The number of people living in fragile, conflict-affected, and vulnerable (FCV) settings is growing rapidly and attention to achieving universal health coverage must be accompanied by sufficient focus on the safety of care for universal access to be meaningful. Healthcare workers in these settings are working under extreme conditions, often with insufficient contextualized evidence to support decision-making. Recognising the relative paucity of, and methodological issues in gathering evidence from these settings, the evidence scanning described in this paper considered which patient safety interventions might offer the ‘better bet’, eg, the most effective and appropriate intervention in FCV settings.An evidence scanning approach was used to examine the literature. The search was limited to FCV settings and low-income settings as defined by the World Bank, but if a systematic review included a mix of evidence from FCV/low income settings, as well as low-middle income settings, it was included. The search was conducted in English and limited to studies published from 2003 onwards, utilising Google Scholar as a publicly accessible database and further review of the grey literature, with specific attention to the outputs of non-governmental organisations. The search and subsequent analysis were completed between April and June 2020.The majority of studies identified related to strengthening infection prevention and control which was also found to be the ‘better bet’ intervention that could generalise to other settings, be most feasible to implement, and most effective for improving patient care and associated outcomes. Other prioritized interventions include risk management, with contributing elements such as reporting, audits, and death review processes.Infection prevention and control interventions dominate in the literature for multiple reasons including strength of evidence, acceptability, feasibility, and impact on patient and health worker well-being. However, there is an urgent need to further develop the evidence base, specialist knowledge, and field guidance on a range of other patient safety interventions such as education and training, patient identification, subject specific safety actions, and risk management. The safety and quality of health care services are increasingly recognised as essential attributes in the provision of universal health coverage (UHC). Patients should not have to make the decision between seeking unsafe care or foregoing necessary medical care. Fragile, conflict-affected and vulnerable settings (FCV) is a term used to describe a range of situations including ‘humanitarian crises, ongoing disruption to public services, significant armed conflict, extreme adversity, or acute, protracted or complex emergencies’ . Health Approximately 2 billion people globally live in FCV settings, with nearly 50% of the global poor expected to live in these settings by 2030 due to widespread political instability, conflict, the impact of climate change and most recently, the COVID-19 pandemic which is having a profound impact on health systems and economies around the world . The WorThose working in FCV settings face formidable challenges to their time and resources, having to make considered, often rapid and pressured, decisions and need to be guided by some form of evidence base to improve the safety of care provided. Provision of a pragmatic evidence base is required to move beyond traditional scientific or academic models due to the challenges in carrying out research in these settings. Further, applying a rigorous, highly academic standard of evidence may not be uniformly possible due to the lack of rigorous research to date . HoweverStrategic objective six of seven identified in the WHO Action Plan is to “Ensure a constant flow of information and knowledge to drive mitigation of risk, a reduction in levels of avoidable harm and improvements in the safety of care” . To provThe objectives of this study are (1) to review and appraise evidence on an area of patient safety interventions in FCV settings through an evidence scanning approach and; (2) to evaluate the limitations of this approach to inform future refinement.Quality of care in fragile, conflict-affected, and vulnerable settings: Taking action [Assessing the quality and safety of health care provided in FCV settings is an emerging field. Research thus far has been relatively unable to use robust methods of evaluation in these complex conditions. However, evidence scanning can provide initial insights into those interventions that may be most useful for improving patient care and reducing avoidable harm. The patient safety interventions utilised for this scanning process were developed through a process of literature review, expert consultation and are explained in the recent WHO publication g action . The repg action . This waStrengthen infection prevention and control (IPC),Implement priority patient safety interventions at the point of care,Provide hands on patient safety training to health care workers,Introduce a context-specific risk management tool.Quality of care in fragile, conflict-affected, and vulnerable settings: Tools and Resources Compendium as one of two intervention areas where resources exist  across all of the sub-intervention areas, which may have facilitated a greater likelihood of research or evidence gathering activities being undertaken to appraise these sub-intervention areas and/or associated tools and resources.The evidence scanning approach aimed to provide an initial first step towards considering future models for safer care in FCV settings through developing evidence tables of patient safety interventions for FCV settings using a rapid structured review. The ‘Reduce avoidable harm’ intervention area was selected by the research team as the intervention area to narrow and focus the search to trial the evidence scanning approach and most relevant to their expertise. This particular intervention also had the advantage of being described in detail in the publication (Box 12) , making The search and subsequent analysis were completed between May and June 2020. The search included studies reported in English. Google Scholar was searched as a publicly available and accessible database, which contains more grey literature that is not held in traditional academic databases. Additional scanning of the grey literature, particularly the outputs of non-governmental organisations (NGOs) such as Médecins Sans Frontières (MSF), was also undertaken by the researchers. Search terms were developed using the 2019 list of low- and lower-middle income countries (LMICs) as defined by the World Bank Country and Lending Groups . The seaStudies published from 2003 onwards were reviewed. The search aimed to find the most robust articles in the field, defined as those in a Cochrane review, in peer-reviewed journals with impact, outcome or output data and significance of findings reported. However, the results included were not limited to this. Given the lack of depth and breadth of evidence on the topic of patient safety interventions, specifically interventions to reduce avoidable harm, in FCVs, it was necessary to consider studies which attempt to assess the evidence for an intervention even where this may not be as robust as wished. As such, we included interventions where a minimal number of studies were identified, studies which suggested that an intervention may have potential, and those in which the evidence was less robust.Two researchers independently searched the selected databases and grey literature across the sub-interventions. The titles and abstracts of articles obtained from the searches were reviewed for relevance to the topic. Papers and reports that did not focus on any of the four sub-intervention areas, or did not meet the country or setting criteria described previously, were excluded. The researchers met to review the full text of selected documents to determine the categorisation of the evidence, where there was a lack of clarity on which sub-intervention the evidence was most applicable to .The intention of the second phase of the evidence review was to both define the interventions with an evidence-base alongside determining what we assessed to be ‘better bet’ interventions for FCV settings. What do we mean by a “better bets” approach? As academics, we understand and appreciate the need for rigorous and evaluative evidence reviews. However, we must also recognize that life and death decisions are constantly being made by policymakers, managers, and frontline providers in FCV settings, often handicapped by inaccessible and incoherent evidence even where directional evidence exists; inadequate resources, infrastructure, and skills to operationalize. Therefore, the existing evidence base needs to be assessed to identify which might be “better bet” interventions to be implemented in austere and adverse health care settings. In this content a “better bets approach” describes the formal and systematic assessment of the existing evidence base to identify interventions most useful and feasible to implement in FCV settings. We acknowledge that the “better bets” approach is a novel method to assess which interventions may be most effective in implementation, summarising the associated biases in the limitations section, but intend to develop the approach and scoring system through further research.. “Generalizability of the studies’ evidence” refers to the extent to which findings can be extrapolated to similar settings[Following completion of the evidence scans, a better bets scoring system was conducted, utilising four criteria as outlined in  settings. “FeasibThe scoring took place in June 2020. Three reviewers, Niki O’Brien (MSc), Alex Shaw (MSc), and Mike Durkin , independently examined each intervention evidence table and applied these four criteria based on a rating scale of 0,1 or 2. Each reviewer independently scored each intervention against these criteria and then scores were totalled to a maximum of 8 points. Comparing the scores, a discrepancy of 2 or more points was considered disagreement. In such cases each reviewer’s rationale for giving the score was presented and each reviewer was able to adjust their score if they considered it necessary based on the rationales presented. The scores were then averaged to produce a mean score. A score of 7 or 8 was anticipated to be a reasonable threshold to identify better bets. The fact that this threshold was not attained cannot be judged as a conclusive assessment of the merit of the interventions but rather may be indicative of the quality and quantity of studies.This work was supported via the NIHR Imperial Patient Safety Translational Research Centre, Institute of Global Health Innovation, alongside input from the UNC Gillings School of Public Health. No other funding sources were utilised.The evidence scanning process resulted in 34 studies being identified across each of the four ‘reduce avoidable harm’ interventions (see full list in Tables S1-S4 in the The most articles were found related to the broad categories of interventions for strengthening infection prevention and control (N = 12), followed by providing hands on patient safety training to health care workers (N = 9) and introduction to a context-specific risk management tool (N = 7). Notably, the fewest number of studies were found for the implementation of interventions to reduce avoidable harm at the point of care (N = 6). There were some challenges in the categorisation of interventions related to training. While the majority of interventions related to training were found in the search for hands on patient safety training for health care workers (and subsequently recorded as interventions in this category), interventions that partly or wholly relied on training were also found and reported in searches for the other priority areas. Of these, five studies reported training interventions in the strengthening ICP priority area, two studies reported training as interventions categorised under point of care and one study utilised training as a risk-management tool intervention. The results were organised and described to outline the sub-interventions, methodology and the results and outputs. The interventions tables developed from the evidence scanning are shown in Tables S1-S4 in the After the better bets scoring was totalled, none of the interventions evaluated for ‘reducing avoidable harm’ yielded an average score of 7 or 8 as seen in Quality of care in fragile, conflict-affected, and vulnerable settings: Taking action [We found relatively few studies on patient safety interventions for reducing avoidable harm in FCVs, particularly before 2016, suggesting that this area of patient safety research is a relatively new field of study. The studies identified varied in their area of focus, methodology and geographic focus, which again indicates that research on patient safety interventions for reducing avoidable harm in FCV settings is in its infancy. However, the authors note that given the topic area, it is possible that more work to evaluate safety interventions has been done at the national or facility level in-country, but the results have not been published, or not published widely enough to be picked up internationally. It is only possible to understand the full extent of avoidable harm interventions, and patient safety interventions and their effectiveness in FCVs more widely, by engaging with in-country stakeholders, including hospital and medical centre administrators and clinicians. Future research and engagement must align with the eight elements of national quality policy and strategy outlined in g action , as wellg action , but adaDespite the relatively small number of results there is a clear focus on infection prevention and control in the published literature, which accounted for 12 of the 34 publications identified. Such a focus may reflect the global discourse and promotion of infectious disease prevention through initiatives such as the “My five moments for hand hygiene” campaign developed and championed by WHO . NotablyPriority interventions at the point of care was the focus area with the least number of identified studies on effectiveness (6/34) as well as the intervention area with the lowest better bets scoring. Again, this suggests a relationship between the number of studies found and the feasibility of better bets scoring offering a true score of effectiveness. However, the lack of studies found in this topic may also suggest that point of care interventions are not a focus of patient safety interventions to reduce avoidable harm in FCV settings. There are several reasons this could be the case. The most obvious hypothesis is that global patient safety campaigns typically focus on single actions or preventative outcomes such as the second global patient safety challenge ‘Safe Surgery Saves Lives’ . ICP recA significant number of the papers found through the evidence scanning process were published between 2016 and 2020 (N = 27), with a noticeable proportion also published between 2011-2015, compared to the number found between 2003, as intended by the search parameters, and 2010. There has been a significant change in the prevalence of violent conflict during this period, which has been particularly dramatic since 2010. For example, the onset of the Arab Spring in 2010, followed by the longstanding Syrian and Yemeni civil wars beginning in 2012 and 2014 respectively, has shifted the geographical focus of violent conflict to the Middle East . In AfriThe global FCV landscape has rapidly changed since this time, due to climate change, increasing inequalities, demographic changes, and political instability . LMICs, The COVID-19 pandemic is going to increase the number of extreme poor globally and is exacerbating existing FCV settings. Until now the full impact of the pandemic on health care provision in FCV settings is yet to be quantified but it can be considered, given that it will be these populations who will be disproportionately impacted due to a lack of resources, that these settings are likely to see a long-term impact on health outcomes and provision of safe care as a result.We recognise the considerable limitations around the evidence scanning and better bets approach and view this work as a starting point to answer a complex problem for those working in these extremely challenging settings. The importance of further research on patient safety interventions in FCV settings and how best to dissect existing evidence given the varied range of challenges and health systems found within and across FCV settings cannot be stressed enough. The primary challenge to the effectiveness of the approach was the lack of existing literature relevant to FCV settings on the selected patient safety topic area: reducing avoidable harm. This is likely due to both a historical lack of funding and research and the challenges of conducting impact research in these settings, but also suggests that much of the relevant research is not being captured in academic publications or accessible grey literature . It was The evidence scanning method was also broad, which as a positive, offered researchers more flexibility in how and where to find evidence, however further definition of keywords and search databases may be beneficial. Another limitation found was the broad nature of the four ‘reducing avoidable harm’ interventions identified by WHO and the lack of a clear distinction between the interventions in some cases . It would be valuable to further vet and refine these interventions, informed by ongoing research and other engagement with those in FCV settings. The evidence scanning also found a wide variety of sub-interventions within each category; it would be beneficial to expand the number of interventions to search within smaller categories to better capture the specificities and scope of patient safety interventions and their effectiveness in future research. As also noted, the approach based on the WHO ‘reducing avoidable harm’ interventions resulted in the inclusion of training interventions across all categories, not just in the hands-on patient safety training for health care workers priority area. It may be helpful to develop hands on patient safety training for health care workers as a sub-category under the other priority areas to reflect that training will be an integral component of all patient safety priorities rather than a standalone priority. The limitations of the better bets scoring process centre around two themes; broadness of the interventions and lack of evidence. The broad nature of the interventions makes it challenging to score them both in comparison with each other and against the four criteria. For future work, and where a larger number of studies might be available, it may be beneficial to group the studies found by the evidence scanning into sub-interventions before undertaking the scoring process.Quality of care in fragile, conflict-affected, and vulnerable settings: Taking action report [There are several limitations that must be acknowledged. While the evidence scanning approach was used to enable a wide and flexible search, relevant papers may still have been missed and evidence selection bias could have occurred during the evidence scanning process. Additionally, in using only one of five areas of interventions as defined by the WHO n report , the resWith increasing numbers of the global poor expected to live in FCV settings by 2030 due to widespread political instability, conflict, impacts climate change and the effects of the COVID-19 pandemic, further research on patient safety in such settings is urgently and rapidly needed. The WHO estimates 60% of preventable maternal deaths globally take place in FCV settings, highlighting the need to address avoidable harm and scale up patient safety interventions . ScanninOur findings, unsurprisingly, were that infection prevention and control was the most reported patient safety intervention in the studies relevant to FCV settings. There is an implication from our findings that system and population level interventions can tend to take precedence in FCV settings over individual interventions such as patient identification, possibly due to the increased complexities with implementing micro interventions. However, clearly there is a compelling need to expand the types of safety interventions routinely implemented. Examining the evidence alongside and through the experience of those working in health systems in FCV settings will allow for an expanded understanding of which set of patient safety interventions should be prioritized for provision of both UHC and safe, quality care for populations in FCV settings. There is also a need to examine how existing evidence on interventions in FCVs relate to organisational and system level patient safety objectives, and with the seven strategic objectives outlined in the WHO Patient Safety Action Plan, as well as the WHO Framework for Quality in Fragile States.As noted, the clear next step is to engage with those working in FCV settings, particularly those in the clinical environment, to understand whether information on the effectiveness of patient safety interventions might exist. Following that, stakeholders such as patients and communities/ clinicians, policy makers and NGOs must also be engaged to assist the global health community more widely in understanding the priority areas for future research in patient safety interventions in FCV settings. However, perhaps the most essential element of future work, and a key consideration throughout the process of identifying next steps, is to ensure research and evidence is developed in such a way that it is free, easily accessible and implementable for those working in already under resourced, fragmented, and overstretched health care environments.


We investigated the mid-term clinical and radiological results of total hip arthroplasty (THA) using a three-dimensional (3D) porous titanium cup and analyzed the micromotion at the interface of the cup using subject-specific finite element (FE) analysis.We evaluated 73 hips of 65 patients  who had undergone THA using a 3D porous titanium cup. Clinical evaluations were performed using the Japanese Orthopaedic Association (JOA) hip score system. We assessed the fixation of the acetabular component based on the presence of radiolucent lines and cup migration using anteroposterior radiographs. Subject-specific FE models were constructed from computed tomography data.The JOA score improved from a preoperative mean of 52.2  to a mean of 87.8  at the final follow-up. None of the patients underwent revisions during the follow-up period. Radiolucent lines were observed in 26 cases (35.6%) and frequently appeared at DeLee and Charnley Zone 3. Following the FE analysis, the micromotion at DeLee and Charnley Zone 3 was significantly larger than that at Zone 2. Furthermore, micromotion was large in the groups in which radiolucent lines appeared at Zone 3.The mid-term clinical outcome of THA using a 3D porous titanium cup was excellent. However, radiolucent lines frequently appeared at DeLee and Charnley Zone 3. FE analysis indicated that micromotion was large at the same site, strongly suggesting that it contributes to the emergence of radiolucent lines. The 3D porous titanium cups are useful in THA, and with improvements focused on micromotion, we anticipate better long-term outcomes. According to national registration reports, the most common reason for revision surgery after total hip arthroplasty (THA) is aseptic loosening –3. SimilSince 2000, acetabular components with a three-dimensional (3D) structure in the porous region have been developed, and their use is associated with experimental efficacy and good survival rates –12. The However, in clinical reports of implants with a 3D porous structure, a high rate of radiolucent lines was observed –18. RadiThe purposes of this study were to investigate the mid-term clinical results of THA using a 3D porous component, including the presence or absence of radiolucent lines, and to analyze the micromotion at the interface of the 3D acetabular component using finite element (FE) analysis.Between May 2014 and May 2016, 66 patients (74 hips) underwent primary THA using the SQRUM TT , ‘range of motion’ score (20 points), ‘walking ability’ score (20 points), and ‘activity of daily living’ score (20 points). A higher score indicated a better condition , 26. IntWe assessed the fixation of the acetabular component based on the presence of radiolucent lines and cup migration using anteroposterior radiographs. The presence of radiolucent lines in the three acetabular zones of DeLee and Charnley  was evalCT scans  of the pelvis were acquired pre- and postoperatively. The scanner settings were approximately 120 kV, 0.68 × 0.68 × 1-mm voxel size. FE models of the pelvis were generated from pre- and postoperative CT data using Mechanical Finder (MF) version 11.0 . Only region of interest (ROI) models were semi-automatically constructed in 3D-planning software; Zed View version 12.0 . The acetabular component Computer Aided Design data were precisely placed in the pelvic ROI model by matching the postoperative CT perfectly in Zed View. A composite ROI of the pelvis and acetabular components was imported into the MF for analysis . Intraclass correlation coefficients (ICCs) were used to assess the intra- and inter-observer (two observers) reliabilities of the cup inclination and the cup migration measurements. ICC values can range from 0 to 1, with a higher value indicating better reliability. ICC values were analyzed in accordance with a previously described semi-quantitative scale  . A pairePatient demographics are shown in Table p < 0.01). One patient developed sciatic nerve disorder, but the symptoms improved during follow-up. Mild ectopic ossification and dislocation were each observed in one patient. No patients underwent revisions during the follow-up period.Paired t-tests showed that the Japanese Orthopaedic Association hip score significantly improved from a preoperative mean of 52.2  to a mean of 87.8  at the final follow-up (p < 0.05). There was a case in which the angle increased by ≥3°, but no migration was observed. There was no significant change in the movement distance of the center of the cup in the vertical  and horizontal  directions from immediately after surgery until the final observation.The mean  cup inclination angles were 44.4°  immediately after the operation and 44.8°  at the final observation. There was a significant difference between the angle immediately after surgery and at the final observation . All cases were stable with a grade of II or higher according to the Modified DeLee and Charnley skeletal fixation score for the acetabulum. Imai et al.  also repIn this study, the reason underlying the frequent appearance of radiolucent lines in DeLee and Charnley Zone 3 was analyzed using an FE model, focusing on micromotion during single leg standing. The micromotion at the point corresponding to DeLee and Charnley Zone 3 was significantly larger than that corresponding to Zone 2. Furthermore, the comparison of cases in which radiolucent lines did and did not appear indicated that micromotion was large in cases in which radiolucent lines appeared at the points corresponding to DeLee and Charnley Zone 3. These results suggest that the frequent appearance of radiolucent lines in DeLee and Charnley Zone 3 could be due to micromotion. Furthermore, SQRUM TT has a low modulus of elasticity in the porous region and close to the cancellous bone, which is designed to cause physiological load transmission and avoid stress shielding . The resPorous factors, which determine the performance of a cementless acetabular component, are important and include porous design, surface processing, and metal species. A successful 3D porous structure requires not only the porosity and friction coefficient, but also the elastic modulus, which predicts micromotion. To date, surface treatments such as hydroxyapatite-coated and alkaline heat treatment have been applied to the porous area, and several authors have reported good clinical results –41. As aWhen performing pressure load tests using cadaver bones, it is difficult to accurately evaluate the stress on the contact surface from the acetabular component implanted and the micromotion at the time of loading. Therefore, the FE analysis method presented here will aid the study of micromotion of the acetabular component, particularly focusing on the elastic modulus of the porous region.The limitations of this study include the lack of implant survival rate evaluation over a long period as part of the clinical evaluation, limited number of FE analysis cases, and lack of implant size analysis. There was a significant difference in the cup inclination angle from immediately after surgery to the final observation, but the difference was minimal, and it is possible that postoperative changes in pelvic tilt had an effect. In addition, the analysis was performed only under the one-leg standing condition. In future studies, analysis under conditions such as walking and moving up and down stairs will provide more detailed results that reproduce more realistic phenomena.The mid-term clinical outcome of THA using a 3D porous titanium cup was excellent. An examination of micromotion by FE analysis showed that the emergence of radiolucent lines was predictable. Future improvements in implants with this research method can lead to longer-term clinical results.


Prior research indicates a positive association between socioeconomic position and health literacy levels. We hypothesize comparable socioeconomic gradients for food literacy. This study aims to determine the level of self-perceived food literacy and health promotion literacy among adults with a low and medium level of education and from various subgroups, as well as the association between these food and health literacy levels. Furthermore, this study aims to explore the associations of self-perceived food literacy (SPFL) and health promotion literacy (HPL) in BMI.A cross-sectional study was conducted among employees with a low and medium level of education. Descriptive analyses were performed to compute SPFL and HPL levels. Analyses of variance were performed to test differences between subgroups. The correlation between SPFL and HPL was computed by Pearson’s r. Multivariate linear regression analyses were used to explore 1) the association between SPFL and HPL adjusted for demographic characteristics 2) the associations between SPFL and HPL in BMI.n = 222) scored low on SPFL and 34.5% scored inadequate or problematic on HPL. No significant educational or weight-status differences were found in SPFL or HPL levels. On most levels, women compared to men and older compared to younger employees scored significantly higher. A small positive correlation between the two mean levels was found, r = .25, P < .001 (n = 203). Multivariate linear regression analyses showed a significant association between SPFL and HPL . No significant associations between SPFL and HPL in BMI were found.The majority (63.1%) of all participants (This study suggests there is room for improvement in SPFL and HPL among adults with a low and medium level of education. Future research should consider comparing low and middle socioeconomic with high socioeconomic groups when exploring food and health literacy. Regarding health promotion activities for adults with a low and medium level of education, it is recommended to focus on improving both food and health literacy. Furthermore, more research is needed to explore direct proxies of weight-status to better understand the role of food and health literacy in overweight patterns. The burden of non-communicable diseases (NCDs) and associated risk factors are major health challenges of the twenty-first century . Among tThe relationship between lifestyle behaviours such as eating behaviour, on the one hand, and health, overweight, obesity and the prevalence of NCDs on the other is well established –9. EatinFood literacy is a specific form of the broader concept of health literacy , definedHealth literacy levels have regularly been reported to be unequally distributed throughout society. Regarding gender, the evidence for the association with health literacy is inconsistent. Some studies show that the level of health literacy in women is to a certain extent higher than in men –33 althoAs food literacy is closely linked to health literacy  and peopThis study aims to determine the level of self-perceived food literacy and health promotion literacy among adults with a low and medium level of education and from various subgroups , as well as the association between these levels. Furthermore, it explores the associations between self-perceived food literacy and health promotion literacy in BMI.The workplace was chosen as the setting for this cross-sectional study because it is part of a research project which aims to influence the behaviour and environments of people with a low and medium level of education. Inclusion criteria for the study population were being 18 or older, being employed, living in the Netherlands, understanding the Dutch language at a sufficient level and having a low or medium level of education .n = 1), healthcare (n = 3), construction (n = 1), public sector (n = 1), infrastructure (n = 1) and logistics (n = 1) – were ultimately willing to participate. The contact persons of these eight companies approached their employees based on the inclusion criteria and by using flyers provided by the researcher (HS).Regarding recruitment, job sectors which mainly employ people with a low and medium level of education  were seln = 4) in a real-life work setting. The researcher asked the questions and the employee answered according to the ‘thinking aloud’ method [Data were collected using a questionnaire that was filled in by participants at their workplace. First, the questionnaire was pilot-tested among a small convenience sample of employees with a low level of education . In the individual setting, participants completed the questionnaire in a private room using a computer assisted modality while the researcher (HS) was present. Participants who had difficulty reading were able to indicate their preference for the researcher to read the questions aloud. In the group setting, participants completed the questionnaire using a paper and pencil modality while the researcher (HS) and other participants were present in the same room. All participants provided written informed consent. Questionnaire completion took 15 to 30 min. Participants were compensated with a healthy snack.α = 0.83) and is comparable to the reliability found in our sample (Cronbach’s α = 0.84). Furthermore, convergent, divergent and criterion validity have been indicated [‘Are you able to alter a recipe yourself?’), Resilience and Resistance , Healthy Snack Styles (e.g. ‘Do you eat fruit as a snack?’), Social and Conscious Eating (e.g. ‘Do you find it important to eat dinner at the same time if you are with others?’), Examining Food Labels , Daily Food Planning , Healthy Budgeting  and Healthy Food Stockpiling (e.g. ‘Do you have 4 or more bottles of sugar-sweetened beverages or lemonade containing sugar in stock?’). These subscales corresponded to the variables used in the analyses of this study. Items which required reversed scoring were recoded. No cut-off point for missing values was described by the SPFLS developers [The Self-Perceived Food Literacy Scale (SPFLS) is a validated, theory-driven, expert-based instrument which measures self-perceived food literacy (SPFL) with respect to healthy eating among adults, using B1 language level . The ovendicated . The SPFndicated . The itevelopers  and therIn order to interpret mean SPFL levels, mean SPFL was divided into the two categories low (1.00–3.49) and high (3.50–5.00). The connotation of the response option 3.00 = ‘Sometimes I do, sometimes I do not’ arguably does not represent having a high level of SPFL while the option 4.00 = ‘Yes, most of the time’ does. Therefore, the cutoff point of 3.49 in the middle of those response options was chosen. This procedure was also conducted in a German study, to our knowledge the first and only study that applied the SPFLS to a general population including people with a low level of education .α = 0.83). Convergent validity was indicated by a positive correlation  between the HPLS and SPFLS. Furthermore, face validity was indicated by a thorough review process of the maintenance of the items’ connotations after conversion to B1 language level, by the first author and three of the co-authors.Since our study was conducted within the context of prevention and health promotion, we used the subscales ‘Health Promotion’ and ‘Disease prevention’ of the short European Health Literacy Survey Questionnaire (HLS-EU-Q16) , 46 in D‘If family or friends give you advice about health, do you understand that advice?’), which were answered on a four-point Likert scale . The subscale of Disease Prevention assesses the ability to access, understand, process and apply information on risk factors for health. This subscale was composed of five items , which were answered on a four-point Likert scale . The answer option ‘I don’t know’ was not used as it is only used when administered orally by an interviewer [The subscale of Health Promotion measures the ability to access, understand and process information on determinants of health in the social and physical environment. This subscale was composed of four items  and self-reported weight (kilograms) were obtained. BMI was calculated by dividing the weight in kilograms by the square of the height in meters. Furthermore, it was divided in three weight-status categories: Healthy weight (18.50–24.99), overweight (25–29.99) and obese (≥ 30.0).Level of education was divided into two levels according to the Dutch standard classification of education : low  were left as ‘missing’ without excluding cases.Data were analysed in SPSS Statistics 26.0. The presence of outliers among the main variables was tested. One outlier on BMI was found and subsequently converted to missing data. Furthermore, one BMI value was below the healthy weight range (i.e. < 18.5 kg/m2 ). This vr < .30), moderate (≥ .30 r < .50) or large (r ≥ .50) [The sample was described by performing descriptive analyses. The mean values for SPFL, HPL, and their subscales as well as the distribution across categories were calculated using descriptive analyses. Analyses of variance (ANOVA) were performed to test the difference in mean SPFL and HPL between the subgroups gender, age, level of education and BMI. First, assumptions for normality were assessed and met. A Tukey’s post hoc test was used to pairwise compare the three BMI categories. Accordingly, significant between-group differences were explored. The correlations between SPFL, HPL and the subscales were computed by the Pearson’s correlation test. A significance level of 0.05 was used (2-sided). Pearson’s correlation coefficients were interpreted as small (≥ .10 r ≥ .50) . The assIn total, 222 participants met our inclusion criteria. As shown in Table SD = .69) and 3.57 for men (SD = .83)  = 3.07, P = .002). Solely the scores on the Examining Food Labels subscale did not differ between men and women  = 3.07, P = .081). The overall level of SPFL was significantly higher among participants aged 40 or older than among participants aged under 40  = 11.63, P = .001). Significantly higher mean scores were found among participants aged 40 or older on the Daily Food Planning  = 5.67, P = .018), Social and Conscious Eating  = 20.00, P = <.001), and Resilience and Resistance  = 10.33, P = .002) subscales. No significant differences were found between participants with a low or medium level of education regarding mean SPFL  = .021, P = .885) or subscales. Similarly, no significant differences were found between the weight-status categories regarding mean SPFL  = .73, P = .484) or subscales.Mean SPFL and the distribution over low and high levels can be found in Table F  = 5.39, P = .021)  = 6.85, P = .010) and the Disease Prevention subscale  = 9.52, P = .002) than participants under the age of 40. No significant difference was found between participants with a low level of education and participants with a medium level of education regarding mean HPL  = .157, P = .693) or subscales. Regarding HPL and weight-status, a significant difference was found for the Disease Prevention subscale  = 3.87, P = .022). A Tukey’s post hoc test showed that participants with obesity scored significantly higher on the Disease Prevention subscale than participants in the overweight subgroup (P = .016). There was no significant difference between participants with a healthy weight and participants with overweight (P = .568) or between participants with a healthy weight and obesity (P = .103).Mean HPL and the distribution over inadequate, problematic and sufficient can be found in Table F 1,13 = 5.39r = .25, P < .001 (n = 203). A small positive correlation was also found between SPFL and the Health Promotion subscale of HPL, r = .24, P = .001 (n = 201). Likewise, a small positive correlation was found between SPFL and the Disease Prevention subscale of HPL, r = .23, P = .001 (n = 201). Furthermore, multivariate linear regression analyses showed a significant association between SPFL and HPL , after adjusting for the covariates gender, age and level of education  and health promotion literacy (HPL) among adults with a low and medium level of education and from various demographic subgroups, as well as the association between these levels. Furthermore, it aimed to explore the relationship between SPFL and HPL in BMI. The results indicate that most adults in our sample had a low level of SPFL and that a third had inadequate or problematic HPL levels.We observed that women scored higher on the majority of the SPFL subscales compared to men. In terms of age, participants aged 40 or older scored significantly higher on SPFL and HPL than participants aged under 40. We found no educational or weight-status differences in the mean values of the overall SPFL scale and its subscales. Likewise, no educational difference was found for HPL. Regarding the Disease Prevention subscale of HPL, participants with obesity scored significantly higher than participants with overweight. The association between SPFL and HPL was positive, though small and also present after adjusting for gender, age and level of education. Finally, no relationships were found between SPFL and HPL in BMI.We observed that women on average had higher SPFL compared to men, except for the subscale ‘Examining Food Labels’. Comparable differences were observed in prior research suggesting that women have a healthier diet than men  and a heRegarding age, we found positive associations with higher SPFL and HPL while other studies seem to consistently find opposite results for health literacy –38. HoweWe found no differences in the mean values of SPFL, HPL and their subscales between adults with a low and medium level of education, though we expected to find an educational difference in SPFL and HPL based on previous studies in food literacy and health literacy , 34, 39.The correlation between SPFL and HPL was positive, though small. Earlier research also indicated a positive association between food literacy and health literacy . MoreoveFurthermore, the absence of associations between SPFL and HPL in BMI was unexpected. The absence of weight-status differences in our sample may be explained by the fact that BMI can be influenced by a broad variety of factors. Our SPFL and HPL measures may not have been comprehensive and direct enough to indicate an association. Low health literacy has in fact been linked to an increased BMI in earlier research , 54. SPFOne limitation of this study was that the purposive sampling method might have induced selection bias as companies’ contact persons who agreed to participate, might have already been engaged in health promotion activities for their employees. In addition, employees completed the questionnaire at their workplace in a setting in which the researcher was present. This might have induced social desirability. However, this presence also assured comprehensibility about the aim and content of the questionnaire. Another limitation was that the original SPFLS was validated in a sample with an above-average rather than a below-average level of education compared to the general Dutch population. Regarding the Health Promotion and Disease Prevention subscales of HPL, no validation in Dutch has been performed yet. However, both the SPFLS  as well One strength of this study was that we derived two subscales to measure HPL from the HLS-EU-Q16, which is expected to be suitable for determining health literacy in populations with limited literacy . TherefoOur results suggest that there is room for improvement in both SPFL and HPL levels among adults with a low and medium level of education, because the majority of our sample had a low SPFL level and a third had inadequate or problematic HPL levels. A contribution to this improvement can be made by addressing causal determinants of health literacy. General literacy is one of the best indicators of health literacy , 61 and Future research should consider exploring differences in food and health literacy between adults with a low and medium level of education on the one hand and adults with a high level of education on the other hand. Comparing low and medium educated groups with high educated groups might add to our understanding of socioeconomic trends in food and health literacy. Subsequently, it might contribute to our knowledge of ways to reduce socioeconomic health inequities. Furthermore, it is recommended to consider food and health literacy in health promotion activities not only for groups with a low but also with a medium level of education.Another direction of future research is to further explore the relationship between food literacy, health literacy and BMI. Based on this study, it is recommended to investigate food and health literacy in ways that more directly influence BMI. This might provide us with a better understanding of the role of food and health literacy in weight-status.In conclusion, the majority of our sample scored low on SPFL and a third scored inadequate or problematic on HPL. Regarding subgroups, women scored higher on the majority of the SPFL subscales (7 out of 8) compared to men. No differences in SPFL or HPL were found between groups with a low and medium level of education. In addition, SPFL and HPL were shown to be positively associated, to a small extent. HPL was associated with SPFL after adjusting for demographic characteristics. No relationships were found between SPFL and HPL in BMI. Regarding future research, the comparison of low and middle SEP groups with high SEP groups when exploring food and health literacy levels should be considered. Additionally, future research should explore more direct proxies of weight-status to better understand the role of health and food literacy in overweight patterns.


The key clinical message is to know that mechanical complications of myocardial infarction are rare but fatal. A high index of suspicion facilitates diagnosis. The presence of acute heart failure should ring an alarm. Other red flags are cardiogenic shock, new murmur, or evidence of hypoperfusion. The key clinical message is to know that mechanical complications of myocardial infarction are rare but fatal. A high index of suspicion facilitates diagnosis. The presence of acute heart failure should ring an alarm. Other red flags are cardiogenic shock, new murmur, or evidence of hypoperfusion. Mechanical complications of myocardial infarction are rare. However, the consequences are catastrophic if missed; here, we present a case highlighting the red flags that can guide the diagnosis of mechanical complications of MI.A 56‐year‐old man with a past medical history of diabetes presented with chest pain of 23‐hour duration. His BP was 150/80, pulse 120, and SO2 89%. His examination was remarkable for congested neck veins but no murmurs. Chest auscultation showed bubbling crepitation.EKG revealed anterior STEMI. Because of acute severe heart failure, we performed a bedside echocardiogram. It showed ejection fraction (EF) of 20% and perforated LV apex with apical pseudoaneurysm. There was effusion around the right ventricle (RV) with tamponade. Emergency coronary angiography revealed total proximal left anterior descending (LAD) artery occlusion. Emergency cardiac surgery was performed to reconstruct the LV apex and revascularize the LAD by venous graft. The rest of the hospital course stay was uneventful.The critical clinical message is to know that mechanical complications are rare. A high index of suspicion facilitates diagnosis. The presence of acute heart failure should ring an alarm. Other red flags are cardiogenic shock, new murmur, or evidence of hypoperfusion Video .Patient verbal consent had been obtained to use the video material.None declared.AM: had contributed to the design and implementation of the research, to the analysis of the results, and to the writing of the manuscript.Published with written consent of the patient.Video S1Click here for additional data file.Supplementary MaterialClick here for additional data file.


To summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and to highlight the latest bench-to-bedside developments.The current evidence regarding the potential for monitoring biomarkers was reviewed and individual modalities of metabolism and/or chemical composition imaging discussed. Perfusion, permeability, and microstructure imaging were similarly analyzed in Part 1 of this two-part review article and are valuable reading as background to this article. We appraise the clinic readiness of all the individual modalities and consider methodologies involving machine learning (radiomics) and the combination of MRI approaches (multiparametric imaging).The biochemical composition of high-grade gliomas is markedly different from healthy brain tissue. Magnetic resonance spectroscopy allows the simultaneous acquisition of an array of metabolic alterations, with choline-based ratios appearing to be consistently discriminatory in treatment response assessment, although challenges remain despite this being a mature technique. Promising directions relate to ultra-high field strengths, 2-hydroxyglutarate analysis, and the use of non-proton nuclei. Labile protons on endogenous proteins can be selectively targeted with chemical exchange saturation transfer to give high resolution images. The body of evidence for clinical application of amide proton transfer imaging has been building for a decade, but more evidence is required to confirm chemical exchange saturation transfer use as a monitoring biomarker. Multiparametric methodologies, including the incorporation of nuclear medicine techniques, combine probes measuring different tumor properties. Although potentially synergistic, the limitations of each individual modality also can be compounded, particularly in the absence of standardization. Machine learning requires large datasets with high-quality annotation; there is currently low-level evidence for monitoring biomarker clinical application.Advanced MRI techniques show huge promise in treatment response assessment. The clinical readiness analysis highlights that most monitoring biomarkers require standardized international consensus guidelines, with more facilitation regarding technique implementation and reporting in the clinic. High-Grade Glioma Treatment Response Monitoring Biomarkers: A Position Statement on the Evidence Supporting the Use of Advanced MRI Techniques in the Clinic, and the Latest Bench-to-Bedside Developments. Part 1: Perfusion and Diffusion Techniques) of this two-part review article.Contemporaneous, accurate, and reliable monitoring biomarkers are required for high-grade glioma treatment response assessment as important challenges limit the use of conventional structural MRI protocols. The current evidence regarding the potential for monitoring biomarkers based on advanced MRI techniques shows that the methodology has developed considerably. Although some techniques have evolved and matured over three decades, several new state-of-the-art methods are poised to contribute to the imaging armamentarium. However, limitations for all techniques remain. High level evidence level 1 or 2) ( or 2 (1)The challenges limiting the use of conventional structural MRI protocols as monitoring biomarkers and the need for novel monitoring biomarkers are also described in Part 1. To complete a summary of the evidence for the use of advanced MRI techniques as monitoring biomarkers in the clinic, and to finish highlighting the latest bench-to-bedside developments, we now focus on the individual modalities of metabolism and/or chemical composition imaging. We also appraise the clinic readiness of all the individual modalities. Furthermore, we consider post-processing methodologies involving the combination of MRI approaches (multiparametric imaging) or machine learning (radiomics).T1-weighted MRI images first increases.The review method is described fully in Part 1. Briefly, experts in advanced MRI techniques applied to high-grade glioma treatment response assessment, convened through a European framework. The consensus decision was to focus on monitoring biomarkers that can reliably differentiate post-treatment-related effects (PTRE) from true tumor progression during (or before) the point when contrast enhancement on longitudinal relaxation time Advanced imaging technique analyses were compiled by subject matter experts and incorporated into a manuscript and circulated to the working group members.To determine clinical diagnostic accuracy, we performed MEDLINE (including PubMed), Embase and Cochrane Register searches for recent systematic reviews and meta-analyses, favoring those which followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Diagnostic Test Accuracy (PRISMA-DTA) methodology . We also1H MRS) is a technique that enables noninvasive characterization of certain biochemicals that are intermediates or end products of cellular metabolism, referred to as metabolites, within tissues based on the chemical shift of molecule resonances in relation to water. The area under a metabolite peak in a magnetic resonance (MR) spectrum is directly proportional to the tissue concentration of this metabolite. The major peaks in the brain include resonances of N-acetyl-aspartate (NAA), choline (Cho), creatine (Cre), and glutamate (Glu), but the total number of quantifiable metabolites depends mainly on the pulse sequence used, sequence parameters , and static magnetic field strength ] for treatment response assessment in high-grade gliomas, 1H MRS was found to have the highest diagnostic accuracy, with a sensitivity of 91% and specificity of 95%, among all the advanced MRI techniques  was assessed.In a meta-analysis comparing the diagnostic accuracy of anatomical and advanced MRI fluoro-ethyl-tyrosine (FET), and the glucose analogue [18F]fluoro-deoxy-glucose (FDG) PET have been included in joint European Association of Nuclear Medicine/European Association of Neuro-Oncology (EANO) guidelines . In the proposed minimum imaging protocol from the Jumpstarting Brain Tumor Drug Development Coalition , DSC-MRI (KS and MÁ-T), DCE-MRI (OH), ASL (PF and VK), diffusion techniques , spectroscopy (ECW and GH), CEST (EAHW), multiparametric imaging (OMH), clinical readiness (OH), radiomics (TB), discussion (TB). All authors have contributed to the conception of the two parts of the article, revised them critically and approved the submitted versions.www.glimr.eu), supported by COST (European Cooperation in Science and Technology), www.cost.eu. GliMR provided travel and accommodation for members who had travelled to early networking meetings.This publication is part of the COST Action CA18206 Glioma MR Imaging 2.0  Talent Programme Veni: 18144- EAHW: The Dutch Research Council (NWO) Talent Programme Veni: 91619121- PF: The Portuguese Foundation for Science and Technology (FCT) Grant UIDB/50009/2020.- RN: Babes-Bolyai University, Grant GTC No. 35277/18.11.2020.- TB: The Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z].- MÁ-T: The ALBATROSS project .KS: Ownership interest in IQ-AI Ltd and financial interest in Imaging Biometrics LLC. TB speaker’s bureau for AbbVie and Siemens Healthineers.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The accumulation of scientific knowledge has been hampered by inconsistent usage of terms and categories. Ontology is the study of categories, their properties, and the relations between them. This presentation considers the definition and measurement of emotional well-being (EWB), a term that has been used inconsistently in research and clinical practice. The category contains eudaimonic and hedonic well-being that represent interrelated but conceptually distinct aspects of mental health. This presentation will review the definition and measurement of EWB and evidence for the validity of the construct. Evidence suggests EWB increases after age 50 and is important for maintenance of cognitive function in old age. Further, low in EWB may be a risk factor for incident ADRD, and is likely to impair cognitive functioning.


The internet is now a major source of health information. With the growth of internet users, eHealth literacy has emerged as a new concept for digital health care. Therefore, health professionals need to consider the eHealth literacy of consumers when providing care utilizing digital health technologies.This study aimed to identify currently available eHealth literacy instruments and evaluate their measurement properties to provide robust evidence to researchers and clinicians who are selecting an eHealth literacy instrument.We conducted a systematic review and meta-analysis of self-reported eHealth literacy instruments by applying the updated COSMIN  methodology.This study included 7 instruments from 41 articles describing 57 psychometric studies, as identified in 4 databases . No eHealth literacy instrument provided evidence for all measurement properties. The eHealth literacy scale (eHEALS) was originally developed with a single-factor structure under the definition of eHealth literacy before the rise of social media and the mobile web. That instrument was evaluated in 18 different languages and 26 countries, involving diverse populations. However, various other factor structures were exhibited: 7 types of two-factor structures, 3 types of three-factor structures, and 1 bifactor structure. The transactional eHealth literacy instrument (TeHLI) was developed to reflect the broader concept of eHealth literacy and was demonstrated to have a sufficient low-quality and very low-quality evidence for content validity  and sufficient high-quality evidence for structural validity and internal consistency; however, that instrument has rarely been evaluated.The eHealth literacy scale was the most frequently investigated instrument. However, it is strongly recommended that the instrument's content be updated to reflect recent advancements in digital health technologies. In addition, the transactional eHealth literacy instrument needs improvements in content validity and further psychometric studies to increase the credibility of its synthesized evidence. Health literacy is an important determinant for achieving positive health outcomes -3. It reThe internet is now a major source of health information . There wThe rapidly increasing use of digital devices  and the internet means that health professionals are transiting the method of health information delivery beyond a traditional face-to-face mode into a web-based model, largely due to its advantages of not being restricted to time and space . To ensuThe emergence of eHealth literacy has resulted in the development of self-reporting instruments to measure it. According to the United States Department of Health and Human Services , a newlyOne previous narrative review of eHealth literacy instruments  simply sA systematic review of self-reported instruments was conducted according to the updated COSMIN methodology. The PubMed, CINAHL, Embase, and PsycInfo databases were searched from their dates of inception up to March 3, 2021. A search strategy based on the COSMIN involved constructing search filters for the key elements of the construct of interest: population(s), type of instruments , and measurement properties (including inclusion and exclusion filters), and then combining them using AND and NOT Boolean operators. The search filter used for the construct of interest  in this study is presented in α, but not with the main purpose of evaluating measurement properties of an eHealth literacy instrument, then the article was not included. Literature providing limited information such as conference abstracts, review protocols, or a note were also excluded.We included studies involving the development of an eHealth literacy instrument or evaluations of its measurement properties published as full-text original articles in peer-reviewed journals written in English. If a study had utilized an eHealth literacy instrument as an outcome measure and determined its measurement properties, such as Cronbach’s Data were extracted from each article to understand the characteristics of the analyzed instrument , the study samples  used to assess the identified instruments, theoretical/conceptual frameworks and specified definitions used for the development of instruments, and the results of measurement properties and floor and ceiling effects of the eHealth literacy instruments.α for all items needed to be evaluated, whereas if a two-factor structure was supported, we needed to evaluate the Cronbach’s α of two subscales. Subsequently, remaining measurement properties such as reliability, measurement error, hypotheses testing for construct validity , and responsiveness were evaluated. The methodological quality of criterion validity was not evaluated since there is no gold standard for eHealth literacy measures.The measurement properties of the instruments were evaluated in 3 steps. First, the methodological quality of the included studies was evaluated using the COSMIN Risk of Bias checklist ,18. Eachα (≥.70) as the rating indicator of internal consistency. Therefore, the following internal consistency-related criteria were added: (1) sufficient (+) for an omega or person/item reliability of ≥.70 for each unidimensional scale or subscale, insufficient (–) for an omega or person/item reliability of <.70, and indeterminate (?) if the values were not reported; and (2) sufficient (+) for a person/item separation index of ≥1.50 for each unidimensional scale or subscale, insufficient (–) for a person/item separation index of <1.50, and indeterminate (?) if the values were not reported [r≥.30 with other comparators such as health literacy and internet-related and health-related variables .Second, the results of each study for measurement properties were rated according to the updated quality criteria for good measurement properties as sufficient (+), insufficient (–), or indeterminate (?) ,21. The reported . Additioreported  were appFinally, all of the results for each instrument's measurement properties were qualitatively summarized or quantitatively pooled through meta-analysis using statistical package meta in R software . The summarized results related to content validity were rated as sufficient (+), insufficient (–), or inconsistent (±) according to the 10 criteria for good content validity . The sumThe database search identified 2355 records , and 1868 records were screened after removing duplicates . In the The characteristics of the included eHealth literacy instruments and studies are presented in The eHEALS-E is the extended version of the eHEALS comprising 20 items developed for the users of online health communities . The e-HThe theoretical/conceptual frameworks, definitions used when developing the identified instruments, and intended use are summarized in The measurement error and responsiveness were not assessed for any of the instruments; therefore, the results for structural validity, internal consistency, cross-cultural/measurement invariance, reliability, and hypotheses testing  were summarized or pooled for each instrument. The summarized or pooled results for the measurement properties of each instrument are presented in α of 0.91  -43 demon of 0.91 , as wellThe second-most-frequent structure of the eHEALS was a two-factor structure. However, the subscale structures were not identical. A two-factor structure as derived from 3 studies (IDs 30-32) ,39,44 deThe DHLI, eHLQ, and TeHLI were each psychometrically evaluated twice. Regarding the DHLI, a seven-factor structure (ID 51)  yielded The remaining instruments were assessed only once. The eHEALS-E demonstrated sufficient high-quality evidence for both structural validity and internal consistency and insufficient low-quality evidence for known-groups validity (ID 49) . The e-HThis systematic review found that 7 eHealth literacy instruments are currently available. The measurement properties were most frequently assessed for the eHEALS in 18 languages, 26 countries, and diverse populations . The conceptualization of a construct to be measured is a basic and initial step when developing a self-reported instrument. The eHEALS was developed based on the definition of “the ability to seek, find, understand, and appraise health information from electronic sources and apply the knowledge gained to addressing or solving a health problem (p. 2)” from the 6 components of literacy in the Lily model: traditional, information, media, health, computer, and science literacies . HoweverContent validity refers to the degree to which the content of an instrument adequately reflects the construct to be measured . The oveThe eHEALS is a pioneering instrument measuring eHealth literacy and was originally developed with a single-factor structure. However, various other factor structures were identified in this study: 7 types of two-factor structures, 3 types of three-factor structures, and 1 bifactor structure. A possible reason for such diverse factor structures is the instrument contents when considering that insufficient content validity can impair structural validity . The theThe three-factor eHEALS structures reported on in a single study by Paige et al  and 3 stThe eHEALS-E is the extended version of the eHEALS developed to cover better the complex factors contributing to eHealth literacy. However, that instrument was extended under the same definition used for the original version in 2006 . TherefoAlong with the evolution of interactive communication technologies on the internet, conceptual extensions have been demanded for eHealth literacy. This has resulted in the development of second-generation instruments  to measure a wider range of eHealth literacy concepts to make them more suitable for people living in the social-media era of eHealth. However, those instruments have been assessed only once or twice, with there being little meaningful synthesized evidence for the measurement properties of each instrument; therefore, further psychometrics studies of them are strongly recommended.e measurement of transactional features afforded by online media. However, this instrument has only been assessed twice in a single study using classical test theory and item response theory (IRT)/Rasch model with a specific population . Therefore, its synthesized evidence for measurement properties cannot be generalized to healthy people or patients of different ages with other diseases. It is therefore suggested that this instrument needs to be assessed in other populations.The TeHLI seems to be psychometrically better than the other second-generation instruments. In addition, this is a theory-driven instrument derived from the TMeHL  and baseThe measurement error and responsiveness were not assessed for any of the instruments identified in this study, so future studies of those properties are warranted. More studies of measurement properties also need to be conducted for the second-generation instruments that have been assessed only once or twice. Further psychometric evaluations will increase the credibility of the synthesized evidence. When developing a self-reported instrument, specifying the definition of the concept to be measured is the most basic and important starting point because this determines the scope of the instrument being developed and affects its measurement properties. Nevertheless, the definitions of eHealth literacy were not clarified for most of the instruments identified in this study. New instruments need to be developed for which the definition of eHealth literacy to be measured is clearly addressed, particularly encompassing the attributes/skills required for the social nature of eHealth in the current digital environment.The assumptions of unidimensionality, local independence, and monotonicity underlying the analyses of structural validity performed using the IRT/Rasch model were not or only partially reported for 11 of 14 studies. According to the COSMIN methodology, the structural validity of a study cannot be rated as sufficient without information about the nonviolation of assumptions underlying IRT/Rasch analysis, even when the model exhibits an adequate fit for structural validity ,21. TherConvergent validity refers to the relationship of an instrument's score  with a comparator instrument that measures similar constructs and has satisfactory measurement properties . The metRegarding the instructions provided for how to respond to items, only those for the eHEALS included the recall period: “…tell me which responses best reflect your opinion and experience right now.” Other instruments did not provide information about the recall period, which may result in bias in response items. In the future, it is recommended to provide information about the item response time frame, such as a “short” recall period or the “current state” .α) was qualitatively summarized and quantitatively pooled in a meta-analysis. This is the first meta-analysis applying Cronbach’s α to eHealth literacy instruments. A limitation of this study is that it only included peer-reviewed journal articles published in English, which may have resulted in selection bias.The first strength of this systematic review is that a two-phase search strategy was performed to exhaustively identify eHealth literacy instruments, as recommended by Lee et al , especiaThis systematic review identified 7 eHealth literacy instruments, and complete evaluations of all measurement properties have not been performed for any of these instruments. The eHEALS, based on the 6 components of literacy in the Lily model, was the most frequently investigated instrument with the smallest number of items (8 items), and the 2 three-factor structures of the eHEALS were better than other structures of the instrument; however, this instrument measures a narrow scope of eHealth literacy and so needs to be reconsidered when being applied to people living in the social media era of eHealth (web 2.0). Revising or updating the contents of the eHEALS is necessary to reflect the skills required for the social nature of eHealth. The TeHLI (consisting of 18 items) was the best instrument for broader measurements of eHealth literacy, although it is restricted by generalizing for only healthy people or patients with other diseases in different ages (younger than 40 years). Further psychometric studies of the second-generation eHealth literacy instruments are strongly recommended. In particular, their content validities should be carefully considered due to the results of this systematic review indicating it had low-quality or very low-quality evidence, meaning that they do not fully capture eHealth literacy.


Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar “pitting” process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed  in vitro RBC culture protocols that fail to generate a majority of typical biconcave RBCs. Our results also reveal that intra-splenic mechanical constraints likely contribute to the final clearance and elimination of aged RBCs. Altogether, we demonstrate that our computational model can provide mechanistic rationales for experimental studies, offer insights into the role of the spleen in the RBC physiology and help the optimization of in vitro RBC culture techniques.The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell (RBC) life cycle. In this study, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan, a critical biological process that cannot be observed in humans. Our simulation results illustrate a specific role of spleen in shaping young RBCs, which points to a probable missing step in current  The spleen, the largest secondary lymphoid organ in the human immune system, works as a drainage network that prevents pathogenic microorganisms from remaining and multiplying in the bloodstream through innate phagocytosis or adaptive responses operated by lymphocytes and antibodies , 2. In ain vivo, most of the hypotheses on the mechanism of RBC removal in the spleen are developed based on either ex vivo or in vitro studies where damaged or surface-altered RBCs are generated to mimic the aged RBCs. On one end, a number of in vitro [ex vivo [in vitro investigations of RBC-macrophage interaction indicate that the biochemical markers on the membrane of RBCs, such as binding of antibodies (NAbs) to the band-3 proteins [in vitro study [The spleen, along with liver and bone marrow, is considered as the primary organs for clearing the senescent RBCs from circulation, although the underlying mechanism of the removal process is not fully understood . During in vitro –27 and e[ex vivo –30 experproteins , 31, incproteins , 33, decproteins , 21 and proteins , can triro study  presentein vitro cultured, customizable RBCs for transfusion or drug delivery agents, but existing culture techniques are facing several challenges, such as the low yield of enucleated and biconcave RBCs [in vitro cultured RBCs after transfusion [in vitro culture systems.In addition to filtering senescent RBCs, the spleen contributes to the function of facilitating the maturation of young RBCs (reticulocytes) . Human Rave RBCs . The abinsfusion . Thus, aIn contrast to the extensive studies on the function of spleen in sensing and clearing diseased RBCs , 45–48, α-chain with 22 triple-helical segments and a β-chain with 17 triple-helical segments and thus is represented by 39 spectrin particles connected by unbreakable springs. Three types of CG particles are introduced to represent the lipid bilayer of the RBC membrane. The red particles represent clusters of lipid molecules. The yellow particles underneath the blue particles represent glycophorin proteins and they are connected to the blue particles by unbreakable springs. The black particles signify band-3 proteins and they tether spectrin filaments to the lipid bilayer. This particle-based model has been widely used to study the biomechanics of RBC membrane under healthy and diseased conditions [In the current work, we employ OpenRBC , a fast nditions –57. Diffnditions –61, explμm, whereas the two horizontal bars represent the elongated endothelial cells on the sinus wall. The thickness of the slit wall is 1.9 μm. The width and height of the slit is 4.0 μm and 1.2 μm, respectively, which are consistent with the slit geometry employed in Pivkin et al. [IES was built by using 4 solid bars, as illustrated in n et al. . The bou2 and 103.5 μm3, respectively. We also reduce the connections between the spectrin filaments and the actin junctions in the reticulocyte model , mimicking an intracellular inclusion, such as a remnant of nuclei or a malaria parasite, with a size larger than the slit (1.25 μm). We drive this reticulocyte through IES with a pressure gradient of 10 Pa μm−1. As illustrated in Although the prevailing notion is that vestigial membrane proteins e.g., CD71) and intracellular inclusions of reticulocytes are removed by red pulp macrophages in the spleen 1 and int, mechani2 and the volume is maintained at 90 μm3, giving a S/V of 1.45 which falls within the physiological range of S/V reported for normal RBCs [−1, respectively, to drive RBCs through IES. Our simulation results show that RBCs are able to pass through IES under these examined driving pressures. in vivo [in vitro [2 and volume of 90 μm3 and our simulation results show that these RBCs are also able to traverse IES under the examined driving pressures.In this section, we simulate mature RBCs with different surface areas passing through IES. At each pressure gradient, we identify the critical RBC surface area-to-volume ratio (S/V), below which RBCs are retained by IES. First, the surface area of the traversing RBC is selected to be 130 μmmal RBCs , 72. Simin vitro  and compin vitro , 48, 49.2, respectively, representing 15.3% and 23% surface area reduction from our normal RBC cases. The cell volume is still maintained at 90 μm3. Pressure gradients of 5, 8, 10, 15 and 20 Pa μm−1 are applied to drive the RBCs through IES, respectively. 2 and volume of 90 μm3 (S/V = 1.22), attempting to traverse IES driven by a pressure gradient of 8 Pa μm−1. −1. Our simulation results also show that RBCs with surface area of 100 μm2 (S/V = 1.11) is not able to traverse IES either. These results are generally in agreement with former ex vivo investigations showing that RBCs with more than 18% average surface area loss are mostly entrapped in the spleen [Over the lifespan of ∼120 days, RBCs constantly lose surface area through releasing vesicles , 73. Sene spleen .2 squeezing through the slit at an elevated pressure gradient of 10 Pa μm−1 from the case shown in in vivo observations on the rate spleen by MacDonald et al. [Next, we examine whether an increase in the local pressure gradient can force the retained RBCs pass through IES. d et al. , the trad et al. –81 and cd et al.  studies.Here, we summarize and map out the state diagram of the RBC dynamic behavior through IES as a function of the cell S/V (corresponding to the aging stages of RBCs) and pressure gradient across IES. As shown in in vitro RBC culture protocols which are driven primarily by the intrinsic ability of erythroblasts to develop into reticulocytes. In vitro culture of fully enucleated, discocytic reticulocytes would likely optimize their survival and function in circulation [Our simulation illustrates that passage of IES allows reticulocytes to remove intracellular non-deformable particles, confirming a former hypothesis on the role of IES in removing the inclusions of reticulocytes , 70. Ourculation .ex vivo experimental study [in vitro experimental studies [in vitro investigation provided new evidence showing a high propensity of macrophages on recognizing and phagocytosing lysed RBC over intact ones [in vitro studies support the mechanism that the senescent RBCs are first retained by IES and then undergo erythrophagocytosis to end their life cycle.The spleen is also one of the terminals for RBCs’ ∼120 day journey in circulation. As RBCs age, their deformability decreases primarily due to reduced S/V , increasal study  reportedal study  conducteal study , 69. Pri studies  suggesteact ones . Our simact ones , 34 by sα4β1, via releasing exosomes [μm through IES (size of 1.2μm) to examine a hypothesis raised by Crosby [μm, but some are or come close to this size, such as remnants of nuclei . Any inclusions larger than the height of the slit, which could vary from 0.25 to 1.2μm [ex vivo studies [Although our simulation results demonstrate the function of the spleen on facilitating the maturation of reticulocytes, it does not exclude other mechanisms that also contribute to the final maturation process of reticulocytes in the spleen. For example, reticulocytes could expel unwanted membrane proteins such as transferrin receptor CD71), CD98 and integrin exosomes –91, whicexosomes , 92, 93.y Crosby . We noteto 1.2μm , may be to 1.2μm , 94. Forto 1.2μm . Smaller1, CD98 ato 1.2μm . In addi studies  have sho studies . In the  studies –67. As r−1, which are greater than the critical pressure gradient of ∼1 Pa μm−1 found in microsphere experiments [−1 were applied to drive RBCs through a slit with size down to 0.6 μm [in vivo measurements were performed by Atkinson and Sherlock [2+ concentrations [2+ loading [The pressure gradients we apply to drive RBCs through IES range from 5 to 20 Pa μmeriments , 29. Thio 0.6 μm . AlthougSherlock  to assesSherlock , 98, bectrations –101, whitrations  and Ca2+ loading , where t loading , 105. We loading , 107 or  loading , sickle  loading , acantho loading , on theiin vivo or in vitro and offer insights into the role of the spleen in the RBC physiology. At the beginning of RBC’s life cycle, traversal of IES allows young RBCs to repel undesired inclusions, shed redundant surface area and transform to biconcave shape, facilitating their maturation. Towards the end of their life cycle, retention by IES makes the aged RBCs amenable to hemolysis, promoting their degradation. These findings can provide mechanistic rationales for experimental studies and guide the optimization of in vitro RBC culture techniques.Taken together, we demonstrate that our computational model can simulate critical biological processes that cannot be observed S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.