Nephrotic syndrome (NS) in children is widely believed to be associated with severe changes in the immune system. Based on lymphocyte subset analysis, we examined the pathogenesis of immune deficiencies in children with NS with varying steroid sensitivity. Our study utilized flow cytometry to retrospectively analyze the ratios of lymphocyte subsets in 204 children with nephrotic syndrome and 19 healthy children.p < 0.05), and CD19 + B lymphocytes were increased in onset (p < 0.05). Compared with onset, the proportion of CD19 + B lymphocytes decreased in SRNS, while the proportion of CD19 + B lymphocytes increased in SDNS, p < (0.01). The ratio of CD8 + T/CD19 + B in onset in SDNS group was significantly higher than that in SSNS and SRNS groups (p < 0.01) and healthy control group (p < 0.05). Compared with onset, the ratio of CD8 + T/CD19 + B in SDNS group decreased significantly (p < 0.01), while the ratio of CD8 + T/CD19 + B in SRNS group increased significantly (p < 0.01). The proportion of CD56 + CD16 + NK cells was significantly reduced in children with INS (p < 0.01).Compared with healthy children, the ratio of CD4 + /CD8 + in onset and remission was decreased in SRNS group (CD8 + T lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during onset of SDNS, while CD19 + B lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during relapse of SDNS. The CD8 + T/CD19 + B ratio may predict the degree of frequent recurrence. There is a certain degree of lymphoid subsets disorder in children with NS. The Idiopathic Syndrome (INS) is a common childhood kidney disease caused by a ruptured capillary wall that allows large molecules to leak from the blood into the urine , 2. The  A course of oral corticosteroids is the initial treatment for INS, and the prognosis is determined by the response to corticosteroid therapy . ClinicaPrevious studies have indicated that the most pathological process of INS is caused by T lymphocytes dysfunction or abnormal secretion of a capillary porousness factor . StudiesTo assess the sensitivity of children to steroids and effectively intervene early, we hoped to find specific biological indicators in children with INS, which would aid in the prognosis of children and cut down the recurrence rate . TherefoIn this study, 204 children (179 boys and 25 girls with an age range of 12–168 months) were included. The control group included 19 healthy children (15 boys and 4 girls with an age range of 48–132 months). A classification of children with NS was made after the initial diagnosis based on their sensitivity to steroids:27 children with SSRS (complete response after 4 weeks of corticosteroid treatment), 52 children with SRNS (no complete response after 8 weeks of corticosteroid treatment), and 45 children with SDNS (two consecutive relapses during steroid therapy or within 14 days of the end of treatment) [The relevant indicators of the patients were observed. All indicators were detected using the corresponding instruments and matching kits. Serum albumin (ALB), serum creatinine (SCr), and endogenous creatinine clearance (Ccr), as well as IgA, IgG, IgM, and complement C3 and C4 levels, were measured using an automated biochemical analyzer (Abbott C16000). A Beckman whole blood cell analyzer (LH750) was used to detect white blood cells (WBC), platelets (PLT), neutrophils (NEU), lymphocytes (LYM), and monocytes (MON). The peripheral blood was tested with flow cytometry (BD Canto II) for the detection of CD3 + T, CD3 + CD4 + T, CD3 + CD8 + T, CD19 + B, and NK subsets.P values were bilateral, and statistical significance was set as p < 0.05. The Kolmogorov-Smirnov test was used to determine the normality of continuous data. The means, standard errors, and medians were presented as means + standard errors. Continuous variables were compared using a parametric ANOVA or nonparametric Kruskal–Wallis test, and pair-to-pair differences were compared using an unpaired T test or Mann–Whitney U test, respectively. In addition to constructing a receiver operating characteristic (ROC) curve and determining the area under the curve (AUC) to gauge the prognosticative strength, it was also determined the optimal critical point to maximize its sensitivity and specificity. All Table In all NS groups, WBC, PLT, NEU, LYM, and MON levels were higher than in healthy children. For WBC levels, those in the SRNS group were significantly higher than those in the SSNS group. PLT levels and LYM and MON ratios were significantly increased in each NS group at onset and remission. The proportion of NEU in the SSNS and SRNS groups was lower in remission than at onset. The IgG levels of each INS group were significantly lower than those of the control group and the remission group, and the IgM levels were significantly higher than those in healthy children. Children with SSNS and SRNS had lower IgA levels than healthy children. The complement C4 levels in all groups did not differ significantly, while complement C3 levels in the INS incidence groups were higher than those in the healthy control group, and SDNS/FRNS decreased in remission.The SDNS/FRNS groups had a significant increase in CD3 + T lymphocyte proportions, especially in CD4 + T and CD8 + T lymphocytes, when compared to the SSNS and SRNS groups. The proportion of CD3 + T and CD8 + T lymphocytes decreased during remission Fig. . CD4 + /We attempted to use lymphocyte subsets to predict the outcome of corticosteroid therapy in the diagnosed SSNS, SRNS, and SDNS/FRNS patients. ROC curves were used to assess the potential utility of CD19 + B lymphocytes at the onset of SRNS. The area under the ROC curve for CD19 + B lymphocytes to predict SRNS was 0.718 . The optimal cut-off value was 17.46%/L, corresponding to 71.2% sensitivity and 70.8% specificity Fig. , Table 2A large amount of data indicates that T cells and B cells are major participants in the pathogenesis of INS. The dysfunction or abnormal regulation of T lymphocytes is related to the pathogenesis of INS . CD4 andResearch has shown that peripheral blood B cell counts and activation levels may influence INS disease occurrence. Compared with the HC group, transitional B cells were significantly increased in the early stage of the disease; some were regulatory B (Breg) cells, which play an immunomotor role by secreting IL-10, IL-35, and transforming growth factor β (TGF-β) . ChangesWe found that NK cells in patients with nephrotic syndrome were changed, and the CD56 + CD16 + NK cells in INS were significantly reduced, which was consistent with Ye et al. . TherefoThis study has several limitations. First, this is a retrospective analysis with a small sample, which may be affected by result bias and confounding factors. The conclusion needs to be confirmed by a diversified study with a large sample. Second, we could not further explore the relationship between T, B, and NK cell subsets, clinical indicators, and steroid sensitivity, resistance, and dependence. Third, the children in onset and remission were different in each NS subgroup, which may be biased by other confounding factors. However, we did find some meaningful changes in INS, and we believe that our study lays the foundation for further research.By analyzing lymphocyte subsets, we found that a more severe lymphocyte subset disorder and abnormal regulation existed in children with SRNS, which may affect the treatment and prognosis of corticosteroids. Compared with SRNS, SDNS showed a greater increase in CD8+ T lymphocytes at onset, whereas B lymphocytes increased mainly in remission. Therefore, we hypothesized that CD8 + T and B lymphocytes might be involved in the mechanism of the frequent recurrence of SDNS. In summary, patients with nephrotic syndrome have impaired immune performance mediated by abnormal cells, together with T cells, B cells, monocytes, and NK cells. Immune factors are also involved in the pathological process of nephrotic syndrome. We used CD3 + T, CD3 + CD4 + T, CD3 + CD8 + T, CD19 + B, and CD8 + T/CD19 + B lymphocytes to predict the degree of frequent recurrence and drug resistance to provide a better basis for clinical practice and monitor the immune status of children.


The objective of the study was to characterize the longitudinal, dynamic intracranial pressure (ICP) trajectory in acute brain injury (ABI) patients admitted to intensive care unit (ICU) and explore whether it added sights over traditional thresholds in predicting outcomes.ABI patients with ICP monitoring were identified from two public databases named Medical Information Mart for the Intensive Care (MIMIC)‐IV and eICU Collaborative Research Database (eICU‐CRD). Group‐based trajectory modeling (GBTM) was employed to identify 4‐h ICP trajectories in days 0–5 post‐ICU admission. Then, logistic regression was used to compare clinical outcomes across distinct groups. To further validate previously reported thresholds, we created the receiver operating characteristic (ROC) curve in our dataset.A total of 810 eligible patients were ultimately enrolled in the study. GBTM analyses generated 6 distinct ICP trajectories, differing in the initial ICP, evolution pattern, and number/proportion of spikes >20/22 mmHg. Compared with patients in “the highest, declined then rose” trajectory, those belonging to the “lowest, stable,” “low, stable,” and “medium, stable” ICP trajectories were at lower risks of 30‐day mortality , , , respectively. ROC analysis demonstrated an unfavorable result, for example, 30‐day mortality in total cohort: an area under the curve (AUC): 0.528, sensitivity: 0.11, and specificity: 0.94.This study identified three ICP trajectories associated with elevated risk, three with reduced risks for mortality during ICU hospitalization. Notably, a fixed ICP threshold should not be applied to all kinds of patients. GBTM, a granular method for describing ICP evolution and their association with clinical outcomes, may add to the current knowledge in intracranial hypertension treatment. To summarize, a novel ICP trajectory that could enable us to move the treatment of ABI from a fixed threshold approach to a more individualized treatment was proposed. ICP values and variability differed across these six identified trajectory groups with favorable vs. unfavorable outcomes. The epidemiological shift toward a larger proportion of physiologically fragile elderly patients calls for more attention. People with Glasgow Coma Scale (GCS) > 12, age less than 16 years old, and those who stayed in ICU < 24 h were excluded from the study. Moreover, for patients with ICU admissions more than once, only data of the first ICU admission of the first hospitalization were included in the analysis. Of these, patients who had ICP recordings were ultimately included.2.3In this study, detailed demographic data were collected on age, gender, race, body mass index (BMI), and smoking history. Coexisting disorders were also collected. Then, the Charlson comorbidity index (CCI) was calculated from its component variables. In addition, we extracted data containing type of injury , mechanism of injury , multiple scoring systems , medication, and neurosurgical interventions on the first day of ICU admission. For some variables recorded more than once within the first 24 h after ICU admission, the one associated with the highest acuity of illness was used. Outcomes were determined by all‐cause mortality (30‐day) and GCS value at discharge from ICU . Favorable outcomes referred to the decrease in mortality and improvement in GCS.2.4Continuous variables were presented as median with interquartile range or mean with standard deviation, and categorical variables as total number and percentage. Proportions were compared using the chi‐square test or Fisher exact tests while continuous variables were compared using the t test  or Wilcoxon rank sum test , as appropriate. Pairwise comparisons were adjusted (Bonferroni's method).33.1GBTM assumes that the population is heterogeneous and composed of several classes of subjects characterized by a number of mean profiles of trajectories.3.2After identifying ICP evolution trajectory groups, we evaluated the associations between trajectory subgroup membership  and clinical outcomes using logistic regression models. In these analyses, we assigned group 1 as the reference. Initially, a crude logistic model was constructed. Then, all models were adjusted for the minimum set of potential confounders, namely, age, sex, race, BMI, smoking history, CCI, type of injury, mechanism of injury, medication , and surgical interventions .3.3We performed multinomial logistic regression models to calculate adjusted odds for trajectory membership based on patient, clinician, and prescription characteristics. Models were adjusted for age, sex, race, BMI, smoking history, CCI, type of injury, mechanism of injury, medication, and surgical interventions. Besides, in order to verify the previously recommended ICP threshold in the 4th edition guidelines for TBI,3.4As a sensitivity analysis, we developed an additional GBTM model including only elderly subjects (age ≥ 55 years) subjects and explored in‐hospital outcomes among this specific group with different characteristics. Moreover, the patterns assumed missing to be completely at random, so multiple imputation approach was used to iterate the original data on the first day of ICU admission Table .26p < 0.05. All analyses were performed with R version 4.0.2 (http://www.R‐project.org) and STATA .Statistical significance was considered to be at two‐sided 44.1n (%): 12.57% vs 3.61%, median ICP > 22 mmHg, n (%): 9.42% vs 2.09%] , the highest ICP trajectory, was characterized by the first decline then rise over time. Group 2 (n = 240) started with the lowest ICP which remained stable over time. Compared with 2, group 3 (n = 354), the largest group, had higher ICPs but remained persistently low. It had double‐digit ICPs, but almost no value can exceed 20 mmHg. Group 4 (n = 146) had ICP values floating around 20 mmHg. Group 5 (n = 45) had elevated ICP‐ fluctuating between 20–30 mmHg. Group 6 (n = 12) was a small cohort with early high ICP that rose first continued to decline over the next 90 h. Of 810 subjects included, 1.6% were classified group 1 , 29.4% group 2 , 43.2% group 3 , 18.6% group 4 , 5.6% group 5 , 1.6% group 6 .Six distinct trajectory groups were ultimately identified by our model. The AvePP of group membership was ≥0.85 with the smallest BIC, AIC and LL, indicating excellent grouping Table . LongituThe demographic and clinical characteristics stratified by the ICP trajectories groups are shown in Table 4.3In the unadjusted models, belonging to groups 2, 3, 4, and 5 was associated with reduced mortality , , ,  and better neurological outcome  (group 1 as a reference), suggesting favorable outcomes in these four groups. After adjusting for potential confounders, the multinomial logistic regression model yielded similar results, only with group 5 having no statistically significant results  Figure .4.4On multinomial analysis, as the age increased, the odds of being in group 3, 4, 5, 6 decreased. For example, odds of being in the group 6  vs the group 2  decreased by a factor of  for each age increase. Also, those treated with medication after ICU admission were more likely to be in the group 5  when compared to group 2. Conversely, treatment with surgery also decreased odds of the membership from group 2 to group 5, indicating favorable outcomes Table .4.5The results of ROC  revealed that the area under the curve (AUC) was only 0.528, accompanied by a low value of sensitivity (0.11) and specificity (0.94) when setting the threshold 22 mmHg as the cutoff value. With regard to GCS value at discharge from ICU, the AUC was 0.523, with a low value of sensitivity (0.95) and specificity (0.10). Similar results were found in elder patients and female patients, suggesting that “one fixed, universal ICP‐treatment‐threshold fits all” approach deserved to be questioned Table . Perhaps4.6Should ICP management in older patients be different to younger ones? In order to elucidate the aforementioned issues, we performed GBTM in this specific subject. We found that the GBTM yielded fundamentally different ICP patterns Figure . Compare5In cerebrovascular disease, high variations in ICPs remain a topic of concern, if unproperly treated, will be accompanied by hydrocephalus.Indeed, this study identified six distinct ICP trajectory groups which were distinguished by different ICP patterns, and in the risk‐adjusted models, these trajectories were significantly associated with clinical outcomes, such as 30‐day mortality. Groups 2, 3, and 4 had stable trajectories with a value of ICP less than 20 mmHg, and naturally, reported a favorable outcome. Nonetheless, in a research conducted by Jha RM et al, two cohorts of patients had unfavorable outcomes despite low ICP.Taken together, in the last four editions of the BTF Guidelines for the management of TBI, the recommended ICP threshold for treatment has changed from 25 mmHgWhen subgroup for age was analyzed, the threshold did not change for mortality but decreased to 18 mmHg for favorable outcome for patients over 55 years of age. Given that subgroup analysis may have been underpowered, and these findings were limited to only this study, the BTF did not support an ICP recommendation that varies by age. In the total model, we found that patients in groups 2 and 3 were older, with higher CCI, more subarachnoid hemorrhage, lower ICP, higher CPP. This may be partially attributed to the special pathophysiological condition of the elderly, including the increase in age‐related comorbidities, use of preinjury antiplatelet/anticoagulants, age‐related atrophy.The present study attempted to add to the current knowledge in developing a new concept of “time‐varying” for ICP. In particular, the application of GBTMs in ABI patients enabled the identification of specific ICP patterns over time and the clinical outcomes associated with distinct trajectories. The “dynamic and individualized” concept is replacing ICP regulation with ABI management, with ICP value regarded as a tool, not a goal. Future study could focus on the individualization of ICP and investigate its conjunction with other parameters including the state of cerebrovascular pressure reactivity, tissue oxygenation quality, and non‐ICP‐related metabolic and energy crisis. Furthermore, this study was based on a population‐based longitudinal cohort from multi‐centers in the United States, a high‐quality data with granular temporal detail, a homogeneous population, accordingly, ensuring the robustness, reliability, generalizability of the findings.This study had several limitations, consistent with those inherent to many large administrative database studies. First, based on electronic records of routine clinical practice, missing data and outliers were common. Apart from this, the use of GCS value at discharge from ICU was suboptimal but necessary because of the lack of data concerning Glasgow Outcome Scale (GOS) at 6 months. Third, variables were extracted by ICD‐9 and ICD‐10 diagnosis codes. Incorrect codes or misclassification bias inevitably exist. Fourthly, the time span of this study is relatively long, the ICP monitoring catheter and treatment may vary in decades. Finally, neuroimaging data including CT and cerebral angiography were not included in the databases.6To summarize, we proposed a novel ICP trajectory that could enable us to move treatment of ABI from a fixed threshold approach to a more individualized treatment. ICP values and variability differed across these six identified trajectory groups with favorable vs. unfavorable outcomes. The epidemiological shift toward a larger proportion of physiologically fragile elderly patients calls for more attention. If validated rigorously, ICP trajectory modeling combined with higher resolution data including waveform analysis may provide additional potentially useful classifications for ICP.The conception and design was made by Fan Yang, Chi Peng, Liwei Peng, and Peng Wang. Fan Yang and Chi Peng contributed to data acquisition and statistical analysis. : Chi Peng, Peng Wang, and Lei Zhao contributed to analysis and interpretation of data. Wei Zuo and Chao Cheng critically revised the article. Zhichao Jin and Weixin Li contributed to study supervision. All authors reviewed the submitted version of the manuscript.The authors declare that they have no competing interests.Appendix S1Click here for additional data file.


Women and infants are among the most vulnerable groups for micronutrient deficiencies. Pregnancy micronutrient status can affect birth outcomes and subsequent infants’ growth.We determined the relationship between maternal iron and vitamin A status at delivery using several biomarkers  and birth outcomes  in rural Uganda. We investigated women who had serum results at the point of delivery and paired them to their infants at birth (n = 1244). We employed multivariable linear and logistic regression, adjusting for clustering at the subcounty level to determine the relationship between maternal micronutrients and birth outcomes.p < 0.030).After adjusting for relevant factors, we found that maternal iron status (ferritin and BIS) and anemia (hemoglobin) were not significantly associated with the assessed birth outcomes. However, there was a significant association between serum sTFR and preterm births . For Vitamin A, we observed a significant positive association between RBP and length-for-age (LAZ) at birth (β = 0.12, These findings indicate that the relationship between maternal iron status and birth outcomes needs to be further investigated, because depending on the biomarker used the associations were either in favor of an adverse birth outcome or not significant. Additionally, they confirm that higher maternal RBP levels could be beneficial for birth outcomes.Clinicaltrials.gov as NCT04233944.The online version contains supplementary material available at 10.1007/s10995-022-03387-5. There is conflicting evidence of the different types of biomarkers used to assess maternal micronutrients status (in this case iron and vitamin A) and their relationship with birth outcomes. Our study aims to address this question by using the three major indicators of iron status  and RBP for vitamin A status, in a relatively large sample of mothers in rural Uganda. In addition, to achieve more precise estimates, we correct for inflammation using C-Reactive Protein (CRP) and α-1 acid glycoprotein (AGP) as per suggested in the most recent literature.Women and infants are among the most vulnerable groups for micronutrient deficiencies CDC, . Iron anDifficulties arise when assessing micronutrient deficiencies in countries where a high burden of infection exists because biomarkers used to measure them are triggered by inflammation  and birth outcomes  after adjusting for relevant factors in rural Uganda. A second objective was to describe the prevalence of iron and vitamin A deficiencies, anemia, and IDA in this population of mothers with and without adjusting for inflammation using the BRINDA correction.The Uganda Birth cohort (UBC) study was a longitudinal prospective birth cohort of pregnant women aged 15–49 years from rural North and South-Western subcounties (geographic administrative units) of Uganda. Funded by the United States Agency for International Development (USAID) the UBC was conducted between 2014 and 2016. The aim was to intensively study pregnant women, their children and households to understand the impact of agriculture, nutrition and health interventions provided by the Uganda Community Connector project (CC) USAID, . PregnanOf the women enrolled, data from 4949 were available by Visit 1. Women and their infants were followed throughout the first year of the child’s life. Data were collected at enrollment, birth Visit 3), and at 3 (Visit 4), 6 (Visit 5), 9 (visit 6) and 12 (Visit 7) months from the date of delivery  of Makerere University School of Public Health, and the Institutional Review Board (IRB) from both Tufts Health Sciences and Harvard T.H. Chan School of Public Health. The UBC study was registered at clinicaltrials.gov as NCT04233944.In this paper, we investigated a subsample of women who had serum sample results at the point of delivery and paired them to their infants measured within 72 h of birth n = 1244) to assess the relationship between biomarkers and birth outcomes  were drawn at the point of delivery , and the resultant serum was frozen and shipped to US and Germany for processing, distribution and analysis. The VitMin Lab in Germany analyzed ferritin (FER), sTFR, RBP, and inflammatory markers C-Reactive Protein (CRP) and α-1 acid glycoprotein (AGP) using a sandwich enzyme-linked immunosorbent assay  =  − [log(sTFR/FER ratio) − 2.8229]/0.1207  using their regression correction approach , preterm births, WAZ, LAZ, WLZ and head circumference. Birth weight (kg) was measured using a Seca 874 digital scale (accuracy ± 50 g) and calculated as the mean of three repeated measurements on each infant (Seca Corporation). Length was measured using a measuring board (accuracy 0.1 cm) (Infant/Child/Adult ShorrBoard®). LBW was defined as the percentage of infants with birth weight lower than 2500 g. Gestational age (days) was calculated as the date from last menstrual period to delivery date. Implausible gestational ages  were excluded from analyses (n = 150). Two outcome variables were derived from gestational age: preterm birth and SGA. A preterm birth was defined as gestational age < 259 days  were calculated using infant’s age, weight and length variables at birth. Birth lengths less than 45 cm were excluded from the WLZ calculation. Other exclusions included WAZ <  − 6 or > 5, WLZ <  − 5 or > 5, and LAZ <  − 6 or > 6. Stunting, underweight and wasting were defined as LAZ, WAZ and WLZ less than − 2 standard deviations respectively. Head circumference (cm) was measured using a tape and computed as a mean of three different measurements on each child at birth.The primary exposure variables included ferritin, sTFR, BIS, hemoglobin and RBP. Other covariates included Wealth Index, food security as measured by the Household Food Insecurity Access Scale (HFIAS)  and folic acid tablets is recommended in Uganda throughout pregnancy  standardized scores for WAZ (underweight), LAZ (stunting) and WLZ (wasting) were − 0.1 (± 1.1), − 1.0 (± 1.7), and 0.6 (± 1.7), respectively. The mean (± SD) gestational age at birth was 274 days (± 22) and 14% of the infants were born SGA. About 20% of all infants were born preterm. The mean (± SD) gestational age of those born preterm was 240.8 days (± 16.4) and at term, 282.7 days (± 13.3). Their range of gestational ages was 168–258 days and 259–315 days, respectively.Table The prevalence of iron and vitamin A deficiencies and anemia in Ugandan mothers is depicted in Table To describe RBP values as a proxy for vitamin A deficiency, we used the recommended cut-off for retinol (RBP < 0.7 µmol/L) WHO, . Some stResults for the associations between maternal iron and vitamin A biomarkers and birth outcomes are shown in Tables Maternal iron status (ferritin and BIS) and anemia (hemoglobin) were not significantly associated with any of the assessed birth outcomes. However, all things considered, higher sTFR levels, indicative of iron deficiency, were associated with a 33% decrease in the odds of delivering a preterm baby . We further tested for influential points using Cook’s distance and identified 75 observations that may have an effect on the relationship between sTFR and preterm birth. Upon omitting them, the significant relationship remained significant .p < 0.030). The bivariate relationship and its magnitude is shown in Fig. p < 0.0046).Regarding vitamin A status Table , we obseThis study found no relationship between ferritin or BIS and birth outcomes, but it did observe an association of lower risk of preterm births and higher levels of sTFR, an indicator of iron deficient erythropoiesis. These results are in line with recent findings in China, Papua New Guinea and Taiwan  found in this study could be explained by the high percentage of IPT use (82%). This treatment, accompanied by other preventive interventions, is a product of national and international programs to reduce malaria in Uganda over the past decade. The prevalence of anemia (14%) was also lower compared to that reported in another study (29%) Below is the link to the electronic supplementary material.


Diets rich in (poly)phenols have been associated with positive effects on neurodegenerative disorders, such as Parkinson's disease (PD). Several low‐molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol‐rich food. It is expected that LMWPM, upon reaching the brain, may have beneficial effects against both oxidative stress and neuroinflammation, and possibly attenuate cell death mechanisms relate to the loss of dopaminergic neurons in PD.O‐sulfate (cat‐sulf), and pyrogallol‐O‐sulfate (pyr‐sulf), in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1‐methyl‐4‐phenylpyridinium (MPP+) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP+ insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat‐sulf pretreatment appeared to boost counter‐regulatory defense mechanisms (preconditioning). When MPP+ is applied, both LMWPM positively modulated glutathione metabolism and heat‐shock response, as also favorably shifting the balance of pro/anti‐apoptotic proteins.This study investigates the neuroprotective potential of two blood‐brain barrier permeant LMWPM, catechol‐Our findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. They are promising molecules to be further explored in the context of preventing and attenuating parkinsonian neurodegeneration. +. LMWPM induces differential modulation of gene expression that overall promotes an adaptative response to better cope with MPP+ insult. Particularly, cat‐sulf, by positively modulating glutathione metabolism, apoptotic proteins balance, and heat‐shock response, it promotes the increase of cell viability and ATP levels restoration.Neuroprotective effects of LMWPM pretreatment in LUHMES neurospheroids are challenged by MPP PD symptoms result from a decrease in dopamine levels which might be caused by a disturbance in dopamine exchange system.Parkinson's disease (PD) is the second most common neurodegenerative disorder and the first motor debilitating degenerative disease.1, 2 Through the past years, it has been shown that oxidative stress is central to the pathology of this disease. Moreover, the substantia nigra of PD patients shows increased levels of oxidized lipids, proteins, and DNA, together with a decrease in reduced glutathione (GSH) levels, the major antioxidant defense in the cells. In PD, a main source of free radicals stems from alterations in complex I of the mitochondrial respiratory chain, which compromises proper mitochondrial functioning and ATP production, leading to cell death. MPTP , the prodrug of the neurotoxin MPP+ (1‐methyl‐4‐phenylpyridinium), has been widely used to study the disease pathophysiology once it leads to outcomes similar to PD. In fact, dopaminergic neurons are selectively vulnerable due to dopamine transporter (DAT) high‐affinity for MPP+, which subsequentially impairs electron transport chain.Dopaminergic neurons in PD display defects in mitochondrial function, increased oxidative stress, and neuroinflammation.4 Thro). For instance, (poly)phenols like resveratrol, epigallocatechin gallate, and quercetin, despite their poor absorption and limited brain availability, were shown to modulate PD‐associated progressive dopaminergic degeneration, mitochondrial dysfunction, apoptosis, protein aggregation, and neuroinflammation. However, the mechanism of action of the low molecular weight (poly)phenol metabolites (LMWPM), which are the most abundant and simple metabolites of (poly)phenols found in circulation, is poorly understood. Such circulating LMWPM can exert genomic modifications in brain cells, presenting a strategy for disease prevention with potential to be explored. Simple phenolic sulfates, in particular colonic‐derived phase II metabolites of dietary (poly)phenols were identified in biological samples of human volunteers which took a berries mixture, cranberries, mango, or black tea. These sulfates, when tested in circulating concentrations (5 µM), were shown to be significantly transported across an in vitro model of the blood‐brain barrier (BBB), holding great promise as possible brain‐targeted compounds. In fact, these metabolites, in particular catechol‐O‐sulfate (cat‐sulf) and pyrogallol‐O‐sulfate (pyr‐sulf), presented strong neuroprotective and anti‐neuroinflammatory activity against common neurodegeneration hallmarks in vitro. However, their role in the context of PD is still unexplored.The prevention and treatment of PD complex pathobiology urgently need novel strategies targeted to multiple genes and proteins. (Poly)phenols, which can be found mainly in fruits and vegetables, exhibit a remarkable multipotent ability to modulate several mechanisms common to all neurodegenerative disorder like oxidative stress, metal toxicity, inflammation and immune response, apoptosis, signal transduction, ion channels, among others (reviewed in Bhullar and Rupasinghe10). F A human 3D neural cell model generated from immortalized human dopaminergic neuronal precursor cells, the Lund Human Mesencephalic (LUHMES) cell line, was used. LUHMES were differentiated into neurospheroids containing post‐mitotic neurons with enrichment in dopaminergic neurons, in an agitation‐based culture system. For induction of a PD‐like phenotype, differentiated LUHMES neurospheroids were treated with the dopaminergic neurotoxicant MPP+. The 3D cell model of PD was then employed to assess the effects of physiological concentrations of both LMWPM cat‐sulf and pyr‐sulf. LMWPM revealed to be differently neuroprotective towards the dopaminergic lesion applied. Moreover, both were able to modulate several genes mainly involved in stress response, and have also shown ability to interfere with glutathione metabolism, comprising promising new molecules to be further explored in the scope of PD.The present study aims to investigate the protective potential of selected human bioavailable LMWPM, simple phenolic sulfates, derived from the human metabolism of dietary (poly)phenols.15 A h22.1+‐induced lesion. Neurospheroids are obtained until 14 days differentiation and are enriched in post‐mitotic neurons  for 24 h  of two LMWPM: cat‐sulf and pyr‐sulf.20 In +: preincubation either with ide or cat‐sulf, but not pyr‐sulf, mitigated the effect on resazurin reduction  and by measurement of the overall ATP content (measure of cell integrity and of bioenergetics functions). We observed that cat‐sulf per se caused a slight decrease of both endpoints, while pyr‐sulf alone induced a decrease in resazurin reduction, but not in ATP levels Figure . Despiten Figure , while b+ Figure .+ lesion.Overall, these data suggest that the two LMWPM tested, besides induced a differential neuroprotection, they may trigger a preconditioning cellular response that may help the cells to cope later with the MPP2.2+ insult. Of the total 93 target genes assessed, 66 were amplified. Both cat‐sulf and pyr‐sulf treatment induced changes on gene transcription, with fold changes ranging from –4.63 to 13.7, for cat‐sulf, and –3.12 to 7.08, for pyr‐sulf. Sixteen genes were modulated by cat‐sulf and 13 by pyr‐sulf, with only five in common , apoptosis , autophagy  or unfolded protein response (UPR) , sharing common functions in the cell , were JUN, TP53, RB1, E2F1, and STAT3  system, which is a critical line of defense against oxidative stress in the brain. We addressed glutathione dynamics after MPP+ insult, according to the experimental setup presented in Figure By inhibiting complex I in mitochondria, MPPhe brain.6 We aGSR), we observed that cat‐sulf preincubation was able to significantly increase its expression after MPP+ lesion compared with MPP+ alone, reaching a maximum of 8‐fold at 6 h after MPP+ lesion phenol‐rich foods, like fruits and vegetables, have been described to present brain health benefits with positive impact in neurodegeneration.25 Des+. The 3D model offers physiological advantages compared with 2D cultures, mimicking better the brain environment complexity, presenting cell–cell interactions more closely related to what is observed in vivo. Moreover, differentiated LUHMES neurospheroids were enriched in dopaminergic neurons, which expressed DAT, TH, and βIII‐tubulin. Some glial fibrillary acidic protein‐positive cells were also observed at 7 days of differentiation, which can suggest that, in a 3D microenvironment, LUHMES cells may be able to be differentiated into glial lineages. Importantly, a consistent differentiated phenotype was obtained after 7 days of differentiation in 3D, resulting in the irreversible conversion of LUHMES neuronal precursors into a dopaminergic‐enriched neuronal population, comparable with the protocol described by Smirnova and colleagues, using gyratory shaking technique for 21 days of differentiation.Differentiated LUHMES neurospheroids emerged as a valuable tool for the assessment of LMWPM potential. In this work, we investigated the LMWPM potential against one of the most important hallmarks of PD, which is the death of dopaminergic neurons, here recapitulated by a dopaminergic lesion caused by MPP+.27 The+ lesion, as reported before, comprising a disease‐relevant cell model to study the potential of LMWPM towards a dopaminergic lesion with significance to PD. Also, although both cat‐sulf and pyr‐sulf alone presented a slight toxicity in LUHMES neurospheroids, we confirmed the neuroprotective effects of cat‐sulf pretreatment after MPP+ lesion, by mitigating the loss of cell viability and restoring ATP levels. Despite pyr‐sulf appeared to be capable to recover ATP levels, it was not able to prevent the loss of cell viability. Such observation suggests that LMWPM, in particular, cat‐sulf may preconditioning the cells to stronger insults. In turn, we may hypothesize that the preincubation with each metabolite may trigger different molecular players, or at least at different extents. This effect resembles hormesis situations, where the cells’ machinery is triggered through the activation of different alert mechanisms, such as the modulation of stress resistance pathways, which may help the cells to cope with further damages. In such conditions, cells increase the production of several proteins including growth factors, phase II and antioxidant enzymes, and protein chaperones. Previous studies have been reporting several evidences of different phytochemicals and their neurohormetic effects that ultimately may increase the resistance to diseases (as reviewed in Mattson). Moreover, hormetic phenomenon was also described in previous studies using simpler and more physiological metabolites like urolithin A that induced the transcription of mitochondrial biogenesis‐related genes, and protocatechuic, gallic, and vanillic acid by activating the sirtuin pathway. Definitely, phytochemicals at subtoxic doses may be able to activate adaptative cellular stress‐response pathways, driving the cells to protective effects. Our study gathers new clues about preconditioning evidence by physiological relevant LMWPM.LUHMES neurospheroids responded to the MPPd before,27 com Neurotrophins are also linked to MAPK and PI3K‐Akt signaling, supporting the hypothesis that such pathways can integrate signals from a range of stimuli and guide the cell to the appropriate response. Moreover, autophagy regulation and protein processing also raised from the cellular pathway analysis for cat‐sulf and are in line with the normal cellular response to stress, whereas the same was not observed in pyr‐sulf treatment. These interconnected pathways may be explained by the PPI, not only those coded by the genes differentially expressed but also those that could interact with them, whose activity could be indirectly affected by cat‐sulf, impacting neuronal cell functions as well. From this analysis, AKT1, a critical mediator of growth factor‐induced neuronal survival, seems to have a central role, interacting with a huge number of other proteins. Its downregulation may affect several proteins and mechanisms such as, decreasing the phosphorylation of components of the apoptotic machinery, which in normal conditions would inactivate it. Also, ATF4, a TF associated to most of the pathways for which a higher number of genes were identified, is linked to cellular stress response. In turn, MAP3K1 protein, does not present many protein associations with differently expressed genes by cat‐sulf, but it is connected to MAPK signaling pathway together with central proteins like AKT1, ATF4, DDIT3, and MYC, suggesting its involvement in common cellular processes. Indeed, MAP3K1 works as an integration point for a variety of biochemical signals, driving the cell response either by activating ERK and NF‐κB pathways for promoting cell survival, or c‐Jun that may induce both pro‐ and anti‐apoptotic effects, depending on the stimuli. By docking analysis, we found a favorable binding capacity between JUN and cat‐sulf, which could elucidate the gene modulation induced by this metabolite. To the best of our knowledge, we are reporting for the first time a potential direct interaction of cat‐sulf with JUN, opening doors for new targeted studies. Also, MYC, one of the proteins associated to cell cycle, seems to be involved in central signaling pathways like MAPK and PI3K‐Akt and it is described as increased in degenerating neurons, supporting the hypothesis that neurodegeneration is related with an inappropriate cell cycle control, similarly to cellular proliferation in cancer. TP53, common to both LMWPM, has already been described as involved in protective mechanisms associated to (poly)phenols, but it is not clear how this can affect downstream metabolism.To test our hypothesis, a PCR array targeting major signal transduction pathways was designed and cat‐sulf and pyr‐sulf effects assessed in terms of gene expression. Interestingly, and despite the limitation of the biased choice of targets within the PCR array, gene ontology analysis revealed the basis of the biological function of the differentially expressed genes induced by both LMWPM: genes appeared to be involved in apoptosis regulation, cell homeostasis, and cell cycle process, suggesting that both LMWPM could impact cell machinery related to stress response. Pathway analysis identified some specific pathways that can be altered by the LMWPM. Cat‐sulf showed to be more effective in neuroprotection‐induced changes in genes regulating, for instance, neurotrophin signaling pathway, which plays an essential role in the proliferation, differentiation, and survival of neurons.33 Neu+. This deregulation in miRNA expression dynamics in response to oxidative stimulus may be associated with impairment of cell viability. For instance, the top predicted miRNA to be involved in the modulation triggered by both LMWPM, that belongs to the miR‐34a family, has been established as closely related to apoptosis induction via p53, and as suppressor of pro‐survival protein Bcl‐2 in the brain. Interestingly, miR‐34a appears to act mostly in the neurotoxic pathways triggering the same targets as the neurotoxic insult MPP+, supporting the idea of a preconditioning effect by LMWPM. In addition, miR‐876‐5p is involved in cell response to oxidative stress, and let‐7g family deregulation has been positively correlated to the prefrontal cortex and blood leukocytes of PD patients.Like TFs, miRNAs may also interfere with gene expression by inducing their post‐transcriptional regulation, playing a key role in fundamental biological functions, including cells’ response to stress. Among the miRNA identified with higher number of target interactions with significantly altered genes, miR‐34a‐5p, let‐7c‐5p, miR‐212‐3p, and miR‐449a are described as being deregulated by an oxidative stress insult of MPP+.42 ThiATF4, BECN1, ATG5, ATG12, DDIT3, AKT1, BCL2L1, MAP3K1) that in fact might help the cells triggering the necessary mechanisms of survival to resist a stronger oxidative insult. When neurospheroids were exposed to MPP+ after LMWPM pretreatment, genes involved in apoptosis response, like BCL2, and mRNA expression of stress response‐related genes, like ATF4, NQO1, GSR and HSP40, emerged as significantly upregulated. Cat‐sulf significantly increased mRNA levels of the anti‐apoptotic BCL2, also increasing the ratio BCL2/BAX mRNA levels. In fact, modulation of apoptosis could be a mechanism of action by which cat‐sulf can be neuroprotective in a PD‐like scenario. Several other studies have highlighted the ability of distinct (poly)phenols, such as resveratrol, curcumin, or caffeic acid to mitigate neuronal damages through the upregulation of the Nrf2 pathway. Although some reports have demonstrated the neuroprotective effects of complex (poly)phenols, since they are not present at physiological concentrations in circulation, their relevance fades in opposition to data that reflect effects of physiological metabolites, as the LMWPM. A recent study has shown the potential of pyrogallol exerting anti‐inflammatory effects through the activation of Nrf2/HO‐1 pathway and inhibiting NF‐κB pathway. Yet, consistent data focusing on LMWPM is still lacking. Our results try to push forward the adoption of studies conditions as physiological as possible for the study of LMWPM, from the 3D cell model of PD to circulating (poly)phenol metabolites with biological relevance, at relevant concentrations.Our analysis uncovered potential mechanisms underlying the distinct neuroprotective effects observed for each of the LMWPM. Focusing on cat‐sulf, it was clear the modulation of a number of genes working as ER stress sensors , the enzyme which converts GSSG into GSH, the LMWPM in study can be counteracting another important PD hallmark. Accordingly, both metabolites have shown a slight tendency to decrease the GSSG/GSH ratio that is increased by MPP+. Moreover, LMWPM appear to be also promoting cell's ability for protein glutathionylation, an important mechanism of post‐translational modification that protect cells from oxidative stress and tightly associated to dopaminergic neuron survival. Previous studies, using dietary (poly)phenols have also demonstrated the ability of quercetin, kaempferol, and apigenin flavonoids to increase intracellular GSH levels by promoting the transcription of g‐glutamylcysteine synthetase. Moreover, myricetin pretreatment prevented H2O2‐induced glutathione oxidation, decreasing also the ratio GSSG/GSH.Additionally, a decrease in GSH levels is one of the earliest biochemical alterations detected in association with PD and GSH itself regulates dopaminergic cell death through a wide variety of homeostatic processes.55 In  In fact, glutathione redox homeostasis seems to be essential to proteostasis maintenance through autophagy regulation. mRNA levels of BECN1 did not change consistently with metabolite pretreatment and MPP+ and we observed a beneficial effect from both cat‐sulf and pyr‐sulf via upregulation of Hsp40 expression. Hsp40 is a co‐chaperone able to stimulate ATPase activity of Hsp70 (DnaK), which is protective in models of PD. Our previous data already reported the upregulation of Hsp40 in SK‐N‐MC cells after incubation with a blackberry‐digested polyphenol extract. Since these proteins often work in concert, the upregulation of Hsp40 transcripts can be suggestive of an Hsp40‐mediated activation of the regulatory mechanism of Hsp70, with ultimate neuroprotective effects.Of relevance to the present work, the redox status of cells, namely in both cytosol and ER. In neurodegenerative diseases like PD, ER stress has been shown to deregulate redox homeostasis, promoting a dramatic increase in protein deposition due to increase of misfolded proteins aggregation.62 In + phenol‐rich supplementation, in triggering preconditioning mechanisms, which help dopaminergic neurons to cope with a later insult that induce oxidative stress, like MPP+ Figure11. Con4l‐Glutamine (Sigma‐Aldrich), 1xN2 Supplement (Gibco), and 0.04 µg mL–1 recombinant basic fibroblast growth factor ). For propagation flasks (Nunc) were precoated with 50 µg mL–1 poly‐l‐ornithine  and 1 µg mL–1 fibronectin (Sigma‐Aldrich).Undifferentiated LUHMES cells were routinely cultivated in proliferation medium  with 2 mM 5 cell mL–1 in 125 mL of proliferation medium and cultured in a humidified atmosphere of 5% CO2, at 37 °C. After 48 h of aggregation, 70% of medium was changed to differentiation medium (proliferation medium without bFGF and with 1 mM dibutyryl cAMP (Sigma‐Aldrich), 2 µg mL–1 tetracycline (Sigma‐Aldrich), and 2 ng mL–1 recombinant human glial cell line‐derived neurotrophic factor  to induce neuronal differentiation. Replacement of 50% of culture medium by fresh differentiation medium was performed every 2–3 days during a maximum of 14 days. Agitation rate was progressively increased from 60 to 70 rpm at differentiation step initiation, and up to 80 rpm by the end of the culture.Undifferentiated LUHMES cells were inoculated as a single cell suspension spinner vessel (Corning) equipped with a magnetic paddle impeller, at a density of 1.2 × 10+ (Sigma‐Aldrich) was added for different timepoints. Cell viability and ATP levels were assessed 24 h after injury, while remaining parameters were assessed after 0, 2, 6, and 24 h of injury with MPP+.Differentiated neurospheroids (7 days of differentiation) were seeded in PLO‐fibronectin coated 96‐ (15 neurospheroid per well) or 12‐well plates . After 24 h, 200 nM idebenone  or 5 µM of each LMWPM (cat‐sulf or pyr‐sulf) was added and, after 24 h of incubation, medium was removed and new differentiation medium containing 5 µM of MPPNeurospheroids were distributed in precoated 96‐well plates in differentiation medium. At endpoint, cell viability was assessed by Presto Blue assay (Invitrogen), and intracellular ATP levels by CellTiter Glo (Promega) according to manufacturer's instructions. Values were calculated as a percentage relatively to control cells (untreated neurospheroids). List of primers used and sequences is presented in Table –∆∆CT method for relative gene expression analysis. Changes in gene expression were normalized using the housekeeping genes RPL22, in the case of RT‐qPCR, and GAPDH, B2M, and ACTB, in the case of RealTime Ready assay.Neurospheroids were distributed in precoated 12‐well plates. Total RNA was extracted from neurospheroids with High Pure RNA Isolation kit (Roche) and quantified using NanoRop 2000c (ThermoScientific). Reverse transcription was performed with Transcriptor High Fidelity cDNA Synthesis kit (Roche), and qPCR analysis was performed as described.68 Lishttp://bioinformatics.sdstate.edu/go/). Cellular pathways were explored using GeneTRial2 software (https://genetrail2.bioinf.uni‐sb.de). Datasets were analyzed for KEGG and BioCarta pathway databases. Network of pathways, their interactions, and genes involved with each pathway were also searched using ClueGO Cytoscape (v 3.7.2) to create and visualize functionally grouped networks. Protein–protein interactions (PPI) between the proteins that were coded by the differentially expressed genes, including their neighboring proteins, was conducted using STRING , considering: confidence—text‐mining, experiments, databases, coexpression; high confidence—0.700; no more than 10 interactions in the first shell and no interactions in the second shell, without clustering. Genes identified in this PPI network were applied to pathway analysis using KEGG mapping analysis tool.Gene ontology enrichment analysis was performed for the identified differentially expressed genes using ShinyGO (edu/go/).69 Celhttps://www.grnpedia.org/trrust/). Potential interactions of the metabolites with TFs were assessed using SwissDock (http://www.swissdock.ch/docking) molecular modeling tool. The 3D structures of the proteins were obtained from Uniprot database and the chemical structures of the metabolites were obtained from PubChem database.Transcription factors (TFs) potentially involved in the transcriptional regulation of the identified genes were identified using the TTRUST database (trrust/).74 Pothttp://userver.bio.uniroma1.it/apps/mienturnet/). Intersections between differentially expressed genes with those identified as involved in neurodegenerative diseases and PD have been searched using Comparative Toxicogenomics Database (http://ctdbase.org).Search for miRNAs potentially involved in post‐transcriptional regulation of the differentially expressed genes was performed with MIcroRNA ENrichiment TURned NETwork (MIENTURNET), used for miRNA‐target enrichment and network‐based analysis (turnet/).75 Int but adapted for cell culture. Briefly, neurospheroids pellets were homogenized with 100 µL of 0.01% Triton X‐100 in PBS and centrifuged . Thiols were quantified by HPLC with fluorescence detection , after sample pretreatment for the separation of the different pools. The total fraction of each thiol represented the sum of free reduced (RSH) + free oxidized (RSSR) + protein bound pools (RSSP). The free total fraction comprised the RSH + RSSR fractions from each thiol. The protein‐bound RSSP fraction was obtained by subtracting the total free fraction to the total fraction.The cysteine‐related thiolomic profile was obtained through the quantification of cysteine (Cys) and glutathione (GSH) fractions: total and free total, as previously reported,77 butGSH and GSSG were quantified by HPLC after derivatization with ortho‐phthalaldehyde as previously described.79t‐test. RT‐qPCR, ATP fold change, neurotoxicity, and neuroprotection data are mean ± SEM from at least three independent experiments (independent spinner vessels) performed with technical replicates. One‐way or two‐way ANOVA analysis with Tukey's and Bonferroni's post multiple comparison test, respectively, were performed to assess statistical differences between conditions.Statistical analysis was performed using GraphPad Prism 9 software. Differences in gene expression from PCR array were assessed by Student's The authors declare no conflict of interest.R.C., I.F., and C.N.S. designed the study and drafted the manuscript; R.C., I.F., A.P.T., J.G.‐P., C.O.S., and S.A.P. conducted cell experiments; R.C., I.F., C.O.S., S.A.P., and D.M. analyzed the results and interpreted the data; S.A.P. D.M., M.L., C.B., and C.N.S. revised the manuscript. All authors read and approved the final manuscript.Supporting InformationClick here for additional data file.


Adjuvant chemotherapy of leucovorin‐modulated 5‐fluorouracil (5‐FU/LV), capecitabine, and adding oxaliplatin to 5‐FU/LV or capecitabine (FLOX/OX) have been standard regimens for high‐risk stage II or III colon cancer (CC). We aimed to evaluate their patterns of use, association with survival, and rate of emergency room visit (ER) or hospitalization during the treatment period. High‐risk stage II or III patients aged >65 years diagnosed between 2007 and 2015, underwent colectomy, and received any of these three regimens were selected from SEER and Texas Cancer Registry (TC) linked with Medicare data. Chi‐square test, Kaplan–Meier survival curves, Cox regression, and logistic regression were used in data analysis. A total of 5621 (1080 stage II and 4541 stage III) patients with median age of 72 years were included in this study. For stage II, 24.4% used 5‐FU/LV, 31.2% used capecitabine, and 44.4% used FLOX/OX; the respective numbers for stage III were 13.8%, 17.9%, and 68.3%. Patients aged <70 years, not in the West region, not in Medicare state‐buy‐in program, and with no comorbidity were more likely to use FLOX/OX. FLOX/OX was associated with improved overall survival (OS) in stage II and III patients and improved cancer‐specific survival in stage III patients compared with 5‐FU/LV. The survival benefit of FLOX/OX was sustained in stage III patients aged ≥70 years. Capecitabine had the lowest ER/hospitalization rate with 19.2% in stage II and 28.9% in III. The use of FLOX/OX was associated with improved survival compared with 5‐FU/LV among CC patients. Capecitabine was associated with the lowest ER/hospitalization rate. FLOX/OX treatment was associated with improved overall survival (OS) and improved cancer specific survival in stage III patients compared with 5‐FU/LV and the survival benefit of FLOX/OX was sustained in stage III patients aged 70 years. Capecitabine had the lowest emergency room visit/hospitalization among the three regimens with 19.2% in stage II and 28.9% in stage III patients. The probability of developing colon cancer increases with age; men and women aged 70 and older have a 1 in 32 or 1 in 34 chance of colon cancer development, respectively. From 2010 to 2016, 35% of colon cancer diagnoses were considered regional (stage II) and 22% were considered distant (stage III+). Patients diagnosed with stage II colon cancer had relative 5‐year survival around 72%, while stage III+ patients had the lowest chance of survival at 14%.The National Comprehensive Cancer Network (NCCN) recommends for high‐risk stage II and III colon cancer patients to receive chemotherapy after colectomy.Prior to the mid‐1980s, 5‐FU/LV was the standard practice of treatment; however, rapid pharmaceutical advances led to the creation of new regimens.One of the largest trials that suggested a survival benefit of adjuvant chemotherapy in patients with stage II colon cancer was the QUASAR (Quick and Simple and Reliable Study). The trial reported that the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70–0.95) and the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (95% CI 0.67–0.91). This was interpreted to state that chemotherapy with fluorouracil and folinic acid improved the survival of patients, even if only by a small percentage.The MOSAIC and NSABP C‐07 trials established the benefit of the addition of oxaliplatin in adjuvant therapy for stage II and III disease, especially in patients under 70 years of age.Many of the above studies investigated adjuvant chemotherapy treatment patterns before 2005 when 5‐FU was the main option, or they examined survival after adjuvant chemotherapy without stratifying by chemotherapy regimen received. Few studies have evaluated treatment adverse events such as emergency room (ER) visits or hospitalizations while patients are receiving chemotherapy. Since treatment options for colon cancer have advanced and expanded since 2005, determining patterns of adjuvant chemotherapy regimen use and associated overall survival rates is of utmost importance. The objective of this study is to explore treatment patterns and survival trends by adjuvant chemotherapy regimen and ER/hospitalization during chemotherapy treatment period in the SEER and Texas Cancer Regis‐Medicare population (Medicare beneficiaries aged 65+) in more recent years.2We used SEER‐Medicare and TCR‐Medicare data that covered cancer diagnosis between 2007–2015 and 2009–2015, respectively (TCR‐Medicare data were available to us since 2009). SEER is a population‐based cancer registry from 17 SEER areas. TCR is one of the largest cancer registries in the United States and is one of the 12 state registries funded by both the SEER program and Centers for Disease Control and Prevention's National Program of Cancer Registries. It includes patients' sociodemographic information such as age, gender, marital status, state‐buy‐in and Medicare enrollment, education and income level, cancer diagnosis and stage, histology type, AJCC tumor stage, tumor grade, and cancer treatment information such as vital status, surgical removal, and number of lymph nodes. Medicare claims include information on cancer treatment type , ER visits, hospitalizations, and corresponding dates. We used the International Classification of Diseases 9th or 10th Revision (ICD‐9 or ICD‐10) procedure codes and Healthcare Common Procedure Coding System (HCPCS) codes  and cancer cause‐specific survival (CSS). Since chemotherapy treatment is associated with toxicities, we used ER visit and hospitalization during the chemotherapy period as a surrogate for severe adverse events or treatment complications related to chemotherapy. Covariates in our study were patients' sociodemographic factors and tumor characteristics.We used frequency and percentage to describe types of regimens used in stage II and III patients. We reported median and interquartile range for treatment duration and survival time by cancer stage and regimen type. We used Chi‐square tests to compare associations between covariates and different regimens. Cochran–Mantel–Haenszel tests were used to evaluate the yearly trend by regimen. Multivariable Cox‐regression models were used to evaluate risk of death for different regimens, and Kaplan–Meier survival curves based on multivariable Cox regression models were used to compute overall and cancer cause‐specific survival probability.3There were 1080 stage II and 4541 stage III patients; 44.4% and 68.2% used FLOX/OX, 31.2% and 17.8% used capecitabine, and 24.3% and 13.7% used 5‐FU/LV, respectively. The median treatment duration for these regimens was around 5 months with IQR [1.7–6.4] months. , no statistically significant survival benefit was detected in stage II patients for OS and CSS comparing FLOX/OX and 5‐FU/LV  and chronic side effects .Our survival analysis suggests that receiving chemotherapy for 3 to 6 months results in a colon cancer overall and cause‐specific survival benefit. The current standard treatment for stage III patients is 6 months of FLOX or CAPOX.A major strength of our study is that we used large population‐based datasets with a 9‐year follow‐up period to evaluate the trends and survival outcomes of chemotherapy for stage II and III patients. It provides a real‐world assessment of how 5‐FU/LV, capecitabine, and FLOX/OX were used in patients >65 years, the association of treatment regimen type with survival, and treatment toxicities between 2007 and 2015. One limitation is that claims data lack information on patients' physical function and frailty; these characteristics may influence the choice of chemotherapy regimen received, treatment toxicity, and survival. Second, cancer registry data do not include patients' cancer recurrence or metastasis which could affect patients' survival. Also, there is no information on patients' microsatellite instability (MSI) status which is an important factor in chemotherapy treatment decisions as patients with MSI‐high tumors will likely not receive 5‐FU/LV.In conclusion, our study addresses the survival benefit and treatment patterns of three adjuvant chemotherapy regimens for stage II and III colon cancer patients. Capecitabine has the lowest toxicities based on hospitalizations/ER. We can conclude that in stage III patients specifically, FLOX/OX has a survival benefit over other three regimens.Emily Jones: Investigation, writing original draft, and review. Hui Zhao: Investigation, methodology, data interpretation, and review. Zhigang Duan: Data analysis, visualization, review and editing. Thinh Nguyen: Investigation and review. Sharon H. Giordano: Investigation, data acquisition, and supervision.This study was supported in part by the NCI P30 CA016672 and by the Duncan Family Institute.Dr. Giordano is supported by a Cancer Prevention & Research Institute of Texas grant (RP160674) and Komen SAC150061.No conflicts of interest to disclose.This study was considered exempt of Institutional review board approval because the data are de‐identified.


Creativity plays an important role in design. However, there have been mixed results about whether music, as an environmental stimulus, improves design creativity performance.Participants were 57 design major students who were randomly assigned to one of three groups, with 19 students in each group: no music, pure music, and music with intelligible semantic information (unrelated to the task) playing in the background. Each participant completed a design task , with two phases in it, one that involved idea generation (divergent thinking) and one that involved idea evaluation (convergent thinking). Performance in the two phases was rated based on six indices of creativity  and overall design creativity (ODC).The results of one-way ANOVAs with Bonferroni correction showed that neither music environment had a significant influence on divergent thinking in idea generation nor convergent thinking in idea evaluation. However, both music environments had a significantly positive effect on novelty and ODC.We discuss the implications of our current results for fostering designers’ creativity performance. Since they were students majoring in design, they constitute an ideal sample for this research. They were informed of the overall goal of the experiment and agreed in writing to participate. The participants were paid CNY 30 at the end of the experiment. All participants spoke Chinese as a first language and reported normal vision  and normal hearing.We recruited 60 industrial design and product design students  with a mean age of 21.6 years  between-subject design was used. Participants were randomly assigned to one of three groups, each with 20 participants. The stimuli material of pure music is  Allegro . Szalma  Allegro .The lab is equipped with a desk and an office chair. In the experiment, Sony WI-1000X wireless Bluetooth noise canceling headphones produced by Sony Ltd., Japan, were used to play music materials for participants. Participants were given the same materials including unlimited amounts of A4 paper, hard crayons, markers, pencils, sharpeners, and erasers. The graphic quality of participants’ drawing schemes was not taken into account in this study. Participants were asked to engage in a design task with two creative phases and propose conceptual design solutions related to the task. To make it easy to obtain multiple solutions, the description of the design tasks was quite open, with few restrictions.Participants all received the same design task description: design a tool for storing painting materials . The fluency, adaptability, and overall design creativity were skewed (|2 × SE SKEW| < Skewness statistics). Skewness was corrected by applying a square-root transformation. The correlations between the transformed and untransformed values were high (>0.95), indicating that the transformation of values did not change the general interpretation of the findings. ANOVAs were conducted on the transformed data, and the Bonferroni correction was used. Descriptive statistics of the non-transformed data are mentioned.fluency = 0.884, ICCflexibility = 0.660, ICCadaptability = 0.537, ICCfeasibility = 0.574. The three experts discussed the values of novelty, usefulness, and ODC, with each parameter providing an average score for statistical analysis  represented by seven subscale scores . Significance values were adjusted using the Bonferroni correction for the three measures. The inter-rater reliability of the ratings was calculated using a 2-way random intraclass correlation coefficient (ICC) analysis for consistency, ICCanalysis .3.The raters’ evaluations of multiple indices of creativity and ODC in the pure music, intelligible semantic, and control groups are shown in 3.1.M = 11.11 ± 6.60), intelligible semantic music group (M = 10.32 ± 7.14), and control group (M = 8.68 ± 4.75), F = 0.74, p = 0.481. The results showed that the two musical environments had no significant effect on fluency in divergent thinking compared with the control condition.In terms of fluency, the ANOVA showed no significant difference across the three groups. The group averages are reported as Means and Standard Deviations: pure music group (M = 4.52 ± 1.43), intelligible semantic music group (M = 4.00 ± 1.77), and control group (M = 3.91 ± 1.15), F = 0.97, p = 0.387. The results showed no differences in flexibility in divergent thinking among the three groups.As for flexibility, the ANOVA showed that there was no significant difference between the pure music group (3.2.M = 4.21 ± 1.04), intelligible semantic music group (M = 3.70 ± 0.87), and control group (M = 4.26 ± 0.50), F = 2.63, p = 0.081, and no post hoc comparisons were conducted. The results indicated no differences in adaptability in convergent thinking among the three groups.In terms of adaptability, the ANOVA showed no significant difference among the pure music group (M = 3.54 ± 0.98), intelligible semantic music group (M = 2.82 ± 0.91), and control group (M = 3.33 ± 0.87), F = 3.09, p = 0.054, this difference was not significant; thus, no post hoc comparisons were conducted. Both the pure music and intelligible semantic music environments had no significant inhibitory effect on the feasibility dimension of convergent thinking.Regarding feasibility, the ANOVA showed that there was no significant difference between the pure music group (3.3.M = 1.47 ± 0.61), intelligible semantic music group (M = 1.26 ± 0.56), and control group (M = 1.21 ± 0.42), F  = 1.28, p = 0.287, and no post hoc comparisons were conducted.Regarding usefulness, the ANOVA showed that there was no significant difference in usefulness between the pure music group (M = 1.37 ± 1.16), intelligible semantic music group (M = 1.53 ± 1.02), and control group (M = 0.42 ± 0.61), F = 7.36, p = 0.001. Post hoc comparisons with Bonferroni correction revealed a significant difference between the pure music group and the control group (p = 0.004); a significant difference between the intelligible semantic music group and the control group (p = 0.001); and no significant difference between the pure music group and the intelligible semantic music group (p = 0.614). The results showed that compared with the control condition, both music environments appeared to promote novelty.In the aspect of novelty, ANOVA showed that there were significant differences across the pure music group (M = 2.16 ± 1.17), intelligible semantic music group (M = 2.05 ± 1.77), and control group (M = 0.45 ± 0.62), F = 6.57, p = 0.003. Post hoc comparisons with Bonferroni correction showed a significant difference between the pure music group and the control group (p = 0.006); the difference between the intelligible semantic music group and the control group was significant (p = 0.011), and the difference between the pure music group and the intelligible semantic music group was not significant (p = 0.845). The results showed that, compared with the control condition, the two kinds of music environment had a promotion effect on design creativity.In terms of overall design creativity, the variance results showed that there were significant differences in design creativity among the pure music group  is consistent with a previous study . StudiesTherefore, novelty can be used as a direct measure of whether creative performance is enhanced by musical background. Besides, our results may also be related to emotion. The music selected in this experiment was high-valence and high-arousal music , which cUnexpectedly, neither fluency nor flexibility had a significant effect on divergent thinking compared to the control condition. This result is at odds with our assumptions that two types of music  would have a positive effect on the divergent thinking process. The difference in results across studies is most likely due to the difference between the AUT, used in other studies, and our design task. The AUT requires participants to consider as many uses as possible for simple everyday objects  and used a design creativity task to investigate the effect of the music environment on multiple indices of design creativity and overall creativity. The results showed that, compared with the control group, the two music environments significantly improved ODC, but only in the novelty dimension. Listening to either type of music did not effectively promote divergent thinking or impair convergent thinking.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Studies involving human participants were reviewed and approved by the Academic Ethics Committee of the Guangdong University of Technology. All participants provided written informed consent to participate in the study.TX and LL designed the study. YS and TX collected and analyzed the data. TX, YS, and YA wrote the first draft of the manuscript and revised the manuscript. All authors contributed to the article and approved the submitted version.This research was funded by grants from the National Social Science Foundation of China (18BYY089), the Young Scholar of Humanity and Social Science Grants from the Ministry of Education of the People’s Republic of China (20YJC760044), and the Higher Education Young Scholar Innovative Programs of Guangdong Province (2018WQNCX022).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.


Given these deficits have elsewhere been shown to be prognostic of future depressive symptoms, these findings suggest that reduced memory specificity/overgeneral memory persists following remission and may be a risk factor for future episodes of depression in those that are in remission. The findings are discussed in terms of how this knowledge might influence clinical understanding of relapse prevention and maintenance of remission in those with a history of depression.Difficulty in accessing specific memories, referred to as reduced memory specificity or overgeneral memory (OGM), has been established as a marker of clinical depression. However, it is not clear if this deficit persists following the remission of depressive episodes. The current study involved a systematic review and meta‐analysis of empirical studies with the aim of establishing whether remitted depression was associated with retrieving fewer specific and more overgeneral autobiographical memories. Seventeen studies were identified as eligible. The results indicated that people with remitted depression recalled fewer specific memories ( Difficulties recalling specific personal memories are a marker of depression.This deficit persists after remission relative to those with no history of depression.Poorer autobiographical memory may be a vulnerability for future episodes.Improving autobiographical memory specificity could protect against relapse.1a long walk in a local park with two friends). Difficulty in accessing specific memories, referred to as reduced memory specificity or overgeneral memory, has been established as a cognitive marker of depression , or events that lasted for extended periods of time (e.g. when I was a teenager I was very active). Difficulty in recalling specific memories is a predictor of future depressive symptoms, independent of depressive symptoms at baseline  were also analysed to help determine if there were specific factors that may predict any observed differences. Given previous findings, it was hypothesized that people with a history of depression would have significantly reduced memory specificity and significantly increased overgeneral memory relative to those who had never been depressed.2https://osf.io/bfcyj/.The study procedure was pre‐registered within the PROSPERO database (ID: CRD42020203509). No deviation was made except for the addition of some moderator variables (see below) given the studies included in the review had these affordances. The data and scripts used for analysis in this study are open access and available at 2.1autobiographical memory and combinations of either specificity or overgeneral. A full list of search terms can be viewed in Data rumination, brooding, executive function, verbal fluency, problem‐solving, etc.; see Williams, The search strategy involved using the search engines ProQuest and Ovid to search for keywords on the Embase, PsycARTICLES and PsycINFO databases. The current systematic search was nested within a larger systematic search, which aimed to collect all articles that examined memory specificity in clinical and non‐clinical samples . A general memory could refer either to a categorical event  or an extended event  or could be presented as a sum of both types of these events. Studies must have reported adequate data to be included in analyses .To be included, studies needed to be written in English, report original empirical data and contain two groups of participants: one defined by a history of clinical depression but currently in remission and another with no historical or current clinical depression. This, therefore, would not include studies that compared people with remitted and current depression  conducted the search separately. One research assistant then extracted all data initially, and the second research assistant then extracted all the data again checking for discrepancies. The first author (/) then checked the data, and any remaining disparities were resolved through discussion. We extracted the number of participants in each group within a given study, their mean age, the proportion of women and the diagnostic tool used to assess for major depression, measure of depressive symptom severity, number of previous episodes of depression, number of cues used, cue valence and duration for cue response. Where a study explicitly reported the education levels and ethnicity of participants, this was also extracted.The mean and standard deviation scores for both the clinical and control group for the measure depression symptom severity used within each study were extracted. Although studies were selected on the basis that neither of the groups of participants being compared had clinical depression, nonetheless there may have been differences in depressive symptoms that might account for group differences in specific or general memories. Therefore, a standardized mean difference for severity scores between groups for each study was computed, and this variable was assessed as a potential moderator through meta‐regression. We extracted the mean and standard deviation for the number or proportion of specific and general memories retrieved across cues on the AMT. Where this information was available for different cue valences, this was also extracted so these could be analysed separately. We also extracted the duration of time participants were given to recall each memory following cue presentation, whether responses could be given verbally or otherwise and the number of cues given to participants.2.4g as the effect size. Forest plots were used to graphically depict the overall effect size and 95% confidence interval and prediction interval, as well as the individual study point estimates and 95% confidence intervals. Between‐study effect size heterogeneity was reported in terms of Q, τ2 and I2. The Q statistic provides an indication that factors outside of sampling error account for effect size estimate variation , number of cues used in the AMT, the duration of time given for retrieval on the AMT, the year of publication and sample size. Given that extreme scores might unduly influence an overall effect, we identified outliers as any study for which its confidence intervals did not overlap with the confidence interval of the pooled effect size. Sensitivity analyses were conducted by removing these studies and then conducting the analyses again to assess for changes in the overall effect.2.5a high risk of bias was noted. If the study did not include enough information to assess clearly whether this was a potential source of bias, some concern was noted. If the study explicitly noted the steps taken to manage the bias mentioned, then a low risk of bias was noted. To assess publication bias in the sample of studies, we generated funnel plots, on which effect size estimates were plotted on the x‐axis, and the inverse of their standard error on the y‐axis. Plots resemble a funnel, with less precise estimates at the base of the funnel and estimates with the smallest standard errors at the top. If there is no publication bias, the funnel plot will, hypothetically, be symmetrical. However, missing studies suppressed by publication bias may cause noticeable asymmetry in a funnel plot. Egger's test  the study involved randomisation between and within the study tasks (e.g. were cue words presented in a fixed or random order), (2) participants' group allocation was concealed from them, (3) participants and personnel were blind to the nature of the study, (4) the coders for the autobiographical memory task were blind to participants' group designation and the nature of the study during coding, (5) there was evidence for incomplete outcome reporting or for the contrary such as with pre‐registration, (5) particular participants were included in the study, but were omitted from analyses for unclear reasons, and (6) scores for particular measures were included in the study, but were selectively omitted from the final report. If these potential sources of bias were observed, then 33.1The search resulted in 17 eligible studies . Given this, as well as previous evidence that differences between people with and without depression may be accounted for by categoric‐type and not extended‐type general memories . The studies in this review were published between 2000 and 2016, with the exception of one preprint published in 2021. The mean age of participants was 20.9 years (range 11–86 years), with case and control samples across all studies having approximately equal age means. The average proportion of women in the studies was 78.18% . All studies used interviews to assess for depression diagnoses or rule out history of depression, and all but two used structured, standardized diagnostic interview tools.n = 8; 44.4%; Beck et al., There were several different measures of depression severity used across samples; however, the most frequently used was the Beck Depression Inventory II , suggesting that people in remission recalled fewer specific memories. Regarding heterogeneity, there was evidence of unexplained variance between the study effect sizes , indicating a basis for test of moderators that might explain this variance. See Figure k = 14; g = −0.262, 95% CI , z = −2.38, p = .017). There was also still evidence for variance between the study effects .There was a small to moderate negative pooled effect for comparisons of specific memories between people with remitted depression compared and people who had never been depressed , and evidence for heterogeneity . One outlier was found , with evidence for unexplained variance between the study effect sizes . Similarly, for studies that examined negatively valenced cues separately, there was a significant difference between the remitted depression and never depressed, also with a small to moderate‐sized effect  and evidence for heterogeneity . One outlier was found , with evidence for unexplained variance between the study effect sizes . Given that the effects for positive and negatively valenced cues largely overlapped in their confidence intervals, valence did not appear to be a factor in group difference in specific memories.On meta‐analysing group differences for studies that examined positively valenced cues separately, the results indicated a significant difference between the remitted depression and never depressed groups, with a small to moderate‐sized effect (3.3.2QM (df = 1) = 0.2, p = .589, b = 0.123, SE = 0.214, 95% CI , z = 0.57, p = .565, nor by age differences between the groups, QM (df = 1) = 0.1, p = 0.657, b = 0.004, SE = 0.009, 95% CI , z = 0.43, p = .663, proportion of women, QM (df = 1) = 0.5, p = .475, b = 0.422, SE = 0.591, 95% CI , z = 0.71, p = .475, number of cues used for retrieval, QM (df = 1) = 0.6, p = 0.418, b = −0.010, SE = 0.012, 95% CI , z = 0.81, p = .415, retrieval duration, QM (df = 1) = 2.2, p = .136, b = 0.038, SE = 0.004, 95% CI , z = −1.50, p = .132, study age, QM (df = 1) = 0.1, p = .657, b = −0.010, SE = 0.019, 95% CI , z = 1.95, p = .051, or sample size, QM (df = 1) = 1.0, p = .307, b = 0.001, SE = 0.001, 95% CI , z = 1.02, p = .307. In assessing the number of past episodes of depression as a moderator, one study on adolescents  indicated no clear evidence for a moderating effect, b = −0.099, SE = 0.070, 95% CI , z = −1.42, p = 0.155. The results did not substantially differ when the adolescent study was included.The differences between the remitted depression and never depressed groups in specific memories were not predicted by differences between the groups in depression symptom severity, 3.3.3p = 0.035. The trim‐and‐fill procedure suggested adding two studies to the right side of the mean, which produced an attenuated effect size that had overlapping confidence intervals with the original estimate of group differences . The results of the P‐curve analysis showed that there was adequate power to detect an effect, 80% (95% CI 41.5–95.9%), and that there was evidence of a ‘true’ effect in the overall findings. Taken together, these analyses indicate that observed group differences in specificity were not the product of ‘p‐hacking’, but there may be some publication bias that attenuates the observed effect.Figure 3.4k = 9; g = 0.254, 95% CI , z = 2.02, p = .043), suggesting that people in remission recalled more categoric people without any history of depression. A test for heterogeneity indicated there was not clear evidence for unexplained variance between the study effect sizes . See Figure There was a small to moderate pooled effect for comparisons of categoric memories between people with remitted depression compared to people who had never been depressed , with no clear evidence of heterogeneity . No outliers were detected. For studies that examined negatively valenced cues separately, there was a small to moderate but non‐significant difference between the remitted depression and never depressed groups  and evidence for heterogeneity . No outliers were found. In summary, a significant effect was found for positively valenced cues, but not for negatively valenced cues. However, given the similarity in their effect size and confidence intervals that predominantly overlapped, this did not provide clear evidence that cue valence was a factor in group differences in categoric memories.On meta‐analysing group differences for studies that examined positively valenced cues separately, the results indicated a significant difference between the remitted depression and never depressed groups, with a small to moderate‐sized effect (3.4.2QM (df = 1) = 2.8, p = .092, b = −.400, SE = 0.245, 95% CI , z = −1.62, p = .092, nor age differences between the groups, QM (df = 1) = .09, p = .752, b = −0.004, SE = 0.12, 95% CI , z = −0.31, p = .753, proportion of women, QM (df = 1) = 0.02, p = .875, b = −0.111, SE = 0.715, 95% CI , z = −0.15, p = .875, number of cues used for retrieval, QM (df = 1) = 0.5, p = .442, b = −0.008, SE = 0.011, 95% CI , z = −0.74, p = .454, retrieval duration, QM (df = 1) = 1.7, p = .190, b = 0.012, SE = 0.010, 95% CI, z = 1.23, p = .216, study age, QM (df = 1) = 0.2, p = .625, b = −0.010, SE = 0.021, 95% CI , z = −0.48, p = .625, or sample size, QM (df = 1) = 0.0009, p = .976, b = 0.002, SE = 0.006, 95% CI , z = 0.29, p = .976. Again, when assessing past episodes of depression, a study with adolescents was excluded , among which there was no clear evidence for a moderating effect, b = 0.028, SE = 0.071, 95% CI , z = 0.039, p = .693. Notably, this analysis had very low statistical power.The difference between the remitted depression and never depressed groups in categoric memories  was not predicted by differences between the groups in depression symptom severity, 3.4.3p = .823, and therefore did not support the presence of publication bias. The trim‐and‐fill procedure did not suggest adding any studies. Although statistical power was low for Eggers test (k < 10), the results were highly non‐significant and not suggestive of a false‐negative result for bias. As there were two or less p‐values less than .05, p‐curve analysis could not be conducted.Figure 4This study systematically sampled and reviewed extant literature to examine whether or not, and to what extent, reduced specificity or overgenerality in autobiographical memory retrieval persists following the remission of depression. To do this, studies that compared groups of people with a history of clinical depression and no current depression to people with no historical or current clinical depression were included. The results of the meta‐analyses indicated that small to moderate deficits in the recall of specific, event‐level personal memories are apparent among people who have remitted from clinical depression. In combination with other existing meta‐analyses showing that the presence of depression diagnoses is also associated with reduced specificity (Liu et al., There was not strong evidence that memory specificity varied based on the valence of cues. This indicates that people with a history of depression recall fewer memories of specific personal events that occurred in particular places and times in their lives regardless of whether this is prompted by a positive or negatively valenced word. Although cue valence does not correspond to the emotional valence of memory in a 1:1 manner, evidence indicates that the majority of responses on the AMT will have an emotional valence consistent with the cue word (Young et al., p‐hacking; however, the risk of bias within studies indicated possible causes for concern across all studies.Interestingly, the observed impairments in autobiographical memory were not explained by differences in current depressive symptoms between the groups. Therefore, it was not residual depressive symptoms or a generally higher baseline level of subclinical depressive symptoms in those with remitted depression that accounted for these differences. The substantial heterogeneity in the analyses of specific and categoric memories was not explained by any of the other moderators either. This heterogeneity is associated with wide confidence intervals around the point estimates, and therefore, although there does appear to be observable group differences, there are unknown factors that predict when these differences are likely to be smaller or larger. The risk of bias assessment provided some evidence of bias for studies reporting specific memories, suggesting an attenuated effect size. However, it is important to note that the heterogeneity between studies may limited the interpretability of this finding. There was no clear evidence of 4.1There were few studies that examined older aged adults, thereby constraining the analysis of age effects primarily to the range of adolescence to middle‐aged adults. Future research in remitted depression in older adult samples is needed. There was a lack of reporting of co‐occurring disorders or related clinical symptoms, and therefore, whether there was an additive effect of further pathology on group differences is unclear. There were few studies that reported on number of previous episodes and no clear evidence that this moderated the observed effects. This may be an important factor to consider in future research though, given that the severity of other deficits in cognitive functioning that persist after the remission of depression does appear to be predicted by higher numbers of previous episodes (Semkovska et al., The current study focused solely on the AMT and on indices of memory specificity/overgenerality in remitted depression. While this was the pre‐stated focus of the study, and the AMT is the most commonly used task within the memory specificity literature (Barry, Hallford, & Takano, Another limitation of this study is that it did not directly compare differences in specificity between people with remitted depression and current depression. Indeed, the differences observed here between those with remitted depression and without any history of depression are notably smaller than those observed between current depression and no history of depression (Barry, Hallford, & Takano, With respect to future research, this study suggests that memory specificity is a suitable target for intervention not only in the treatment of active depression (Barry, Hallford, Hitchcock, et al., As reduced specificity/overgenerality of personal memories appears to be transdiagnostic in nature (Barry, Hallford, & Takano, 4.2In conclusion, this review provides evidence that people who are in remission from clinical depression have difficulties retrieving specific autobiographical memories and instead recall more categoric memories, relative to those that have no history of depression. Although these effects are only small to moderate in size, it is a factor that is known to predict future depressive symptoms. Knowledge that this difficulty persists even when people are otherwise free from depression may inform programmes designed to reduce depressive relapse and the immense personal and societal burden of this illness.No conflicts to declare.Data S1. Supporting InformationClick here for additional data file.Data S2. Supporting InformationClick here for additional data file.