Immunotherapy (IO) and radiotherapy (XRT) are two of the most important treatment modalities in metastatic non-small cell lung cancer. There is data to suggest that XRT can enhance the IO’s efficacy. However, little is known regarding how to best combine them. In this retrospective, single-center study, we analyze data of 453 patients who have received various combinations of XRT and IO, or IO alone, to assess the treatment parameters that correlate with longer overall survival (OS). XRT doses between 30 and 40 Gy correlated with longer overall survival, while XRT doses below 10 Gy, fractions of 4.1 to 8 Gy and XRT to the bone correlated with worse overall survival. These results require validation with prospective studies. p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy , XRT fractions of 4.1–8 Gy  and XRT to the bone . Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. Conclusion: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis. Background: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. Methods: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. Results: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25–1.0,  Immunotherapy (IO) has revolutionized oncology, with a marked impact on the treatment of lung cancer. Checkpoint inhibitors, specifically antibodies targeting the programed cell-death-1 (PD-1) and its ligand (PD-L1) interactions, have become part of the standard of care for non-small cell lung cancer (NSCLC). Pembrolizumab is now indicated for most patients as first-line treatment for metastatic disease, either as a single-agent or in combination with chemotherapy, depending on the expression levels of tumor PD-L1 protein . AtezoliSTING) and interferon signaling. Additional studies suggest radiation to induce enhanced antigen presentation, immune cell infiltration and activation [Ionizing radiation (XRT), another pillar of the anti-cancer therapeutic options, can impact the immune system and is suggested to synergize with IO. The PACIFIC study demonstrated the benefit from addition of IO following chemo-radiotherapy treatment on stage III non-resectable NSCLC ; howevertivation . Retrosptivation ,15, whiltivation , and somtivation . As retrtivation ,19. A retivation . A largetivation  , details about the cancer , the type of immunotherapy administered  and the specific immunotherapy drug given and the line of immunotherapy treatment. Radiotherapy treatment details were extracted from the administrative records and clinical charts of the Department of Radiotherapy at Sheba Medical Center. For patients that have received more than one XRT course, the course that occurred closest to the initiation of IO was chosen for further analysis. Additional parameters collected concerning the patients’ general condition at the time of initiating IO were the Eastern Cooperative Oncology Group performance status (ECOG-PS), albumin levels and neutrophil-to-lymphocyte ratio (NLR). Blood test data were included if conducted within a month prior to initiation of immunotherapy. (KRAS), Epidermal growth factor receptor (EGFR) and others), type of immunotherapy, specific immunotherapy drug used and blood albumin (below or above the lower limit of the norm). Timing of XRT initiation relative to immunotherapy was interrogated as categorical, comparing any timing prior to IO initiation to any timing after that point. Additional analyses included radiotherapy-treated patients at various pre-specified time windows . Target organs of XRT were grouped as lung and mediastinum, bone, cranium , gastro-intestinal and soft tissue. SRS-treated patients were excluded from the analysis due to small numbers.Categorical and ordinal variables were tested for significance by Chi-square test. Categoric parameters included sex, histology, presence of mutations  steps, the highest dose group being above 50 Gy. The mode of radiotherapy  was not evaluated separately in this study. Fraction sizes were examined in arbitrary cohorts of up to 2 Gy, 2.1–4 Gy, 4.1–8 Gy and larger than 8 Gy. As a sensitivity analysis, the total XRT dose and fraction size were also investigated as continuous variables. All continuous parameters were tested for variance homogeneity by Levene’s test. Comparisons were done by Student’s t-test, or ANOVA for more than two groups. In the event the distribution is found to be significantly different than normal, Welch’s t-test was used. Continuous variables included age, NLR and treatment line of IO. p-value of 0.05 or lower. The primary endpoint of this study was overall survival, calculated from the initiation of IO till death or censured at last follow-up. All of the above parameters were tested for correlation with overall survival (OS) by Cox regression as a univariate analysis, followed by multivariate analyses. Multivariate analysis included age, sex, all XRT parameters and any additional factor that demonstrated significance in the univariate analysis. Significance was defined as a Blood test results  were not available for the entire study cohort. Therefore, multivariate analyses were done both without these parameters, including the entire cohort, as well as with these parameters, thus including a smaller number of patients. The study was approved by the institutional ethics committee .A total of 563 lung cancer patients received IO during the study period. Of these, 85 patients were excluded for any of the following reasons: a diagnosis different from NSCLC; received IO but not as treatment for metastatic disease ; or treated under a blinded clinical trial. In addition, 25 patients that received SRS were excluded, leaving 453 patients that were included in the study. Blood tests of the albumin levels and NLR were available for 374 patients.No XRT was delivered for 167 (36.9%) of the study cohort. XRT was given prior to IO for 182 (40.2%) of the cohort and 104 (22.9%) received XRT after IO initiation. XRT was initiated before and completed after IO initiation for 21 patients out of the 182 patients in the XRT-prior-to-IO group. As can be seen , the thrAt a median follow-up of 23 months , 280 (74.9%) of the patients died. The median OS was 10 months (95% CI 8–12). The characteristics of the patients included in this study, according to the timing of XRT relative to IO initiation, are presented in Following a previous report of a beneficial impact of XRT given prior to pembrolizumab , we evalWe speculated that if XRT impacts the efficacy of IO, it’s effect would be most evident when given around the time of IO initiation. We therefore compared patients that initiated XRT treatment prior to IO initiation to patients that received XRT after initiation of IO, but only within a limited time frame of one month before or after IO initiation. As seen in p = 0.049). In contrast, patients treated with doses of 10 Gy or less had a worse outcome than non-irradiated patients . We next examined the prognostic value of fraction size, with patients grouped by this parameter compared to the non-irradiated group. As seen in p = 0.027). No dose-per-fraction-dependent size effect was seen in this analysis, as the group of patients receiving fractions larger than 8 Gy did not have a worse outcome than the non-irradiated group; notably, the size of this group was relatively small. Total XRT dose was not correlated with survival when tested as a continuous variable , similar to fraction size as a continuous variable . The distribution of total doses and fraction sizes as administered in different number of fractions is demonstrated in p = 0.04; We reasoned that the inconsistency of our results regarding XRT timing relative to IO initiation might stem from the variability of the XRT regimens utilized as well as the heterogeneity of the study population. We therefore evaluated additional XRT parameters of the treatment given. We examined the impact of total dose of XRT given on patients’ survival. For this goal, patients were grouped by the total XRT dose in steps of 10 Gy and each group was compared to non-irradiated patients. As seen in p < 0.001). Timing of the XRT, as well as age, sex, histology or mutations of the tumors were not significantly correlated with survival. We next proceeded to evaluate all of the parameters available for these patients as potential prognostic biomarkers in a univariate analysis. As mentioned above and as seen in The impact of different tumor histologies was further examined by Kaplan–Meier analysis, demonstrating largely overlapping survival curves when the entire cohort was included, but some separation and a trend for better outcome for squamous cell cancer patients was seen when only irradiated patients were included . A similp = 0.019) seen here, but which was not significant when the blood test results were included in the analysis. The role of XRT site, total XRT dose, XRT fraction size and timing of XRT, as well as ECOG-PS, albumin, NLR, treatment line and type of IO were interrogated by multivariate analyses . Here, oThis report is one of the largest and most detailed retrospective analyses of IO-treated, advanced NSCLC patients. We focused on the impact of XRT on these patients and initially aimed to reproduce previously reported results indicating a benefit for XRT administration prior to IO. The earlier study we have attempted to validate was a retrospective analysis of data from a prospective study, but included only 98 patients, without any correction for confounding factors . BesidesNumerous studies are currently assessing XRT in combination to IO treatments in various scenarios. The majority of these studies include a similar XRT regimen for all study participants and are testing the role of addition of IO to this treatment . Only a Importantly, some of our results contradict commonly accepted but unproven paradigms, such as the use of eight Gy XRT fractions in combinations with IO . This paImportantly, the cohort we have described, consisting of real-world advanced NSCLC patients, demonstrates, as expected, a worse outcome than reported in clinical studies, with a median OS of 10 months. Specifically, more than 30% of our cohort had an ECOG-PS higher than one; such patients would not have been included in any clinical trial. The parameters of XRT that correlated with worse outcome are also those of palliative XRT treatments administered commonly to poor PS patients. For example, patients in a general poor condition are commonly treated by a single large fraction of eight Gy as palliative treatment. Indeed, a total dose of less than 10 Gy and a fraction size of 4–8 Gy were correlated with poor outcome in our study. Accordingly, when corrected for ECOG-PS and other prognostic factors, the impact of this radiation dose and fraction size was not significant. The complex interplay between the patient’s general condition, the burden of disease, the activity level of the patient’s immune system and the impact of the IO and XRT treatments is far from being elucidated at this time.The main limitation of this study is its retrospective nature. Similar to all real-world studies, it was hampered by missing data and the obvious bias of treatment assignment being dictated by clinical need. Another potential caveat of our study is the possibility of missing data due to patients receiving XRT treatment in others centers, although this is unlikely considering our center is a tertiary oncology referral center. Moreover, the pertinent information regarding the clinical, pathologic and treatment parameters were successfully collected from the entire identified cohort, besides the blood test results, which were available only for 82.6% of the cohort (374 of 453 patients). The limitation of the study being a single-center study actually facilitated the complete capture of data from the local medical records. Another factor to consider in the analysis of our results is a potential for lead-time bias when comparing patients that got XRT before versus after IO initiation. However, since no significant difference was seen in favor of XRT before IO, the impact of this bias is minor in our study, but might be playing a role in other retrospective analyses .This study points at details of XRT regimens that might synergize with IO, such as a total dose of 30–40 Gy. Importantly, our study identifies XRT characteristics that are possibly antagonistic with IO, such as a total dose of 10 Gy or less, a fraction size of 4.1 to 8 Gy and irradiation to bone lesions. After correction for potential confounding factors using multivariate regression, none of the tested parameters of XRT remains statistically significantly when correlated with survival. However, our results should be taken into consideration in the design of future studies and in the analysis of the ongoing studies investigating the role of XRT in patients treated with IO.


The unfamiliar and menacing epidemic has undoubtedly increased the anxiety of students. Therefore, the strategies to reduce anxiety are urgently required. The present study principally investigated a protective mechanism of future orientation in anxiety during the low-risk period of COVID-19 outbreak. The study was conducted in 528 non-infected students (range = 16–24 years) recruited from five universities in China. The participants completed questionnaires between January 22, 2021, and January 24, 2021. Chain intermediary analyses were performed after controlling for gender and age. Results indicated that future orientation lowers anxiety through (a) optimization in primary and secondary control, (b) resilience, and (c) chain mediating path of optimization in primary and secondary control coupled with resilience. We investigated how individuals deal with risk factors after encountering adversity and how their psychological flexibility stimulates and promotes them to achieve a well-adapted developmental state. This study provided reference suggestions on reducing anxiety levels during an emergency. According to the expectancy model of fear , the evePeople who aim for future and possess strong motivation to execute their plans are less anxious about existing emergencies . HoweverAlthough the effects of severe challenges that lead to stressful situations and setbacks of individual emotions have been proven, individuals do not experience negative emotions in a stressful situation alone. Positive emotions can be developed by constructing personal resources such as resilience –19. ResiNotably, OPS and psychological resilience are not separate intermediaries. The process model of mental resilience  suggestsConsequently, the study investigated the relationship between future orientation and anxiety in non-infected students during the low-risk period of COVID-19 outbreak. We propose three hypotheses in this study :Future orientation could reduce anxiety throughH1: the mediating effect of OPS;H2: the mediating effect of resilience;H3: the chain mediating path between OPS and resilience.Based on previous studies, over 500 participants were enrolled in this study –33. In tM = 19.16 years, SD = 0.94). The majority of all participants were from cities , with the remainder  were from towns. Among them, 93.75% of the subjects were from two-parent families (n = 495), included 266 males and 262 females. The author's research ethics committee approved the study.Participants were required to fill in their sex , their family's living status , and their age and family structure. The age of all participants ranged from 16 to 24 years old , initially developed by Connor and Davidson, is a 25-item scale used to evaluate resilience , and it Future orientation questionnaire (FQD) is mainly used to examine the development of future orientation of youths, and it was initially developed by Nurmi et al. . FQD witSelf-rating anxiety scale (SAS), first developed by , is usedThe OPS scale includes five subscales: selective primary control , selective secondary control , compensatory primary control , compensatory secondary control , and optimization . The 44-item OPS scale was designed by Heckhausen et al.  and furtSPSS 25.0 software was used for statistical analysis. First, perform descriptive statistics and Pearson correlation analysis on the research variables. Previous studies have found that some demographic factors, such as gender and age, are related to anxiety –54. Baser = −0.17, p < 0.01). OPS and future orientation were found to have a positive correlation ; however, OPS was found to be negatively correlated with anxiety . Resilience was found to be positively correlated with future orientation  and negatively correlated with anxiety . Moreover, OPS displayed a positive correlation with resilience .t = 5.220, p < 0.001). Future orientation  and OPS  predicted resilience. Resilience negatively predicted anxiety . Furthermore, the bootstrap method indicated the significant mediation effects of OPS . From the functional perspective of the evolutionary theory, the pursuit of control is an individual's innate biological instinct , 59. WheFurthermore, this study revealed that future orientation could reduce anxiety by increasing resilience (H2). Block and Kremen  reportedThis study also revealed that future orientation reduces anxiety of students through the chain mediation of OPS and resilience (H3). Individuals with high future orientation ordinarily have high motivation for achievement , 70; peoThere are some limitations, for example, we failed to conduct in-depth research and failed to understand other sociological information. Considering that students come from families with guaranteed income may be less anxious, but students come from families with less financial security may be the opposite. In our future research, we aim to use a longitudinal design or experimental paradigm to further support this research hypothesis. Finally, the questions that we aim to explore in our future studies are: how do the protective factors of resilience and anxiety constitute an utterly dynamic system; how does it interact with various risk factors; and how do OPS and resilience stimulate and promote each other, which help students maintain a good state of emotions, abilities, and social interactions in the process of growth?Collectively, we explored the protective factors for anxiety. We investigated how students deal with the risk factors after encountering adversity and how their psychological flexibility stimulates and promotes them to achieve a well-adapted developmental state. The findings showed that future orientation reduces anxiety through the indirect paths of OPS and resilience and the chain mediating pathway of OPS and resilience, which provide students the reference suggestions and intervention guidance on reducing anxiety in case of emergencies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The First Affiliated Hospital of Xi'an Jiaotong University. The patients/participants provided their written informed consent to participate in this study.YC: conceptualization, methodology, formal analysis, writing—original draft, and visualization. CL: conceptualization and writing—review and editing. JZ, HX, and CG: conceptualization, project administration, writing—review and editing, and supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


At each reduction of the BMI z-score by one point, the odds of presenting with insulin resistance and hyperuricemia at follow-up significantly decreased . Improvement of dietary habits and lifestyles may improve lipid and glycemic profiles and serum uric acid values in a pediatric population.Cardiometabolic risk factors are frequent in children and adolescents with excess weight. The aim of this study was to evaluate the effects of lifestyle modifications on alterations in lipid and glycemic profiles and uric acid values in a pediatric population at increased cardiovascular risk. The study involved 276 subjects with a mean age of 10.6 (2.3) years. Body mass index (BMI) z-score and biochemical parameters (serum low-density lipoprotein (LDL) cholesterol, triglycerides and uric acid and homeostasis model assessment to quantify insulin resistance (HOMA index)) were assessed at baseline and at the end of a median follow-up of 14.7  months. Throughout follow-up, all children received a non-pharmacological treatment based on increased physical activity, reduced sedentary activity and administration of a personalized, healthy and balanced diet. All children attended periodic quarterly control visits during follow-up. Multivariable statistical analyses showed that each BMI z-score point reduction at follow-up was associated with an 8.9  mg/dL decrease in LDL cholesterol ( Healthy lifestyles and diets are recommended for everyone and at all ages, to maintain good health and prevent non-communicable diseases. In the presence of cardiovascular risk factors, all guidelines propose a dietary-behavioral intervention as a first step ,2,3,4. TWe studied a cohort of 276 children and adolescents (4–18 years), consecutively referred from 16 December 2002 to 12 September 2017 to our Unit for Cardiovascular Risk Assessment in Children  by their primary care pediatricians, because of evidence of excess weight and/or alterations in the lipid and/or glycemic profile and/or plasma uric acid values. Exclusion criteria were: impaired glucose tolerance, diabetes, any form of secondary hypertension, and treatment with antihypertensive drugs. The Unit for Cardiovascular Risk Assessment in Children included a pediatrician, a cardiologist, a nephrologist and a nutrition expert. The team interacted to cover all clinical aspects related to the patients.In all children, anthropometric and biochemical parameters were assessed once at baseline and a second time at the end of follow-up. Between the baseline and the final follow-up assessment, periodic visits were performed every three months, during which the children’s anthropometric parameters were again recorded. The median follow-up was 14.7  months. Between the baseline and final assessments, a minimum of three visits and a maximum of six visits were performed in each child. All children consecutively referred to our center who had two complete assessments (at baseline and follow-up) of all outcomes  were considered for analysis . Follow-2. Waist-to-height-ratio (WtHr) was calculated by dividing WC by height. BMI z-scores were calculated using the Centre for Disease and Control prevention charts available at https://www.cdc.gov/growthcharts/clinical_charts.htm (accessed on 27 January 2022). Weight class was defined according to the International Obesity Task Force classification . HOMA index was calculated by dividing the product of serum insulin (µU/mL) and serum glucose (mmol/L) by 22.5 . GlomeruThe definition of dyslipidemia was based on the reference values of the National Cholesterol Education Program (NCEP) Expert Panel on Cholesterol Levels in Children: LDL cholesterol ≥ 130 mg/dL, HDL cholesterol < 40 mg/dL, triglycerides ≥ 100 mg/dL (children < 10 years), or ≥130 mg/dL (children ≥ 10 years) . DyslipiInsulin resistance was defined as the presence of HOMA Index values > 90th percentile according to sex and age in normal-weight children and adolescents .Hyperuricemia was defined as the presence of uric acid values greater than the 90th percentile for sex and age according to  90th perhttps://sip.it/2017/09/25/la-sip-presenta-la-piramide-dellattivita-motoria/) (accessed on 28 January 2022).All the children and adolescents were advised to perform at least two/three hours of structured physical activity every week , to incrwww.who.int/nutrition/publications/guidelines/sodium_intake/en/) (accessed on 27 January 2022).The participants received general advice for a healthy and balanced diet  with adequate salt consumption  according to the World Health Organization (WHO) guidelines . Balanced dietary patterns for what regards the content of macronutrients  and correct content of free sugars, saturated fatty acids and fiber were then proposed to all participants.Depending on the pathological conditions , specific recommendations were provided. When a child presented more than one of these conditions, a combination of the different dietary patterns was proposed. For each pathological condition, the rationale for the dietary intervention was explained to caregivers, to stimulate caregiver and family empowerment.Excess weight OW or OB subjects were supplied with a weekly dietary scheme, whose caloric content had been calculated on the basis of both the basal metabolic rate by the Schofield equation [equation  and the equation , throughAlterations of lipid profile Children with hypercholesterolemia were advised to completely eliminate foods containing trans-fatty acids, to reduce energy intake from saturated fatty acids to less than 5–10%, and to limit consumption of some meats, dairy products, chocolate, baked goods and fried and processed foods. Instead, the consumption of foods containing mono- and polyunsaturated fatty acids was favored. The intake of dietary cholesterol was not allowed to exceed 100 mg per 1000 kcal of the diet; to this end, the intake of foods of animal origin such as meat, egg yolks, shellfish and whole milk dairy products was limited, whereas the consumption of foods containing soluble fiber  and phytosterols was favored. In case of increased triglyceride levels at baseline, dietary advice included, besides aiming at a reduction of body weight, a limitation of calories deriving from free sugars to less than 10% of total calories, and in particular a reduction in the intake of fructose through the complete abolition of sugary drinks. In the case of mixed dyslipidemia, all the above indications were recommended and, in all participants, the consumption of fish  was encouraged to increase the intake of ω3 [ke of ω3 ,25.Insulin resistance The dietary-behavioral treatment implemented to reduce HOMA index values coincided with that to reduce excess weight (see above). From a qualitative point of view, the consumption of non-starchy vegetables and fruits rich in fiber, vitamins, and minerals citrus fruits, legumes and preferably whole grains, lean meats, fresh cheeses, fish and nuts, and unsweetened dairy products was encouraged. On the other hand, the intake of sugary drinks, fruit juices, carbonated and soft drinks, starchy vegetables, such as potatoes, pumpkin and corn, processed snacks and canned foods sugary sweets, ice cream and chocolate was limited.Elevated uric acid Children with high uric acid levels were instructed to completely eliminate all sugary drinks from their diet  and to reduce consumption of sweet foods. To caregivers, a list of foods with high purine content was provided, with the recommendation to reduce as much as possible the intake of these foods . The recommended foods with low purine content comprised non-fat dairy products, fresh fruit and vegetables, cereals and derivatives. Eggs, fish, chicken and white meats were allowed in moderation.At each periodic visit, information to assess the compliance with diet modifications, increase in physical activity, decrease in time spent watching television or with video-games was requested from family members according to a panel of questions, and the answers were reported in the medical record. Reinforcement of dietary and of lifestyle recommendations was given when necessary.t-test for paired data or the Wilcoxon signed-rank test for continuous variables, and by the McNemar test for categorical variables.The characteristics of the cohort, overall, at baseline and at follow-up, were described as mean and standard deviation (SD) or median and interquartile range (IQR) if the variables were continuous, and as frequencies and percentages if they were categorical. Univariate analyses to compare the characteristics of the children at baseline and at follow-up were conducted through the L − 1)/(L × S) where L, M, and S parameters specific for age are available at this link https://www.cdc.gov/growthcharts/percentile_data_files.htm (accessed on 28 January 2022). The distribution of weight class and WtHr ≤ 50% or >50% at baseline and at follow-up was described by bar plots and the proportions were compared by an extension of the McNemar test for the marginal homogeneity of categorical data with more than two levels [The Z-score value was calculated by the equation o levels , or by tThe distributions of dyslipidemia, insulin resistance and hyperuricemia at baseline and at follow-up were displayed through alluvial plots.The impact of gender, age, puberty transition, the difference between BMI z-score at baseline and at follow-up, family history of dyslipidemia/diabetes on LDL cholesterol or HDL cholesterol or triglycerides or HOMA index or uric acid plasma values at follow-up. The models were adjusted for values of LDL cholesterol or HDL cholesterol or triglycerides or HOMA index or uric acid plasma at baseline.The impact of gender, age, puberty transition, the difference between BMI z-score at baseline and at follow-up, family history of dyslipidemia/diabetes on dyslipidemia or insulin resistance or hyperuricemia at follow-up. The models were adjusted for the presence of dyslipidemia or insulin resistance or hyperuricemia at baseline. The same linear and logistic regression models were performed including the difference between WtHr at baseline and at follow-up as covariate instead of the difference between BMI z-scores.http://www.R-project.org) (accessed on 28 January 2022). All p-values were two-sided, with p-values < 0.05 considered statistically significant.Statistical analyses were performed with R 4.1.2 (The study involved 276 children with a mean age of 10.6 (SD = 2.3) years . p < 0.001). The proportion of NW subjects had significantly increased, whereas the proportion of OB subjects was significantly lower than at baseline (p < 0.001) (p < 0.001) (p = 0.002), whereas we did not observe any significant change in the number of subjects with dyslipidemia and in those with uric acid values > 90th percentile. However, a significant reduction in LDL cholesterol levels was observed .At recruitment, 14% of children were NW, 35% were OW, and 50% were OB A, and 70< 0.001) A. Only 5< 0.001) B. ChangeChanges in the prevalence of dyslipidemia and elevated HOMA index and uric acid values are described in p < 0.001, p < 0.001, p = 0.001, p < 0.001, p < 0.05, p < 0.001, p < 0.001, p = 0.01, Multivariate analyses showed that each one-point reduction in BMI z-score was associated with a reduction of 8.9 mg/dL in LDL cholesterol and 20.3 mg/dL in triglycerides . However, in spite of the intervention, a certain number of subjects still experience an increase in BMI and a worsening of the metabolic picture, even if in a smaller percentage than those who improve.Overall, we obtained a clear improvement in the weight status of the study population. The percentage of children with obesity was significantly reduced and, in parallel, the number of subjects with normal body weight and those who were in excessive weight but without evidence of obesity increased. The magnitude of BMI reduction was strongly associated with an improvement in the metabolic risk profile. Importantly, only a small minority of children (less than 6%) worsened their weight class, whereas a higher proportion (about 27%) experienced improvement. A Cochrane meta-analysis including 70 randomized clinical trials, based on both diet and physical activity interventions, showed that the intervention led to a significant reduction of the BMI z-score .Numerically few data are available on the effects of nonpharmacological treatment on the metabolic profile of children/adolescents and, as highlighted in the meta-analysis by Ho et al., studies often analyzed only small samples of children . Dyslipip = 0.04) without any significant reduction in HOMA index in the DASH group [The meta-analysis of Ho et al.  includedSH group . A graduSH group . A high SH group . In our SH group .In our population, the number of children with a WtHr > 50% significantly decreased after the intervention. Approximately 29% of subjects with a WtHr > 50% at baseline had a WtHr < 50% at the end of the follow-up period. Replacing BMI z-score by WtHr  in the statistical models had no additional effect on outcomes, although from a theoretical point of view, waist circumference should be better associated with metabolic alterations than BMI z-score. However, our result confirms the validity of WtHr in determining pediatric cardiovascular risk, but also suggests that this parameter does not provide any substantial advantage over BMI. It is possible to assume, however, that more accurate estimates of central adiposity  could have led to different results. In a small sample of Japanese children, dietary intervention combined with exercise treatment led to a reduction in the areas of subcutaneous and visceral fat, quantified in CT images obtained by a body fat scan, in association with a significant decrease in plasma values of total cholesterol, triglycerides and insulin . AbdominIn children, as well as in adults, an association has been demonstrated between obesity and uric acid levels ,42,43. TVegetarian diets in adults are assumed to be healthy; however, it is unclear whether this is also true for children and adolescents. So-called “plant-diets” have been shown to have a protective effect on the risk of type 2 diabetes, cardiovascular disease, and obesity in adults . ExistinA strength of our study is that, whereas most previously published studies on this topic were limited to analyzing the differences between pre- and post-intervention values in children who lose weight compared with those who do not, we also provide a precise estimate of the effect of our intervention. For each point of BMI z-score lost, we described a reduction of about 9 mg/dL of LDL cholesterol, 20 mg/dL of triglycerides, 1.6 of HOMA index and 0.4 mg/dL of uric acid. In the available studies, anthropometric variables were not always indexed, and the influence that age and puberty have on lipid and glucose patterns and uric acid values in developmental age was often not considered. In our study, all variables were analyzed as both continuous and indexed variables, and all models were adjusted for the onset of puberty.A weakness of our study is that we could detect only one indirect parameter of adiposity (waist circumference). A more correct estimation of visceral fat and its changes in relation to those of hematochemical parameters could give interesting additional information. Moreover, as our society has become increasingly multiethnic, other factors, such as sociocultural influences, may contribute, beyond biological factors, to the success of non-pharmacological treatment directed at a population of children and adolescents with excess weight. The presence of community workers specifically trained to promote healthy behaviors that take into account cultural background, psychosocial stressors, and economic limitations would likely have improved compliance among our population and allowed for better outcomes. Unfortunately, our center is not equipped with this kind of support.In conclusion, in children it is not easy to evaluate the effect of a nonpharmacological treatment on metabolic variables that may represent a cardiovascular risk factor. In fact, children are growing organisms in which these parameters change physiologically. Moreover, body weight, a factor strongly associated with metabolic parameters, undergoes important modifications at this age. By using models that correct these confounding factors, our study shows that a change in lifestyle and dietary habits is able to induce an improvement in weight, lipid profile, glycemic and uric acid values. For all metabolic parameters considered, baseline values are strongly associated with those found at follow-up. This means that the more a child presents a metabolic impairment, the more difficult it will be, with the same weight reduction, to bring back its parameters in a normal range. These considerations confirm and emphasize that an early intervention aimed at normalizing the lipid, glycemic and uric acid values is essential for the realization of a real prevention of cardiovascular disease in a world where this is the first cause of death.


Depression is common in people with fibromyalgia (FM) and osteoarthritis (OA) and has been linked to adverse health outcomes in these conditions. The purpose of this study was to examine differences in predictors of depression among individuals with FM and OA using a range of health, demographic, and psychological variables. Of the total 963 participants, 600 were diagnosed with FM, and 363 with OA. The Quality of Well-Being Scale (QWB) was used to assess health status. The Fibromyalgia Impact Questionnaire (FIQ) and the Arthritis Impact Measurement Scale (AIMS) were used to measure disease-specific impact. Additionally, participants completed self-efficacy and helplessness assessments. Depression was measured using the Center for Epidemiological Studies Scale (CES-D). The results of a moderated linear regression showed that higher depression scores were associated with lower health status and a greater condition impact, especially in the FM group. Self-efficacy and helplessness predicted depression in both groups, but more strongly in FM. White participants with OA were more depressed than their non-White counterparts, while the opposite was true for FM. These findings indicate that improving health status and psychological well-being might alleviate depression in both FM and OA. In the United States (U.S.), chronic health conditions are a leading cause of death and disability , and theFibromyalgia syndrome (FM) is a chronic musculoskeletal pain condition that is often accompanied by fatigue, headaches, sleep disturbances, memory, and mood difficulties . Two to Osteoarthritis (OA) is a chronic degenerative joint disease that occurs when the cartilage between the bones deteriorates. As a result, people with OA often experience joint pain and irritation of adjacent bone tissue ,10. In tFM and OA are prevalent chronic pain conditions with high associated health care costs ,14. DespAs with other chronic conditions, people with FM and OA often experience psychological difficulties and report higher rates of depression than those in the general population ,23,24,25Using both general and disease-specific metrics, researchers have found that higher impact of the disease predicted higher depression scores in people with OA and FM ,34,35,36When examining the association between psychological variables and depression, researchers have found that higher levels of self-efficacy and lower levels of helplessness predicted lower depression in people with FM ,39,40,41Specific demographic characteristics have also been associated with depression in people with FM, such as being female, not married, young, being from a minority group, low socioeconomic status, and low levels of education ,49. SeveAmong those with FM, concurrent depression negatively impacted quality of life and resulted in significantly higher health care costs than those with FM who were not depressed ,52. At tEven though researchers found that patients with FM reported greater depressive symptomatology than OA patients ,29,49, fThe purpose of the present study was to investigate whether the predictors for depression differed for people with OA and FM. The predictors included demographics variables , health variables , and disease-specific health), and psychological variables .Of the total 963 participants, 600 had an FM diagnosis, and 363 had an OA diagnosis. The data were taken at the baseline assessments. The studies were approved by the Institutional Review Board of San Diego State University . The mean age of patients with OA was M = 69.21 (SD = 5.63), and the mean age of participants with FM was M = 53.92 (SD = 11.45). The majority of participants in both groups were White , female  and completed at least some college. Informed consent was obtained from all participants involved in this study before participating in the research.Age, gender, ethnicity (minority versus non-minority), highest level of education, and family income were assessed through a demographic questionnaire.The Quality of Well-Being Scale (QWB) was used to measure general health status . The QWBParticipants’ perceived helplessness in coping with OA or FM was measured with the Arthritis Helplessness Index (AHI) questionnaire. The scale was developed for assessing the impact of arthritis, and it was adapted for FM by replacing the word “arthritis” with “fibromyalgia.” The scale consists of 11 items, for which participants are asked to use a six-point scale ranging from 1 (strongly disagree) to 6 (strongly agree) to indicate how much they agree or disagree with each statement. Items were then reverse coded so that higher scores reflected greater helplessness. Adequate internal reliability, test–retest reliability over one year, and construct validity have been demonstrated ,60. The The Arthritis Self-Efficacy Scale (ASES) was used to measure perceived self-efficacy for management of and coping with the condition. It was adapted for the FM group by substituting the word “arthritis” for “fibromyalgia” . The ASEThe Fibromyalgia Impact Questionnaire (FIQ) was used to measure the impact of fibromyalgia on FM participants. The FIQ is a brief 10-item self-administered assessment that measures physical functioning, feeling good, work status, pain, fatigue, sleep, stiffness, anxiety, depression, and well-being . The higThe Arthritis Impact Measurement Scale (AIMS) was used to measure the disease-specific impact on OA participants. The scale consists of nine subscales to assess mobility, physical activity, dexterity, household activities, activities of daily living, anxiety, depression, social activity, and pain . The relThe Center for Epidemiological Studies Scale (CES-D) was used to measure depression levels . The CESAll participants were recruited from two larger studies investigating the effects of social support and education on health care use and health status. Participants were recruited by mass mailing to members of a large health maintenance organization (HMO) in San Diego, California. Additionally, flyers were posted in HMO waiting rooms, email requests to refer qualified patients were sent to HMO physicians, and advertisements were placed in Sunday newspapers. Participants in the OA study were required to be 60 years or older.Participants in both the FM and OA groups were required to have a physician’s diagnosis prior to the start of this study, which was later confirmed by a review of the participants’ medical records. In addition, for FM participants, during the initial meeting, trained research assistants performed manual tender point exams using the American College of Rheumatology (ACR) diagnostic criteria . To be eDescriptive data are shown in A moderated linear regression was used to test the hypothesis that the predictors for depression would differ as a function of type of chronic condition (OA versus FM). Depression was the dependent variable, and the total CES-D score was used. The demographics , physical  and psychological  variables were the independent variables, and the type of chronic condition was the moderator.p < 0.001), condition impact  and chronic condition type.As shown in p < 0.001) and self-efficacy , significantly interacted with chronic condition type.We examined the relationships among psychological variables. Specifically, Finally, the results of the moderated linear regression for each of the demographic variables are presented in p = 0.003) and ethnicity  in predicting depression. Significant interactions were plotted. To further probe the interaction, Among all demographic variables, chronic condition was a significant moderator of education  were associated with depression in people with FM. Specifically, lower levels of self-efficacy and greater helplessness predicted higher depression scores, and this was particularly true in the FM group. These results are consistent with previous research findings indicating that pain conditions may undermine one’s belief in self-efficacy and, as a result, increase depressive symptomatology . The finAmong participants in the present samples, high perceived helplessness predicted higher depression scores, particularly for the FM group. These results are not surprising, given that both self-efficacy and helplessness are conceptually similar constructs that describe the opposite ends of the perceived control spectrum. Helplessness was reported to mediate the relationship between pain and depression with FM and was indirectly linked to subjective well-being through its influence on illness uncertainty ,83. IndiThe results from the present study indicated that participants with FM had significantly higher depression scores than the OA participants across all demographic predictors. Younger participants were significantly more depressed than older participants. In addition, people with lower incomes were more depressed than those with higher incomes. A significant interaction indicated that in the FM group people with lower educational levels had higher depression scores than those with high educational levels; however, there was no difference in the OA group. These findings are consistent with those reported by Güven et al. , who fouThere were limitations of this study. Because this was correlational research, no conclusions about cause and effect can be drawn. Another significant limitation was the lack of minority participants. Some researchers have reported that there may be a higher prevalence rate of FM among racial minority women . Still, In summary, the present study extends current knowledge about the predictors of depression in populations with chronic conditions by comparing two distinct illnesses OA and FM. Our results suggest that while people with chronic conditions are likely to benefit from psychological optimization, treatment for patients with FM should be particularly sensitive to physical symptoms and psychological factors such as self-efficacy, helplessness, and patient education. Thus, intervention studies testing the effects of self-efficacy and helplessness for people with chronic conditions are needed. For people with OA, the predictors of depression had a less pronounced effect than those for people with FM. The reason may be that depression was less prevalent for people with OA and the range of depression scores was more restricted than the range for people with FM. However, depression was related to poorer health outcomes for people with either OA or FM. Taken together, the findings of the present study suggest that health status and levels of self-efficacy and helplessness should be considered in treatment planning to maximize the well-being and health of individuals with either OA or FM.


Spondias pinnata is a tropical tree omnipresent in the coastal and Western Ghat section of India that is used for culinary purposes and as a local analgesic. Therefore, we aimed to study the anti-inflammatory effects of S. pinnata in an etoposide-induced mucositis rat model.Mucositis, one of the vulnerabilities of chemotherapy, affects the physiological activities and therapeutic strategies of patients because it can affect the normal cell population. Etoposide is a commonly used chemotherapeutic agent for cancers such as oral, lung, and gastrointestinal. In addition to the abnormal metabolic processes in the body caused by tumorigenesis, new metabolic alterations can occur, such as oxidative stress, antioxidant imbalance, and inflammatory reactions, all of which can contribute to existing patient vulnerability. Therapeutic adjuvants can help overcome these toxic effects. +-K+ ATPase. The animals were grouped into: (1) normal control, (2) etoposide-induced mucositis , (3) S. pinnata control group, and (4) etoposide followed by S. pinnata bark extract . Animals were sacrificed after 24, 48, 72, and 96 h and compared with that of the normal control group (n=6). Statistical analysis was performed using EZR software.Small intestinal tissue homogenates from albino Wistar rats were used to estimate the levels of glutathione (GSH) and nitric oxide (NO), and activities of total antioxidant (TAO), myeloperoxidase (MPO) and Na+-K+ ATPase activity in the mucositis group. A tendency to recover from the decreased TAO and GSH levels existed in the treated group, showing the protective effects of S. pinnata bark extract against mucositis. In addition, this extract also showed anti-inflammatory effects as reflected by the recovery in MPO levels at the end of 96 h. Maintenance of Na+-K+ ATPase activity in the treated group demonstrates the protective effects of the extract against the increased levels observed in the etoposide-induced mucositis group.We observed a significant decrease in the TAO and GSH levels with a marked increase in NO, MPO, and NaS. pinnata bark extract against the oxidative and inflammatory changes that occurred during the development ofmucositis. This would decrease the pathological burden during chemotherapy and prevent any hurdles in therapeutic modalities.This study revealed the protective effects of  Chemotherapy is the most common therapeutic strategy used worldwide during cancer treatment. Although this therapy is most promising, it attacks several normal body processes, worsening patients’ physiological vulnerability. Mucositis is one such outcome . EtoposiAlmost all chemotherapeutic agents cause mucotoxic effects that can make the life of cancer patients more miserable. Mucositis is the painful ulceration of the mucosal lining right from the oral cavity distributed across the gastrointestinal tract (GIT), affecting its normal functioning. Sonis  has explThe pathophysiology of mucositis is still obscure; its occurrence lasts for about 3 weeks; and are of two types: direct and indirect. Chemotherapy interferes with the normal turnover of intestinal epithelial cells through one or both of these processes ,5. Gener+-K+ ATPase, an active enzyme of the intestinal epithelium, is required for the maintenance of the electrolyte balance attributed to its increased activity during chronic and acute inflammatory conditions of the GIT as well as is a signal transducer for muscle and nerve conduction [+-K+ ATPase, which results in the production of pro-inflammatory cytokines and various other chemokines such as tumor necrosis factor-a, interleukin-5, nuclear factor-kB through mitogen-activated protein kinase, and p38 associated pathways [Nitric oxide (NO), a principal inflammatory marker, is synthesized by inducible NO synthase (iNOS) during inflammation. Myeloperoxidase (MPO), the activity of which increases during systemic inflammation, also has been found to upregulate the activity of iNOS . Reducednduction ,10. Na+-pathways ,12, is nChemotherapy not only can pose a socioeconomic burden on patients but also can lead to psychological encumbrance due to the inexhaustible metabolic changes and side effects. Therefore, considering the infinitesimal molecular changes in an individual are necessary. In addition, several oxidative fluctuations followed by inflammatory archetypes can differ from one patient to another. The use of chemotherapeutic regimens, with their diverse combinations, action mechanisms, exposure, and patient capacity to withstand these, has become a crucial area of concern ,14.Spondias pinnata, also called the hog plum, is a deciduous tree belonging to the Anacardaciae family. The tree is found along the Western Ghats and the coastal belt of India and is used as a culinary and medicinal supplement. Methanolic and ethanolic bark extract studies with this plant have revealed the antibacterial, anticancer, anti-helminthic, analgesic, and antipyretic properties attributed to the presence of polyphenolic compounds [ompounds .S. pinnata for its anti-inflammatory effect if any.Many naturally occurring herbs and herbal products have been used to relieve the severity of mucositis caused by chemotherapy. With this basic knowledge, we intended to study the protective effect of Institution’s Animal Ethics Committee approved the study with EC Number: KMC/MNG/IAEC/05-2018),The study was conducted from June 2020 to December 2020 at Department of Biochemistry, Kasturba Medical College, Mangalore.S. pinnata, bark was collected locally from Dakshina Kannada, and was identified and authenticated by Prof. Vasundhara Rao (retired professor), Department of Botany, Govt. College, Mangalore University and an ayurvedic physician.We separated, shade-dried, and powdered the bark in a grinder. We extracted 100 g of the powder repeatedly with methanol (30%) using the Soxhlet apparatus over 72 h. We collected the concentrated bark extract and removed the solvent using a rotary evaporator. This semisolid extract was lyophilized and stored atroom temperature (27-30ºC) until use.ad libitum. We divided the rats into four groups, subdividing each into a, b, c, and d subgroup related to the time of sacrifice, as follows:We procured 78 rats from the central animal house, Kasturba Medical College, Mangalore, India, and housed these in polypropylene cages with husk as bedding material and standard food and water Group-1: Normal control group;Group-2: Mucositis model (EP): Subdivided into 2a, 2b, 2c, and 2d;S. pinnata control group (SP): Subdivided into 3a, 3b, 3c, and 3d; andGroup-3: S. pinnata and mucositis treatment group (EP+SP): Subdivided into 4a, 4b, 4c, and 4d.Group-4: We considered the time of etoposide injection as 0 h and then calculated the time of exposure.S. pinnata bark extract once a day at 0, 24, 48, and 72 h. Group 4 was treated with S. pinnata once a day at 0, 24, 48, and 72 h, after EP administration and was considered as the treatment group. Animals were sacrificed at 24, 48, 72, and 96 h after intervention by euthanasia followed by cervical dislocation.For Group 1, rats without any treatment and housed at normal temperature, humidity, and normal dietary conditions were considered as normal controls. For Group 2, mucositis was developed by etoposide administration in a single dose (65 mg/kg bodyweight) by intraperitoneal injection. Group 3 received 200 mg/kg bodyweight of +-K+ ATPase, for which the tissue homogenate was prepared using a sucrose buffer.After sacrifice, the intestine was dissected, and 10% tissue homogenate was preparedusing phosphate-buffered saline, except for Na+-K+ ATPase activity: The method adopted was that by Adam-Vizi and Seregi [Estimation of Nad Seregi  in whichet al. [Estimation of MPO activity: The method adopted was described bySuchitra et al.  the enzyet al. [Estimation of NO levels: The method adopted was described byMenaka et al. . The levEstimation of reduced GSH: The method adopted was described by Ellman using DTNB. The values are expressed as mg/g of tissue .et al. [Estimation of TAO: The method adopted was described by Korecevic et al.  activityt-test to find the differences between groups, considering p<0.05 as statistically significant.Normal data are expressed as mean±standard error of the mean. Non-normal data are expressed as the median with a 95% confidence interval. We performed the statistical analysis usingEZR statistical software, version 1.54. . We used one-way analysis of variance and the Kruskal–Wallis test for multiple comparisons and the Mann–Whitney U- and sample We observed a highly significant increase in MPO activity in the rats exposed to etoposide . MPO activity remained in the normal levels in the SP control groups , and recovery occurred in the EP+SP groups (Groups-4a, 4b, 4c, and 4d; A significant increase occurred in the EP groups over a period of 24-96 h. We observed an insignificant decrease in NO levels among the SP control groups over 24-96 h when compared with that of the normal control group. We also observed a significant decrease in NO levels in the EP+SP groups over 24-96 h. However, the levels remained high in the EP+SP groups when compared with the SP and normal control groups. Surprisingly, the results showed that the NO levels remained higher in EP+SP 24 h and EP+SP 48 h than the EP 24 h and EP 48 h levels respectively .A significant decrease in TAO activity occurred among the EP groups over 24-96 h. We observed non-significant difference among the SP control groups sacrificed at different intervals and a significant increase in TAO activity in the EP+SP groups over 24-96 h, which showed a tendency to return to the normal level at 96 h. .A statistically significant, gradual decrease in GSH levels occurred in the EP groups, a significant increase in GSH levels occurred in the SP control groups over 24-96 h, and a gradual increase in GSH levels occurred in the EP+SP groups, with progress over the time. The levels remained significantly low in the EP+SP 24 h group in comparison with that of the normal control group; however, the levels had a tendency to increase toward normal .We observed a more than 50% decrease in the enzyme activity after 24 h, followed by a sudden increase in the activity after 48 h, with gradual hike at 72 and 96 h in the EP groups as compared with the other groups .Cytotoxicity is a major side effect of chemotherapy. Inflammation and mucosal tissue injury are attributed to cytotoxicity. In addition, etoposide induces a severe form of mucositis, during which ROS generation triggered by etoposide leads to an inflated inflammatory response ,4,21. ReDNA damage is a key process that affects the cell cycle at different levels. The changes during the development of mucositis highlight ROS-sensitive sequences, which elicit the inflammatory mechanisms. ROS stimulates the assembly of leucocytes in the damaged tissue, actuating neutrophil production. Activated neutrophils escalate the production of inflammatory marker MPO, a hemoprotein stored in the leukocyte granules. This increase is the basis for the inflammation due to ROS .In the present study, we found an insignificant initial decrease in MPO activity at 24 h after etoposide exposure, which looks accidental and yet interesting. However, a sharp increase at 48 h and a subsequent increase thereafter can be regarded as aggravated mucositis. MPO catalyzes oxidation of the phenolic ring of etoposide to yield phenoxyl radical as shown below .2 Etoposide--O•+RO2HEtoposide-OH+RO•+RH Etoposide-OH +R•Etoposide--Oet al. [The dip in the observed MPO levels could be caused by the time taken by etoposide metabolism, and an increase in the levels could be due to the enhanced radical production as a result of this metabolism. This mechanism increases the existing free radical pool to augment the propagating chain reaction that leads to the amplification of pro-inflammatory cytokines. Thus, formation of phenoxyl radicals from the etoposide parallels the increase in MPO activity at a later stage, as seen in our study. This finding also is corroborated by Atwal et al.  who haveS. pinnata over 96 h, showing that this extract can be beneficial in treating the inflammation caused by chemotherapy. Catalytic activity of MPO also is influenced by NO in anaerobic conditions, and the increased activity of MPO decreases the bioavailability of NO for its normal functioning in the body [We found a decrease in the MPO levels in the mucositis model treated with the body . This coS. pinnata, as the NO levels showed a tendency toward normal in the mucositis groups treated with the extract. NO, synthesized by the action of iNOS, is a short-living molecule that can easily diffuse through the tissues [In our study, we observed an increase in NO levels with the time of exposure to etoposide, emphasizing possible drug toxicity on the intestinal tissue to develop mucositis. Moreover, NO levels in the SP control groups corresponded to those of normal levels in rats and a decrease in the levels observed over 96 h. These results provide evidence of the protective action of  tissues . iNOS ac tissues . At a hi tissues .S. pinnata. This finding is similar to that by Kumar, in which S. pinnata fruit showed high radical scavenging activity attributed to its phenolic and tannin content [Worsened antioxidant levels can occur in patients receiving chemotherapy . In the  content . Our stuS. pinnata. Our findings are supported by evidence from Iqbal et al. [S. pinnata bark extract attenuated the ethanol-induced hepatotoxicity, as well as by those from our previous study, reinforcing the maintained normal TAO levels of the same group [GSH shows a wide range of paradigms in cancer therapies ,32. In tl et al. , in whicme group .+-K+ ATPase [+-K+ ATPase at 24 h after etoposide administration and also saw a parallel enhancement in inflammatory status. An interesting finding is an eventual rise in the level over the 96 h of administration, which could be attributed to the increased cellular destruction due to mucositis. Evidence from the literature also indicates that both the phosphorylation of amino acid residues and the localization of a-subunit of the enzyme can lead to its increased activity [S. pinnata along with etoposide showed that the conservation of the sodium pump activity can ensure the protective action of this bark extract against tissue injury and inflammation.Development of diarrhea is a key feature during mucositis, caused by the altered ionic status of the cellular environment. Maintenance of the chemical and electrical gradient between intra- and extra-cellular spaces is primarily done by Na+ ATPase . In our activity . NeverthS. pinnata bark extract promises for minimizing the ill effects caused by chemotherapy and can help in planning further treatment strategies.Over the time, etoposide exposure causes oxidative stress-mediated mucosal tissue injury. The mechanisms discussed above, if monitored during chemotherapy, could be beneficial in curbing the general psychological and pathological burdens of the patient caused by mucositis and its consequences. Considering the basic needs of patients such as difficulty in consuming a proper diet, GMR and MC: Research concept and design. GMR and AM: Collection and assembly of data, data analysis and interpretation, and writing the manuscript. MC: Expert advice for the concept and manuscript. All authors read, revised and approved the final manuscript.


The findings show that training of amateur long-distance XCS improved maximal oxygen uptake (p = 0.008) and had a positive effect on fat reduction, measured in percentages (p = 0.038) and in kilograms (p = 0.023), but did not change blood lipids or other parameters. Further research could focus on other aspects of the annual training cycle: the competition period, and women in a larger group of athletes. Training with roller skis and a cross-country skiing training machine  can support health and prevent obesity, overweight, and cardiovascular disease.Monitoring the training of amateur long-distance cross-country skiers (XCS) can help athletes’ achieve a higher exercise capacity and protect their health. The aim of this study was to assess body composition changes and lipid profiles in middle-aged amateur long-distance XCS after four months of training, including specialized roller ski training. The results of the time-to-exhaustion (TTE) test and blood tests and changes in body composition were analyzed with basic descriptive statistics: the paired Wilcoxon test was used to compare the results . Spearman’s rank correlation coefficient (R) was used to assess the influence of various variables on maximum oxygen uptake (VO In physically active people, training’s pro-health effects are noticeable. Among these changes are improvements in cardiovascular capacity, the musculoskeletal system, body composition, and lipid metabolism . PhysicaPhysical effort should be considered as a preventive and therapeutic method, and an alternative to more expensive methods  to achieve the same goals .Regular exercise, e.g., training of amateurs for long-distance cross-country races, can have health benefits in terms of exercise tolerance, lipid metabolism, and obesity prevention. Ren et al.  reportedAlthough physical activity has a positive effect on the lipid profile and reduces body fat, the WHO found that over 25% of the world population is still insufficiently active, and an increase in this figure is observed in developed countries. Among recommended physical activities is aerobic endurance combined with resistance training . Recent The growing popularity of long-distance cross-country ski races among amateurs raises questions about the impact of increased physical activity on health. Training volumes in this group far exceed public health recommendations . NegativThe risk of myocardial infarction is 50 times higher in sedentary people who suddenly start exercising compared to those who regularly exercise at a moderate or high level of exercise . Hence, 2max in middle-aged cross-country skiers. This knowledge can be used by trainers, doctors, and physiotherapists in the prevention and treatment of obesity and cardiovascular diseases, which may be conditioned by changes in these variables.While most of the literature concerns professional cross-country skiers or those who are obese and overweight, data are missing for amateurs. Monitoring changes in body composition and lipid profiles can be a critical factor in protecting against CHD risk, and public health. It is also necessary in this group to manage overloads in training and competition. Abnormal parameters in the lipid profile and body composition may contribute to the appearance of dysfunction in the circulatory system: it is important to systematically control these indicators, especially in the group of physically active middle-aged men. The aim of this study was to assess the changes in body fat content and lipid profiles in amateur middle-aged long-distance XCS after four months of specialized training. The hypothesis was that endurance training would not affect the lipid profile, while it would probably reduce body fat mass and show positive effects on VOSixteen well-trained amateur male XCS participated in the study. They had no experience in professional sport and did not receive any financial reward. The participants were not professional athletes, and they worked professionally and could spend up to one and a half hours daily on physical training. Their average age in the first test was 37.5 years (SD ± 6.6) and 37.9 (SD ± 6.8) in the second test. The research was carried out from May to September and was synchronized with the preparation period of the annual training cycle. During the study and the week before each test, the participants did not change their eating habits . The day before the study, they did not supplement their diet with caffeine and 48 h before the study they did not perform intensive efforts.The inclusion criteria were as follows: (1) written consent of participants; (2) at least three long-distance cross-country ski races completed in the previous season; (3) sports medicine doctor’s consent. The participants had no diseases and were not using any medications. The exclusion criteria were: lack of consent for participation in the study, poor health (any disease occurrence), or lack of medical consent.Participants followed the training plan, the core of which was roller skiing. Roller skiing is essential for summer training because it is a perfect substitute for cross-country skis, used widely by professional athletes. This research was conducted in accordance with the principles of the Helsinki Declaration, which obtained the approval of the Bioethics Committee of the Faculty of Human Nutrition and Consumption at Warsaw University of Life Sciences (No. 38p/2018).During the four months, participants performed the recommended training in five energy zones: these were determined individually by measuring the concentration of lactate and ergospirometric values during the TTE test . The firThe training plan included five training sessions per week. Two days were for endurance training, two days were for strength training , one training session was complementary, and two days were for rest. Their duration depended on the training period and ranged from 90 to 150 min for endurance units and from 60 to 90 min for strength training.The participants had a training plan prepared by a licensed trainer. They were informed that its full implementation was crucial during the research. No problems with its implementation were reported.These summaries show data on training intensity and hours over the study’s four training months.2 max  and was performed on the HP Cosmos CPET treadmill  and the Cosmed Quark/k4B2  with increasing speed and incline. The test started at a speed of 6 km/h and a 0% treadmill inclination. Then, every 3 min, the speed was increased by 1 km/h, and the inclination by 1%. The test was continued until the athlete’s subjective feeling of exhaustion . The VO2max values were defined as the highest oxygen uptake values obtained in the test. Heart rate was monitored with a Garmin ANT + heart rate monitor .Body weight and composition were measured on the Tanita MC-980 MA Plus Body Composition Analyzer , with an eight-point electrode system. The test was carried out with fasting before the TTE test began. Body weight, body fat percentage (expressed as a % and in kg), lean mass (muscle mass as a % and in kg), and body mass index (BMI) were measured. The study was conducted in the morning (from 8 a.m. to 10 a.m.). Participants had an empty bladder and did not eat a meal prior to measurements. Tests were carried out under standardized conditions at the Sports Diagnostics Center. The TTE test (ergospirometric test) was conducted to determine VOFasting blood was drawn from the antecubital vein in dry tubes (fasting for 12 h) during the May and September tests, after the body composition measurement and before the TTE test. The spectrophotometric method determined the lipid profile: total cholesterol, HDL-C, and triglycerides. LDL-C was calculated by the Friedewald formula . The Cob2max). Statistical significance was set at p < 0.05 for all analyses.Statistical calculations were performed using Statistica 13.1 software  for MS Windows 10. The normality of data distributions was tested using the Shapiro–Wilk W-test. The Brown–Forsythe test for homogeneity of variance was carried out. Results are expressed as median and interquartile range—IQR. The Wilcoxon test was used to compare the measurements from the first and second tests. Spearman’s rank correlation coefficient (R) was used to assess the influence of various variables on maximum oxygen uptake , and maximum oxygen uptake . There were no significant changes in HDL-C, non-HDL-C, LDL-C, triglycerides, BMI, maximum heart rate, and body weight.Comparisons of body weight and adipose tissue as well as the exercise parameters and lipid profiles of the first and second tests are shown in 2max (mL/kg/min) (p = 0.049 and correlation = −0.5278). Other variables did not significantly correlate with this parameter. The correlation concerned changes between the values before and after the training period.Correlations for maximum oxygen uptake can be found in This study investigated the effect of four months of training on body composition and lipid profile in middle-aged male amateur long-distance XCS.The training plan may contribute to better adaptation to competition efforts and to reducing the negative impact of strenuous exercise on the cardiovascular system, which must be monitored individually. It appears that the training itself, based on aerobic exercise, and despite the increased volume, has a positive effect on the body. Negative changes occur while participating in competitions, caused by intensity and inflammation . These cp = 0.008), which is used to assess the exercise capacity of endurance athletes. Rusko [2max stabilizes later. Professional skiers, however, are able to increase it by increasing both the volume and intensity of training [According to our results, the largest significant change was recorded in maximum oxygen uptake  and reduced their body fat mass. There were no significant changes in HDL-C, non-HDL-C, LDL-C, triglycerides, BMI, maximum heart rate, and body weight. Nevertheless, it is worth pointing to the pro-health trends that were observed in these variables. Thus, the hypothesis of this research was confirmed only in part.Four-month training of sixteen well-trained male amateur long-distance XCS increased their maximum oxygen consumption (VODue to the relatively small sample size, further research could focus on assessing changes in other parts of the annual training cycle, e.g., the competition period, a larger group of athletes, and the inclusion of women. Other indicators such as troponin and selected hormones such as insulin should be assessed for changes in the overall analysis.


Mental disorders are common in patients with pulmonary arterial hypertension (PAH) and contribute to impaired quality of life (QoL). The impact of mental disorders on access to health care, differences in clinical parameters and treatment in patients with PAH is unclear. In this study we sought to assess the impact of mental disorders and other health disparities on health-care-utilization in patients with PAH.In a cross-sectional observational study of patients with PAH, mental disorders were characterized using a structed clinical interview. In addition, patients completed a self-administered questionnaire to assess QoL, symptoms of anxiety and depression, lifestyle-factors and educational status. Number of outpatient visits and communication events per year were calculated as a surrogate for health-care-utilization and were compared by the presence of mental disorder. Linear regression analysis was conducted to assess the impact on health-care-utilization.117 patients with PAH participated in this study  years). Significant differences between patients with or without mental disorders were found in anxiety, depression and QoL. There were no significant differences in clinical parameters. Patients with mental disorders had higher rates of outpatient visits and communication events than patients without mental disorders. Linear regression revealed a gain of 2.2 communication events per year in the presence of any mental disorders.Mental disorders in patients with PAH are common and significantly affect health-care-utilization. This higher demand in patients with mental disorder needs to be addressed by physicians, psychiatrists and specialized nurses offering therapeutic strategies. Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary vascular resistance due to remodeling of pulmonary vasculature , 2. SympMental disorders such as major depression disorder (MDD) or panic disorder (PD) are common in patients with PAH, and patient's quality of life, mental health, and access to medical care have been addressed in recent studies –10. The Health disparities are defined as significant differences in health or outcomes with correlation to greater obstacles to healthcare based on ethnicity, sex, age, socioeconomic status, occupation, mental health, cognitive or physical disability . Health This cross-sectional observational study included patients with a confirmed diagnosis of PAH from one PH referral center . This patient cohort is a subsample of a larger cohort that was originally described by Olsson et al. . All patLCO). Lifestyle factors included smoking status , duration of smoking and mean number of cigarettes per day to calculate the number of packyears  for Diagnostic and Statistical Manual of Mental Disorders, fifth Edition (DSM-V) by a medical student carefully trained and under the supervision of a senior physician to determine the presence of MDD and PD and covered the past 4 weeks prior to the interview . The HosTotal number of outpatient visits and patient communication datasets were derived from a clinical research database as well as the date from first and last outpatient visit or communication event respectively. Patient communication is defined as any kind of unscheduled communication event  documented in the clinical research database by a physician or a specialized nurse. Time-variables comprising the time in years between first and last date of outpatient visit or communication event were calculated and set into relation to the number of visits and communications. This allowed us to calculate outpatient visits and communication events per year for each patient.25-Q75) or as mean and standard deviation (SD). Categorical variables are presented as number (n) and percent (%). Comparisons of continuous parameters were conducted using t-test or Mann-Whitney U test and comparison of categorical parameters by using Chi-square-test or fisher's exact test, unless indicated otherwise. Linear regression models calculated on dependent variables outpatient visits per year and correspondences per year in a stepwise forward setting. Independent variables were age, sex, packyears, HADS-A and HADS-D scores, QoL, education, WHO FC, 6MWD and the diagnosis of any MDD or PD. All tests were two-sided, p-values < 0.05 were considered statistically significant.IBM SPSS Statistics  and Stata 13.0  statistical software programs were used for statistical analysis. Continuous parameters are presented as median and interquartile range (Qp < 0.001).A total of 117 patients were enrolled in this study. Patient characteristics are shown in p = 0.022, p = 0.001).Detailed results are stated in p = 0.003) and per 50 m 6MWD there was a loss of 0.1 visits per year (p = 0.007). Impact on communication events per year was only determined by the presence of MDD or PD. If a patient had any current MDD or PD, correspondence increased by 2.2 communication events per year (p = 0.001) with the linear regression analysis stating a constant of 2.4 communication events per year. This results in a near two-fold number of communication events in the presence of MDD or PD. The other covariates sex, packyears, HADS-A and HADS-D scores, QoL, education and WHO FC had no significant impact on the number of outpatient visits or communication events per year.Impact on number of outpatient visits and communication events was tested using clinical parameters, the presence of MDD or PD, QoL and lifestyle factors. Linear regression analysis showed a significant impact of age and 6MWD on the number of visits per year. Per 10 years of patients age there was a loss of 0.2 visits per year . MH has received honoraria for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer, all outside the present study. KO has received honoraria for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, United Therapeutics and Pfizer, all outside the present study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Thousands of papers on primary aldosteronism (PA) have been published in the last two decades. This study aimed to evaluate the research hotspots and future trends in PA research using bibliometric analysis. A total of 2,365 PA research papers between 2000 and 2020 were included. The dominant position of the United States in global PA research throughout this 20-year period was evident, and it was also the country most frequently involved in international cooperation. The University of Padua was the most productive institution and a leader in research collaboration. The Journal of Clinical Endocrinology & Metabolism was the most productive journal in terms of the number of publications on PA. Further, Mulatero P, Reincke M, Beuschlein F and Wu VC all made significant contributions to PA research. Five hotspots have been identified: (1) metabolic syndrome associated with PA; (2) molecular mechanisms of PA; (3) adrenal adenoma and adrenal cortex; (4) hypertension associated with PA; and (5) clinical monitoring parameters and diagnosis in patients with PA. Our results suggest that the molecular mechanisms of PA will remain research hotspots in the future. International collaboration is also expected to widen and deepen in the field of PA research. Primary aldosteronism (PA), characterized by an increased aldosterone production, is the most frequent form of secondary hypertension , 2. PA pBibliometric analysis is a novel scientific method used to evaluate contributions to a research field, including those by countries, institutions, authors, and journals. Further, bibliometric analysis can predict the hotspots and trends within a certain research area through information visualization –19. HoweIn the present study, we performed a comprehensive bibliometric analysis of PA research literature from 2000 to 2020, taking into account the number of annual publications, countries, international cooperation, institutions, journals, authors, and keyword co-occurrence visualization analysis. Furthermore, perspectives on progress in the field of PA research over the past two decades were considered. Overlay visualization maps of co-occurring keywords and double-clustering analysis were also performed in order to confirm the trends and hotspots in PA research. We hope that this study will provide new perspectives and a basis for future PA research.via the China Medical University library website. The retrieval strategy was TS = primary aldosteronism.The Web of Science is one of the most influential databases of scientific literature. In this study, all data were retrieved from the Web of Science Core Collection (WoSCC) The publication period in the present study was limited to the period from 2000 to 2020. Non-English language, non-article, and non-review publications were excluded. WoSCC data including titles, author information, abstracts, keywords, journals, and references were downloaded in.txt format. To avoid the bias caused by frequent database updates, all literature retrieval and data downloads were completed on the same day . Two investigators (CW and JY) independently performed the search and had an agreement of 95% (kappa = (P0 − Pe)/(n − Pe) = 0.95 > 0.75), showing significant consistency (http://bibliometric.com/) and VOSviewer 1.6.15  for bibliometric analysis. Apache ECharts (https://echarts.apache.org/), a JavaScript-based data visualization tool, was used to visualize the annual number of publications and the number of cumulative publications in different countries/regions. The online bibliometric analysis platform was used to visualize international collaboration between countries. VOSviewer was used for analysis and visualization of bibliometric networks such as authors, institutions, journals, co-citations, and the keywords used in the articles , and Hirsch index (h-index). IFs were obtained from the 2019 Journal Citation Reports (JCR) to assess the scientific value of research . The valarticles . Networkarticles . The rowarticles .As shown in According to the WoSCC database, 69 countries or regions contributed to publications on PA between 2000 and 2020. The top 24 countries or regions in terms of the number of publications (n > 10) on PA are presented on a world map in The most productive institutions were also evaluated in our study. As shown in Journal of Clinical Endocrinology & Metabolism (n = 165), Hypertension (n = 142), and Journal of Hypertension (n = 111) were the top three journals in terms of the number of publications on PA , and they were also the top three journals with the highest average number of citations per paper . Hypertension, Journal of Clinical Endocrinology & Metabolism, and European Journal of Endocrinology had the highest IFs of any journals in 2019 . The highest h-index was 35, belonged to Hypertension. Among the top 10 most productive journals, Journal of Clinical Endocrinology & Metabolism, Hypertension, Journal of Hypertension and European Journal of Endocrinology were classified as Q1 according to the JCR 2019 standards , quartile in category (2019), and h-index. The top 10 most productive journals in the field of PA research are listed in ns on PA Table 3.vs. 3,421 vs. 3,392 times, respectively, The top 10 most productive authors in the field of PA research are presented in With an appearance of more than 20 times, 34 of the most frequent keywords were extracted from the included publications and are displayed in The above 34 high-frequency keywords were divided into five clusters. All representative articles involved in each cluster were mined to further summarize hotspots in the field of PA Finally, five hotspots were identified using BICOMB and gCLUTO software packages:Cluster 0: Metabolic syndrome associated with PA.Cluster 1: Molecular mechanisms of PA.Cluster 2: Adrenal adenoma and adrenal cortex.Cluster 3: Hypertension associated with PA.Cluster 4: Clinical monitoring parameters and diagnosis in patients with PA.To explore the changes of hotspots over a period of time, a network visualization map of keyword co-occurrence was generated using VOSviewer software, and the results showed that the keywords “KCNJ5”, “K(+) channel mutations”, “somatic mutations”, and “KCNJ5 mutations” began to appear in the last 5 years Figure 7In the era of the information explosion, bibliometric analysis can help scientific researchers to manage their knowledge and visualize knowledge structures more intuitively. By presenting visual results, bibliometric analysis can help new researchers in a specific field to grasp the overall trends in the field being investigated. It can also reveal milestone manuscripts, the most productive authors and institutions, and current research hotspots, as well as future trends –27. In oThe number of publications in a particular research field can reflect the productivity and developments in the field over time . In the The number of publications in a research field is an important indicator for evaluating the scientific research level of a country or institution , 28, 29.Journal of Clinical Endocrinology & Metabolism published the highest number of PA-related papers and had the highest number of total citations .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.