the database search terms relating specifically to integration, collocation and mental illnesses.Pooled analysis within this review proved unfeasible, due to the relatively small number of studies identified and the heterogeneity of effects and outcomes investigated.Mental health disorders contribute significantly to global disease incidence and prevalence, with one billion people affected by mental disorders6One major proposed organisational intervention is the colocation or integration of mental health professionals within the primary care environment to deliver psychological therapies. The colocation of mental health professionals within primarily practices refers to the location of these professionals within the same offices/clinical space as the primary care practice staff. These professionals are full members of the primary healthcare team receiving both self-referrals from patients but also referrals from all other team members, which can include general practitioners (GPs), clinical pharmacists, practice nurses and healthcare assistants.Previous systematic reviews have demonstrated improvement in clinical outcomes such as depression through MHWs providing talking therapies  in primary care,This systematic review was carried out in accordance with the recommendations contained in the Cochrane Handbook for Systematic Reviews of Interventions10.1136/bmjopen-2020-042052.supp1Supplementary dataThe PICOS  framework was followed in identifying the eligibility criteria. All quantitative studies published before 1 July 2019 were eligible for the review, including randomised controlled trials (RCTs), practice-based evidence studies and cost-effectiveness studies. We included studies with participants of any age and gender. Qualitative studies, studies with full text unavailable, and studies not in English were excluded. Systematic reviews were also excluded but were used for result comparisons. Studies did not need to report a certain outcome measure in order to be eligible for inclusion , Beck’s Depression Inventory (BDI) or Clinical Outcomes in Routine Evaluation – Outcome Measure (CORE-OM)). It was also preferable to have studies which included standard GP care as a comparator, but as studies with this were limited in number it was not used to restrict the eligibility criteria.The Medline, Embase, PsycINFO, HMIC and Global Health databases were searched via Ovid. The reference lists of related literature reviews were further searched for relevant sources. The search strategy was created by using Medical Subject Headings and search terms related to four elements: (1) mental health disorders, (2) the primary care setting, (3) MHWs and (4) colocation and integration. The Medline search can be found in 10.1136/bmjopen-2020-042052.supp2Supplementary dataWe used Covidence softwareData were extracted using a standardised table  which liThe Cochrane bias tool was used to assess the risk of bias of randomised trials while the ROBINS-I tool was used to assess the risk of bias of non-randomised trials.Pooled analysis within this review proved unfeasible, due to the relatively small number of studies identified and the heterogeneity of effects and outcomes investigated, for example, due to different models of integration or colocation.It was not appropriate to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our researchFollowing removal of duplicates, 1863 titles and abstracts were screened to assess their suitability for inclusion within this review. Subsequently, 52 full-text papers were screened, of which 37 were deemed to be irrelevant. Fifteen papers were identified to be includedStudy characteristics are summarised within 29We used two separate tools to carry out risk-of-bias assessment on all included studies.10.1136/bmjopen-2020-042052.supp3Supplementary data10.1136/bmjopen-2020-042052.supp4Supplementary data10.1136/bmjopen-2020-042052.supp5Supplementary data10.1136/bmjopen-2020-042052.supp6Supplementary dataThe study outcomes are summarised in 10.1136/bmjopen-2020-042052.supp7Supplementary dataet al reported similar outcomes. OQ-45 Scores decreased significantly for patients with more than one appointment. There was also a significant reduction in OQ-45 Scores between patients that had either had 1, 2 or 4 or more appointments. This was also maintained during follow-up (p range 0.032–0.001). However, three papers suggested that clinical improvements are not likely to be significantly greater than with usual GP care.39There were three main scales found among the papers included, GHQ,In terms of service utilisation and referrals, there are seven papers that used these factors as one of their main evaluation outcomes.et alet al35 38Five interventions were evaluated in terms of patient satisfaction levels.There is evidence from this review that the integration of MHWs in primary care practices provides meaningful mental health benefits to varied populations, including minority groups and those with comorbid chronic diseases.et al,The delivery of mental health treatments within the primary care environment has been consistently shown to be clinically effective,Quality improvement strategies have generally been focused primarily on reducing the burden of disease within the healthcare system where they are implemented.43–45However, cost containment has become necessary in recent years with healthcare systems worldwide being under strain from rising healthcare costs, recession and the burden of an ageing population.9One area where there is agreement between studies, concordant with the findings of this review, is in referral changes associated with MHW integration. Decreases in the frequency of referrals to mental health specialists are well demonstrated in similar studies focused on both specific MHWsIn recent years, the growing emphasis on the importance of patient and practitioner satisfaction has been frequently highlighted in terms of healthcare suitability and delivery.18–20 49We did not include non-English language studies; therefore, relevant evidence from non-English studies may have been missed. This review has been unable to use a substantial number of papers related to the effectiveness, cost effectiveness and other potential benefits of delivering specific psychological and psychosocial treatments within primary care. This is as a result of them not being focused specifically on the effectiveness of the MHW itself. It was also difficult to include studies relating to collaborative care as it was not possible to determine whether the study’s effects were owed to the MHW; some studies had more than one MHW within this collaborative care process which further increased uncertainty. Other studies were focused on introducing certain interventions within primary care practices which were irrelevant to the review, including those of phone treatment, internet treatment and self-help. With more time and resource availability, this study would have also included a broader literature search that removed the database search terms relating specifically to integration, collocation and mental illnesses. This is hypothesised to be able to find slightly more relevant studies to review but will also increase the number of papers having to be screened exponentially. The addition of mixed method studies and qualitative studies could have given a broader perspective and additional findings; however, this paper was solely interested in quantitative evaluations.Further research is needed to compare the clinical effectiveness of the integrated MHW with standard GP care with only five papers in this study comparing this. There also needs to be a greater emphasis on reporting what the usual care provided by primary care practitioners is, in order to accurately assess the clinical differences in care provided. Rigorous cost-effectiveness studies need to be created, which should assess cost effectiveness to both the service provider and the broader healthcare system, and illustrate any societal costs associated with the intervention.The WHO has advocated in recent years that the primary healthcare environment is the optimal environment for the treatment of a plethora of conditions, including mental health disorders.52The NHS in England plans to increase the number of MHWs within primary care. This study suggests that further research is needed to evaluate both the clinical effectiveness and cost effectiveness of this policy to ensure it is a good use of health system resources. Clarity is also needed on the best type of health professional to take on MHW roles within primary care.


Research requires high-quality ethical and governance scrutiny and approval. However, when research is conducted across different countries, this can cause challenges due to the differing ethico-legal framework requirements of ethical boards. There is no specific guidance for research which does not involve non-medicinal products.To describe and address differences in ethical and research governance procedures applied by research ethics committees for non-pharmaceutical palliative care studies including adult participants in collaborative European studies.An online survey analysed using descriptive statistics.Eighteen principal investigators in 11 countries conducting one of three European-funded studies.There was variation in practice including whether ethical approval was required. The time to gain full approvals differed with the United Kingdom having governance procedures that took the longest time. Written consent was not required in all countries nor were data safety monitoring committees for trials. There were additional differences in relation to other data management issues.Researchers need to take the differences in research approval procedures into account when planning studies. Future research is needed to establish European-wide recommendations for policy and practice that dovetail ethical procedures and enhance transnational research collaborations. What is already known about the topic?Variation in ethical review practice is recognised but mainly from the ethical committees’ perspective.Little evidence on the experience of gaining ethical approval for multi-site, transnational research in practice.What this paper adds?Variation continues to exist in ethical and research governance approval procedures across Europe.Interpretation of General Data Protection Regulation (GDPR) differs across Europe which has implications about how research is conducted.Variation in practice was not related to the perceived vulnerability of patients in palliative care trials rather standard procedures applied in most countries.Implications for practice, theory or policyResearchers need to be aware of differences in research governance procedures when planning international research in particular time to gain full approval.The differences in approval procedures need greater review.Future policy development is recommended to guide research ethical and governance procedures across Europe.To ensure that research is ethically robust, ethical and governance review is required to carefully examine projects before approval. These procedures can be organised at national or local levels but little is known about the varying degrees of practice both within and between countries. Ethical examination requires assessment of the potential risk a research study may have. When research involves potentially vulnerable participants such as in palliative care, this scrutiny becomes even more important.16 and the researchers’ perspective.7 While the Declaration of Helsinki promotes a set of ethical standards,8 in practice committees, sometimes even on a regional level, apply their own interpretation of these criteria in their approval processes. This can result in disparity with some criteria being more stringently applied than others, particularly when the research participants are receiving palliative care and perceived as vulnerable.911For researchers to conduct international collaborative research, there needs to be an appreciation of ethical and governance requirements in the countries involved. International variation in ethical review has been noted in the experiences of ethical review boards12 will also affect these processes. Data restrictions may include access to medical records leaving identification of potential research participants to clinical staff who may not prioritise research. At the same time, gaining Good Clinical Practice certification or its equivalent is a mandatory requirement in some countries enabling more robust research practice.Ethics committees also assess how researchers approach and access data about potential participants. The introduction of the European-wide General Data Protection RegulationsTo describe and address differences in ethical and research governance procedures applied by research ethics committees for non-pharmaceutical palliative care collaborative European studies including adult participants.An online descriptive study was conducted to describe and compare the ethical and review governance procedures across three European studies (Seventh Framework Programme)  with datAn online survey was used to capture the experiences. The survey was developed through consultation between the research teams and piloted on two study-naïve researchers. Ethical approval was obtained from Lancaster University (FHMREC14107). A link to the online survey was sent to 18 principal investigators in 11 countries conducting one of the three studies (responses stored on password-protected computers). The principal investigator either completed the survey or delegated it to another member of their research team. The survey comprised 20 tick box and free text domains and a narrative ‘general comments’ section. It covered questions about local ethical and governance approval procedures including necessity for ethical approval, research governance processes, timeframes, additional approvals, access to patient records, consent and Good Clinical Practice requirements. Data were analysed using descriptive statistics and content analysis.Seventeen investigators responded (no response from Poland). Ethical approval was not required in Denmark (ACTION) and in the Netherlands (InSup-C) as the studies were not seen as trials in the same way as a drug study. In Germany (InSup-C), ethical approval was only required for patient participation rather than family carer or health care staff.Eight of the 17 investigators were required to go through formal ethical review in addition to other approval processes. Only the United Kingdom required this on PACE. Only investigators in the United Kingdom were invited to attend the ethics committee meeting. Changes to the protocol were required post-ethical review in Belgium (InSup-C), Finland (PACE), Italy (ACTION and PACE) and the United Kingdom (PACE). The time taken to gain ethical approval varied as did additional research governance requirements . The PACVerbal consent was seen as sufficient for interview studies in some countries such as Germany and the Netherlands in InSup-C. Where ethical approval was not required for a study (e.g. ACTION in Denmark) or certain participants such as carers or staff in InSup-C in Germany and the Netherlands, the teams chose to implement high levels of ethical practice including gaining consent.A formal data safety monitoring committee was only mandatory in the United Kingdom (ACTION) which, in turn, led to this being required in all participating nations. However, in the Netherlands, it was stated that as ‘. . . our study was classified as low risk, we don’t need a whole data monitoring committee, but just a person who monitors our data collection process’. Good Clinical Practice certification was needed in only four countries . In DenmResearchers were permitted to screen for potential participants by reviewing clinical notes in four sites: Finland (PACE), Hungary (InSup-C), Italy (ACTION only) and Slovenia (ACTION). Research nurses performed this function in the United Kingdom (ACTION and InSup-C), Denmark (ACTION), Finland (PACE), Italy (PACE), Switzerland (PACE) and Slovenia (ACTION). The United Kingdom was alone in needing public and patient consultation (PPI) in research design to gain approval.The value of collaborative transnational research programmes is paramount. This study aimed at providing, for the first time, palliative care researchers with a comparative view of practice in ethical and governance approval processes in 11 European Countries. The main findings were (1) considerable diversity in ethical review practice between the participating countries exists; (2) the study settings and design may influence the speed of approval decisions; and (3) overall, the United Kingdom had the longest ethical and research governance approval procedures.As with all surveys, the responses given may not be a true representation of what happened in practice. There was some missing data, which may have skewed the results. However, nearly all responses were returned while the studies were ongoing; hence, lapses in memory were likely to be minimal. Although members of the research team completed the survey, ultimately the authors were in essence describing their own experiences, which could cause some bias.13 and interventional studies7 in other research fields or non-trial research about palliative care.2 Differences still exist in ethical and research governance approval processes across Europe, especially in relation to how long studies take to be approved and what ethical committees classify as research, which need their approval. These results can help to inform researchers planning international studies by focusing attention on the variability of ethics and governance procedures for particular research designs, processes for screening potential participants, the involvement of the public in establishing research priorities and developing studies, and data management. Moreover, our results may help to increase attention to the need for agreed standards for approval procedures for non-pharmaceutical European studies, at least through training of ethical committees, as is happening in pharmaceutical studies.The study corroborates and expands on previous findings reported for both observationalIdeally, such an agreement should also include different standards for observational and interventional designs. The two randomised controlled trials, PACE and ACTION, underwent the shortest and the longest approval procedure, respectively. The longer time required for the approval of the ACTION trial may be longer because the study involved patients receiving an intervention rather than training staff to deliver an intervention, such as in PACE, and the patient group seen as more vulnerable.14 the longest approval in United Kingdom is somewhat concerning. Indeed, prolonged ethical approval processes, especially when they concern the research lead country, increase research costs, delay recruitment and can slow collaborative endeavour. On the other hand, high levels of scrutiny are needed to promote ethically conducted research, especially when research involves vulnerable subjects. A balance between the ethical need to reduce the length of approving procedures, in order to make research results promptly available to the public, and the need for a careful ethical examination should be achieved.Finally, considering the United Kingdom was the first Country to lead European Union FP5 and FP6 projects,6 any effort to obtain this goal is needed. The differences in ethical review are remarkable given all countries want researchers to adhere to the Declaration of Helsinki, which states in guideline 1 that it applies to  medical research involving human subjects, including research on identifiable human material and data.8 In reality, however, countries are trying to find ways to get to a risk-adaptive governance structure for the ethical review of research. Our results point to the necessity to harmonise the ethical review of this kind of low-risk research across Europe.Future research is therefore required in all of these areas to establish Europe-wide recommendations for policy and practice that dovetail ethical procedures and enhance transnational research collaborations. Indeed, even acknowledging that would be difficult to reach an international standardised approach due to different national legal frameworks concerning human research,Click here for additional data file.Supplemental material, Survey_questions for Ethical and research governance approval across Europe: Experiences from three European palliative care studies by Nancy Preston, Johannes JM van Delden, Francesca Ingravallo, Sean Hughes, Jeroen Hasselaar, Agnes van der Heide, Lieve Van den Block, Lesley Dunleavy, Marieke Groot, Agnes Csikos and Sheila Payne in Palliative Medicine


Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord. The exact mechanism for the selective death of neurons is unknown. A growing body of evidence demonstrates abnormalities in energy metabolism at the cellular and whole-body level in animal models and in people living with ALS. Many patients with ALS exhibit metabolic changes such as hypermetabolism and body weight loss. Despite these whole-body metabolic changes being observed in patients with ALS, the origin of metabolic dysregulation remains to be fully elucidated. A number of pre-clinical studies indicate that underlying bioenergetic impairments at the cellular level may contribute to metabolic dysfunctions in ALS. In particular, defects in CNS glucose transport and metabolism appear to lead to reduced mitochondrial energy generation and increased oxidative stress, which seem to contribute to disease progression in ALS. Here, we review the current knowledge and understanding regarding dysfunctions in CNS glucose metabolism in ALS focusing on metabolic impairments in glucose transport, glycolysis, pentose phosphate pathway, TCA cycle and oxidative phosphorylation. We also summarize disturbances found in glycogen metabolism and neuroglial metabolic interactions. Finally, we discuss options for future investigations into how metabolic impairments can be modified to slow disease progression in ALS. These investigations are imperative for understanding the underlying causes of metabolic dysfunction and subsequent neurodegeneration, and to also reveal new therapeutic strategies in ALS. Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disorder primarily characterized by selective degeneration of both the upper motor neurons in the brain and lower motor neurons in the brain stem and the spinal cord . The dea. With the advancements in genetic analysis technologies, it is expected that other new genes will be discovered in the future glucose in the CNS of wild type and SOD1G93A mice at the onset and mid-symptomatic stage of disease using high pressure liquid chromatography, 1H and 13C nuclear magnetic resonance spectroscopy. We found a reduction in the levels of the total and 13C-glucose derived glycolytic metabolites lactate and alanine, but not glucose glucose, including [4-13C]glutamate, [4-13C]glutamine and [2-13C]GABA were significantly decreased at mid-symptomatic stages of disease. This can be explained by reduced glucose entry into the TCA cycle as well as impairments in glutamate production from α-ketoglutarate glucose metabolism and the glutamate-glutamine cycle in prefrontal cortex and hippocampus of rats [Currently, there is no effective treatment for ALS. Riluzole, and recently edaravone are the only approved drugs –178. Ril of rats . These s of rats , 186 has of rats . While iAlthough little attention is given to metabolic therapies in ALS, targeting glucose metabolism has the potential to slow the onset and progression of ALS. Compounds that enhance glucose uptake and its metabolism via glycolysis and PPP could be beneficial by improving ATP generation and reducing oxidative stress. Interestingly, glycolysis activation has been shown to reduce disease progression in other neurodegenerative disorders such as Parkinson’s disease . RecentlAlternative and anaplerotic metabolic substrates that refill lost TCA cycle intermediates could also be used to improve energy supply in ALS. In bypassing the rate limiting steps that are linked with impaired neuronal glucose metabolism, such substrates can restore mitochondrial ATP production . MetabolWhole body metabolic changes are consistently observed in animal models of ALS as well as patients with ALS. In CNS tissues, defects in energy producing pathways are common. Among the common perturbations are a decrease in glucose uptake, and impairments in glycolysis and the PPP. In addition, abnormalities in mitochondrial function and ATP generation have been observed. Compounds that activate glucose metabolism, particularly via glycolysis, and the PPP may have the potential to slow disease progression. Although various investigations targeting glucose metabolism have shown beneficial outcomes in animal models, to which extent this translates to effective therapies in humans remains to be confirmed. Given the heterogeneity of disease, metabolic changes in patients with ALS are also likely to be highly variable. Therefore, individually tailored treatments may be needed to achieve the best outcomes for people living with ALS. This is an area of research that warrants further investigation.


A major challenge encountered by clinicians is differentiating presentations characterized by significant thrombocytopenia due to overlapping clinical symptoms and signs in the setting of ambiguous laboratory results. Immature platelets represent the youngest platelets that can be measured in peripheral blood by current hematology analyzers. These young platelets are larger, with higher RNA content recently released from the bone marrow. Thrombocytopenic presentations caused directly or indirectly by immune responses can lead to compensatory bone marrow responses seeking to normalize the platelet count; thus obtaining absolute immature platelet counts may be informative while triaging patients. Over the last decade, their use has expanded beyond being an early biomarker of bone marrow reconstitution post-hematopoietic stem cell transplantation to being used to establish bone marrow responses to infection and thrombocytopenias due to immune etiologies. Its accessibility as part of more detailed platelet indices obtained with routine laboratories makes it a promising option to understand the bone marrow's real-time response to disease states characterized by thrombocytopenia. This review will look at the immature platelet count as a biomarker, while presenting current attempts trying to understand how it could be used in thrombocytopenias occurring secondary to a given immune etiology. Immunological processes that affect platelet production and/or platelet counts represent clinical challenges not only to diagnose but also to treat. Indeed, over the years a better understanding of some of these immune processes causing thrombocytopenia has led to more timely and targeted treatment approaches resulting in better outcomes. However, difficulties still remain when overlapping clinical pictures make a definitive diagnosis challenging. This can be exemplified by microangiopathic hemolytic anemia presentations where a given etiology may not be immediately apparent , and eveImmature platelets have been shown to be much larger, with higher RNA content, and more biochemically active than their mature counterparts . They caNevertheless, tests that have the potential to be used clinically need to undergo scrutiny that at times may come into a collision course with the constrains of the technology behind them. The number of reports describing the utility of immature platelet counts has been mostly positive favoring it as a gauge to zero-in on a narrower group of potential etiologies. Yet, technological differences exemplified by changes in dyes with improved specificity for platelet elements, changes in gating, size correction, testing platform used, and wavelengths influence the analytical limits of this test –18; whilMeasurement of immature platelet counts requires establishing better defined reference intervals , 17. ImpWhen the first data of changes in baseline %-IPF in the setting of ITP was reported, it raised the possibility that a real-time response by the bone marrow in this disease was possible to measure . PatholoHowever, few reports have found limited utility in using immature platelets to differentiate ITP where one hematology analyzer found some value to measuring it while the other had discrepant results . RegrettIn the TTP literature, without a doubt the discovery that deficiency either innate or immune-mediated (acquired) of the metalloprotease ADAMTS13 is at the center of its pathology has changed the way in which patients are diagnosed and triaged , 43. ThiA-IPCs have been shown to predict response to TPE in patients with high ADAMTS13 inhibitors who may require longer treatment protocols to restore platelet counts . HoweverInfectious processes may lead to decreases in mature platelets as the body fends off the infectious agent(s). Notably, even though thrombocytopenia can be seen in infections, A-IPCs are generally maintained so that at least platelet production attempts to keep up with the higher consumption ; yet sucInflammation-inducing disease processes that lead to impaired thrombopoiesis can be triaged looking at immature platelets as shown in patients with impaired liver function/cirrhosis . SimilarInflammation has also been shown associated with hypertension and this may lead the cardiovascular disease sequelae among other complications . For exa+) for the presence of anti-PF4-heparin antibodies have A-IPC similar to the reference range unlike patients who test negative whose immature platelets are well-below this range (+ patients may have immature platelet responses that attempt to maintain the platelet count though not necessarily leading to an increase in net immature platelet production. Future investigation should expand upon these observations.Immature platelets have been used to establish when a given drug has no effect over thrombopoiesis . Antibodis range . This imExpansion over the last decade of the literature showing potential uses of immature platelet measurement in a variety of thrombocytopenic clinical settings , 71, 72,Yet, it must be acknowledged that these promising reports, favor the establishment of well-controlled clinical trials that look at how immature platelet counts could affect disease management without compromising therapy timing . LikewisIn summary, immature platelets are equivalent to reticulocyte counts in the setting of anemia and thus provide valuable information to the clinician when treating thrombocytopenic patients. These immature platelet counts provide the nearest to real-time information of bone marrow response to the etiology causing the thrombocytopenia, with the added benefit that once therapy is initiated it can guide a clinician to determine when therapy is causing a net shift in the production of these young platelets.HR and RM contributed to drafting, editing, and finalizing manuscript to its current form. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Patient awareness, clinician detection, and management of chronic kidney disease remain suboptimal, despite clinical practice guidelines and diverse education programs.This protocol describes a study to develop and investigate the impact of the National Kidney Foundation Kidney Score Platform on chronic kidney disease awareness, communication, and management, by leveraging the Behavior Change Wheel, an implementation science framework that helps identify behavioral intervention targets and functions that address barriers to behavior change.We interviewed 20 patients with chronic kidney disease and 11 clinicians to identify patient and clinician behaviors suitable for intervention and barriers to behavior change . Leveraging the Behavior Change Wheel, the Kidney Score Platform was developed with a patient-facing online Risk Calculator and a clinician-facing Clinical Practice Toolkit. The Risk Calculator utilizes risk predictive analytics to provide interactive health information tailored to an individual’s chronic kidney disease risk and health status. The Clinical Practice Toolkit assists clinicians in discussing chronic kidney disease with individuals at risk for and with kidney disease and in managing their patient population with chronic kidney disease. The Kidney Score Platform will be tested in 2 Veterans Affairs primary health care settings using a pre–post study design. Outcomes will include changes in patient self-efficacy for chronic kidney disease management (primary outcome), quality of communication with clinicians about chronic kidney disease, and practitioners’ knowledge of chronic kidney disease guidelines. Process outcomes will identify usability and adoption of different elements of the Kidney Score Platform using qualitative and quantitative methods.As of September 2020, usability studies are underway with veterans and clinicians to refine the patient-facing components of the Kidney Score Platform before study initiation. Results and subsequent changes to the Kidney Score Platform will be published at a later date. The study is expected to be completed by December 2021.Results of this study will be used to inform integration of the Kidney Score Platform within primary care settings so that it can serve as a central component of the National Kidney Foundation public awareness campaign to educate, engage, and empower individuals at risk for and living with chronic kidney disease.PRR1-10.2196/22024 Chronic kidney disease affects 37 million Americans . ChronicChronic kidney disease is usually asymptomatic. Optimal management slows the progression of kidney disease and reduces cardiovascular events ,5. IndivAmong the population served by Veterans Affairs (VA), 1 in 6 has chronic kidney disease. It is the fourth most diagnosed disease within the Department of Veteran Affairs, and over 13,000 veterans develop end-stage renal disease each year . DiagnosImplementation science frameworks, which take into account multiple interacting domains and processes that factor into successful program implementation, can help assure that the aforementioned gaps in chronic kidney disease awareness and education are addressed with interventions that are feasible and generalizable in real-world setting . ConsistWe selected the Behavior Change Wheel  as a fraFrom June 2016 to September 2016, the NKF conducted in-depth interviews with 20 nondialysis-requiring chronic kidney disease patients and 11 clinician experts in chronic kidney disease care including nephrologists and primary care practitioners . These iExamples of clinician barriers were limited awareness of chronic kidney disease clinical practice guidelines, challenges in modifying organizational workflows for diabetes and hypertension, no financial incentives for chronic kidney disease recognition (capability); limited availability of chronic kidney disease training in medical school and absence of formal chronic kidney disease awareness campaigns (opportunity); low prioritization of chronic kidney disease by health care organizations and by health care payers; and limited data analytics to highlight chronic kidney disease care gaps (motivation). Clinician enablers included chronic kidney disease clinical decision support in the electronic health record, performance measures for chronic kidney disease testing, and risk adjustment strategies for chronic kidney disease diagnosis and severity (capability); systemic quality improvement focused on chronic kidney disease care processes and inclusion of chronic kidney disease interventions in risk factor education  (opportunity); and use of practice facilitation teams to improve chronic kidney disease care and use of registries to demonstrate opportunities in chronic kidney disease care (motivation).Based on the aforementioned behavior change targets, the NKF’s multidisciplinary team of experts in web technology design, user interface development, information architecture, adult learning, and patient education partnered with experts in kidney care, patient education, and app design to develop the Kidney Score Platform online interface. Using the Behavior Change Wheel intervention functions education, persuasion, and enablement, the interface was designed to improve awareness and understanding about kidney disease among people at risk for and living with chronic kidney disease .The 3 other policy categories described in the Behavior Change Wheel that will not be applied to the evaluate the Kidney Score Platform are fiscal, legislation, and social planning.The free online interface utilizes a rule engine and risk predictive analytics to provide interactive health information tailored to the individual’s chronic kidney disease risk and health status. After entering risk factor information as well as laboratory findings in the Kidney Score Platform’s online interface, end users receive educational programming tailored to their current clinical status and risk for chronic kidney disease development or progression. Information is organized into context-specific easily digestible snippets, an approach aligned with the growing body of health education on how interactive content and tools such as apps, online health assessments, calculators, games, and quizzes can significantly affect comprehension, attitudes, self-efficacy, and health-related behavior change  20-22].-22.20-22Clinician-identified barriers and enablers for optimal discussions about chronic kidney disease informed the creation of the Kidney Score Platform’s Clinical Practice Toolkit. Leveraging the Behavior Change Wheel intervention functions of education, persuasion, enablement, and modeling, the toolkit assists clinicians in discussing chronic kidney disease with individuals at risk of and those living with chronic kidney disease who may have different health literacy levels . The tooPractice assessment is an algorithm that extracts chronic kidney disease-related data from the electronic medical record to assist clinical practices in identifying (1) patients at risk for chronic kidney disease who have not been tested for kidney disease; (2) patients with underlying undiagnosed chronic kidney disease based on laboratory testing; (3) patients with chronic kidney disease who could benefit from improved understanding of chronic kidney disease and the choices for medical management of chronic kidney disease.CKDinform 2.0 is an online continuing education activity based on Kidney Disease Outcomes Quality Initiative clinical practice guidelines that review chronic kidney disease testing, detection, and care [and care .Rapid Estimate of Adult Literacy in Medicine—Short Form (REALM-SF) is a validated 7-item word recognition test that provides clinicians with a quick assessment of a patient’s health literacy and capacity to understand health information [The ormation .Teach-back videos provide examples for practitioners of how to utilize the Kidney Score Platform online tool to communicate with individuals at risk for or living with chronic kidney disease. These short videos, featuring an expert clinician investigator and an individual living with chronic kidney disease, provide several examples of the teach-back method being utilized to assess patient comprehension of chronic kidney disease–related concepts  including instructions conveyed during the office visit about medication safety use.Change Package is a free publicly available online compendium of tools or actionable process improvements that clinicians in primary care settings can implement to integrate Kidney Score Platform chronic kidney disease education and related interventions into their practice workflow [workflow . By inclworkflow .The policy strategies from the Behavior Change Wheel that enable and support the testing and use of the Kidney Score Platform include communication/marketing, regulation, guidelines, and service provision . These aVeterans will interact with the Kidney Score Platform online interface individually while awaiting their clinical encounter via tablets or laptops (communication/marketing). As depicted in Prior to veteran recruitment, we will offer the accompanying clinical practice toolkit to primary care teams (service provision). Practitioners will be encouraged (but not mandated) to utilize the clinical practice tools, particularly completing CKDinform 2.0 and watching the chronic kidney disease teach-back video (communication/marketing). These tools will prepare practitioners for conversations with veterans as well as reinforce chronic kidney disease clinical practice guidelines on detection, patient education, and intervention . Pre and postsurveys will be conducted to assess the impact of the clinical practice toolkit on practitioners’ perception of chronic kidney disease, chronic kidney disease knowledge, and important topics for chronic kidney disease patient education.2 from recent laboratory tests in the medical record or those receiving dialysis treatment, as the Kidney Score Platform is not geared toward individuals with severe chronic kidney disease. Kidney transplant recipients will also be excluded, as their care is delivered predominantly in the subspecialty care setting rather than the primary care setting. We will also exclude veterans enrolled in hospice services, as chronic kidney disease awareness and self-management are less important for this population. Other exclusions include pregnancy, vision impairment, and severe dementia, identified by the problem list in the electronic health record or during the consent process. All primary care clinicians working as part of a Patient Aligned Care Team (PACT) in participating VA Medical Centers will be eligible for participation in the study.Veterans with and at risk for chronic kidney disease and their primary care clinical teams represent the target population. English-speaking veterans utilizing VA primary care services between the ages of 18 and 75 with diabetes or hypertension as defined in the electronic health record will be eligible for this study. Exclusion criteria include an estimated glomerular filtration rate <15 mL/min/1.73mVeterans work collaboratively with their PACT multidisciplinary team members to meet their health care needs. PACTs often include clinicians, nurses, medical assistants, social workers, and pharmacists, among other allied health professionals. The study team will work with each PACT team’s care coordination staff to identify veterans who meet the inclusion criteria with appointments during the intervention’s phase. Collaborating with primary care champions at each site, the project team will explore variations in recruitment process based on the site’s resources, clinical flow, and use of telehealth for care delivery due to the COVID-19 pandemic.Recruitment of clinicians from each PACT team will occur during a presentation of the project, during which the research team can answer questions. Clinical champions from each participating VA have been engaged in project co-design and will help ensure adequate and diverse clinician participation.A member of the project team will describe the innovation and its goals and purpose to eligible veterans. Individuals that can correctly explain the project protocol and answer simple teach-back questions (in part to assess for dementia) will be asked to provide consent. Eligible providers will also be asked to provide consent to participate after they hear about the project and its goals.Sociodemographic data , co-morbid conditions , and baseline laboratory data , will be collected from all consenting participants from the electronic health record, including participants who do not complete surveys for primary outcome collection (see below). All individually identifiable data will remain within the VA data system. Practitioner sociodemographic data , role, panel size or practitioner caseload, and years of experience will be self-reported.The primary outcome is change in self-efficacy for chronic kidney disease management, measured by the Patient Activation Measure . We willUsing the Reach Evaluation-Adoption Implementation and Maintenance (RE-AIM) framework for program evaluation , we willt test calculations, we would need to enroll 103 veterans to engage with the Kidney Score Platform and complete the pre and postsurveys to detect a 4-point clinically meaningful change in the PAM, assuming that the PAM would not change among individuals not exposed to Kidney Score Platform [The study is powered to detect changes in Patient Activation Measure (PAM) score, a validated measure of an individual’s knowledge, skill, and confidence in managing one’s health . Data frPlatform . AccountPlatform  related Impact of the Kidney Score Platform on change in participant PAM scores (primary outcome) will be conducted with linear mixed models, adjusting for age, gender, diabetes status, kidney disease severity, and clinic site. Additional analyses will look for effect modification by clinician knowledge of chronic kidney disease. Similar methods will be used to assess secondary outcomes: self-reported communication with practitioners about chronic kidney disease and ability of veterans to describe the tests used to detect chronic kidney disease.As of September 2020, usability studies are underway with veterans and clinicians to refine the patient-facing components of the Kidney Score Platform before study initiation. Results and subsequent changes to the Kidney Score Platform will be published at a later date. The study is expected to be completed by December 2021.This paper illustrates a theory-informed and evidence-based approach to developing and testing an intervention to enhance communication about kidney disease among patients and health care professionals. To develop all of the elements of the Kidney Score Platform, we leveraged the Behavior Change Wheel framework to directly target behaviors that were identified as barriers to optimal chronic kidney disease awareness and communication during preparatory interviews, using evidence-based intervention functions . To testWhile several chronic kidney disease education programs and awareness campaigns exist across the United States, there are limited examples in the literature of how theoretical frameworks can be leveraged to develop and test interventions to enhance kidney-related communication among clinicians and patients and improve self-efficacy and overall health among individuals with kidney disease. To our knowledge, this is one of the few chronic kidney disease awareness interventions developed and proposed to be tested according to an individual behavioral change theory . Theory-informed interventions are more likely to be effective than interventions not based on theory, though a formal study is required to test whether the slow deliberate process (such as that used to develop the Kidney Score Platform) leads to greater effectiveness within the context of health care delivery.Results of the anticipated study examining the impact of Kidney Score Platform on patients and clinician chronic kidney disease awareness and communication will be shared with participants and will used to refine the different elements of the platform and their integration within primary care settings including new care delivery workflows, such as telehealth. Study results will be most applicable to care delivery in VA administration settings involving in-person and phone or video visits. While this is one limitation to this study, we anticipate that the Kidney Score Platform’s impact on awareness, self-efficacy, educational, and communication outcomes among veterans and their clinicians will be generalizable to other settings and novel care delivery mechanisms. If so, the robust process by which the Kidney Score Platform was developed can serve as a model for the creation and implementation of other innovations that focus on behavior change as a means of enhancing kidney health. The refined Kidney Score Platform that will emerge from this study has the potential to significantly impact the lives of the approximately 37 million US adults affected by chronic kidney disease, as it will serve as a central component of the NKF’s national public awareness initiative to educate, engage, and empower individuals at risk for and living with chronic kidney disease.


Innovative models of family engagement and support are needed in the intensive care unit (ICU) during times of restricted visitation such as the COVID-19 pandemic. Limited understanding of the factors affecting the uptake and outcomes of different family support models hinders the implementation of best practices. We aimed to conduct a rapid pre-implementation evaluation of stakeholder-perceived facilitators and barriers to design implementation strategies to support a novel program using medical students to facilitate family-centered care in the ICU.We conducted a 2-step process. In step 1, we gathered contextual data via interview-style open-ended questions sent to clinicians and navigator stakeholders via email. We used electronic data collection due to the physical distancing requirements, the need to prioritize brief data collection for respondent burden, and the need for rapid knowledge gain. A codebook based on the Consolidated Framework for Implementation Research (CFIR), an integrated framework from the field of implementation science, was used to analyze the findings. In step 2, a pilot of the intervention was implemented with 3 navigators over 2 weeks. Implementation strategies were developed to target barriers identified by the pre-implementation evaluation.Fourteen (70%) of the identified stakeholders responded to the survey. Ten constructs encompassing all five CFIR domains were present in responses as implementation influencers, with the Intervention domain most frequently represented. Through these results and operational feedback from navigators during the pilot period, stakeholders selected multiple implementation strategies: audit and provide feedback, develop educational materials, conduct ongoing training, promote adaptability, assess and redesign workflow, identify and prepare champions, and engage community resources.We demonstrated how a conceptually based pre-implementation program evaluation can be used to rapidly inform optimal implementation strategies. We report key factors to inform design and implementation strategies for a novel ICU family engagement navigator program that may be useful to others wishing to adopt similar programs.The online version contains supplementary material available at 10.1186/s43058-020-00098-2. Contributions to the literatureFamily engagement is a key component of high-quality care for critically ill patients, but restricted visitation policies due to COVID-19 challenge the delivery of family-centered care.We conducted a formative evaluation to rapidly inform the design and implementation of a medical student-led multicomponent family engagement navigator program.Our results provide actionable facilitators and barriers for other organizations seeking to implement similar programs.Our study demonstrates successful application of a novel rapid methodologic approach that allowed efficient knowledge gain to inform program design under the time pressure generated by the COVID-19 pandemic.Family-centered care, the inclusion of family members as part of a collaborative team including patients, families, and healthcare teams, is recognized as a key component of high-quality ICU care . HoweverThe application of implementation science, a field focused on promoting the uptake of evidence-based practices, may provide new insights into the development of new family engagement and support models. Implementation science leaders have called for innovations in methodology that enhance the pace of knowledge translation , 9. In tThe pre-implementation evaluation was conducted at an urban tertiary care teaching hospital in North Carolina with over 100 ICU beds.Family engagement navigators are intended to fill three primary roles: (i) facilitate communication between the patient’s care team and the family member, (ii) promote humanization of the patient, and (iii) provide emotional support to the family. Using collaborative exchange with others implementing a similar program in another health system , we devePolicies set forth expectations related to what types of information can be shared by navigators and specifications for maintaining privacy. Navigator staff are the people providing the communication support role—in our setting, we are leveraging the skills of medical students who are removed from direct patient care for this role. Procedures provide standardized and concise instructions for navigators to initiate contact, respond to difficult situations, and disengage when appropriate. A resource guide serves as an important tool for navigators to access education materials. Strategic organizational partnerships between navigators and ICU teams are needed to ensure consistent and non-duplicative effort. A communication strategy creates awareness of the navigator program among patients, families, and ICU providers. Establishing a monitoring and evaluation plan and system allows for evaluating the extent to which the family engagement navigation program is achieving its intended objectives. Lastly, oversight ensures that the program is being implemented in a standardized manner and is on track to achieve outcomes.Stakeholders including intensivists, nurses, researchers, and medical students worked together to develop a conceptual model for the program. Figure This program model is intended to provide a standardized approach for implementing a family engagement navigator program to deliver family-centered care, with the short-term goals of (i) increasing communication encounters among family members, patients, and the healthcare team; (ii) improving family knowledge about the logistics of communication during their loved ones’ hospitalization; (iii) increasing the use of humanization strategies such as the “get to know me” board; and (iv) increasing the amount of time available to bedside providers for clinical care. The intermediate-term goals include (i) family, patient, and provider satisfaction with the program and (ii) increasing family engagement with decision-making. Ultimately, the desired long-term outcomes of the family engagement navigation program are (i) reduced stress disorders among family members including anxiety and post-traumatic stress disorder, (ii) reduced stress disorders among patients, and (iii) alignment of patient care with their stated goals. The Template for Intervention Description and Replication (TIDieR) checklist  is availWe conducted a 2-step rapid pre-implementation process. In step 1, we gathered contextual data via survey sent to clinicians and navigator stakeholders via email. We used electronic data collection rather than in-person interviews due to the physical distancing requirements, the need to minimize respondent burden during the early days of the crisis, and the need for rapid knowledge gain. In step 2, a pilot of the intervention was implemented with 3 navigators over 2 weeks. An overview of the pre-implementation workflow is shown in Fig. In step 1, we used a purposive sampling stratified by role  to identify 20 clinicians and potential navigators who were especially knowledgeable about family engagement and likely to communicate their experiences and opinions in an expressive, reflective manner. The sampling technique was chosen to maximize the information yield and scope while efficiently using limited resources for data analysis. We sent the surveys via email in April 2020 and received responses within 2 weeks. Stakeholders included 11 clinicians (8 intensivist physicians and 3 ICU nurses), and 9 medical students signed up to be navigators. Participation was voluntary, and responses were anonymous.The open-ended survey questions were designed to mimic interview style and encourage detail-rich responses using REDCap electronic data capture tools . We expeThe CFIR provides a comprehensive taxonomy of operationally defined constructs that are likely to influence the implementation of complex programs . CFIR coWe deductively analyzed responses to open-ended questions using CFIR constructs to organize and interpret respondents’ perceptions and determine the most critical pre-implementation factors likely to influence the successful adoption of the model within the ICU organizational setting. A member of the study team developed a codebook using the CFIR codebook template  and analDuring the pilot implementation, three student navigators supported 1–2 families at a time over a 2-week period. During this time, navigators attended to operational and workflow processes including time resources required to deliver family engagement support and processes for exchange of information with clinical teams. Pilot navigators kept daily logs of the process measures . Using contextual data obtained from step 1 and data from step 2 navigators, the study team identified specific implementation strategies that are likely to be feasible and effective organized by the Expert Recommendations for Implementing Change (ERIC) taxonomy .Of the 20 stakeholders identified for the survey, 14 (70%) responded to the email invitation . Respondents spent an average of 10 min responding to the survey. In general, participants were enthusiastic about the program and expressed confidence that it would succeed. Respondents’ insights and feedback from the navigators during the pilot implementation fell within several relevant CFIR constructs spanning all five of the framework domains  and adaptable components (other types of support). Nearly all respondents identified patient needs and resources as a source of potential barriers to the program’s success. Specific barriers in this category included access and familiarity with technology: “Any barriers to electronic communication will be obstacles for the intervention: lack of wifi, lack of reliable phone, etc.” Respondents also frequently identified language barriers: “Some of us [navigators] are fluent in Spanish but it will be difficult for families that speak other languages.” Respondents noted that increased demands on family members’ time may limit their availability to communicate: “Availability to talk [might be a barrier], in terms of their occupation and other things they have to do.” Thus, respondents noted that the adaptability of the program was a facilitator of overcoming these barriers, as it allowed for the implementation of the model to families with variable needs and different combinations of support provided.Another CFIR intervention construct, complexity, can be a barrier to effective implementation. Respondents identified that the process of providing family support process is well-defined, but the process of identifying new patients and exchanging information between navigators and the clinical team may require multiple steps and is not straightforward. From the pilot process, navigators reported that supporting family engagement required multiple calls each day, comprising an average of 1 h per day per family. Respondents and navigators provided potential solutions to this barrier such as creating medical record note templates  and sharRespondents recognized an international initiative to enhance family engagement for ICU patients  and feltTwo subconstructs of implementation climate, a construct in the inner setting domain, were identified as key contextual factors for program implementation. Tension for change was universally reported to be high—respondents recognized the vital role of family engagement in the ICU but acknowledged that communication is challenging during restricted visitation. Respondents reported keen awareness of the negative impact of visitation restriction on family distress and patient personhood: “I would be terrified if I couldn’t visit my loved one in the ICU,” “I hope we can find a way to help patients feel human without their families at bedside.”I wonder if this will stall if the [navigator] isn’t allowed to discuss medical issues. Most families want to know the day plans, test results, etc. They want to know what to expect—to do this adequately you have to give them some real informationFamilies might ask for information that cannot be shared by (the navigator), not understanding the role of the family navigator, not feeling completely satisfied with [navigator] communication compared to attending communication.Compatibility, another implementation climate subconstruct, was also identified as a critical factor in the implementation of the family engagement navigator program. Both clinicians and navigators expressed concern about potential role confusion without explicit definition and awareness of navigator roles. Multiple respondents worried that families and navigators may experience frustration if navigators cannot provide clinical updates:Accordingly, respondents expressed strong opinions that this intervention be additive not substitutive for communication with the clinical team.Although respondents felt that the program could be a good fit into the existing operational workflow, they worried that poorly designed information exchange may result in inconsistent information provided to families and operational processes were viewed as necessary to promote consistency of communication with families. Respondents indicated that the inner setting culture would benefit program implementation because family engagement was an organizational priority even prior to COVID-19, and the participating ICUs had good track records of embracing new ideas.Adequate knowledge about an intervention and positive attitudes toward it are important to adoption . AlthougEngagement is an important component of implementation success. Respondents indicated that the process of staffing the navigator workforce by self-selection was a major facilitator by ensuring that motivated and engaged individuals were involved in the program. Respondents also reported that another major facilitator stakeholder engagement was readily identifiable “champions,” or people in the organization who are likely to go above and beyond what might be expected, for the program . A key cUsing contextual data obtained from step 1 and stakeholder feedback from step 2, we identified specific implementation strategies that are likely to be feasible and effective. These contextually appropriate implementation strategies are shown in Table During this unprecedented pandemic, ICU leaders are charged to develop novel models of family engagement during restricted visitation. Our CFIR-informed rapid pre-implementation evaluation revealed several important insights that we used to inform our program and may help others design or adapt similar programs.The use of the CFIR as an implementation framework aided in the analysis and interpretation of our data. The CFIR provided a practical framework for understanding stakeholder concerns, describing barriers and facilitators to implementation, and identifying appropriate next steps to implementation. Multilevel  processes were developed to support the implementation of the family engagement navigator. This pre-implementation assessment of the intervention characteristics, inner and outer settings, characteristics of individuals, and process provided a realistic assessment of feasibility, acceptability, and appropriateness of this model to be implemented in our ICU setting.Our study is an exemplar of how implementation science methodology can be applied at a pace that allows efficient knowledge gain to inform program design under rapidly evolving time pressure such as the COVID-19 pandemic. Implementation science leaders have called for a novel methodology to speed the translation of knowledge to practice , 9. ThisThis study had several limitations. First, we used purposive sampling which is a non-probability sampling technique that could limit the representativeness of the sample. However, this a technique widely used in qualitative research for the selection of information-rich cases . We straSuccessful adoption of novel approaches to ICU family engagement may be improved with the integration of implementation science methods, including a rapid pre-implementation assessment to inform and adapt program design. We demonstrated successful application of a rapid methodologic approach that allowed efficient knowledge gain which can be a useful exemplar to others aiming to rapidly address new clinical challenges and incorporate new evidence in settings like the COVID-19 pandemic.Additional file 1. : Template for Intervention Description and Replication (TIDieR) checklist.Additional file 2. : Family Engagement Navigator EHR note template.


Pediatric organ failure and transplant populations face significant risks of morbidity and mortality. The risk of organ failure itself may be disproportionately higher among pediatric oncology patients, as cancer may originate within and/or metastasize to organs and adversely affect their function. Additionally, cancer directed therapies are frequently toxic to organs and may contribute to failure. Recent reports suggest that nearly half of providers find it difficult to provide prognostic information regarding organ failure due to unknown disease trajectories. Unfortunately, there is a lack of uniform methodology in detecting the early symptoms of organ failure, which may delay diagnosis, initiation of treatment and hinder prognostic planning. There remains a wide array of outstanding scientific questions regarding organ failure in pediatrics but emerging data may change the landscape of prognostication. Liquid biopsy, in which disease biomarkers are detected in bodily fluids, offers a noninvasive alternative to tissue biopsy and may improve prompt detection of organ failure and prognostication. Here, we review potential liquid biopsy biomarkers for organ failure, which may be particularly useful among pediatric oncology patients. We synthesized information from publications obtained on PubMed, Google Scholar, clinicaltrials.gov, and Web of Science and categorized our findings based on the type of biomarker used to detect organ failure. We highlight the advantages and disadvantages specific to each type of organ failure biomarker. While much work needs to be done to advance this field and validate its applicability to pediatric cancer patients facing critical care complications, herein, we highlight promising areas for future discovery. Remarkable therapeutic advancement in pediatric oncology may be limited by long-term toxicity, and in particular, acute and/or chronic organ dysfunction/failure , 2. The Among critically-ill pediatric oncology patients, overall ICU mortality ranges from 12-15 % in those with solid and hematologic malignancy, and can be as high as 60% in stem cell transplant (SCT) recipients . Organ fIn this review, we evaluate currently available biomarkers, their diagnostic accuracy, clinical applicability and potential impact on the prediction and early detection of organ failure. The role of chemokine and cytokine expression in the progression of organ failure has been more extensively characterized and are not included in this review –19. HereCell-free DNA are small degraded fragments of DNA, derived from the apoptosis of nucleated cells and circulate freely in the blood plasma . Under nCfDNA has been studied in the blood of patients undergoing cardiac surgery to predict late acute kidney injury (AKI). The ROC generated from cfDNA of patients had improved detection of AKI (AUC = 0.804) compared to the ROC generated from the serum creatinine of patients (AUC = 0.688) . Karlas While the above studies utilize total plasma cfDNA, a recent study has shown that in the plasma of lung transplant patients, donor-derived cfDNA (ddcfDNA) could be identified and quantified, with patients with increased levels of ddcfDNA having a higher risk of allograft failure . Thus, dWhile these studies highlight the potential of cfDNA as a novel biomarker for organ dysfunction, further work is required to identify tissue-specific DNA which would more reliably diagnose organ failure in children.Micro RNAs (miRNA) are small, single-stranded, non-coding ribonucleotides that negatively regulate gene expression at the post-transcriptional level and play a role in cell proliferation, differentiation, repair and apoptosis . While eWhile the prognostic value of miRNAs has been reported for the prediction of outcomes for oncology patients as well as the prediction of multiple types of organ failure, there is a scarcity of data on its use to predict organ failure in pediatric patients , 44. SchMiRNA profiling has also been shown to be useful in distinguishing the etiology of organ failure. Patients with acute liver failure (ALF) as a result of either HCV or cirrhosis were both found to have elevated levels of miRNA122. , 48. WeiWhile the use of miRNA as a biomarker for organ failure is promising, further work is needed to determine the prognostic significance of these abnormal miRNAs in order to maximize their clinical utility in pediatric organ failure.Endothelial progenitor cells (EPCs) are a subpopulation of stem cells that have been identified in the peripheral blood in response to endothelial damage secondary to insults, including vascular injury and ischemia. They are believed to be critical to maintain vascular integrity and endogenously restore and repair damaged vascular endothelium. Although EPCs have been studied as biomarkers for organ dysfunction, current studies in regards to EPCs and their role in cancer focus on their role as prognostic biomarkers .Increased levels of EPCs are associated with decreased cardiovascular mortality amongst patients with coronary artery disease . MoazzamIn a pediatric study, EPCs were reported to be highly correlated with pulmonary arterial hypertension in pediatric patients with congenital heart disease . EPCs haWhile the role of EPCs as a biomarker for organ failure is promising, these cell levels are altered by multiple other factors including age, underlying chronic diseases such as diabetes mellitus, frequency of dialysis and the use of immunosuppressive drugs thus limiting its current value and application to pediatrics .Exosomes are micro vesicles, roughly 30-100 nm in diameter, released from cells after fusion with an intermediate endocytic compartment . These mSole et al examined miR-29c in urinary exosomes to determine whether patients with lupus nephritis would develop end-stage renal disease. They found that the contents of these microvesicles correlated with renal chronicity but not with renal function, suggesting that it could possibly be used as an early biomarker for development of renal fibrosis . ExosomeNjock et al analyzed exosomes in the sputum to find biomarkers for idiopathic pulmonary fibrosis. They found exosomes containing mir-142-3p were negatively correlated with the diffusing capacity of the lungs and therefore severity of the disease . LambrecNucleosomes are complexes composed of a histone core surrounded by DNA base pairs. Under normal physiological conditions, nucleosomes are released during apoptosis. However in pathological conditions, as in the case of organ failure, the normal phagocytic clearance mechanisms are overwhelmed and nucleosomes are released into circulation . These nNucleosome levels have also been shown to be capable of differentiating the acuity and pathogenesis of organ failure. In a cohort of surgical and non-surgical ICU patients, patients who were septic had higher levels of nucleosomes upon admission than those who were not. This, however, was comparable to already established clinical scoring systems and did not provide additional predictive benefit . Craig eMitochondria are cellular organelles whose DNA (mtDNA) has been found to reflect a potential damage-associated molecular pattern. They are released extracellularly during necrosis in response to inflammation and have been found to be associated with the severity of a variety of diseases. Thus, mtDNA may be a potential biomarker for organ failure , 70. PubTimmermans et al found mtDNA levels to be elevated in patients with septic shock. Di Caro et al additionally demonstrated this facet in pediatric patients . DhondupHistones are proteins found extracellularly and within the nucleus that have been found to be elevated in patients with cancer and are associated with cell death and toxicity , 82. AbrOther studies have analyzed the relationship between high levels of circulating histones and multiple organ failure. In patients with multiple organ dysfunction syndrome, there was a strong correlation between circulating histone levels and markers of organ injury, disease severity and p-SOFA scores. Furthermore, the authors observed that sera from patients with high histone levels were non-selectively toxic to primary cells from a variety of organs, including the lungs, livers and kidneys and therefore a possible mediator for multiple organ dysfunction syndrome .Biomarkers are surrogate indirect indicators of a pathological or physiological process. In pediatrics, there has been limited progress in the identification and development of biomarkers to predict organ failure, its severity and outcome and its response to therapy. Identifying suitable biomarkers for organ dysfunction in pediatrics could potentially help improve risk stratification and possibly patient outcomes. It may also help to reduce the psychological stress, patients and their families may experience for more invasive procedures as well as reduce the health care costs and risks associated with these procedures which often require sedation.Currently for biomarkers reported in the literature, there is a high degree of heterogeneity in the levels amongst patients based on age, sex and existing comorbidities. Levels of cfDNA for example are much higher in elderly patients due to decreased level of clearance by phagocytosis whilst changes in cfDNA methylation occur rapidly during childhood , 88. LimAdditionally in order to develop meaningful and clinically useful biomarkers, further research is needed to establish the optimal timing and method of sample collection as well as standardization of laboratory techniques. It should also be noted that none of these potential biomarkers in this review are truly organ-specific and may be a marker for multiple diseases thereby limiting its usefulness. Further work is therefore needed in distinguishing each biomarker from their respective molecular or cellular background in order to enhance its clinical utility. Presently there are multiple ongoing pediatric clinical trials to identify biomarkers in pediatric patients with lung, cardiac and renal injury amongst others –95.Current ongoing or planned trials for pediatric oncology patients include the identification of biomarkers to detect cardiac injury and renal injury post chemotherapy –99.Although there is still much work to be done, among pediatric oncology patients, there is promising utility for several of the biomarkers reviewed. Future studies might examine (i) the use of cfDNA and mtDNA post hematological or solid organ transplant in detecting organ rejection (ii) the use of MiRNA to determine risk of AKI among patients with post-surgical tumor resection (iii) serial sampling of EPCs in predicting progressive organ failure (iv) the use of histones as a predictor for multi-organ dysfunction syndrome and (v) the use of exosomes and nucleosomes to predict persistent or chronic organ failure in pediatric cancer patients.Although many potential biomarkers exist to predict organ failure among pediatric cancer patients, all come with shared and unique challenges that limit their clinical value at this time. Additionally, while much research has been focused on heart failure and sepsis, a leading cause of multi-organ failure, there has been little headway in the application of these potential biomarkers to lung injury, for which there is currently no prognostic score or standard severity grading and diagnosis remains reliant on clinical markers. Despite the need for further studies, the data is promising. Pediatric oncology and critical care investigators should be encouraged to investigate these biomarkers further as they hold great potential for future use.LD, SY, and DR were all major contributors in writing and editing this manuscript. RS, DP, KM, and SL were major contributors in editing the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Accurately identifying the magnitude of gender-based violence (GBV) in humanitarian settings is hindered by logistical and methodological complexities. The ‘Neighborhood Method’, an adapted household survey that uses primary and secondary reporting to assess the prevalence of GBV in humanitarian settings, reduces the length of time and cost associated with traditional surveys. Primary female adult respondents disclose incidents of physical violence, intimate and non-intimate partner rape for themselves, other females in their homes (standard reporting) and other women and children in their social networks (secondary reporting). This study examines the reliability and validity of this inclusion of secondary reporting to determine the comparability of the Neighborhood Method to a traditional survey approach.Drawing on data from 1180 women reporting on 3744 females in respondent households and 15,086 in neighboring households across four humanitarian settings , reliability of secondary reporting was measured through intra-class correlation coefficients (ICCs) and Cohen’s kappas. Validity was assessed using two-sample z-tests for differences between standard versus secondary reporting.Prevalence estimates comparing a respondent’s household with a neighboring household show closer agreement (ICC: 0.999–0.986) than self-reports vs. secondary reporting on a female counterpoint in a neighboring home (ICC: 0.939–0.98). Kappa statistics analyzing the reliability of two separate neighbors reporting on a third neighbor showed moderate agreement beyond chance alone . Prevalence rates corresponded between standard and secondary reports  in 18 out of 24 compared populations.For prevalence of GBV, secondary reporting about neighbors can serve as a useful adjunct to standard survey methodology. Findings offer important initial insights into the consistency and accuracy of secondary reporting as a tool for field epidemiologists in humanitarian settings. Accurate measurement of mortality, violence, and human rights violations in conflict- and disaster-affected populations is critical for informing advocacy, program response, resource allocation, and policy. This is especially true for gender-based violence (GBV), which is known to be prevalent in humanitarian emergencies and is detrimental to the health and wellbeing of vulnerable communities. GBV comprises acts  that are perpetrated against a person’s will and are based on unequal distribution of power, particularly gender inequities and norms . GBV encTraditionally, the humanitarian community has relied on qualitative and numerator-based service delivery data to inform programming and policy decisions related to GBV. However, such an approach does not provide a full picture of the scope and magnitude of GBV . There aIn order to capture GBV data that are as reliable and accurate as possible in disaster-affected populations, we must first consider best practices in measuring this sensitive topic more generally. There is evidence, for example, that data quality is improved by making GBV the exclusive focus of a survey as opposed to embedding questions into broader surveys about reproductive or mental health . SimilarWhile there is a reasonably developed body of evidence on good practice around fostering safe and valid disclosure of GBV in survey research, less well documented in the GBV literature are good practices related to sampling approaches. Acknowledging that numerator-based approaches are limited in their ability to ‘tell the whole story’, researchers often resort to the option of an expensive, time-intensive and logistically complex population-based sampling approach. Research into alternative sampling methods better suited to conflict and disaster settings are only beginning to emerge.One promising approach is secondary reporting , in which information is systematically gathered about ‘clusters’ of individuals from a respondent who hypothetically knows about the experiences of these other individuals . SecondaOur own previously published work on GBV employed secondary reporting in internally displaced persons (IDP) camps in Uganda , conflicThis analysis uses survey data from 1180 women reporting on 3744 females in respondent households and 15,086 females in neighboring households across the four humanitarian settings named above. Multi-stage cluster sampling was used to select primary respondents for each of the four studies , 18, 20.The Neighborhood Method is a population-based approach to measuring GBV that is based on a random sample of adult women reporting on their own experiences of GBV as well as the GBV experiences of others within their social networks . This meAfter receiving informed consent from participants, trained local interviewers used a standardized protocol to ask respondents basic questions about their household demographics and those of their closest neighbors . Interviewers then asked an open-ended question about the ‘biggest challenges facing women and girls in their community’. This question often resulted in respondents initiating a discussion on the topic of GBV and would be prompted later in the interview if not spontaneously raised. The study team drew upon the strengths of qualitative and quantitative methods by using a slow and semi-structured interview schedule to allow for enhanced trust-building between the interviewer and the respondent. The survey instrument measured three distinct forms of GBV: intimate-partner rape , non-intimate partner rape , and physical violence  . InterviTo examine the consistency of patterning and of overall rates of prevalence between primary and secondary reporting, we made three comparisons: incidence of violence self-reported by the respondent vs. (i) incidence reported by the respondent about her neighboring female head-of-household and (ii) incidence reported by the respondent about her sisters (Uganda study only). We also compared (iii) incidence of violence reported by the respondent about other women and children living in her own household vs. incidence reported by the respondent about other women and children in her neighbor’s household.consistency of patterning. To determine which variation of the ICC coefficient constituted the most appropriate measure, we used several pieces of information: for the comparison of self- and secondary reporting, a two-way analysis of variance for the prevalence of gender-based violence was deemed appropriate. The methods (i.e. secondary reporting and self-reporting) are considered “fixed” effects as they are the only methods of interest in this report [We assessed the reliability of secondary reporting across all study groups by calculating an intra-class correlation (ICC) coefficient. The coefficient was used to determine the amount of measurement error between secondary reporting using the Neighborhood Method and traditional self-reporting, and to gauge the extent to which secondary reporting could replace or reliably supplement traditional self-reporting. In this situation, we were interested in looking at overall s report . The unis report , 3 is ths report , and wasIn addition to examining the overall reliability of secondary reporting using the ICC, we also examined reliability at the level of individual interviews using additional data collected in the study of Somali refugees in Ethiopia. In that study, the research team conducted 23 ‘matched’ interviews in which two neighbors were asked to report on the experiences of violence for two common neighbors  ‘moderate’ agreement between matched neighbor reporting, suggesting, in this case, moderate reliability or consistency in patterning between both secondary reporting and self-reporting [Finally, when ICCs were calculated in sub-group analyses for adult women ≥18 years of age and girls < 18 years of age, a lower ICC of 0.722 was found for reports of rape perpetrated against girls in a respondent’s household vs. a neighboring household as shown in Tables eporting .Table 4Table correspondence in rates of prevalence.For secondary reporting about neighboring households compared to respondents’ households, there were no significant differences for 18 out of 24 such comparisons, suggesting more consistent Of the six comparisons of respondents’ households vs. neighbors’ households that did show statistically significant differences in GBV, two study samples  had lower prevalence of violence reported in the neighbors’ households. For the remaining four study samples , higher prevalence of violence was reported in the neighbors’ households compared to the respondents’ households.Finally, secondary reporting about respondents’ sisters (data collected in Uganda only) yielded statistically significantly lower prevalence rates than self-reporting for physical violence and rape by an intimate partner. No statistically significant difference was found for the less frequent reporting of non-intimate partner rape.With the lack of any clear basis for establishing a ‘gold standard’ of prevalence of sexual violence and clear potential for risks associated with reporting in insecure environments, surveys of violence against women in humanitarian settings are widely seen as likely to involve under-reporting. This limitation has also been documented in wealthier countries , and undand lower risk for GBV. However, in terms of estimated prevalence of GBV based on primary and secondary reports, there is clear variation with respect to the reporting population that is being addressed. Amongst women reporting on themselves and their neighbors, secondary reporting on neighbors generally resulted in a lower estimate of prevalence than self-report. In contrast, prevalence estimates based upon secondary reports of GBV in neighbors’ households and reports of GBV within the respondents’ household showed much higher levels of statistical correspondence.The results presented above illustrate that ICCs showed a generally high level of consistency in identifying individuals and households at higher The lower prevalence estimates for neighbors vs. selves may represent a respondent’s lack of knowledge about her neighbor’s experience with GBV or a bias against disclosing information about one’s neighbors. Although it is theoretically possible that the higher incidence from self-reporting could reflect that the standard self-reporting approach may be biased towards over-reporting, this is unlikely given the literature showing that GBV tends to be underreported due to stigma and other negative repercussions for the survivor , 7, 8.For the comparisons between a respondent’s household and prevalence reported about the neighbor’s household, we note that the standard approach is in fact a form of secondary reporting, as respondents are asked to report on other women and children living in their own household. Data about the respondent’s household is similarly based on the assumption that an adult female has complete and accurate information about the women and children living under her care. This information is, therefore, also subject to similar biases of knowledge, non-disclosure, and social desirability as the respondent likely views herself as being responsible for the wellbeing and safety of others in the same household. Reporting about one’s household, however, still reflects a common and standard approach for assessing population health in conflict and development settings, and we thus compare it with the novel approach of asking about the respondents’ neighbor’s household. For comparisons between ‘standard’ secondary reporting about respondents’ households vs. novel secondary reporting about neighboring households, statistical tests for the most part failed to detect any significant difference in the prevalence of GBV, suggesting correspondence in overall rates of prevalence and that secondary reporting about neighboring households may be as valid as reporting about respondents’ own households on GBV.Additionally, in cases where there was less consistency in patterning between secondary reporting and self-reporting, higher reported rates of violence in neighboring homes for children suggest that this novel type of secondary reporting may foster higher rates of disclosure, especially if social desirability bias prevents females from reporting events in their own households. These findings raise the potential that secondary reports on neighbor’s children may be more reflective of the truth than self-report on children in the respondent’s household. If supported by additional testing, this finding could have important implications for measuring violence against children – a growing measurement trend – and suggests that secondary reporting has the potential to reveal better data for younger populations than current assessments.when looking across household data. The possibility exists that the consistency between self-reported household rates vs. neighbor rates involves under-reporting on both populations through true limitations of knowledge or reluctance on the part of the interviewee. There was little data available for us to assess the use of secondary reporting on respondents’ sisters’ experiences, as we did not use this form of reporting outside of Uganda. One barrier to collecting this data in other settings is the low likelihood of sisters knowing about each other’s experiences, especially for sensitive topics such as GBV, where chronic civil unrest and large population movements may limit communication and such intimate knowledge. Other factors that may influence the variability in patterns of difference between standard and secondary reported GBV incidence include the geographic distribution of households, where rural households in some settings may be too dispersed for respondents to accurately know their neighbors’ experiences, and cultural norms in different populations that are relevant to disclosure of GBV.Taking both reliability and validity into consideration, overall findings suggest similar levels of reporting between the Neighborhood Method and standard self-reporting Limitations of this analysis include the lack of a true ‘gold standard’ for validity testing, such that self-reporting methods as means of measuring GBV incidence is not itself definite. We are thus limited to conducting validity testing for the non-inferiority of secondary reporting compared to the usual, standard approach. While our primary and secondary samples were powered to compare prevalence rates, we acknowledge that other factors such as internal variation and larger confidence intervals will also factor into whether our comparisons showed significance. Finally, the four studies included in this paper all focused on gender-based violence, thus limiting the generalizability of the results to understand the use of secondary reporting for other population health concerns.In a humanitarian culture driven by an imperative to deliver assistance, often at the expense of rigorous assessment and evaluation, alternative measurement approaches better suited to contexts of war and disaster are needed. Without some rate-based measure of GBV, trends or assessments of preventative measures will not be easily evaluated. This analysis offers important initial insights into the reliability and validity of secondary reporting as a tool for field epidemiologists in humanitarian settings. Further exploration of secondary reporting will strengthen our understanding of whether and when secondary reporting is a viable alternative or supplement to standard methods.