The risks of HBP attributed to SO2 and CO pollution would be higher in school-aged children in the low greenness group: the attributable fractions (AFs) were 26.31% and 20.04%, but only 13.90% and 17.81% in the higher greenness group. The AFs were also higher for normal-BMI children and adolescents in the low greenness group , while the AFs were not as high as expected for obese children in the low greenness group (AFs = 10.64% and 8.61%), nor was it significantly lower in the high greenness group (AFs = 9.60% and 10.72%).Among all the subjects, 52,515 had the first onset of HBP. During the follow-up, HBP's cumulative incidence and incidence density were 23.88% and 7.72 per 100 person-year respectively. Exposures to SO2/CO exposure on the risks of HBP among children and adolescents, and the benefit is BMI sensitivity. It might offer insights for policymakers in making effective official interventions to prevent and control the prevalence of childhood HBP and the future disease burden caused by air pollution.Greenness could alleviate the damage effects of SO High blood pressure (HBP) in children was once considered a rare disease, but it is now a public health concern worldwide . Today, 2) and carbon monoxide (CO) might be important risk factors for hypertension , those with abnormal data , and those diagnosed with HBP at baseline or with only one record of blood pressure . Therefore, the eligible participants included in the study had more than twice completed annual medical examinations. The annual follow-up with medical check-ups was usually between September–November or April–June. We further excluded another 404,148 subjects with missing data on SO2/CO/NDVI around schools after linking the annual physical examination survey to the gaseous pollution data. Eventually, we enrolled 219,956 participants in the final analysis . The subjects were followed up annually until the onset of HBP, loss, and the end of the study, whichever came first. Children and adolescents are automatically out of the cohort when they reach the age of 18 or graduate from high school. The flow chart is shown in A total of 3,290,046 participants entered the open cohort. During data processing, we excluded participants with missing information on weight, height, birthday, and blood pressure (2) is calculated as the weight (kg) divided by the square of height (m). BMI groups were categorized into three levels  according to growth reference data for 5–19 years old children from the WHO definition , weight (kg), and systolic and diastolic blood pressure  were measured and recorded by trained physicians. Height was accurately measured to 0.1 cm with portable stadiometers and weight was accurately measured to 0.1 kg with a standardized scale. All participants were required to stand barefoot with light clothing, naturally straight torsos, straight heads, and eyes straight in front, as well as upper limbs hanging naturally and the legs straight. Height and weight were measured twice, and the mean was recorded. Body Mass Index  and DBP (mmHg) were measured 3 times, respectively, by Korotkoff I sound and V sound (vanishing sound), and the average value was calculated and recorded. After each measurement, the cuff was loosened for about 2 mins. Systolic and diastolic high blood pressure (SHBP and DHBP) were defined as SBP and DBP above or equal to the 95th percentile of the reference population by age, sex, and height. HBP was defined as the presence of either SHBP or DHBP .2 and CO concentrations were calculated at a spatial resolution of 10 km from 2014 to 2018 in the CHAP dataset (available at: https://weijing-rs.github.io/product.html). The dataset is generated using a space-time extremely randomized trees (STET) model from big data, including satellite remote sensing, meteorology, multi-resolution emission inventory, and land utilization data  with a resolution of 30 m by 30 m. The formula of NDVI is: getation . A low pCategorical variables were described by frequencies and rates, and continuous variables were described by means and standard deviation (SD).Nnew was the number of new HBP incidents during the follow-up, Yi was the year between entry into the cohort and the onset of HBP, loss, and the end of the study, whichever came first; ni represented the number of participants corresponding to Yi.The cumulative incidence of HBP was calculated as the number of new HBP during the follow-up period divided by the total number of participants. The incidence density (ID) was calculated by: ID = 2/CO/greenness and the HBP risks. The Event Status of participants was recorded as “1” when they were diagnosed with HBP, and “0” when HBP subsided or was not present until the end of the study. Event Time was calculated in years, from the entry of the cohort to the latest event status record. The Cox model can also evaluate the hazard ratio (HR) of HBP attributable to SO2/CO/NDVI by sex. We also considered that a participant's blood pressure at annual follow-up was correlated with that at baseline. Although participants having HBP at baseline were excluded, it is still necessary to consider the impact of multiple measurements on risk assessment, which potentially overestimated the role of risk factors on outcomes. We, therefore, used the generalized estimation equation (GEE) model to address the problem of correlation between individuals repeating multiple measurements at baseline, follow-up, and ending. For estimating the quantitative association between SO2/CO/NDVI and SBP/DBP, β represents the regression coefficient obtained after adjusting age, sex, BMI, and city, results of which could also be validated with Cox regression results for HBP. We also tested for interactions using GEE regression with robust standard errors. Given interactions between NDVI and SO2/CO  μg/m3 and 0.97 (SD: 0.14) mg/m3. Among the participants without HBP at baseline, 52,515 were identified with new HBP during the follow-up, the cumulative incidence was 23.88%, and an incidence density was 7.72 per 100 person-year. The levels of NDVI exposure, BMI, and SO2 and CO concentrations were higher, but the average age, height, and weight were lower in the HBP group than in the non-HBP group (p < 0.001). The location of survey schools in Beijing and Zhongshan, their SO2 and CO concentration distribution and the NDVI levels in 2014 are shown in There were 219,956 children and adolescents without HBP at the baseline included in the analysis, 46,652 in Beijing and 173,304 in Zhongshan. The characteristic of the study subjects is displayed in 2 and CO with the risk of HBP after adjusting age, sex, BMI, greenness, and city. We found that the risk of HBP in children and adolescents increases with the concentration of SO2 and CO  and ] and were less associated with DBP levels . The HR of HBP was 1.58 and 1.42 respectively [95%CI:  and ]. NDVI was negatively correlated with SBP and DBP. Therefore, it could protect HBP: an increase in NDVI was significantly associated with SBP  and DBP levels , and the HR of HBP was 0.90 [95% CI: ].Based on the above preliminary results, we further analyzed the quantitative association of SO2 and CO among children and adolescents. The results showed that eliminating SO2 and CO exposure around schools could get a considerable theoretical benefit, but the benefit could vary by the levels of greenness. Improvement of SO2 and CO exposure benefits more in the low-level group of NDVI than in a high-level group of NDVI. The lower greenness group had a higher risk of HBP induced by SO2 and CO pollution. 2 and CO in the low NDVI group of areas were 26.31% and 20.04% respectively, which were higher than those in a high NDVI group of areas (13.90% and 17.81%).AF values were used to evaluate the theoretical benefits of HBP reduction through improving SO2 and CO. As shown in 2 and CO-induced HBP risk was higher for normal-weight children and adolescents with a low-level greenness, the AFs of which were 30.90% and 22.64%, while only 14.41% and 18.65% for those living with a high-level greenness. However, the risk of HBP attributable to SO2 and CO was not as high as expected for obese children in a low-level greenness (AFs = 10.64% and 8.61%), nor was it significantly lower in the high-level greenness (AFs = 9.60% and 10.72%).We also did a stratified analysis by BMI. Those who live in low-level green areas with normal nutritional status obtain great theoretical benefits. For obese participants, there was no significant difference between low and high-level greenness in the AFs of SO2/CO exposure with childhood BP has yet to be studied in depth, particularly in a longitudinal study with potential causal inference. As far as we know, this was the first study that used a longitudinal, two-center, dynamic cohort in China to confirm that greenness can alleviate the damage effects of SO2/CO exposure on the risks of HBP among children and adolescents. The study also approved that improving individual exposure to SO2/CO can significantly benefit those with low-level greenness and normal weight. Our findings supported the reduction of the HBP risks among children and adolescents by improving greenness and reducing gaseous pollution around schools by a variety of measures.Previous studies indicated that HBP in childhood or adolescence was a significant predictor for adult HBP and cardiovascular diseases , 41. How2 and CO increased arterial blood pressure and HBP among children aged 5–17 in northeastern China  and particle (PM10 and PM2.5) pollution triggers pulmonary oxidative injury and systemic inflammation, leading to oxidative stress, with consequences of endothelial injury, vasoconstriction, thrombosis, and changes in blood pressure (2, which are absorbed mainly through stomata. Absorption is not the only way in which plants improve air quality. The higher the tree canopy cover, the better the barrier effect, and the more pollutant mixtures from high in the air can be limited. Tree species, plants cover rate, length of the leaf season, pollution concentration, and precipitation in different cities will all affect the air purification of greenness, thus bringing about different levels of health benefits (Viewpoints vary on the mechanism underlying HBP or BP affected by gaseous pollutants. One theory posited that gaseous (NOpressure . Anotherpressure . There wpressure –48. We hpressure . Studiesbenefits –53. Howe2 and CO primarily via leaf stomata and reduce air temperatures by transpiration, influencing microclimate, which can then promote physical activity and social engagement, and link to mental health benefits (2, CO, and greenness with the risk of HBP, indicating that girls are more subjected to pollutants and greenness differences than boys. The participants were grouped into four age groups every 3 years as an interval and analyzed in subgroups. The group of 7–9 years old was more sensitive than the other groups. The association between CO and HBP outcomes was weaker in the 13–15 years old group, their association of NDVI with HBP was even the opposite. The result might be because of the indoor and outdoor activity time among children with academic pressure. However, no detailed age sensitivity to gaseous pollutants has been reported in previous studies. In addition, two typical northern and southern cities were included in our study to reflect China's overall situation in and to improve the result scalability. Considering the differences between cities, we also tested the data for both cities separately. Although the two cities may have some differences in detail, the overall results appear to be consistent with the combined results after we adjusted for the city in our main results, as shown in 2, and CO pollution were similar in Zhongshan. Still, the greenery protective effects were more stable across genders in Zhongshan than in Beijing, probably due to pollutant proportions and the plant species in the two cities. Therefore, we also did some sensitivity analysis, as shown in In addition to the above findings, secondary results are shown in the above figures and benefits , 54, 55,This study has the following strengths: first, we used a dynamic longitudinal cohort covering almost all school-age students for 12 years. Second, this study focused on northern and southern cities in China, making the results more representative and balanced. Third, we used the restricted cubic spline analyses to explore the non-linear association between exposure and ending, which might be more relevant to reality. At last, in addition to exploring the independent association between gaseous pollutants and green space with BP separately. We also assessed the benefits of improving a single pollutant under different greenness conditions to provide theoretical ideas for policy development.2 and CO on blood pressure was still observed.There were still some limitations: firstly and most importantly, we used a convenient sample to develop a cohort study and only collected physical examination and environmental data. No family background or lifestyle habits were included. As a result, our study did not investigate some confounders, like salt intake, parents' education level, temperature, and traffic noise, which might lead to fluctuation in the theoretical benefits of greenness , 56, 57.2 and CO exposure among students, but its benefit was more effective for normal-weight participants than those obese. It was suggested that some targeted measures should be taken to reduce the specific gaseous pollutants. According to the characteristic of various districts, improving green space construction and preventing childhood obesity could reduce the burden of childhood HBP and subsequent cardiovascular disease risks.In summary, our study supported a positive correlation between air pollution and HBP risks among children and adolescents, and a negative correlation between greenness and HBP risks. Meanwhile, the greenness reduces the risks of HBP attributed to SOThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Biomedical Ethics Committee of Peking University Health Science Center. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.YZ and SC conceived the study design, performed the analysis, interpreted the findings, and wrote the manuscript. LC, YW, and JW prepared, analyzed, cleaned the data, interpreted the findings, and helped with manuscript preparation. TM, MC, and QM cleaned the data, interpreted the findings, and helped with manuscript preparation. JL, LW, WL, XL, JZ, and XW helped with manuscript preparation. JM and XG contributed to the conception of the work. YX and JZ worked on study design and data collection and helped with manuscript preparation. YD contributed to the conception of the work and helped with manuscript preparation. All authors read and approved the final manuscript.


Diabetic Retinopathy (DR) is a leading cause of preventable visual impairment in the working age population. Despite the increasing prevalence of DR, there remain gaps in our understanding of its pathophysiology. This is a prospective case-control study comparing the genetic profiles of patients with no DR vs. non-proliferative DR (NPDR) focusing on intraretinal microvascular abnormalities (IRMA) and venous beading (VB) in Caucasians. A total of 596 participants were recruited to the study; 199 with moderate/severe NPDR and 397 with diabetes for at least 5 years without DR. Sixty-four patients were excluded due to technical issues. In total, 532 were analysed; 181 and 351 were in the NPDR group and no DR group, respectively. Those with severe IRMA and VB had distinctly different genetic profiles from each other and from the no DR group, which further supports the theory that these two features of DR might have different etiologies. This also suggests that IRMA and VB are independent risk factors for the development of PDR and may have different pathophysiologies. If these findings are confirmed in larger studies, this could pave the way for personalised treatment options for those more at risk of developing different features of NPDR. Diabetic Retinopathy (DR) is a leading cause of preventable visual impairment in the working age population, with recent rising prevalence observed in elderly people due to increasing longevity ,2,3. DesKnown risk factors such as poor glycaemic control and duration of diabetes  do not eStudies have found that DR is driven by multiple genes . Twin stModerate/severe non-proliferative DR (NPDR) is characterized by the presence of three features: deep haemorrhages (DH), venous beading (VB), and intraretinal microvascular abnormalities (IRMA). VB and IRMA are considered important risk factors for the progression to PDR and subsequent visual loss . DespiteVery few studies have examined the individual risk of the progression of VB and IRMA since the landmark trials of the 1980s (Diabetic Retinopathy Study (DRS), and The Early Treatment of Diabetic Retinopathy Study (ETDRS)). A more detailed characterization of these three features may improve the prediction of visual prognosis and help us better understand the pathophysiology. In addition, the genetic profile of DR has previously been studied without investigating the genetic risk factors for these individual lesions. In this study, the differences between no DR and NPDR were examined. However, the focus was VB and IRMA, as DH is very common in moderate and severe NPDR. The study aimed to identify, if any, genetic differences between subjects with these features.This is a novel approach. Previous studies have looked at genetic associations in subjects with DR vs. no DR. We used a candidate gene approach to increase the likelihood of identifying differences between our targeted features (VB and IRMA) within the DR disease class.The study was granted approval by the South West–Cornwall and Plymouth Research Ethics Committee , the Health Research Authority and Trust management of Oxford University Hospitals NHS Trust, and King’s College Hospital NHS Trust, and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants.PubMed.gov search engine was used, entering the terms ‘non-proliferative diabetic retinopathy’, ‘genetics’, and/or ‘SNPs’, between 2016 and 2019. Approximately 100 single nucleotide polymorphisms (SNPs) of interest were identified. The literature review identified a number of studies that reported positive associations between a variety of SNPs and DR when DR was compared to no DR or NPDR vs. PDR. Reports show conflicting results because of different study populations, varying sample sizes, and different endpoints [This was a prospective case-control study, involving Caucasians with T1DM and T2DM. Previously, our group performed a search of the literature of studies examining genetic associations with diabetic macular edema (DME) and T2DM . This wandpoints . We seleSubjects were recruited from retinal clinics and diabetic retinopathy screening clinics at King’s College Hospital NHS Foundation Trust and Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust. Caucasian subjects with T1DM or T2DM aged 18 or over and able to give informed consent were invited to join the study. Those recruited to the no DR group were required to have been diagnosed with diabetes at least 5 years prior to enrollment. Enrollment was between 2017 and 2019.The study required one visit, and all data were collected during the subject’s scheduled regular appointment. Those recruited to the no DR group of the study had fundus photography as part of their routine care. After mydriasis, two images, one centered on the optic disc and one centered on the macula, were taken with a digital fundus camera . These images were examined for signs of DR. If they met all the inclusion criteria , they were recruited to the control arm of the study.Those recruited to the NPDR group of the study had ultrawide field scanning laser ophthalmoscope (UWFSLO)  Optomap images taken after mydriasis as part of the patient’s routine care. All patients who met the inclusion criteria (aged 18 years or older and a diagnosis of NPDR) and were willing to participate, were recruited as cases to the study. Exclusion criteria: previous pan-retinal photocoagulation (PRP) laser and prior intravitreal anti-VEGF injections or intravitreal steroid injections.A short questionnaire was administered. This recorded the number of years’ duration of DM; whether T1DM or T2DM; and whether there was a history of angina, stroke, renal disease, or laser treatment for diabetic eye disease. Current medication and smoking status were recorded, and the participants’ most recent recorded glycated hemoglobin level (HbA1c) was obtained from their clinical notes.A buccal cell sample was taken from the inside of the mouth of each participant with a buccal collection brush and stored in a tube of Cell Lysis Solution  as per the standard operating procedure. The samples were purified using the Gentra Puregene Buccal Cell Kit, Qiagen, Manchester, UK. In this cohort, a ratio of 1.6–2.1 at A260/280 was deemed acceptable to be used for further analysis.The Oxford Genomics Centre, Wellcome Trust’s Infinium Global Screening 24v2.0x bead-chips was selected as it covered many genes and included most of the SNPs of interest and was most appropriate for this study. The DNA samples from 199 patients with NPDR and 397 diabetic patients with no DR were collected. The case-control comparisons were between those with moderate–severe NPDR and no DR; those with VB and no DR, and those with IRMA and no DR. The level of VB and IRMA included were both Grade 3 of the ETDRS classification .The Early Treatment Diabetic Retinopathy Study (ETDRS) used seven standard field 35 mm film stereoscopic color photographs, each image being 30° to 35° wide, to assess DR severity levels. Field 1M is centered on the temporal edge of the optic nerve, field 2 on the macula, and field 3M on the temporal macula. The four outer fields image the superior temporal, inferior temporal, superior nasal, and inferior temporal fundus. A seven-field overlay, equivalent to ETDRS 30-degree seven standard field 35mm stereoscopic color photographs, was superimposed on the Optomap image using Adobe Photoshop CS2 . The two central ETDRS fields covered the macula and optic disc. This enabled the ETDRS seven-field area of the posterior pole to be assessed .The images were graded according to the ETDRS diabetic retinopathy severity scale (DRSS) grading system. The seven standard ETDRS fields were graded by quadrants centered on the optic disc; superior temporal, superior nasal, inferior nasal, and inferior temporal . This meThe grading quadrants were then extended to the periphery, using the same quadrants  as well as an additional middle temporal area . Each quA grading audit was performed. A sample of 10% of images was re-graded by the primary grader, a sample of 10% of images was graded by another experienced grader, and the results compared.Intra-grader agreement was found to be 87.5% within one DRSS step and 100% within two DRSS steps. Inter-grader agreement was found to be 85% within one DRSS and 100% within two DRSS steps. When differences were found, cases were discussed and consensus was sought.In total, 596 participants were recruited to the study, including 199 with moderate/severe NPDR (NPDR group) and 397 with diabetes for at least 5 years but no DR (no DR group). Twenty samples failed to yield enough DNA to be analysed, leaving 576 samples that were sent to the Wellcome Centre Human Genetics, University of Oxford to be analysed. Of these, 44 were removed from the analysis as they failed to yield meaningful data. In total, 532 samples were analysed, of which 181 and 351 were in the NPDR and no DR groups, respectively.The demographic and features analysis included the 532 participants whose samples could be analysed and are displayed in p < 0.0001; had a lower HbA1c, p = 0.0003; and a shorter duration of diagnosed DM, p = 0.0049. As participants in the control group might develop DR in later life , the findings are likely to become more significant, hence the analysis was not adjusted for age. There was no difference between sex for cases and controls . In both groups, T2DM was much more prevalent . Information about the type of DM was not available for four subjects. When looking at the prevalence of DR among those with T1DM and T2DM, those with T1DM were more likely to have DR than those with T2DM, p < 0.00001, Chi Square = 23.86. Analysis of the NPDR group revealed the mean age of those with IRMA showed a trend to be lower than those without . Those with IRMA had a slightly longer duration of DM, IRMA mean of 21.30 years, and without 16.26 years (p = 0.309) and slightly lower HBA1c, IRMA mean 8.53, and without 8.81 (p = 0.378). The findings for VB were similar to those with IRMA in terms of age; patients were slightly younger, but the duration of DM was shorter, and HBA1c was slightly higher (the opposite of IRMA), although these results were not statistically significant. In The no DR group was significantly older, p = 0.015) for the group NPDR vs. no DR, followed by the SLMAP SNP rs17058639 (p = 0.035) and CFB rs1048709 (p = 0.042). None of the SNPs selected showed any association with those with VB. Four of the VEGFA SNPs, the Rho GTPase activating protein 22 (ARHGAP22) SNP rs4838605, and the TGF-b1 SNP (rs1800470)  showed statistically significant associations with the presence of IRMA. CFH, C5, and VDR showed no significant associations with DR, VB, or IRMA.The TGF-b1 SNP rs1800470 showed the highest correlation  vascular endothelial growth factor (VEGF); (b) ischaemia-mediated growth factors and cytokines, and (c) the complement pathway. These three groups were chosen because anti-VEGF is used as a therapy for diabetic retinopathy and is therefore likely to be relevant to the development of DH, VB, and IRMA. Cytokines and growth factors associated with ischaemia may also be of interest as both VB and IRMA are believed to be driven by ischaemia. These include HFE, SLMAP, VDR, TGF-b1, and ARHGAP22. A complement factor was selected as it has been implicated in other retinal vascular conditions. Seven SNPs of interest could not be examined as they were not on the Illumina Array. Another five SNPs were excluded due to a high frequency in the general population making statistical analysis impossible.An examination of the demographic data of both groups found that those with NPDR were likely to be younger. As the NDPR group had a longer duration of DM, it is reasonable to suggest that the no DR participants with the significant alleles may develop NPDR in the future with the increasing duration of DM. By including patients in whom the duration of DM was more than 20 years as opposed to 5 years in this study, this hypothesis could be confirmed.An analysis of the NPDR group showed no significant association with age, sex, duration of DM, or HbA1c levels when looking at the presence or absence of VB or severe IRMA. However, it is interesting that patients with VB (16.02 years) have shorter durations of DM as compared with those with IRMA (21.30 years) despite being very similar in age at 56.70 years for VB and 56.90 years for IRMA. This may suggest that VB develops first and then progresses to PDR without developing IRMA. Indeed, this theory would be consistent with the observation that VB is rarely observed alone, while severe IRMA may occur with or without VB.p-value of this was 0.015. The result ties in with the findings that TGF-b1 has a role in angiogenesis, maintaining retinal capillaries, and is involved in cellular proliferation and differentiation, its inhibition leading to the breakdown of the blood–retina-barrier (BRB) and impaired retinal perfusion [The strongest association in the comparison between NPDR and no DR was found with SNP TGF-b1 rs1800470. The erfusion . Previouerfusion . The loserfusion ,18. Our erfusion ,20,21.SLMAP was also positively associated with NPDR vs. no DR in our study. SLMAP has a role in vascular endothelial dysfunction and may be a marker of microvascular dysfunction in diabetes. A previous study found this SNP to be associated with a higher risk of DR . VasculaThe role of complement in the development of DR is not completely understood. The complement system helps regulate the immune response and inflammation, and its dysfunction is linked to autoimmune disease . DM affep = 0.083 and 0.065, respectively).One VEGF SNP showed a positive association with NPDR, as well as an ARHGAP22 SNP, although these were not statistically significant (p = 0.106. SLAMP was found to show a positive association with the development of NPDR vs. no DR (p = 0.035) but not with IRMA. This finding may be explained by SLMAP being positively associated with DH, but as DH was so common in the NPDR group, its genetic associations were not studied separately. SLMAP has been implicated in vascular endothelial dysfunction in diabetes, potentially leading to DH. Furthermore, if confirmed in future studies of its importance in VB, the pathophysiology of VB may be related to vessel wall damage secondary to endothelial dysfunction. Nonetheless, most interestingly, none of the ischemic-driven genes showed any significance. This may be due to the relatively small number of patients with VB; however, significant associations were shown with IRMA with a similar number of patients.No association was found between any SNPs studied and the presence of VB. SLMAP rs17058639 was not significant but showed a trend association, p = 0.09, rs699947 p = 0.046, rs13207351 p = 0.035, and rs1570360 p = 0.05 showed a correlation with IRMA compared to those without. There was a weaker association with one VEGF SNP and NPDR vs. no DR. As previously described, VEGF has an important role in retinal angiogenesis and endothelial cell permeability and is activated by microvascular changes resulting from elevated blood glucose levels and hypoxia [Four of the VEGF SNPS; rs2010963  hypoxia .p = 0.02, suggesting it has a role in the development of DH and IRMA.TGFb-1 rs1800470 also showed a positive association with IRMA compared to those without, p = 0.048) was found to be significant in the group with IRMA compared to no IRMA. The ARHGAP22 may be involved in endothelial cell migration and angiogenesis, specifically capillary tube formation, and thereby influence IRMA development.Rho GTPase activating protein 22 (ARHGAP22) rs4838605 . The association with IRMA may not be highly significant due to the low number of study participants; however, the differences between the results for the group with IRMA and the group with VB were clear.The diabetic retinopathy severity scale (DRSS) was developed based on the findings of the ETDRS. Using mathematical modelling, DH, VB, and IRMA were found to be independent risk factors for the progression from NPDR to PDR and eventually visual loss . There iThe study size was relatively small, and the SNPs selected may be biased towards the authors’ research interests. Nonetheless, the SNPs were pre-selected and the two focused features, VB and IRMA, showed clear differences in their genetic profile relative to no DR and to each other, despite a slight difference in the numbers in each group . The no DR arm was not imaged with UWFSLO but with two color fundus images, as this is standard of care. Peripheral lesions may therefore have been undetected in this group; nonetheless, the grading of VB and IRMA was based on the central seven fields, so it is comparable. We did not correct for age, duration of diabetes, and diabetic control, the most important risk factors for DR ,37,38,39The different genetic findings for those developing VB and IRMA further strengthen the theory that these two features of DR have different etiologies. If these findings are confirmed in larger studies, this could pave the way for personalized treatment options for those more at risk of developing different features of NPDR. To date, little is understood about the etiology of VB and IRMA. Both are frequently found adjacent to areas of ischaemia, suggesting ischaemia’ s role in their etiology. This study suggests that they might be considered independent risk factors for the development of PDR and behave differently in terms of genetic origin in addition to their differing responses to anti-VEGF treatment. This study adds further weight to the different pathophysiologies of VB and IRMA, further suggesting that IRMA is ischaemia driven. What drives the formation of VB remains unclear.


Our systematic review with meta-analysis suggests a strong association of serum Mg concentrations with incident fractures. Further research is needed to confirm our results among other populations and to assess whether serum Mg is potentially relevant in the prevention of fractures, which continue to increase and represent a significant health burden due to the associated disability.Magnesium, an essential cation for numerous cellular processes, is a major component of bone. However, its relationship with the risk of fractures is still uncertain. The present systematic review and meta-analysis aim to investigate the impact of serum Mg on the risk of incident fractures. A systematic search was conducted using several databases including PubMed/Medline and Scopus from inception to 24 May 2022, including observational studies investigating serum Mg and the incidence of fractures considered as outcomes. Abstract and full-text screenings, data extractions, and risk of bias assessments were conducted by two investigators independently. Any inconsistencies were resolved by consensus with a third author. The Newcastle–Ottawa Scale was used to assess the study quality/risk of bias. Among 1332 records initially screened, 16 were retrieved as full-texts; of them, four papers were included in the systematic review with a total of 119,755 participants. We found that lower serum Mg concentrations were associated with a significantly higher risk of incident fractures (RR = 1.579; 95%CI: 1.216–2.051;  Fragility fractures are unquestionably a common relevant public health problem in terms of patient’s health, quality of life, as well as social and financial burden ,2,3. TheFragility fractures not only entail direct costs but also expenses deriving from the disability they cause. The disability adjusted life years (DALYs) attributed to fragility fractures are two million every year in Europe, which exceeds those attributable to hypertensive heart disease ,4. ThereThe mineral components of the body are factors accepted as key determinants of bone health. This is another relevant target for prevention given its potential modifiable nature. Evidence in this regard has focused mainly on calcium and vitamin D despite the fact that there are many other minerals and dietary components that may also contribute . There iMg, a crucial element for a number of cellular processes, including over 600 enzymatic reactions, all oxidative phosphorylation processes, protein synthesis, energy production reactions, nucleic acid synthesis and stability, as well as glycolysis , is alsoEven if the Mg cation has the biological plausibility to be a key element in bone health, the body status of Mg in relation to the incidence of fractures is until uncertain today. The studies found currently in the medical literature mainly refer to its intake with diet, with results showing that Mg is associated with an increased bone mineral density ,19,20,21There are also studies with discordant results and not always optimal designs that evaluate the association of serum Mg with the incidence of fractures. Therefore, the aim of the present systematic review and meta-analysis was to investigate the impact of serum Mg on fracture risk, including observational studies dealing with this specific problem.This systematic review adhered to the PRISMA statement  and follTwo investigators (NV and SC) independently conducted a literature search using several databases, including PubMed/Medline and Scopus, from database inception to 24 May 2022, involving observational studies investigating serum Mg and the incidence of fractures considered as outcomes. The search strategy included the concepts of Mg and fractures (magnes* AND fractur* in Pubmed) and adapted for Scopus. Any inconsistencies were resolved by consensus with a third author (LJD). No automation tool was used.For the inclusion of studies in the meta-analysis, we considered the following criteria: (i) observational studies ; (ii) evaluation of Mg in serum at the baseline evaluation; (iii) reporting data regarding incident osteoporotic fractures; and (iv) written in English. Studies were excluded if they: (i) did not include humans; (ii) assessed Mg from other sources ; or (iii) were cross-sectional. The studies were grouped according to the estimates reported. Two reviewers (SC and NV) independently screened the studies, and a third senior investigator (LJD) was available in case of divergency. Two investigators (NV and SC) independently extracted the key data from each included article by means of a standardized Excel spreadsheet. A third investigator (LJD) independently revised the data. Data extracted from each article comprised: author names, year of publication, country, condition, study design, main condition, demographic information, follow-up duration (in months), type of fractures, number and type of confounders used in multivariate analyses. The primary outcome was the incidence of any osteoporotic fracture, total and by site . All the outcomes were compatible each other. For assessing the study quality/risk of bias, we used the Newcastle–Ottawa Scale (NOS) . The NOS2 metric and χ2 statistics. Given the significant heterogeneity , and for outcomes having at least ten studies, we plan to conduct a series of meta-regression analyses, according to follow-up, serum Mg levels, mean age and percentage of women. All analyses were performed using STATA version 14.0 (StataCorp). The primary analysis investigated the incidence of fractures by serum Mg levels at the baseline. We calculated the risk ratios (RRs), adjusted for the highest number of potential confounders available in each analysis with their 95% confidence intervals (CIs), applying a random-effect model . For allPublication bias was assessed by visually inspecting funnel plots and using the Eger bias test . The trip-value less than 0.05 was considered statistically significant.For all analyses, a A total of 119,755 participants were followed up for a mean of 79 months (range: 24 to 161). The mean age was 62 years, with a mean percentage of 33% women. The analyses were adjusted for a mean of 15 potential confounders.p = 0.001; I2 = 46.9%). The results were not affected by any heterogeneity  nor publication bias . After trimming, nine studies were to the left of the mean, and the recalculated effect size was only slightly reduced .As reported in The Newcastle–Ottawa Scale did not indicate any possible risk of bias since, in all the studies included, the outcomes were well-described and according to validated criteria, the follow-up was long enough and for detecting future fractures, and the follow-up was adequate for detecting the outcomes of interest, i.e., fractures.In the present systematic review and meta-analysis, we aimed to examine the impact of serum Mg on the risk of incident fracture in the available suitable studies. Starting from over 1300 studies of the original search and after reviewing them according to the latest PRISMA recommendations, four studies with a total of 119,755 participants were available and were included in the analyses. All the four studies included in the meta-analysis were of high quality . We observed a strong relationship of a lower serum Mg concentration with a higher risk of incident fractures. These results confirm the key role that Mg may play on bone health and entail an open opportunity that can help in fracture prevention since hypomagnesemia is a potentially modifiable factor.p = 0.02) and total hip, spine, and wrist fractures (p = 0.02). None of these individual statistically significant associations remained after an adjustment for multiple testing  was also significant (2.13 [1.13–3.99]) in the fully adjusted analysis. These results strongly confirm the possibility of intervening in low Mg status to prevent fractures in Caucasian men [–3.41, whp < 0.01), with a dose-response relationship between serum Mg quartile and incident hip fracture risk. These results were consistent for both men and women. Considering serum Mg concentration as a continuous variable, each 1-mg/dL increase in serum Mg was associated with a 14.3% decreased risk in the incidence of hip fracture . The fraction of serum Mg concentration attributable to the population for incident hip fractures was 13.7% (95% CI: 3.7% to 22.7%), which was considerably higher than that of serum calcium, serum phosphate, and parathyroid hormone (PTH) levels [The third study used a nationwide database of patients undergoing dialysis in Japan. The authors identified 113,683 patients on dialysis treatment without a history of hip fracture at baseline. Multivariate logistic regression analyses showed that patients in the lower quartile of serum Mg had a 1.23-fold higher risk of hip fracture compared to those in the highest quartile  levels .p = 0.03). Participants with lower Mg and lower BMD had a 9.21-fold higher risk of fractures  when compared to participants with higher serum Mg concentrations and high BMD. Therefore, adding Mg levels and lumbar spine BMD resulted in a significant improvement of the prediction of fractures [The fourth study included in our meta-analysis was a longitudinal study conducted among 358 patients undergoing hemodialysis treatment. The cumulative incidence rates of fractures were strikingly different in participants with lower serum Mg (below 2.6 mg/dL) vs. those with higher Mg circulating concentrations: 17.6% vs. 5.2% with a multi-adjusted HR of 2.31 . For example, the increased all-cause and cardiovascular mortality risk of patients with CKD persist even after adjustments for traditional cardiovascular risk factors, indicating that other specific factors for the kidney may contribute to this risk . RecentlBone metabolism disorders and the tendency to develop vascular calcifications in CKD patients seem to be deeply connected. Reduced bone formation has been associated with coronary calcifications in CKD patients not yet on dialysis . Some stThere is consistent evidence suggesting that Mg has beneficial effects on bone health. Yet, most of the available studies refer to dietary Mg as an exposure and very few to serum Mg concentrations. In this regard, there is convincing evidence that dietary Mg is associated with increased BMD, while the evidence is less homogeneous when it comes to fractures ,21,49.Several mechanisms may help to explain our findings of a strong association between serum Mg and incident fractures. This includes the modulation of osteoclastic and osteoblastic activity demonstrated for Mg ,15,50,51Regarding the modulation of osteoblastic and osteoclastic activity, in addition to the initial investigations by Rude et al. showing an increased number of osteoclasts in experimental animals receiving an Mg-deficient diet , there aSome of these recent studies have been carried out in experiments seeking to develop and improve Mg-based bone implants, an area of recent and growing interest due to the fact that Mg is both biocompatible with and biodegradable in the human body and stimulates bio-responses at cellular and molecular levels, with the potential promotion of bone remodeling . A studyAnother study explored whether the coculture of osteoblasts and osteoclast in Mg-based implants may influence bone metabolism and remodeling upon degradation. In this study by Wu et al., cocultures containing both bone-forming osteoblasts and bone-resorbing osteoclasts significantly enhanced the formation of osteoblasts, whereas they decreased osteoclastogenesis in the cultures with high concentrations of Mg extract .Thus, Mg-based alloys have become a relevant category of materials that is attracting more and more attention due to their high potential use as orthopedic temporary implants, being a viable alternative to non-degradable metals implants. Generally, temporary orthopedic implants need to be removed from the body after a certain period. Conversely, biodegradable implants, such as Mg-based implants, eliminate the requirement of a second surgery to remove the planted implants .2D, the active form of the hormone by renal hydroxylation, have Mg as a cofactor [2D synthesis and impaired PTH response, have been implicated in the described condition “Mg-dependent vitamin D-resistant rickets” [2D and 25OHD [2D and 25OHD [Another key mechanism that may help explain our findings is the relationship between vitamin D and Mg. The effects of vitamin D as a key regulator of calcium and phosphate metabolism is well known . It is kcofactor ,55,56,57cofactor ,59,60,61cofactor . Hypocalcofactor . These erickets” ,63. It hnd 25OHD , whereasnd 25OHD , confirmnd 25OHD . Thus, ind 25OHD .Another of the key mechanisms that can help explain our results is related to the antioxidant and anti-inflammatory properties of Mg ,67,68,74Clinical studies have demonstrated that low serum Mg concentrations as well as diets poor in Mg are robustly related to low-grade systemic inflammation ,76,77. OLow serum Mg concentrations are primarily due to a poor Mg diet, a prevalent feature of the Western diet. According to the Dietary Guidelines for Americans, about 49% of the USA population , had an Mg intake below the estimated average requirement . There aThe findings of the present meta-analysis should be interpreted with its limitations. First, only four studies were identified as suitable for the analyses according to PRISMA recommendations. Although it is a small number, these studies were of good quality and the number of participants was adequate . Another limitation is that the studies were conducted in Japan and Europe and two of the studies included hemodialysis patients. Future studies conducted in other populations  are needed to test whether our results are replicated and extendable to those populations. The other limitation concerns serum Mg, a method used to evaluate Mg status in daily clinical practice. Mg is mainly an intracellular ion, with only 1% of total body Mg contained in the blood. Thus, serum Mg may not accurately reflect the global body Mg status because it drops only when the tissue deposits are exhausted; therefore, it is unable to disclose most of the mild to moderate Mg deficits, which are often underestimated and unrecognized. Furthermore, subclinical Mg deficit symptoms are generally not specific and are not easily connected to unobserved electrolyte alteration by the clinician ,82. NeveOur systematic review with meta-analysis suggests a strong association of serum Mg concentrations with the risk of incident fractures. Further research is needed to replicate the present results in other populations as well as to assess the potential significance of serum Mg in the prevention of fractures, which continue to increase and represent a significant health burden due to the associated disability.


Background: The purpose of this study was to clarify the structural relationship of quality of life (QOL) in survivors of breast cancer, including difficulty in daily life and negative experiences in daily activities, as health-related indicators. Methods: Participants were survivors of breast cancer for more than 2 years after primary breast cancer surgery and belonged to self-help groups. The assessment used FACT-B (QOL), HADS (anxiety and depression), SOC (sense of coherence), WHODAS 2.0 (difficulties in daily life), and CAOD (negative experiences in daily activities). Bayesian structural equation modeling (BSEM) was performed to analyze the hypothesized model. If the causal model was significant, multiplication of the path coefficient from emotional distress (anxiety and depression) to QOL, and from SOC to emotional distress, was considered a direct effect on QOL, and from SOC to difficulty in daily life, from difficulty in daily life to negative experiences in daily activities, and from negative experiences in daily activities to anxiety and depression were considered indirect effects on QOL. Results: The participants comprised 73 survivors of breast cancer. The goodness of fit of the model in the BSEM was satisfactory. The direct effect was 0.274, and the indirect effect was 0.164. Conclusions: An additional finding of this study is that coping with difficulty in daily life and negative experiences in daily activities related to QOL may improve QOL. Survivors of breast cancer are prone to experience psychological problems, so it is important to consider specific methods to improve their quality of life (QOL). This is due to the fact that many breast cancer patients have high survival rates after treatment and live for a long time as survivors. Psychological problems such as anxiety, depression, and poor body image are found in 20–40% of survivors of breast cancer 1 year after surgery and in 15% 5 years after diagnosis  shows thWhen we consider the QOL of our patients, it is necessary to consider their difficulties in daily life and subjective factors . The Wor“Occupational dysfunction”, defined as a prominent factor affecting daily life difficulties, refers to the negative experiences individuals encounter when engaging in everyday activities. It represents a significant health-related issue that has primarily emerged within the realm of preventive occupational therapy . This coHowever, the structural relationship between difficulty in daily life and occupational dysfunction (negative experiences in daily activities) in the QOL of patients and survivors of breast cancer has not been investigated. Therefore, we developed a hypothetical model to construct a structural equation model of QOL based on difficulty in daily life, considering that difficulty in daily life and negative experiences in daily activities are included as variables in QOL . The hypParticipants in this multicenter cross-sectional study were survivors of breast cancer who belonged to 7 self-help groups (SHGs) and responded to recruitment requests between June and August 2021. Survivors of breast cancer who belonged to a SHG who agreed to participate in this study, and those who were eligible, were invited to participate in the study. The eligibility criteria were (i) at least 2 years after primary breast cancer surgery, (ii) 20 years old or older, and (iii) individuals who could understand the questionnaires and give their consent to the explanation of this study. Individuals with dementia, neuropsychiatric diseases, and physical disabilities before the first surgery for breast cancer were excluded. SHGs are voluntarily formed in small groups aiming at mutual assistance and achievement of specific goals , and breGeneral information such as sex, age, dominant hand, family structure, employment, and period of participation in SHGs and medical information such as diagnosis, date of surgery, age at the date of surgery, operation type, and stage classification were collected from the participants. The assessment used the Functional Assessment of Cancer Therapy-Breast (FACT-B), Hospital Anxiety and Depression Scale (HADS), 13-item version of SOC (SOC-13), WHODAS 2.0, and Classification and Assessment of Occupational Dysfunction (CAOD). Response to the surveys was requested by mail or web forms.The FACT-B , a canceThe HADS is an anxiety and depression scale  answeredThe 13-item version of the 7-item SOC-13  was usedThis study utilized the self-administered version of the WHODAS 2.0, which consists of 36 items ,10. ThisThe CAOD is a tool utilized to assess occupational dysfunction, which refers to the negative experiences individuals face when they are unable to effectively perform activities of daily living . Particip-value (PPP), with a PPP >0.10 indicating a good fit of the model [Confirmatory factor analysis was applied to each of the five assessment scales to measure their structural validity, and reliability coefficients were analyzed. The GFI was obtained from a model created with the corresponding sub-items influenced by each factor and covariance assumed among all factors. Each scale’s sub-items were considered based on the GFI, adjusted GFI (AGFI), and RMSEA, and Cronbach’s alpha coefficient was calculated to confirm the internal consistency of each scale. A GFI of >0.85  and AGFIhe model . Furtherp-value of <0.05. Statistical analyses were performed using the following software: SPSS Statistics 27 , SPSS Amos ver. 25.0 , and R (version 4.1.2).Statistical significance was determined using a This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee of Kitasato University School of Allied Health Sciences  as well as from each participating SHG. The participants were provided with a clear explanation of the study’s purpose and content, and informed consent was obtained from all individual participants included in this study.The characteristics of the participants are shown in The scores for each assessment scale are shown in A confirmatory factor analysis was performed on the sub-items of each assessment scale. The goodness-of-fit indices, including GFI, AGFI, and RMSEA were as follows: FACT-B; GFI = 0.980, AGFI = 0.901, RMSEA = 0.057, HADS; GFI = 0.896, AGFI = 0.835, RMSEA = 0.000, SOC-13; GFI = 0.901, AGFI = 0.847, RMSEA = 0.000, WHODAS 2.0; GFI = 0.777, AGFI = 0.702, RMSEA = 0.043, CAOD; GFI = 0.875, AGFI = 0.797, RMSEA = 0.044. These values confirm that the original factor structures of the assessment scales were supported by the data. Cronbach’s alpha for each scale was 0.805 for FACT-B, 0.928 for HADS, 0.864 for SOC-13, 0.902 for WHODAS 2.0, and 0.928 for CAOD.A hypothetical model of causality in QOL was developed , and BSEIn addition to the direct association supporting the conventional finding that improvement in SOC, which is the individual’s ability to cope with stress, leads to improvement in QOL mediated by emotional distress, an indirect association was indicated showing that a decrease in difficulty in daily life and impaired negative experiences in daily activities leads to improvement in QOL mediated by emotional distress for the structural relationship of QOL in survivors of breast cancer. The direct association from “SOC” to “QOL” via “emotional distress” supported the findings of previous studies ,7,8. TheEstablishing psychosocial support strategies in the context of survivorship of breast cancer is important for improving QOL . As a diThere are many SHGs for breast cancer patients in Japan, although they vary widely in size and activities. Therefore, the participants in this study may not be considered general survivors. The participants in this study were survivors of primary breast cancer surgery for more than 2 years after surgery in the Japanese culture. The majority were survivors who had completed postoperative therapy, but some were still undergoing treatment at the time of the assessments. In addition, participants were included regardless of their experience with cancer recurrence. Therefore, different cultures, treatment statuses, and experiences with cancer recurrence may lead to differences in the results of the assessments. There were selection biases that need to be carefully considered to determine whether the insights gained from this model can be generally applied. In addition, an assessment of subjective indicators needs to control for mood as a potential confounding factor . Even thThe present empirical research has shown a structural relationship between QOL mediated by difficulties in daily life and negative experiences in daily activities in survivors of breast cancer. The present model indicates that difficulty in daily life and negative experiences in daily activities are mediating variables and that support not only directly decreases difficulty in daily life but also addresses the negative experiences in daily activities as a subjective aspect that arises from difficulty in daily life that may improve QOL. The influence of difficulties in daily life, which were not revealed by the support for anxiety, depression, and SOC shown in previous studies, was clarified. Therefore, it is important to focus on the difficulties in daily life and negative experiences in daily activities of individual survivors of breast cancer and provide support to improve them. These direct and indirect approaches to addressing difficulties in daily life are very significant because they can provide a basis for the development of support strategies to increase QOL. Expected research in the future would be based on a longitudinal study to examine whether difficulty in daily life could affect changes in QOL.


This paper describes the general status, trends, and evolution of research on talent identification across multiple fields globally over the last 80 years. Using Scopus and Web of Science databases, we explored patterns of productivity, collaboration, and knowledge structures in talent identification (TI) research. Bibliometric analysis of 2,502 documents revealed talent identification research is concentrated in the fields of management, business, and leadership (~37%), sports and sports science (~20%), and education, psychology, and STEM (~23%). Whereas research in management and sports science has occurred independently, research in psychology and education has created a bridge for the pollination of ideas across fields. Thematic evolution analysis indicates that TI has well developed motor and basic research themes focused on assessment, cognitive abilities, fitness, and youth characteristics. Motor themes in management and sports science bring attention to talent management beyond TI. Emerging research focuses on equity and diversity as well as innovation in identification and technology-based selection methods. Our paper contributes to the development of the body of TI research by (a) highlighting the role of TI across multiple disciplines, (b) determining the most impactful sources and authors in TI research, and (c) tracing the evolution of TI research which identifies gaps and future opportunities for exploring and developing TI research and its broader implications for other areas of research and society. ConceivThe research on TI exists primarily within the fields of gifted education , sports In the next section we briefly discuss definitions of talent, then provide context for our bibliometric approach to studying TI research.1.1.Definitions of talent vary depending on the context and field. In gifted education, Gagne  broadly Some characteristics of TI deployment and research are shared across fields. For example, TI researchers in education, sports, and psychology are concerned with early identification practices, adequate resources to nurture identified talent, and mechanisms to sustain high performance over time . From prDetermining who has potential or talent is not an easy task. TI requires decision-making and the involvement of stakeholders, making TI a dynamic, complex, and resource-intensive process . The TI Considering the above-mentioned perspectives, we conceptualize TI as the process whereby stakeholders devise strategies to detect potential for high achievement in selected areas of human performance across the life span. This definition allows flexibility to incorporate perspectives on talent as characteristics, aptitudes, and potential for high performance in settings like academics , cognitive abilities , physical abilities , as well as employee performance and productivity within organizations . We intentionally include the field(s) of management, business, and leadership that conceptualize talent as human capital in the workforce. This view allows us to highlight the implications of TI for lifelong personal development.1.2.Bibliometric analysis is a strategy to map scientific work to identify the main streams of research over a period of time, contexts, and fields . We takeTo date, a few bibliometric studies related to TI have been published. These studies have approached TI at the subdiscipline level: for example, Our current paper aims to describe trends in TI research across multiple fields over the last 80 years to ultimately understand the past, present, and future of TI research. This bibliometric analysis provides new ways of viewing TI by implementing a performance and science mapping strategy. First, we use performance analysis to identify the scholarly productivity of researchers and the journals’ influence through publication and citation patterns. Second, we use science mapping to explore the collaborative, conceptual, and country-level networks in TI research. Bibliometric analysis also has the potential to motivate cross-disciplinary pollination of ideas . Thus, i1.3.We aimed to answer the following research questions:RQ1. What are the patterns of publications and citations on TI from 1943 to 2022?The goal of this question is to determine the annual scientific production and growth estimated by volume and document citation from a multidisciplinary angle to TI since the publication of RQ2. Who are the leading and influential researchers in TI?The goal of this question is to produce a list of the most cited and productive researchers in TI across research fields.RQ3. What are the top journals in TI research?The goal of this question is to explore publication venues in order to understand academic communities that study TI. This question has the potential to identify research areas that can benefit from cross-pollination of research ideas among TI fields.RQ4. Which countries’ scholarly productions on TI are most frequently found in the Scopus-WOS databases between 1943 and 2022?The goal of this question is to determine collaboration networks across countries and which countries are more visible or impactful in TI research.RQ5. What is the intellectual structure of the knowledge base on TI?The goal of this question is to identify the patterns of scientific collaboration among researchers by mapping co-authorship and pattern of co-citation of influential works across fields.RQ6. How have thematic and conceptual trends in TI evolved?The goal of this question is to identify the most frequent keywords used in TI, mapping networks of key concepts, and producing cluster analysis and time slicing maps of recurrent themes in the adoption of keywords over time.2.2.1.October 31, 2022. Both databases broadly cover the areas of science, the social sciences, and humanities. We limited our search within title, abstract, and keywords (TITLE-ABS-KEY). We searched for the term “talent identification” and equivalent terms such as “talent search,” “talent detection,” and “talent management” as keyword terms cited in recent systematic reviews and meta-analyses of talent identification  AND TITLE-ABS-KEY (develop*)] AND [LIMIT-TO ]WOS[TI = ] OR AB = [“talent search” OR “talent identification” OR “talent management” OR “talent detection”] AND [AB = (develop*)]n = 1,943) and WOS . We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to structure our data. Because of the broad, global, and multidisciplinary focus of this paper, we did not filter results by a specific knowledge field, language, or time span. However, we filtered the results to only include peer reviewed journal articles (AR), using the database advanced filters. This decision was made on the basis that journal articles adhere more closely to publication indexation standards in reference formatting than other publication sources.The search produced 4,555 document references: Scopus  website.2.2.We conducted performance and mapping network analysis of our data using the R Bibliometrix package and the visualization tools Biblioshiny 4.0  and VOSVh-index, m-index, and g-index. The m-index is a measure of publication citations whereby the index is the result of h number of articles with h number of citations. For example, an h-index of 10 signals that 10 publications under the same category have been cited at least 10 times. The m-index is the result of dividing the h-index by the number of years a journal or author has been active. The g-index is the largest perfect square in a list of articles, authors, or journals ranked by number of citations in descending order “such that the top g articles received together at least g2 citations.” The global h-index was extracted from the ScimagoJR website which offers current rankings for most online scientific publications. This global index represents all types of publications, not only those related to TI.To address scholarly productivity, we used author, journal, and article level metrics to rank the most influential items in the database. Metrics included global and local performance indices commonly used to measure the relative impact of publications. Specifically, we used the local a priori constraints , patterns of collaboration among authors and countries , and thematic maps using keyword clusters  . We usedstraints . This ap3.Overall, the merged database included a wide variety of empirical and conceptual articles in the six discipline categories. Most articles related to TI were found in the field of management (~37%), followed by sports science (~20%). Education, psychology, and STEM categories only accounted for a combined (~23%) of all publications included in the analysis. A summary of the merged database characteristics is presented in 3.1.th century. In our data, only 62 (2.4%) articles were published between 1943 and 2000, corresponding to the fields of education, psychology, management, and sports. The fields of sports science and management showed an explosive growth pattern since the year 2000. All fields display a sharp upsurge of publications after 2000, which can be attributed to increased online publications and internet access. On average, the field with the most publications per year post 2000 was management , followed by sports  and multidisciplinary research . Fields of education, psychology, and STEM produced, on average, fewer than ten articles per year according to Scopus and WOS databases. Two systematic reviews published in 2000 by Reilly and colleagues in the Journal of Sport Sciences caused the abrupt spike of citations in the field of sports.The research in TI has maintained consistent growth over the past 80 years. The average year growth for research publication in TI across multiple areas was 7.19%. The number of publications and citations demonstrates the increasing interest in TI from multiple fields. 3.2.h-index, a measure of impact based on the h number of articles with h number of citations. We ranked authors from multiple fields using this metric. Consistent with the accelerated growth in publications across fields, the top 30 researchers have continuously contributed to the literature of TI as revealed by their h-index, number of publications, and overall total citation count. Overall, the field of sports is well represented with 20 researchers, followed by management with seven researchers in the list. With the exception of Hugh Scullion and David G. Collings (in management), the top 10 most productive and influential researchers in TI published articles related to talent in sports. Only three researchers, David Lubinski and his collaborator Camilla Benbow (psychology and education) as well as Áine MacNamara (multidisciplinary) were classified within the most cited and influential researchers in TI. Although the h-index is regarded as a measure of academic influence, it is important to highlight that the h-index does not take into account whether an author publishes solo or with co-authors. Therefore, h-index alone is not an appropriate estimate for scientific productivity or author reputation , sports (n = 12), multidisciplinary (n = 3), psychology (n = 1), and education (n = 1). The most important journal in TI research is the Journal of Sport Sciences with a local h-index of 41, total of 114 publications in TI and over 7,400 citations. In contrast to the list of top authors, management-related publication venues dominate the list. The most prominent journal in management was the International Journal of Human Resource Management with a local h-index of 26, 73 publications, and 1,839 citations. Most high-ranked journal publications occurred within the last 10 to 20 years, which is consistent with the expansion of fields and the popularization of TI research. The average Scimago h-index for the top 30 journals was 90.1, which was greater than the average h-index of 72 for all journals included in the database. PloS One was the journal with the highest general h-index in the whole database. This multidisciplinary journal ranked seven with a local h-index of 14, and a general h-index of 367. Only two journals in psychology and education were included in the list. Frontiers in Psychology and Gifted Child Quarterly (GCQ) took positions 13 and 14, respectively.We ranked the most relevant journals publishing TI articles using R-bibliometrix local International Journal of Human Resource Management has the largest number of co-citations in the data followed by the Journal of World Business and Human Resource Management Review. These journals share the most links with other journals and a large number of co-citations with each other. The Journal of Sports Sciences has a strong connection with the Journal of Sports Medicine with many co-citations between the two journals. Of note, there is a bridge between the management and sports clusters. The bridge is comprised primarily by journals in psychology, education, and multidisciplinary research venues. Whereas education and psychology were underrepresented in this network, journals like Frontiers in Psychology, Gifted Child Quarterly, High Ability Studies, Psychological Bulletin, and PloS One serve as scholarly bridges for TI research across the most productive fields.Another important indicator of source relevance and influence is the pattern of co-citations across different journals. We produced the cluster and network represented in 3.4.Country-level scholarly production is largely influenced by a country’s scientific policy, resources, and access to research databases. As expected, out of 88 countries represented in the Scopus WOS data, the top ten countries were among the most industrialized economies and contributed 54.1% of the total publications in TI research. These countries include the United Kingdom (13%) and the United States (11.9%), as well as fast-growing economies like India (4.2%), South Africa (3.4%) and China (3.2%). By examining the volume of citations attained by country, the UK, the US, and Australia are the most influential countries with ~27% of the total citations in Scopus and WOS. Citation volume is a positive measure of a country’s influence on TI research. However, co-authorship analysis provides a stronger metric of a country’s influence. A closer look at cross-country dynamics reveals multiple collaborative clusters among countries . The UK 3.5.Transforming gifts into talents  forming the red cluster. This cluster was located at the intersection of the four quadrants indicating level of importance and development within the structure of knowledge in TI. Talent management keywords are related to the study of talent in the workplace. This cluster included words such as human capital retention, human resource management, leadership development, among others. The second most frequent word was “talent identification” forming the blue cluster (frequency: 277). This cluster was a motor theme indicating the increasing popularity of high level of development of TI in sports. This cluster included well-researched keywords such as anthropometry, football and soccer expertise, maturation and relative age, among others. The third most common word was “talent” forming the orange cluster in the basic quadrant (frequency: 257). Keywords like talent development performance training motivation indicate themes of high importance yet limited development in TI. The fourth cluster was formed by the word “somatotype” present in 16 studies studying the relationship of morphological profiles and performance. This theme had a relative low development and low importance which implies a declining tendency in TI research. Finally “talent search” by itself formed a small niched theme indicating high levels of development but limited in scope. Talent search in psychology and education is a specialized strategy for talent identification based on above-level testing in traditional academic contexts to provide sufficient headroom on the measurement tool to capture intellectual or academic performance at an early age . In otheThe first 50 years of TI research were characterized by few studies. Only 62 (2.4%) articles were published between 1943 and 2000 . During Between 2001 and 2010, researchers’ interest in TI peaked with the publication of 286 articles or 11.4% of all publications . DiversiThe period between 2011 and 2020 showed great productivity in TI research with 1,559 articles or 62.3% of all publications . The maiTI research continues its expansion and growth in the last 2 years. Current trends in TI research signal diversification of research topics in niche, motor, basic, and emerging areas . As of N4.This bibliometric analysis described trends across 80 years of research in TI represented by over 2,000 articles and more than 5,000 authors. This work contributes to the development of the body of TI research by (a) highlighting the role of TI in multiple disciplines, (b) determining the most impactful sources and authors in TI research, and (c) tracing the evolution of TI and hence identifying gaps and future opportunities in exploring and developing TI research.4.1.TI research and practice continue to play a paramount role for human progress. This fact is evidenced by the increasing adoption of the concept of talent, TI research and practices across the fields of education, psychology, STEM, management, sports, and multidisciplinary areas. A quest for discovering, acquiring, developing, and retaining talent is the cornerstone of the sports and workplace industries . The oft4.2.M = 26, SD = 21). The Journal of Sport Sciences, the International Journal of Human Resource Management, Frontiers in Psychology, and PloS One have taken the lead in scientific publications compared to traditional journals devoted to the study of giftedness and high ability like Gifted Child Quarterly, High Ability Studies, or Intelligence.Our performance analysis of the existing body of TI research, as found in Scopus and WOS, illustrates that although TI originated in psychology and education, it has rapidly permeated two major fields, namely sports science and management. Over 900 journals have included articles about TI, several with high citation indices. For example, the top 30 journals collectively have over 750 publications about TI  from the Virtual Center for Advanced Potential (VCAP) at Schmidt Futures The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The identification of interventions for rehabilitation and related evidence is a crucial step in the development of World Health Organization's (WHO) Package of Interventions for Rehabilitation (PIR). Interventions for rehabilitation may be particularly relevant in schizophrenia, as this condition is associated with a high risk of disability, poor functioning, and lack of autonomy. Aiming to collect evidence for the WHO PIR, we conducted a systematic review of Clinical Practice Guidelines (CPG) on interventions for rehabilitation of schizophrenia.Methods for the systematic identification and critical appraisal of CPG were developed by WHO Rehabilitation Programme and Cochrane Rehabilitation under the guidance of WHO's guideline review committee secretariat. The Appraisal of Guidelines for Research & Evaluation Instrument (AGREE II) was used to evaluate the methodological quality of identified CPG.n = 54) of the recommendations, and very low only in two cases (1.52%). N = 45 (34.62%) were based on experts' opinion.After full text screening, nine CPG were identified, for a total of 130 recommendations. Three were excluded because their total AGREE-II scores were below cut-off. Six CPG were approved by the Technical Working Group and included for data extraction. Only one CPG with specific focus on rehabilitation of schizophrenia was retrieved. Other CPG were general, including some recommendations on rehabilitation. Some CPG gave no indications on the assessment of rehabilitation needs. Discrepancies were detectable, with different CPG emphasizing different domains. Most recommendations addressed “symptoms of schizophrenia,” while “community and social life” was targeted by few recommendations. International CPG were often conceptualized for high-income countries, and CPG accounting for their implementation in lower income contexts were scarce. Quality of evidence was high/moderate for 41.54% (The concepts of recovery and rehabilitation in schizophrenia are relatively new in medical sciences and somewhat ill-defined. An unbalanced distribution in the domains addressed by available CPG is therefore understandable. However, the need for more focus in some areas of rehabilitation is obvious. More clarity is also required regarding which interventions should be prioritized and which are more feasible for global implementation in the rehabilitation of schizophrenia. The World Health Organization (WHO) has the strategic priority of achieving Universal Health Coverage (UHC), that means “all people receive quality health services that meet their needs without being exposed to financial hardship in paying for the services” . UHC incThe development of the PIR takes a stepwise approach composed of five consecutive steps: (a) selection of health conditions considering amenability to and the need for rehabilitation, (b) identification of evidence-based interventions for rehabilitation, (c) development of the package with agreement on interventions along with resource requirement descriptions, (d) external peer review, and (e) production of the alpha version of the PIR . This paSchizophrenia has been selected as one of the priority targets of the PIR. Although not as common as other disabling conditions possibly affecting humans, psychosis resembles the historical antonomasia of mental disability due to its profound long-term effects on individuals, families, and societies. One in 135 people (0.72% of the population), or over 56 million people worldwide, are affected by schizophrenia . ProportRehabilitation helps a child, adult or older person to be as independent as possible in everyday activities and enables participation in education, work, recreation and meaningful life roles such as taking care of family”  without targeting the cause of the health condition.” Regardless of the specific definition, health systems around the world are urged to put into place appropriate rehabilitation services for people with mental health conditions  which consistently provide evidence of the efficacy of interventions such as Cognitive Remediation, Family Psychoeducation, Social Skills Training, and Cognitive Therapy . FurtherThis systematic review of CPG has been developed in full compliance with the methodology presented in the introductory WHO PIR protocol of research . These s*) AND (schizophrenia OR Psychosis) AND .” A filter to include only publications in English language was applied. First search was performed in April 2020, and then it was re-run in March 2021. Only publications from 2010 were considered, aiming to include up-to-date recommendations only.Systematic literature search: CPG have been searched in the following databases: Guidelines International Network (GIN), Scotland's Guidelines International Network (G-I-N), United Kingdom's National Institute for Health and Care Excellence (NICE), Australia's National Health and Medical Research Council (NHMRC), Scottish Intercollegiate Guidelines Network (SIGN), Canadian Medical Association Infobase of Clinical Practice Guidelines (CPG Infobase), New Zealand Guidelines Group (NZGG), United States' National Guideline Clearinghouse (NGC), United Kingdom's eGuidelines, Psychinfo, Pubmed, Google scholar (first 250 results only). The search string used was: “ tool by two authors (RS and YE) : a speciCPG fitting AGREE II criteria were given a final consensus for inclusion according to the using the WHO prioritization criteria  .Data extraction was independently performed by two authors using a standardized form which includes information on the type of recommendation, dosage, target group, strength of recommendation and quality of the background evidence in support to the recommendation.Topics/areas considered by the selected CPG into each main type of recommendation (assessment and intervention) have been extracted. Recommendations regarding the management of the acute phase of illness, recommendations on medications and side-effects, as well as service recommendations were excluded, therefore leading to a selection of non-drug-related recommendations on the long-term course of the treatment. The topics (functioning domains) from different CPG have been compared independently by two authors and integrated. If needed, agreement by discussion was reached involving a third author. The process has been repeated for all the CPG until final agreement on the topics was reached.Results of the literature search are shown in German Association for Psychiatry, Psychotherapy and Psychosomatics Revised S3 guidelines on schizophrenia (DGPPN) (–  (DGPPN) .The American Psychiatric Association Practice Guideline for the Treatment of Patients with Schizophrenia (APA) (– ia (APA) .Scottish Intercollegiate Guidelines Network: management of schizophrenia (SIGN) (– a (SIGN) .National Institute for Health and Care Excellence Psychosis and schizophrenia in children and young people: recognition and management (NICE-1) (– (NICE-1) .National Institute for Health and Care Excellence Psychosis and schizophrenia in adults: prevention and management (NICE-2) (– (NICE-2) .National Institute for Health and Care Excellence Rehabilitation for adults with complex psychosis (NICE-3) (– (NICE-3) .In addition to the selected CPG, relevant WHO guidelines including mhGAP Evidence-based recommendations for management of psychosis and bipolar disorders in non-specialized health settings as well as management of physical health conditions in adults with severe mental disorders were included for the development of PIR. However, these resources have not been included in this review.The topics (functioning domains) extracted from included CPG are presented by type of recommendation (assessment/intervention) in For assessment recommendations, “Mental/Emotional functions” and “Education and Vocation” were the functioning domains with the highest number of recommendations. Assessment recommendations for “Interpersonal interactions and relations,” “Exercise and fitness,” and “Speech, language and communication” were provided in NICE-3, and “Activities of daily living” in NICE-1 and NICE-3. In terms of providing specific assessment recommendations, “self-management” or “community and social life” domains were not addressed in the CPG.Regarding intervention recommendations, all six CPG provided many recommendations addressing “symptoms of psychosis” which was the domain with the highest number of recommendations. A high number of interventions were also provided for “Education and Vocation” and “Self-management,” 12 and nine, respectively. All CPG, except for SIGN and NICE-1 respectively, addressed “Education and Vocation” as well as “Mental/cognitive functions” and “Interpersonal interactions and relations.” A total of six domains, out of 13 were targeted by low number of recommendations (4 or less) including “community and social life” (addressed by NICE-3), and “activities of daily living” (addressed by NICE-3 and DGPPN).n = 27) of the recommendations. The same number of recommendations had a moderate QoE  while n = 20 (15.38%) had low QoE. Only two recommendations (1.52%) had very low QoE, and nine (6.92%) were based on U.K. prevalence studies. A total n = 45 (34.62%) of the recommendations is based on experts' opinions. Experts' opinions are used for recommendations on generally good clinical practice . Within these strong recommendations, n = 25 is based on Experts' opinion. A minority of recommendations  is conditional, while the rest  indicates no strength of recommendation and is based on Experts' opinion.The QoE for given recommendations was high for 20.77% , which urges nations and professionals to work toward empowering people to regain independence and live a life in full autonomy through the implementation of recovery-oriented interventions, most of which may be categorized as rehabilitation interventions .Despite the scarcity of CPG on rehabilitation of schizophrenia, we identified general CPG that included several recommendations that are, either directly or indirectly, relevant to the assessment of rehabilitation needs and to the provision of rehabilitation interventions. To our knowledge, this is the first systematic overview of recommendations in this important field of intervention, which will be used to inform the WHO PIR and, hopefully, it may also be of interest to countries and professionals aiming to fully implement the concept of rehabilitation, in line with the WHO WMHR.strong. This is in line with current standards of CPG development, as in addition to the evidence base, other considerations, such as for example values, preferences, feasibility and equity considerations should also be considered in drafting recommendations and their strength. We note, therefore, that in the field of rehabilitation there is a discrepancy between the scarcity of data on one side, and the high value attributed to rehabilitation interventions by professionals and by a variety of different stakeholders, including people with living experience of mental health conditions, on the other side. Increasing research and knowledge about this complex subject could increase clarity on what the key elements of rehabilitation in schizophrenia are. Research in this field however is hard to conduct due to long follow-up times, heterogeneous settings, complex outcomes, and lack of resources.In terms of quality of available evidence, only a minority of target domains and recommendations are supported by high-quality evidence. Notably, expert opinions often supported recommendations on good clinical practice as well as on specific interventions, even in absence of a supporting background body of evidence. This applies, for example, to recommendations on physical activity, or those on the combination of individual and family interventions, or those in favor of supported employment. Despite this relatively low quality of background evidence, the strength of many of these recommendations was Looking at the total number of recommendations on specific topics (functioning domains, a deeply personal, unique process of changing one's attitudes, values, feelings, goals, skills, and/or roles. It is a way of living a satisfying, hopeful, and contributing life even with limitations caused by illness. Recovery involves the development of new meaning and purpose in one's life as one grows beyond the catastrophic effects of mental illness” (A whole system approach to recovery from mental ill health which maximizes an individual's quality of life and social inclusion by encouraging their skills, promoting independence and autonomy in order to give them hope for the future and which leads to successful community living through appropriate support” (The concept of rehabilitation is tightly related to the concept of recovery which, in the field of mental health, gained prominence after the implementation of deinstitutionalization with ever greater relevance of community services and interventions to help people achieve recovery. Recovery from a mental illness has been described as “illness” . A more support” . Ultimatsupport” . Furthersupport” . Still, support” , 38, witsupport” , 40. TheThis review needs to be interpreted in the light of some limitations. First, CPG should be considered with a recognition of their inherent limitations. These recommendations are formulated based on the currently available evidence and do not encompass all potential actions required to mobilize community resources and opportunities, strengthen social cohesion and social capital, and overall integrate formal and informal care services while considering the local context. Nonetheless, the absence of these considerations does not imply that such actions should be excluded from intervention programs. All parties involved should acknowledge the importance of tailoring rehabilitation projects to accommodate individual, familial, and cultural contexts, as well as the location of service delivery, in order to ensure effective implementation. Clinicians are therefore urged to make a concerted effort to integrate evidence-based CPG with the specific needs of individuals who have experienced mental disorders. By doing so, they can provide guidance that empowers individuals to utilize resources, tools, and opportunities that align with their personal aspirations, as well as their social and clinical circumstances. A second limitation is inherent to the systematic review methodology itself, due to the potential exclusion of titles, and therefore potentially relevant information, not emerging from the literature search. In this regard, the strings used for this research were developed on the basis of the WHO indication on the systematic search of literature for the development of the PIR for all conditions. Another limitation arises from the sole inclusion of English language CPG, which was driven by feasibility considerations. We recognize that the omission of CPG in other languages could pose a significant constraint, as the outcome of the current review may predominantly reflect Western practices. Consequently, contexts in which alternative approaches, involving for example non-specialist community workers, volunteers, activists, and peers, play pivotal roles may not have received sufficient visibility.In conclusion, six CPG based on available evidence, relevant WHO guidelines and expert opinion will inform the development of the WHO PIR for schizophrenia and related psychosis. This review revealed an imbalance in the domains addressed and a lack of indications in poor-resource settings. Priority targets and interventions in the rehabilitation in schizophrenia are still unclear in terms of significance and feasibility.The scientific community is called to embrace the challenge posed by the WHO WMHR 2022 . To promConceptualization: RS, YE, CB, and LT. Methodology: YE, MR, CB, and LT. Software: RS and YE. Formal analysis: RS. Investigation: RS, YE, and MR. Resources: CB and LT. Data curation: RS, YE, MR, and LT. Writing—original draft preparation: RS and LT. Writing—review and editing: CB, YE, and MR. Project administration: YE, CB, and LT. All authors have read and agreed to the published version of the manuscript.