A higher proportion of awardees also had achieved academic promotion  and subsequent NIH funding , while there was no difference in publication rates (p = 0.555). Participants in the Harvard Catalyst KL2/CMeRIT program demonstrate greater early career success than nonparticipants though the nonparticipants also fared relatively well.The Harvard Catalyst KL2/CMeRIT program is a 2-year mentored institutional career award that includes KL2 grants funded by National Institutes of Health (NIH) and CMeRIT grants funded by Harvard Catalyst nonfederal funds. The purpose of this study was to compare outcomes for early-stage investigators funded by the KL2/CMeRIT program to a group of applicants who were not chosen for support to assess the potential impact of the program on early career outcomes. Career data, including academic promotions, subsequent grant funding, and publication rates, from both successful and unsuccessful 2008–2018 KL2/CMeRIT applicants were compiled throughout the year 2020. Data were obtained directly through outreach to both groups and through assessment of online resources. The cohort comprised 487 individuals, 109 awardees, and 378 nonawardees. Awardees were more likely to be subsequently involved in clinical and translational research than nonawardees (92% vs 75%,  Harvard Catalyst was founded in 2008 under a grant from the National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) Program of the National Center for Advancing Translational Sciences. The CTSA Program is a national consortium of more than 60 research institutions (Hubs) with the overall goal to advance clinical and translation research –3. HarvaHarvard Catalyst’s KL2 program is a 2-year mentored institutional career award funded by the NIH. In 2012, the CMeRIT program, funded directly by the participating institutions was added to supplement the KL2 grant, given a very high demand for training and funding of early-stage clinical and translational investigators. The content and aim of KL2 and CMeRIT components are identical and thus the two form one joint program. The program provides funding and advanced training in clinical and translational research to senior fellows and early career faculty to pursue a mentored research project.The expectation is that the research produced in this mentored program will provide the basis for a successful NIH research grant, such as a K08, K23, R01, or other similar grants. In addition to their research project, awardees also pursue educational programs of their choice that provide optimal training focused on their career objectives. This may include Harvard Catalyst-based courses or other suitable translational science education paths. The program also includes dedicated mentoring, grant writing, and other career development opportunities only accessible to KL2/CMeRIT scholars. Ultimately, the program aims to identify talented clinical and translational investigators who would benefit from mentorship and additional training to make the critical leap into independent research.To determine the impact of the KL2/CMeRIT program on the careers of early-stage investigators, Harvard Catalyst initiated the KL2/CMeRIT Outcomes Project to track and analyze over 10 years’ worth of data from successful and unsuccessful applicants to the program. We hypothesized that individuals who received KL2/CMeRIT awards would demonstrate a higher level of early career success than applicants who were not chosen for funding.Applications were solicited on the Harvard Catalyst website and at each of the participating hospitals. Each application was reviewed and scored by three reviewers using the NIH scoring system and the applicant was interviewed by the primary reviewer. The top 50% of applications were discussed and scored in a meeting with the entire review committee.https://www.aamc.org/initiatives/urm/). The study was exempt from IRB approval.This study includes data from all applicants to the Harvard Catalyst KL2/CMeRIT program from 2008 to 2018, whether they were accepted or not, with a minimum follow-up period of 2 years. In addition to an overall comparison of measures of academic success between program awardees and nonawardees, the study examined the impact of the KL2/CMeRIT awards on women and groups underrepresented in medicine (URiM) as defined by the Association of American Medical Colleges  was asked as part of the standard application process. In terms of information on race and ethnicity, at the beginning of the KL2/CMeRIT program, applicants were invited to report such data through a separate survey, outside of the formal application process. Some of the early data were not identifiable and could not be determined to be an applicant or an awardee. In recent years, applicants to the KL2/CMeRIT program were given the option to report this data in the application itself. All applicants were also given the option to not respond to these questions. This project understands that because of the deidentified responses, the project is not able to capture all the URiM data through the program’s history.The first step of the KL2/CMeRIT Outcomes Project was to define key outcome measures of academic success. These metrics would be used to compare the success of program graduates and applicants who were not accepted into the program. The program chose four keys outcome areas: (1) continued involvement in clinical and translational research, (2) academic promotion, (3) subsequent NIH funding, and (4) publications. The follow-up time was the same for the successful and unsuccessful applicants.The process of gathering the data for this project began in July 2020. The Harvard Catalyst Evaluation Program, in partnership with the KL2/CMeRIT Program and the Harvard Catalyst Finance Department, identified participant names and populated appropriate outcomes data. Data collectors considered outcomes data reliable if it could be tied to a specific individual with absolute certainty. Data collectors used a combination of unique identifiers such as first, middle, and last names as well as email addresses and employment history sourced through internal Harvard Medical School databases to confirm any external data. External data sources included PubMed, NIH RePORTER, and publicly available information on directories such as LinkedIn and academic biographies from other universities or employers. If there was any uncertainty on the validity of a certain outcome metric for an individual, that individual’s data was not included in the outcome analysis for that particular metric. If an individual applied more than once to the program, only their most recent application record was used for analysis. For a detailed description of applicants who applied multiple time, please see Supplemental Tables.Exclusion criteria were also set so that only awardees who spent a minimum of 1 year in the program were included in the analysis. One year of program involvement was used as the threshold to ensure the awardees included in the analysis interacted with the program at a level that could potentially yield significant impacts from the program’s offerings, especially the mentoring, grant writing, and other educational components unique to the KL2/CMeRIT program. There were 121 awardees of which 12 (10%) departed the program before 1 year. Of those 11 (92%) did so because of having received additional NIH funding shortly thereafter . This study focused only on the 109 investigators who completed at least 1 year of the program to help ensure that the specific mentoring and education components provided by the program contributed to their success. Data collection was completed by the end of September 2020.CTSA Common Metric Operational Guideline: Careers in Clinical and Translational Research. clic-ctsa.org) to determine involvement in clinical and translational research.The category “Continued involvement in clinical and translational research” tracked whether successful and unsuccessful applicants were still involved in clinical and translational research as of July 2020. This project utilized the metric framework developed by the Center for Leading Innovation & Collaboration for the Common Metrics Careers in Clinical and Translational Research metric . Therefore, subsequent NIH funding was tracked to indicate if the program made it more likely that a graduate received K, R, or other funding from the NIH as PI. This data were sourced directly from the NIH Research Portfolio Online Reporting Tool (RePORTER). Sourcing data from RePORTER ensured this metric would have a high level of data completion across both groups.Because it can take several years for an investigator to obtain research funding from the NIH, the project opted to use a smaller pool of awardee and nonawardee data for this metric, limiting the analysis to only those individuals who had applied to the program between the years of 2008–2015. Similarly, only individuals who were reported to be involved in clinical and translational research were included in the subsequent NIH funding metric.The number of publications provides a measure of research productivity. Data were collected on publication volume of a given investigator as of July 2020. A portion of the data was sourced from Harvard Catalyst Profiles, a searchable online profile of all faculty at Harvard Medical School, Harvard School of Dental Medicine and Harvard T.H. Chan School of Public Health. Harvard Catalyst Profiles links PubMed data to a specific, identifiable researcher, making it easier for data collectors to confirm the overall publication volume for a single investigator. When an individual was not present in Harvard Catalyst Profiles, a data collector made a best effort to find publication data through PubMed or official biographies at other academic institutions. If data collectors were not able to confidently source an investigator’s publications, they were excluded from the analysis. No specific accounting was made for journal impact factor or other measures of “publication success” beyond the simple number of successful publications. Additionally, it was determined that the various career lengths made the overall volume calculations meaningless. Using the first publication date as a starting point, data collectors determined how long a given investigator had been actively publishing, up to July 2020. This data were used to determine an individual’s annual publication rate.t-tests. For all statistical analyses, p < 0.05, two-tailed, was used as an indication of significance.Chi-square analyses were performed to compare categorical proportions between two or more groups. Two-group comparisons of continuous values were made using the Student’s The final database included 487 unique individuals of which 109 (22%) were KL2/CMeRIT grant awardees and 378 (78%) were nonawardees.Table The total number of men and women in the cohort was nearly equal with 245 (50%) women and 252 (50%) men. Of the 245 women applicants to the program, 50 (20%) were awarded and 195 (80%) were not awarded. Our records do not include any individuals without gender data, with nonbinary responses or from any investigators who chose to not answer the gender question. Of the 59 URiM applicants to the program, 10 (17%) individuals were awarded a KL2/CMeRIT grant and 49 (83%) did not receive an award (Table p < 0.001)  have been retained in clinical and translational research whereas of the 363 nonawardees with reliable data, 271 (75%) have been retained in clinical and translational research (p = 0.016). Five nonawardees had unreliable data and were excluded from the analysis.Of the 109 awardees, 88 (81%) had received at least one academic promotion after being admitted to the program. Of the 373 nonawardees with reliable data, 257 (69%) had received at least one promotion after their application to the program (p = 0.034)  were retained within the Harvard academic system and of the 376 nonawardees with reliable data, 245 (65%) were retained at Harvard  received NIH funding within the first year of the program and were not included in the analysis. In comparison, of the 378 nonawardees, 6 (2%) received grant funding within the first year of their unsuccessful application to the KL2/CMeRIT program.p = 0.047).Using the previously described inclusion criteria for subsequent NIH funding , 65 awardees were included in this analysis. Of those, 47 (72%) received subsequent NIH funding. Of the 180 nonawardees who met inclusion criteria, 105 (58%) received subsequent NIH funding (p = 0.230)  received subsequent NIH R awards versus 65 (36%) of nonawardees (30) Fig. .p = 0.555).Data collectors were able to collect publication data on all 109 program awardees, but only 361 nonawardees had viable and available publication data. The mean (±SD) number of publications for awardees was 2.94 ± 2.59 publications per year and the mean number of publications for nonawardees was 2.77 ± 2.9 publications per year (p < 0.001). Of the 103 awardees, 83 (81%) had received at least one academic promotion after being admitted to the program, and of the 373 nonawardees with reliable data, 257 (69%) had received at least one promotion after their application to the program (p = 0.020). Using the previously described inclusion criteria for subsequent NIH funding, 60 awardees were included in this analysis. Of those, 42 (70%) received subsequent NIH funding. Of the 180 nonawardees who met inclusion criteria, 105 (58%) received subsequent NIH funding (p = 0.108). The mean (±SD) number of publications for awardees with reliable data was 2.91 ± 2.62 publications per year and the mean number of publications for nonawardees was 2.77 ± 2.9 publications per year (p = 0.626).Because there was no formal application process in 2008 and the first cohort was sourced from other Harvard Catalyst educational programs, there were no unsuccessful applicants in that year. We therefore performed a separate analysis excluding the 2008 awardees. After excluding the 2008 cohort, 95 of the 103 awardees (92%) have been retained in clinical and translational research whereas 271 of 363 nonawardees (75%) with reliable data have been retained in clinical and translational research (p < 0.001). However, none of the other outcomes were significantly different between funded and nonfunded women, although funded women fared better overall than unfunded women  were retained in clinical and translational research whereas of the 184 nonawarded women with reliable data, 129 women (70%) were retained in clinical and translational research (p = 0.787), academic promotion ; retention at Harvard Medical School , subsequent NIH funding , NIH R funding , or publication rate . However, this analysis is limited by a considerably smaller sample size than the other populations and the statistics may be misleading due to the small sample size.When comparing the results of the 10 URiM awardees to the 47 nonawarded URiM individuals with reliable data, there were no significant differences between the groups in continues involvement in clinical and translational research . In addition, when looking at the entire cohort, awardees were more likely to be promoted, retained in the Harvard system, and were more likely to receive subsequent NIH funding.In this study, we attempted to discern the impact of obtaining funding through our KL2/CMeRIT program on the future academic successes of early-stage investigators compared to a group of applicants to the program who were not funded. While this is not a controlled experiment, in that we do not know what would have happened had the unselected been funded or vice versa, the results support the general notion that funding through the program helped maintain the individuals in the field of clinical and translational research. Critically, the number of faculty continuing in clinical and translational research was very high (92%) and was also seen in women who are traditionally underrepresented as PIs . Women wThe overall higher rate of retention in clinical and translational research, higher promotion, and funding rates could be due to a number of factors and may not simply be due to the actual quality or effectiveness of the program. Clearly, having funding provides protected time to pursue research, but also creates a positive incentive to pursue such research, which then leads to subsequent funding. In addition, the KL2/CMeRIT grant provides access to educational offerings, such as individual advisory committees, grant writing courses, biostatistics, and many others, some of which are not accessible to nonawardees.Obtaining funding sooner means that individuals enrolled in the program had a head-start leading to a simple temporal advantage. Moreover, it is possible that our selection process identified individuals with superior potential, and thus the greater success in this group could reflect those inherent personal characteristics and not the strength of the program. Nevertheless, we were surprised and happy to learn that a large percentage of nonfunded individuals did not give up on their quest to pursue research and were also ultimately successful. This certainly attests to the perseverance of many individuals and of course implies potential additional success had they been funded.Given that we only had a limited amount of data on each person, we did not attempt to identify additional features that could indicate the impact of this funding on broader academic success. For example, we did not specify the specific types of R or other grants that were received, nor did we attempt to gauge the impact factor of the journals in which publications occurred or the citation rate for those articles, both of which might provide more granular data on the success of the candidates. Similarly, the follow-up time on the candidates was limited. While some of the earlier scholars had follow-up data extending out as much as 10 years, more recent graduates had data extending only out 3 years. Trends over time in the composition of a given class of scholars could influence the number of participants and thus could provide somewhat misleading data. For example, in recent years we have implemented targeted initiatives to encourage URiM individuals to apply to the program and have been able to achieve a very high rate of URiM enrollment. Therefore, our data might be biased to the relatively few URiM awardees who completed the program in its earliest years.This work has intentionally only focused on the academic outcomes and not personal or social findings. For example, we do not know if those who were not selected delayed beginning a family nor do we have any sense of overall job satisfaction or general level of happiness. Such measures are clearly critical, since academic advancement and success only represents a single, relatively narrow compositional thread in one’s life story. Nevertheless, since the program is an academic one, focusing on future academic success is appropriate. Also, we were unable to compare the KL2/CMeRIT program to another grant program, which might have provided valuable information on the impact of the unique components of the KL2/CMeRIT program on scholars’ future successes. Additionally, for applicants that applied more than once we only included the final application. Another limitation of our study was that we were not blinded to the status of the applicants while completing the analysis. A major strength of our study is the detailed longitudinal assessment of awardees and nonawardees allowing us to assess the impact of the program on a cohort of Harvard early career faculty.In conclusion, the Harvard Catalyst KL2/CMeRIT program is successful in advancing clinical and translational researchers, especially women. Participants in the program generally fared better than those who did not as measured by a number of criteria. However, the interpretation of those differences remains uncertain and could be due to factors beyond the quality of the program itself. Further study of this and other CTSA training programs from across the country over more extended periods of time will be needed to fully understand the impact of these programs on the long-term success of clinical and translational researchers.


Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistent antiphospholipid (aPL) antibodies. The introduction of Sapporo's classification criteria allowed uniformity in the classification of this pathology, representing a considerable advance in its diagnosis. However, currently some doubts about the application of these criteria still persist. The aim of this study was to contribute to the better understanding of APS by the assessment of aPL prevalence, the association between clinical and laboratory tests, and evaluation of the aPL confirmatory profile.In this study, 1,179 samples from patients with suspected APS of both genders, without age restrictions, who were advised to test for complete aPL's profile were analyzed. The samples were tested for lupus anticoagulant (LAC), anticardiolipin immunoglobulin (Ig) G/IgM and anti-β-2-glycoprotein I IgG/IgM antibodies. Patient samples with isolated test requests for analysis and samples from patients under the influence of anticoagulants or in an infectious process were excluded.The overall positivity found was 17.9% and the most frequent aPL was LAC. The antibodies were determined in isolation and in association. The prevalence of triple positivity was 0.8% and double positivity was 1.8%. Positivity was higher in inpatient/emergency services compared with outpatient services. There was a higher positivity in individuals over 41 years, males, patients with systemic lupus erythematosus, kidney complications, and deep vein thrombosis/thrombophlebitis. The positivity confirmation with second sample was 39.5% and the confirmation profile shows that 50.6% of samples confirmed with same positivity profile; 17.3% with a different profile and regarding to these, 2.5% of the samples confirmed positivity with a different antibody from the previously detected.This study suggests that the aPL's positivity tends to increase with age, showing that the aPL's testing should be avoided during an acute event and reinforces the need for complete aPL laboratory profile in the second sample and subsequent determinations. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder diagnosed based in clinical and laboratorial manifestations.The diagnostic criteria currently used to classify this pathology are the Sapporo criteria,Although knowledge about the clinical manifestations of APS has evolved in recent years, the etiology remains unclear, making it difficult to predict who will develop APS, or what is the reason for its occurrence. Clinical manifestations are prevalent in the general population and may have a multifactorial etiology which makes laboratory investigation essential to the diagnosis of APS.Therefore, this work aims to provide a contribution to the APS diagnosis problematic, from a laboratory perspective, assessing the aPL prevalence, determine the positivity profile by sample provenance, gender, age, and associated pathologies. The confirmation profiles in second sample will also be evaluated. Information from the association between clinical events and laboratory tests in the “Tâmega e Sousa” population can contribute to increase knowledge about the local reality of APS and help making clinical and laboratory decisions which can allow more rational and adequate use of the tests currently available.Data from patient samples with suspected APS analyzed in the Immunohemotherapy and Clinical Pathology laboratory services of Tâmega e Sousa Hospital Center, between February 2015 and January 2018, were collected. Patients of both genders, without age restrictions and with a request to complete the laboratory profile of APS that includes aCL immunoglobulin (Ig) G and IgM, aβ2GPI IgG and IgM, and LAC, were included in this study. Patient samples that requested for isolated tests for analysis and samples from patients under the influence of anticoagulants or in an infectious process were excluded.Blood samples collection and preparation: venous blood samples were collected by venipuncture in vacuum tubes. One 3.2% trisodium citrate tube and a serum-separating tube were collected from each patient . The citrate tubes were double-spin  and processed by the ACL TOP autoanalyzer . The samples collected in serum-separating tubes were centrifuged at 3,800 RPM for 10 minutes and processed by the Phadia 250 autoanalyzer .Determination of aCL and aβ2GPI: analysis of aCL IgG and IgM and aβ2GPI IgG and IGM was performed by the Phadia 250 autoanalyser by the fluoroenzyme immunoassay method, using the commercial, validated ELIA Cardiolipin IgG and IgM and ELIA aβ2GPI IgG and IgM reagent kits . We used the Sydney criteria cut-off of >40 MPL-U/mL for aCL IgG and IgM. As there is no proposed Sydney criteria cut-off for aβ2GPI IgG and IgM, we used the cut-off values of >10 MPL-U/mL as suggested by the manufacturer. Results with low titers (doubtful) were not considered.Determination of LAC: LAC was determined by the ACL TOP coagulometer using the commercial, validated reagent kits dilute Russell's viper venom time (DRVVT) screen and confirm silica clotting time (SCT) screen and confirm reagents . The result was considered positive when the DRVVT and/or SCT normalized ratio was >1.2. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) commercial, validated reagent kits were also used to discard other coagulation alterations not related to LAC. Recombiplastin 2G reagent was used to determine the PT and SynthASil reagent to measure aPTT .χ2) was used to compare variables. Aρvalue less than 0.05 were considered statistically significant.Statistical analysis was performed using IBM Statistical Package for the Social Sciences, version 21 for Windows. Statistical analysis included descriptive analysis, with absolute and relative frequencies, arithmetic means, and standard deviations. The results were presented in tables. When appropriate, Pearson's Chi-square test  years. Mean age was 45.2 (±14.8) and 50.5 (±14.6) years in females and males, respectively. Prevalence of females was higher with a female-to-male ratio of 2.4:1. The most frequent age group was between 41 and 60 years in both genders . From eTo assess the overall antibodies prevalence, all patients with a complete laboratory profile of APS in first sample were selected. The sample prevalence from patients with at least one positive aPL was 17.9%. Evaluating the positivity for each aPL individually, it was found that LAC was the most frequently found (11.8%). Positivity for other aPL's was aβ2GPI IgM, 3.4%; aβ2GPI IgG, 3.0%; aCL IgM, 2.0%; and aCL IgG, 1.4%.Assessing the positivity profile, it was found that antibodies can appear isolated or in association. The aPL's combinations found in the positive samples are shown inχ2 = 5,296;ρ = 0.021). Assessing the positivity prevalence to each aPL individually, it was found that the statistical difference was due to LAC . Positivity was higher in inpatient/urgency services (16.1%) when compared with outpatient services (9.6%). In the remaining aPL's, no statistically significant difference was found.The aPL's prevalence in the first sample by sample source are shown inχ2 = 11.781;ρ = 0.019) with the highest prevalence of positive aPL's in the group aged over 41 years . Evaluating the positivity prevalence to each aPL individually, only to LAC, statistically difference was found  which was higher in males , there were 132 (62.9%) patients who tested for the second time, while the positivity confirmation was not evaluated in 78 (37.1%). From 132 patients with second determination, 83 (39.5%) were positive and 49 (23.4%) were negative in the second testing. The positivity confirmation was also evaluated individually for each aPL . Analyzing the results can be verified that, from the 81 samples evaluated, only 55 (67.9%) confirmed positive in second determination. Regarding the confirmation profile, it can be observed that 41 (50.6%) from 55 samples confirmed positive with the same profile. From the 14 (17.3%), who were confirmed positive by different profiles, the difference was caused by negative for one or more aPL's in 5 (6.2%), there was positive for new aPL's in 7 (8.6%), and the positivity was confirmed by a different aPL from previously detected in 2 (2.5%).In addition to isolated positivity analysis per aPL in second sample, the confirmation profile was also evaluated . For thOur study was performed in a population suspected of APS of which the majority of individuals were not APS patients. No studies were found in the literature that report positive aPL's prevalence data in first determination and before the APS diagnostic. However, comparing our data with other studies that assessed aPL in patients with diagnosed APS, it appears that the prevalence of aPL's found in our population was lower for most antibodies. Les et al, in a study that includes 70 patients, observed that the LAC prevalence was 28.6%; aCL, 8.6%; and aβ2GPI, 4.3%.In our population, the prevalence of samples with triple positivity was 0.8%, with double positivity was 1.8%, and with double and triple positivity and including LAC was 1.4%. Clinical studies found in literature confirm that presence of triple positivity in patients with APS, or in patients only with aPL's, represents an increased risk of thrombotic and/or obstetric events, especially when in association with LAC.The highest positivity prevalence observed among inpatients compared with outpatients, indicates that aPL's may be associated with acute disease. These findings are in accordance with the literature recommendations which advise that, ideally, the aPL's determination should be done when patient is clinically stable and not during an acute event. The laboratory test results interpretation performed near an acute thromboembolic event can be difficult, since the acute phase factors, such factor VIII and fibrinogen, tend to be increased which may interfere with the coagulometric test results. In addition, acute events can induct the appearance of transient aCL's.The aPL prevalence was higher in males and in the group aged over 41 years, suggesting that the aPL's positivity tends to increase with age. However, in our population the mean age observed in males was higher than females that may have influenced the data age related in males. It is difficult to establish a comparison between aPL's prevalence by gender and age with other studies because the vast majority of studies reported the APS incidence data and not the aPL's prevalence found. Asherson et al reported a primary APS ratio between women and men of 2:1We found that LAC was the most frequent antibody in all pathologies. These results are in accordance with those of other studies found in literature. Wahl et al performed a meta-analysis with adult patients in 18 studies and demonstrated that, in SLE patients, the risk of thrombotic events is more strongly associated with LAC than other aPL's.With regard to positivity confirmation in second sample, in this study, the aβ2GPI IgG was the aPL with higher percentage of confirmation, while LAC shows the lowest. In literature, the transient character of aPL's is documentedThe data from our study allow us to conclude that confirmatory profile was quite variable, not allowing to identify a uniform trend of aPL's appearance or disappearance. However, our data reinforces the recommendations by Devreese et al that strongly emphasized that positive tests should be repeated at least 12 weeks after the initial positive test to exclude false positives, clinically unimportant, or transient antibodies.This study had some limitations inherent to its retrospective feature. One of the limitations was the loss of “follow-up” in second samples from patients with positive aPL's. In addition, it was not assessed if patients received corticosteroids treatment between first and second determinations. Clinical diagnostic also presented limitations. Diagnoses were made by the patient's doctor, so different diagnostic criteria may have been used in each pathology. Finally, there was no laboratory homogeneity in all samples, in the time that mediates clinical symptoms and laboratory determination. The same applies to laboratory determinations between the first and second samples.The intent of this study was to approach APS syndrome from a laboratorial perspective, trying correlate the aPL data with clinical events. Of the most relevant data obtained, we highlight the followings:The higher prevalence of aPL's observed in hospitalized patients shows that aPL's can be associated with acute disease states which reinforces the recommendation that, ideally, the determination of aPL's should be made when patient is clinically stable and not during an acute event. If the determination of aPL's is made during the acute disease, the positive results must be repeated at least 12 weeks after the initial determination.Regarding the positivity confirmation, and according to our research, our study was the first one that evaluates the seroconversion and the antibody positivity confirmation profile between first and subsequent determinations and before APS diagnostic. Based on our data, it can be added to our previous recommendation that in second sample and in the subsequent determinations, complete laboratory APS profile must always be repeated and not only the positive aPL's detected in the first sample.The highest prevalence of positive aPL's was found in the group aged over 41 years suggesting the aPL's positivity tends to increase with age.The LAC was the most commonly detected aPL in all clinical manifestations.New studies that include a larger number of patients, with assessment of the complete laboratory APS profile in all determinations, may be useful to consolidate the data obtained in our study. The follow-up of patients, with a regular aPL's laboratory evaluation, could also be useful to understand the behavior of aPL's over time. An aPL's screening in the general population could also be useful to understand the degree of thrombotic risk in the healthy population which has never suffered from any thrombotic and/or obstetric event.


The differences were not statistically significant for indirect social exclusion behaviors  or cyberbullying . The effects in the reduction of the bullying behaviors decreased after the implementation of the program, achieving even greater reduction in victimization behaviors after 3 months than immediately after the end of the program. These results indicate that the ANA program is effective in reducing bullying behaviors in a group of children. Implications for practice and future research are discussed.Bullying can have serious physical and emotional consequences. In recent years, interest in this phenomenon has been growing, becoming a public health problem in the first world. The aim of this study was to evaluate the effects of the Action for Neutralization of Bullying Program (ANA) in Spanish children. This study used a quasi-experimental design that included a pre-test evaluation, 2 months of intervention, a post-test, and 3 months of follow-up. A sample of 330 children aged 7–12 years  from third to sixth grade participated in the study. One hundred and fifty-nine were girls (48.2%). The program consisted of eight group sessions in which empathy, assertiveness, communication skills, conflict resolution, and group cohesion were worked on. The results showed statistically significant reductions in verbal abuse behaviors ( Bullying has been defined as a distinct type of aggression characterized by repeated and systematic abuse of power ,2. This Acknowledging and knowing the effects of bullying is vital to understand the necessity to implement programs to prevent it from happening. Bullying is a detrimental factor against mental health and well-being at physical, mental, and social-emotional levels in children ,11. ChilIn recent years, there has been growing awareness of the need to anticipate the occurrence of this type of school violence. Many studies have focused on identifying the important contextual and individual factors . Some imOn the other hand, peer status has been found to have the greatest effect size as a risk factor for bullying victimization. In terms of the individual factors, for bullies, it has been found that externalized problems, related cognitions, and low academic performance are the most powerful risk factors for bullying perpetration. However, for victims, internalized problems and lack of social competence appear to be the strongest risk factors . Socioemr = 0.12) for self-reported victimization and bullying measures [Much of the meta-analytical work has not been particularly optimistic about the results offered by previous intervention programs, concluding that the effect sizes of the interventions are generally small or very small ,22. Somemeasures . Furthermeasures ,25. The measures . This grAcción para la Neutralización del Acoso) applies components that have been shown to be effective in previous research; specifically, it promotes the development of empathy [The Action for Neutralization of Bullying program , and thought and closure.Session 2. Theme: Empathy. Activities: What empathy is and what it is for, how would I feel if..., identifying emotions (group dynamics), and thought and closure.Session 3. Theme: Empathy. Activities: summary of the previous session, identifying situations (group dynamics), I congratulate my classmates (group dynamics), and thought and closure.Session 4. Theme: Assertiveness. Activities: what is assertiveness? What is assertiveness good for? What happens if I am not assertive? I am assertive, I control what happens to me, I congratulate my classmates (group dynamics), and thought and closure.Session 5. Theme: Communication skills. Activities: What are communication styles? Practicing assertive communication (role paying): eye contact, volume and tone of voice, verbal fluency, posture, gestures, and verbal content of the message. I congratulate my classmates (group dynamics) and thought and closure.Session 6. Theme: Conflict resolution. Activities: What is a problem? Solving problems, the 5-step method , practice classroom situations 1 (role playing), I congratulate my classmates (group dynamics), and thought and closure.Session 7. Theme: Conflict resolution. Activities: Remembering the 5-step troubleshooting, “Brave people wanted!” (group dynamics), practice classroom situations 2, 3, 4, and 5 (role playing), I congratulate my classmates (group dynamics), to prevent bullying, we expect you to “be brave”, and thought and closure.Session 8. Theme: Group cohesion. Activities: The ball of wool (group dynamics), revision of topics worked on throughout the program, and thought and closure.This study aimed to evaluate the effects of the ANA program in a sample of Spanish children. Its hypotheses were as follows: (I) the implementation of the program would reduce the bullying behaviors perceived by the victims, (II) the active involvement of teachers in the implementation of the program would help to maintain the results in the long term, (III) the implementation of the program would improve the social-emotional competencies of the participants, and finally, (IV) the implementation of the program would improve the general welfare of the participants.This study used a quasi-experimental design and included a pre-test evaluation, 2 months of intervention, a post-test, and 3 months of follow-up. The sample was selected by convenience. Given that the application of the program in its entirety, including follow-up, covered a complete academic year, it was not possible to establish a control group (waiting list) because it would mean that this group would not eventually receive the treatment.This study was approved by the Bioethics Commission of the University Miguel Hernandez of Elche. The program was presented to the educational center and obtained approval from the center’s administrators. The center obtained informed consent from the parents. At the end of the study, the results were presented to the center’s administrators and to the teachers, children, and parents.M = 9.27; SD = 1.09) from third to sixth grade participated in the study: 159 were girls (48.2%) and 171 were boys (51.8%). Participants were recruited from a school located at Elche. Socioeconomic status of the school students (obtained at a different time point) is rated between intermediate and high according to the Family Affluence Scale  and betale (FAS ) Data weTo assess the program’s effectiveness in reducing bullying behavior, the self-reported Peer Bullying Questionnaire was used . AlthougTo assess the extent to which the application of the program can improve participants’ social-emotional competencies, the Spanish version of the Social Emotional Health Survey-Primary-Revised was applied ,38. The To assess the program’s effect on the overall well-being of the children, the KIDSCREEN-10 index  was applM) and standard deviation (SD) were calculated. To find differences, Student’s and Fisher’s tests were applied. Following Cohen’s [2 equal to 0.009, 0.059, and 0.138, respectively.Descriptive statistics such as mean  = 4.42; p = 0.03; η2 = 0.014) and physical abuse  = 24.36; p < 0.001; η2 = 0.074).t = 4.76, p < 0.001), direct social exclusion , threats , aggression with objects , and physical abuse . The differences were not statistically significant for indirect social exclusion behaviors  or cyberbullying . No significant differences were found for the Spanish version of the Social-Emotional Health Survey-Primary-Revised (p < 0.001). The differences were statistically significant for the KIDSCREEN-10 index .To assess the effects of the program (hypothesis I), the differences between the pre-test and post-test were calculated for each of the bullying behaviors. There were statistically significant reductions in verbal abuse behaviors  = 18.49, p < 0.001, η2 = 0.12; direct social exclusion: intraF  = 12.28, p < 0.001, η2 = 0.075; threats: intraF  = 7.37, p = 0.001, η2 = 0.05; cyberbullying: intraF  = 1.59, p = 0.21, η2 = 0.01; indirect social exclusion: intraF  = 7.08, p < 0.001, η2 = 0.05; object-based aggression: intraF  = 4.79, p = 0.009, η2 = 0.03; physical abuse: intraF  = 18.87, p < 0.001, η2 = 0.11. For the subjective health and well-being variable measured with the KIDSCREEN-10 index, the results were intraF  = 12.29, p < 0.001, η2 = 0.10. Finally, for the variables of the Spanish version of the Social-Emotional Health Survey-Primary-Revised, the results were as follows: optimism: intraF  = 7.16, p = 0.001, η2 = 0.05; gratitude: intraF  = 1.15, p = 0.310, η2 = 0.01; zest: intraF  = 3.98, p = 0.020, η2 = 0.03; persistence: intraF  = 1.15, p = 0.320, η2 = 0.010; prosociality: intraF  = 2.20, p = 0.113, η2 = 0.02; co-vitality: intraF  = 4.69, p = 0.010, η2 = 0.04.To assess the “maintenance effect” that teachers might have had on the maintenance of these results, it was determined whether the changes in the observed variability of the mean scores for the three measured time points were statistically significant. For the subscales of the Peer Bullying Questionnaire, the results were as follows: verbal abuse: The present study evaluated the effectiveness of the ANA program in children between 7 and 12 years of age, ranging from third to sixth grade. After the implementation of the program, a significant reduction in bullying victimization was observed in the participants.Observable improvements in other programs generally have not been sustained over time ; therefoWith respect of the direct changes produced after the application of the ANA program, the results show the main reductions in verbal abuse behaviors, threats, aggression with objects, physical abuse, and direct social exclusion behaviors. However, no differences were found in indirect social exclusion and in cyberbullying. This contrast in the changes observed between the first bullying practices mentioned and indirect social exclusion might be explained by the nature of these behaviors. Since the first ones make reference to more observable or direct components of bullying, the second one indicates an indirect component which could be less conscious for the children and thus, more difficult to change . The lacThe differences observed in the different types of bullying behavior, based on gender, are consistent with previous literature that also found that boys generally have higher bullying victimization scores, which would imply bigger reductions in these scores .In addition to the reductions observed in victimization, there was also clear improvement in the subjective well-being of the children, which could have been a direct or indirect effect of the decrease in victimization. This effect may be influenced by a decrease in the levels of stress or emotional distress typically reported by children involved in bullying behaviors, both as victims and as aggressors ,13,16. PFinally, it is worth noting that there were no significant changes in social-emotional competencies. Training in social-emotional competencies, although desirable, is not the main objective of the program. The results suggest that for the improvement of well-being, it is not necessary to provide victims with more coping skills and that it is enough to stop the bullying. However, a slight improvement in these skills was observed, and was most likely due to the relationship between bullying behaviors and these skills ,20.These results indicate that while implementing the ANA program, the bullying behaviors in children decreased at the same that their subjective well-being was increased. One of the strengths of the program is the demonstrated long-term maintenance of its effects after implementation. However, these interesting results achieved by the ANA program have to be interpreted with caution due to some weaknesses related with the study design, as further discussed in the following section.This study had several limitations. First, because the sample was composed of 330 students from the same center, the results may not be generalizable to other schools with differences in environmental variables . Second, considering the quasi-experimental design of the study, the effectiveness of the program requires more research due to the lack of a control group. With this design, albeit it leads to some valuable conclusions, it leaves open many alternative explanations for the changes observed in the sample, therefore not allowing to treat the program as the certain causal explanation for the observed changes. Nevertheless, the gains and positive effects produced by the program must be considered. Future research on the program that includes the group of observers in the data collection would allow comparison of the self-reported and perceived levels of bullying and subjective well-being, at least by the observers. In line with the observers, a more contextual approximation would be optimal. Since the problem of the bullying is partially explained by family context, it would be interesting to also assess the prosocial or antisocial tendencies of the children’s families to evaluate their influence in the program changes ,18. AddiAnother issue that is a general problem of these types of program evaluation research studies, based solely on survey instruments, is that these instruments have the problem that they lack reliability across contexts . In this


Although the functions and structural roles of sterols have been the subject of numerous studies, the reasons for the diversity of sterols in the different eukaryotic kingdoms remain unclear. It is thought that the specificity of sterols is linked to unidentified supplementary functions that could enable organisms to be better adapted to their environment. Ergosterol is accumulated by late branching fungi that encounter oxidative perturbations in their interfacial habitats. Here, we investigated the antioxidant properties of ergosterol using in vivo, in vitro, and in silico approaches. The results showed that ergosterol is involved in yeast resistance to tert-butyl hydroperoxide and protects lipids against oxidation in liposomes. A computational study based on quantum chemistry revealed that this protection could be related to its antioxidant properties operating through an electron transfer followed by a proton transfer mechanism. This study demonstrates the antioxidant role of ergosterol and proposes knowledge elements to explain the specific accumulation of this sterol in late branching fungi. Ergosterol, as a natural antioxidant molecule, could also play a role in the incompletely understood beneficial effects of some mushrooms on health. Since the discovery of cholesterol by Chevreul in the early nineteenth century, a huge diversity of sterols has been identified in the different kingdoms of eukaryotic cells . ErgosteERG genes and the crosstalk between different environmental signals and pathways  ● + HR   Sterol + R(2) Electron Transfer (ET)● → [Sterol] ●+ + R−   Sterol + R(3) Electron Transfer followed by Proton Transfer (ET-PT)● → [Sterol]●+ + R− → [Sterol(-H)]● + HR   Sterol + R(4) Radical Adduct Formation (RAF)● → [Sterol-R] ●   Sterol + RThe HAT and ET-PT mechanisms lead to the formation of the same end-products, namely free-radical sterols. However, ET-PT involves an intermediary step that corresponds to the ET reaction with the formation of a radical cation from sterol. The RAF mechanism consists of the formation of a bond between the radical and the sterol, allowing for the stabilization of the radical. In a previous thermodynamic study of ergosterol, it was shown that the Gibbs free energies of the RAF reactions were endergonic or close to zero, meaning that these reactions are unfavorable . TherefoThe radical cations (RC) formed from neutral sterols by the loss of an electron are high-energy intermediates with ΔG values higher than 500 kJ/mol a. The hiThe computed dipoles suggest that upon oxidation, the ergosterol RC may move in the cell membrane (between the core and the surface of the membrane) because of an increased polarity between the stable molecules and their respective RCs. In addition, the higher ionization energy for the ergosterol free radical indicates a greater electronic stability of this species compared with the zymosterol free radical. It is also interesting to compare the Map of Electrostatic Potential MEP; c, which We then computed the Gibbs free energy evolution for the reaction of each sterol with the DPPH radical, as gathered in While a full mechanistic study is beyond the scope of this article, we characterized the transition state for the HAT reaction between ergosterol and the DPPH radical see . The actFrom these results, we can conclude that the characteristics obtained in the oxidation modelling of these sterols indicate that cholesta-5,7,24-trienol and ergosterol, but also to a lesser extent zymosterol, can act as antioxidants via the ET-PT mechanism. ET greatly increases the polarity of sterols and could induce the migration of sterol RC towards the surface of the lipid bilayer, a location that may favor deprotonation to complete the ET-PT mechanism.erg6Δ, erg2Δerg6Δ, and WT strains revealed that the accumulation of zymosterol in place of other sterols, namely ergosterol, made yeasts more sensitive to oxidative perturbations induced by t-BOOH  The first mechanism is related to the structural effect of sterols. In contrast to the destabilizing effect of lipid peroxidation products, sterols could exert a stiffening effect on the plasma membrane. It has been reported that the addition of cholesterol to the lipid bilayer could maintain the structure of lipoperoxidized membranes based on its ability to counteract fatty acid disordering . This ef(ii) A second hypothetical mechanism is based on the antioxidant activity of sterols themselves. It is well known that sterols are able to be oxidized and the literature dealing with oxysterols is increasingly abundant . Severalerg6 and erg2 gene deletion on metabolic pathways or regulatory networks other than the ergosterol biosynthetic pathway. Indeed, yeasts have multiple antioxidant systems that can act to protect cells from oxidative damage [erg mutant (erg5Δ) could be at the origin of the higher sensitivity to t-BOOH of the mutant in comparison with the wild type strain. The redox state of the mutants used in our study (erg6Δ and erg2Δerg6Δ) could also display this unbalance.(iii) Finally, the higher sensitivity of the EBP mutant strains compared with the WT could originate from the effect of e damage . Rather e damage , it was S. cerevisiae) led to a decrease in the rate of phospholipid oxidation induced by cumene hydroperoxide and haemin , was the most sensitive strain tested in our study , while the wild type strain presented 87% ,22-tetraenol; The basis of the specificity of sterols in each eukaryotic kingdom is intriguing. In particular, the reason for ergosterol accumulation by fungi is unclear, because its synthesis requires more energy than that of cholesterol , and strur study . Even ife strain . A possiThe results of our study strongly suggest that ergosterol is an antioxidant molecule that prevents phospholipid oxidation in the cellular context. This role has rarely been associated with sterols, and it will be interesting to study this function in cholesterol and phytosterols. In eukaryotic cells, sterols are not homogeneously distributed in the plasma membrane, but enrich specific membrane domains. In mammalian and plant cells, these domains, called lipid rafts, are very small  and transitory in time . The plaBy using in vitro and in silico approaches, we showed in our study that ergosterol acts as an antioxidant molecule that could be involved in yeast resistance to oxidation. In the cellular context, the antioxidant function of ergosterol could be of prime importance for yeasts and other fungi to resist oxidative stress. Specifically, free ergosterol accumulated in the plasma membrane of fungi cells could allow for the protection of phospholipids against oxidative perturbations. Thanks to a computational study based on quantum chemistry, we demonstrated that the antioxidant ability of ergosterol operates through an electron transfer, followed by proton transfer mechanism, and is related to the presence of the two conjugated double bonds of the B-ring of the sterol structure. Outside the cellular context, ergosterol might be used as a natural antioxidant molecule to prevent the oxidative degradation of foods. Finally, the antioxidant function of the ergosterol molecule could play a role in the incompletely understood beneficial effects of some mushrooms on health.


Various effects of forest healing on health have been reported, but a certification system to assess the effectiveness of forest healing programs does not exist. In this study, a systematic review (SR) on the “health benefits of forests” and “meta-analysis of forest therapy” was conducted after analyzing the status and level of evidence of 75 forest healing programs that were conducted post-certification in South Korea. The SR for “health benefits of forests” distinguished between activities and time, resulting in 90.9% of walking activities for more than an hour under psychological health, and 100.0% of exercise activities for less than an hour under physiological health. However, the effect of indirect activities performed for more than an hour was unknown. Thus, we confirmed that many indoor activities in the field had low effect size or no established basis regarding the feasibility of its operation. The SR on “meta-analysis of forest therapy” to check whether the program was effective. The highest number of healing effects were obtained for blood pressure (32), followed by psychological depression (24). The findings of this can serve as baseline data to facilitate future development and dissemination of evidence-based forest healing programs. In 2018, the public value of forests in $186 million, of which $1.52 million (8.3%) was contributed by forest recreation function, which was the fourth highest contributor. This contribution had increased by $574,761 compared to $1.43 million in 2014, whereas the value contributed by “forest healing” increased from $2.02 million in 2014 to $4.30 million in 2018 [San-eum, which means “the shade of the mountain”. Since then, the total number of national and public therapeutic forests steadily increased to 5 by 2015 and 32 by 2020  to validate their activities. This study utilized the certification system of forest education programs conducted by the Korea Forest Service, the Ministry of Gender Equality and Family, and the Ministry of Environment .To establish the basis for the healing programs, the effectiveness of the programs were verified through clinical trials. However, there are difficulties in verifying the effectiveness of all diversifying subjects and programs through clinical trials, and in order to find a method to verify the effectiveness of the program that can be used continuously in the future, this study analyzes the operation status of forest healing programs operated in the field. It was attempted to verify the effectiveness of the program by reflecting the results of previous research. Through the results of this study, it is intended to provide basic data for evaluating forest healing programs in the future.To determine the current status of forest healing programs, 75 forest healing programs that are operated by the Korea Forest Welfare Institute, the main body of forest welfare, were analyzed. Under these 75 programs, there were 278 detailed programs, out of which 268 were included in the present study after excluding the overlapping programs. Therefore, a total of 268 detailed programs were analyzed and then classified into six categories by referring to the contents written by the forest healing instructor who developed the programs .The participants of the forest healing program were divided according to two classifications: disease states and target groups, with the categories of disease states being normal, chronic, addictive, and environmental diseases. Accordingly, these conditions included the absence of disease ; continuous, potential, and pathological conditions (chronic diseases) ; substanThe classification of the six major therapeutic approaches is based on a previous study ; the difActivities for the senses are divided into five categories: visual, olfactory, auditory, tactile, and palate. These subdivisions can be understood as: programs that utilize color perception ; programs that utilize fragrances such as herbs, flowers, and fruits (olfactory); programs where participants listen to the wind and leaf swaying sounds from nature (auditory); programs where participants touch petals, leaves, branches, and seeds (tactile); and programs where participants eat food and drink tea  .The activity, season, and location classifications were based on the contents written by the forest healing instructors. For instance, activities were divided into dynamic, static, and dynamic–static activities; seasons were divided into the seasons  or simply all of them if year-round; and lastly, locations were divided into indoor, outdoor, and both indoor–outdoor.In addition, the classification of forest healing programs included activity types , education personnel, and participation fees, whereas the classification criteria were selected based on prior research. When classifying types, if there were one or more characteristics of the activity contents, all of them were included in the type, whereas a frequency analysis of the 268 detailed program activities was conducted according to the six major classifications.After the frequency analysis, a systematic review (SR) was performed to determine the strength of evidence for forest healing program effects. The detailed programs were then classified according to activity, type, and duration categories.An SR was conducted to analyze the activity-specific effects in forests. When selecting each case, the keywords provided in A total of 1903 search results were exported to the EndNote Citation Manager software  with 1288 electronic database searches in PubMed, 25 in PsycINFO, 81 in Web of Science, and 509 in Scopus searches. After removing 209 duplicates, the titles and abstracts of the 1694 publications were reviewed. Two reviewers independently screened (EK and GK) the full text for 265 articles, after removing 1429 non-randomized studies or explicitly unrelated subjects, to identify the studies to be included in the systematic literature review. This discrepancy was resolved through discussion. In addition, the final 33 studies were included by reviewing references from existing systematic literature reviews retrieved, adding four qualified studies that were not identified through searches .To understand the effectiveness of activities in the forest, we also looked at how consistent or mixed positive results have been reported throughout the first round of research, including using the 33 selected studies . The 33 To understand the effectiveness of forest healing programs, meta-analyses on existing forest healing programs were selected using the SR process. When selecting the paper, the keywords were searched in three electronic databases: PubMed, Cochrane Library, and Scopus, as shown in A total of 616 searches were exported to the EndNote Citation Manager software (version Endnote 20) with 254 from PubMed, 113 from the Cochrane Library, and 249 from Scopus searches. After removing 13 duplicates, the titles and abstracts of 603 publications were reviewed. Two reviewers (SK and EK) independently screened the full text of 13 studies, after eliminating 589 non-meta-research or apparently unrelated subjects, to identify the studies to be included in the systematic literature review. Disagreements were resolved through discussion, and the final three studies were included .In order to understand the effectiveness of forest healing programs, the analysis was based on the confidence interval (95% CI) using the results of the last three selected studies. If the CI value included zero, it was regarded as “No Effect,” whereas if it did not include zero, it was regarded as an “Effect.” This was intended to determine whether the activities carried out in the forest were effective. Duplicate papers were excluded at this point as significant overlap occurred during the forest healing META analysis. Forest healing program activities were divided into the same criteria used earlier, and a total of 63 activities were effective, whereas 5 activities were ineffective in the META paper.An analysis of the frequency of subjects according to the disease states confirmed the following hierarchy: normal > addictive > chronic = environmental diseases; with normal disease states accounting for 90.67% of program activities. Therefore, this can generally be seen as a program activity that considers most  possible subjects . FurtherAccording to the frequency analysis of the six major methods, the order of most to least frequent were plant therapy > psychotherapy > exercise therapy > water therapy > climate therapy > diet therapy; plant therapy accounted for 67.63%, whereas diet only accounted for 0.72%. When classifying detailed programs, there were instances where no specific therapeutic approach was used, whereas others that constituted multiple therapies simultaneously .According to the frequency analysis results for the five sensory activities, the most to least frequent were tactile > olfactory > auditory > visual = palate, with tactile sense activities accounting for 34.22% of the detailed program composition. Furthermore, there were also programs that did not include sensory activities in the composition of detailed programs, while others utilized all five senses.Furthermore, the results of the frequency analysis of activities show that more than half of the activities were dynamic activities, accounting for 59.70%, and the frequency order given as dynamic activities > static activities > dynamic–static activities.According to the frequency analysis of the seasons, the order of highest to lowest frequency by season were summer > spring = fall > winter. There were 45 activities (60.00%) available in spring, summer, and fall, whereas 25 activities (33.33%) were available for all four seasons. This indicates that fewer programs are operated in winter than in other seasons due to environmental restrictions on outdoor activities .The frequency of forest healing programs for sessions >60 min was higher than <60 min, with 74.25% of the detailed programs running for more than 60 min. Among the detailed programs, the minimum program duration was 10 min for one-day programs, and the maximum program duration was 240 min for two-day and one-night programs.The results of the frequency analysis of the venue showed that the outdoor area accounted for 57.09% of activities, by order of outdoor > indoor > outdoor–indoor, which indicates that the forest healing program actively utilized the places created in the healing forest .According to the frequency analysis of the visit characteristics, the order was one day visit = day- and night visits > regular visit. Within the day- and night visits type, it was higher in the order of one night and two days (34.67%) than two nights and three days (12.00%). This is the largest number of one-day visits, with the total program time of one-day programs consisting of 2–6 h, and regular visit programs consisting of 3–15 sessions.In addition, we analyzed the number of education personnel and participation fee items using 75 programs to analyze the content of forest healing program activities. Education personnel in the forest healing program consist of 5–300. Furthermore, 17 programs were free of charge with green subsidies, and besides free programs, the minimum cost was 1000 KRW, whereas the maximum cost was 165,000 KRW.An SR was conducted to determine the effectiveness of forest healing activities and to support the level of evidence for forest healing program effects. The duration of sessions was divided into more or less than 1 h, and activities were divided into staying, walking, exercise, and indirect. Staying included viewing, watching, and meditation in one place, and walking included activities such as walking around and observing the surroundings. Exercise included trekking and forest sports. Finally, indirect included natural materials, audiovisual materials, programs that utilize natural materials, and programs that include audio-visual materials .To determine the current status and effectiveness of the forest healing programs currently implemented, it was divided into static and dynamic activities and further detailed activities, and the criteria were the same as those used by SR. According to the analysis, it was higher in the order of walking > indirect > exercise > staying, with walking accounting for 46.27% .To understand the level of evidence for the effectiveness of forest healing programs, we applied the activity category and time effectiveness of the SR, as well as the activity frequency of programs to illustrate the activity, time, and effectiveness of the ongoing forest healing programs . The bacAccording to the results, the most psychologically beneficial activity was walking, with 80.0% of sessions <1 h and 90.9% of session >1 h showing positive outcomes . Physiological activities are considered to be highly effective exercise for both >1 h and <1 h, each showing great physical effects. However, detailed programs were not actively implemented.Furthermore, walking activities are both psychologically and physically >60.0% effective, indicating that the level of detailed programming is more active than other activities.In the case of indirect activities, no studies were available for activities >1 h. Therefore, detailed forest healing programs are currently underway with the effectiveness yet to be evaluated.These results indicate that for psychological benefits, walking activities work regardless of duration, whereas staying activities is 48.5% more effective for shorter durations than >1 h. This can be explained by a sense of boredom when a static program is run for >1 h. Additionally, % p + m showed that the physiological benefit of >1 h of walking activity is >60% effective, whereas <1 h of exercise is 100% effective. However, the main measurement tool of staying is heart rate variability, which is determined by movement, and this indicator may vary depending on the design of the study because there is a significant difference between measurements with or without sufficient rest.We compared the activities of detailed forest healing programs used after certification and the composition of forest healing programs supported by META . WalkingIn the final three selected META studies, the results were divided into either effect or no effect through the CI index, and the effectiveness of the forest healing program was identified through research methods conducted in each paper . Most ofForest healing programs are not only helpful for people who aim to improve their lifestyle but can also be therapeutic in recovering, rehabilitating, treating, and preventing diseases. These government-run facilities play a supplementary role in improving health by utilizing nature as a means of facilitating therapeutic purposes. Currently, primary outcomes (effects) of these programs are verified by assessing the purpose for a specific target group in developing forest healing programs; however, the number of verification studies are limited and biased toward fragmentary effects. In addition, efforts have been made to evaluate the effectiveness of the program by utilizing program satisfaction surveys in the field, but this is insufficient to evaluate health outcomes, or overall facility and operational effectiveness. Therefore, in this study, we performed a meta-analysis of previous research to evaluate the level of quantitative and qualitative evidence for the programs currently in operation in Korea. As there has not been an established basis for evaluating forest healing programs, we analyzed forest healing programs in detail to identify the most common characteristics and variables which determine forest healing effects through systematic review and meta-analysis.Currently, 90.67% of those who participate in the forest healing programs form part of planned programs for the general public. It can be said that forest healing programs have broader implications considering all subjects rather than only targeting individuals with a specific disease or conducting professional activities only required by a specific target group. This does, however, mean that specialization and advancement of forest healing programs are needed . HoweverIt has been reported previously that a program operated over multiple sessions is more effective than over a single session . HoweverThe documents have shown that most walking and staying activities, such as meditation for >1 h, are most effective psychologically and physiologically; however, there are far more indoor activities that are less effective because of operational convenience (easier). A review of the quantitative distribution of the ground by disease and activity showed that some studies did not actually show the expected physical changes or did not utilize appropriate indicators, timing, and duration to measure the changes. In addition, if forest healing activities currently conducted for the public become certified for certain diseases (such as depression and blood pressure), it will improve the professionalism of these forest healing programs in the future.This study aimed to examine the forest healing programs certified in Korea through SR and meta-analysis. We determined the current status of certified forest healing programs and divided them into duration and activities to determine the effectiveness of forest healing. Through rigorous analysis, we identified the criteria for effectiveness and potential complications of domestic forest healing programs. To date, the criteria for forest healing programs are diverse and have not been standardized, thereby allowing independent forest healing programs to be established using other certification systems. However, by classifying forest healing programs based on the results from previous studies, our results are able to accomplish the following: establishing a forest healing program certification system according to criteria such as (1) activity, (2) disease state, (3) duration, (4) location, and (5) environment; classify forest healing programs according to six major methods and which of the five senses are stimulated by activities; and provide insight to improve the quality of existing programs through our critical analysis.Although various studies are currently being conducted, there are no clear criteria for evaluating the basis due to limitations such as targets, indicators, and periods, which will require continuous efforts to systematically measure health conditions for people using forest healing programs.This study analyzed the current status of forest healing programs operating in Korea and evaluated the evidence for their effects. To upgrade, develop, and operate these programs, it is necessary to establish a well-organized system based on the existing quantitative and qualitative effects. Our study reported that the largest number of healing programs were designed for participants without diseases, and included plant therapy, activities with tactile stimulation, and occurred outdoors, for a duration of one day, with sessions longer than 60 min. According to the analysis of forest healing cases, the program operations that were expected to have insufficient or low effectiveness for forest healing were prioritized depending on the on-site conditions. In addition, the medical basis for the statistically significant therapeutic effects found for depression, anger, and hypertension are being investigated. It is imperative that factors be identified and reviewed for patients with high probability for therapeutic response from forest healing program enrollment.


While the Veterans Health Administration (VHA) MOVE! weight management program is effective in helping patients lose weight and is available at every VHA medical center across the United States, reaching patients to engage them in treatment remains a challenge. Facility-based MOVE! programs vary in structures, processes of programming, and levels of reach, with no single factor explaining variation in reach. Configurational analysis, based on Boolean algebra and set theory, represents a mathematical approach to data analysis well-suited for discerning how conditions interact and identifying multiple pathways leading to the same outcome. We applied configurational analysis to identify facility-level obesity treatment program arrangements that directly linked to higher reach.n = 51) were compared to those in the lowest 40 % (n = 51). Configurational analysis was applied to identify specific combinations of conditions linked to reach rates.A national survey was fielded in March 2017 to elicit information about more than 75 different components of obesity treatment programming in all VHA medical centers. This survey data was linked to reach scores available through administrative data. Reach scores were calculated by dividing the total number of Veterans who are candidates for obesity treatment by the number of “new” MOVE! visits in 2017 for each program and then multiplied by 1000. Programs with the top 40 % highest reach scores  of the facilities in the higher-reach group with 85 % consistency (40/47).Specific combinations of facility-level conditions identified through configurational analysis uniquely distinguished facilities with higher reach from those with lower reach. Solutions demonstrated the importance of how local context plus specific program components linked together to account for a key implementation outcome. These findings will guide system recommendations about optimal program structures to maximize reach to patients who would benefit from obesity treatment such as the MOVE! program.The online version contains supplementary material available at 10.1186/s12913-021-06774-w. Obesity poses a major challenge to healthcare systems, including the Veterans Health Administration (VHA) , 2. ObesRecent estimates of the prevalence of obesity among Veterans receiving care in VHA are over 40 % . Like maReach is a critical component of program evaluation. As Glasgow and colleagues emphasize, “understanding the degree to which a program reaches those in need is vital” . HoweverThe National Center for Health Promotion and Disease Prevention (NCP) leads weight management policy and provides support to MOVE! weight management coordinators in VHA. In 2017, NCP collaborated with VHA’s Healthcare Analysis and Information Group (HAIG) to field a comprehensive survey of weight management programming across VHA. The operational survey was administered to 140 medical centers and achieved a 100 % response rate. It provides standardized and detailed information about local obesity treatment programming at each of the 140 facilities. Applying configurational analysis methods offers a unique opportunity to explore the link between reach and these facility-level treatment arrangements, including bariatric surgery, pharmacotherapy, and a wide range of treatment options within the MOVE! CLI program.n = 51) and facilities within the bottom two quintiles (n = 51) were included in the analyses. Facilities with reach within the middle quintile (n = 25) were dropped from the analysis to build in a meaningful gap between the higher reach  and lower reach  facilities; 102 facilities were in the analytic sample.Our primary outcome was reach, which broadly defined is the extent to which a treatment reaches the population of interest . In thisConfigurational analysis draws upon Boolean algebra and set theory to offer a formal, case-based and mathematical approach to cross-case analysis that identifies a “minimal theory,” i.e., a crucial set of difference-making combinations that uniquely distinguish one group of cases with an outcome of interest from another group without that same outcome . The anaBMC Health Services Research [Configurational methods have been applied in political science and sociology since the 1980s and are increasingly being used in health services research. A study by Kahwati et al., for example, used configurational methods to identify facility structure, policies, and processes related to the VA MOVE! program distinguishing 11 higher-performing facilities from 11 lower-performing facilities . More reResearch –22.To create the analytic dataset for the configurational analysis we merged two different datasets. The first was the 2017 HAIG survey of facility-level weight management programs, which had 78 items. The HAIG survey achieved a 100 % response rate, with all 140 medical centers responding.  and repeated the process to generate a new condition table. We continued relaxing the consistency threshold until there were at least two potential configurations of facility-level conditions that met the specified consistency level and the ≥ 15 % coverage threshold. We then assessed all configurations that satisfied those thresholds.Using this approach, we inductively analyzed the entire dataset and reduced the number of factors to those most likely to inform model development in the next steps of configurational analyses. We developed models by iteratively using model-building functions within the Coincidence Analysis  software package in R . We asseReach measures for the higher reach group ranged from 3.3 to 13.1 per 1000 Veterans; measures for the lower reach group ranged from 0 to 2.3 per 1000 Veterans.During the data reduction process, four different categories of factors and ten different conditions were represented by the range of configurations that met our dual threshold criteria , the presence of refill restrictions is on the solution pathway for high complexity facilities (SP3).The five pathways listed in Fig. Figure combinations of specific conditions consistently and uniquely distinguished higher reach facilities from lower reach facilities. The final model comprised five solution pathways that each led to higher reach, indicating that multiple combinations can lead to the same outcome; this demonstrates equifinality in solutions. The final model included 78 % of the higher reach sites with 85 % consistency indicating a meaningful and reliable solution.No single condition explained the 51 facilities with the higher-reach outcome; rather, VHA convened a State-of-the-Art (SOTA) conference in 2016 to address the epidemic of obesity in the U.S., including among Veterans. Recommendations included the need for integrated multi-component treatment  to engagIt is important to note that three of the solution pathways are context-based; the solution pathway depends on the complexity of the medical center. A key tenet within implementation science is that programs must be adapted to local conditions to optimize and sustain outcomes –31. Withn = 102 medical centers in the final dataset), our findings may not apply to settings outside the VHA. Information about weight management programming at each facility relied on self-reporting by VHA staff who may or may not have had close involvement with MOVE!, pharmacotherapy treatments, or bariatric surgery. Though coverage was high (78 %), 11 of the 51 higher reach facilities were not included in any of the five solution pathways, indicating a possible role for additional factors beyond those in the model.This configurational analysis was conducted using a dataset comprised of program survey responses from all VHA medical centers, combined with administration data to compute reach scores. Though the dataset is large (In this evaluation, configurational analyses revealed specific combinations of facility-level obesity treatment programming that consistently and uniquely distinguished higher-reach from lower-reach facilities. These findings represent Boolean conjunctions, where multiple conditions together yield an outcome. In health services research, configurational analysis appears to be well-suited to identify how the interplay of specific conditions leads to a complex phenomenon like higher reach within a large system of care.These results also illustrate equifinality: there is more than one way to achieve higher reach to patients who may benefit from obesity treatment. In this respect, configurational analysis can help address a long-standing challenge in health services research: how to account for local context in cross-case analysis. Our solution for higher reach included three context-dependent pathways, which we could identify because configurational analysis has the capacity to model Boolean disjunctions, where different paths lead to the same outcome. As organizational context can play as large a role in determining outcomes as program components themselves , 33, theAdditional file 1. Examples of items from 2017 HAIG Survey.