Oral cancer therapy is associated with a loss in health-related quality of life (HRQOL) and can also lead to post-traumatic growth (PTG). The current study analyzed the relationship between HRQOL, PTG and influencing clinical factors after treatment. The coherent clinical data of 15 patients were retrospectively analyzed over a 1-year study period. HRQOL and PTG were studied using the University of Washington Quality of Life Version 4 (UW-QOL v4) and Posttraumatic Growth Inventory (PTGI) questionnaires. The results revealed that HRQOL was significantly decreased in a pre- to postoperative manner (P=0.011). Sex demonstrated a nearly significant effect on HRQOL (P=0.058). PTG was experienced the most after surgery, and continuously decreased over the 1-year study period. Patient age had a significant effect on PTG (P=0.040). A significant correlation was also established between HRQOL and PTG (P<0.05). HRQOL and PTG are important influencing factors during postoperative tumor follow-up care and should be simultaneously recorded to address individual patient needs and improve quality of treatment. Tumors of the head and neck region are a heterogeneous group of neoplasms and are among the most common cancer worldwide . With a Cancer diagnosis and treatment are traumatic life events that can trigger post-traumatic stress disorder (PTSD) ,16, but Both HRQOL and PTG are important influencing factors during post-therapy cancer follow-up care. For this reason, a better understanding of the relationships between HRQOL, PTG, and influencing clinical factors is important in specifically addressing individual patient needs and improving quality of treatment. To the authors' knowledge, this study is the first to report a combined HRQOL and PTG evaluation in patients with OSCC.(RO), ‘new possibilities’ (NP), ‘personal strength’ (PS), ‘appreciation of life’ (AOL), and ‘spiritual change’ (SC)]. Of the 30 patients with OSCC who initially agreed to participate in the trial, 15 completed all questionnaires (n=15) over the one-year study period and were included in the final statistical evaluation .Coherent clinical data (seamless data acquisition over the entire observation period) of 15 patients with OSCC mainly treated surgically between January 2011 and June 2012 were retrospectively analyzed. Data included patient characteristics, such as age, sex, marital status, and denominational affiliation; pathological characteristics, such as localization of the primary tumor and TNM classification; and therapy characteristics, such as surgical reconstruction modality and adjuvant therapy. Clinical data of patients can be found in All HRQOL and PTG subscales were analyzed using a Friedman test. Significant test scores were further examined with a pairwise comparison using the Bonferroni-Dunn post hoc test. To investigate all possible influencing factors  on PTG, further correlation tests were performed. Mann-Whitney U tests for independent samples, and Wilcoxon tests for paired samples, were used to compare two groups. In addition, a descriptive statistical evaluation of pre- and postoperative HRQOL, as well as presentation of the different influencing variables on HRQOL, was performed. A Spearman's correlation analysis was performed to describe the relationship of HRQOL and PTG. All analyses were performed using SAS 9.4-, Statistica 10.0  and SPSS 24  software. All tests resulting in a P-value <0.05 were considered statistically significant.HRQOL evaluation revealed that both physical and socio-emotional HRQOL decreased in a pre- to-postoperative manner in all patients  and B.The mean UW-QoL v4 value in the physical function increased from 11 points preoperatively to 25 points postoperatively, indicating a decrease in physical HRQOL. In the area of physical function score, swallowing , chewing  and speech  were the main factors responsible for postoperative deterioration in HRQOL. The mean value of the socio-emotional function increased from the preoperative (21 points) to postoperative (28 points) stage. Socio-emotional HRQOL was strongly influenced by patients' shoulder function , and mood  which showed high mean values over the entire study period and was only subject to a few fluctuations. This result, however, was not statistically significant (P=0.88).Statistical analysis of the preoperative UW-QoL v4 data with the one-year postoperative data indicated a significant decrease in the physical  but not in the socio-emotional HRQOL  over the one-year study period.Correlation analysis results between various clinical baseline characteristics and the physical and socio-emotional HRQOL revealed that sex had a nearly significant effect on HRQOL (P=0.058). In general, men indicated a poorer HRQOL than women. On average, single patients reported a slightly poorer overall HRQOL than married patients. However, this difference was not significant (P=0.113). Furthermore, no significant effect of denominational affiliation (P=0.908) and patient's age (P=0.261) on HRQOL could be observed.On average, patients with tumors classified as T1/T2, free microvascular flap reconstruction, and no additional radiotherapy (RT) were characterized by the poorest HRQOL scores. Patients (T1/T2) who received local defect reconstruction reported a better HRQOL. In T1/T2 carcinomas, socio-emotional HRQOL was rated as worse than physical HRQOL, regardless of the type of therapy used. In patients without free microvascular flap reconstruction and RT, no major difference could be observed between physical and socio-emotional HRQOL. In general, patients with T3/T4 carcinomas rated their physical HRQOL worse than those of other groups.Relating to others’ (RO), ‘new possibilities’ (NP), ‘personal strength’ (PS), ‘appreciation of life’ (AOL), and ‘spiritual change’ (SC), composed of different number of questions, were separately evaluated. The mean values were used for comparison. The mean overall PTG score was 72.2±35.7 .For PTG evaluation, three postoperative questionnaires  were available for each patient. Mean PTG values per question (MV) for all patients are shown in appreciation of life’  and ‘relating to others’ . ‘Personal strength’  and ‘new possibilities’  values slightly decreased in comparison. The lowest values were found in the ‘spiritual change’ subscale . ‘Appreciation of life’ showed the highest decrease over all three timepoints (1 to 12 months postoperatively). Initially, a moderate decrease  from 1 to 6 months postoperatively was found, whereas a strong decrease from 6 months to 12 months postoperatively (MV 4.4 to MV 3.2) was observed. Additionally, for ‘new possibilities’ and ‘personal strength,’ such decrease was, however, found with initial lower values . ‘Relating to others’ showed a strong decrease from 1 month to 6 months postoperatively (RO MV 4.5 to MV 3.9). The global analysis showed a significant trend for all subscales . Pairwise comparisons revealed significant differences between PTG subscales. For RO, between 1 month and 1 year (P<0.0001) and 6 months and 1 year (P=0.024). For NP, between 1 month and 1 year (P<0.0001) and 6 months and 1 year (P=0.019). For PS, between 1 month and 1 year (P<0.0001) and 6 months and 1 year (P=0.003). Also, significant differences could be observed between AOL subscale after 1 month and 1 year (P<0.0001) and 6 months and 1 year (P=0.002), and SC between 1 month and 1 year (P=0.006).Results show that patients most strongly felt PTG shortly after surgery (1 month postoperatively). Mean values of all subscales revealed a PTG decrease over the study period, which was also observed uniformly for all subscales. The biggest changes were found in ‘new possibilities’ subscale, the difference was statistically significant (P=0.040). A graphical representation is shown in Analysis revealed slightly higher mean values in all five subscales for patients younger than 60 years of age  than those over 60 years . However, just for the ‘No significant correlation between PTG and sex or PTG and marital status has been found. The P-value from the ‘relating to others’ scale (P=0.04) indicates a significant correlation between the intensification of ‘relating to others’ and ‘spiritual change.’new possibilities’, and ‘appreciation of life’ . All other correlation tests were not significant, as depicted in Statistical analyses results revealed a significant negative correlation between physical and socio-emotional HRQOL and the PTG subscales, ‘Head and neck cancers continue to be characterized by poor survival outcome and reduced HRQOL of patients ,22. Howeet al . However, the particular value of the recent study lies in the complete dataset with no missing values over the entire study period. This is an important difference from many other studies where data are incomplete. Men rated their HRQOL worse than women, which, however, was on borderline significance (P=0.058). The influence of sex on postoperative HRQOL is debatable. While Rogers et al  reportedet al ,27.Social support facilitates the coping process and reduces emotional discomfort. The ability to trust others and the feeling of support, understanding, and acceptance are considered important prerequisites for the emergence of PTG . The oppIn this study, all patients with OSCC reported a postoperative PTG. PTG was most strongly felt immediately after treatment (one month) and decreased over the one-year study period. The data in the literature on the development of PTG in the follow-up interval are not definite .et al . Sharp et al (The findings of the study revealed slightly higher mean PTG values in all five subscales for younger patients than older patients. However, for the rp et al  and otherp et al  reportedAlthough numerous studies have highlighted the effect of sociodemographic factors on PTG ,37, no sA higher level of psychological distress is generally assumed to correlate with a higher level of PTG . We founAfter extensive tumor surgery, postoperative HRQOL and PTG are the most important factors for patients dealing with this traumatic life event. Many individually different factors can affect HRQOL and PTG, which can be assessed with available standardized questionnaires. Due to the suspicion of coherence in patients with OSCC, these should be used in clinical practice for postoperative combined screening to address individual patient needs and improve cancer follow-up care.


A significant decrease in red blood cell (RBC) survival has been observed in patients with renal failure, which is supposed to contribute to renal anemia. The aim of this observational study was to determine RBC survival in hemodialysis (HD) patients treated with roxadustat or recombinant human erythropoietin (rhuEPO) compared with healthy persons.RBC lifespan was measured by Levitt’s CO breath test with newly developed automatic instrument ELS Tester.p < .05). In multivariate analysis of factors affecting RBC lifespan in the whole HD patients, anemia treatment drugs (rhuEPO/roxadustat) and levels of hemoglobin were the significantly independent factors. RBC survival was not found to correlate with either weekly rhuEPO dosage  or weekly roxadustat dosage  in our cohort.A total of 102 patients receiving long-term HD from two independent dialysis centers enrolled in the study, of whom 62 were treated with rhuEPO and 40 were on roxadustat therapy. A total of 25 healthy participants were recruited to match HD participants according to age and sex. Median RBC survival times in rhuEPO, roxadustat, and control groups were 65.0 , 75.5 , and 108.0  d, respectively. Patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO (Abbreviations RBC: red blood cell; HD: hemodialysis; rhu EPO: recombinant human erythropoietin; ESRD: end-stage renal disease; EPO: erythropoietin; ROS: reactive oxygen species; CKD: chronic kideny disease; ESAs: erythropoiesis-stimulating agents; HIF-PHD: hypoxia-inducible factor prolyl hydroxylase; CO: carbon monoxide; Hb: hemoglobinHD patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO, large prospective studies with long-term follow-up are warranted to verify the results in future.  Renal anemia is one of the most frequently observed complications in patients with end-stage renal disease (ESRD), and contributes substantially to patients’ morbidity and mortality . Anemia The decrease of the RBC life span in renal anemia may be due to accelerated eryptosis, the apoptosis-like suicidal cell death of erythrocytes, which enables the disposal of defective cells without breaking down the cell membrane integrity and release of cytosolic material ,9. Prior2+-permeable cation channel on erythrocyte and triggered eryptosis [Oxidative stress, which is a permanent challenge for erythrocytes , is an iryptosis . EPO, whryptosis , is impoThere has been little research conducted to investigate the treatments for reduced RBC survival in CKD. Observations of the effect of erythropoiesis-stimulating agents (ESAs) on RBC lifespan are controversial . RoxadusAfter the approval of roxadustat for marketing in the treatment of renal anemia in December 2018 in China, part of patients with maintainence HD changed anti-anemia drugs from rhuEPO to roxadustat of their own accord. The aim of this observational study was to determine RBC survival in HD patients treated with roxadustat or ESAs compared with healthy persons.This was a cross-sectional observational study assessing RBC survival in HD patients treated with recombinant human erythropoietin (rhuEPO) or roxadustat and healthy participants in China. Patients were recruited independently from the Provincial Hospital Affiliated to Shandong First Medical University Dialysis Unit and Caoxian People’s Hospital Dialysis Unit. Dialysis patients were stratified according to anti-anemia drugs (rhuEPO or roxadustat) and healthy participants were included in the third arm of the study. This study was approved by the Ethics Committees of the Provincial Hospital Affiliated to Shandong First Medical University and Caoxian People’s Hospital , and all patients gave written informed consent to participate. This study was conducted in accordance with the principles of the Declaration of Helsinki.2) and hemoglobin concentrations within the reference range were invited to enroll in this study and were matched according to age and sex to HD patients.Persons older than 18 years who had been established on maintenance HD therapy for at least 3 months were eligible to participate in this study. Eligible patients had a cause of anemia that was secondary to CKD and a blood hemoglobin concentration above 90 g/L. All participants were either using rhuEPO or roxadustat for at least 3 months. Healthy volunteers with kidney function  and a high-flux polysulfone membrane . Few patients received the treatment of hemodiafiltration (HDF) using a high-flux polysulfone membrane dialyzer  usually with one time per month. HD access was through native arteriovenous fistulas, constructed from synthetic grafts or tunneled catheters. Blood flow was set at 200–300 mL/min, and dialysate flow was set at 500 mL/min. The ultrafiltration rate was determined by each patient’s estimated dry bodyweight. All the patients in the rhuEPO group received rhuEPO intravenously, and were administered 1 or 2 times per week.Clinical data, including age, gender, HD vintage, single-pool Kt/V, causes of ESRD, comorbidities, weekly EPO or roxadustat dose, post-dialysis dry weight, and 24-h urine volume were collected.Whole blood samples were drawn at the arterial site of the AV access or tunneled catheters before HD was started on the day of RBC lifespan measurement. A complete blood count was assessed by an automatic blood cell analyzer . The concentrations of sera albumin (ALB), creatinine, blood urea nitrogen (BUN), uric acid (UA), calcium (Ca), and phosphate (P) were quantified using automatic biochemical analyzer . The concentrations of sera ferritin, intact-parathyroid hormone (i-PTH), EPO, vitamin B12, and folate were quantified using automatic chemiluminescence analyzer . The doses of rhuEPO are expressed as IU/kg body weight per week. We used the EPO resistance index (ERI) as the metric of EPO resistance, defined as the weekly weight-adjusted rhuEPO dose (U/kg/week) divided by Hb level (g/dL).vs. that in the accompanying atmospheric air sample using Levitt’s formula, the instruments CO detection limit is 150 ppb, with an accuracy of 50 ppb and precision within 50 ppb [15N-glycine labeling technique and the CO breath test using this instrument were significantly and strongly correlated , which suggested that the CO breath test is a reliable method for quickly determining human RBC lifespans in clinical applications [Breakdown of heme results in the production of carbon monoxide (CO), and the alveolar CO concentration can be used to estimate RBC lifespan . Alveolan 50 ppb . In a reications . Operatiα error level of 5% was calculated to be at least 40 subjects per group.The sample size was determined based on our preliminary study of RBC survival on 15 patients in each group. In that study, mean RBC survival in those with rhuEPO was 70.3  compared to 86.5 ± 20.0 d in those with roxadustat. The sample size required to obtain 85% power at χ2 test, and one-way ANOVA were used with Dunnett’s test for multiple for multiple comparisons. The linear regression model was applied to assess the factors influencing the RBC survival in HD patients. Only variables with p < .05 in the univariate linear regression analysis were used in the multiple linear regression. Categorial variables, including sex, anti-anemia drugs, and diabetes, were transformed into dichotomous dummy variables , skewed continuous variables were logarithmically transformed into normal distributions. Statistical significance was considered as p < .05.Statistical software SPSS version 25.0  was employed for statistical analysis. Quantitative data were expressed as mean ± SD, median and 25th–75th percentile, median and range, or number (%). For comparison of clinical features and RBC lifespan of patients, t-tests, Mann–Whitney U test, Kruskal–Wallis test, vs. 113.6 ± 13.6 g/L; p < .001).A total of 102 patients receiving long-term HD from two independent dialysis centers participated in this observational study, of whom 62 were treated with rhuEPO and 40 were on roxadustat therapy. A total of 25 healthy participants (15 men and 10 women) were recruited to match HD participants according to age and sex. Mean age of the healthy participants was 52.7 ± 12.4 years with serum creatinine levels at 63.9 ± 15.7 μmol/L. Hemoglobin concentrations in healthy controls were significantly higher than for all HD patients , and the serum levels of creatinine, ALT, Ca, P, bicarbonate, PTH, EPO, vitamin B12, folate, and CRP were also comparable between the two groups. In this cohort, patients received roxadustat had significantly higher levels of BUN and lower levels of β2-MG compared with patients treated with rhuEPO. In our cohorts, no patient received oral iron tablets, and in the roxadustat group patients received fewer doses of intravenous iron supplementation. Then ferritin levels were significantly lower than that of patients in rhuEPO group .General characteristics for HD participants are listed in Although the patients changed their anti-anemia drugs from rhuEPO to roxadustat totally voluntarily in our dialysis units, we also reviewed the baseline data of our roxadustat group patients before the use of roxadustat. Five patients of the roxadustat group received roxadustat at the beginning of HD therapy, so 35 patients had the baseline data. The weekly rhuEPO dosages, the hemoglobin concentrations, the serum ferritin levels, and intravenous iron supplementation dosages of these patients were comparable with the rhuEPO group. The serum β2-MG levels were also significantly lower of the roxadustat patients before the use of roxadustat compared with that of rhuEPO group .p < .001). Patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO (p < .05). The median RBC lifespan of the roxadustat group was 16.2% higher than that of the rhuEPO group,p < .05). The RBC lifespan was not associated with sex, age, HD vintage, exogenous iron dosage, serum levels of BUN, SCR, β2-MG, Ca, ferritin, or transferrin saturation. In the further multivariate analysis, anemia treatment drugs (rhuEPO or roxadustat), and levels of hemoglobin were the significantly independent factors associated with RBC lifespan in HD patients.In our cohort, longer RBC survival was observed in HD patients treated with roxadustat compared with patients on rhuEPO therapy. Since previous studies have reported that RBC lifespan were correlated with other clinical and laboratory parameters, such as levels of BUN, SCR, and ALB, univariate and multiple linear regression analysis were further conducted to determine the factors influencing the RBC lifespan of HD patients in our cohort . In univr = −0.087, p = .500) or rhuEPO resistance index (weekly rhuEPO dose adjusted by weight and hemoglobulin level) . In our 40 HD patients treated with roxadustat, RBC survival did not correlate with weekly roxadustat dosage .In our 62 HD patients treated with rhuEPO, RBC survival did not correlate with weekly rhuEPO dosage  was the significant factor associated with RBC lifespan either in the univariate or multivariate analysis. These results suggest that roxadustat seemed to be more effective in improving RBC longevity than rhuEPO. In our study, the median RBC lifespan of roxadustat group was 16.2% (10.5 d) higher than that of rhuEPO group. Since roxadustat was a newly approved drug to treat renal anemia in China, the median duration time of roxadustat treatment in our patients was only 6 months. Polenakovic and Sikole suggested that the effect of rhuEPO on RBC survival might be related to the duration of treatment . WhetherA variety of factors have been reported to associate with RBC lifespan with inconsistent results. While not being part of the primary data analysis, we found a weak positive correlation between serum phosphate levels and RBC lifespan, which was not confirmed in multivariate analysis. In animal experiment, phosphate depletion contributes to the enhanced vulnerability and accelerated sequestration of erythrocytes . The corAlthough reduced RBC lifespan was considered to be a contributor to renal anemia, observations of the correlation between EPO responsiveness and RBC survival are controversial ,7. In ouThe major limitation of our study is that it was a cross-sectional observational study with small sample size, a cause-effect relationship could not be established. Large prospective studies with long-term follow-up are needed to verify the results in future.In summary, this preliminary cross-sectional observational study showed that HD patients treated with roxadustat had significantly longer RBC survival time than patients treated with rhuEPO.


To describe ethnic differences in concentrations of lipids and lipoproteins, and their changes, during pregnancy to postpartum.n = 806) were healthy, pregnant women, 59% were ethnic minorities. Outcomes were triglycerides, total cholesterol, HDL- and LDL-cholesterol, analysed from fasting blood samples drawn at gestational age (weeks) 15, 28 and 14 weeks postpartum. We performed linear regression models and linear mixed models to explore the total effect of ethnicity on the outcomes, adjusting for gestational age /week postpartum, maternal age and education. The analyses are corrected for multiple testing using the Bonferroni correction.This was a population-based cohort study conducted in primary antenatal care in Norway. The participants ) and higher in women of South Asian (primarily Pakistan and Sri Lanka) origin ) and East Asian  origin ) compared with Western Europeans ). Women of Asian and African origin had a smaller increase in triglycerides, LDL- and total cholesterol from gestational age 15 to 28. At gestational age 28, LDL-cholesterol levels were lowest among East Asians ) compared with Western Europeans ). Triglycerides and HDL-cholesterol were lower postpartum than at gestational age 15 in all groups, but the concentration of LDL-cholesterol was higher, except in Africans. South and East Asian women had lower HDL-cholesterol and higher triglycerides postpartum, while African women had lower triglycerides than Western Europeans.We found significant differences in the concentrations of lipids and lipoproteins and their changes during pregnancy and the early postpartum period related to ethnic origin.The online version contains supplementary material available at 10.1186/s12884-022-04524-2. During normal pregnancy, physiological changes in glucose and lipid metabolism occur to ensure continuous supply of nutrients to the growing foetus , 2. AfteThe increase in maternal lipid levels has physiologic advantages. The early changes in lipid metabolism promote the accumulation of maternal fat stores in early and mid-pregnancy, allows fat mobilization as a maternal energy source in late pregnancy and facilitate transport of lipids across the placenta . TriglycHigh maternal concentrations of triglycerides, cholesterol, and LDL-cholesterol and low HDL-cholesterol are found to be associated with several pregnancy complications, such as pregnancy-related hypertension , pre-ecl. Data from questionnaires and physical examinations including anthropometric measurements were collected according to a detailed protocol. The three study visits were scheduled to take place at gestational age (GA) (weeks) 15, at GA 28 and about four months postpartum.The Stork Groruddalen study is a longitudinal, population-based cohort study of 823 healthy pregnant women (59% from non-Western ethnic minority groups) representative for the largest ethnic groups in Norway, set up in 2008 at three Child Health Clinics in Groruddalen, Oslo, Norway. The study methods have been described in detail elsewhere . In shorWomen were included in the study if they 1) lived in one of the three study districts, 2) planned to give birth at one of the two study hospitals, 3) were < 20 weeks pregnant, 4) could communicate in Norwegian, Arabic, English, Sorani, Somali, Tamil, Turkish, Urdu or Vietnamese and 5) could give informed written consent . Women wr = 0.97) [Fasting triglycerides, total cholesterol and HDL- and LDL-cholesterol, all measured in mmol/L at inclusion, in GA 28 and 14 weeks postpartum, were primary outcomes. Blood samples were drawn in the morning after an overnight fast and sent for routine analyses at the Akershus University Hospital and the Hormone Laboratory, Oslo University Hospital . Fasting = 0.97) . The anaEthnicity may be defined as the social group a person belongs to, implying a shared culture, history, geographical origin, language, lifestyle factors, physical, genetic and other factors . In thisAge of study participants and timing of lipid measurements (GA and weeks postpartum) were used as continuous variables. Gestational age was derived from the first day of the woman’s last menstrual period (LMP), unless LMP date was unknown/uncertain, LMP derived term differed > 14 days from ultrasound derived term (from week 18–20 routine scan) or the pregnancy was a result of in vitro fertilization. Ultrasound term was used in these cases (7% of women). Weeks postpartum at visit 3 was calculated based on offspring`s data of birth. GA/week postpartum was mean centred at each visit. Educational levels were categorised as “primary school or less”, “high school/secondary school” or “college/university” . Body height (cm) was measured to the nearest 0.1 cm with a fixed stadiometer (checked against a standard meter before study start and twice yearly). Pre-pregnancy body weight (kg) was self-reported at GA 15, but measured together with total fat mass  at all visits. There was a strong correlation (0.96) between self-reported pre-pregnancy BMI and BMI at GA 15, but some ethnic differences in weight gain before the first visit was found .2) was calculated /height (meter)2). Breastfeeding was classified as “exclusive breastfeeding”, “partly” (mixed breastfeeding/formula) and “never”, during the past 14 days prior to the postpartum visit. [From the cohort, we have information about a large variety of factors that may be on the causal pathway between ethnicity and lipid levels (i.e. mediators). However, we considered maternal body fat to be the most important possible mediating variable to be included in supplementary analyses, and hence fat mass index (kg/mm visit. .n = 12) due to low numbers, and women with missing values for fasting lipids (n = 5) at enrolment, leaving an eligible sample of 806 women with valid data from GA 15 on lipids and lipoproteins. Of these, 759 (94%) women attended at GA 28 and 653 (81%) women attended 14 weeks postpartum  and numbers/proportions (%). Shapiro–Wilk and the Kolmogorov Smirnov tests indicated that all outcome variables, except triglycerides, were normally distributed. However, we ran models without transforming the triglyceride data, as the linear regression is quite robust to diversion from normality. We performed a rather high number of statistical tests in the current study. To reduce the multiple testing problems, we controlled conservatively the type I error using the Bonferroni correction and set the significance cut-off at αAs our aim was to explore the total effect of ethnicity on the concentrations of lipids and lipoproteins, a direct acyclic graph (DAG) was drawn prior to analyses to depict causal structures of possible pathways and associations between ethnicity and the outcomes Figure S. Per defTo examine ethnic group differences at each of the three time points, we ran linear regression models adjusting for GA or weeks postpartum (Model 1), additionally adjusted for maternal age (Model 2), and additionally adjusted for educational level (Model 3).We checked the effect of including an interaction term between ethnicity and GA for the four outcomes at each visit, but this did not change the estimates of the ethnic differences (ethnic minority groups compared with Western). We compared the original models with models including interaction terms using the Bayesian information criterion (BIC) . The BIC estimate of the models without interaction terms were smaller than the models with interaction terms. Thus, we present the more parsimonious models not including the interaction term.Linear mixed effect regression models were fitted with an interaction term between time and ethnic group to explore ethnic differences in changes in the outcomes from GA 15 to GA 28 and from GA 15 to 14 week’s postpartum, using similar model building as the cross-sectional analyses.2) in the cross-sectional analyses (Model 4). Lastly, we also included maternal breastfeeding, considered as an important mediator, in the analyses of postpartum outcomes (Model 5).In Model 4, we also assessed the effect of ethnicity after having closed the mediating path through fat mass by including the simultaneously measured fat mass index  with 95% confidence intervals (CIs). For consistency when reporting ethnic differences, we used women with Western European origin as reference group. Stata/SE 16.1 was used for all analyses. RStudio version 3.3.2 (2016–10-31) was used to create the figures.Ethnic minority women were younger, had lower level of education and were more often multiparous compared with women of Western European origin Table . Ethnic Nearly all women with non-Norwegian background were immigrants (born in their country of origin), except for women of Pakistani origin (20.5% born in Norway with immigrant parents) Table . ConcentEstimates obtained from the cross-sectional analyses Model 1) changed marginally after additional adjustments for maternal age (Model 2) and education (Model 3) (Table S changed Changes in the concentrations of lipids and lipoproteins (during pregnancy and from GA 15 to 14 weeks postpartum) are presented in Tables SAt 14 weeks postpartum, the concentrations of triglyceride and HDL-cholesterol were reduced compared with GA 15 in all ethnic groups, while concentrations of LDL-cholesterol were higher in all groups, and no changes were observed for total cholesterol (except for women of African origin) Fig. a-d. The 2) , minor loss to follow-up  and measThrough our systematic search we identified only five studies assessing ethnic differences in lipids and lipoproteins in pregnancy; three from Europe –33 and tPregnancy is considered a “natural stress test” for women, as complications like GDM and preeclampsia seem to be early markers of metabolic disturbances, endothelial dysfunction and/or hypertension that predict future risk of type 2 diabetes , and CVDIt was beyond the scope of this study to assess the very complex interplay between dysglycaemia and dyslipidaemia and the possible relations with pregnancy complications, such preeclampsia and GDM. We have previously shown that women of South Asian origin have a higher risk of GDM and insulin resistance during pregnancy and postpartum , higher The pregnancy induced elevations in lipid concentrations usually drop within 24 h postpartum. We founSocioeconomic status, contextual and cultural factors, and the degree of social integration in the country of residence, impose a strong influence on lifestyle of ethnic groups who have left their country of origin, not least the diet , over geThe most consistent associations between lipid concentrations and foetal growth and other pregnancy outcomes seem to be present for triglycerides . We onlyIn conclusion, increased awareness among clinicians about the striking differences in concentrations of lipids and lipoproteins observed during pregnancy to postpartum between several ethnic groups living in the same the country seems indicated. A better understanding of causes for these observed ethnic differences in lipids and whether they can be linked to ethnic differences in pregnancy outcomes and long term effects for women and their children are needed. Further, larger studies are recommended to study whether these effects are similar across ethnic groups.Additional file 1:Figure S1. Flow chart of study sample selection. Percentages for "did not attend" and "missing" are based on total number of participant (n=811) at visit 1 and by ethnic group.Additional file 2:Figure S2. Causal diagram for the association between ethnicity and plasma lipid. S is defined as a binary selection variable. Our study participants have S=1. U = women included at different time points from early pregnancy to 14 weeks postpartum. The total effect of ethnicity on plasma lipids is found by adjusting for gestational week, education and age.Additional file 3:Table S1a. Concentrations of lipids and lipoproteins (mmol/L) at gestational age (GA) 15 by ethnic groups. Values in mean and 95% CI. Table S1b. Concentrations of lipids and lipoproteins (mmol/L) at gestational age (GA) 28 by ethnic groups. Values in mean and 95% CI. Table S1c. Concentrations of lipids and lipoproteins (mmol/L) at 14 weeks postpartum by ethnic groups. Values in mean and 95% CI. Table S2a. Changes in concentrations of lipids and lipoproteins (mmol/L) from gestational age (GA) 15 to 28 by ethnic groups. Values in β and 95% CI. Table S2b. Changes in concentrations of lipids and lipoproteins (mmol/L) from gestational age (GA) 15 to 14 weeks postpartum by ethnic groups. Values in β and 95% CI.


Several studies have suggested no change in the outcome of patients with traumatic brain injury (TBI) treated in intensive care units (ICUs). This is mainly due to the shift in TBI epidemiology toward older and sicker patients. In Finland, the share of the population aged 65 years and over has increased the most in Europe during the last decade. We aimed to assess changes in 12-month and hospital mortality of patients with TBI treated in the ICU in Finland.We used a national benchmarking ICU database (Finnish Intensive Care Consortium) to study adult patients who had been treated for TBI in four tertiary ICUs in Finland during 2003–2019. We divided admission years into quartiles and used multivariable logistic regression analysis, adjusted for case-mix, to assess the association between admission year and mortality.A total of 4535 patients were included. Between 2003–2007 and 2016–2019, the patient median age increased from 54 to 62 years, the share of patients having significant comorbidity increased from 8 to 11%, and patients being dependent on help in activities of daily living increased from 7 to 15%. Unadjusted hospital and 12-month mortality decreased from 18 and 31% to 10% and 23%, respectively. After adjusting for case-mix, a reduction in odds of 12-month and hospital mortality was seen in patients with severe TBI, intracranial pressure monitored patients, and mechanically ventilated patients. Despite a reduction in hospital mortality, 12-month mortality remained unchanged in patients aged ≥ 70 years.A change in the demographics of ICU-treated patients with TBI care is evident. The outcome of younger patients with severe TBI appears to improve, whereas long-term mortality of elderly patients with less severe TBI has not improved. This has ramifications for further efforts to improve TBI care, especially among the elderly.The online version contains supplementary material available at 10.1007/s00701-021-05034-4. Traumatic brain injury (TBI) is a major cause of hospitalization and death worldwide, consequently causing a major socioeconomic burden . EstimatDespite recent advances in multimodal monitoring, including intracranial pressure, partial brain tissue oxygenation, cerebral autoregulation monitoring, and microdialysis , 51, it The reason for unimproved outcomes has been speculated to be the changing epidemiology of patients with TBI toward older patients with more concomitant comorbidities . FinlandWe conducted a retrospective register-based study using the Finnish Intensive Care Consortium (FICC) database. The FICC database has previously been described in detail . The FICNeurosurgery and neurointensive care are provided at only five university hospitals in Finland. Four of these five units  participate in the FICC. These hospitals cover approximately two-thirds of the Finnish population. From the FICC database, we extracted all patients admitted with a diagnosis indicating TBI between 2003 and 2019 in these four units. TBI was defined if the patient had an Acute Physiology and Chronic Health Evaluation (APACHE) III diagnosis indicating TBI with an International Classification of Diseases, 10th revision, diagnosis of S06.X.We included adult patients (age ≥ 18 years) and excluded foreigners (data available for 2003–2013) and non-emergency admissions. We conducted full data analysis due to the low number of missing data.We extracted all covariates from the FICC database. Age was defined upon admission. The Glasgow Coma Scale (GCS) score was defined as the worst measured GCS score during the first 24 h in the ICU, or the last reliable GCS score was used for intubated and/or sedated patients, according to the Simplified Acute Physiology Score (SAPS) II definition . Preadmiχ2 test. We tested continuous data for normality using the Kolmogorov–Smirnov test. Normally distributed data are reported as means with standard deviations and were compared between groups using a t-test. Nonparametric data are reported as medians with interquartile ranges (IQR) and were compared across two groups using the Mann–Whitney U test and across several groups using the Kruskal–Wallis test.For the statistical analyses, we used IBM SPSS Statistics 27 for Macintosh . We report categorical data as numbers with percentages. Categorical data were compared across groups using a two-sided p-test, p-value over 0.05 indicating good calibration), and explained variance .To test the association between admission year and mortality, we used multivariable logistic regression. We adjusted for illness severity using age, sex, admission type, significant comorbidity, GCS score, modified SAPS II score , and treating hospital . We confWe grouped patients into equally sized quartiles as much as possible according to admission year . We conducted separate analyses for 12-month mortality and hospital mortality, as well as a second analysis, including preadmission functional status as a covariate (excluding 149 patients). In sensitivity analyses, we included admission year as a continuous variable. We performed subgroup analyses in predefined subgroups according to GCS score groups , age groups , mechanical ventilation status (yes/no), and ICP monitoring status (yes/no).We followed the Strengthening the Reporting of Observational Studies in Epidemiology statement  for repoThe study included 4535 patients treated in the ICU due to TBI Fig. . The medThe number of ICU-admitted patients with TBI increased from approximately 150–200 per year in the beginning to slightly over 300 patients per year toward the end , out of which 540/1155 (47%) occurred during the index hospitalization. The unadjusted 12-month mortality decreased from 31.2 to 23.4% between 2003–2007 and 2016–2019. The unadjusted hospital mortality decreased from 17.8 to 9.7% between 2003–2007 and 2016–2019.p-value was 0.264, and Nagelkerke R2 was 0.42. For predicting hospital mortality, the AUROC for the illness severity model was 0.91 (95% CI 0.90–0.92), the Hosmer–Lemeshow p-value was < 0.001, and Nagelkerke R2 was 0.50.The AUROC for the illness severity model predicting 12-month mortality was 0.85 (95% CI 0.84–0.86), the Hosmer–Lemeshow Including all patients, a clear trend toward reduced odds of 12-month mortality and hospital mortality as a function of time was seen Table . The redSubgroup analysis showed a trend toward lower odds of 12-month mortality in the GCS 3–8 group, mechanically ventilated patients, and ICP-monitored patients . Furthermore, a reduction in the odds of hospital mortality was seen in patients 70 years and older, although the odds for 12-month mortality were unchanged.https://pxnet2.stat.fi/PXWeb/pxweb/fi/StatFin/]). The epidemiological shift is well demonstrated in our study by increased age, more concomitant comorbidities, poorer pretrauma functional status, lower GCS scores, lower SAPS II scores, and a reduced need for operations, ICP monitoring, and mechanical ventilation. For example, a similar decline in the need for operative treatment has been reported in North America [The epidemiology and cause of TBI and patient characteristics have changed during the past decades . In most America . Of noteThe increased share of older patients, patients being dependent on ADL, and patients having significant comorbidities poses major challenges. We found that although hospital mortality decreased in patients aged 70 years and over, possibly indicating improved intensive care or more restricted admission criteria, 12-month mortality did not change. Thus, there is a clear need to establish whether intensive care for elderly patients with TBI is justified.Regarding the outcome of TBI in general, a thorough review covering the last 150 years reported no improvement in mortality since 1990, after two decades of a marked decrease in mortality rates . More reAlthough there has been no single randomized controlled trial showing a benefit in terms of patient outcome regarding a single therapeutic agent or intervention Below is the link to the electronic supplementary material.


The resulting nonlinear model is accurate in backcomputing SMT solubility and allowed for extensive screening of green solvents. Since the experimental characteristics of SMT solubility are limited, the data pool was extended by new solubility measurements in water, five neat organic solvents , and their aqueous binary mixtures at 298.15, 303.15, 308.15, and 313.15 K. Experimentally determined order of decreasing SMT solubility in neat solvents is the following: N,N-dimethylformamide > dimethyl sulfoxide > methanol > acetonitrile > 1,4dioxane >> water, in all studied temperatures. Similar trends are observed for aqueous binary mixtures. Since N,N-dimethylformamide is not considered as a green solvent, the more acceptable replacers were searched for using the developed model. This step led to the conclusion that 4-formylmorpholine is a real alternative to N,N-dimethylformamide, fulfilling all requirements of both high dissolution potential and environmental friendliness.Solubility enhancement of poorly soluble active pharmaceutical ingredients is of crucial importance for drug development and processing. Extensive experimental screening is limited due to the vast number of potential solvent combinations. Hence, theoretical models can offer valuable hints for guiding experiments aimed at providing solubility data. In this paper, we explore the possibility of applying quantum-chemistry-derived molecular descriptors, adequate for development of an ensemble of neural networks model (ENNM), for solubility computations of sulfamethizole (SMT) in neat and aqueous binary solvent mixtures. The machine learning procedure utilized information encoded in  Sulfamethizole  is a sulfonamide antibiotic drug that is mainly used for urinary infection treatment. Its bacteriostatic activity is typical for sulfonamides and is closely associated with the inhibition of dihydropteroate synthetase, which impedes binding of p-aminobenzoic acid (PABA) and the synthesis of folic acid involved in bacteria multiplication process. Sulfamethizole is characterized by quite low aqueous solubility (1050 mg/L at 310.15 K) ,10. MultIt should be noted that solubility enhancement is not the only criterion for solvent utilization since potential toxicity is another key factor restricting their utilization in pharmaceutical and chemical industry. Hence, screening of efficient solubilizers should adhere to the sustainable chemistry concept and ought to be as environmentally neutral as possible. For this reason, variety of solvent selection strategies are used for an assessment of a wide range of hazards including aquatic, air, persistency, irritation, chronic and acute toxicity, flammability, reactivity, and release potential . ApplicaIn the recent decade, the solubility of various sulfonamides in neat and binary solvents has been widely studied, both experimentally and theoretically ,68,69,70All chemicals used in this study were of analytical grade and were used without purification. Sulfamethizole  and 1,4-dioxane (CAS: 123-91-1) were purchased from Sigma-Aldrich . Acetonitrile (CAS: 75-05-08), N,N-dimethylformamide , dimethyl sulfoxide , and methanol (CAS: 67-56-1) were obtained from Avantor . The nitrogen (grade 5.0) used in differential scanning calorimetry DSC measurements was obtained from Linde . All details were summarized in max = 284 nm) applying A360 UV-VIS device . In all cases, the samples were diluted with methanol, so that the absorbance was measurable and did not exceed the calibration curve range.The solubility measurements were performed based on the shake-flask procedure reported in our previous papers ,12,13,15After determining the solubility, the sediments remaining in the test tubes (in the case of pure solvents) were dried on air and subjected to Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) measurements. The FTIR spectra were recorded using the diamond attenuated total reflection (ATR) technique. For this purpose, a PerkinElmer  spectrophotometer was used. DSC thermograms were determined using a DSC 6000 Perkin Elmer  calorimeter. Nitrogen flow was set to 20 mL/min, and the heating rate was 5 K/min. The DSC device was calibrated using indium and zinc reference standards supplied by Perkin Elmer . All measurements were performed in standard aluminum pans.σ-profile, sP(σ′). In the case of mixtures, the σ-profile is summarized with concentration-dependent weighting. Such distribution functions are used for derivation of the σ-chemical potential, Sμ(σ), by iteratively solving the exact equation:μS(σ) represents the chemical potential of an average molecular contact area of size effa in the ensemble S at temperature T, Sμ(σ) contains the crucial representation of molecular interactions [Sμ(σ) distribution is typically provided in a discrete representation as a set of 61 points in the range of charge density between σ = ±0.03 e/Å2. However, heuristic analysis [σ∈<−0.03,−0.01> characterize affinity for HB donors (HBD), the range σ∈<−0.01,0.01> characterizes nonpolar interactions and is regarded as a measure of hydrophobicity (HYD), and the high positive polarity interval σ∈<0.01,0.03> quantifies affinity for HB acceptors (HBA). Since the whole 61-point Sμ(σ) distribution possesses redundant information, data reduction is to be applied prior to the practical application as molecular descriptors used for machine learning purposes. Here, a simple approach was adopted by averaging μ(σ) values within Δσ = 0.02 regions. Hence, the resulting six descriptors can be summarized as follows:The COSMO-RS  ,74,75 isractions . The μS interfaced with BIOVIA TmoleX 2021 . The level of theory used at this stage corresponded to RI-DFT BP86 (B88-VWN-P86) with def-TZVP basis set for geometry optimization and def2-TZVPD basis set for single point calculations with inclusion of the fine grid tetrahedron cavity and inclusion of parameter sets with hydrogen bond interaction and van der Waals dispersion term based on the “D3” method of Grimme et al. . This mePairs formation was assessed by computing the affinity of SMT for the solvent molecule using a standard thermodynamic cycle. The same level of computations was used as for other types of computations but augmented with correction for zero point vibrational energy ZPE. Hence, the values of Gibbs free energies of reaction A + B = AB  were computed using a concentration-independent protocol offered by COSMOtherm. Affinities of SMF dimers formation were computed in a similar manner.solute) and HB acceptor of the binary solvent (HBAsolvent), DA = HBDsolute − HBAsolvent.DA index as the measure of mutual affinity of HB donor of solute (HBDsolute) and HB donor of the binary solvent (HBAsolvent), AD = HBAsolute − HBDsolventAD index as the measure of mutual affinity of HB acceptor of solute  were used for quantification of solute–solvent affinities. Three major contributions can be distinguished coming from specific and nonspecific interactions. The former can be attributed to hydrogen bonding of the solute molecule, which can act either as a donor or acceptor with solvent molecules, offering its acceptor or donor sites, respectively. For nonspecific interactions, the low polar regions of molecular centers should be considered. Hence, mutual affinities can be defined by introducing the following indices:accuracy: RMSD < 0.035 (root mean square deviation);precision: number of outliers out of domain ≤3 (of 175), ~less than 1.7%;x) between 0 and 1 for at least 99% of predicted or backcomputed values.reliability: predicted solubility within the formal range of log was used for Statistica Automated Neural Networks (SANNs) growth. In this study, default SANN settings were assumed. This includes one layer architecture, multilayer perceptron (MLP), 70:15:15 data set splitting into training, validation, and test sets, and the sum of squares (SOS) error function. For the input layer, six COSMO-RS descriptors were used. The output layer was the logarithm of molar fraction solubility. The second stage involved successful accumulation of networks fulfilling the following formal criterions of SANN acceptance:h* statistics was used [In order to evaluate the applicability domain, the well-known protocol based on was used ,80,81.σ-sigma potentials. Finally, extensive screening was performed for finding new promising binary solvents as potential solubility enhancers of SMT. Particular attention was paid to the green nature of solvents.The organization of the paper reflects the steps undertaken for realization of the desired goals. First, the data set of sulfamethizole solubility was collected by new measurements in five aqueous binary mixtures with organic solvents. Then, an ensemble of artificial neural networks, ENN, was developed, taking advantage of molecular descriptors characterizing xSMT = 3.4 × 10−5. Hence, it is not surprising that any of the utilized organic solvents can act as an efficient cosolvent with the highest solubility enhancement observed in the case of DMF and DMSO. For these organic solvents, the solubility advantage, defined as the logarithm of molar fraction solubility,SA for 1,4-dioxane and acetonitrile are much lower and are equal to 1.5 and 1.9, respectively. Utilization of methanol as a solvent results in enhancement of solubility by about two orders of magnitude compared to the solubility provided by water (SA = 2.1). The solubility advantage offered by propylene glycol is also comparable (SA = 2.3), which can also be inferred from published data [x2* = 0.6 (x2* represents the mole fraction of organic solvent in solute free binary solution). In such a composition, solubility of SMT is 220 times higher than in pure water (SA = 2.3) and exceeds the solubility in neat 1,4-dioxane by about seven times. In the case of an acetonitrile–water system, a similar cosolvation behavior can be observed. The highest solubility advantage, SA = 2.55, can be observed for x2* = 0.6. Hence, both the 1,4-dioxane–water system and the acetonitrile–water system can offer additional benefits worth consideration in practical applications. In the case of methanol–water solvents, moderate deviations from the linear trend can be observed for both low and high organic solvent contributions in the binary mixture.The starting point of this study was the augmentation of a limited pool of available solubility data of SMT with new measurements. Aqueous binary systems were selected due to the most probable practical implications. The obtained results were collected in hed data ,72. HencAlthough it is interesting to notice a high solubility of SMT in DMF, this particular solvent is regarded as hazardous and reprotoxic with restriction consideration imposed by the European Chemicals Agency’s (ECHA) Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) . Hence, Since the aim of this work is to develop a solubility model of SMT based only on the COSMO-RS solution characteristics, it is important to determine whether the solid state that is in equilibrium with liquid has not undergone any polymorphic or pseudopolymorphic transformations. For this purpose, the FTIR and DSC measurements were carried out for the solid residues obtained after the shake-flask solubility determination procedure was performed for neat solvents. Fortunately, in all cases, both IR spectra and DSC thermograms for precipitates are similar to those recorded for pure SMT see .μ(σ), computed according to COSMO-RS theory [μ(σ) as a function of charge density were plotted for solvents used in this study. The analysis also includes sulfamethizole in aqueous binary solvents containing propylene glycol for which the solubility values have been documented by Delgado et al. [μ(σ) in μ(σ) of solvent with respect of solute and is associated with the left ordinate. Both lines represent quite similar trends allowing for qualitative ranking of solvents. Two the most efficient solvents might be properly selected for experimental tests, even though such inference is only qualitatively correct. Nevertheless, there is a quite rational expectation that information provided by μ(σ) functions might be used as valuable molecular descriptors for machine learning protocol.From the provided experimental data, it was concluded that after excluding DMF due to its nongreen character, DMSO becomes the first choice solvent for SMT. On the other hand, in the literature, there were many examples ,93,94 ofS theory  with an S theory . In Figuo et al. ,72. Addio et al. ,95, the μ(σ) positive values of charge density distribution. To the contrary, it acts as a proton donor with all considered solvents molecules. The schematic representations of the most energetically favorable structures are characterized in r values provided in From μ(σ), which, after data reduction, resulted only in six molecular descriptors per system. The representative distributions of these six measures were presented in μ(σ) profiles of protic solvents  are significantly different from the ones corresponding to aprotic media . This effect is particularly pronounced in the case of neat solvents (1.0), as evidenced by an upward trend for large σ intervals (HB acceptors affinity area) for aprotic solvents and an opposite downward trend for protic ones.Machine learning protocol utilized the distributions of μ(σ), characterizing HB accepting and HB donating abilities and hydrophobicity, are utilized in SANN development. It seems that the contribution coming from HB accepting ability is slightly more pronounced, which was already addressed by inspection of the potential occurrence of intermolecular complexes.The ENN was constructed by successful collection of SANNs fulfilling the acceptance criterions. Since accuracy expressed in terms of RMSD was not the only inclusion criterion, it is expected that obtained ENN is sufficiently coherent for predictive purposes. The quality of obtained ENN was documented in The accuracy of developed ENN encourages prediction of SMT solubility for systems not studied experimentally. This was performed via computations of molecular descriptors values for a variety of binary mixtures comprising combinations of 180 solvents used in practice for solubility determination. The list of solvents comes from the in-house database of solubility data published in the literature. From the perspective of the aim of this paper, binary mixtures are the most interesting. However, it is not practical to test all possible combinations of neat solvents given the restriction not from the computational perspective but from that of the potential miscibility limitations. In order to avoid studying artificial combinations, which, in practice, might result in binary biphasic systems, only pairs of miscible liquids were considered. This was ensured by an additional literature search. Hence, for the screening purposes, 275 binary systems were studied in six compositions at room temperature. Additionally, the pool of considered solvents was extended by including solvents suggested by the PARISIII application ,99,100 ax2* = 0.2) mixture (1.071) < acetonitrile–water (x2* = 0.6) mixture (1.461) < DMF-N-methylformamide (x2* = 0.4) mixture (1.500) < acetonitrile (1.881) < methanol (1.893) < DMF (2.156) < methanol-formamide (x2* = 0.4) mixture (2.164) < DMF-formamide (x2* = 0.8) mixture (2.174) < formamide (2.295) < propylene glycol (4.499) < 1,4-dioxane–water (x2* = 0.6) mixture (4.633) < 1,4-dioxane (5.267) < DMSO (11.660). The unexpected scoring of DMSO, which is generally considered as a safe solvent, is worth commentary. According to the algorithm applied in the PARISIII program, DMSO was ranked as the least green solvent among all of the solvents mentioned above. This counterintuitive conclusion originates from the fact that the default settings assume equal contribution of all environmental impact scores to the overall environmental index. The only serious environmental aspect of DMSO is related to the extremely high value of the photochemical oxidation potential index (PCOP). However, from the perspective of pharmaceutical practice, this index seems to be of minor importance. If PCOP is excluded from the analysis for the re-evaluation of the environmental index values, the following series is obtained: water (0.020) < propylene glycol (0.189) < DMSO (0.260) < 4-formylmorpholine (0.509) < methanol (0.763) < 1,4-dioxane–water (x2* = 0.6) mixture (0.853) < methanol-N-methylformamide (x2* = 0.2) mixture (0.936) < N-methylformamide (0.959) < 1,4-dioxane (0.967) < acetonitrile–water (x2*=0.6) mixture (1.461) < DMF-N-methylformamide (x2* = 0.4) mixture (1.500) < methanol-formamide (x2* = 0.4) mixture (1.801) < acetonitrile (1.881) < DMF (2.156) < DMF-formamide (x2* = 0.8) mixture (2.174) < formamide (2.295). It is worth noting that, regardless of the total environmental index evaluation, 4-formylmorpholine is the top ranged solvent and can be regarded as a green alternative for DMF.For each solvent included in the final list, the values of six molecular descriptors were determined analogically to the training set and were used as inputs for the development of the ENNM. Estimated SMT solubilities were confronted with solubility in DMF to find solvents with comparable or better effectiveness. It is interesting to summarize that during this phase, several systems were identified as potential solubility enhancers of SMT. The results of the solubility computations for selected binary systems are provided in μ(σ) profiles, which is a good indicator of potential solubilizing abilities. There are many potential binary systems with solubility advantages similar to that of DMF and the majority of them comprise DMF, DMSO, 4-formylmorpholine, formamide, and N-methylformamide in binary mixtures with themselves or other solvents such as water or light alcohols. It is also worth adding that all systems for which the values were plotted in h* = 0.122. All systems used in the screening procedure for which the computed hat value exceeded this threshold were excluded from the analysis. In this group, binary mixtures involving nonpolar solvents such as cyclohexane, toluene, benzene, and other hydrocarbons were found in a variety of binary formulations. This is rather expected due to character of the data set used at the training stage. Halogenated solvents were typically rejected from the analysis—for example, chloroform, carbon tetrachloride, and chlorocyclohexane mixed with other solvents. Additionally, promising green hydrotropes such as dihydrolevoglucosenone, gamma-valerolactone, sulfolane, glyme, diglyme, and transcutol were also identified as unsuitable for the detailed analysis due to high hat values. Some esters were located outside of the applicability domain—for example, ethyl acetate and propyl acetate. However, some surprising exclusions were found—for example, DMSO mixture with ethanol  or 2-propanol , as well as some light alcohols mixtures such as methanol + ethanol and methanol + propanol. This is probably due to the limited diversity of the training set of SMT solubility data. Identification of formally acceptable solubility enhancers compensated for these surprising exclusions.To complete the screening, an additional analysis was performed. The values of SMT solubility predicted using ENNM were plotted as a function of the affinity complementarity index. As was mentioned in the methodology section, AC is the sum of the relative acceptor, donor, and nonpolar indices describing the overall similarity of SMT affinity profiles with respect to a given solvent molecule. The cloud of points was generated using ENNM for hundreds of solvent mixtures at room temperature, as shown in Finally, it is also interesting to provide information about the affinities of SMT for the solvents found during the screening phase. Hence, in The search for efficient and green solvents is a general tenet of the sustainable chemistry concept. This is as important, as it is a not trivial and not straightforward task. The necessary compromise between often contradictory constraints prohibits easy replacement of hazardous solvents with greener ones. In this study, the general approach for this task is offered with quite spectacular success. Here, in the case of sulfamethizole, similarly to the already documented case of theophylline , the ensx2* = 0.6) and acetonitrile–water (x2* = 0.6), were found to be more efficient and were ranked as more environmentally friendly than pure organic components.Since the knowledge of SMT solubility was too limited, the results of new measurements were provided for five aqueous binary systems. This analysis was enriched with green solvents screening procedure based on the several common environmental risks assessment. The application of water–organic mixtures seems to be a promising strategy in seeking greener solvents. For instance, two of the binary water–organic mixtures, 1,4-dioxane–water (In this study, the range of SMT solubility values was extended to include much more effective solvents. Following the performed experiments, the high solubilizing potentials of DMF and DMSO were documented. Since the former solvent cannot be used in pharmaceutical practice, the search was undertaken for greener replacement with high solubility enhancement. The application of ENN enabled finding real alternatives for DMF with even higher solubilizing power. Hence, finding 4-formylmorpholine is the main outcome of this study, showing the efficacy of the proposed approach.


Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD.We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3–12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD.d 0.21; 95% CI − 0.46, 0.88 and 0.10; 95% CI − 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks , but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell.Data from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF  on September 28, 2015. Funding was provided by the U.S. Department of Defense.The online version contains supplementary material available at 10.1186/s13229-021-00447-5. Clinical heterogeneity and genetic diversity in autism spectrum disorder (ASD) support approaches to treatment from the perspective of key biochemical pathways , 2. BiomWe previously reported consistent improvements on clinical measures in treatment of young men with ASD using a SF-rich preparation compared to PL . BenefitThis report describes the results of our 36-week randomized parallel double-blind placebo-controlled, phase 2 clinical trial of oral GR, the stable metabolic precursor of SF from a GR-rich extract of broccoli seeds, and myrosinase, the enzyme that converts GR to SF (hereafter referred to as “SF”), in 45 children with ASD, ages 3–12 years  , 11, andTo determine biochemical effects of SF in peripheral blood mononuclear cells , and based on the results of our pilot study , we chosChildren ages 3–12 years with ASD were recruited from UMass outpatient clinics (approximately 60%), local and regional autism societies and pediatricians (20%), and 20 percent were self-referred. All visits (one screening and 5 subsequent visits over 36 weeks) took place in the Clinical Research Center or Department of Pediatrics at the UMass Memorial Medical Center in Worcester, MA.The study was approved by the Institutional Review Boards (IRB) at the U.S. Department of Defense (A-18817.a), UMass Medical School (H00007832) and Johns Hopkins University (00084331), conducted under IND 127062 and registered as NCT02561481. All participants and their caregivers were consented at the screening visit. A Research Monitor and Data Safety Monitoring Board met regularly with the study staff to review progress and safety concerns.Criteria for inclusion were a diagnosis of moderate to severe ASD, ages 3–12 years and a parent or guardian for consent; for exclusion: seizure within 1 year, impaired renal, hepatic or thyroid function, current infection or treatment with antibiotics, medications that may modify the testing of ASD , and chronic medical disorders. Of the 62 children who qualified for the study on initial screening, 5 were excluded because of misdiagnosed ASD or inability to participate   was admiVineland Adaptive Behavior Scale, Second Edition (VABS-II) , was conLeiter-R  is a nonThe OACIS, our primary outcome measure, is an instrument for rating the severity of symptoms in 10 categories, including the general level of autism, social interaction, aberrant and repetitive behavior, verbal and nonverbal communication, hyperactivity, anxiety, sensory sensitivities and restricted and narrow interests. Each category is rated from 1  to 7 (most severe). The OACIS-S (severity) was rated at the initial visit, then used as a reference point at follow up visits when the OACIS-I (improvement) was scored.The Social Responsiveness Scale-2nd Edition (SRS-2), a secondary outcome measure, is a 65-item rating scale measuring deficits in social behaviors in 6 subscales related to ASD . The SRSThe Aberrant Behavior Checklist (ABC), a secondary outcome measure, is a 58-item behavior rating scale used to measure behavior problems across 5 subscales . The ABCMedical histories of all children were reviewed, including evaluations leading up to the diagnosis of ASD and subsequent therapies and treatments. Children’s responses to fever  and deveWe were unable to produce or obtain SF-rich preparations for this study like those used in our previous study . Based oIn a 2-week pilot study of 10 boys  with ASD, oral GR and myrosinase  demonstrated bioavailability of 47.0% ± 13% (range 29.4–68.4%) of GR dose , close tAfter screening, 57 children were assigned by the Research Pharmacy, double-blinded, and randomized 1:1, to either treatment with SF or identical placebo for 15 weeks (Phase 1), then open-label treatment of all children with SF from 16 to 30 weeks (Phase 2), followed by no treatment from 31 to 36 weeks (Phase 3). Six clinical visits were scheduled: Screening , 7, 15, 22, 30 and 36 weeks. Screening included ADOS-2, Vineland, and Leiter scales, and the OACIS-S. Participants were assessed by senior clinicians (A.W.Z. or S.L.C.) with physical examination at each visit along with assessment using the OACIS-I  at visitSF was administered as GR-rich broccoli seed extract tablets containing myrosinase as described above, in an approximate dosage equivalent to 1 µmol SF/lb/day (2.2 µmol/kg/day) body weight. This dosage is roughly equivalent to the dosage that was used in our previous clinical trial of SF in male adolescents and adults with autism . The totTwo phone visits with caregivers took place between visits 1 and 2, and 3 and 4, to review the children’s progress and answer questions. Participants’ other concomitant medications, including psychopharmaceuticals, vitamins and dietary supplements were recorded and could be continued. Caregivers were asked to inform the study staff when changes were made to their children’s medications. Blood and urine specimens were collected at each visit for complete blood count (CBC), comprehensive metabolic profile , thyroid stimulating hormone (TSH) and urinalysis.Samples for biomarkers were obtained from study participants at each visit. Eight mL of whole blood was drawn into Vacutainer CPT tubes  at room temperature and processed for PBMC isolation . After cSulforaphane and other isothiocyanates (ITC) are conjugated by glutathione (GSH) which then undergoes further enzymatic modifications to give rise sequentially to the cysteinylglycine–, cysteine– and N-acetylcysteine–ITC conjugates, all of which are dithiocarbamates (DTC) and are detected in the cyclocondensation reaction-HPLC assay as described previously .−ΔΔCT method  and there was no significant difference between the groups at baseline  = 2.37, p = 0.14] and Maximal Reserve Capacity  over the treatment period  had valid Seahorse data for analysis. For the placebo-controlled (Phase 1) of the study ATP-Linked Respiration increased for the individuals treated with SF but not for those treated with PL   = 3.42, p < 0.05; Quadratic F = 11.29, p < 0.001; r = 0.50; p < 0.01]  with each research subject required to participate for 36 weeks, with 6 outpatient visits that induced considerable anxiety for the children, especially due to phlebotomies for clinical laboratory safety and biomarker studies at each visit when clinical assessments were done. We confirmed that children received the SF, as shown by cyclocondensation measurements, and there were no signs of toxicity on clinical laboratory tests or serious adverse events. Both the bioavailability of SF as judged by cyclocondensation values and the spread of those values were remarkably like those previously reported in studies of adults, dosed with a similar quantity of a SF-rich preparation (150 μmoles SF or about 2.2 μmoles/kg body weight) , 36. ThiThere was considerable treatment fatigue over time, as shown by increases in parents’ SRS-2 and ABC scores at 22 and 30 weeks for most subscales, when all were taking SF and scores trended back toward the baseline, irrespective of the subjects’ length of exposure to SF. Improvements were also noted on the ABC and SRS-2 by caregivers in the absence of SF. These factors, along with known placebo effects in clinical trials in ASD, contributed to difficulties in estimating clinical changes , 38. ChiThe source of SF in this trial was GR with added myrosinase, the combination of which has been shown to provide adequate substrate for SF in small trials in typical adults –27, althThe clinical efficacy of SF in ASD in children in this trial and our previous trial in young men  comparesBiomarkers provided strong evidence for the biologic effects of SF, especially with respect to markers of glutathione redox status, inflammatory cytokines and mitochondrial function. Decreases in the plasma redox ratio of free and total glutathione were present at 15 and 30 weeks on treatment, primarily due to increases in oxidized GSSG. These results are consistent with SF-induced increased turnover of anti-inflammatory GSH as well as cellular export of GSSG in an attempt to control intracellular oxidative stress . HO-1 fuincrease with fever and in response to SF [The findings for heat shock proteins, HO-1 and cytokines suggest dynamic changes over time in the children’s metabolism, possibly inherent in ASD or due to SF. Heat shock proteins are expected to se to SF , which wse to SF . Cytokinse to SF .Mitochondrial function improved in the SF group as compared to the placebo group during the placebo-controlled phase of the study and improvement in mitochondrial parameters correlated with improvements on the ABC scale. This suggests that the clinical response to SF was associated with changes in mitochondrial function and that large intrasubject variability in this study was linked to underlying biological responses. The increase in ATP-Linked Respiration associated with improvement in ABC scores suggests that those individuals who showed improvements in behavior also had improved mitochondrial capacity to produce ATP. Individuals who showed an improvement in ABC scores also showed a decrease in Proton Leak Respiration, suggesting that their mitochondria were better able to regulate oxidative stress. It is also possible that the increase in ATP production was related to the improvement in the ability of the mitochondria to handle oxidative stress. Since mitochondrial function is very intricately linked to inflammation and oxidative stress, the changes in mitochondrial function measured may have been related to changes in oxidative stress and inflammation, as has been suggested in other studies , 52. Notincreased maximal respiratory capacity at baseline  [decreased levels with SF, whereas levels increased in children without developmental regression. These important differences may be a few among many that underlie the heterogeneity of ASD and emphasize the importance of delineating clinical subgroups and accounting for differential responses in therapeutic trials.There are important differences in components of mitochondrial function in subgroups of ASD, notably in children with distinct histories of neurodevelopmental regression that may confound analysis of responses to treatments , 51. We  stress) . HoweverAll clinical trials in children with ASD have inherent limitations due to clinical heterogeneity, cyclic variability in behaviors, sleep, feeding and bowel function (among others), and anxiety associated with adaptation to the intervention itself and necessary clinical visits. This study was no exception, and many of these factors limited the statistical significance of our clinical assessments. Biomarker data from our pilot and main studies helped to establish dosing and turnover of SF as well as cellular effects of SF. Clinical effects of GR + myrosinase as the source of SF were more difficult to ascertain in children than those in our previous trial of a SF-rich preparation in young men with ASD .We found that SF was safe, but based upon the OACIS, our primary clinical outcome measure, its effects were not significant. Effect size estimates showed small improvements with SF, though not significant, for the general level of autism on the OACIS-I scale. There was significant improvement on one of the secondary measures (ABC) but not on the SRS-2. Improvements in sociability and communication were observed on the SRS-2, as well as irritability, stereotypy, hyperactivity, and inappropriate speech on the ABC with a non-randomized analysis of the length of exposure. SF also had significant positive effects on oxidative stress, cytoprotective markers and cytokines, as well as mitochondrial function. These were promising findings that require further investigation of both the clinical effects and mechanisms of action of SF.Additional file 1. Additional Files: Table S1(A–D). Methods. Table S2. Characteristics of children who completed all visits vs children who dropped out of the study after 15 weeks. Table S3. OACIS-I scores not including severely affected subjects. Table S4. Descriptive analysis for raw total SRS-2 scores and subscale scores over all visits. Table S5. SRS-2 score means at each visit by intervention group, sulforaphane (SF) versus placebo (PL) (change from baseline). Table S6. SRS-2 washout effect (30–36 weeks) sulforaphane (SF) versus placebo (PL). Table S7. Descriptive analysis for total ABC scores and subscale scores. Table S8. ABC score means at each visit by intervention group, sulforaphane (SF) versus placebo (PL) (change from baseline). Table S9. ABC washout effect (30–36 weeks) sulforaphane (SF) versus placebo. Table S10. Length of exposure by fever response: SRS-2. Table S11. Length of sulforaphane (SF) exposure analysis by fever response: ABC. Table S12. Length of sulforaphane (SF) exposure by regression: SRS-2. Table S13. Length of sulforaphane (SF) exposure analysis by regression: ABC. Table S14. Mixed models accounting for treatment effect, visit and subject-specific random effect: SRS-2 total score and all subscales. Table S15. Mixed models accounting for treatment effect, visit and subject-specific random effect: ABC total score and all subscales. Table S16. Glutathione (GSH) variable means at each visit by intervention group, sulforaphane (SF) versus placebo (PL). Table S17. Descriptive analysis for glutathione (GSH) for total sample. Table S18. Univariate regression (ß) coefficients for sulforaphane (SF) compared to placebo (PL) for biomarkers (change from baseline). Table S19. Mean biomarker gene expression at 15 weeks of sulforaphane (SF) exposure (both groups) by regression (change from baseline).


Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject  and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills. Delays de novo genetic changes   are baseMSNs incorporate multiple MRI modalities into the estimated structural covariance, both microstructural and morphological, to overcome the limitations of using individual features with particular spatio-temporal trajectories. These provide a more comprehensive description of the brain, improving the predictive ability of clinical symptoms and behaviour from brain data . CorrespIn our previous work, we used this method to characterize the developing brain at the neonatal timepoint using structural and diffusion indices , reporti22.1This study included a sample of term-born healthy neonates participating in the Developing Human Connectome Project (dHCP); (http://www.developingconnectome.org/), scanned at the Newborn Imaging Centre at Evelina London Children’s Hospital, London, UK. Images are openly available on the project website. This project has received ethical approval (14/LO/1169) and written informed consent was obtained from parents. As part of the dHCP project, subjects are invited for a follow-up visit to assess infant development at 18 months. This assessment includes The Bayley Scales of Infant and Toddler Development (Bayley-III) (BSID)  explorin2.2Neonatal MR brain images were acquired on a 3 T Philips Achieva scanner without sedation, using a dedicated 32-channels head coil system . AcquisiT2-weighted (T2w) images were obtained using a turbo spin-echo (TSE) sequence, acquired in sagittal and axial planes with TR= 12 s, TE= 156 ms, SENSE factor 2.11  and 2.58  with overlapping slices (resolution 0.8 ×0.8 ×1.6 mm). T1-weighted (T1w) images were acquired using an Inversion Recovery TSE sequence with the same resolution using TR= 4.8 s, TE= 8.7 ms, SENSE factor 2.26  and 2.66 . Structural images were reconstructed to a final resolution of 0.5 × 0.5 × 0.5 mm, using slice-to-volume registration . Structu2 (20 repeats), b= 400 s/mm2 (64 directions), b= 1000 s/mm2 (88 directions), b= 2600 s/mm2 (128 directions) (2), and fractional anisotropy (FA) and mean diffusivity (MD) maps were generated using MRtrix3  . Diffusiections) , Gibbs-rections) , and theections) . Images ections) . A tenso MRtrix3 . Neurite MRtrix3 . Diffusi MRtrix3 , and ima2.3MSN construction for this cohort was described previously in 2.4Mean age at developmental assessment was 18.69 ± 1.04 months (range 17.16–24.46 months), mean corrected age for gestational age (GA) at birth was 18.68 ± 1.00 months (range 17.30–24.33 months), the latter used for Bayley-III score calculation. The Bayley-III  is a comSocial-emotional development was determined by the Q-CHAT , a paren2.5We utilized Connectome-based Predictive Modeling (CPM)  to exploPredictive networks were determined as significant if passed both cross-validation methods. These were defined by taking edges appearing in at least 90% of testing runs in the LOOCV. For clarity and ease of interpretation, predictive edges were examined in the context of the seven clusters reported before in 2.62 for the brain network measure was calculated as (SSE reduced model-SSE full model)/SSE reduced model. Although PMA at scan, ICV and time from birth to scan were significantly correlated , no variance inflation factor (VIF) exceeded 5 (The association between whole-network average strength (across the entire cortex) and the eight developmental measures was examined by averaging a symmetric triangle of the connectivity matrix, excluding self-connections. This was entered together with PMA at scan, sex, ICV, IMD and time from birth to scan into a general linear model where the developmental measure was the dependent variable. Partial Rceeded 5  and ther33.1Demographics of the sample and mean behavioural scores are presented in 3.2rs =0.196, p = 0.007, p permute=0.019, RMSE=9.53) and the language composite score   and was therefore retained as the only robust predictive model.Neonatal MSNs successfully predicted the Q-CHAT score (E=16.30) . HoweverThe positive and negative predictive networks for the Q-CHAT included 1.6% and 2.8% of all possible connections, respectively. The proportion of edges within each of the seven clusters included in the predictive networks is presented in The proportion of predictive edges connecting between clusters is presented in 3.32) , receptive language sub-scale , cognitive composite , and Q-CHAT , p < 0.05, R2 full= 0.13, R2 partial= 0.03). Further, network strength within the somatosensory and auditory cluster was associated with language composite  and expressive language sub-scale   of neonatal MSNs reported previously , we examal=0.04) .Fig. 6Sc4In this study, we found that neonatal MSNs can successfully predict social-emotional behaviours at 18 months in a large group of healthy term-born babies. We show that the pattern of cortical maturation at birth already captures variability in infant development. This association between brain structure at birth and infant developmental outcomes was not limited to information held in individual edges of the network but was also evident in summary measures of network strength over the entire cortex, specifically in somatosensory-auditory, insular and medial frontal areas. On a regional level, the predictive networks were complex and widespread across the cortex, albeit suggesting specific important involvement of primary and posterior cortical regions. No consistent or significant results were found for the cognitive or motor measures.Both language and social-emotional development result from a combination of fetal and postnatal brain programming, together with in- and ex-utero experiences. However exactly how these factors come about and interact to create these complex behaviours is still under investigation. Our results indicate that some of the neural foundations crucial for developmental capacities in infanthood, observed through the pattern of structural covariance, originate during the fetal period and are already present at birth. Social-emotional abilities were predicted by the individual edges comprising the network and associated with the average whole-network strength , Fig. 5 Specifically, as a predictive network, neonatal MSNs reflect that optimal brain functioning is reliant on a delicate equilibrium of positive and negative structural covariance, where the skeleton for future infant development is established long before overt behaviours could be assessed. Our results suggest that within functional cortical divisions , greater structural similarity at birth is associated with better language and social-emotional skills in infanthood. This was also observed on a whole-brain level. This is in agreement with the hypothesized basis of structural covariance in the brain, whereby regions participating in similar functions show comparable structural signatures, implying joint developmental trajectories.Predictive networks included 1%− 3% of edges, consistent with other studies utilizing CPM . The resr = −0.52). It is not only that producing and understanding speech is critical to communicating with others, but it is also postulated that social interaction and social learning experiences are crucial for the proper development of language skills  and correlated . Structures identified include but are not limited to the temporo-parietal junction, prefrontal cortex, superior temporal gyrus, and amygdala . From a In previous work with smaller sample size and the inclusion of both term and preterm neonates, cortical FA at birth was found to significantly predict cognitive and language scores at two years using support vector regression , with laThe ontogeny of different cortical regions, and of different behavioural skills is distinct. Grossly speaking, the first cortical regions to mature are the primary areas of motor, sensory, visual and auditory functions, followed by their associative regions, and lastly maturing are the higher-order  regions . This is4.1CPM has its own limitations as outlined in , for exaAs a limitation we should also highlight that the brain-behaviour associations reported here exclude subcortical structures and the cerebellum as structural features. In this work we focused on surface-based measurements as developmental indices and therefore our analysis was limited to the cortex. Future work should examine the contribution of subcortical regions and the cerebellum, as they are likely to also be implicated in the development of social-emotional, cognitive, language and motor abilities. Moreover, the cortical parcellation for generating the networks’ nodes was based on 150 regions. While we are aware network analysis is highly reliant on parcellation scheme, we have shown in a previous paper see , that MSWhen interpreting scores from developmental assessments, such as the ones used in this study, one should understand their nature: One assessment at 18 months is only a transient screenshot of infant development and is not necessarily indicative of future difficulties at the individual level. Both language delays and the appearance of social-emotional difficulties at an early age do not inevitably mean the continuation of language difficulties or a later autism diagnosis. In addition, these features or delays might not be evident at 18 months but only emerge at a later age. Therefore, any interpretation of infant assessments in the context of future functionality should be done with caution and preferably include follow-up at preschool and school-age .4.2In this work, we showed that multi-feature multi-modal cortical similarity at birth represented by MSNs are predictive of social-emotional abilities in a large group of infants. Cortical regions involved were widespread, with predictive features including connectivity within and across functional cortical domains. Earlier developing cortical regions seemed to be specifically important in this context. These results support the use of neonatal cortical profiles for means of early detection and support of developmental difficulties.10.13039/100011102European Union Seventh Framework Programme . Infrastructure support was provided by the 10.13039/501100000272National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, 10.13039/100009360King’s College London and the NIHR Mental Health Biomedical Research Centre at Guy’s and St Thomas’ Hospitals NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The study was funded in part by the Wellcome Engineering and Physical Sciences Research Council Centre for Medical Engineering at King’s College London (grant WT 203148/Z/16/Z) and the 10.13039/501100000265Medical Research Council (UK) . D.F’s PhD is supported by the Sackler Institute for Translational Neurodevelopment at King’s College London and the Medical Research Council Centre for Neurodevelopmental Disorders, King’s College London. J.O.M. is supported by a Sir Henry Dale Fellowship jointly funded by the 10.13039/100004440Wellcome Trust and the 10.13039/501100000288Royal Society (grant 206675/Z/17/Z). J.O.M., D.E. and G.M. received support from the Medical Research Council Centre for Neurodevelopmental Disorders, King’s College London (grant MR/N026063/1). D.C. is supported by the 10.13039/501100003130Flemish Research Foundation . For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.The developing Human Connectome Project was funded by the European Research Council under the The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.