Globally, childhood obesity is on the rise and the effect of objectively measured movement behaviour on body composition remains unclear. Longitudinal and causal mediation relationships of accelerometer-based sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) with dual-energy X-ray absorptiometry-measured fat mass were examined in 6059 children aged 11 years followed-up until age 24 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort. Over 13-year follow-up, each minute/day of ST was associated with 1.3 g increase in fat mass. However, each minute/day of LPA was associated with 3.6 g decrease in fat mass and each minute/day of MVPA was associated with 1.3 g decrease in fat mass. Persistently accruing ≥60 min/day of MVPA was associated with 2.8 g decrease in fat mass per each minute/day of MVPA, partly mediated by decrease insulin and low-density lipoprotein cholesterol. LPA elicited similar and potentially stronger fat mass-lowering effect than MVPA and thus may be targeted in obesity and ST prevention in children and adolescents, who are unable or unwilling to exercise. Childhood obesity remains a global epidemic. Here, using objective measurements, the authors show that sedentary time increased from 6 h/day in childhood to 9 h/day in young adulthood, and was cumulatively associated with increased total and trunk fat mass. Both light or moderate-to-vigorous physical activity similarly partly reversed risk. Most of the objectively measured movement behaviour studies in paediatric populations on which the PA guidelines are based are cross-sectional or short-term longitudinal reports, and the rest are questionnaire-based evidence5. More than 140 randomized controlled trials have reported little or no effect of school-based PA interventions on children and adolescent’s body mass index (BMI)7. Identified knowledge gaps in the paediatric population include the lack of long-term longitudinal evidence on the relationships of objectively measured sedentary time (ST), light PA (LPA), and MVPA on progressive changes in objectively measured body composition8.Childhood obesity remains a global epidemic and the latest World Health Organization (WHO) physical activity (PA) guideline recommended at least 60 min/day of moderate-to-vigorous PA (MVPA) on average in children and adolescents less than 18 years as a way to maintain a healthy weight12. A few biological pathways on the associations between ST and adiposity identified in an experimental animal model and small sample-sized human studies include elevated inflammation, altered lipid and glucose metabolism, and muscular atrophy12. It remains unclear whether movement behaviours may causally influence body composition during growth and development or whether the association is due to other health determinants or reverse causation bias5. Clarifying potential causal temporal associations among movement behaviours and body composition is an important enquiry that has implications for mounting effective childhood obesity prevention programs4. Longitudinal evidence on the importance of timing for PA intervention effect in the growing paediatric population is limited5. It is known that males generally engage in PA more than females, potentially yielding better health among males5. However, it is important to clarify whether exposure to the amount of ST or PA typical of a particular sex, significantly influences body composition during growth from childhood through young adulthood.Moreover, whether movement behaviours exert their effect on body composition directly or via metabolic pathways is not fully knownIn this work, we examine the longitudinal associations of cumulative accelerometer-measured ST, LPA, and MVPA, with repeated measures of BMI, waist circumference, total fat mass, trunk fat mass, and lean mass at ages 11, 15, and 24 years in the total cohort of 6059 children and according to sex. Next, we assess the extent to which the associations of movement behaviours with body composition are mediated by glucose, insulin, lipid indices, and inflammation. Furthermore, we examine potential causal and temporal interrelations  among activity levels and body composition across the follow-up using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK. We identify that during growth from childhood to young adulthood, ST increased from 6 to 9 h/day, LPA decreased from 6 to 3 h per day, and MVPA had a U-shaped increase, averaging ~50 min/day. Over the 13-year follow-up, each minute/day of ST was associated with 1.3 g increase in fat mass. However, each minute/day of LPA was associated with 3.6 g decrease in fat mass and each minute/day of MVPA was associated with 1.3 g decrease in fat mass. Persistently accruing ≥60 min/day of MVPA was associated with 2.8 g decrease in fat mass per each minute/day of MVPA when compared with children who persistently had MVPA < 40 min/day. Higher fat mass at age 11 years may potentially lead to lower MVPA by mid-adolescence, whereas higher MVPA in mid-adolescence may lead to lower fat mass in young adulthood, thus ≥60 min/day of MVPA should be prioritized in early childhood. MVPA may potentially lower fat mass via a decrease in insulin and low-density lipoprotein cholesterol. These findings present promising evidence for updating future health guidelines. Decreasing ST by at least 3 h/day and increasing LPA by the same amount during growth from childhood through young adulthood should be strongly recommended with specific emphasis on mid-adolescence timing. LPA elicited a similar effect as MVPA and thus may be targeted in obesity prevention in children and adolescents, who are unable or unwilling to exercise.Of 14,901 children who were alive at 1 year of age, 7159 children participated in the age 11-year clinic visit, 5509 adolescents participated in the age 15-year clinic visit and 4026 young adults participated in the age 24-year clinic visits  the positive associations of ST with total fat mass  of the total fat mass gained during growth from childhood until young adulthood. Among adults, >10 h/day of ST has been associated with an increased risk of incident cardiovascular events19. These findings provide answers to the American Academy of Pediatrics, the European Childhood Obesity Group’s and systematic reviews and meta-analysis identified gaps in knowledge on the independent impact of ST on adiposity from childhood through young adulthood7. Of note, cumulative ST was associated with increased total and trunk fat mass in females but not in males. This might be related to males accumulating fewer minutes in ST and physiologically had lesser fat mass.We observed that increased ST was associated with increased fat mass via an increase in muscle mass. While the pathophysiological mechanism may not be fully understood, it is known that skeletal muscle mass regulation of lipoprotein lipase activity is impaired during physical inactivity20. A meta-analysis of cross-sectional studies concluded that reallocating ST with LPA was not significantly associated with any adiposity outcomes20. In the present longitudinal study, cumulative LPA was associated with decreased total fat mass and trunk fat mass from childhood through young adulthood. Although this association may be partially suppressed by increased insulin levels, the paediatric population especially those with chronic diseases or mobility challenges could benefit from LPA. Obesity has been strongly associated with metabolic syndrome and our finding may suggest that an LPA-induced decrease in total and truncal adiposity may lower the risk of metabolic syndrome in the paediatric population21. The mediation analyses revealed that LPA may not lower fat mass via glucose or lipid pathway but partly by decreasing low-grade inflammation22 but further experimental and mechanistic studies are warranted. Among adults, LPA has been associated with a reduced risk of all-cause mortality24. In our cohort we observed that each 1 min/day spent in LPA was associated with a 3.6 gram reduction in total fat mass which may be clinically significant3. This implies that cumulative LPA decreased total body fat mass by 950 g to 1.5 kg during growth from childhood to young adulthood, approximately 9.5–15% decrease in overall 10 kg gain in fat mass during the 13-year observation period. Exposure to LPA appears to have a higher fat mass-lowering effect than MVPA in consonance with a previous report on the longitudinal relationships between movement behaviour and inflammation but more studies across different ethnic and racial groups are needed22. We observed that while LPA decreased from 6 h/day in childhood to 3 h/day in young adulthood, ST increased from 6 h/day in childhood to 9 h/day in young adulthood. The significant loss in time spent in LPA was gained by ST, thus, these findings could contribute to updating future PA guidelines which currently largely focus on an average of 60 min/day of MVPA which 80% of adolescents do not meet25. A paradigm shift towards increasing and sustaining LPA of at least 3 h/day may yield several health benefits but more longitudinal evidence is warranted22.There is a substantial lack of longitudinal evidence on the intensity of accelerometer-measured PA in relation to body composition outcomes in the paediatric population, especially, for those who lack motivation or are unable to achieve the recommended guideline of at least 60 min/day of MVPA5. Persistently accruing ≥60 min/day of MVPA throughout the 13-year follow-up period was associated with decreasing waist circumference, total fat mass, and trunk fat mass from childhood through young adulthood. We observed that each 1 min/day spent in MVPA was associated with a 1.3 gram reduction in total fat mass. When compared to children who persistently spent <40 min/day in MVPA, participants who persistently accumulated 40 to 59.9 min/day in MVPA had a 1.4 gram reduction in total fat mass per each minute/day of MVPA, but those who persistently spent ≥60 min/day of MVPA from childhood through young adulthood had a 2.8 gram reduction in total fat mass per each minute/day of MVPA. Time spent in MVPA including at least 60 min/day of MVPA during growth from childhood through young adulthood was associated with 70 to 170 g (approximately 0.7–1.7%) reduction in 10 kg gain in total body fat mass from childhood through young adulthood. Thus, MVPA intensity of ≥60 min/day may be necessary to significantly attenuate total and truncal adiposity in the long term. MVPA may lower fat mass via decreased low-density lipoprotein cholesterol and insulin pathways. Earlier, in the same cohort, a 2-year change in MVPA as a continuous variable measured between ages 11.8 and 13.9 years was significantly and inversely associated with a 2-year change in total fat mass, without accounting for changes in plasma lipid, glucose, insulin, and inflammation26.To accumulate at least 60 min/day of MVPA on average in children and adolescents has been recommended by the WHO, however, the guideline is largely based on iso-temporal accelerometer cross-sectional studies and a few short-term longitudinal studies13. Hence, at least 60 min of MVPA before age 11 years should be highly prioritized to prevent childhood obesity, since a higher BMI z-score in childhood has been associated with an increased risk of premature death by age 40 years27. Another explanation for the U or J-shaped curve may be due to different cutpoints used in adolescence (MVPA > 2296 counts per minute) and young adulthood (MVPA > 2020 counts per minute), since the average count per minute in the entire cohort steadily declined across the 13-year follow-up period30. While the results in 917 participants with at least two time-point valid accelerometer measures suggested that MVPA was associated with lower total fat mass in females but not in males, the analyses using a larger sample size of both 2457 and 6059 participants with less strict inclusion criteria of at least one time-point accelerometer measure indicates that increased MVPA was associated with lower total fat mass in both males and females. This disparity in findings is likely due to a lower sample size, i.e 334 males of 917 participants in comparison with 964 males of 2457 participants or 2881 males of 6059 participants. These consistent sex-specific findings suggest that PA is beneficial to both males and females irrespective of the exposure time to PA which might depend on inherent biological characteristics.Importantly, MVPA in mid-adolescence may potentially lower total fat mass in young adulthood but increase lean mass via an increased glucose pathway. There was a significant drop in MVPA in mid-adolescence compared to childhood and young adulthood resulting in a U or J-shaped curve. This drop in MVPA in mid-adolescence may be related to a high total fat mass in childhood which was associated with reduced MVPA by mid-adolescence in the temporal causal path, suggesting that obesity may decrease a child’s interest in participating in MVPA7. On the other hand, our study has some limitations. Our participants were mostly White; therefore, we are unable to generalize our findings to other racial and ethnic groups. Moreover, as with all observational studies, residual biases due to unmeasured confounders may distort observed associations such as the unavailability of quantitative sleep variables. Also, cohort attrition could lead to bias, however, participants who lacked certain movement behaviour and body composition variables had similar characteristics to those included in the analyses. The non-availability of fasting blood samples at baseline measures of ST, PA, and fat mass at age 11 years may limit the mediation analyses. Moreover, the misalignment between data collection of blood samples at the 17-year clinic visit with accelerometer and adiposity data at either 15 or 24-year clinic visit may bias the mediation analysis results. However, we conducted additional mediating analyses only with accelerometer and adiposity data and blood samples using only 2-time point measures at ages 15 and 24 years for predictor, mediator, and outcomes, and the results were substantially similar to the original analysis involving accelerometer and adiposity data at 11, 15 and 24 years with blood samples at 15, 17 and 24 years. Furthermore, we repeated the mediation analyses in the cohort of 2457 participants who had at least one PA valid measure and the results were consistent. Also, we repeated the 15 and 24-year specific mediation analyses including only blood samples at 15 and 24 years with PA and fat mass at 15 and 24 years in the expanded cohort of 2457 participants and the results were similar to previous findings. These consistencies in findings support the validity of the mediation analyses.The ALSPAC dataset provides an extensive array of gold-standard and repeated measures of movement behaviours, body composition, and covariates throughout the follow-up period in a large paediatric population. Using advanced statistical models, we tested the likelihood of reverse causality, temporality, potential causal explanatory pathway, and consistency of the findings for the first time in a paediatric population. Our findings aptly fill several knowledge gaps recently identified in movement behaviour research and would be useful in updating future PA guidelinesIn conclusion, ST increased from 6 to 9 h/day, LPA decreased from 6 to 3 h/day, and MVPA had a U-shaped increase from childhood through young adulthood. ST increase was associated with increased total fat mass and truncal fat mass while cumulative LPA and MVPA were associated with lower total fat mass and truncal fat mass. Over a 13-year follow-up period, persistent exposure to ≥60 min/day of MVPA was associated with decreased total fat mass and truncal fat mass and MVPA may potentially lower total fat mass via a decrease in insulin and low-density lipoprotein cholesterol. Each minute/day of ST was associated with 1.3 g increase in total fat mass. However, each minute/day of LPA was associated with 3.6 g decrease in total fat mass and each minute/day of MVPA was associated with 1.3 g decrease in total fat mass. LPA elicited a similar effect as MVPA and thus may be targeted in obesity prevention in children and adolescents, who are unable or unwilling to exercise. Accumulating 3-4 h/day of LPA may lower total fat mass ten times more than accumulating 60 min/day of MVPA. Higher total fat mass at age 11 years may potentially lead to lower MVPA by mid-adolescence, thus ≥60 min/day of MVPA should be prioritized in early childhood. Further experimental and intervention studies are needed to clarify the mechanisms through which movement behaviours alter body composition in a growing asymptomatic paediatric population. Future guidelines could emphasize the importance of early LPA and MVPA intervention before mid-adolescence for optimal obesity prevention. Decreasing ST by at least 3 h/day and increasing LPA by the same amount during growth from childhood through young adulthood should be strongly recommended with specific emphasis on mid-adolescence timing.31. In this study, 6059 participants who had at least one time-point valid measure of ST and PA and one time-point DEXA body composition measure were included in the analyses. Moreover, 2457 participants had at least one time-point valid measure of ST and PA with complete DEXA measures at three time-points during the 13-year follow-up . All participants were asked to complete one clinic visit that lasted about 2–3 h. As compensation for participating in the study, participants received a £40 e-voucher valid at most online retailers or high street stores in the UK. Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool .Data were from the ALSPAC birth cohort, which investigates factors that influence childhood development and growth. Pregnant women resident in Avon, UK with expected dates of delivery between 1st April 1991 and 31st December 1992 were invited to take part in the study. Altogether 20,248 pregnancies were eligible, and 14,541 pregnancies were initially enroled. Of the initial pregnancies, there were 14,676 foetuses, 14,062 live births and 13,988 children who were alive at 1 year of age. An attempt was made to bolster the initial sample with eligible cases who had failed to join the study originally when the oldest children were approximately 7 years of age. As a result, when considering variables collected from the age of seven onwards  there are data available for more than the 14,541 pregnancies mentioned above. By the age of 24-year clinic visits, 906 new pregnancies not in the initial sample (known as Phase I enrolment) have been added, resulting in an additional 913 children being enroled . Thus, the total sample size for analyses using any data collected after the age of seven is therefore 15,447 pregnancies, resulting in 15,658 foetuses and 14,901 children who were alive at age 1 year. At age 7 years, regular clinic visits of the children were commenced and are still ongoing into adulthood. Using the REDCap electronic data capture tools, study data at age 24 years clinic visit were collected and managedTM  accelerometer worn on the waist for 7 consecutive days, ST, LPA, and MVPA were assessed at 11- and 15-year clinic visits, whereas at 24 years movement behaviour was assessed using ActiGraph GT3X+ accelerometer device worn for four consecutive days35. Strong absolute agreement between the ActigraphTM models (intraclass correlation coefficient 0.99 (95% CI = 0.98–0.99) has been reported, thus it is acceptable to use different models within a study29. Providing data for at least 10 h per day (excluding sequences of 10 or more minutes with consecutive zero counts) was considered a valid day and children were only included in the analyses if they provided at least 3 valid days of recording. The devices capture movement in terms of acceleration as a combined function of frequency and intensity. Data are recorded as counts that result from summing postfiltered accelerometer values (raw data at 30 Hz) into 60-second epoch units. Data were processed using Kinesoft software, version 3.3.75 (Kinesoft), according to established protocol28. Activity counts per minute threshold validated in children and adolescents were used to calculate the amount of time spent; the Evenson cutpoint MVPA, >2296 counts per minute; for LPA, 100–2296 counts per minute; and for ST, 0 – <100 counts per minute was used at ages 11 and 15 years whereas, at the 24-year clinic assessment, the 2020 counts per minute Troiano cut point was used36. The Evenson cutpoint used in stratifying activity threshold has been suggested as the most appropriate cut point for youth having shown the best overall performance across all intensity levels36. Pearson bi-variate correlations (r2) between cumulative 11, 15, and 24 years ST and LPA are (−0.70), ST and MVPA (−0.33), LPA and MVPA (0.19), p-value < 0.001 for all. For each age clinic visit, at age 11 years, the correlations between ST and LPA are (−0.59), ST and MVPA (−0.27), LPA and MVPA (0.12), p-value < 0.001 for all. At age 15 years clinic visit, the correlations between ST and LPA are (−0.47), ST and MVPA (−0.35), LPA and MVPA (0.35), p-value < 0.001 for all. At age 24 years clinic visit, the correlations between ST and LPA are (−0.18), p = 0.009, ST and MVPA (−0.22), p = 0.002, LPA and MVPA (0.14), p = 0.043. These correlation matrices are similar to a meta-analysis of cross-sectional accelerometer report37. MVPA was classified as <40 min/day as low (reference), 40 – <60 min/day as moderate, and ≥60 min/day as high. The 40 – <60 min/day of MVPA was based on the lowest tertile cutpoint (39.95 min) for MVPA in the total population. The cut point between the middle and highest MVPA tertile was 59.8 min/day in line with the current PA guideline1.With an ActiGraph39. Body composition  was assessed using DEXA scanner  at 11, 15, and 24-year clinic visits41. Repeated DEXA measurements for 122 children were performed on the same day, and the repeatability coefficient (twice the standard deviation of the difference between measurement occasions) for body fat mass was 0.5 kg42. Lean mass-to-total fat mass ratio was computed at all three-time points.Height was measured to the nearest 0.1 cm with Harpenden wall-mounted stadiometer , weight to the nearest 0.1 kg was measured using , waist circumference to the nearest 1 mm at the midpoint between the lower ribs and the pelvic bone with a flexible tape was assessed, and BMI was computed as weight in kilograms per height in metres squared39. Fasting blood samples at ages 15, 17, and 24 years were collected, spun, and frozen at –80 °C, using standard protocols, and a detailed assessment of fasting glucose, insulin, high-sensitivity C-reactive protein, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides has been reported (coefficient of variation was <5%)40. Fasting insulin was measured using an ultrasensitive automated microparticle enzyme immunoassay (Mercodia), which does not cross-react with proinsulin and the sensitivity of the immunoassay was 0.07 mU/L43. Participants were briefly asked about their personal and family  medical history such as a history of hypertension, diabetes, high cholesterol, and vascular disease at the 17-year clinic visit. Biological sex variable was collected by ALSPAC staff at delivery, from medical records, or birth notifications. All participants had attained puberty at the 17-year clinic visit which was estimated from time in years to age at peak height velocity objective assessment derived from Superimposition by Translation And Rotation mixed-effects growth curve analysis44. The participant’s mother’s socioeconomic status was grouped according to the 1991 British Office of Population and Census Statistics classification45. Questionnaires to assess smoking behaviour were administered at the 13, 15, and 24-year clinic visits. A specific question regarding whether participants smoked in the last 30 days was used as an indicator of current smoking status.Heart rate and systolic and diastolic blood pressure were measured with Dinamap 9301 Vital Signs Monitor  at ages 11 and 15, and Omron M6 monitor at age 24 yearsN = 6059) and repeated the analyses among participants who met with more strict inclusion criteria. A Little’s missing completely at random (MCAR) test was conducted to ascertain data missingness46. With Little’s MCAR test: Chi-Square = 1159.60, degree of freedom = 260, p-value < 0.0001, we concluded that the variables were not missing completely at random. Regression-modelled multiple imputations were conducted using SPSS version 27 . 20 cycles of imputation with 10 iterations generated 20 imputed data sets and the specified constraints for the imputation process were the observed minimum and maximum values. In line with previous evidence38, the percentage of missing values would be sufficiently addressed with 20 imputations: the variable with the highest missing value  had an estimate that was 98% efficient after 20 imputations (computed using Rubin’s formula)46. The distributions of imputed variables were similar to the observed data when checked with histogram normality plot. Presenting pooled imputed results after conducting multiple imputations is preferred to presenting non-imputed results47.Eligible sample size varied by covariates and exclusions via listwise deletion of missing values ranging from 27.6% to 50.1% for covariates at either 11, 15, or 24-year clinic visits. The study participants were those who had at least one time-point measure at ages either 11, 15, or 24 years .The descriptive characteristics of the participants were summarized as frequencies and percentages, means and standard deviation, or medians and interquartile ranges. We explored sex differences using independent 48. The optimal model with the lowest Bayesian Information Criteria was one with sex as a main effect, a random intercept modelled for the participants and family cluster to account for within-individual correlations. Whilst the GLMM with a full information maximum likelihood is robust for handling missing at random predictor and covariate data, we elected to additionally conduct 20 cycles of multiple imputations to account for missing data. The GLMM accounted for baseline ST, LPA, MVPA predictors, body composition outcomes, and covariates and their repeated measures. Model 1 was unadjusted. Model 2 was adjusted for sex, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, and other time-varying covariates measured at three time-points such as age, low-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, high-density lipoprotein cholesterol, heart rate, systolic blood pressure, glucose, insulin, smoking status, and total fat mass or lean mass depending on the outcome. Model 3 was an additional adjustment for ST or LPA, depending on the predictor. Model 4 was an additional adjustment for LPA or MVPA, depending on the predictor to mutually adjust for activity levels. A different GLMM was conducted for each sex and sex-specific analyses were not adjusted for sex. BMI and lean mass-to-fat mass ratio outcomes were not adjusted for total fat mass and lean mass.We examined the separate longitudinal associations of each of the 13-year ST, LPA, and MVPA progression (11 through 24 years) with each of BMI, waist circumference, total fat mass, trunk fat mass, lean mass, and lean mass to fat mass ratio measured at ages 11, 15, and 24 years using generalized linear mixed-effect models (GLMM) with an identity link. The GLMM is robust for handling highly correlated variables such as ST and LPA49. The examined mediation mechanism between PA and body composition is partly based on previous studies in which higher PA was associated with a better metabolic profile with the latter, in turn, associated with a reduced risk of obesity50. The natural direct and indirect effects were estimated and presented52. Analyses were adjusted for age, sex, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, family history of hypertension and cardiovascular diseases, smoking status, heart rate, glucose, insulin, ST, LPA, MVPA, total fat mass, or lean mass depending on the mediator, predictor, or outcome. The relationships between exposures, outcomes, and confounders are portrayed in the directed acyclic graph in Supplementary Fig. 53. However, when the magnitude of the longitudinal association between the predictor and outcome is increased upon inclusion of a third variable, a suppression is confirmed53. This means that suppression occurs when the mediational path has an opposite effect, i.e. instead of a decrease in the point estimate of the direct effect between an exposure and an outcome in relation to the total effect, there is rather an increase in the direct effect above the total effect’s point estimate53. We additionally examined the mediating or suppressing role of lipids, an inflammatory marker, and either total fat mass or lean mass depending on the outcome variable on the longitudinal associations of cumulative ST, LPA, and MVPA with cumulative total fat mass and lean mass. We considered a statistically significant mediation or suppression of <1% as minimal, and ≥1% as partial. Path analyses were conducted with 1000 bootstrapped samples55.Mediating path analyses using structural equation models separately examined the mediating role of cumulative glucose and insulin on the longitudinal associations of cumulative ST, LPA, or MVPA with each of cumulative total fat mass, trunk fat mass, and lean mass. The mediation analysis was conducted in line with the Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies (AGReMA)p-value < 0.05), changes in the earlier variables are considered to temporally precede changes in the later, and vice versa. Likewise, if a path from ST, LPA, and MVPA at time t-2 (15 years) to each of total fat mass and lean mass at time t-3 (24 years) reach significant , changes in the earlier variables are considered to temporally precede changes in the later, and vice versa. A stronger predictive effect is determined by a larger standardized regression coefficient. Error terms were included in the cross-lagged model.Lastly, we used structural equation modelling with autoregressive cross-lagged design to examine the separate temporal associations of ST, LPA, and MVPA with each of total fat mass and lean mass. The cross-lagged models first tested the separate associations of ST, LPA, and MVPA at 11 years with each of total fat mass and lean mass at 15 years. Next, the separate associations of total fat mass and lean mass at 11 years with ST, LPA, and MVPA at 15 years were examined. Thereafter, we examined the separate associations of ST, LPA, and MVPA at 15 years with each of total fat mass and lean mass at 24 years. Lastly, the separate associations of total fat mass and lean mass at 15 years with ST, LPA, and MVPA at 24 years were examined. These models were adjusted for all the covariates measured at 11 and 15 years or 15 and 17 years for metabolic factors. In the cross-lagged design, the potential association could be; ST, LPA, and MVPA leading to obesity risks, obesity risks leading to ST, LPA, and MVPA, or bidirectional associations of ST, LPA, and MVPA with obesity risks. If a path from ST, LPA, and MVPA at time t-1 (11 years) to each of total fat mass and lean mass at time t-2 (15 years) reach significant . Covariates were identified based on previous studies and are portrayed in the directed acyclic graph , whilst mediation analyses and auto-regressive cross-lagged temporal causal path structural equation modelling were conducted using AMOS version 27.0. Chicago: IBM SPSS.Collinearity diagnoses were performed and accepted results with a variance inflation factor <5, considered differences and associations with a 2-sided Further information on research design is available in the Supplementary InformationPeer Review FileReporting SummarySource Data


Phenotypic age acceleration, which reflects the difference between phenotypic age and chronological age, is an assessment to measure accelerated aging. Klotho is a protein related to slower aging, but its association with accelerated aging remains unclear.Based on data from the 2007–2010 National Health and Nutrition Examination Survey, phenotypic age was calculated using chronological age and 9 aging-related biomarkers. A total of 4388 participants aged 40 to 79 years with measured serum Klotho and calculated phenotypic age were enrolled. The association between serum Klotho and phenotypic age acceleration was estimated using multivariable linear regression models. The possible nonlinear relationship was examined with smooth curve fitting. We also conducted a segmented regression model to examine the threshold effect.p for nonlinearity < 0.001), with the inflection point at 870.7 pg/ml. The phenotypic age acceleration significantly decreased with the increment of serum Klotho  in participants with serum Klotho < 870.7 pg/ml, and increased with the increment of serum Klotho  in participants with serum Klotho ≥ 870.7 pg/ml.The association between serum Klotho and phenotypic age acceleration followed a U-shaped curve (There was a U-shaped association between serum Klotho and accelerated aging among the middle-aged and elderly US population. Populations around the world are aging at an unprecedented rate than those in the past. An extension of life is usually fraught with chronic disease and fragility, representing a challenge to health care systems . HoweverKlotho was originally proposed to have anti-aging properties in 1997, when Kuro-o et al. reported that Klotho-deficient mice exhibit a short lifespan and multiple aging-related phenotypes, such as arteriosclerosis, hypoglycemia, osteoporosis, emphysema, skin atrophy and gonadal dysplasia . Klotho National Health and Nutrition Examination Survey (NHANES) is a cross-sectional and nationally representative survey that collects a representative sample of around 5,000 people per year, aiming at estimating the health and nutritional status in the United States. The survey has been approved by the National Center for Health Statistics of the Centers for Disease Control and Prevention and all participants provided written informed consent for the study.Considering the availability of both Klotho and C-reactive protein (CRP) in serum, data were collected from NHANES 2007–2010, while serum CRP is an important biomarker to evaluate phenotypic age acceleration. There were 7296 participants aged 40 to 79 years between 2007 and 2010, and we initially excluded those who were pregnant or with missing data on serum Klotho or with incomplete data to calculate phenotypic age acceleration. Subsequently, we excluded those with missing data on important covariates, including smoking, sleep, hypertension, drinking, body mass index (BMI), education, marriage, and energy intake, leaving 4388 subjects eligible for further analyses  according to the manufacturer’s instructions. Duplicate samples were detected and the average was calculated as the final result.Phenotypic age was calculated by using chronological age and 9 aging-related biomarkers, including albumin, creatinine, glucose, CRP, lymphocyte percent, mean cell volume, red blood cell distribution width, alkaline phosphatase, and white blood cell count . Phenoty2) and categorized by 25 and 30 kg/m2.Sociodemographic characteristics , health condition (diabetes and hypertension) and information of other health behaviors , were obtained from self-reported questionnaires. Race was categorized into Mexican Americans, other Hispanic, non-Hispanic white, non-Hispanic black and other races. Based on the educational level, participants were categorized into three groups, including not graduate from high school, high school graduation, and college education or above. Marriage status was categorized as married/living with partner, widowed/divorced/separated and never married. We used the poverty income ratio (PIR), calculated by the family size-specific threshold, to define family income . The health condition data were composed of hypertension and diabetes history. Participants who met one of the following conditions were considered to have diabetes: (1) people who had been informed of diabetes by doctors or other health professionals; (2) people who were taking insulin; (3) people who were taking diabetic pills. Participants were considered to have hypertension if they met one of the followings: (1) they had been informed of hypertension by doctors or other health professionals; (2) they were taking a prescription for hypertension. Smoking status was classified as never (those who reported smoking fewer than 100 cigarettes in their lifetime), former (reported ever smoking at least 100 cigarettes in their lifetime but do not currently smoke), or current (smoked at least 100 cigarettes and currently smoke some days or every day). Drinking status was defined as yes if the participants had at least 12 alcohol drinks 1 year. Physical activity was calculated according to the metabolic equivalent (MET). A MET value for each activity was assigned according to the suggested MET scores by NHANES. A total activity score was calculated by summing the MET-hours of each activity in a week. Dietary intake was estimated by two 24-h dietary recall interviews. The first recall interview was collected in an NHANES Mobile Examination Center, and the second dietary recall interview was conducted by telephone after 3–10 days. The average energy intake of the two 24-h recalls was used for analysis. BMI was calculated using the participant’s weight in kilograms divided by height in meters squared  or median with interquartile range (IQR) for continuous variables and numbers (n) with percentages (%) for categorical variables. Tests of differences in characteristics across Klotho categories were performed using one-way ANOVA or the Kruskal–Wallis test for continuous variables and χA multiple linear regression model was applied to evaluate the association between serum Klotho levels and phenotypic age acceleration. Serum Klotho was entered as a categorical variable (quintiles) and as a continuous variable . Four models were constructed. In the crude model, no confounders have been adjusted; in model 1, we adjusted for covariables that change the effect value by at least 10%; in model 2, covariables were further chosen when in univariable analysis, the P value was less than 0.1; and the covariables related to phenotypic age acceleration reported by previous research were further adjusted in model 3. We further applied a smoothing curve and a two-piecewise linear regression model to examine the possible nonlinear association between serum Klotho and phenotypic age acceleration. A likelihood ratio test was conducted to compare the one-line linear regression model with the two-piecewise linear model.To assess possible effect modification, stratified analyses were performed according to age, sex, smoking, drinking, hypertension and diabetes. Interaction across subgroups was tested using the likelihood ratio test.We also performed sensitivity analyses using multiple imputation, based on 5 replications and a chained equation approach method in the R package MICE.p < 0.05 was considered statistically significant.Overall, all statistical analyses were performed using R (ver 4.2.1), SPSS (ver 26) and Free Statistics (ver 1.5). Sample weights were not adjusted in the present study. A two-sided value of Table In the multivariable linear regression analysis, the phenotypic age acceleration decreased as serum Klotho increased . A non-linear relationship was found between Klotho and phenotypic age acceleration when classifying Klotho into quintiles, with multivariate-adjusted β (95% CI) across the first to fifth quintiles of 2.35 (1.57 ~ 3.13), 1.17 (0.39 ~ 1.95), 0.63 (-0.15 ~ 1.41), 0, and 0.83 (0.04 ~ 1.61) (Table p for nonlinearity < 0.001)   Fig. A. The U-01) Fig. B.Fig. 2DAccordingly, in the threshold effect analysis, the concentration of serum Klotho associated with the lowest phenotypic age acceleration was 870.7 pg/ml after full adjustment Table . PhenotyWe further performed exploratory subgroup analyses to assess the association between serum Klotho and phenotypic age acceleration in two groups of participants separated by the inflection point of serum Klotho (870.7 pg/ml).p for interaction > 0.05)  Fig. . P valueWe further performed a series of sensitivity analyses to test the robustness of the association. First, multiple imputation of missing data did not substantially change the associations Table . Second,In this cross-sectional study, we demonstrated a U-shaped association between serum Klotho and accelerated aging in the middle-aged and elderly US population. Serum Klotho was negatively associated with phenotypic age acceleration below the inflection point, and it was positively associated above the inflection point. Our study indicated that an optimal range for serum Klotho might exist to identify healthy aging.The Klotho gene was identified by Kuro-O et al. in 1997 as a gene closely related to aging. Mice with a defect in the Klotho gene have a short life span and degeneration of multiple age-sensitive traits . The KloIn recent years, Klotho has emerged as a powerful regulator of the aging process by regulating many pathways , 16, 17.−/− mice show a high vitamin D activity and exhibit features of premature aging, which can be reversed by normalizing vitamin D [The mechanism underlying the U-shaped association between serum Klotho levels and accelerated aging remains unknown. Klotho plays the anti-aging role by regulating many pathways that contribute to aging, such as phosphate homeostasis, oxidative stress, insulin/insulin-like growth factor 1 signaling, and Wnt signaling . Moreoveitamin D , implyinitamin D , which hitamin D –28. The itamin D .Although interaction between diabetes and Klotho (≥ 870.7 pg/ml), sex and Klotho (≥ 870.7 pg/ml), as well as diabetes and Klotho (< 870.7 pg/ml) on accelerated aging was observed in the present study, due to chance given multiple testing and similar directionality of most of the associations, these results may not have significant clinical implications. Moreover, the different outcomes in diabetes and non-diabetes groups might be partially due to the skewed sample size. Future studies of a larger sample size are needed to replicate these observed interactions.This is the first to evaluate the dose–response relationship between serum Klotho and accelerated aging. However, there are also some limitations. First, considering the cross-sectional nature of the NHANES data, the establishment of causality was precluded. Second, serum Klotho in the NHANES database was only tested in participants aged 40–79 years old and the role of serum Klotho in youngers was inconclusive. Third, although we adjusted for as many confounders as possible, the possibility of unmeasured confounders cannot be ruled out. Finally, phenotypic age calculated by using chronological age and 9 aging-related biomarkers was employed to assess aging in the present study, considering data availability in NHANES database. A number of aging measures have been proposed in previous studies, the most prominent being epigenetic clocks based on measures of DNA methylation . Given tWe found a U-shaped association of serum Klotho with accelerated aging in the middle-aged and elderly US population. Further studies should be performed to confirm these findings and explore the underlying mechanisms.


Postoperative bronchus stump insufficiency  and American Society of Anesthesiologists (ASA) score 4  were independent factors for early mortality. Conclusion: Pneumonectomy for thoracic malignancies remains a high-risk major lung resection with significant postoperative morbidity and mortality. Attention should be paid to the preoperative selection of patients.Background: Pneumonectomy is a major surgical resection that still remains a high-risk operation. The current study aims to investigate perioperative risk factors for postoperative morbidity and early mortality after pneumonectomy for thoracic malignancies. Methods: We retrospectively analyzed all patients who underwent pneumonectomy for thoracic malignancies at our institution between 2014 and 2022. Complications were assessed up to 30 days after the operation. Mortality for any reason was recorded after 30 days and 90 days. Results: A total of 145 out of 169 patients undergoing pneumonectomy were included in this study. The postoperative 30-day complication rate was 41.4%. The 30-day-mortality was 8.3%, and 90-day-mortality 17.2%. The presence of cardiovascular comorbidities was a risk factor for major cardiopulmonary complications (54.2% vs. 13.2%,  Surgery has a major place in the treatment of thoracic malignancies. With the evolution of surgical techniques and the performance of sleeve resections, the need to perform a pneumonectomy has been reduced. However, in some cases, pneumonectomy remains the only surgical way to treat thoracic malignancies . NonetheThe current study aims to investigate perioperative risk factors for postoperative morbidity and early mortality for patients undergoing pneumonectomy, not only for NSCLC but also for other thoracic malignancies.In this retrospective single-center cohort study, we investigated patients undergoing pneumonectomy for thoracic malignancies. The current study’s data were gathered from a prospective database using a retrospective analysis. With the introduction of patient data into the database, patient data were anonymized so that the patients could not be recognized anymore. This study was conducted according to the revised Declaration of Helsinki. Before the beginning of this study, it was approved by the local university ethics committee . Due to the retrospective nature of the study and the anonymization of the patients’ data, an additional patient’s Informed Consent Statement was waived.The current study included all patients who underwent pneumonectomy for NSCLC, small-cell carcinoma (SCLC), pulmonary metastases, thymic tumors, and other thoracic malignancies.<18 years oldpatients undergoing a lung resection different than pneumonectomyundergoing pneumonectomy for benign or infectious disease without malignancyundergoing pneumonectomy because of a previous surgical complicationundergoing extrapleural pneumonectomy for pleural mesotheliomaundergoing pneumonectomy in the context of a lung transplant or organ retrieval for donationFrom the study, patients were excluded if they were:In the period from February 2014 to November 2022, we identified 169 patients who underwent pneumonectomy out of 2521 patients undergoing an anatomical lung resection.n = 7destroyed lung from pneumonia: n = 2pulmonary tuberculosis: n = 1post-stenotic pneumonia after sleeve resection: n = 1destroyed lung from aspergillosis: n = 1hemoptysis by aplasia of the pulmonary artery: n = 1anastomosis insufficiency after lung transplantation: n = 2anastomosis insufficiency after sleeve resection: n = 2pleural mesothelioma: n = 7other reasons: 145 patients were included in the study.24 patients with the following diseases were excluded from the study:Morbidity or complication was defined as the appearance of a new disease unexpectedly up to 30 days or during the same hospital stay after the operation. Complications were divided into minor and major complications according to the Clavien–Dindo classification system. Clavien–Dindo grade I–II complications were defined as minor complications and required only minor or pharmaceutical treatment. Clavien–Dindo grade III–IV complications were characterized as major complications. In addition, cardiopulmonary complications with grade ≥ III in the Clavien–Dindo classification system were defined as major . The death of any patient for any reason was characterized as mortality. Concerning mortality, patients were followed for up to 90 days after the operation. Mortality was divided into 30-day and 90-day mortality. In all patients, before performing the pneumonectomy, preoperative staging was performed with positron emission tomography–computed tomography (PET-CT). In cases of suspected or positive mediastinal lymph nodes in the PET-CT, an invasive staging with bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) followed.All patients were operated on under general anesthesia and with an open thoracotomy. In order to evaluate how surgical experience influenced the operation’s outcome, we divided the surgeon’s experience into ‘’senior consultant’’ and ‘’junior consultant/trainee’’ according to the surgeon’s previous surgical activity and the surgeon’s status in our department at the time of the operation.Neoadjuvant chemotherapy or radiotherapy was characterized as preoperative therapy.The following preoperative comorbidities were investigated: hypertension, obesity, cardiovascular comorbidity, chronic kidney disease, gastric ulcer, chronic obstructive pulmonary disease (COPD), insulin-dependent diabetes, liver disease, and myasthenia gravis.Body Mass Index (BMI) > 30 was defined as obesity. Patients with other comorbidities that required only regular medication were characterized as other comorbidities. Patients aged >70 years were defined as elderly. COPD was classified according to lung function . No patiPatients regarding their smoking status were divided as current smoker, never smoker, smoker 1 month before the operation, and unknown smoking status.p-value < 0.05 was considered statistically significant. A p-value between 0.05 and 0.07 was considered a trend. All analyses were performed using the SPSS 22.0 software .To evaluate connections between different parameters, Fischer’s exact test and the Mann–Whitney U test were used when appropriate. Univariate and multivariate logistic regression models were used to select independent predictors for morbidity and mortality. A n = 92, 63.4%) with a mean age of 60.6 years (range: 23–86 years). Elderly patients comprised 20% of the study population (n = 29). In 11.7% of the patients, a previous lung operation had been performed (n = 17). Most of the study population were male patients , IVA , and IVB , a pneumonectomy in palliative intention was performed. The most frequent histological type was squamous cell carcinoma (39.3%). In 1 case, a pneumonectomy was performed because of an NSCLC recurrence.A pneumonectomy was performed in most cases for NSCLC (84.1%). For Stages IIIA, an operation was performed for the clinical TNM-Stadium T1–2 N2, T3 N1, and T4 N0. For Stage IIIB, pneumonectomy was performed for T3 N2. For stages IIIC (n = 1), pneumonectomy was performed because of a lung abscess after neo-adjuvant therapy for NSCLC. In 2 patients (n = 2), despite neo-adjuvant chemotherapy, a pneumonectomy was needed.In 5 cases with NSCLC after the pneumonectomy, a postoperative stage IB was revealed. In 1 patient, the bronchus intermedius was infiltrated, and for the complete resection of the tumor, a pneumonectomy was needed. In 1 patient, an upper bilobectomy was planned for NSCLC; a pneumonectomy was performed because of an additional destroyed lower lobe from chronic pneumonia. In another patient (The next largest group was patients with lung metastases (8.3%). Here, the most frequent histological type were patients with metastases from sarcoma. n = 60 patients) of the study population, at least one complication per patient was diagnosed. In almost half of these patients, a major cardiopulmonary complication was diagnosed . Postoperative atrial arrhythmia was the most frequent complication. In 41.4% (n = 25). The status of 29 patients (20.0%) was unknown 90 days after the operation. Postoperative complications and mortality are described in The 30-day mortality was rated up to 8.3%, while the 90-day mortality was 17.2% (p = 0.035) and patients with cardiovascular comorbidities . In addition, preoperative cardiovascular comorbidities were a risk factor for postoperative major cardiopulmonary complications. A total of 54.2% (n = 13) of patients with cardiopulmonary comorbidities developed major cardiopulmonary complications postoperatively . Statistical significance was shown for elderly patients , smokers up to one month before the operation (p = 0.363), pneumonectomies in palliative intention, and extended pneumonectomy  and pneumonectomies performed from senior consultants showed increased postoperative morbidity. However, in these cases, no statistical significance was detected. Perioperative risk factors are summarized in Patients with ASA 4 (p: 0.07). The logistic regression analysis is demonstrated in In the logistic regression analysis, the existence of preoperative cardiovascular comorbidities showed a trend toward being an adverse independent factor for postoperative morbidity after pneumonectomy (p = 0.001), deep vein thrombosis (p = 0.001), patients with ASA score 4 (p = 0.008), and bronchus stump insufficiency (p < 0.001) showed a statistical significance for increased 30-day-mortality after pneumonectomy. In addition, right pneumonectomy (p = 0.07) showed a trend for increased mortality. Patients with COPD (p = 0.740), obesity (p = 0.649), insulin-dependent diabetes (p = 0.559), and re-operation for bleeding (p = 0.166) showed increased mortality rates. However, no statistical significance was shown. These risk factors are summarized in Myasthenia gravis (p = 0.044) and postoperative bronchus stump insufficiency (p = 0.029) were identified as adverse independent factors for mortality. The other two preoperative clinical factors, Myasthenia gravis, and deep vein thrombosis, were not identified as independent prognostic factors. The logistic regression analysis of risk factors for postoperative mortality after pneumonectomy for thoracic malignancies is demonstrated in Patients with ASA Score 4  showed a trend for bronchus stump insufficiency. Preoperative therapy showed an increased rate of bronchus stump insufficiency. Three patients with bronchus stump insufficiency received preoperative chemotherapy and radiation. However, no statistical significance was shown (p: 0.360). The risk factors for bronchus stump insufficiency are demonstrated in We further investigated risk factors for bronchus stump insufficiency in the study population. An extended pneumonectomy  are independent factors for early mortality. In addition, preoperative cardiovascular comorbidities were identified as a risk factor for major postoperative cardiopulmonary complications. Pneumonectomy is a major surgical procedure associated with a high risk of complications. Postoperative morbidity is reported between 10% and 45%, and mortality is 4–8% ,16,17,18In 8.3% of cases, a pneumonectomy was performed for the resection of pulmonary metastases. Pneumonectomy for the resection of lung metastases is a rare indication. The surgical strategy in treating lung metastases is based on lung-sparing wedge resections and segmentectomies . Hassan The appearance of a postoperative complication can be associated with preoperative comorbidities. The incidence of cardiovascular comorbidities in patients with thoracic malignancies increases with age ,7,8,9. TAs mentioned above, a patient’s preoperative general status and pre-existing comorbidities are crucial criteria in selecting patients for surgery. This selection is more important in our case if the complete resection of the lung is planned. Patients with preoperative clinical risk factors such as Myasthenia gravis and deep vein thrombosis, which as conditions display the suspicion of reduced general condition, should be carefully evaluated for surgery. Different scores evaluate the patient’s preoperative condition and some also the possibility of postoperative complications ,26,27. TPostoperative bronchus stump insufficiency was identified as an independent risk factor for mortality after pneumonectomy. The rates for bronchus stump insufficiency after pneumonectomy range from 0.5 to 4.4%. Increased rates for bronchus stump insufficiency are found after a right pneumonectomy and range from 9% to 14%. Mortality after bronchus stump insufficiency ranges between 25% and 71%. As preoperative risk factors for bronchus stump insufficiency have been identified, preoperative radiotherapy, diabetes, right pneumonectomy, postoperative mechanical ventilation, tumor residuals on the bronchus stump (R1/R2-resection), and radical lymphadenectomy ,17,18. IPreoperative (adjuvant) therapy can provide better overall survival and disease-free interval with a higher pathological complete response rate or major pathologic response by shrinking tumors . In thisThe current study is limited by its retrospective nature. Data in this study were retrospectively extracted from an anonymized institutional database. Missing information could theoretically influence the results of this study. In addition, a selection bias is possible. Possibly, patients with untreated preoperative comorbidities or elderly patients in reduced general condition were excluded from the pneumonectomy procedure. Furthermore, an additional limitation is the variety of thoracic primary tumors that were included. What is more, the limited number of patients in some patient groups could have influenced the statistical result. Moreover, the classification of COPD was made, taking into account only the lung function. Furthermore, because of the limited number of patients in the current study and in order to avoid repeating results, risk factors for mortality were calculated only for 30-day mortality and not also for 90-day mortality. However, our study contains real-life clinical data and depicts the everyday clinical praxis in a large Thoracic Surgery Department. For this reason, we believe that patients who need a major lung resection such as pneumonectomy should not be excluded from a potentially curative resection only because of their preoperative comorbidities, but they should be carefully evaluated.Pneumonectomy for thoracic malignancies is still a major surgery with increased postoperative morbidity and mortality. The patient’s condition before surgery is crucial for selecting patients for pneumonectomy. Preoperative clinical conditions such as cardiovascular disease, Myasthenia gravis, and deep vein thrombosis that influence the patient’s general status should be carefully evaluated in patients’ selection.


Attalea funifera seed oil with or without resveratrol entrapped in organogel nanoparticles in vitro against A375 human melanoma tumor cells. Organogel nanoparticles with seed oil (SON) or with resveratrol entrapped in the seed oil (RSON) formed functional organogel nanoparticles that showed a particle size <100 nm, polydispersity index <0.3, negative zeta potential, and maintenance of electrical conductivity. The resveratrol entrapment efficiency in RSON was 99 ± 1%. The seed oil and SON showed no cytotoxicity against human non-tumor cells or tumor cells. Resveratrol at 50 μg/mL was cytotoxic for non-tumor cells, and was cytotoxic for tumor cells at 25 μg/mL. Resveratrol entrapped in RSON showed a decrease in cytotoxicity against non-tumor cells and cytotoxic against tumor cells at 50 μg/mL. Thus, SON is a potential new platform for the delivery of resveratrol with selective cytotoxic activity in the treatment of melanoma.This study aimed to evaluate  Resveratrol is a polyphenol found in peanuts, red grape bark, and red wine, and is a promising multi-target anticancer agent with the potential of being used in various tumor chemoprevention and chemotherapies . ParticuNanoparticles have been used to increase drug ,9,10,11 Organogel nanoparticles have been used with 12-hydroxystearic acid (12-HSA) as the preferred gelling agent ,24 becauIn addition, medium-chain triglyceride oils are of interest for their incorporation into organogels as they confer high stability, skin permeation, and enhanced sensory characteristics compared to unsaturated fatty acid oils . FurtherAttalea funifera is a palm tree endemic to Brazil and is cultivated to provide a source of fiber to manufacture brooms and handicrafts  ; resveratrol ; alamarBlueTM, a cell viability reagent with resazurin ; trypan blue solution ; DMEM (Dulbecco’s modified Eagle’s medium/high modified) ; fetal bovine serum (GibcoTM); trypsin-EDTA (ethylenediaminetetraacetic acid) solution ; DMSO (dimethyl sulfoxide) ; methyl methanesulfonate .The chemicals used in the assay were as follows: TweenAttalea funifera Mart. (Arecaceae), endemic to the Atlantic rainforest, is commonly found in the northeast and southeast of Brazil, and is popularly known as piaçava in Brazil; it has synonyms such as Attalea acaulis Burret, Lithocarpos cocciformis O.Targ.Tozz. ex Steud. and Sarinia funifera (Mart.) O.F.Cook /IC50 [tumor cells]. IC50 is the half inhibitory concentration of a sample or drug.For the treatment, samples were dissolved in DMSO (5 mL/L) to obtain solutions from 6.25 to 500 µg/mL. The negative control (NC) consisted of cells that received the culture medium and DMSO (5 mL/L) and the positive control (PC) consisted of cells that received the culture medium and the cytotoxic agent methyl methanesulfonate . These were incubated in the same standard cell culture conditions for 24 h. Then, the culture medium was removed, and 50 µL of 0.01% resazurin hydrochloride  or Tukey’s multiple range test (p ≤ 0.05). The analyses were carried out with GraphPad® Prism 5 software .All assays were carried out in triplicate, and the results expressed as the arithmetic average ± standard deviation. Significant differences were assessed using the analysis of variance (ANOVA) and Student’s A. funifera seed oil were established as a successful new platform for resveratrol delivery with low aqueous solubility. SON and RSON formed functional organogel nanoparticles with melting temperatures above that of the human skin. In addition, high-efficiency resveratrol entrapment was observed in the organogel nanoparticles. These organogel nanoparticles (SON and RSON) showed stability in terms of the evaluated parameters  over 90 days. Resveratrol alone at 50 μg/mL was cytotoxic for non-tumor cells, and was cytotoxic for tumor cells at 25 μg/mL. In contrast, resveratrol entrapped in RSON had no cytotoxicity against non-tumor cells and it was cytotoxic against A375 cells at 50 μg/mL with a SI of 2.96. Finally, RSON showed selective cytotoxic activity with potential applications in melanoma treatment. However, further in vitro and in vivo studies are needed to elucidate the underlying molecular mechanisms.Organogel nanoparticles with


Measures used included the Revised Fibromyalgia Impact Questionnaire, Carver Brief COPE scale, Chronic Pain Acceptance Questionnaire Revised, Pain Catastrophizing Scale, Brief Illness Perceptions Questionnaire, Depression and Anxiety Stress Scales, and European Health Interview Survey Quality of Life 8-item Index. Using structural equation modelling, the final model indicated that fibromyalgia symptom severity had a significant direct influence on illness perceptions and psychological distress. In turn, illness perceptions had a significant direct influence on maladaptive coping, pain catastrophizing, pain acceptance, and QoL. Pain catastrophizing and maladaptive coping influenced psychological distress, and in turn distress impacted QoL. Acceptance of pain was found to be influenced by maladaptive coping and in turn acceptance of pain influenced QoL.This study aimed to examine the extent to which illness beliefs, coping styles, pain acceptance, pain catastrophizing, and psychological distress mediate the relationship between fibromyalgia symptoms and quality of life (QoL) in a female cohort diagnosed with Fibromyalgia ( Fibromyalgia (FM) is a painful medical condition associated with poor treatment outcomes and quality of life (QoL) , the aim of the study was to extend the CSM to explore the potential interrelationships between these variables in a FM cohort. It was hypothesized that consistent with the posits of the CSM that illness perceptions, pain acceptance, pain catastrophizing, and coping styles would mediate the relationship between FM symptoms and patient-reported outcomes .A total of 151 participants with a mean age of 45.98 years (SD = 10.57) completed a self-administered online questionnaire. Of the 151 participants, the majority of participants were married (39.07%) or single (23.18%), lived with a partner (60.26%) or alone (29.14%), lived in their own home (44.37%) or in private rental (38.41%), were on a pension (27.15%) or unemployed (37.75%).On average, participants had experienced symptoms of FM for 11.58 years (SD = 10.75), with 58.90% having experienced fibromyalgia symptoms for more than 5 years. Seventy-seven per cent of participants reported taking medication to help manage the fibromyalgia symptoms. Comorbidity in the participant cohort was also high with 83.44% reported being diagnosed with another physical health condition, with the most common being arthritis (26.49%) and chronic fatigue syndrome (8.61%).The Revised Fibromyalgia Impact Questionnaire (FIQ-R) . The FIQ-R is a 21-item scale (zero to ten response format) used to measure the functional impact, the overall impact of symptoms, and the intensity of symptoms. An overall score (0–100) was obtained by weighting the subscale scores and summing them together with higher scores indicating a greater perceived impact of fibromyalgia symptoms. An error was made when administering the questionnaire, as participants were asked to rate their symptom severity from none to a lot instead of the individualized answers to the questionnaire. Cronbach alpha analysis indicated that the modified scale had strong internal consistency (0.89).The Brief Illness Perception Questionnaire (BIPQ) . The BIPQ is an eight-item scale (zero to ten response format) used to measure cognitive and emotional representations of illness. Consistent with previous research to improve scale consistency Knowles et al. . The Brief COPE is a 28 item (zero to three response format) that assesses fourteen conceptually different coping response types. Consistent with recommendations by the scale author     used to measure stress, anxiety, and depression levels. An overall score is obtained by adding the items together and multiplying them by two. Total scores range from 0 to 126, with higher scores indicating greater psychological distress. Cronbach alpha analysis indicated that the modified scale had strong internal consistency (0.93).The European Health Interview Survey-Quality of Life 8-item Index (EUR0HIS-QoL 8-item index)  and were invited to complete a 20-min online survey. Inclusion criteria were being aged 18 years or older and having a diagnosis of Fibromyalgia. Research was approved by Swinburne University of Technology’s Human Research Ethics Committee (SUHREC). Informed consent was obtained from all research participants. Data were collected from 7 to 9 August 2018.p > 0.05. There were 26 cases with missing values of over 30%, and these were removed due to the large sample size, consistent with recommendations by Tabachnick and Fiddell  Version 25. Preliminary data screening was conducted to ensure suitability of the data for further analysis. Analysis of missing values revealed that data were missing completely at random, Little's MCAR test = 7516.83 (8199),  Fiddell , leaving Fiddell .χ2] p > 0.05; Normed Chi square [χ2/N] = 1–3, Tucker–Lewis index [TLI] > 0.95, Steiger-Lind Root-Mean-Square Error of Approximation [RMSEA] < 0.08, and Standardized Root–Mean-Squared Residual [SRMR] < 0.06).Exploratory analysis and visual inspection of the data indicated that all the study variables met the necessary assumptions for statistical analysis . Correlational analyses were undertaken to compare the relationship between the study variables. A SEM was specified using the AMOS (Version 27) by an iterative process of adding pathways and removing variables that did not add significantly to the model’s fit. As recommended by Hu and Bentler , pathwayAs shown in Table χ2 (9) = 15.57, p = 0.08, χ2/N = 1.73, CFI = 0.985, TLI = 0.965, RMSEA = 0.070, SRMR = 0.048). The total amount of variance accounted for in each of the variables was also good, 36% of illness perceptions, 14% of maladaptive coping, 15% of pain acceptance, 41% of pain catastrophizing, 64% of psychological distress, and 44% of QoL.To evaluate the hypothesis, a model of the study variables was conducted. Based on an iterative process guided by Hu and Bentler , adaptivβ = 0.60, p < 0.001) and psychological distress . Illness perceptions had a significant direct influence on maladaptive coping , pain catastrophizing , pain acceptance , and QoL . Pain catastrophizing and maladaptive coping influenced psychological distress , and in turn distress impacted QoL . Acceptance of pain was influenced by maladaptive coping  and in turn acceptance of pain influenced QoL   of their illness as a way of improving QoL. In addition to addressing comorbid psychological distress, improvement in QoL is likely to be enhanced through reducing pain catastrophizing and promoting strategies to increase pain acceptance. It is noted that while leading pain societies currently recommend the use of cognitive-behavioural therapy in their multicomponent treatment plan for FM (Thieme et al., Limitations of this study include self-reported FM diagnosis and severity, and potential for self-selection bias. As data were collected from a FM female-specific online group, results may not reflect the experience of people with more mild symptoms who do not utilize the group. Additionally, as fatigue and cognitive impairment are common components of FM (Arnold et al., In conclusion, this is the first study to validate the complete CSM in a female cohort with FM using SEM. The findings from this study provides evidence for the interactions between self-reported FM symptom severity, illness perceptions, maladaptive coping, pain acceptance, pain catastrophizing, psychological distress, and QoL. Consistent with the CSM, illness perceptions mediated the relationship between FM severity and QoL, and both pain acceptance and maladaptive coping mediated the relationship between illness perceptions and QoL, and maladaptive coping mediated the relationship between illness perceptions and psychological distress. The study findings suggest that future interventional studies aimed at enhancing QoL in FM cohorts should target psychological variables such as pain acceptance, pain catastrophizing, and maladaptive coping strategies, and illness perceptions.


Research examining the connections between individual adverse childhood experiences (ACEs) and how groupings of interrelated adversities are linked with subsequent health is scarce, limiting our understanding of risk during a period of rapid expansion of ACE screening in clinical practice. The study objective was to conduct a psychometric analysis to derive latent domains of ACEs and related life events and assess the association between each domain and health outcome.Participants (3 months-11 years) were recruited from the University of California San Francisco Benioff’s Children Hospital Oakland Primary Care Clinic. Children were screened with the Pediatric ACEs and Related Life Events Screener (PEARLS) (n = 340), which assessed 17 total ACEs and related life events, including forms of abuse, household challenges, and social risks. Domains were constructed using confirmatory factor analysis and associations between the three identified domains and 14 health outcomes were assessed using multivariable linear and logistic regression models.Maltreatment , Household Challenges , and Social Context . Measurement invariance was supported across both gender and screening format. All domains were associated with poorer general and behavioral health and stomachaches. Maltreatment and Social Context were additionally associated with eczema while only Social Context was associated with increased odds of reporting headaches and somatic symptoms.Three PEARLS domains were identified: Maltreatment, Household Challenges, and Social Context that all had an independent statistically significant association with poorer child health. The results provide a timely and more nuanced representation of risk that can inform clinical practice and policy using more targeted resources and interventions.In an underserved, urban west-coast pediatric population, the PEARLS found three adversity domains of The online version contains supplementary material available at 10.1186/s12887-023-04163-2. Studies have consistently shown that adverse childhood experiences (ACEs) are associated with chronic conditions and proximal poorer health outcomes in childhood/adolescence and later in adulthood –3. RaciaACE assessments and related stressful life events have been traditionally implemented and applied as either single adversities or as a cumulative ACE score , the latter of which is a powerful tool in assessing risk of toxic stress . HoweverThe Pediatric ACEs and Related Life Event Screener (PEARLS) was developed to measure both ACEs and related life events, including multiple social risk factors . Previou≥ 18 years, and not a sibling of an existing study participant. Participation in the larger parent study included four study visits for survey completion , biospecimen collection , and participation in a social or psychosocial intervention. Participants were compensated up to $300 for their time participating in the entire study (12 months). The 555 participants had a mean age of 5.9 years (standard deviation [SD] = 3.5) and were predominantly male (52.4%), non-Hispanic Black (56.0%), had caregivers with some college education (65.1%), and were low-income. Caregivers were asked about the child’s ACEs using the PEARLS. Responses were collected in item-level screening format (n = 185) , and aggregate-level screening format (n = 182) . Those screened for aggregate-level responses were later asked to provide item-level responses . We limited the present analysis to those with item-level responses, yielding a final sample of 340 children. Written informed consent and where appropriate, oral consent, was obtained. The study was approved by the university institutional review board.We used data from the Pediatric ACEs and Resiliency Study, a randomized control study designed to: (1) examine the relationship between ACEs and health outcomes in children and caregivers over time, (2) validate an ACEs screening in a pediatric health care setting, and (3) assess preventative interventions for children with or at risk for toxic stress. Primary results and details of the study design have been presented elsewhere , 22. BriACEs and related life events were measured using the PEARLS, a 17-item pediatric ACEs screen developed for use in clinical practice , 22. Thet-scores and norm-referenced, in which lower t-scores represent poorer general health (t-score range 14.7 to 66.1) [≥10 days [coded 1]) and electronic health record (EHR)-based measures for the 12 months preceding recruitment for emergency department (ED) visits and hospitalizations (any visit [coded 1] vs. none [coded 0]). We assessed child behavioral health as a dichotomous variable using the Behavior Rating Inventory of Executive Function (BRIEF 2/P versions administered to appropriate age group) tool, in which a Global Executive Composite scale t-score ≥ 65 was considered clinically significant for poor executive functioning (< 65 [coded 0] vs. ≥ 65 [coded 1]) [z-scores and percentiles were calculated using 2000 Centers for Disease Control and Prevention growth charts (≥ 95th percentile classified as obese [coded 1] vs. not obese [coded 0]). We used caregiver-reported data on presence of headaches/dizziness and stomachaches in the previous 12 months. EHR ICD-10 codes were retrieved to determine the presence of: (1) acute infections ; and (2) somatic symptoms  in the 12 months prior to recruitment (presence of conditions [coded 1] vs. no condition [coded 0]).We assessed key pediatric clinical, mental, and behavioral health outcomes frequently observed in other ACE literature. Child general health was measured via the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 7-item questionnaire that assessed caregiver-reported physical, mental, and social health, pain, fatigue, and perceived quality of life. Each item response was categorized as excellent (coded 5), very good (coded 4), good (coded 3), fair (coded 2), and poor (coded 1), and the scores were summed across the seven items and analyzed as a continuous variable. Total continuous raw scores were converted into to 66.1) . We alsooded 1]) . AttentiSocio-demographic covariates were identified a priori based on existing literature on childhood adversities and health outcomes, and they were child age (continuous), sex , race/ethnicity , caregiver education , and family income  [≥ 0.40 were used as an inclusion cut-off. One to three-factor models were tested. Model fit was evaluated using indices of absolute fit and standard guidelines of indices, including the model chi-squared statistics, comparative fit index (CFI ≥ 0.95), Tucker Lewis index (TLI ≥ 0.95), and root mean square error of approximation (RMSEA ≤ 0.06) [Confirmatory factor analysis (CFA) was used to model the latent structure of the PEARLS items using mean- and variance-adjusted weighted least squares estimation (WLSMV) on the tetrachoric correlations of binary PEARLS screen responses . These l ≤ 0.06) –29. Give ≤ 0.06) , a secon≥ 6 years based on school age), gender, and PEARLS screening format (item-level vs. aggregate-level screening). This approach is consistent with the procedure recommended for use with categorical measures outlined by Svetina et al. (2020).Next, we estimated a series of nested multiple group CFAs to determine configural , metric , and scalar  measurement invariance by age group  . Thirty p ≤ .05. All analyses were performed with R 3.3.2 [For sensitivity analysis, we compared the averaged results from the multiple imputation to the complete case analysis. Statistical significance was set at  R 3.3.2 , STATA v R 3.3.2 , SPSS 26 R 3.3.2 , and Mpl R 3.3.2 .Our study sample (n = 340) was predominantly non-Hispanic Black n = 188, 55.3%) and low-income , with a mean age of 5.8 years (SD = 3.5). Majority of the participants’ caregivers had some college education . Participants reported experiencing an average of 3.2 ACEs and related life events (SD = 3.2) . Exposure to domestic violence was included in the Maltreatment domain because literature suggests that a child just witnessing domestic violence has been recognized as a type of child maltreatment [Household Challenges, consisted of seven items that describe the disturbances in the child’s household: caregiver mental illness, caregiver substance abuse, divorce or separation, caregiver physical illness, caregiver incarceration, death of caregiver, and child separation from caregiver (score range 0–7). Domain 3, labeled Social Context, captures four items in the PEARLS that may influence the child’s social environment: neighborhood violence and whether the child experienced discrimination, housing insecurity, or food insecurity (score range 0–4).Model fit statistics from the CFA demonstrated that a three-factor model with a second order summary factor adequately fit the data  Table , and exhreatment –38. DomaMaltreatment (SD = 1.2), 1.5 for Household Challenges (SD = 1.6), and 0.8 for Social Context (SD = 1.0).Correlations among the three domains ranged from 0.85 to 0.88. The subscales had acceptable internal consistency and reliability, with alphas ranging from 0.70 to 0.87 and omegas from 0.55 to 0.73 Table . The aveA summary of the fit statistics for the multiple group CFAs for age group, gender, and PEARLS screening format is shown in Table Maltreatment, Household Challenges, and adverse Social Context factors. The Social Context domain was additionally associated with headaches  and somatic symptoms . There was a positive association between eczema and both the Maltreatment  and SocialContext domains  , or mental health resources.Establishing domains within the PEARLS as predictors of various health outcomes has immediate implications for clinical practice and policymaking. First, distinct domains provide the opportunity for targeted and tailored treatment and linkage to referrals and resources. Limited accessible supports for children and families who experience adversity and following up positive endorsements of adversities with appropriate, specific interventions and resources are two of the biggest barriers to clinicians supporting trauma screening , 47. If There are some limitations to consider when interpreting these results. First, our study, similar to many other ACEs studies, relied on caregiver-report. Some questions, such as those related to child abuse, may be sensitive and anxiety-inducing to report, potentially leading to underreporting of ACEs . This maMaltreatment, Household Challenges, and Social Context domains while also tailor referral and intervention needs based on domain positivity. All three domains were associated with poorer health in children and complement the current practice of assessing cumulative risk of childhood adversity which can help guide clinical practice and policy.As a prevention tool, PEARLS screening early in childhood offers an opportunity to link families to resources prior to the onset of negative health outcomes and to mitigate and decrease exposures to childhood adversity. The PEARLS is an efficient way to cumulatively assess Below is the link to the electronic supplementary material.Supplementary Material 1


Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary.To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC.Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan–Meier curve was generated to test survival time.P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival .The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival. Approximately more than 2 million women worldwide are diagnosed with breast cancer (BC) each year. The number of women dying from BC has fallen thanks to screening and effective treatment. However, radical mastectomy, chemoradiotherapy, and targeted therapy all have different degrees of harm to BC patients, leading to long-term sequelae of BC treatment. For BC patients and survivors, long-term sequelae as well as many psychosocial determinants, such as health care system factors, work constraints, spirit, and coping, seriously affect the life quality of BC patients and survivors , 2. BC iIt has been confirmed that LEP can significantly promote proliferation of BC cells compared with that of normal breast cells , and onlPresent study aims to detect the expression of LEP and LEPR in BC patients, and further explore the impact of LEP/LEPR on occurrence and survival of BC.Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. Patients meeting these criteria were included: (I) Female patients with breast cancer or benign breast disease; (II) Age between 30 to 70 years; (III) No Chemotherapy, radiotherapy and endocrinotherapy before surgery; (IV) pathologically confirmed after surgery. Patients with diabetes or malignancies other than breast cancer were excluded from analysis. The flow chart was shown in Fig. All procedures performed in this study involving human participants were performed in accordance with the ethical standards of Shanxi Medical University Committee and with the 1964 Helsinki declaration and its later amendments (approve number: 2011134). Rabbit LEP (A-20) and Rabbit LEPR (M-18) antibody to human were purchased from Santa Cruz, USA. Rapid immunohistochemistry EnVision™ Kit 5004, and diaminobenzidine (DAB) were purchased from Fuzhou Maixin Biotech, China.2O2, the sections were incubated with a drop of LEP/LEPR antibody at 4°C for overnight , immersed with EnVision™ solution, stained with DAB and counter-stained with hematoxylin. After dehydration, transparent sections were mounted and examined with microscope. Human adipocyte tissues were used as positive controls, and samples without incubation of LEP or LEPR antibodies were used as negative controls.BC and breast fibroma tissues were prepared as tissue microarray samples using a tissue microarray preparation machine , and then sliced into 4 um serial sections. After incubation at 60°C for 4 h, the sections were immediately dewaxed, hydrated, and hot repaired under high pressure. After blocking endogenous peroxidase activity using HLEP is expressed on cytosol and LEPR is expressed on both cytosol and membrane. Yellow or yellowish brown staining was considered as positive. The percentage of positive cells under optical microscope was calculated. Samples with less than 10% positive cell were given 1 point, 2 points when 10–50% cells were positive, and 3 points when ≥ 50% cells were positive. Signal intensity was scored as weak (1 point), moderate (2 points), or strong (3 points). Both scores were multiplied , and theP < 0.05 was considered statistically significant.All the data collected in this study were analyzed using SPSS 22.0 software. Normally distributed measurement data were expressed as mean ± standard deviation (SD), and the comparisons were examined by Student-t test and Mann–Whitney test (non parametric distribution). Categorical data were expressed as n (%), and the differences between the two groups were examined by chi-square analysis or Fisher's exact test. The correlation between LEP/LEPR expression and clinical characteristics were analyzed by chi-square analysis. Survival time was calculated from surgery to death of patient or the last follow-up time. Kaplan–Meier methods was used for survival analysis. Of these 132 patients, 10 patients were with well-differentiated, 60 patients were with moderately differentiated, and 62 patients were with poorly differentiated BC. Median age of these patients was 46 (30–70) years old. Sixty-six patients with benign breast diseases and 30 para-carcinoma tissues, which were normal breast tissues and 4 cm away from the tumor tissues from the 132 cancer patients, were included in controls. Among the patients with benign breast diseases, 37 had fibroadenoma, 15 had multiple intraductal papilloma and 14 had lobular proliferative diseases. They were aged between 34 and 68 years old with median age of 43 years old.2, P = 0.142) and WHR  between BC patients and benign ones. Baseline characteristics of patients with breast cancer were shown in Table There was no difference of BMI  and 73.33% (11/15) of multiple intraductal papillomas disease, respectively, which resulting high rate of LEP and LEPR in all patients with benign disease. However, the expression decreased to 45.1% and 51.% in patients with benign disease regardless of multiple intraductal papilloma.P > 0.05), as well as the expression of ER, PR (P > 0.05). However, the positive rate of LEP expression in patients with lymph node metastasis was 91.8%, which was significantly higher than 67.5% in patients without lymph node metastasis (P = 0.002). We also found that LEPR expression was correlated with Ki-67 expression (P = 0.002), as shown in Table The expression of LEP and LEPR did not showed association with menopausal status, histological type, tumor size, tumor grade and metastasis status , but the expression rate of LEP in patients with lymph node metastasis was significantly higher than that of patients without lymph node metastasis (p = 0.002). It indicated that LEP is involved in the proliferation process of BC and plays a very important role in the development of BC. Moreover, this study also found that the expression of LEP and LEPR were balanced when stratified by patients’ age, menopausal status, tumor size, tumor pathological classification, distant metastasis and the expression of ER and PR, which was consistent with previous study [LEP expression might be correlated with lymph nodes metastases of BC. Garofalo et al. found that LEPR expression rate was 51.5% in BC tissues of patients with lymph node metastasis, which was significantly higher than 41.2% in BC tissues of patients without lymph node metastasis . In contus study , 37.P = 0.002). Ki67 was related to cell proliferation cycle and its expression has been correlated with the development of a variety of malignant tumors. The results suggested that LEPR could promote BC cell proliferation after activation.Another finding of present study was that LEPR expression was correlated with Ki-67 (Previous study has shown an association between high LEP expression levels and poor prognosis in several cancers . Other rThere were also several limitations of present study. First, there was unavoidable biases due to the retrospective nature of present study. Second, this was a study with small sample size which resulting in limited reliability. Thus, all conclusions should be interpreted cautiously.In conclusion, the positive rate of LEP and LEPR expression in BC tissues was significantly higher than that in benign breast tissues and normal para-carcinoma tissues. The LEP and LEPR expression were significantly correlated with lymph node metastasis and Ki-67 expression, respectively. High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival.


Zinc-biofortified potatoes have considerable potential to reduce zinc deficiency because of their low levels of phytate, an inhibitor of zinc absorption, and their high consumption, especially in the Andean region of Peru.The purpose of this study was to measure fractional and total zinc absorption from a test meal of biofortified compared with regular potatoes.67Zn and 70Zn stable isotopes) in which 37 women consumed 500-g biofortified or regular potatoes twice a day. Urine samples were collected to determine fractional and total zinc absorption.We undertook a single-blinded randomized crossover study (using P < 0.01). However, total zinc absorbed was significantly higher .The zinc content of the biofortified potato and regular potato was 0.48 (standard deviation [SD]: 0.02) and 0.32 (SD: 0.03) mg/100 g fresh weight, respectively. Mean fractional zinc absorption (FZA) from the biofortified potatoes was lower than from the regular potatoes, 20.8% (SD: 5.4%) and 25.5% (SD: 7.0%), respectively (The results of this study demonstrate that biofortified potatoes provide more absorbable zinc than regular potatoes. Zinc-biofortified potatoes could contribute toward reducing zinc deficiency in populations where potatoes are a staple food.clinicaltrials.gov as NCT05154500.This trial was registered at  Zinc deficiency is common in populations that consume diets with a low content of animal products and a high consumption of vegetables and cereal crops. Animal foods make an important contribution to zinc requirements because they contain highly bioavailable zinc, whereas the zinc in some cereals and vegetables may have lower absorption because of the presence of phytate. Child undernutrition is persistently high in the central Andes of Peru, and numerous smallholder families fail to meet their basic needs of energy, iron and zinc .Although various strategies, including agricultural diversification, may have the potential to alleviate micronutrient deficiencies, cultural and economic factors may limit access to animal source foods and low-phytate staple foods, and so the introduction of zinc-biofortified crops could be an effective and sustainable alternative approach when they are part of the usual diet . The zinAccording to the FAO, after rice and wheat, potato was the most consumed food worldwide in 2019, with an average consumption of 66 kg/per capita/y . Potato The International Potato Center (CIP) has developed zinc-biofortified potatoes using conventional breeding. As potatoes contain low levels of phytate , zinc abThe study was a randomized crossover single-blinded study with biofortified and regular potatoes in women living in the city of Huancavelica, Peru. Women aged 18–45 y that met the following criteria were included: BMI 18.5–25 kg/m2; able to come to the study center to eat the prepared potatoes on 2 occasions with a washout in between 30 d, and to remain in the study center for 7–8 h and to comply with all the study procedures; and able to understand and sign the consent form. We excluded subjects according to the following criteria: severe anemia  ; C-reactAssuming a SD of 0.2 (SD of the log-transformed) difference within pairs from a similar previous zinc study , a type The regular non-biofortified commercial potato variety “Amarilla” (yellow) and the zinc-biofortified yellow potato CIP311623.75 were grown in Cacara, Paucartambo, Pasco, Perú. The potatoes were harvested in May 2021 and were transported to Lima where the test meals were prepared in June–July.For the preparation of the potato meals, the potatoes were washed and scrubbed using a brush to remove any earth that might contaminate the potato. The potatoes were boiled for ∼60 min, after that those potatoes were peeled , mashed, and homogenized. Portions of 250 g were aliquoted into labeled plastic bags. This procedure was undertaken before the beginning of the study and all the prepared cooked potato meals were stored at −18°C in individually labeled packets. Finally, the frozen, prepared potatoes were transported from Lima to Huancavelica.3 on a hot plate for 2 h and analysis was done by Inductively Coupled Plasma Mass Spectrometry  at the CIP ). R: A language and environment for statistical computing. R Foundation for Statistical Computing, https://www.R-project.org/.)Calculations and statistical analyses were performed using R version 4.1.2 . Normally distributed data tested by Shapiro–Wilk are reported as mean ± SD if normally distributed or as median (with interquartile range) if not normally distributed. FZA and total absorbed zinc (TAZ) values are reported as geometric means (lower SD and higher SD). Potential carryover and meal sequence effects were investigated with a mixed effects model (subjects as the random effect) using the “lmer” function in R. The significance , which indicates that carryover effects were unlikely to be present. There was no effect of meal sequence either (P = 0.198). The geometric mean FZA was significantly lower (P < 0.01) for the biofortified than for the non-biofortified variety, 20.8% (–SD 15.5% and +SD 28.1%) and 25.5% (–SD 18.5% and +SD 35.1%), respectively. The total amount of zinc absorbed from a 500 g potato meal was 0.49 mg (0.36–0.66 mg) for the biofortified variety and 0.40 mg (0.29–0.55 mg) for the regular variety. On average, 22.5% more zinc was absorbed from the biofortified variety than from the regular variety (P < 0.01), for the same amount of potato (P = 0.128). The FZA of regular potatoes compared with plasma Zn had a correlation coefficient of −0.25 but was not significantly correlated (P = 0.134).The mixed effects model results for the interaction of “potato meal” and “meal sequence” was not significant  was lower than the meal prepared with regular potatoes (25.5%). These values are very much higher than FZA from a 300 g meal of porridge prepared with 50-g biofortified wholewheat flour  and of a hydroponically biofortified wheat porridge served as chapattis with a cauliflower–potato sauce  . AlthougTaking into consideration the mean intake of potatoes in women of childbearing age from the same urban highland area of study (181 g/d) , the biofortified potato meal would contribute 13% of the estimated average requirement (EAR) for zinc for women of childbearing age . HoweverThe concentration of PA in the biofortified potatoes used in this study was about half that found in regular potatoes; a 500 g meal contained 113-mg PA compared with 210 mg in a 500 g meal of regular potatoes. These levels are low compared with daily intakes of 300–800 mg reported for mixed diets . HoweverPrevious studies on biofortified food crops have evaluated the bioavailability of zinc in cereals and beans ,22,23 buOur study shows that biofortified potatoes supply a higher quantity of absorbable zinc than regular potatoes. The advantage of potatoes is that they have a relatively low-phytate content, their consumption is widespread, the quantity of potatoes eaten daily is high, and they have a relatively low cost and high acceptability. Physiologic requirements for zinc can be difficult to meet, especially in low-income populations with a limited variety of foods in their diet . In the The authors’ responsibilities were as follows – GB, RL-D, SF-T, MBZ, CZ: conceived the study; RL-D, GB, CZ: conducted the study and analyzed the data; RL-D: wrote the manuscript; and all authors: contributed to the design of the study and read and approved the final manuscript.The authors report no conflicts of interest.Biotechnology and Biological Sciences Research Council (BBSRC) through a Global Challenges Research Fund (GCRF) Grant (BB/S014039/1) and via the Institute Strategic Programme Grants ‘Food Innovation and Health’ (BB/R012512/1) and its constituent project BBS/E/F/000PR10343 and ‘Food Microbiome and Health’ (BB/X011054/1) and its constituent project BBS/E/F/000PR13630. We gratefully acknowledge USAID Feed the Future Crops to End Hunger award to CIP (DIS-B-AID-BFS-IO-17-00005). For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising.This research was funded by the Data described in the manuscript, code book, and analytic code will be made available upon request with an embargo end date of 9 mo.