In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)–based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.KTRs aged 18-80 years with a stable graft function  risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year.We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.10.13039/100002491Bristol-Myers Squibb.The trial has received a financial grant from EudraCT no. 2013-001178-20.  In 2013-2014, belatacept was believed to be superior to cyclosporin A in terms of its CV effects after kidney transplantation; however, not many studies had compared belatacept with tacrolimus. The use of a CV risk calculator instead of hard endpoints provided the chance to investigate the 2 regimens after a relatively short follow-up. The difference in the CV risk was smaller than we expected, although belatacept did lower the blood pressure. Our study again showed that an early prescription of belatacept carries the risk of rejection. Our main learning point is that belatacept, after 15 years of use, should still be regarded as a treatment option for individuals who suffer from tacrolimus-related side effects; however, it is unsuitable for broad implementation for all kidney transplant patients, despite its promising introduction.,,The risk of cardiovascular disease (CVD) in patients with kidney failure is much higher than in the general population across all age groups.,First, evidence indicates that a declining graft function and graft loss are the potentially modifiable risk factors for CVD and all-cause mortality in this population, which make the strategies for optimizing the graft function important.2 higher than that in the CsA group. Furthermore, in a metaanalysis comparing belatacept with CNIs, treatment with belatacept was associated with lower blood pressure, a lower incidence of diabetes, and a more favorable lipid profile.Belatacept, a modified form of cytotoxic T lymphocyte–associated antigen-4-Ig , binds to CD80 and CD86 on antigen presenting cells, thus blocking CD28-mediated costimulation of T cells. The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trials (BENEFIT) have shown promise for belatacept as an option for designing a more favorable immunosuppressive regimen.However, it is not yet proven whether these findings translate into overall CVD reduction. Soveri et al,A shortcoming of belatacept treatment that has hindered its implementation in kidney transplantation has been the relatively high rate of early rejection, as well as the lack of studies comparing its efficacy with low-dose TAC, the current standard of care in KTRs. In the present study, our aim was to investigate the following: (1) the effects of conversion from a low-dose CNI-based therapy to belatacept on the estimated risk of CVD and all-cause mortality by using the aforementioned risk calculator developed by Soveri et al,This was a prospective, randomized, open-label, parallel-group, investigator-initiated, and international multicenter trial (EudraCT no. 2013-001178-20). Patients were randomized in a 1:1 ratio to either continue treatment with a CNI-based regimen or switch to belatacept for a study duration of 12 months. An open design was chosen because CNIs were given as tablets daily and belatacept was administered as infusion every 4 weeks.2), 3-60 months after transplantation treated with TAC or CsA, were eligible for inclusion. Patients were excluded if they were Epstein-Barr virus IgG seronegative, had severe de novo or recurrent kidney disease, had a history of vascular or antibody-mediated rejection in the present transplant, or had a history of recent malignancy.Patients were recruited from 9 transplant centers in Denmark (DK), the Netherlands (NL), Norway (NO), and Sweden (SE). KTRs aged 18-80 years with a stable graft function . Written informed consent was obtained from all patients, and the trial was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.For patients randomized to the study arm with belatacept, the previous CNI treatment (TAC or CsA) was tapered in the initial period as follows: 100% on day 1, to 70%-80% on day 7, to 40%-60% on day 15, 20%-30% on day 23, and none on day 29 and beyond. Belatacept was dosed 5 mg/kg intravenously on days 1, 15, 29, 43, and 57 and then every month thereafter in the 12-month study period . Patient,The primary endpoint of this trial was the estimated CV risk using a prediction model developed for KTRs by Soveri et al.The estimated 7-year risk of MACE and all-cause mortality in the 2 treatment groups was calculated as a linear combination of the following variables: age, previous coronary heart disease, previous smoker, current smoker, creatinine level, diabetes mellitus, low-density lipoprotein (LDL) cholesterol, the number of transplants, and the total time on kidney replacement therapy . Secondat test on a 2-sided significance level of 0.05, assuming a standard deviation of 0.64 , a sample size of 51 per group was required to obtain a power of 0.8 (80%) to detect a 30% calculated risk reduction in MACE. The analysis of covariance (ANCOVA) model was expected to have a slightly greater power than the 2-sample t test; therefore, a sample size of 102 patients was seen as sufficient for this study. To account for 8% drop-out, a total of 110 patients, 55 per treatment arm, were included in the study. Randomization to treatment arm was performed using a computerized procedure, stratified by the center, in a 1:1 ratio.We performed a power calculation hypothesizing that the intervention arm decreases the risk of MACE by 30%. We came to that estimate by extrapolation of the reduction in the calculated risk in the previously mentioned study by Soveri et alOwing to a skewed distribution, the primary variable  was log transformed . The primary endpoint was the comparison of the log of the estimated MACE and mortality risk between the treatment groups (CNI- vs belatacept-based immunosuppression) at 1 year. For patients who discontinued the study before 1 year, the last available estimate of CV risk was used in the analysis of the intention-to-treat (ITT) population.t test or ANCOVA, with correction for baseline variables and/or center. A 2-sided P value of <0.05 was considered statistically significant. Analyses were performed using SAS version 9.4 software (SAS Institute).The primary analysis on the primary endpoint was performed using ANCOVA with treatment as a group variable and the baseline log risk for MACE and mortality and center as the covariate. All other comparisons on primary and secondary endpoints were based on ITT comparisons of treatment groups using the 2-sample A total of 112 patients from 9 centers signed the patient informed consent form. Of these, 1 patient was a screen failure (history of rejection) and was never randomized. Of the 111 randomized patients, 6 withdrew the consent before any study drug was given, 4 in the belatacept arm and 2 in the CNI arm. Thus, 105 patients were administered study medication: 54 in the belatacept arm and 51 in the CNI arm (defining our ITT population). In the belatacept arm, 5 patients were withdrawn from the study: 3 withdrew owing to adverse events (AEs), 1 withdrew consent, and 1 moved out of the country. Similarly, there were 2 withdrawals in the CNI arm; 1 withdrew owing to AEs and 1 withdrew consent. The remaining 49 patients in each treatment arm were defined as the per protocol (PP) population . BecauseThe primary endpoint was the estimated 7-year risk of MACE and all-cause mortality per the risk calculator developed by Soveri et al. . After 1In the belatacept arm, the mean (standard deviation) estimated 7-year risk of MACE at baseline was 0.15 (0.13), and it remained unchanged even after 1 year to 0.15 (0.15). Similarly, the risk estimation for the CNI continuation arm was 0.14 (0.14) at baseline and 0.15 (0.15) after 1 year. After applying the ANCOVA models and adjusting for hospital centers, the log mean risk prediction decreased by 2.31  for the belatacept group and 2.25  for the CNI group. The difference between interventions in log mean risk prediction for MACE was 0.06 .The estimated 7-year mortality risk in the belatacept arm at baseline was 0.21 (0.19), which increased nonsignificantly to 0.23 (0.20) after 1 year. Correspondingly, for the CNI continuation arm, the predicted risk of mortality was 0.19 (0.18) at baseline and increased nonsignificantly to 0.21 (0.19) after 1 year. After applying the ANCOVA models and adjusting for hospital centers, the log mean risk prediction decreased by 1.94  for the belatacept group and 1.92  for the CNI group. The difference between interventions in log mean risk prediction for mortality was 0.02 . An overview of the variables used in risk calculation is presented in P = 0.33) and mortality (P = 0.56) in the subgroups.Subgroup analysis was also performed to investigate whether the time since transplantation influenced the results in risk calculation. Treatment arms were divided on the basis of the median time after transplantation, thus creating an early and late group (before and after 26 months). There was no difference between the belatacept and the CNI group in the calculated risk of MACE  after 1 year of treatment. For central systolic pressures, the difference of 6.1 mm Hg between the study groups  was borderline significant. There were no differences between the treatment arms in the central pulse pressure, pulse wave velocity, and augmentation index  or deaths observed in the study population.All patients in both study groups reported at least 1 AE during the duration of the study . The majDuring the study, 8 acute rejection episodes were suspected, and graft biopsies were obtained for further investigation. Acute rejection was confirmed in 4 of the 7 suspected cases in the belatacept group, and in a single case in the CNI group. Three of the rejection episodes were considered severe (Banff grade IIA or higher): 2 in the belatacept group and 1 in the CNI-treated group. One patient (belatacept) proved refractory despite the antirejection treatment with methylprednisolone and T-cell–depleting antibodies. All other rejection episodes recovered on treatment with corticosteroids or antithymocyte globulin as per local practices.P = 0.09).In this randomized study, in which stable kidney transplant patients were converted from a CNI-based maintenance immunosuppressive regimen to belatacept, no difference in the calculated 7-year risk of MACE or all-cause mortality could be demonstrated even after 1 year of follow-up. We were unable to find a significant effect on any of the 3 modifiable CV risk factors that were used as input variables in the risk calculator . The belatacept arm had significantly lower diastolic blood pressure, measured both centrally (SphygmoCor method) and peripherally. We found a similar improvement in systolic pressure ; however,2 higher than the other 3 comparator groups. A belatacept-conversion study by Grinyo et al2, and a low immunologic risk profile, making the population reasonably comparable to ours. Belatacept patients in that study showed an average improvement in eGFR of 4.9 mL/min/1.73 m2 compared with CNI patients. At baseline, patients using TAC (56%) had an average trough level of 7.2 ng/mL, whereas patients on CsA (44%) had an average trough level of 160.2 ng/mL. In our study, the mean trough levels of TAC (5.7 ng/mL) and CsA  at the time of randomization were lower compared with those in both these studies.,2. However, this hypothesis is not supported by Budde et al2, contrary to our findings. Of note, patients in our study with biopsy-proven acute rejection (BPAR) had a decrease in eGFR of 2.7 mL/min/1.73 m2, compared with an increase of 1.1 mL/min/1.73 m2 in others. The low number of events precludes any meaningful interpretation of these data, and the general lack of improvement in eGFR cannot be explained hereby.Of the 3 modifiable risk factors in the calculator, we had expected a significant change in eGFR in the intervention arm. Our findings are in contrast with those of the BENEFIT studies, as well as other belatacept-conversion studies reported in the literature.,The second element of the calculator is diabetes status. Multiple studies have corroborated the diabetogenicity of TAC in transplantation.Expectations regarding the effect on lipid profile, the third element in the calculator, were limited. Although CsA has been implicated in dyslipidemia,P = 0.09), most likely owing to the relatively small sample size of this study. CNIs are known as potent vasoconstrictors and contribute to posttransplant hypertension.On trying to explain the lack of significant improvement in CV risk, we need to consider another bias besides the low CNI trough levels. Patients were already treated with CNI for a median of 26 months since transplantation. Serious negative side effects of CNI treatment could be less likely found in the control group, because patients suffering from these side effects could have been converted to alternative immunosuppression earlier on and thus not be eligible for this study. The only positive effect that we found for belatacept was a significant improvement in diastolic blood pressure, measured both centrally (SphygmoCor method) and peripherally. For systolic pressure, a similar improvement was found ; howeverRegarding safety, AEs occurred in both the groups; however, serious AEs were reported almost twice as often in belatacept-treated patients (29.6% vs 15.7%), and they were more likely to discontinue their study treatment than patients treated with CNI (5.6% vs 2.0%). Rejection was seen more often in the belatacept patients. Four episodes of BPAR occurred in the belatacept group versus 1 single episode in the CNI group (7.4% vs 2.0%). Three patients showed signs of vascular inflammation in the biopsy, corresponding to Banff grade II, 2 of whom were in the belatacept group. All 3 patients were treated according to the local protocol with high-dose steroids and T-cell–depleting antibodies, despite which 1 belatacept patient suffered graft loss and reinitiated the dialysis treatment. The other 2 patients recovered with antirejection treatment. The median number of days between transplantation and randomization was 225 in those treated with belatacept with BPAR, whereas no rejection was seen in any patient after 1 year after transplantation (mean 818 days after transplantation for those without BPAR). This trend of rejection after early conversion corroborates the findings by Budde et al,,The rate of rejection in this study is in line with that in earlier reports. For example, in the trial by Grinyo et al,Besides rejection, urinary tract infections, nasopharyngitis, and other respiratory tract infections were more often seen in the belatacept arm . The pre2) and patients converted early after transplantation (within 6 months) were more likely to develop opportunistic infections.Not a single case of pneumocystis-jirovecii pneumonia, cytomegalovirus, polyoma- or Epstein-Barr virus–associated disease was seen in the belatacept patients. Three cases of cytomegalovirus infection were seen in CNI patients. Previous reports have been inconclusive on opportunistic infections in belatacept treatment. The follow-up study to the first belatacept-conversion trial noted a slightly higher incidence of viral infection (11% vs 14%).,There was one case of lung cancer in the belatacept group in the present study. Previous studies have not indicated a higher risk of malignancy for belatacept beyond posttransplant lymphoproliferative disorders.A major strength of the current study is the international multicenter approach, making it representative of the European transplantation practice. However, this study also has important limitations, which must be considered. The study duration of 1 year was most likely too short to show a significant difference in kidney function between the 2 study groups. We have overestimated the potential reduction in MACE and mortality in patients who use low-dose TAC instead of CsA. Another limitation was the heterogeneous time from transplantation to trial enrollment, and the small number of patients treated with CsA and the relatively large span of eGFR at baseline also contributed to the heterogeneity. Patients with a severely diminished graft function were less likely to benefit from conversion.In conclusion, we have shown no effect on the calculated CV risk or kidney function in this study comparing conversion to belatacept with continuation of CNI-based immunosuppression. We did show a significant difference in diastolic blood pressure. We reconfirmed the increased chance of rejection when converting to belatacept. After more than 10 years of clinical experience, the place of belatacept in kidney transplantation is still not fully established; however, it may be an attractive option when patients suffer from significant side effects of CNI, such as nephrotoxicity or posttransplant diabetes mellitus. However, it is hard to define a significant benefit of belatacept for patients who do well on a low-dose TAC-based therapy without severe CNI-related side effects. Further studies are needed to define the place of belatacept in kidney transplantation.


Clozapine is the most effective intervention for treatment-resistant schizophrenia (TRS). Several studies report ethnic disparities in clozapine treatment. However, few studies restrict analyses to TRS cohorts alone or address confounding by benign ethnic neutropenia. This study investigates ethnic equity in access to clozapine treatment for people with treatment-resistant schizophrenia spectrum disorder.A retrospective cohort study, using information from 11 years of clinical records (2007–2017) from the South London and Maudsley NHS Trust. We identified a cohort of service-users with TRS using a validated algorithm. We investigated associations between ethnicity and clozapine treatment, adjusting for sociodemographic factors, psychiatric multi-morbidity, substance misuse, neutropenia, and service-use.p = 0.001; Black Caribbean aOR = 0.64, 95% CI , p = 0.019; Black British aOR = 0.61, 95% CI , p = 0.016). It was additionally observed that neutropenia was not related to treatment with clozapine. Also, a detention under the Mental Health Act was negatively associated clozapine receipt, suggesting people with TRS who were detained are less likely to be treated with clozapine.Among 2239 cases of TRS, Black service-users were less likely to be receive clozapine compared with White British service-users after adjusting for confounders (Black African aOR = 0.49, 95% CI , Black service-users with TRS were less likely to receive clozapine than White British service-users. Considering the protective effect of treatment with clozapine, these inequities may place Black service-users at higher risk for hospital admissions and mortality.The online version contains supplementary material available at 10.1007/s00127-022-02257-3. Studies show ethnic inequalities in healthcare. For instance, ethnic minorities received poorer analgesic care  and repoTreatment-resistant schizophrenia (TRS) is defined as a failure to respond to two trials of antipsychotics with an adequate dose  and affeClinicians and minority ethnic service-users may resist clozapine treatment because of benign ethnic neutropenia (BEN). This is a condition of low baseline level of white cells that is more common in people of African, Arabian, and Mediterranean background , 29. CloThis study addresses these limitations by investigating ethnic disparities in the prescription of clozapine in a cohort of people with TRS, while adjusting for several potential confounders, including sociodemographic information, psychiatric multi-morbidity, substance misuse, service-use, and neutropenia. Our hypothesis is that ethnic minority services-users, specially Black people, are less likely to be treated with clozapine than their White British counterparts.In this retrospective cohort study, we used data from the electronic health records (EHRs) of the South London and Maudsley (SLaM) National Health Service (NHS) Foundation Trust. SLaM's catchment area comprises four London boroughs , with a population of 1.3 M (2018 estimates). Access to the information to SLaM's clinical records is made via the Clinical Record Interactive Search system (CRIS) established in 2007–2008 , 32. At Moreover, CRIS provides several data linkages to national registries, including the Zaponex Treatment Access System (ZTAS) . The ZTACRIS was established under a robust data protection and governance framework and received approval from the Oxford C Research Ethics Committee (18/SC/0372) to be used as a de-identified dataset for secondary data analysis , 32. ThiThe sample comprises SLaM service-users who met the following inclusion criteria: (1) had a primary diagnosis of a schizophrenia spectrum disorder (ICD-10: F20–F29), (2) were taking antipsychotics between 1 January 2007 and 31 December 2017, (3) lived in the SLaM catchment or were homeless, (4) were 18 years or older at the time of that first antipsychotic after 2007, and (5) met a proxy definition for treatment resistance, via a validated algorithm.TRS was identified in an automated way, via the development and validation of several algorithms against a gold-standard, manually coded, dataset of TRS cases in a previous study . In lineThe algorithms developed to identify TRS in a large dataset were based on an automatic coding of trials of antipsychotic treatment and episodes of hospitalisation , 16. An Clozapine prescription between 1 January 2007 and 31 December 2017 (the study’s outcome), as well as information regarding the antipsychotic treatments used in the TRS algorithms, was retrieved using NLP applications , 33. TheEthnicity was based on the 16 ethnic categories used by the NHS, which were aggregated into eight categories due to small sample sizes. These were: (1) White British; (2) Other White [Irish and Other White background]; (3) Black African [Black African and White and Black African]; (4) Black Caribbean [Black Caribbean and White and Black Caribbean]; (5) Black British or Other Black background; (6) South Asian ; (7) Asian British or Other Asian ; and (8) Other Ethnicity [Other Mixed background and any Other ethnicity].Potential confounders included sociodemographic information, psychiatric diagnoses, substance misuse, other clinical and functional status factors, evidence of neutropenia (including benign ethnic neutropenia), and information regarding service-use. Sociodemographic confounders included gender, age at the date of TRS, homelessness ever before TRS, and neighbourhood deprivation. The latter was the index of multiple deprivation of the English Indices of Deprivation  assignedPsychiatric diagnoses included the schizophrenia spectrum diagnosis and psychiatric comorbidities. Considering the possibility of multiple diagnoses within the schizophrenia spectrum being mentioned in clinical records at TRS date, the diagnoses were categorised according to the highest hierarchy: schizoaffective disorder (F25), schizophrenia (F20) or other diagnoses . Psychiatric comorbidities reported at any time before the TRS date comprised: (1) developmental disorders ; (2) anxiety-related disorders , (3) bipolar , (4) depression or other mood disorders excluding bipolar (F32–F39), and (5) personality disorder (F60–F61).Evidence of substance misuse comprised having ever been diagnosed with any substance use-related disorder  and previous use of cannabis. Cannabis use was identified using an NLP application , 37. Oth9/L) in SLaM or ZTAS records, on two separate occasions at least 1 month apart. Information regarding BEN was retrieved from ZTAS sociodemographic information; thus, data on BEN were only available for service-users with records on ZTAS. No evidence of BEN or neutropenia, or no information on neutrophil counts, was coded as lack of evidence of neutropenia. Information on evidence of neutropenia was retrieved up to the point of clozapine prescription or the end of the observation window.Given that a proportion of patients with neutropenia will be classified as having benign ethnic neutropenia (BEN), in this study, patients with BEN were included together with other patients who had evidence of neutropenia. Neutropenia was assumed when there were low neutrophil counts . Logistic regression analyses were performed to investigate the association between ethnicity and clozapine prescription, controlling for each category of possible confounders. A fully adjusted model is presented, considering the number of covariates. Statistical analyses were conducted using STATA 15 .M = 40.9, SD = 12.6) and 64% were men. Ethnic composition was: 32% were White British; 18% were Black Caribbean; 17% were Black British; 16% were Black African; 7% were from Other White background; 4% were Asian British, and 3% were South Asian  and personality disorders . A substance use disorder was less frequent in South Asian people (< 5%). Cannabis use was less common in White British (55%) and South Asian people (41%) and more common in the Black Caribbean (70%) and Black British people (76%). According to HoNOS ratings, hallucinations were less common in Black Caribbean people (76%), and depressed mood was more common in Other ethnicity (75%).Black African = 8.45, 95% CI , p < 0.001; ORBlack British = 6.64, 95% CI , p < 0.001, ORBlack Caribbean = 3.76, 95% CI , p < 0.001. The relative risk was not meaningfully calculated for other ethnic groups due to the small number of people with neutropenia , with the highest levels among Black African (15%), Black British 12%), Black Caribbean people (7%) and lower in the White British (2%). Analyses revealed a 3 to 8 fold higher relative odds for neutropenia among these ethnic groups, compared with the White British: OR%, Black An episode of involuntary hospitalisation under the MHA Part 2 was more frequent among Black African (66%) and Black British (59%), than White British people (38%). Police detention was more common among Black African (26%) and less frequent in White British people (11%).p = 0.001). Black Caribbean and Black British or Other Black people also less likely to receive clozapine . These results were adjusted for sociodemographics, psychiatric diagnoses, substance misuse, evidence of neutropenia, and type and frequency of service-use. No significant differences were observed for other ethnicities (Other White background or Asian background and any Other ethnicity). In the models adjusting only for the HoNOS items regarding symptoms and impairment, which due to substantial missing data were not included in the fully adjusted model, there were lower rates of clozapine treatment among Black African and Black Caribbean people. Sensitivity analyses, restricting the cohort to people who met the proxy criteria for TRS before the end date of the CRIS data linkage with ZTAS (31/03/2016), revealed similar findings to the fully adjusted model with the all cohort .In this cohort of people with TRS, 75% of the Black African people, 89% of the South Asian and 87% of White British people received clozapine Table . Resultsp = 0.132), nor in the fully adjusted model . Furthermore, people who had more than 30 days of hospitalisation, in the 3 months before the date they met proxy criteria for TRS, were more likely to be treated with clozapine , than those who were not hospitalised (results not shown in tables). Those who were admitted under the MHA, at any point before TRS date, were less likely to receive clozapine. This was observed for all types of detentions: hospitalisation initiated by clinical staff , police conveying to a place of safety , and forensic detention .It was also observed that neutropenia was not associated with treatment with clozapine; neither in a crude model , as well as frequency and type of service-use. No differences in clozapine treatment rates were observed between White British and people of any Asian background, Other White ethnicity, or any Other ethnicity.Our results are consistent with the majority of studies, which report that minoritised ethnic people, particularly people from a Black background, are less likely to receive clozapine, the drug of choice for TRS , 20–23. 9/L). Thus, mild neutropenia, as well as benign ethnic neutropenia, should not prevent treatment with clozapine. This is in line with the recommended guidelines [In this study, there were ethnic disparities in evidence of neutropenia (including benign ethnic neutropenia) confirming the greater prevalence of this condition among Black people . The preidelines , 41.Minoritised ethnic people more frequently received involuntary care via the use of the MHA. Higher detention rates are observed in multiple previous studies , 42 and The mechanisms that led to the reduced likelihood of Black people being treated with clozapine are not fully understood in this study. Disparities in physical health, not measured in the study, could be related to the observed inequalities. For instance, diabetes, hypertension and cardiovascular disease seem to be more prevalent among Black communities than White British people –47. The Having that limitation in mind, the findings of this study contribute to the accumulation of evidence regarding ethnic inequalities in care in the UK , 5, 8. TWe used data from a large mental healthcare provider in the UK in an area whose population is very diverse (about 58.5% of residents are of an ethnic minority background) . The serSome limitations include the use of an algorithm to identify TRS. The rules of the tested algorithms are not as fine-grained as those used to develop the manually coded gold-standard dataset. Moreover, it is likely that we are missing cases of TRS where there was no prescription of clozapine, given that we prioritised the precision of the algorithm. Unlike other cohort studies, a proportion of service-users were coded as having the outcome at the point of cohort entry, due to being treated with clozapine. Establishing a TRS cohort whose ascertainment criteria did not include clozapine would substantially reduce the sample size and compromise the achievement of this study aims. Given the focus on ethnicity, we believe the study’s cross-sectional design does not affect the reliability of the findings. There was substantial missing information in the HoNOS assessment, and preliminary analyses revealed that people whose TRS date corresponds to the date of clozapine or ZTAS registration had a higher proportion of missing data. Furthermore, we did not evaluate service-users preferences of care and/or rejection of treatment with clozapine , nor othThis study reveals that Black service-users with TRS have half the odds of being treated the recommended treatment, clozapine, after accounting for several possible confounders. Thus, further research is needed to understand the drivers of ethnic inequities in access to clozapine. Reduced odds of having treatment with clozapine may place Black people at greater risk of negative outcomes, such as higher hospital readmission  and mortNeutropenia, a potential driver of ethnic inequalities , was notSupplementary file1 (DOCX 57 kb)Below is the link to the electronic supplementary material.


BMAL1 and PER2. We found significant group differences in sleep onset and sleep duration, cortisol secretion profiles, and in the expression of both clock genes. Our data suggest that the analysis of circadian molecular rhythms may provide a new approach for diagnosing ADHD in children and adults.Attention deficit hyperactivity disorder (ADHD) is a very common disorder in children and adults. A connection with sleep disorders, and above all, disorders of the circadian rhythm are the subject of research and debate. The circadian system can be represented on different levels. There have been a variety of studies examining 24-h rhythms at the behavioral and endocrine level. At the molecular level, these rhythms are based on a series of feedback loops of core clock genes and proteins. In this paper, we compared the circadian rhythms at the behavioral, endocrine, and molecular levels between children with ADHD and age- and BMI-matched controls, complementing the previous data in adults. In a minimally invasive setting, sleep was assessed via a questionnaire, actigraphy was used to determine the motor activity and light exposure, saliva samples were taken to assess the 24-h profiles of cortisol and melatonin, and buccal mucosa swaps were taken to assess the expression of the clock genes  Attention deficit hyperactivity disorder (ADHD), with a prevalence of 5.29% (95% CI = 5.01–5.56) in childhood and adolescence ,4,5,6. TThe circadian clock system is responsible for adapting physiological processes and behavior to the 24 h day–night rhythm. It is a major driver of sleep–wake rhythms ,15. The The SCN is responsible for regulating the rhythmic secretion of various hormones such as cortisol and melatonin. Alterations of these secretions have been described in ADHD in children and adults, but with partially inconsistent results ,17,18,19PERIOD-genes . The PER proteins then inhibit the transcriptional activation by CLOCK and BMAL1. This results in a circadian rhythmic oscillation of PER transcription [At the molecular level, circadian rhythm regulation works through interlocked positive and negative transcriptional–translational feedback loops of a set of core clock genes and their protein products. For example, heterodimers of CLOCK and BMAL1 activate the transcription of the negatively-regulating cription ,21,22. Scription ,24,25.Baird et al. 2012) examined circadian rhythmicity at the molecular, endocrine, and behavioral levels in adult ADHD for the first time, and found disturbed rhythmicity at all levels [12 examinEthical approval for the conduct of the study including the use of all human tissues was given by the ethics committee of Rostock University (Registration-number: A2012-0116), and written informed consent was obtained from each study participant and caregiver. The study was conducted according to the ethical guidelines of the Declaration of Helsinki.We used a head to head comparison design with two groups: a group of ADHD patients and a non-affected group (controls). The ADHD sample was recruited at the Department for Child and Adolescent Psychiatry and Neurology, Rostock University Medical Center. Inclusion criteria were an ADHD diagnosis according to ICD 10  F 90.x, The Children’s Sleep Habits Questionnaire (CSHQ) is a parent-report screening survey published by Owens et al. in 2000, which has been validated for school-aged children . It has The actigraph used was a wrist-worn sensor resembling a small watch . Participants wore the actigraph all day for at least 5 consecutive days on the wrist of the non-dominant hand. For the study protocol, see The hormones melatonin and cortisol were determined from the saliva samples. These were collected in parallel oral mucosa samples every 4 h, with an additional collection at 10 rpm to map the dim-light melatonin onset . We used the cosinor2 toolbox in R  to compon 4.0.3 . Notablyon 4.0.3  and compTwelve boys diagnosed with ADHD and 11 healthy controls, matched for sex, age, height, and weight were included. For results in age, height, and weight see There was no significant group difference between children with ADHD and the control group, neither for the sum score nor for the subscales Bedtime Resistance, Sleep Anxiety, Night Wakenings, Parasomnias, Sleep-Disordered Breathing, Daytime Sleepiness, Sleep Onset Delay, and Sleep Duration see .The analysis of the actigraphic data is shown in The cosinor fits indicated significant 24 h rhythmicity for melatonin and cortisol in both groups see .p = 0.002). See The percent-rhythms were not significantly different between the groups. Comparing the mesors, acrophases, and amplitudes of the cosinor fits across the groups, we found that the acrophase of the cortisol rhythm was significantly lower for the ADHD group  gene rs1801260 was investigated in different cohorts with controversial results. Kissling et al. (2008) assessed 143 adult subjects in a German population and found a significant relation between this SNIP and ADHD [BMAL1 and PER2 in the control, but not in the ADHD group [There have been several studies on clock genes that have focused on structural changes in the DNA such as single-nucleotide polymorphisms (SNIPs). One SNIP of the circadian locomotor output cycles protein kaput , the SCN is the cerebral structure integrated in the circadian regulation of physiology and behavior [12, the SBMAL1 and PER2. These alterations seem to be robust markers for ADHD in both children and adults. In relation to the recommendations for the study design and sample characteristics of Dáz-Román et al. (2016) [In summary, we did not find significant groupwise differences in the sleep questionnaires’ total score and its subscores. Actigraphic parameters did not show significant differences between the groups. There were slight differences in the secretion profiles of melatonin and cortisol. The clearest difference between both groups according to the circadian parameters were found in the alterations of the expression profiles of two clock genes, . (2016) , our set. (2016) ,50, but In our study, we regarded the clock gene expression profiles to be sensitive markers to distinguish ADHD patients from the healthy controls. This was similar to the results of Baird et al. 2012) in adults 12 in adu. Can clo


The treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents can be challenging and involve a combination of pharmacologic and non-pharmacological approaches. Using recent literature, we aim to identify the effectiveness of cognitive behavioral therapy (CBT) and methylphenidate (MPH) in reducing the symptoms and improving the quality of life. The investigators conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Investigators independently conducted a routine search on PubMed and Google Scholar for articles published within the last five years through July 30, 2022. Fourteen studies were identified as generally good quality but with some limitations. The final analysis included 2098 patients with an age range of three to eighteen. Nine studies reporting the efficacy of MPH in children, adolescents, or both had different formulations and doses. Six studies documenting the effectiveness of CBT had varying sessions, duration per therapy, modality of administration, and participants. The diagnostic assessment measures showed that the parent symptom rating was the highest and appeared in 11 studies, reflecting the burden on the family. In addition, a structured-self-rated questionnaire rating appeared in eight studies, and two diagnostic assessment measures, teacher symptom rating and investigators, appeared in six.The studies demonstrated significant reductions in the primary symptoms of ADHD at assessment, which led to improved behavioral and functional status with a reduced impact on family and society. Further trials are needed to understand the benefits of CBT and MPH when combined to reduce psychiatry co-morbidities and improve learning and overall quality of life in the long term. IntroductionAttention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition in childhood, affecting approximately 4-6% of children and adolescents . The DiaBoys are two to four times more likely to be diagnosed than girls . In addiIn addition, over 65% of ADHD patients present with psychiatric comorbidities, including depression, anxiety, and learning disorders, which affect academic performance and family life, with enormous social and economic problems when left untreated . In chilClinical practice guidelines recommend a combination of pharmacotherapy and cognitive behavioral therapy (CBT) for treating ADHD in children and adolescents aged six to eighteen years . The psyResearch has shown that pharmacological treatments, particularly stimulants and atomoxetine, psychosocial therapies, and their combination are well-established interventions for children and adolescents with ADHD . TreatmeThe primary care provider roles include diagnosis, medication management, and referrals to other resources, both educational and behavioral . The AmeCBT has been described as "a form of psychological therapy that uses cognitive and behavioral techniques to support individuals to change unhelpful behaviors and thought patterns that occur in situations of fear and to learn better ways of coping with them, thereby relieving their symptoms and becoming more effective in their lives" ,10. CBT This review aims to systematically evaluate the effectiveness of MPH and CBT, in treating children and adolescents with ADHD using available literature. The study also establishes the most efficacious treatment in the current period.MethodsGuidelinesThis systematic review of empirical literature was performed in agreement with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 .Search DatabasesThree investigators independently searched PubMed, PubMed Central, Medical Literature Analysis and Retrieval System Online (MEDLINE), and Google Scholar.Search StrategyA systematic literature search using boolean logic to perform a database search and boolean search operators "AND" and "OR" were used to connect the keywords. PubMed search for free full-text articles, conducted in humans and published in English from 2017 until July 30, 2022, using medical subject headings (MeSH) terms keywords in the MeSH database are as follows Attention deficit hyperactivity disorder OR ADHD OR Hyperkinetic syndrome OR ("Attention Deficit Disorder with Hyperactivity/drug therapy" [Majr] OR "Attention Deficit Disorder with Hyperactivity/therapy" [Majr]) AND Cognitive behavioral therapy OR Psychotherapy OR Behavioral therapy OR  AND Methylphenidate OR methylphenidate hydrochloride OR Central nervous system stimulants OR ("Methylphenidate/administration and dosage" [Majr] OR "Methylphenidate/adverse effects" [Majr] OR "Methylphenidate/pharmacology" [Majr] OR "Methylphenidate/therapeutic use" [Majr] OR "Methylphenidate/therapy" [Majr]). We also performed a direct search on Google Scholar using the keywords Attention Deficit Hyperactivity Disorder (ADHD), Hyperkinetic Syndrome, Attention Deficit Disorder With Hyperactivity, Cognitive Behavioural Therapy (CBT), Psychotherapy, Behavioral Therapy, Methylphenidate OR Methylphenidate Hydrochloride, Central Nervous System stimulants, treatment, efficacy, children, and adolescents. The PICO  will be outlined  and transferred to the excel sheet, where we removed duplicates. In addition, we performed a manual check to remove any article to which the topic was non-related. Three reviewers independently reviewed papers based on title, keywords, and abstract. In addition, two reviewers thoroughly reviewed full-text articles that passed the initial screening to determine their suitability for inclusion in the systematic review. The quality of the paper included in the study was assessed by the primary author and two secondary authors using the Cochrane risk of bias tool for randomized controlled trials. We interpreted the result from the biases using the agency for healthcare research and quality (AHRQ) standards. Finally, the papers selected were of good quality. Finally, the investigators used the PRISMA diagram to check the quality of systematic reviews for inclusion.Additionally, we used the scale for assessing narrative review articles (SANRA) checklist to determine if a narrative review was of good quality. Finally, in the event of disagreement, we reached a consensus after discussing it with a fourth author. The PRISMA flow diagram is below in Figure ResultsAfter a strategic search of various electronic databases, the total number of articles found was 10438 . Records were removed before screening by PubMed filter inclusion criteria = 9722. We removed 52 duplicates with excel. The authors manually screened by title 664 studies and removed 619 articles with a non-related topic. We retrieved 45 records and excluded 21 studies after reviewing abstracts and full text using the eligibility criteria. The investigators identified 24 studies, and 10 did not meet the inclusion criteria after the quality assessment. Finally, we included 14 articles in our review. The PRISMA flow diagram is in the methods section  and Conners Teacher Rating Scale-Revised , the AD/HD Rating Scale-5 parent and teacher versions , the Early Childhood Inventory-4 , and the Child Behavior Checklist . The Preschool Age Psychiatric Assessment  was developed based on the Child and Adolescent Psychiatric Assessment (Angold and Costello 1995) for children two to five years of age. Still, no validation reports in that population have been published to date. The Vanderbilt ADHD Teacher and Parent Rating Scales have been validated in children aged six to twelve but are also applicable to preschool children . The Conners scales and AD/HD Rating Scale-5 are specific to ADHD behaviors and based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) ADHD criteria. In contrast, the Child Behavior Checklist and Preschool Age Psychiatric Assessment assess a wide range of behaviors and do not reflect criteria for ADHD alone . Physicians must remain cautious in diagnosing ADHD in preschool children, monitoring very young children for the emergence of symptoms and impairments over time [CBT InterventionThe CBT interventions in six studies included in this review had different measures of assessing the effectiveness of the ADHD treatment -18,23,24MPH TreatmentThe nine studies included in this review have different formulations of MPH ,14,18-22Additionally, in the first randomized, placebo-controlled trial of an ER MPH formulation for preschool children aged four to six years, doses of up to 40 mg were effective and well tolerated . It is lLimitationsThis study has some critical limitations. The major one is the limited number of articles documenting the use of MPH and CBT alone to treat ADHD. Furthermore, a systematic, non-descriptive review of CBT sessions was included  and provFinally, our search strategy excluded studies published before the last five years and not freely available full text on PubMed. The inclusion of these might have provided more clarity.The purpose of this review is to critically evaluate the efficacy of CBT and MPH in treating ADHD in children and adolescents to improve their core symptoms and functional capacity from published literature. The findings from the review of 2098 patients undergoing either or both treatment interventions showed significant reductions in the primary symptoms of ADHD at assessment, which led to improved behavior and functional status with an overall reduced impact on family and society. Additionally, accurate diagnosis by physicians using the rating scales is key to treatment choice. We observed how CBT helps with behavior management and the role of psychologists, parents, and teachers in ensuring effective therapy. Further trials are needed to understand the benefits of CBT and MPH when combined to reduce psychiatry co-morbidities and improve learning and overall quality of life in the long term.


Attention-Deficit/Hyperactivity Disorder (ADHD) is consistently associated with a host of social problems, such as victimization and difficulties in maintaining close friendships. These problems are not limited to offline relations but also manifest in the online social world, as previous research shows that ADHD is associated with problematic use of social media. Given the ubiquitous nature of social media, the goal of the current review is to understand why adolescents with ADHD demonstrate more problematic social media use than their typically developing peers. To this end, we provide a narrative review on the evidence for the link between ADHD and social media use, and consequently present an integrative framework, which encompasses neurobiological mechanisms  and social mechanisms, including influences from peers and parents. We conclude that empirical work shows most consistent evidence for the link between problematic social media use and ADHD (symptoms), while intensity of social media use is also associated with several other behaviors and outcomes. Finally, we hypothesize how existing interventions for ADHD may work on the identified mechanisms and provide at-hand clinical recommendations for therapists working with adolescents with ADHD who exhibit problematic social media use. Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent psychiatric condition characterized by inattention, hyperactivity and impulsivity . ADHD isproblematic social media use can be seen as an enduring preoccupation with and inability to stop using social media, as well as a persistent neglect of one’s health and functioning in several life domains, such as sleep, family, friends and school [Previous work has linked ADHD to more frequent and more problematic use of social media ,10. The d school ,12. Whild school ,14,15). d school ,20,21,22social media within this broader field. Social media can be defined as ever-changing, immersive and continually engaging [Most research on ADHD and media use in recent years has examined either general screen time or digital media use, or zoomed in on specific digital domains such as watching television or internet addiction. We first provide a comprehensive overview of what is known about ADHD and digital media, and then situate studies on ADHD and engaging , as theyengaging . We discengaging , complemengaging , but seeengaging , and proengaging .Several longitudinal studies from the communication sciences literature appear to suggest a temporal relationship between media use and subsequent ADHD characteristics, although most studies in this field did not include groups with clinical ADHD diagnoses, and potential confounds of this work and the implications have been widely debated. In the domain of television consumption, a Brazilian cohort study with adolescents from the general population found that ADHD symptoms at age 22 were related to television time at age 11, and total screen time at age 18 . AnotherIn addition, a large longitudinal study in adolescents without significant ADHD symptoms found that higher engagement in digital media activities  was associated with more self-reported ADHD symptoms two years later . This str = 0.12 [r = 0.03 [Three recent meta-analyses reach less straightforward conclusions. A small relation between ADHD characteristics and media use is demonstrated by one meta-analysis (r = 0.12 ), while r = 0.03 ), and a r = 0.03 ). Causalr = 0.03  note theintensity of social media use and ADHD symptoms. A study that examined adolescents at risk for psychopathology demonstrated that the daily number of text messages sent, as well as daily reported time on digital media, were related to self-reported ADHD (and conduct disorder) characteristics as measured on the same day, and these digital media measures were related to lower self-regulation over an 18-month follow-up period [Next, several empirical studies observed links between the p period . Other wp period . Interesp period . Taken tproblematic social media use and ADHD characteristics. In a large survey (n > 20.000), adolescents reported an association of addictive social media use with hyperactivity, but also with conduct problems and sedentary behavior [Other studies demonstrated an association between behavior , while abehavior . Moreovebehavior . An intebehavior . TherefoAll in all, the evidence for a temporal relationship between social media use and ADHD appears to be mixed and nuanced due to potential confounders, and there are many questions remaining about the mechanisms through which this occurs. Empirical work to date shows most consistent evidence for a relation between problematic social media use and ADHD (symptoms), while intensity of use is linked to ADHD in addition to several other behaviors and outcomes. Consequently, rather than the conclusion that social media potentially may lead to ADHD as a disorder, findings may suggest that they potentially exacerbate or lead to heightened symptoms of inattention, hyperactivity and impulsivity. For future research, it will be important to bridge the distinct literatures from communication sciences and psychiatry to advance our knowledge in this field.To gain traction on the link between social media use and ADHD, we use neurobiological models of brain development ,18,21, dDuring adolescence, major changes take place in cognitive and social-affective regions of the developing brain ,46, and Moreover, neuroimaging research has shown that brain activity in the ventral striatum is dependent on the social context. For example, risky driving in the presence of peers recruits the reward regions of the brain to a greater extent in adolescents, but not (young) adults . A uniquThe dual pathway model suggests two subtypes of ADHD characterized by relatively distinct pathways in the brain, i.e., those with dysregulation of inhibitory control systems and altered reward processing ,20. A lasocial media may be even more rewarding, which in adolescents with ADHD goes hand in hand with a limited capacity for cognitive control. Thus, from the neurobiological perspective, it is understandable that regular use of social media might turn to problematic use in adolescents with ADHD.The neurobiological characteristics of ADHD manifest themselves on a behavioral level as impaired executive functions, such as response inhibition, working memory and planning ,66, and Adolescence has been described as a time of ‘social orientation’  during wA large body of literature illustrates early social difficulties in children with ADHD, which continue and cascade during adolescence, and may manifest in novel ways . SociallOne hypothesis posits that due to a lower quality of peer relations and greater experience of peer rejection and victimization in the offline world , adolescOther work notes that social difficulties in adolescents with ADHD in offline and online social situations are generally similar, such that social media is merely a different platform for manifestation of the same problems ,83,84. Sconnectedness of the offline and online social world, such that negative online experiences potentially magnify, transform or cause problems in offline social relationships, and vice versa [Taken together, the findings reviewed here provide evidence that peer relations are at the top of the online priority list for adolescents with ADHD. Current evidence supports the hypothesis of compensating impaired offline social relations by trying to connect with peers online, albeit especially in girls with ADHD. At the same time findings reveal that online peer problems appear to mimic offline peer problems. Importantly, researchers also note the ce versa ,82,83,88While adolescents become increasingly oriented towards peers, parents and the larger family also continue to have a considerable influence on the child’s behaviors (reviewed in ). Here, ADHD is a highly heritable condition, which explains why a disproportionate amount of parents of children with ADHD show elevated ADHD characteristics themselves . ParentsNext, children with ADHD often challenge parenting behaviors. Parents of children with ADHD show fewer positive and more negative parenting behaviors and report greater levels of parenting stress . One paA third and slightly more indirect way to understand the link between ADHD and high intensity/problematic social media use is examining the general family situation. In families of children with ADHD, parent–child relationships are characterized by more negativity relative to families without ADHD , and adoIn the previous sections, we described literature that consistently demonstrated higher levels of problematic social media use in adolescents with ADHD, and provided an integrative framework that encompasses neurobiological and social mechanisms to explain this association. In this section, we provide recommendations for clinicians on how to target these three mechanisms pertaining to social media use when working with adolescents with ADHD  is crucial, as this predicts internalizing as well as externalizing problem behaviors in their children . A qualiSecond, parenting interventions may focus on improving parenting style, given the association between lax parenting and problematic social media use . ResearcBehavioral parent training could also target problematic social media use directly, although evidence for this intervention almost exclusively comes from studies on school-age children. A recent randomized controlled micro-trial on brief personalized parent training showed that several behavioral therapeutic techniques  were effective in reducing problem behaviors that were selected by parents . This deIn the next section, we highlight two related avenues in treatment and research that may be useful future directions in the treatment of problematic social media use in adolescents with ADHD (symptoms). First, characteristics of problematic social media use have much in common with addiction , and interventions that are beneficial to combat other forms of addiction  could also be promising to target problematic social media use. Second, sleep problems and  media use are heavily intertwined, and interventions targeting one of those aspects potentially also impact the other. Although the link between social media and sleep is highly intuitive, there is currently a scarce body of empirical work examining this relation. Indirect indications for the effectiveness of cognitive behavioral therapy (CBT) as intervention for problematic social media use comes from literature on internet/gaming “addiction” ,122,123.Media use in general is associated with sleep problems in children and adolescents, as more screen time is linked to adverse sleep outcomes . Key mecA study investigating adolescents with ADHD found that, on average, they spent 5.31 h on nighttime media use  . MoreoveThe paucity of studies on ADHD, social media use and sleep, as well as the correlational nature of the existing body of work, leave many open questions. First, the studies reviewed above tentatively suggest that excessive social media use could cause sleep problems. The opposite direction is also likely, as sleep problems may cause executive dysfunctioning , which mThis review has several strengths, including an integrative framework that encompasses neurobiological and social components, the connection of theories from research in adolescence and research on ADHD with clinical research, as well as a hands-on list of clinical recommendations. However, several limitations warrant mentioning. First, the current review is a narrative review and our search process was not entirely systematic. However, we do believe that we have included the most recent and relevant findings on ADHD and problematic social media use in adolescence. Second, most of the clinical recommendations are based on indirect associations, as there are hardly any intervention studies directly measuring their impact on problematic social media use. Future research could build on our work and design interventions based on the described mechanisms that target problematic social media use more directly, in order to examine the effects in children and adolescents with ADHD. The evidence summarized in this review shows that adolescents with ADHD (symptoms) are likely to display a high intensity and problematic use of social media. From a neurobiological perspective, we explain the appeal of social media from an imbalance between the development of brain regions involved in reward together with limited cognitive control, especially in the social domain. In the social world of adolescents, we note the connectedness of the offline and online social world of peer relationships, such that negative experiences in one social domain may magnify or change experiences in the other. In the family situation, parents may impact social media use by setting an example with own use, employing parental monitoring techniques and by the transfer of emotions from family conflicts to social media. In our clinical recommendations, we illustrate how existing evidence-based interventions can be utilized to improve social media use, and highlight the need of future research into interventions that may specifically target social media use in adolescents with ADHD.


Adults with ADHD exhibit a neuropsychological profile that may present deficits in many cognitive domains, particularly attention and executive functions (EFs). However, some authors do not consider executive disfunction as an important part of the clinical profile of the syndrome; this could be related to the use of inappropriate neuropsychological tests, probably not adapted and not sufficiently ecological. Moreover, new data are required on specific correlation of attentive-executive symptoms with socio-demographic factors. Therefore, the aim of this study is to analyze the neuropsychological performance of a group of adults with ADHD, also evaluating the influence of gender, age and education level.via a battery of 4 neuropsychological tests and 1 self-administered questionnaire. Gender, age and years of education differences were assessed.We retrospectively collected health-related personal data of 40 adult ADHD patients, clinically diagnosed and evaluated Attention and EFs deficits have been highlighted mainly on the d2-R and 5-point neuropsychological tests, which therefore seem to be more sensitive in measuring the attention-executive dysfunction in an adult ADHD population, than TAP Go/No-go and ROCFT. ADHD patients also manifested subjective behavioral impulsivity disorders on BIS-11. There were no statistically significant gender differences in cognitive performance. On the contrary, younger patients performed worse on subscales TAP Go/No-go errors and 5-points number of drawings, while participants with a higher education level performed better on subscales d2-R speed of execution and d2-R errors. This supports a reduction in the number of errors and the execution time as a function of older age and a higher level of education. Finally, patients with higher education also self-reported greater impulsivity in planning.Our preliminary findings suggest that adult ADHD is not a lifelong stable disorder, but it may change over time. Moreover, attention-executive deficits may be influenced and partially counterbalanced by experience  and a higher level of education. This could underlie the development of specific psycho-behavioral and cognitive compensatory strategies. The use of self-administered questionnaires is therefore recommended to highlight attentional and executive difficulties that may not result in neuropsychological tests. According to the fifth edition of the diagnostic and statistical manual of mental disorders DSM-5; , attentiContrary to what was claimed in previous years, this disorder is not limited to children and adolescents, but for approximately 50% of patients ADHD-related problems persist during adulthood to varying degrees . Based oHowever, some authors do not consider executive dysfunction as an important part of the clinical profile of ADHD syndrome . Part ofAs mentioned above, it could be very challenging to make a correct diagnosis of ADHD by identifying all the behavioral and cognitive facets that describe the specific profile of the patient. Indeed, ADHD is often not detected in time or, even worse, misdiagnosed . MoreoveThe health-related personal data of adult patients (≥ 18 years old), formally diagnosed with ADHD in our institution  were retrospectively collected and included into this case series study, after reporting by the clinicians who made the diagnosis (between February 2019 and May 2022).The diagnosis was made by experienced neuropsychologists and neurologists following the latest guidelines and according to the DSM-5 criteria, also including structured diagnostic interviews  such as the Barkley adult ADHD rating scale-IV ; concurrent major depression at the moment of the neuropsychological evaluation; diagnosis of intellectual disability (IQ < 70); existence of a documented refusal.Finally, the collected data came from a non-medicated group of patients, whom did not take specific ADHD pharmacotherapies such as Methylphenidate or Lisdexamfetamin at the moment of data collection and diagnosis.Data related to neuropsychological assessments performed by ADHD adults have been collected retrospectively. Health-related personal data were collected between February 2019 and May 2022.Cognitive status assessment: The attentive-executive functioning of the patients was explored through a battery of selected and validated tests and questionnaires, which particularly consisted of 4 neuropsychological tests handled by a qualified neuropsychologist and a self-administered questionnaire. The neuropsychological tests used were the d2-R  were collected.Since there was no specific control group in this retrospective case series study, we convert the raw scores obtained by ADHD participants into percentiles, based on the Gaussian distribution curve. This transformation is done using specific correction tables for each test that refer to the standardization of the instrument in the normal Italian population . This procedure includes correction factors such as age, gender and educational level. Following the guidelines of the Swiss Association of Neuropsychologists, percentiles have the advantage of characterizing a performance as pathological (percentile ≤5°), borderline (percentile >5 and ≤16°) or normal (percentile >16°), as a function of specific correction factors for the reference population. Accordingly, the results of each test considered was organized into the categories “Pathological,” “Borderline” and “Normal.” For the assessment of the differences based on socio-demographic characteristics, the categories “Pathological” and “Borderline” were merged and compared to the category “Normal.” This binary classification of the results obtained at psychometric tests has a crucial clinical value for the characterization of the disorders. In fact, a borderline performance in a patient who has no concomitant neurological or psychiatric disorders other than ADHD, is considered equally pathological and therefore symptomatic and specific of ADHD cognitive impairment. Expecting cell counts below 5, gender differences were assessed using the Fisher exact test. Instead, differences regarding age and years of education were assessed using the Mann–Whitney test because of the limited sample size. For the same reason, the statistical significance threshold was set at 10%. All statistical analyses were performed with Stata/IC 16.0 .Forty adult ADHD patients, aged between 18 and 55 years old, were recruited into the study (between February 2019 and May 2022). However, two patients did not give their consent to the re-use of health-related personal data; therefore, the total sample size is 38 participants . The mean age is 28.3 ± 9.7 years old, while the mean number of education years is 11.6 ± 3.1.For clinical reasons there are few missing data on neuropsychological tests , while some BIS-11 self-questionnaires were not completed correctly by several patients . For this reason, the total sample for this scale is N = 27.TAP Go/No-go subscores, ROCFT_copy, d2-R errors, 5-points number of drawings and 5-points errors. Instead, patients were mostly classified as “Pathological” or “Borderline” in the speed of execution and concentration performance subscores of the d2-R test, in the strategies of the 5-points test and in the self-questionnaire BIS-11 .TAP Go/No-go errors and in the 5-points number of drawings were significantly younger than the others . Regarding education, “Pathological” and “Borderline” patients were characterized by a significantly lower number of years of education according to the results of the d2-R speed of execution  and d2-R errors  tests, while the opposite consideration yields for the self-administered questionnaire BIS-11 planning impulsivity .The evaluation of the differences in the test’s results, according to socio-demographic characteristics , did not produce any statistically significant results for gender. Moreover, it should be noted that a small sample size (N = 38) could be correlated to an increase of type II error in the statistical test . On the other hand, contrary, we found 2 significant relationships for age and 3 for years of education. These statistically significant relationships are presented in Accordance with the present literature, many of the adult ADHD patients recruited had attention and processing speed deficits . The d2-Although many studies have shown a gender difference in the attentive-executive functioning of ADHD patients, highlighting predominantly attentional problems in females  and impuThe bivariate analysis also evidenced that higher educated ADHD participants were more rapid and produced less errors in the d2-R test. Additionally, younger ADHD patients did more errors in the Go/No-go subtest of the TAP and produced less drawings on the 5-points test. Subsequently, this highlights that both the level of education and the chronological age influence the attention-executive performance of ADHD adults. It would therefore seem that younger ADHD adult patients have a higher level of impulsivity than older ones, which is reflected in a greater number of errors in the Go/No-go of TAP. Younger patients also manifested more difficulties in strategic planning and monitoring, which is reflected in the fewer number of drawings produced in the 5-point test. Contrariwise, a higher level of education allows adult ADHD patients to be faster and more performing, making even fewer distracting errors and/or omissions in a “scholastic” paper-pencil test such as the d2-R.These new and interesting results are in line with the literature on the subject. In fact, it is well known that the impulsive component in ADHD is more overwhelming in children and adolescents and tends to decrease in adulthood . In thisLimitations of the present study are the restricted sample size and the absence of a control group. Consequently, the interpretation of the results must be made with extreme caution, because some significant relations may be missing (due to the aforementioned type II errors) and also the sample could be not representative of the entire adult ADHD population. Therefore, the discussed findings must be considered as preliminary, to be corroborated with further evidence based on higher sample sizes, in order to ensure their correct generalization. Anyway, even considering the sample size, the highlighted significant relationships between cognitive performance and socio-demographic factor have a good statistical power. Furthermore, the transformation procedure employed to convert raw score into percentiles, based on specific correction tables for each test that refer to the standardization of the instrument in the normal Italian population, allows to compare the performance of our ADHD participants with a specific reference sample, as if this were a generic control group. A further limitation is the small number of tests administered to assess attention and EFs. In particular, it would have been appropriate to use additional tests to differentiate the functioning of reasoning and planning, defined as “cold” EF, from “hot” EF involving emotions . Then, oThis retrospective case series study confirms that in order to correctly test and evaluate the various aspects of EFs, it is necessary to use appropriate neuropsychological tests. In this sense, our results show that the use of ROCFT is not adequate in an adult ADHD population as it is for childhood ADHD. Our findings therefore highlight that to evaluate the planning, strategy and monitoring/updating skills in adult ADHD patients it is necessary to use more suitable neuropsychological tests such as the 5-points test. In addition, our result suggest that it is clinically important to always employ self-administered questionnaires to better evaluate the functional impact on everyday life of inattentive and dysexecutive symptoms. Furthermore, our choice to directly investigate how the cognitive performance of adults with ADHD varies according to specific socio-demographic factors, has allowed us to highlight the possibility that adult ADHD is not a stable disorder, but is constantly changing. Indeed, related attention-executive deficits may be influenced and partially compensated by experience  and a higher level of education. This could underlie the development of specific compensatory strategies that allow ADHD adults to counterbalance, at least in part, the difficulties related to their clinical condition. This aspect must therefore be taken into consideration during the neuropsychological assessment of adult ADHD patients, especially for those who are older and with a higher level of education. In this sense, it seems of fundamental importance to also use self-administered questionnaires, which can help highlight attentional and executive difficulties that may not be so overwhelming on neuropsychological tests, because they are globally compensated by specific psycho-behavioral and cognitive strategies.From this perspective, it would be particularly interesting to re-evaluate ADHD adults over the years, observing possible changes in the cognitive performance. Further investigations involving a specific control group and a larger cohort of non-medicated patients, to avoid possible effects related to the use of pharmacotherapy over time, could accordingly lead to more powerful and generalizable results. Moreover, it would be relevant to link neuropsychological performances of ADHD adults with specific data of functional brain imagery, to verify if the cognitive changes are linked to neural modulations or if they are simply the result of behavioral and cognitive strategies implemented by patients over the years. This would bring new evidence to complement the review of Finally, following the meta-analysis of The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Cantonal Ethics Committee, Repubblica e Cantone Ticino (project-ID 2022-01085 CE 4122). The patients/participants provided their written informed consent to participate in this study.MC conceptualized, designed and supervised the whole study, revised and corrected the raw data of the participants and drafted the manuscript. GZ, EB, and SR evaluated and screened patients and also collected data. ES performed the statistical analysis and wrote part of the method and the results. AI reviewed the final version of the manuscript and collaborated to the submission. LM designed the study, reviewed the final version and submitted the manuscript. LS conceptualized, designed and supervised the whole study, wrote part of the manuscript and reviewed the final version. All authors read and accepted the final version of the paper and reported above for publication was completed and contributed to the article and approved the submitted version.Open access funding was provided by the Università Della Svizzera Italiana.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Understanding the influence of surfactants on the assembly of peptides has a considerable practical motivation. In this paper, we systematically study the anionic surfactant-assisted assembly of diphenylalanine (FF). FF forms broom-like structures in a concentration of sodium cholate (NaC) around the CMC, and assembles into linear and unidirectional rods in the presence of low and high surfactant concentrations. FF’s improved hydrogen bonding and controlled assembly rates are appropriate for other anionic surfactants. At this stage, the use of FF as the simplest protein consequence can be helpful in the investigation of further protein–surfactant interactions. Natural and spontaneous self-organized amyloid fibril assemblies have encouraged the study of peptides as bio-supramolecular structural building blocks ,2,3. TheMultiple strategies have been successfully used for the assembly of peptides, such as solvent-induced, sonication-assisted, ionic, vaporization-induced, coordination-assisted, and surfactant-assisted assembly, as well as organic or water gelation, etc. ,30,31,32Although previous reports focused on the organization of the various FF structures, the influence of surfactants on FF-assembly remains unknown, and exerting control over FF-assembly is still very important. Therefore, in this study, we analyzed the interactions between FF and surfactants by studying the microstructures of FF assembly in the presence of different surfactants. We started by examining an anionic surfactant sodium cholate (NaC). Then, we studied other anionic and cationic surfactants. The appropriate concentrations of anionic surfactants assisted FF’s assembly into a broom-like structure. We also proposed a hypothesis to explain the interactions between surfactants and peptides.FF can self-assemble into hexagonal crystalline microtubes and microrods in water . Here, wWe performed optical microscopy observations in an aqueous solution to show the morphologies of the assembled aggregates above the fixed FF concentration of 10 mmol/L . The micThen, we increased the concentration of FF with a fixed NaC at 10 mmol/L. When the FF is above 30 mmol/L, the aggregates assemble smaller 20–50 μm-long broom-like crystals . The broIn addition, we probed the thermal stability by thermogravimetric analysis (TGA). We present the thermal degradation curves of pure FF, pure NaC, and mixtures before and after filtration in −1 and 1602 cm−1, respectively, confirming the β-sheet secondary structures of the FF rods. The XRD spectra of the FF rods with or without NaC share the same sharp peaks, indicating the same hexagonal structure of the FF microrods [We performed Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) to illustrate the effects of NaC on the secondary structures and molecular interactions of this system. The spectra are shown in icrorods . HoweverWe analyzed more anionic surfactants such as sodium dodecyl sulphate, dodecyl sodium sulfonate, and sodium deoxycholate . It turnThe typical nucleation and growth scenario is appropriate for this system. Nucleation starts when the FF concentration exceeds supersaturation and the nucleation barrier is crossed. Next is the aggregation of nuclei and the growth process. With a pure FF/water system, the FF molecules aggregate near the nuclei and support the growth of long microrods. Hydrogen bonding is a key force, and water mediation is necessary in order for FF to grow microrods ,40,41. WFF and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were bought from Sigma-Aldrich. All the surfactants were sodium dodecyl sulphate, dodecyl sodium sulfonate, and sodium deoxycholate. The cetyl trimethyl ammonium bromide (CTAB), tetradecyl trimethyl ammonicum bromide (TTAB), and cetanecyl trimethyl ammonium chloride (CTAC) were bought from the Aladdin company, with a purity of 95–98%.All of the samples were prepared as follows: a freshly prepared FF/HFIP solution  was diluted to a final FF concentration of 10 mmol/L by oscillating after adding different surfactant solutions. Then, all of the samples were freeze-dried for the next characterizations.The optical microscope  measurements were taken with the solution or the dried fibers on the glass slides.Scanning electron microscope (SEM) measurements were taken on JEOL JSM6700F or Hitachi S-4800 field-emission scanning electron microscopes. The samples with the gold coating were transferred onto the microscope stage and examined at 10 kV.The transmission electron microscopy (TEM) images were obtained on a JEOL JEM-1400 transmission electron microscope (120 kV). A drop of the dispersed solution of the samples was dropped onto a TEM grid (a copper grid with a 200 mesh) and then dried for observation. Images were recorded with a Gatan multiscan charge-coupled device (CCD) for the collection and processing of digital micrographs. −1 over 50–800 °C under a nitrogen atmosphere.Thermogravimetric analysis (TGA) measurements were performed at DSC 822e  with a scanning speed of 10 °C·minFourier transform infrared (FTIR) spectra were carried out on a VERTEX-70/70v FT-IR spectrometer  using a KBr pellet method.−1.X-ray diffraction (XRD) measurements were completed on a DMAX-2500PC diffractometer with Cu Kα radiation (λ = 0.15418 nm) and a graphite monochromator. Samples were examined within 1–30° in the 2θ mode at a speed of 1° minIn conclusion, we have studied the effects of surfactants on the assembly of FF. The anionic surfactants have a considerable influence on the forms taken by FF—from long, linear rods to broom-like structures—by modulating the surfactant concentration around its CMC. The broom-like structures became smaller and more unified when the FF concentration increased. These effects are mainly influenced by the hydrogen between the carboxylate ions of anionic surfactants and the carboxy groups of FF molecules. Moreover, narrow spaces affected the FF assembly rate due to plenty of micelles being formed. Our findings should be useful for understanding the interactions between surfactants and peptides, and for the provision of further insight into biological amphiphile–protein interactions.