Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood mental health disorders. Stimulant drugs as the most commonly used treatment and first-line therapy for ADHD have side effects. One of the newest approaches to select the best choices and optimize dosages of medications is personalized medicine.This historical cohort study was carried out on the data taken from the period of 2008 to 2015. Eligible subjects were included in the study randomly. We used mixed-effects logistic regression models to personalize the dosage of Methylphenidate (MPH) in ADHD. The patients’ heterogeneity was considered using subject-specific random effects, which are treated as the realizations of a stochastic process. To recommend a personalized dosage for a new patient, a two-step procedure was proposed. In the first step, we obtained estimates for population parameters. In the second step, the dosage of the drug for a new patient was updated at each follow-up.Of the 221 children enrolled in the study, 169 (76.5%) were male and 52 (23.5%) were females. The overall mean age at the beginning of the study is 82.5 (± 26.5) months. In multivariable mixed logit model, three variables  had a significant relationship with improvement. Based on this model the personalized dosage of MPH was obtained.To determine the dosage of MPH for a new patient, the more the severity of baseline is, the more of an initial dose is required. To recommend the dose in the next times, first, the estimation of random coefficient should be updated. The optimum dose increased when the severity of ADHD increased. Also, the results show that the optimum dose of MPH as one proceeds through the period of treatment will decreased. Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood mental health disorders . The estThe etiology of ADHD is multi-factorial . It is aStimulant drugs as the most commonly used treatment and first-line therapy for ADHD have side effects including abdominal pain, nausea, loss of appetite, nervousness, insomnia, compulsive behaviors and movement disorders . UnclearOne of the newest approaches to select the best choices and optimize dosages of medications is personalized medicine (PM). PM tries to enable patients to receive an earlier diagnosis and optimal treatments with the least complications and the lowest costs . In PM cThis study evaluates the relationship between dosage of methylphenidate (MPH) and other important factors with response (improvement) in ADHD patients under the framework of a mixed-effect logit model; then proposes an optimal dose on the basis of the individualized factors of each patient.This historical cohort study was carried out on the data taken from the period of 2008 to 2015 on Children with a diagnosis of ADHD who were admitted in the psychiatric clinic as a referral center and a main pediatrics hospital in Iran . The Ethics Committee of the Tehran University of Medical Sciences approved this study. The researchers followed the principles of the Helsinki Declaration.Being within the age range of 3 to 13 years,Filling the questionnaire for scaling the severity of ADHD ),Having at least one follow-up visit.The children with the primary diagnosis of ADHD ,Other drugs instead of MPH were prescribed,The children didn’t respond to the treatment up to the last available follow up.(i.e. the MPH have not had any effect on them during the study time)The exclusion criteria were as follows:Of about 5000 available records, based on eligibility criteria, patients’ records were assessed randomly. 40% of the reviewed records did not satisfy inclusion criteria. The sampling was completed when the sample size reached 221.Gender, birth weight, the age of the first diagnosis, severity of ADHD at baseline, weight per visit, type of comorbidity (if present), time intervals of visits (comparing with the first visit), dose of MPH, consumption of risperidone and fluoxetine were recorded as the basic data of the participants.To Evaluate and score the severity of ADHD, a reliable Persian version   of ConneA milligram per kilogram scale was used to document the dosage of MPH.The basic characteristics, for quantitative variables, were summarized by mean (±standard deviation), and for qualitative variables, by frequency (percentage). The comparison of the explanatory variables between the two genders was assessed by t-test and nonparametric tests of Mann-Whitney U and chi-square. The significance level was set to 5% for all tests. The statistical analysis was carried out using R version 3.5.1 (package mle4) and STATA version 14.i, where Yij indicates the binary response variable, the subscript i denoted the study subject. Here p0 will symbolize a target value for P(Yij = 1). Dij is the drug dosage administered for i-th subject and j-th time point, and d is the corresponding fixed coefficient. In this model Xij is the vector of covariates corresponding to fixed-effects parameter vector β, β0 is a fixed intercept and bi is a random-effect coefficient for the subject i. we assume it has N.We applied a generalized linear mixed model with the binomial response and a logit link,β = ln(OR)) and their 95% confidence intervals (CIs) were calculated in Table The vector of covariates includes gender, age of the onset of ADHD, severity of disease at baseline, birth weight, weight in follow-ups, time interval (the time passed after the commencement of treatment), taking risperidone, taking fluoxetine, being accompanied with affective disorders (mood and bipolar disorders), anxiety disorders , social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), phobia, and anxiety disorder), oppositional defiant disorder (ODD) and, other comorbidities , learning disorder (LD), stutter, Tic, and major depressive disorder (MDD)). The adjusted regression coefficients . In order to predict P(Yij = 1), we used all available responses, and then the 90th percentile of these probabilities was determined.2.n (n > 1), based on the values of the covariates of the previous time of this individual the estimate n was obtained from the following equationFor time tbi is predicted by the adaptive Gauss-Hermite approximation to the log-likelihood.Evaluating 298 records, the sample size of 221 was achieved that means 77 records didn’t meet the eligibility criteria.This 77 records were excluded because CPRS-R:S was not correctly completed in 22 records, the main complaint was not ADHD in 19 records , other drugs were prescribed instead of MPH for 16 records, 14 records did not have any follow up, and for 6 records the age was less than 3 years old.Of the 221 children enrolled in the study, 169 (76.47%) were male and 52 (23.53%) were female. The basic characteristics of patients between two sexes are not significantly different. The basic characteristics of these individuals are shown in Table In this study, six children had attention deficit disorder (ADD)  and 143 children had comorbidities with ADHD . These comorbidities were found to be as follows: anxiety disorder (GAD: 33 (14.93%), SAD: 18 (8.14%), Phobia: 6 (2.71%), OCD: 8 (3.62%), Anxiety: 7 (3.17%)); affective disorder (Mood: 5 (2.26%), Bipolar: 1 (0.45%)); Mental retardation: 4 (1.81%); Learning disorder: 20 (9.05%); TIC: 11 (4.98%); MDD: 3 (1.36%); Stuttery: 1 (0.45%); ODD: 43 (19.45%).p = 0.251) was observed between males (61.63%) and females (65.77%).The overall improvement rate was calculated to be 62.70%, and no significant difference  including the weight of the patients in each follow-up, the severity of ADHD at the baseline, time interval of receiving the MPH, and dosage of MPH. These variables were imported to the multivariable mixed-logit model. As a result of the analysis based on this model, three variables (except weight) had a significant relationship with improvement. Table .Table 2In order to calculate the optimal dose, we use the coefficient of the final multivariable random effect model Table .Table 3P(Yij = 1) is p0 =0.9866. The histogram of predicted values of P(Yij = 1) and random effect are shown in Fig. The target value for PYij =  is p0 =0p0, 1.9377 is the estimate of fixed intercept, and 51.3817 is the mean of the severity of ADHD at baseline. The diagram of this equation is shown in Fig. Where 4.2990 is the logit of the predicted value Also at the n-th time point (follow-up), the dosage can be calculated based on the following formula:p0 is the target probability of improvement, severity is the severity of ADHD at baseline (based on CPRS-R:S) and time is the number of months on treatment. The diagram of the dosage recommendation for different time points is shown in Fig. i and for computing the optimal dosage is available in Additional file Where In this study, the clinical severity at baseline, logarithm of dosage of MPH, and time duration of receiving the MPH were associated with improvement of ADHD.The dosage of MPH in logarithmic scale had a meaningful association with improving from ADHD, in which the chance of improvement increased 2.36 times as one unit adding in the dosage of MPH in the logarithm scale.According to multivariable random effect logistic model Table , the oddAs ADHD can cause social, emotional and economic failure and also increased mortality , pharmacIn this study, although the rate of males and females was not the same, as the demographic data were not different, we didn’t make subgroups of males and females to analyze the data.We used generalized linear mixed models (GLMMs) method to personalize the dosage of MPH in ADHD. Generalized linear models (GLMs) are used to investigate and analyze the relationship between clinical, demographic, and genetic covariates on the response variable such as patient recovery. But these models aggregately study the relationships and characteristics of individuals. To investigate the relationships of the response with the unique characteristics of the studied subjects, another family of statistical models, usually called GLMMs (or random-effects (REs) linear models) is used. Using these models can be a valuable tool and a comprehensive conceptual framework for the development of personalized medicine .The fact that GLMMs have the concepts that allow explaining patient populations as a whole (the fixed effects) and, simultaneously, concepts that allow describing patients as individuals (the REs) suggests that these models include the key ideas for providing PM with a precise statistical language , 25. ThuIn this study we proposed a drug dosage individualization procedure than could be considered as an extension of the individualization algorithm proposed by Diaz et al. for continuous responses to dichotomous responses , 27.Based on the result of this study, in order to determine the dosage of MPH for a new patient , the greater the severity of baseline is, the higher the initial dosage is required.To recommend the dosage in the next times, first, due to the information of the patient the random coefficient should be updated then the dosage should be calculated for him/her. According to the results of this study, in patients with the same severity of disease and same response to the treatment, with increasing the period of receiving MPH, the optimum dose of MPH decreased on the log scale by the rate of 0.08 mg/kg. Furthermore, the more the severity of ADHD is, the higher of the optimum dose is needed, i.e. considering that response to the treatment is similar among patients, at the same time the optimum dose of MPH increased by the rate of 0.06 mg/kg as the severity of ADHD based on CPRS-R:S increased. As seen in Fig. To best of our knowledge, few studies on factors affecting treatment in ADHD have been published. In a Cochrane systematic review by Osland et al. in 2018, mentioned 3 studies that evaluated the MPH in ADHD . In a crIn another study evaluating the treatment of ADHD in children with tic A, The dosage of average 25.9 mg/d of MPH was proposed for ADHD . TherefoThe strengths of this study include its conduct with a large and diverse sample of children with the main diagnosis of ADHD and the mean follow up period of 22.42 month. Also, we used the CPRS-R:S version of it because of its reliability and validity in the Persian version . FurtherIn this paper, we propose a two-step procedure to make personalized dosage recommendations. The key idea of this method is to utilize subject-specific random effects from longitudinal responses specifying unique individual information that could contribute to post-treatment outcomes. In order to determine the dosage of MPH for a new patient, the greater the severity of baseline is, the higher the initial dose is required. Furthermore, in the next visits, to recommend the dose, the estimation of the random coefficients should be updated. The optimum dose increased when the severity of ADHD increased. Also, the results show that the optimum dose of MPH as one proceeds through the period of treatment, will decrease.Additional file 1.


Background: The association between attention-deficit hypersensitivity disorder (ADHD) and the risk of developing colorectal cancer (CRC) is, as yet, to be investigated, and thus, we have conducted this nationwide, cohort study to examine the association in patients from Taiwan.Methods: In this study, 798 individuals with newly diagnosed ADHD and 2,394 (1:3) age-, gender-, and index year- matched controls without ADHD were enrolled, between 2000 and 2013, from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database in Taiwan. The cumulative incidence of CRC was assessed in each cohort by the Kaplan–Meier method. The multivariate Cox proportional hazards model was used to estimate the crude, and the adjusted hazards ratios (HRs) with 95% confidence intervals (CIs), was conducted to estimate the association between ADHD and CRC.Results: The Kaplan–Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with ADHD than in those without it . After adjustments for age, gender, comorbidities, and other covariates, the ADHD group was associated with an increased risk of CRC in comparison to the non-ADHD group . In addition, the usage of methylphenidate was not associated with the risk of developing CRC in patients with ADHD.Conclusion: This retrospective cohort study depicts the evidence that ADHD was associated with the increased risk of CRC. Further studies are needed to confirm the association and the underlying mechanisms. Colorectal cancer (CRC) is a major health challenge, representing the most common cancer and the third most frequent cause of cancer-related deaths in Taiwan  . Some reAttention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric neurodevelopmental and neurobehavioral disorders with a worldwide average prevalence estimated at 5% in children and 3.4–4.4% in adults, which results in attention deficit, hyperactivity, and increased impulsivity , and up ADHD have bidirectional relations , for exaThe NHIRD was established in 1995, and as of June 2009, included contracts with 97% of the medical providers with ~23 million people in the program, or more than 99% of the entire population in Taiwan . The detThis was a retrospective cohort study. Patients with ADHD between January 2000, and December 2013, were selected from the LHID and categorized according to the ICD as 314. All diagnoses of ADHD were made by board-certified specialists such as psychiatrists, pediatricians, neurologists, or physiatrists with specialty in child and adolescent development. The subject selection process is as presented in We followed up both cohorts from January 1, 2000, until the date of CRC diagnosis , withdrawal from the NHI, or the end of 2013.The covariates included the age, gender, monthly insured premiums, comorbidities, locations, urbanization levels of residence, and the levels of hospitals for medical help. In the analysis, since the north Taiwan is the center of politics and economics, in the country. In addition, most of the healthcare resources, for example, 12 medical centers among total 23, located in the northern Taiwan. Therefore, the northern Taiwan was listed as the reference in our study for the locations.We noticed the covariates that were potential confounders in the association between ADHD and CRC including age, gender, and the underlying chronic diseases related to the risk of developing CRC. Those chronic diseases, which were taken into account, included chronic obstructive pulmonary disease (COPD) , diabetes mellitus (DM) (ICD-9-CM code: 250), coronary artery disease , hypertension , hypercholesterolemia , alcohol-related diseases , peptic ulcer ; liver cirrhosis and chronic hepatitis (ICD-9-CM code: 571), inflammatory bowel disease (ICD-9-CM codes: 555 and 556), and psychiatric comorbidities such as oppositional defiant disorder , conduct disorder , autism spectrum disorder ; tic disorder (ICD-9-CM code: 307.2); intellectual disabilities ; anxiety (ICD-9-CM code: 300); depression ; and bipolar disorder . All the diagnosis of the psychiatric disorders was conducted by the board-certified psychiatrists, pediatricians, neurologists, and physiatrists.t-tests when appropriate. In addition, we used the Kaplan-Meier method to estimate the cumulative incidence of CRC in the study cohorts and performed the log-rank test to compare the difference between these two curves. We computed the hazard ratios (HRs) presented together with 95% confidence intervals (CIs) using the Cox proportional hazards models after adjusting for the potential confounders mentioned above. All the confounders, as covariates and comorbidities, including the psychiatric diagnoses, were calculated separately. All analyses were performed using the SAS version 9.4  and the statistical significance was set to 0.05 in the 2-tailed tests.We examined the descriptive statistics of the demographic characteristics and baseline comorbidities between the exposed and non-exposed cohorts by conducting chi-square tests or Student's-A total of 3,192 patients were enrolled in this study, including 798 adult patients with ADHD and 2,394 patients in the non-ADHD control cohort. The age, gender, monthly insured premiums, comorbidities, locations and urbanization levels of residence, and the levels of hospitals for medical help are as summarized in p < 0.001) (p = 0.03).The Kaplan-Meier analysis for the cumulative incidence of CRC in the ADHD and non-ADHD cohorts with the log-rank test revealed a significant difference over the 13-year follow-up period (< 0.001) . In the p < 0.001), and after adjusting for age, gender, comorbidities, geographical area of residence, urbanization level of residence, and monthly income, the adjusted HR was 3.458 . For the participants older than 50 years, in both the ADHD and non-ADHD cohort, the risk of CRC was 6.887 , in comparison to the subgroup aged from 20 to 49. In contrast, the ADHD group was uniformly associated with an increased risk of CRC for all the factors.In p < 0.001), when compared with the non-ADHD control group. The Kaplan-Meier analysis revealed that the study subjects had a significantly higher 14-year cumulative incidence of ADHD than the controls. Furthermore, the ADHD-cohorts older than 50 years had a nearly 6.9-fold increased risk of CRC . This study revealed that patients with ADHD had a nearly 3.5-fold risk of CRC, and this report could be a reminder for the clinicians who care the patients of ADHD in the follow-up. To the best of our knowledge, this is the first nationwide, population-based cohort on the topic of the association between ADHD and the risk of developing CRC.In this study, we examined the association between ADHD and the risk of CRC. After adjusting the covariates, the adjusted HR was 3.458 for the ADHD group  claim database system; therefore, some registry bias may have been involved in the calculation of the CRC risk. In addition, the family history of colorectal cancer is present, up to one third of patients . The lacThis retrospective cohort study provided evidence of a nearly 3.5-fold increased risk of CRC in ADHD. The results of this study could serve as a reminder for the clinicians who care for the patients of ADHD in the follow-up. Further prospective studies are necessary for confirming our findings, we therefore recommend meticulous evaluation and aggressive risk reduction for CRC for the patients with ADHD.https://nhird.nhri.org.tw/en/index.html).The datasets analyzed in this article are not publicly available. Requests to access the datasets should be directed to Data are available from the National Health Insurance Research Database (NHIRD) published by the Taiwan National Health Insurance (NHI) Administration. Due to legal restrictions imposed by the government of Taiwan in relation to the “Personal Information Protection Act”, data cannot be made publicly available. Requests for data can be sent as a formal proposal to the NHIRD . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.J-MH, C-CL, N-ST, and W-CC conceived, planned, and conducted this study. C-CL, J-MH, N-ST, C-HC, and W-CC contributed to the data analysis and interpretation. J-MH, T-CL, C-HC, C-YC, P-KC, C-AS, and C-WH contributed to this data interpretation. C-CL wrote the first draft. J-MH has played major role, in this revision, in the concept, data interpretation, data analysis, and the re-writing of this manuscript. N-ST and W-CC conducted the critical revisions of this article. All authors approved this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The Intensive Care Delirium Screening Checklist (ICDSC) demonstrates good psychometric characteristics in research settings. However, evidence about these characteristics in pragmatic ICU settings is inconsistent. This study evaluated psychometric properties and user-friendliness of the ICDSC when administered by ICU nurses in daily practice.This prospective study included 77 patients from a surgical intensive care unit. To examine the psychometric characteristics, the scores on the ICDSC (performed by bedside nurses) were compared with the scores on the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) (performed by researchers as gold standard). The user-friendliness was evaluated by 34 ICU nurses with a 20-item questionnaire.The ICDSC had an area under the curve of 0.843. It showed a good diagnostic accuracy with a sensitivity of 81.0%, a specificity of 87.7%, and a 53.1% positive and 96.4% negative predictive value. The overall Cronbach’s alpha coefficient for all ICDSC scores was high (0.839). Overall, ICU nurses experienced the ICDSC as easy-to-use. The scale was usable in most surgical ICU patients. Yet, some nurses (11.8%) had problems to score the items ‘inappropriate speech’ and ‘symptom fluctuation’ in intubated patients.The ICDSC is a valid and user-friendly tool for delirium screening in daily ICU nursing practice. Yet, some problems were reported in intubated patients. Therefore, validation studies with specific focus on intubated patients are needed. Delirium, an acute and/or fluctuating disturbance in attention and awareness, in combination with a change in perception or cognition, is a common and serious clinical syndrome in the intensive care unit (ICU) –3. DelirSeveral screening tools for improving delirium recognition in the ICU have been developed. Based on systematic reviews –12 and tA prospective study was performed on an 18-bed surgical intensive care unit (ICU) of a general hospital in Belgium. Adult patients (18 years or older), Dutch speaking, and consecutively admitted to the hospital for an elective surgery with a planned ICU admission (enrolled during 6 months), were included. Those with severe sensory impairments , neurosurgical indications and expected ICU discharge within 24 h were excluded. Written informed/proxy consent was obtained before study inclusion. Additionally, all ICU nurses of the participating unit were eligible for inclusion. The Medical Ethics Committee of the University Hospitals Leuven approved this study.Baseline data in patients, collected before surgery using patient interview or based on chart review, were age, sex, marital status, education level, social living circumstances, type of surgery, number of medications, cognitive functioning and presence of confirmed dementia. Cognitive functioning was measured using the 12-item Mini-Mental State Examination (MMSE) . The totNurses’ data including age, sex, education level, work experience as a nurse and delirium training received the last 5 years, were collected through a questionnaire.Delirium was both measured with the Intensive Care Delirium Screening Checklist (ICDSC)  and the The CAM-ICU is a diagnostic algorithm for delirium, which was completed based on a cognitive assessment using questions with nonverbal answers and simple commands (e.g. Attention Screening Examination). Delirium was diagnosed when there was a positive rating on the criteria acute onset OR fluctuation, AND inattention AND altered level of consciousness OR disorganized thinking . The levThe severity of delirium was evaluated using the short form of the Confusion Assessment Method Score for delirium severity (CAM-S) , includiThe user-friendliness of the ICDSC for the bedside nurses was measured with a 20-item questionnaire . Study nurses performed four assessments  in enrolled patients, unless patients had an earlier ICU discharge. The assessments took place during the same 8-h shift of the bedside nurses’ ratings, including the performance of the CAM-ICU and CAM-S, as described above. Those CAM-ICU and CAM-S assessments were considered as gold standard. At the end of the patient enrollment period, the bedside nurses received a questionnaire to collect their baseline characteristics and the user-friendliness of the ICDSC. The completion and return of those questionnaire was seen as informed consent.Both bedside and study nurses were educated in administering the instruments (i.e. CAM-ICU or ICDSC) by two experts in delirium (ED and KM). Study nurses were trained using the manual of CAM-ICU. The education also included the assessment of clinical cases in real practice and follow-up discussion. Interrater reliability for the CAM-ICU  was κ = 1.00, which indicates perfect agreement. Bedside nurses were trained to rate the ICDSC during a baseline 1-h course followed by three follow-up sessions.To explore patient and nursing data including the data about the user-friendliness of the ICDSC, descriptive analysis  were used.0), prevalence index (PI) and bias index (BI). The P0 express the ratio of exact agreement between the two assessment methods (i.e. CAM-ICU and ICDSC) per total number of assessments, while the κ corrects for chance [0 and κ can be seen due to prevalence and bias effects [Paired delirium ratings of bedside and study nurses were evaluated to examine: 1) the diagnostic accuracy of the ICDSC for the CAM-ICU, 2) the level of agreement between the ICDSC and the CAM-ICU, and 3) the concurrent validity between the ICDSC and the CAM-S. Diagnostic accuracy of the ICDSC was explored based on the receiver operating characteristic (ROC) curve in combination with the sensitivity, specificity, positive and negative predictive values for the different cutoffs of the ICDSC. Additionally, “delirious” (positive CAM-ICU and ICDSC score ≥ 4) and “non-delirious” (negative CAM-ICU and ICDSC < 4) patient groups were evaluated using the Cohen’s kappa coefficients (κ), the proportion of observed agreement . n = 6), because of severe hearing or visual difficulties (n = 1), or inability to understand Dutch (n = 1). Four patients discontinued the study because they were postoperative not responsive for more than 5 consecutive days   and 308 CAM-ICU (=77 × 4) observations were expected to be performed. However, because of a shorter ICU stay or unresponsiveness of included patients during study participation, 508 ICDSC and 168 CAM-ICU observations were completed, generating 143 paired observations. For 25 paired observations, delirium assessments were not performed during the same 8-h shift; and therefore excluded from further analyses.n = 27, 79.4%), had bachelor degree alone  or with an additional degree in intensive care , and had more than 6 years of work experience on the intensive care unit . Only 4 nurses (12%) followed a training in delirium for the last 5 years.Of the 49 bedside nurses, 34 of them filled out the questionnaire (i.e. response rate = 69.4%). Their mean age was 29.8 years (±SD 6.3 years). Most of the nurses were female (Postoperative delirium (i.e. minimum one positive CAM-ICU score) occurred in 17 of the 77 patients (22.1%), or in 21 of the 143 paired observations (14.7%). According to the ICDCS, 104 of the 508 observations (20.5%) presented an overall ICDSC score of 4 or more, representing a possible delirium.The ICDSC yielded an area under the ROC curve of 0.873 : 0.779–0.966) Fig. . The dia0 = 0.87; κ = 0.56, 95% CI: 0.38–0.74, p < 0.001), with prevalence and bias indexes of 0.63 and 0.08, respectively.Agreement in defining delirious and non-delirious patients was moderate  as for the non-delirious subgroup . A non-significant correlation between both scales  was seen within the delirious group (21 paired observations).Correlation between paired ICDSC scores with CAM-S scores was moderate both for the total group (rPearson = 0.604–0.661) to moderately  (rPearson = 0.469–0.588) with the sum of the other items  and compatible with the language used in practice . Furthermore, most of them agreed that the way in which the items are defined is free of values and judgement , and differences in the response options of the items are mainly or entirely clear . Although most nurses mainly or entirely agreed that the ICDSC items in themselves are clear, one nurse mainly disagreed for items 3, 4, 5 and 7  could be made or that the instructions facilitated to choose the correct answers . Although 28 nurses (82.4%) mainly or entirely agreed that the ICDSC is a handy instrument to use in practice, 14 nurses (41.2%) mainly disagreed that the instrument adds value to their daily practice. Last, 7 nurses (20.6%) completed the ICDSC ratings in less than 1 min, 23 nurses (67.6%) in 1 to 2 min and 4 nurses (11.8%) in 3 to 5 min.Most respondents mainly or entirely agreed that the concepts of the ICDSC items are clear  which reduces the kappa coefficient. However, importantly, the magnitude of kappa was not influenced by a systematically different classification method between the two scales (bias index = 0.08).The concurrent validity of delirium severity between the ICDSC and the CAM-S was moderate, yet, correlations within the subgroups of nondelirious and delirious patients separately were somewhat lower. Yet, for use as severity instrument in delirious patients, further research testing that specific aspect is necessary. Indeed, the ICDSC was only tested against the CAM-S, which may be insufficiently extensive to evaluate delirium severity. On the other hand, the long form of the CAM-S includes - against the four core items - also the items disorientation, memory impairment, perceptual disturbances, psychomotor agitation/retardation and altered sleep-wake cycles, items also found in the ICDSC . TherefoFurthermore, reliability analysis revealed good internal consistency with a value which is in line with those in previous studies (0.72–0.86) , 21. Oven = 12), sensitivity analysis in this subgroup was not performed. Hence, more research on the ICDSC’s psychometric properties within different subgroups of ICU patients is needed. Second, although all nurses indicated to have appropriate knowledge from training and clinical experience to score the ICDSC items, almost one third indicated the need for help to rate the scale. The reason for this discrepancy cannot be determined as no information regarding the content of the requested help was available. Yet, it indicates that the implementation of the ICDSC in daily practice require more than a simple educational session. Indeed, a comprehensive training session, not only before but also educational support during the implementation process is necessary.In general, the user-friendliness of the ICDSC was evaluated as good. Yet, important findings about the ICDSC were identified. First, regarding the clarity of the individual items, none of those items were evaluated as entirely clear for all nurses but, unfortunately, no comments about the perceived difficulties were given. However, four nurses commented that the items ‘inappropriate speech or mood’ and ‘symptom fluctuations’ were difficult to rate in intubated patients. Therefore, these nurses rated the two items as mainly unclear. Hence, we can assume that the difficulties with these two items were not associated with the concepts but with their use in a subpopulation of non-verbally active ICU patients. Yet, one could argue that using the ICDSC in intubated patients affects its psychometric properties. Indeed, a previous study  revealedLast, a small majority of nurses agreed that the ICDSC adds value to their nursing practices. One possible reason could be that screening without further action is useless. Indeed, screening should be part of a global delirium management protocol which was not implemented in this study. Because of the small sample size, we were not able to compare the characteristics of nurses who agreed versus those who disagreed. Nevertheless, the importance of delirium evaluation with a screening instrument is well established. Delirium screening based on clinical impressions showed inferior sensitivity compared to screening with a screening tool . Hence, Some methodological limitations need to be indicated. First, one might criticize the reference standard we used to diagnose delirium; e.g. the CAM-ICU algorithm rated by the study nurses and not the criteria of the Diagnostic and Statistical Manual of Mental Disorders  evaluated by an experienced physician. Yet, the reliability and validity of this reference standard was warranted because all research nurses followed an extensive training session in delirium using a validated diagnostic model also used in prior research , 29, 30,The ICDSC seems to be a valid and user-friendly tool for delirium screening in clinical ICU nursing practice. However, further validation studies with specific focus on intubated patients and on the aspect of monitoring delirium severity are required.


Curcuma aromatica Salisb, has anti-inflammatory and anti-tumor effects. However, the role of curdione in IPF is still unclear.Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by excessive fibroblast to myofibroblast differentiation with limited therapeutic options. Curdione, a sesquiterpene compound extracted from the essential oil of The effects of curdione were evaluated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. C57BL/6 mice were treated with BLM on day 0 by intratracheal injection and intraperitoneal administered curdione or vehicle. In vitro study, expression of fibrotic protein was examined and the transforming growth factor (TGF)-β-related signaling was evaluated in human pulmonary fibroblasts (HPFs) treated with curdione following TGF-β1 stimulation., as evidenced by low expression of α-SMA, collagen 1 and fibronectin in a dose dependent manner. Mechanistically, curdione suppressed the phosphorylation of Smad3 following TGF-β1 treatment, thereby inhibiting fibroblast differentiation.Histological and immunofluorescent examination showed that curdione alleviated BLM-induced lung injury and fibrosis. Specifically, curdione significantly attenuated fibroblast to myofibroblast differentiation in the lung in BLM induced mice. Furthermore, curdione also decreased TGF-β1 induced fibroblast to myofibroblast differentiation in vitroOverall, curdione exerted therapeutic effects against pulmonary fibrosis via attenuating fibroblast to myofibroblast differentiation. As curdione had been shown to be safe and well-tolerated in BLM-induced mouse model, curdione might be useful for developing novel therapeutics for IPF. Idiopathic pulmonary fibrosis (IPF) is the most common type of idiopathic interstitial pneumonia, with a five-year survival rate of less than 30% . PreviouCurcuma aromatica Salisb [Previous studies have consistently demonstrated that curdione, a sesquiterpene compound extracted from the essential oil of a Salisb , possessa Salisb , oxidatia Salisb , tumor ga Salisb  and funga Salisb . More ina Salisb . As is kTo address this feasibility, we induced pulmonary fibrosis in mice and then assessed the impact of curdione on the disease development. Remarkably, treatment with curdione provided protection for mice against BLM-induced pulmonary fibrosis as manifested by attenuated lung injury and fibrosis, and markedly reduced fibroblast to myofibroblast differentiation in the lung. In line with this observation, curdione also decreased the expression level of fibronectin, collagen 1 and α-SMA in TGF-β1 stimulated HPFs and significantly inhibited TGF-β/Smad3 signaling. Together, our studies suggest that administration of curdione might be a viable approach to the treatment of IPF in clinical settings.Sixty male C57BL/6 mice (8 weeks old) were obtained from the Beijing Vital River Laboratory Animal Technology Co., Ltd.  and housed in a specific pathogen-free (SPF) animal facility at the Tongji Medical College with sterile acidified water and irradiated food. The Institutional Animal Care and Use Committee of Tongji Hospital  approved the protocols used for the animal experiments in the present study.Curdione was purchased from Shanghai yuanye Bio-Technology Co., Ltd. , and Bleomycin was obtained from MedChemExpress LLC . Antibodies against β-actin, Gapdh, α-SMA, fibronectin, collagen I, p-Jnk, Jnk, p-p38, p38, p-Erk1/2, Erk1/2, p-Smad2, p-Smad3, Smad2/3 were purchased from Cell Signal Technology Inc. . BCA Protein Assay Kit was supplied by Boster Biological Technology co. Ltd. . RT-PCR assay kit was obtained from Takara . Hydroxyproline assay kit was obtained from Nanjing Jiancheng Bioengineering Institute . Cell Counting Kit-8 was available from DojindoChemical technology co. LTD .All animals were divided randomly into four groups: (i) PBS group, (ii) DMSO group, (iii) BLM + DMSO group, (iiii) BLM + curdione (BLM + CUR) group. For BLM + DMSO group or BLM + CUR group, mice were anesthetized with intraperitoneal injection of pentobarbital sodium (60 mg/kg) and then intratracheally administered 1.75 mg/kg BLM in sterile PBS using established techniques . Next, m2. HPFs were treated with stimulated with curdione (160 μM or 300 μM) or equal amount of DMSO 1 h before stimulation with human recombinant TGF-β1  for 48 h.HPFs were purchased from ScienCell Research Laboratories, Inc. . HPFs were cultured in fibroblast medium supplemented with 10% fetal calf serum,1% FGS and 1% solution of penicillin and streptomycin at 37 °C in a humid atmosphere containing 5% CO3 cells per well, then subjected to serum starvation for 24 h by reducing FBS to 2%. Next, the cells were treated different concentrations of curdione  or 2‰ of DMSO for 1 h and 48 h, and then 5 mg/ml CCK8 was added to the wells and incubated for additional 2 h. After mix well, the optical density was measured at 450 nm.Cell viability was assayed by the Cell Counting Kit-8. Briefly, cells were seeded in 96-well plates at 4 × 10Lung specimens were washed with PBS and hydrolyzed with 0.6% hydrochloric acid at 95 °C for 5 h. Hydrolysates were neutralized with sodium hydroxide and diluted with distilled water. Hydroxyproline level in hydrolysates was colorimetrically determined by absorbance at 550 nm with p-dimethylaminobenzaldehyde and expressed as μg/mg wet tissue.The left lungs were fixed by intratracheal infusion of 4% aqueous buffered formalin for 24 h, then subjected to paraffin embedding and sliced into 4 μm sections. After dewaxing, the sections were subjected to hematoxylin and eosin (H&E), Sirius red and Masson staining using established techniques . The sevTotal RNA was isolated using TRIzol reagent . RNA quantity and quality were measured using the NanoDrop 2000 spectrophotometer . Complementary DNA synthesis was performed using the M-MLV reverse transcriptase kit  as previous reported . RT-PCR Lung tissues and cultured cells were homogenized in RIPA lysis buffer supplemented with a protease inhibitor cocktail, as previously described . The proFor the Immunofluorescence assay, the slides were first probed with Fibronectin or Collagen 1 or α-SMA antibody at 4 °C overnight. After rinsed with PBS, cells were incubated with Alexa 488-conjugated anti-rabbit antibody , as previously described . The secLiver function and renal function was assessed by measuring blood Alanine aminotransferase, Aspartate aminotransferase, urea and serum creatinine at the Department of Clinical Laboratories of Tongji Hospital.P < 0.05 was considered statistically significant.Experimental results were expressed as mean ± standard deviation. Differences were analysed by one-way ANOVA using GraphPad Prism 7.0  was used to generate graphs. We first sought to evaluate the effects of curdione on the development of pulmonary fibrosis. For this purpose, the mice were administered with curdione for every 2 days, followed by BLM injection as described . First, To confirm the above data, levels of hydroxyproline, an amino acid formed upon hydrolysis of connective-tissue proteins such as collagen, were detected in all group. Indeed, compared with control group, significantly higher levels of hydroxyproline were detected in BLM-induced mice, while curdione administration attenuated BLM-induced hydroxyproline content by 1.6-fold Fig.  f.To further evaluate the effects of curdione on pulmonary fibrosis, western blot analysis of fibrotic markers was adopted in lung homogenates. Consisted with above data, the expression of fibronectin, collagen 1 and α-SMA was lower in BLM + CUR group Fig.  a than BGiven the important role that fibroblast to myofibroblast differentiation plays in the progression of pulmonary fibrosis , we examBased on the above observations, HPFs were used to validate the effects of curdione on fibroblast differentiation. Interestingly, administration of curdione significantly inhibited fibroblast differentiation to myofibroblast in dose dependent manner as evidenced by the significantly reduced levels of fibronectin, collagen 1 and α-SMA after TGF-β1 treatment for 48 h analyzed by western blot Fig.  a, RT-PCTGF-β/Smad signaling has been suggested to be critical for an optimal and sustained fibroblast differentiation upon TGF-β stimulation . TherefoIn the current study, we verified the therapeutic effects of curdione on pulmonary fibrosis. Herein, our study demonstrated that curdione treatment might effectively reduce lung injury and fibrosis induced by BLM and attenuate the differentiation of fibroblast to myofibroblast. The potential mechanism of the protective effects of curdione on pulmonary fibrosis might be attributed to the inhibition of TGF-β/Smad3 signaling. Together, our study might provide a new idea for treatment of IPF.Curdione is a kind of traditional Chinese medicine, which is extracted from the rhizome of curcuma, zedoaria. Accumulating evidence indicated that curdione has anti-inflammatory, anti-apoptotic and anti-tumor effects –8, 17. HFirst of all, we determined the safety of curdione in vivo by comparing the liver and renal functions of mice with or without curdione. Considering that the solvent DMSO may be toxic to some extent, we set up a pure DMSO group to eliminate interference. Interestingly, the results showed curdione had excellent safety as manifested by no obvious damages were detected on liver and renal function in mice treatment with curdione. Next, we verified the effects of curdione on pulmonary fibrosis. Curdione could significantly reduce the degree of pulmonary fibrosis in BLM-induced mice as manifested by H&E, Masson and Sirius red staining. Furthermore, after application of curdione, Ashcroft score of lung sections and hydroxyproline content in lung tissues decreased significantly. In addition, the fibrosis indicators fibronectin, collagen 1, and α-SMA all showed varying degrees of decline by western blot, RT-PCR and immunofluorescence. Administration of curdione could also weaken the effect of bleomycin on body weight loss in mice, which might reflect in part the therapeutic effects of curdione on pulmonary fibrosis.Accumulation and persistence of fibroblast to myofibroblast differentiation executed central role in fibrotic process . To furtIn addition to fibroblast differentiation, inflammation and oxidative stress also played a key role in IPF pathogenesis. Studies have shown that the contents of inflammatory cells  and fibroblasts as well as their oxidative stress levels were significantly increased in patients with pulmonary fibrosis . PreviouPrevious studies have revealed that TGF-β could induce Smad2 and Smad3 phosphorylation to promote fibroblast differentiation . This diIn conclusion, curdione might attenuate the progress of pulmonary fibrosis and suppress the differentiation of fibroblast through TGF-β/Smad3 signaling. However, our study only demonstrated the inhibitory effect of curdione on the development of pulmonary fibrosis, further study is needed to determine whether curdione could reverse the disease in a fully established pulmonary fibrosis mouse model. Besides, more mechanisms of curdione on pulmonary fibrosis needed to be explored so that we could have fuller evidence to support the potential clinical value of the agent.Additional file 1: Figure S1. Curdione attenuated the infiltration of inflammatory cells in the lung sections following BLM induced. (A) Left panel: a representative immunostaining result for F4/80 (macrophage marker). Right panel: bar graphic figure for immunostaining. (B) Left panel: a representative immunostaining result for CD3 (lymphocyte marker). Right panel: bar graphic figure for immunostaining. Images were taken under original magnification × 400. Twelve mice were included in each study group. Experimental results were expressed as mean ± standard deviation. The data were analysed by one-way ANOVA. *P < 0.05; **P < 0.01.


The effect of branched alkyl chain on the wettability of the PMMA surface has been explored. To obtain the adsorption parameters such as the adhesional tension and PMMA-solution interfacial tension, the surface tension and contact angles were measured. The experimental results demonstrate that the special properties of polyoxypropene (PO) groups improve the polar interactions and allow the extended surfactant molecules to gradually adsorb on the PMMA surface by polar heads. Therefore, the hydrophobic chains will point to water and the solid surface is modified to be hydrophobic. Besides, the adsorption amounts of the three extended anionic surfactants at the PMMA–liquid interface are all about 1/3 of those at the air–liquid interface before the critical micelle concentration (CMC). However, these extended surfactants will transform their original adsorption behavior after CMC. The surfactant molecules will interact with the PMMA surface with the hydrophilic heads towards water and are prone to form aggregations at the PMMA–liquid interface. Therefore, the PMMA surface will be more hydrophilic after CMC. In the three surfactants, the branched G-C16PO4S with two long alkyl chains exhibits the strongest hydrophobic modification capacity. The linear L-C12PO4S is more likely to densely adsorb at the PMMA–liquid interface than the branched surfactants, thus L-C12PO4S possesses the strongest hydrophilic modification ability and shows smaller contact angles on PMMA surface at high concentrations.The adsorption behaviors of extended anionic surfactants linear sodium dodecyl(polyoxyisopropene) Wetting phenomena on solid surfaces ,2,3 have3, -CO, and -OCH3 groups [12(EDMAB), BDDAB) [γSL) of these conventional surfactants gradually decreased with the increase in surfactant concentration, which indicates that the surfactants will adsorb on PMMA surface by hydrophobic interactions. In recent years, research has been published about the adsorption behaviors of zwitterionic surfactants [γSL decreases with the increase in surfactant concentration.It is well known that polymethylmethacrylate (PMMA) is one of the most widely used acrylate plastics because of its excellent aging resistance and biocompatibility ,16. PMMA3 groups . Therefo3 groups  and cati, BDDAB)  on the P, BDDAB)  nonionic, BDDAB) ,22 and a, BDDAB)  on the Pfactants  and catifactants  on the Pfactants ,27,28. TThe extended surfactant is a kind of novel surfactant, which contains a polyoxypropene (PO) chain inserted between the hydrophobic alkyl group and hydrophilic polar group . Chen et16GPB, C16GPC, and C16G(EO)3PC have a stronger hydrophilization capacity than similar surfactants with a linear structure. However, the branched structure inevitably increases the difficulty of forming aggregations; therefore, the adsorption amounts of branched C16G(EO)3PB on the PMMA surface are lower than the linear C16(EO)3PB. Zhang et al. [However, there are few reports involving the wettability of extended anionic surfactants on the PMMA surface. In particular, the effect of branched extended anionic surfactants on the wetting of the PMMA surface needs to be further explored. Wu et al.  exploredg et al.  utilizedg et al.  investig12PO4S, G-C12PO4S, and G-C16PO4S) were utilized to evaluate their adsorption properties at air–liquid and solid–liquid interfaces by measuring their surface tension and contact angles, respectively. It is helpful to understand the influence of the surfactants’ branch degree on the wettability of a medium energetic polymer surface.Herein, different branched extended anionic surfactants (L-C4 sulfate (L-C12PO4S), branched sodium dodecyl(polyoxyisopropene)4 sulfate (G-C12PO4S), and branched sodium hexadecyl(polyoxyisopropene)4 sulfate (G-C16PO4S) were provided by the Sasol corporation (South Africa). The molecular structures of the three surfactants are depicted in The linear sodium dodecyl(polyoxyisopropene)The surface tension values of the surfactant solutions were detected using an interfacial tension meter  at 30 °C via the Wilhelmy plate technique.  Each conBefore the contact angle test, the PMMA surface was cleaned according to the literature . The conγCMC. As shown in the surface tension curves , G-C16PO4S with enhanced oleophilicity possesses smaller CMC.The surface tensions of the three extended surfactants were measured at different concentrations, and the isotherms of equilibrium surface tensions as a function of concentration are plotted in n curves , the CMCΓmax) and saturated adsorption area (Amin1) can be calculated by Gibbs equations as followsThe saturated adsorption amount  for the three surfactants. However, the Γmax1 of the branched G-C12PO4S is relatively low, resulting in a slightly higher γCMC. As the alkyl chain gets longer, the hydrophobicity enhances while the steric hindrance rises. As a result, the Amin1 of the branched surfactants (G-C12PO4S and G-C16PO4S) are both approximately 1.33 nm2.The values of 12PnS) and sodium nonylphenoxy polypropyleneoxide sulfates (PPnS), it can be seen that their CMC values decrease with the increase in the PO units. This can be attributed to the increasing lipophilicity as the PO chain gets longer. By comparing, it is observable that the surface activity parameters of L-C12PO4S, G-C12PO4S, and G-C16PO4S are reasonable.Moreover, some reported ,33 paramθ) of the three extended surfactant solutions on PMMA surface. It can be seen from −8~3 × 10−5 mol L−1) with a value of 72°. When the concentration of the surfactant solutions approaches 6 × 10−5 mol L−1, the contact angles begin to decrease significantly. At high concentration of 1 × 10−2 mol L−1, the contact angle of linear L-C12PO4S (21.9°) is smaller than that of branched G-C12PO4S (28.5°), but higher than that of G-C16PO4S (12.8°). It also must be pointed out that the θ values all decrease obviously after CMC for extended surfactants.Significantly, the variation in contact angles for these extended anionic surfactants at PMMA surface is quite different from those of conventional surfactants. According to the literature, the contact angle of the cationic surfactant CTAB solution at PMMA surface will decrease dramatically to approximately 51.0° at the CMC, and then change slowly with the increase in bulk concentration ,35. The Comparing γSV) and the interfacial free energy of solid–liquid (γSL). Based on Young’s equation, the contact angle is related to γSV, γSL, and γLV . Therefore, the value of the adhesional tension is γLVcos θ (Equation (3)).The surfactants’ adhesional tension that reveals their adhesion capacity on the solid–liquid interface is defined as the difference between the interfacial free energy of solid–air  for L-C12PO4S, G-C12PO4S, and G-C16PO4S is respectively 0.996, 0.990, and 0.973. Interestingly, the slopes of the three extended surfactants are all about 0.3, which means the extended surfactants that adsorb at the air–liquid interface are all approximately three times higher than those at the PMMA–liquid interface.ΓSL/ΓLV and the surfactants’ saturated adsorption area (Amin1) at the air–liquid interface, the saturated adsorption area (Amin2) of the surfactant molecules on the PMMA surface before CMC is calculated and also listed in For comparison, the slopes of the adhesional tension curves of some conventional and special structural surfactants are summarized in 12(EDMAB) [19 are all negative, demonstrating that they absorb at the PMMA-water interface via hydrophobic interactions. Meanwhile, the conventional surfactants exhibit slopes of about −0.3, which indicates that they are likely to tile at the PMMA–liquid interface with about 1/3 of the adsorption amounts at the air–liquid interface. Therefore, the adsorption amounts of both the conventional surfactants (slopes ≈ −0.3) and the extended surfactants (slopes ≈ 0.3) in this work at the air–liquid interface are approximately three times higher than those at the solid–liquid interface. However, the adsorption behavior between the conventional surfactants and the extended surfactants are quite different. However, it must be pointed out that the slope values of the extended surfactants in this work are all positive at a low concentration, which means that surfactant molecules adsorb on the PMMA surface by ionic heads with the hydrophobic tail towards the water.In general, the slopes of conventional surfactants such as nonionic surfactant TX-100,  anionic 2(EDMAB) , and BDD4− group. Besides, the C16PC27 and C16GPC28 surfactants have the -OH and -N(CH3)3+ groups. The C16PB27 and C16GPB28 molecules have the -OH, -N(CH3)3+ and -COO− groups. The C16(EO)3PC27 and C16G(EO)3PC28 molecules have the -OH, -N(CH3)3+ and EO groups. The C16(EO)3PB27 and C16G(EO)3PB28 surfactants have the -OH, -N(CH3)3+, EO and -COO− groups. Furthermore, the C326 and C626 surfactants all have two polar xylyl and two -N(CH3)3+ groups. The 18C40 molecule has -N(CH3)3+ and -COO‒ groups, while the 18S40 molecule has -N(CH3)3+, -OH and -SO3− groups. Moreover, the BCB24 molecule has the polar xylyl, -N(CH3)3+ and -COO- groups, while BSB24 molecule has the polar xylyl, -N(CH3)3+, -OH and -SO3− groups.Comparing the structures of the surfactants, it is worth noting that these specific surfactants with positive slopes have more than one hydrophilic group. As for the three extended surfactants in this work, they all have a PO chain and -SOMulti-hydrophilic groups can undoubtedly increase the polar interactions with the PMMA surface. Therefore, these surfactants can adsorb on the PMMA surface by polar interactions that more easily rely on their special structures . Since the hydroxyl group can form hydrogen bonds, EO group has a good hydrophilic effect, and PO group owns a partly hydrophilic and partly lipophilic nature; these special structural surfactants can easily interact with PMMA surfaces.16(EO)3PC and C16(EO)3PB in 2CH2)n groups increase the steric hindrance and reduce their adsorption capacity [16PB27 and 18C40, the slope of C16PB is only 0.136 due to its ether hydroxypropyl. Among them, the PO group has a stronger interaction with the PMMA surface due to its partially hydrophilic and partially lipophilic nature [The size of hydrophilic part controls the positive value of the slope. As for Ccapacity . This isc nature , so the −1, [γSL) can be calculated by using Young’s equation, and the obtained results are plotted in Amin3) and after CMC (Amin4) are calculated by Gibbs equation and listed in The variation of solid–liquid interfacial tension reveals the adsorption behavior of extended surfactant molecules on a solid surface. The surface free energy of PMMA is about 39.5 mN m−1,  and the γSL increases gradually with the increase in the bulk concentration. At a high concentration, γSL decreases sharply as the bulk concentration increases. A linear relationship exists between the concentration and γSL in the two stages. There is a maximal γSL in the PMMA–solution interfacial tension curve for each surfactant, and the values of γSL vary with the structure of extended surfactants.As seen in γSL gradually increases. As a consequence, the hydrophobic tails that point to water strengthen the hydrophobic modification of the PMMA surface. Because of the electrostatic repulsion among the surfactant molecules, the adsorption amount on the solid surface at this stage is low  and a larger Amin (4.56 nm2) than L-C12PO4S. Besides, the longer alkyl chain results in a stronger hydrophobic interaction. Accordingly, G-C16PO4S has a larger adsorption amount and smaller adsorption area than G-C12PO4S. Furthermore, the values of Amin3 calculated by the Gibbs equation are consistent with the theoretical Amin2 obtained by adhesional tension, which implies the reliability of the results.In the first stage, the extended surfactants interact with PMMA surface by polar groups, so e is low . Though γSL decreases significantly when the bulk concentration increases. Combined with the previous research, the change trends of γSL have three cases as the surfactant concentrations increase: (1) γSL rises firstly and then keeps a stable value; (2) γSL rises firstly and then declines, and the slopes of the two stages are almost equal; (3) γSL rises firstly and then declines, and the slope of the second stage is 2–3 times higher than the first stage. Zhang et al. [γSL values increases as the bulk concentration increases and then γSL reaches a plateau value around CMC, which indicates that BSB molecules adsorb on PMMA surface only by polar interaction. Therefore, the hydrophobic adsorption stage does not occur. Hu et al. [γSL rises firstly and then declines, and the slope of the decreasing stage is almost the same as the increasing stage. The saturated adsorption areas of surfactants  on the PMMA–liquid interface before CMC (Amin3) are, respectively, 2.78 and 3.06 nm2, which is very close to the Amin4 after CMC (2.99 nm2 and 4.57 nm2). This implies that the hydrophobic chains of the surfactants are towards the water at the beginning, but the surfactants may form the bilayer adsorption film with the hydrophilic heads towards the water as the bulk concentration increases. Lv et al. [γSL after CMC are much larger than the slopes at a low concentration, which demonstrates that the adsorption amount of the surfactants on the PMMA surface remarkably increase. Therefore, the adsorbed surfactants are more likely to form aggregations on the solid surface than bilayer adsorption.In the second stage, the hydrophobic tails of the surfactants interact with the PMMA surface, while the hydrophilic heads point to the solution. Consequently, the solid surface is modified to be hydrophilic, and g et al.  studied u et al.  investigv et al.  found a γSL represents the maximum hydrophobic modification capability of the extended surfactants. It is visually observable that branched G-C16PO4S whose γSL reaches 30.75 mN∙m−1 possesses the strongest hydrophobic modification ability. Furthermore, the minimum value of γSL at high concentration can manifest the maximum hydrophilic modification ability of the surfactants. It can be seen that γSL of linear L-C12PO4S reaches 9.62 mN∙m−1, suggesting that L-C12PO4S has the strongest hydrophilic modification capability.At the turning point of adsorption behavior, the maximum value of γSL for different PMMA sheets in the literature, the maximum hydrophobic modification capacity (ΔγSL) is represented by the difference between the maximum γSL and the initial γSL for pure water, whereas the maximum hydrophilic modification capacity corresponds to the minimum γSL at high concentrations. It is observable that L-C12PO4S, G-C16PO4S, BCB, and BSB possess strong hydrophobic modification ability with ΔγSL of more than 10 mN∙m−1. Comparing their structures, the strong hydrophobic modification ability can be attributed to the strong polar interactions and the small steric hindrance. On one hand, the stronger the polar interactions, the more surfactants will adsorb at the PMMA surface. On the other hand, less steric hindrance leads to relatively higher adsorption amounts, thus manifesting strong hydrophobic modification ability. The branched C16GPB, C16GPC, and C16G(EO)3PC have a higher hydrophilic modification ability on the PMMA surface compared to the linear surfactants with similar structures. However, the branched structure increases the difficulty of forming aggregations on the PMMA surface, thus the hydrophilic modification ability of C16G(EO)3PB is lower than that of the linear C16(EO)3PB.The maximum hydrophobic and hydrophilic modification abilities of the special structural surfactants in the literature are summarized in WA) of the surfactant solutions on the solid surface, which can represent the work required to separate a unit area of liquid from the solid surface, can be computed by Equation (5). Moreover, combined with Young’s equation, WA can be obtained as shown in Equation (6).The work of adhesion (γLVcos θ) and surface tension (γLV).According to the equation, the adhesion work is the sum of adhesional tension (WA) for the extended surfactants at the PMMA surface has been calculated and plotted in WA of the surfactant solutions is almost constant at low concentrations because the γLV and γSL change little. As the concentration increases, WA decreases, which is caused by the decrease in both γLV and adhesional tension. When the concentration exceeds the CMC value, the adsorption of surfactants at the air–liquid interface is saturated and the γLV is constant. However, the surfactants continue to adsorb at the PMMA–liquid interface and, accordingly, the γSL decreases, which leads to an increasing trend of WA.The work of adhesion , the adsorption of surfactant molecules at both the solid–liquid interface and the air–liquid interface can be ignored, and the contact angles remain about 72° and the other adhesion data keep constant.In the first stage (1 × 10−7~6 × 10−5 mol L−1), the adsorption amounts at both the air–liquid and solid–liquid interface increase as the bulk concentration increases, which results in a decreasing γLV and an increasing γSL. However, the contributions of γLV and γSL are offset, resulting in little change in the contact angles. At the same time, surfactants rely on ionic heads to adsorb at the solid–liquid interface, and the hydrophobic chains point toward the solution. The contact angles exhibit a slightly increasing tendency on account of the hydrophobized PMMA surface.In the second stage (5 × 10−5~1 × 10−3 mol L−1), the surfactants’ adsorption amounts at the air–liquid interface tend to be saturated and the γLV tends to reach a plateau value when approaching the CMC value. However, the γSL suddenly decreases, which triggers a sharp decline in the contact angles. The adsorption behavior starts to transform, and surfactant molecules are more inclined to adsorb on the PMMA surface through hydrophobic interactions. Since the adsorption amounts of surfactant molecules increase significantly at this stage, it is presumed that the adsorbed surfactants are forming aggregations at the solid–liquid interface, as we discussed above.In the third stage (6 × 10−3~1 × 10−2 mol L−1), the adsorbed surfactant molecules at the solid–liquid interface also tend to be saturate; thus, the contact angles display a stable tendency.At the last stage  on the PMMA surface were investigated. Based on the structural dependence of extended anionic surfactants on the wettability of PMMA surface, the following conclusions are obtained:In this work, the adsorption mechanism and wetting properties of branched extended anionic surfactants  Before CMC, the contact angles change little as the surfactants’ concentration increases because the decrement of γγLVcosθ-γLV curve. At low concentrations, the special property of PO groups allows the extended surfactants to adsorb on the PMMA surface by polar interactions; thus, the solid surface is modified to be hydrophobic. Besides this, the surfactants’ adsorption amounts at the air–liquid interface are all approximately three times higher than those at the PMMA–liquid interface before CMC;(2) Before CMC, the adhesional tension decreases with the increase in bulk concentration, and a linear relationship exists between the adhesional tension and surface tension. After CMC, the adhesional tension exhibits a vertical upward trend in the SL increases gradually with the increase in the bulk concentration. At high concentrations, γSL decreases significantly as the bulk concentration increases. In this stage, the surfactants are prone to forming aggregations and their hydrophobic tails will interact with the PMMA surface with their polar heads pointing to the water. Accordingly, the PMMA surface is modified to be hydrophilic;(3) There are two stages for the three extended surfactants in PMMA–solution interfacial tension. At low concentrations, γ12PO4S with the least steric hindrance shows the strongest hydrophilic modification ability. On the contrary, the branched G-C16PO4S molecules with two long alkyl chains exhibit the strongest hydrophobic modification capacity.(4) In the three extended surfactants, linear L-C


Pleopeltis polypodioides fronds to temperatures up to 50°C and dehydrated fronds up to 65°C for 24 h. The effect of heat stress was evaluated using morphological changes, photosystem (PS) II efficiency, and metabolic indicators. Pinnae of dried fronds exposed to more than 40°C curled tighter and became brittle compared to fronds dried at lower temperatures. Exposure to > 50°C leads to discolored fronds after rehydration. Hydrated fronds turned partially brown at > 35°C. Chlorophyll fluorescence (Ft) and quantum yield (Qy) increased following re-hydration but the recovery process after 40°C treatment lasted longer than at lower temperatures. Similarly, hydrated fronds showed reduced Qy when exposed to > 40°C. Dried and hydrated fronds remained metabolically active up to 40°C. Hydroperoxides and lipid hydroperoxides in dried samples remained high up to 50°C, but decreased in hydrated fronds at > 40°C. Catalase (CAT) and glutathione (GSH) oxidizing activities remained high up to 40°C in dehydrated fronds and up to 35°C in hydrated fronds. Major fatty acids detected in both dehydrated and hydrated fronds included palmitic (C16:0) and stearic (C18:0) acids, oleic (18:1), linoleic (C18:2); and linolenic (C18:3) acids. Linolenic acid was most abundant. In dried fronds, all fatty acids decreased at > 35°C. The combined data indicate that the thermotolerance of dry fronds is about 55°C but is at least 10°C lower for hydrated fronds.Although heat and desiccation stresses often coincide, the response to heat especially in desiccation tolerant plants is rarely studied. We subjected hydrated  All fronds were collected after a rain event during March to May from 2016 to 2019 and prior to experimentation maintained in a humid chamber at high RH. All fronds were between 4.5 and 5 cm long. The outline of the workflow is illustrated in Because Pleopeltis fronds are highly responsive to environmental conditions and are efficient in water uptake compared to plants with intact rhizomes , we focuHeat treatment was applied for 24 h in darkness. Assays of heat treated dry and hydrated (fully and partly submersed) samples were compared with 25°C dry and fresh control, respectively.Detached, fresh fronds were dried at 25°C for 72 h, which reduces the RWC to < 5% . After dDetached fresh fronds were placed in DI water in 20 mL glass vials such that either the entire frond  or just the apical end (4 mL water) was submersed and exposed to the same temperature as dried fronds. The reason for different levels of submersion was to test the effect of oxygen deprivation in fronds that were fully submersed compared to 100% humidity. The data were compared with hydrated fronds (without immersion) at 25°C.0, which is equivalent to Ft if the leaf sample is dark-adapted) and quantum yield (Qy) using a FluorPen FP100 . F0 was measured by applying a light pulse (455 nm of 0.09 μmoles m–2s–1 for 30 μs) and recorded as Ft. Similarly, Qy measurements were obtained by applying a saturating light that measures maximum value of fluorescence (Fm) from PS II (approximately 3000 μmol m–2 s–1 for 0.8 s) to dark-adapted dry fronds and dim-light (∼10 μM m–2 s–1) exposed fronds. Preliminary measurements showed no difference between dark or dim-light adapted measurements. The difference between minimal fluorescence F0 and maximal fluorescence Fm divided by Fm, i.e., (Fm-F0)/Fm. We used this ratio to describe quantum yield (Qy) of PS II system. Normal photosynthetic activity shows maximum Qy of about 0.83 . Because obtaining reliable fluorescence measurements from curled (dried) fronds was difficult, the Ft and Qy measurements were obtained from flattened fronds that were dried between paper towels and glass plates for 5 days at room temperature. Dried and submersed fronds were examined after temperature treatments. Fronds were rehydrated on water-saturated foam under dim light, and were measured after 1, 5, and 24 h. Qy and Ft were identical in dark and dim-light-maintained fronds, we therefore report data of fronds measured under dim light (10 μM m–2 s–1). The Ft and Qy measurements were obtained from the base, center, and the tip of each of six fronds and shown as average of these positions.The F–1) of the water in which the fronds were submersed. Conductivity was measured with a MW 301 EC meter  in 4 mL samples for partially and 20 mL samples in fully submersed fronds and reported as μS normalized to 10 mL. After heat treatments, fronds were kept at room temperature for an additional 24 h to assess re-uptake of ions. Elemental analysis was performed by Inductively Coupled Plasma – Optical Emission Spectrometry  in 15% HNO3.Cell membrane permeability was deduced from the conductivity  at 25°C for 3 h before the fluorescence of the supernatant was determined .The reduction of resazurin as described in 560 – 0.004)/0.0763.Hydroperoxide (and other water-soluble peroxide) content was measured using the ferrous ammonium sulfate/xylenol orange, FOX I assay  at 560 n560 − 0.1305)/0.0383, determines the BHT equivalent in nM.The FOX II assay was used to quantify lipid peroxides, LOOHs  accordin240 of H2O2 for 180 s . 500 μL supernatant was transferred into a fresh centrifuge tube, mixed with 400 μL 40 mM sodium phosphate buffer pH 7.0, 100 μL 10 mM sodium azide , 200 μL DI water, and vortexed. After adding 200 μL (4 mM) GSH  and 100 μL 2.5 mM H2O2, the solution was mixed and incubated for 1 min. The reaction was terminated by adding 500 μL of 10% trichloroacetic acid . The solution was incubated at RT for 30 min and centrifuged . The supernatant (500 μL) was mixed with 1.5 mL 0.1 M sodium phosphate buffer (pH 7.2) and 1 mL 5, 5’-dithiobis-2-nitrobenzoic acid . After inversion, OD 409 was determined. Enzyme activity is reported as μM GSH consumed min–1 × mg protein–1.The consumption of GSH was measured as described earlier . The assProtein content for the enzyme assays was determined according to –1. The temperature profile started at 100°C for 2 min, ramped (10°C × min–1) to 280°C and held for another 8 min. Identification of compounds was based on the National Institute of Science and Technology library 2008 in Chemstation software (E.02.02.1431). The quantity of individual fatty acids was determined based on retention time and slope of derivatized palmitic acid , linoleic acid , linolenic acid , oleic acid , and stearic acid . Tissue samples were analyzed under identical conditions as standards.Fatty acids were extracted from tissue equivalent to 100 mg fresh weight, derivatized to their methyl esters, and quantified  using anpost hoc test was performed using Excel data analysis tool pack  with Tukey-Kramer ool pack .Pinnae of dried Pleopeltis fronds curled tighter with increasing temperature treatment . Dried tt) of treated dried fronds measured lower than (control) dry fronds at 25°C  increased over time and reached control levels within 5 h for temperatures up to 35°C  control but measurable at all temperature ranges, i.e., 30–65°C  controls  = 18, P < 0.0001]. The Qy of 5 h re-hydrated fronds was lower than in controls  but greater than after 1 h re-hydration   = 312, P < 0.0001]  = 217, P < 0.0001]  = 711.6, P < 0.0001], which suggests that hydration is beneficial for samples exposed to temperatures below 40°C. Unchanging but measurable Ft values in ≥ 45°C fronds and the lack of recovery of Qy after 40°C indicates degradation of PS II.Despite some increase after 30 and 40°C treatments, F 0.0001] ; in cont 0.0001] . After rcontrols . Howevery suppression was stronger than in partly submersed fronds  = 19.6, P < 0.0001] below 45°C but their reducing capacity exceeded that of submersed tissue at higher temperatures  = 4.9, P = 0.05]  = 3.7, P = 0.03]  = 3.1, P = 0.05]. Like dry fronds, submersed fronds showed a steady decline in CAT activity and the extent of submersion had no effect  = 363, P < 0.0001]  = 13.3, P = 0.01] compared to 30–40°C treated samples , stearic (18:0), oleic (18:1), linoleic (18:2), and linolenic (18:3) acid were detected in controls and heat-treated fronds but linolenic acid (18:3) was the dominant FA at all temperatures and the total amount of fatty acids in fully submersed fronds was higher than in dried and partly submersed samples .The extent of unsaturation correlated with peroxidation; therefore, we examined the degree of unsaturation for each temperature. The percentage of unsaturated fatty acids  in 30°C, dried and partly submersed samples was 12 and 5% lower than at 25°C . Exposury  and quantum yield (Qy) of dried fronds were lower than in fresh fronds but readily detectable , which can lead to increases in Zeaxanthin and other pigments even under dark conditions  following re-hydration was time dependent. Qy values of fronds exposed to 30°C reached control values within 5 h of re-hydration but required at least 24 h in fronds exposed to higher temperatures  in re-hydrated fronds after 65°C was not detectable (t and Qy measurements indicate that the maximal heat tolerance of dehydrated Pleopeltis is 60°C. These data indicate that chlorophyll and/or the reaction center remain intact in spite of absence of PS II activity. The lack of photosynthetic activity may protect the photosynthetic apparatus from damage.The recovery of the photosynthetic performances (Feratures . The slo complex  and/or P complex . Fronds  complex , which s complex . Photosytectable , and indtectable . Thus, st and Qy of partly and fully submersed (t increased. Similar to observations in dried tissue, this unequal response indicates a dichotomy between chlorophyll stability and reduced photosynthetic efficiency, possibly as a result from inactivation of the oxygen evolving system (t at > 40°C and non-detectable Qy (Fubmersed  fronds eg system  and/or tg system . The redtable Qy  indicateAn increase in conductivity of the external medium indicates cell membrane damage and efflux of ions . High co+ (Leaching from leaves is broadly defined as removal of substances from plant leaves by action of rain, fog, dew, and washing . Other f+  consiste+ . Loss of+ . Taken t+  and cati+  suggest Metabolically active cells rely on a steady supply of reduced compounds; therefore, the concentration of reduction equivalents is a measure of metabolic health. However, assessing the metabolic status of dried Pleopeltis through aqueous redox dyes is problematic because tissue rehydrates in the dye solution. Therefore, our data report the reduction capacity of dried fronds immediately after hydration. Nonetheless, the temperature and hydration variability of the data indicates that the measurements provide a meaningful estimate of the reduction capacity. The declining reducing capacity with increasing temperatures  is likelHydrated fronds showed higher metabolic activity than dried fronds up to 40°C  but simiThe increase of ROS  in dry aPleopeltis, like most plants, responds to heat by enhanced production of ROS , which i2O2, is sensitive to elevated temperatures (In addition to elevated ROS, the decreased availability of antioxidants or activity of reducing enzymes likely enhances ROS toxicity. CAT, an important enzyme for the detoxification of Heratures  and has eratures . The heaeratures  and barleratures  that laceratures  and heateratures . Thus, Geratures  is imporeratures .Hydrated fronds accumulate high levels of hydro-  and lipiPleopeltis fronds changes with temperature and hydration (Stress-responsive metabolites in plants include fatty acids . Our datydration . Increasydration , which mydration . Additioydration , suggestydration . Both paydration . Additioydration , which cydration . Althougydration , their pydration .The decline of all fatty acids at elevated temperatures  links thThe mechanism of Pleopeltis response to heat stress is complex. Our biochemical data indicate that > 40°C causes heat stress in Pleopeltis fronds. Despite obvious stress signals, dried fronds recovered after exposure up to 55°C while thermo-tolerance of hydrated fronds was limited to 40°C. The difference in heat tolerance between hydrated and dried fronds indicates that dehydration protects Pleopeltis from heat damage. Our data further illustrate the adaptability of this epiphytic fern to cope with environmental stress.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SJ and KH conceived the experiments, analyzed the data, and wrote the manuscript. SJ performed the research. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Drawing on data from the Clinical Practice Research Datalink, Price et al reported UK regional variations in primary care prescribing and referral rates to adult mental health services for young people with attention-deficit hyperactivity disorder (ADHD) in transition from child and adolescent mental health services. Overall, considering that around 65% of young adults with childhood ADHD present with impairing ADHD symptoms and up to 90% of individuals with ADHD may benefit from ADHD medications, the study by Price et al shows that the rate of appropriate treatment for youngsters in the transition period varies from low to very low across the UK. As such, there is a continuous need for education and training for patients, their families, mental health professionals and commissioners, to eradicate the misconception that, in the majority of the cases, ADHD remits during adolescence and to support the devolvement of appropriate services for the evidence-based management of adult ADHD across the UK. In past years, I have attended several working groups meetings aimed at fostering evidence-based practices in the management of attention-deficit hyperactivity disorder (ADHD) in the UK. One of the key issues that is often discussed in these type of meetings is around the challenges related to the continuity of care during and beyond the transition from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS), which should occur between the ages of 16 to 18. Arguably, this is a very vulnerable phase in life for a number of youngsters, including those with ADHD, because of pressures to define career pathways and living arrangements, that may increase the levels of stress and require additional coping skills and resilience.It is important to appreciate any geographical disparity in the management of ADHD to better tailor any specific action aimed at improving the quality of care. Therefore, ‘What do data tell us about regional variations in the prescriptions of ADHD medications during the transition period ?’ is a frequent question I have been asked at these meetings. Like the rest of my colleagues attending the working groups, I remember feeling slightly uncomfortable and somehow embarrassed myself by the paucity of data that I was aware of, having to admit ‘Well, ehm… I am not sure there are peer-reviewed, published data on this’.1 have contributed to fill this gap. Drawing on the Clinical Practice Research Datalink (CPRD), a large primary care database containing records of about 11 million patients, the aims of the study by Price et al1 were to: (a) examine regional differences in the prevalence of prescriptions of ADHD medications in primary care for young people aged 16–19 years in the UK; (b) estimate the proportion of patients referred to AMHS; (c) map regional variations in prescribing patterns and referrals rates to the location of services for adult ADHD.Fortunately, Price and colleagues1 should be considered within the context of the current knowledge on the persistence of ADHD after adolescence, as well as of the available guidelines and evidence synthesis on ADHD treatment. An often cited meta-analysis2 showed that up to 65% of young adults with a childhood diagnosis of ADHD present with impairing ADHD symptoms and up to 71% with functional impairment, even without a formal diagnosis of ADHD. For school-age children with ADHD, the 2018 NICE guidelines3 recommend the use of medication , with the following hierarchy: (a) methylphenidate; (b) lisdexamfetamine (or dexamphetamine if lisdexamfetamine is not well tolerated); (c) atomoxetine or guanfacine. Behavioural parent training is recommended only when there is a comorbid oppositional defiant disorder or conduct disorder. For adolescents, cognitive–behavioural therapy is suggested if impairing symptoms are still present after the pharmacological treatment. In adults, medication is the recommended first-line approach, with methylphenidate or lisdexamfetamine (or dexamphetamine if lisdexamfetamine not well tolerated) as first line, followed by atomoxetine. Non-pharmacological treatments are indicated in case of difficulty adhering to medication, if medication is ineffective or not well tolerated, or if patients prefer them.The study by Price et al4 of randomised controlled trials (RCTs) (time points closest to 12 weeks) showed superiority of many ADHD medications over placebo in reducing the severity of ADHD core symptoms, with effect sizes for amphetamines (from ~0.8 to 1) that are not only the highest for the medications used in psychiatry, but also among the highest in general medicine.5 Furthermore, evidence from observational within-individual designs to account for confounding by indication shows a protective effect of ADHD medications on a number of important outcomes in children  and in adults .6Overall, these recommendations are in line with available meta-analytic evidence. As for short-term effects, the most comprehensive network meta-analysis7As for the long-term effects of medications, although as a result of ethical and practical aspects it is challenging to prove them using the standard RCT design, a number of discontinuation RCTs (i.e. RCTs in which patients who have been on medication are either randomised to continue the treatment or to placebo) are emerging, showing the persistence of effects beyond the ‘short term’.8 It has also been reported that around 90% of patients with ADHD respond to at least one type of medication for ADHD.9 Finally, based on rigorous meta-analytic evidence, the effects of non-pharmacological treatments on core symptoms of ADHD in children and adolescents are uncertain, when relying on masked/probably masked ratings,13 even though additional methodological sound research in adults is needed.The percentage of individuals with ADHD who should be treated with medication is not well established, but sequential RCTs show that only 18–23% of patients might respond to an initial trial of behavioural interventions.1 tells us. In the area with the highest prescribing rate (Scotland), the percentage of patients with at least one prescription of ADHD medication was 47% at 14–15 years and 27% at 19–20 years; in the region with the lowest rates of prescription (Yorkshire & Humber), the rate dropped from to 27% to 6%. Furthermore, the mean age of termination (or interruption) of pharmacological treatment was 16.6 years (s.d. = 2.63), in sharp contrast with the notion that in the majority of cases, impairing ADHD symptoms persist after adolescence.Given this evidence, one should expect a substantial persistence of pharmacological treatment in young people with a history of childhood ADHD. But this is not what the study by Price et al14 study and from efforts to implement the MTA approach in the real clinical world15 is that, to be effective, ADHD medications need to be optimised with an accurate titration and follow-up. As such, ‘at least one prescription’ is just a rough indication of effective treatment.It should be highlighted that these figures provide only an underestimated rate of individuals with ADHD who are properly managed with the pharmacological treatment. Indeed, one of the key lessons that the field has learned from the well-known Multimodal Treatment of ADHD (MTA)1 could not assess adherence to treatment. Therefore, the first finding of the study can be summarised as follow: there is a regional variability in the prescription of ADHD medication across geographic areas in the UK, but overall the rate of prescriptions  varies from low to very low. This finding should be considered in the context of the documented underrecognition of ADHD, which varies by deprivation16 and the gap between the recognised prevalence of ADHD versus its community prevalence in the UK.17Additionally, given the limitations of real-world databases such as the CPRD, Price et al1 found no clear identifiable associations between reduction in prescribing, referral rates to AMHS and location of services specialised in the care of adults with ADHD. However, this finding should be considered with caution, as CPRD data referred to the period 2005–2013, while the service mapping was completed in 2018.In relation to the second study objective, the authors found that the average percentage of patients referred to AMHS was 11% only, ranging from 4% to 21%, and the figures were even lower when excluding individuals with a prescription of any other psychotropic medications . Finally, Price et al18) guidelines preventing GPs from prescribing ADHD medications in adults. It is also possible that a number of prescriptions continue being renewed without proper specialist input, which would be a major problem per se. Finally, ADHD medications might not be prescribed because these young people access non-conventional medications thought to improve ADHD or non-pharmacological approaches; in both cases, this would suggest that a sizeable portion of patients are not treated as per current guidelines.The study findings may be accounted for by a number of possible factors. First, it is interesting to note that the mean age of termination of medication coincides with the period when young people complete the General Certificate of Secondary Education and may leave school, suggesting that they may deem that treatment for a condition that they erroneously perceive as only an ‘academic’ problem is not necessary anymore. Second, it is possible that general practitioners (GPs) do not continue the prescription because of a lack of shared care plans agreements, paucity of ADHD specialised services or, in some areas ) we do know now that ADHD can have serious consequences in adults as well. There is a need to provide education and training to patients, families, GPs and other professionals involved in the care of ADHD, as well as commissioners. In particular, GPs and adult mental health professionals should receive education and training on the importance of monitoring medication use and supporting adherence.Regardless of the possible explanation, the study by Price et alhttps://www.ukaan.org/) is pivotal in this regard. Additional research is needed on the psychosocial impact of ADHD, the efficacy, effectiveness, and safety of pharmacological interventions for adults with ADHD, and the profile of young adults with ADHD that require transition to adult services, with the goal to develop local protocols to monitor and support the mental health of young people with ADHD.Public awareness campaigns addressed at adolescents with ADHD should be promoted, to strengthen adherence to treatment in adulthood. The role of professional groups such as the UK Adult ADHD Network (From my side, I will keep on providing my modest contribution delivering training and attending working groups, where I am sure I will feel less embarrassed next time I am asked about regional variations in prescribing of ADHD medications for young people in transition from CAMHS to AMHS.