Introduction: POLD2 is an indispensable subunit of DNA polymerase δ, which is responsible for the synthesis of the backward accompanying strand in eukaryotic organisms. Current studies have found an association between POLD2 and the development of a variety of cancers. However, its value in cancer immunotherapy has not been fully established.Methods: POLD2 expression was analyzed using RNA expression and clinical data from TCGA and GTEx databases. The prognostic impact of POLD2 on tumor patients was analyzed using clinical survival data from TCGA. Gene enrichment analysis was performed using the R package “cluster analyzer” to explore the role of POLD2. We used the TIMER2 database to analyze the relationship between immune cell infiltration and POLD2 expression in TCGA. We downloaded relevant data from TCGA and analyzed the relationship between POLD2 and immune checkpoints, immunosuppressive genes, immune activating genes, chemokines and chemokine receptors.Results: POLD2 was significantly overexpressed in most tumors compared to normal tissue. High POLD2 expression was significantly associated with advanced tumor stage, significantly shorter overall survival and progression-free survival. Also, we found that POLD2 expression correlated strongly with immunomodulatory genes, and significantly negatively with most immune checkpoints . Pathway enrichment analysis suggests that low expression of POLD2 promotes immune regulation-related pathways and high expression promotes metabolic and DNA repair-related pathways. Furthermore, tumor microenvironment analysis suggests that high POLD2 expression inhibits infiltration of CD8+ T cells and CD4+ memory T cells.Discussion: In conclusion, POLD2 may be a molecular biomarker for pan-cancer prognosis and immunotherapy. It may serve as a potential target for new insights in human tumor prognosis prediction and immunotherapy assessment. POLD2 (DNA Polymerase Delta 2) is a subunit of the DNA polymerase delta (DNA Pol δ) complex, the major replication enzyme in eukaryotic chromosomal DNA replication, involved in DNA replication and many forms of DNA damage repair processes. POLD2 interacts with the other three subunits to form a scaffold for the assembly of DNA Pol δ, maintaining the stability and function of the complex. . MeanwhiPOLD2 may be the promoter of chromosomal translocations. When chromosomal translocations occur, normal proto-oncogenes are transformed into oncogenes that cause malignant transformation of cells, that is why we believe that POLD2 has the potential to act as a cancer marker. High expression of the POLD2 gene is associated with low overall survival in patients with uroepithelial carcinoma of the bladder and may affect the overall survival of patients by inhibiting the pro-apoptotic effects of chemotherapy . In humaIn addition, we have found that POLD2 plays an important role in immunity. In some patients, POLD2 has a homozygous missense mutation, which affects the stability and enzymatic activity of DNA polymerase δ complex  Sánchez. We learThis article focuses on the potential of POLD2 in tumor immunotherapy. The article investigated the expression levels of POLD2 in different cancers and examined the potential impact of POLD2 in the tumor microenvironment. In addition, the article investigates the correlation of POLD2 with immunomodulatory genes and immune marker sets, such as tumor mutation burden (TMB) and microsatellite instability (MSI). Overall, this work provides evidence to elucidate the immunotherapeutic role of POLD2 in cancer and contributes to further functional experimental studies of cancer therapy.https://www.cbioportal.org/) and ensured that the acquisition and application methods were consistent with relevant guidelines and regulations. To verify the prediction value of POLD2 in immunotherapy response, gene expression data and clinical data of GSE78220, IMvigor210, and GSE67501, which are the immunotherapy cohort of metastatic melanoma, uroepithelial carcinoma and renal cell carcinoma, were downloaded from the Gene Expression Omnibus (GEO) database.We downloaded RNA expression and clinical data for The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) from the UCSC-XENAdatabase . These dIn the TCGA project, the TIMER2 database was used to assess the correlation between POLD2 expression and tumor immune infiltration . We usedCorrelation analysis of POLD2 was performed for all genes using TCGA data. We calculated the correlation coefficients and selected the genes associated with POLD2 for gene set enrichment analysis (GSEA). GSEA was performed using the R package “clusterProfiler” to obtain gene KEGG pathway analysis and HALLMARK analysis .p < 0.05 was a significant statistical result.We used TCGA data to analyze the correlation between POLD2 and immune regulation. The correlation between POLD2 expression and immune activation genes, immune suppression genes, chemokines and chemokine receptors was presented by heat map. Univariate Cox regression analysis and Kaplan-Meier mapper  allows tp values determined by t-tests. Kaplan-Meier survival curves were used to assess the correlation between POLD2 and prognosis. Spearman correlation test was used to assess the correlation between POLD2 expression and targets of study, including tumor mutation burden (TMB) and microsatellite instability (MSI). All statistical p values were two-sided with p < 0.05 denoting statistical significance.We will present the data in the form of mean ± standard error (SD). POLD2 mRNA expression values from different datasets were used to create low and high POLD2 expression groups based on p < 0.05). Considering the small number of paracancerous tissue samples in the TCGA database, we included normal samples from the GTEx database for comparative analysis. The results showed that the expression of POLD2 was significantly increased in ACC, BLCA, BRCA, CESC, CHOL, COAD, ESCA, GBM, HNSC, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, OV, PAAD, PRAD, READ, SKCM, STAD, TGCT, UCEC, and UCS . These results indicate that the high expression of POLD2 may have a negative impact on the prognosis of cancer. In addition, through univariate COX analysis: OS results show that POLD2 is a risk factor for ACC, BLCA, COAD, HNSC, KICH, LGG, LIHC, LUAD, MESO, SARC, and THCA patients, and a protective factor for DLBC, ESCA, KIRP, OV, and PAAD patients . T cell.CD8. Is negatively correlated with POLD2 expression in tumors (p < 0.05). T cell.CD4.memory.resting is negatively correlated with POLD2 expression in tumors (p < 0.05).We use the ESTIMATE algorithm to evaluate the expression of POLD2 in the tumor microenvironment through the TIMER database. It was found that in ACC, BRCA, CESC, COAD, DLBC, ESCA, GBM, HNSC, KICH, KIRC, LAML, LIHC, LUAD, LUSC, OV, PAAD, PRAD, SKCM, STAD, TGCT, THCA, UCEC, and POLD2 is negatively correlated with ImmuneScore (p < 0.05), this indicates that the high expression of POLD2 plays an important role in mediating immune evasion. After that, we used the expression of POLD2 in TCGA to analyze MSI and TMB, respectively (p < 0.05), while POLD2 was positively correlated with TMB in STAD, SKCM, SARC, PRAD, PAAD, MESO, LUSC, LUAD, LIHC, LGG, KIRC, KICH, HNSC, GBM, and BRCA (p < 0.05). And POLD2 is negatively correlated with MSI in SARC(p < 0.05), and POLD2 is positively correlated with MSI in UCEC, STAD, SARC, PAAD, OV, LUSC, LIHC, KIRC, and HNSC(p < 0.05). This indicates that POLD2 may be used as a new tumor marker.Immune monitoring and immune escape are of great significance to the survival of cancer patients. Cancer cells can use immune checkpoint genes to evade immune surveillance. By examining the relationship between POLD2 and immune checkpoint genes , we founectively . We founp < 0.05). In the analysis of 23 immunosuppressive genes (p < 0.05). The results indicate that POLD2 may cause immunosuppression. In addition, we also studied the correlation between the expression of POLD2 and chemokines and their receptor genes (p < 0.05). The expression of chemokines CCL4, CXCL16, CCL23, CXCL12, CCL16, and CCL14 was negatively correlated with the expression of POLD2 (p < 0.05). In most cancers, most chemokine receptors are negatively correlated with the expression of POLD2 (p < 0.05).We researched the correlation of 46 immune activation genes with POLD2 in pan-cancer . In mostve genes , PVRL2 wor genes . The resp < 0.05). This indicates that POLD2 may cause the loss of the function of key genes in the mismatch repair mechanism in the cell, resulting in DNA replication errors that cannot be repaired, leading to higher somatic mutations, and ultimately leading to the occurrence of tumors.Here we use the expression profile data of TCGA to evaluate 5 MMRs genes: the relationship between MLH1, MSH2, MSH6, PMS2, and EPCAM mutations and the expression of POLD2 . We founp < 0.05). It can be seen that the high expression of POLD2 is related to tumor occurrence and poor prognosis. We made a functional judgment on POLD2. The results showed that POLD2 was positively correlated with proliferation and cellcycle in LUAD (p < 0.05). POLD2 was positively correlated with DNArepair in BRCA (p < 0.05). POLD2 was negatively correlated with DNAdamage, quiescence and apoptosis in UM (p < 0.05).We used GSEA to identify the functional enrichment of high expression of POLD2 and low expression of POLD2 . The resp = 0.033, p = 0.0014, p = 0.93, The correlation between POLD2 expression and ICB response was validated by analyzing data from the immunotherapy cohort of uroepithelial carcinoma (IMvigor210). Significant differences were found in POLD2 expression in patients with different efficacies. POLD2 was highly expressed in patients with respond by analyzing the data from GSE78220 (We extract 20 genes closely related to POLD2 expression for PPI network analysis. There are 20 points in the network, and there are 5 proteins interacting with POLD2 .via the FAK/AKT signal pathway (POLD2 is a subunit of the DNA polymerase delta complex, which encodes a protein involved in DNA replication and repair . Many re pathway . In addi pathway . Moreove pathway . DespiteIn this study, comparing the normal tissues, we analyzed the expression of POLD2 in various tumors in TGCA and the relationship between abnormal expression and prognosis. It was found that compared with the neighboring normal tissues, POLD2 was significantly overexpressed in a variety of tumors. In addition, survival analysis showed that the overexpression of POLD2 was poorly correlated with OS and DSS, while analyzing the survival curve of patients, it was found that the high expression of POLD2 was correlated with the lower survival rate of patients. And as the cancer stage progresses, the expression of POLD2 shows an upward trend in most cancers. These indicate that the high expression of POLD2 is associated with the poor prognosis of cancer patients, and it may result in a lower survival rate of patients.In the normal body, the immune system performs an immune surveillance function, which can identify and eliminate abnormal cells in the body. Nonetheless, tumors may evade the immune system through different mechanisms, leading to further growth and invasion. For instance, cancer cells can use immune checkpoint genes such as PD-1 and CTLA-4 to evade immune surveillance. We examined the relationship between POLD2 expression and immune checkpoint genes, and then further analyzed the correlation with the degree of immune infiltration in human cancers. And it was found that high POLD2 expression plays an important role in mediating the immune escape of many tumors. MSI is a major predictive biomarker for the efficacy of immune checkpoint inhibitors , and TMBFurthermore, POLD2 plays a vital role in the occurrence and development of tumors. In our study, pathway enrichment analysis demonstrated that the high expression of POLD2 is associated with abnormal pyrimidine and purine metabolism, which play a vital role in the occurrence and development of cancer in the early stage . At the Although having explored and integrated information from various databases, we acknowledge that our research has certain limitations. First of all, though we have obtained some meaningful insights into POLD2 in human cancer from data mining, it will be beneficial to clinical applicability if these findings are verified by cell or animal experiments. In addition, more clinical trials are needed to verify the immune checkpoint function of POLD2.In summary, the results of the present study clarify the strong correlation between POLD2 expression and the prognosis of various cancers. Since POLD2 is overexpressed in a variety of human cancers and is associated with worse survival, it may serve as a potential target for cancer management. Furthermore, our research provides insights into the underlying mechanism by which POLD2 overexpression may regulate tumor immunity. In the future, more basic and clinical researches based on POLD2 and tumor microenvironment may help us to optimize the clinical strategy of cancer treatment.In this study, a pan-cancer analysis of POLD2 was performed, and the results showed that the upregulation of POLD2 expression is associated with the poor prognosis of many tumors. Furthermore, POLD2 is also involved in tumor immune escape, which may be used as an immune checkpoint for cancer treatment. Our research showed that POLD2 is a potential prognostic biomarker, which can be used for clinical tumor prognosis prediction and immunotherapy assessment.


The continuous performance task (CPT) may help identify coexistent attention deficit hyperactivity disorder (ADHD) in autism spectrum disorder (ASD). The Quantified behavior Test (QbTest) combines a CPT and motion-tracking data to assess ADHD symptoms. This study aimed to evaluate the QbTest performance of children and adolescents with ASD plus ADHD, including estimating the effects of single-dose methylphenidate (MPH). To achieve these aims, (1) the QbTest performances were evaluated in ASD alone, ASD plus ADHD, and ADHD alone, and (2) the effects on the QbTest performance of single-dose MPH before and after intake were estimated across the groups. It was assumed that the ASD plus ADHD performance, including the MPH response, would preferably resemble the performance in ADHD alone, rather than ASD alone.Retrospective data were analyzed for 482 children and adolescents: 69 with ASD alone, 142 with ASD plus ADHD (ASD/ADHD), and 271 with ADHD alone. For 343 subjects, the QbTest was performed before and up to four hours after a single-dose MPH intake. A summary index of the CPT and motion-capture data was provided for QbTest cardinal parameters.p > 0.05); the lowest scores in ASD and the highest in ADHD. Those with ASD/ADHD and ADHD had similar QbActivity and QbImpulsivity scores, but significantly higher than those with ASD. After MPH intake, scores for QbActivity decreased similarly in ASD/ADHD and ADHD, as well as scores for QbImpulsivity. QbImpulsivity increased in ASD. QbInattention scores decreased similarly in all groups after MPH intake.Of 12 QbTest parameters assessed before given MPH, the ASD/ADHD group had scores in line with the ASD group regarding four parameters and the ADHD group regarding nine parameters. Significant differences between groups were seen with respect to QbInattention (Children and adolescents with ASD plus ADHD exhibited more atypical QbTest performances than those with ASD alone, while most of their performances were similar to those observed in ADHD alone. In addition, a single dose of MPH mitigated attention deficits and decreased hyperactivity while improved impulsivity in these children. Prospective studies should further clarify the role of the QbTest in the diagnostic and therapeutic interventions in ASD with ADHD. Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are distinguished neurodevelopmental conditions in the current classification systems , 2. BothOver the past two decades, epidemiological, clinical, genetic, neuropsychological, and neuroimaging studies have generated increasing evidence for commonalities between ASD and ADHD –10. In 2Objective measures for assessing neurocognitive aspects, like sustained and selective attention, information processing, abstract concept formation, or complex problem-solving abilities, may play a role in increasing diagnostic accuracy and optimizing treatment response in ADHD e.g., , 18). In. In18]).Over the past 15 years, evidence has emerged for the effects of stimulant medications on CPT performance in children with ADHD  approved by the United States Food and Drug Administration (FDA) to supplement the standard clinical assessment and evaluation of treatment interventions in ADHD   is a comD e.g., , 39–41).–41.www.qD e.g., , 42), al, alwww.qD  referred at a child and adolescent psychiatry clinic in one of a few general hospitals located in western Sweden during the period 1 January 2004 to 31 December 2017. All children with a suspected neurodevelopmental disorder presented at the clinic went through a diagnostic process according to the clinic’s standard diagnostic procedure. Although data were not available, it was likely that all children referred to the clinic due to some ADHD symptoms were assessed with the QbTest, irrespective of later being assigned a neurodevelopmental, behavioral, or mental disorder diagnosis. In addition, children with ASD were likely suspected or there were reports of attention deficits, irrespective of the diagnosis of ADHD, considering that those with ASD who received MPH had more atypical QbTest scores than those who did not (see below).The current study involved a retrospective chart review of the data of children and adolescents  = 1.60 (2), p = 0.45), but a statistically significant difference was found regarding age distribution, (F (df) = 3.74 (2), p = 0.02). Among the children in both groups (ASD and ASD/ADHD) who had ASD, 72 (34.1%) had been previously diagnosed with Asperger’s disorder or high functioning autism, 15 (7.1%) with a pervasive developmental disorder (PDD) not otherwise specified (NOS), and 124 (58.8) with autism. In addition, 55 (26.1%) had some speech/language, learning, and/or motor difficulties. In the present study, we equated autism, Asperger’s syndrome, and PDD NOS with ASD. Among children with ASD, three (4.3%) received psychotropic medications other than MPH, while among children with ASD/ADHD, nine (6.3%) were drug-naïve, two (1.4%) received psychotropic medications other than MPH, and six (4.2%) were already treated with stimulants. In the ADHD group: 26 (9.6%) children also had some speech/language, learning, and/or motor difficulties. In the ADHD group, 15 (5.5%) children were drug-naïve, six (2.2%) received psychotropic medications other than MPH, and 10 (3.7%) were already treated with stimulants. For the remainder of the whole sample, regardless of whether a diagnosis had been assigned, no data were available regarding previous or current psychopharmacological treatments. Irrespective of possible previous or current psychopharmacological treatments, QbTest scores before MPH given on the testing day were analyzed for the study's first aim.Based on the above inclusion/exclusion criteria, the following 482 children were included: 69 children with ASD (mean age 13.78 (3.09) years; 49 (71%) males), 142 children with ASD and co-occurring ADHD  years; 89 (62.7%) males), and 271 children with ADHD (mean age 12.63 (3.26) years; 172 (63.5%) males). The ADHD group included children with ADHD from a previous QbTest study . There wp < 0.01), but not for the QbActivity (p = 0.05) and the QbImpulsivity (p = 0.09) compared with those not receiving MPH. For the ASD/ADHD and ADHD group, children receiving MPH had significantly higher scores for the QbActivity, QbImpulsivity, and QbInattention (p < 0.01) before MPH was given, compared with those not receiving MPH.In line with the second aim, separate analyses were conducted that included a subgroup of children with ASD, ASD/ADHD, or ADHD who underwent the QbTest assessment twice on the same day. Once the baseline testing had been completed, the children were given a single dose of MPH. Up to four hours after MPH intake, the children were again tested with the QbTest . Data for 28 children with ASD, 95 with ASD/ADHD, and 220 with ADHD were available for both pre- and post-MPH assessments Table . Conside2]), and micro-events , while QbInattention and QbImpulsivity includes CPT data, like omission errors , reaction time and reaction time variation (in milliseconds [ms]), or commission errors . However, not all parameters have the same weight in these cardinal parameters  ) values for the QbTest parameters of the three groups are presented in Table p > 0.05); the ASD group had the lowest, and the ADHD group the highest scores. The ASD/ADHD and the ADHD groups had similar QbActivity and QbImpulsivity scores and significantly higher than the ASD group.The mean (standard deviation [p = 0.57). Cohen’s d effect sizes were small to large (see Table The mean (SD) values for the QbTest scores before and after given MPH (pre-/post-MPH) are presented in Table In the present study was evaluated the QbTest performance among children with ASD and co-occurring ADHD, as compared to those with ASD or with ADHD alone, and the effects of single-dose MPH on that performance was also assessed.Considering the QbTest parameters for attention, children in the ASD group and in the ASD/ADHD group had similar reaction times and reaction time variations, but lower compared to the children in the ADHD group. At the same time, those with ASD/ADHD exhibited more omission errors compared to those with ASD, but similar compared to the ADHD group. The QbInattention data, revealed that children with ASD/ADHD had more overall attention deficits than those with ASD alone, and fewer than those with ADHD alone. Several previous studies reported that children with ASD/ADHD make more omission errors and exhibit increased reaction time variability than children with ASD and/or controls , 47–49. Considering the QbTest parameters for impulsivity, children with ASD/ADHD had similar numbers of commission errors as the children with ASD and ADHD, respectively. QbImpulsivity scores, were similar between children with ASD/ADHD and ADHD, but higher than among the children with ASD. Findings from previous studies are partially consistent with ours; two papers reported that children with ASD/ADHD had similar commission errors compared to typically developing youths , 52, whiRegarding the QbTest parameters for activity, children with ASD/ADHD had more atypical scores than children with ASD. Still, scores were poor as were for children with ADHD. This pattern implies that children with ASD/ADHD were more hyperactive than children with ASD, but similarly to those with ADHD. In this regard, hyperactivity traits as quantified by the QbTest, could be a marker to differentiate ASD with co-occurring ADHD from ASD alone. It has previously been suggested that QbTest could be used to differentiate children with ADHD from their unaffected siblings or unrelated controls .After a single dose of MPH, children with ASD/ADHD and children with ADHD improved on all QbTest parameters, but the improvement had small clinical relevance for measures of impulsivity . The children with ASD, on the other hand, did not significantly improve in commission errors and deteriorated significantly in the QbImpulsivity parameter, although simultaneously improving clinically relevant on the other QbTest parameters. Comparing how much the pre-test scores changed after the administration of a single dose of MPH, there was a similar improvement regarding deficits in two measures of attention , as well as the QbInattention parameter among the children with ASD, ASD/ADHD, and ADHD. Therefore, a single-dose MPH does likely improve attention deficits regardless of the disorder. Commission errors, as an impulsivity parameter, also improved similarly across the groups. However, the QbImpulsivity parameter showed deterioration in children with ASD. Conversely, this parameter exhibited similar improvements in the children with ASD/ADHD and ADHD after a single dose of MPH. We have previously observed that a single MPH dose can worsen impulsivity, especially in adolescents with ADHD . Peled, The present study has several limitations. First, the study was based on chart reviews and the reliability of the data could be questioned. Second, it was not available how it was decided to perform the QbTest, irrespective of later being assigned any neurodevelopmental diagnosis, behavioral, or mental disorder to a child. This is particularly relevant considering that those who received MPH had more atypical QbTest scores, and in the ASD/ADHD group more children had predominant attention deficits than in the ADHD group, which could bias the results. Third, the diagnostic procedures at the clinics have likely changed over time and diagnostic criteria used. Since this was a retrospective study using clinical data, one must expect that the clinicians may not have been blinded to the results of the QbTest. Accordingly, their diagnostic and therapeutic decisions may have been influenced, which imposes the possibility of bias. However, the fact that the results represent a non-selected clinical sample is the study's strength. Fourth, the data on concurrent psychopharmacological treatments at the time of assessment was incomplete, and only a small number of subjects could be classified as drug-naïve. Different doses of MPH were given during the QbTest, without communicating the rationale for this decision. Fifth, intellectual functioning can affect CPT performance , and theChildren with ASD and co-occurring ADHD exhibited more atypical QbTest performances than children with ASD. However, most of their QbTest patterns were similar to those observed in children with ADHD. Regarding the cardinal QbTest parameters, children with ASD/ADHD had more attention deficits, higher activity levels, and greater impulsivity than children with ASD. Children with ASD/ADHD had lower attention deficits but similar activity and impulsivity levels compared with those with ADHD. A single dose of MPH mitigated the deficits in attention in children with ASD/ADHD, in line with the children in the ASD and ADHD groups. MPH also improved impulsivity and decreased motor activity similarly in the ASD/ADHD and the ADHD groups. The results of our study indicate that combining a CPT with motion analysis could help differentiate ASD and ASD with ADHD in clinical practice and could provide additional information on immediate responses to MPH in these children. Considering the study's limitations, our results call for further prospective studies to confirm the role of the QbTest in the diagnostic process in children with symptoms of ASD and ADHD and during the evaluation of MPH response.


From clinical experience, majority of patients in adult forensic services who have childhood diagnosis of ADHD self-report onset of substance misuse around the age of 12.Aim of the study was to explore if routine screening of childhood substance use is considered by ADHD diagnostic services.PsycINFO and Embase databases were searched with the keywords: Attention Deficit Hyperactivity Disorder, ADHD, primary care/general practice, family physicians ,paediatrics, and children/adolescents, child and adolescent psychiatry, diagnostic assessments, substance / drug use, prescription drugs and drug screening.24 articles were retrieved for age groups 12 to 17 years. Studies identified substance misuse as highly comorbid with ADHD but more so in conduct disorder. Studies identified diversion risk in adolescents.Both ADHD and amphetamine misuse disorders are Axis 1 disorders . Literature links substance misuse in ADHD to conduct disorder. There needs to be research into the diagnostic overlap between conduct disorder and ADHD and how this fits into the trauma model of adult offender treatment pathways. Treatment pathways for ADHD or conduct disorder and childhood onset substance misuse disorder are not clear both in primary or secondary care. Literature appears to put emphasis on early diagnosis and prescription stimulant treatment outside the social and psychological context and cites outcomes of the short term studies as reason for continued prescriptions in adolescence and beyond. There is need for studies exploring perspectives and trajectories of amphetamine use in adults who were diagnosed with ADHD in childhood, adolescence and as adults.No significant relationships.


The Covid-19 pandemic has led to huge disruptions and multi-domain healthcare crisis, with additional impact on children and young people (CYP) affected by Attention Deficit and Hyperactivity Disorder (ADHD).We conducted an online survey and obtained responses from 62 Paediatricians who provide ADHD services for CYP about their experience of Service disruption and adaptations during the first Covid-19 lockdown in the United Kingdom between March and June 2020. The responses were both quantitative and qualitative.The Paediatricians reported huge service disruptions such that almost half ceased the assessment of new patients with ADHD, and only 5% were able to offer physical monitoring for most patients. However, all respondents had adopted telemedicine, which allowed them to maintain high levels of non-physical service provision for existing patients. The Paediatricians used risk stratification strategies to determine which patients were more likely to benefit from the limited available face to face appointments for physical monitoring. The Paediatricians demonstrated clinical pragmatism to meet the needs of their patients such as starting medication without physical exam especially if the patient's behaviour was so challenging that it was presenting a crisis at home, and setting aside monthly limits for stimulant medications. Some respondents reported helpful cross-service collaborations to support CYP with ADHD and their families.The Covid-19 pandemic has had adverse effect on many CYP with ADHD and caused huge disruption to the ADHD services that support them. As the pandemic continues to cause disruptions to ADHD services, the service adaptations emerging from the literature including some of those identified in this study could be useful to support more stable and sustainable ADHD services, both during and after the pandemic. This is to ensure that affected persons continue to access adequate ADHD-related care; which could reduce their risk of Covid-19 infection. Unfortunately, ADHD services were not spared by the massive disruption engendered by the pandemic and related lockdowns Recognising the potential protective role of ADHD treatment in reducing the risk of Covid-19 infection transmission th wave of Covid 19 infection and were re-introducing restrictions due to the rapid spread of the Omicron variant. Thus, there continues to be a need to reflect on the strategies to support ADHD services for providing sustainable care for CYP with ADHD while the pandemic continues. Some of the adjustments and lessons learnt will remain useful after the pandemic and help to inform future service adaptions due to as yet unknown challenges such as a new pandemic. The current study explored the Covid-19 pandemic experiences of United Kingdom (UK)-based Paediatricians who assess and treat CYP with ADHD. We sought the Paediatricians' views on Service disruptions and the adjustments they made during the first Covid-19 lockdown in the UK between March and June 2020. The findings of the study add to the increasing pool of studies helping to shape practice in the management of ADHD during the continuing Covid-19 pandemic and beyond.Two years into the pandemic, service disruptions continue to be caused by Covid-19. At the time of writing this paper, many countries were in their 42.An online custom-designed questionnaire was developed by two Consultant Neuro-developmental Paediatricians with further input from a Consultant Child and Adolescent Psychiatrist. The questionnaire included structured and open-ended questions related to practice during the first Covid-19 pandemic lockdown in United Kingdom between March and June 2020. The structured questions were: experience of redeployment to other clinical areas to support Covid-19 patients; proportion of new and follow-up patients seen for face to face and or remote consultations; proportion of follow-up patients having their height, weight and Blood Pressure monitored according to UK guidelines; experience of starting, titrating or changing medications with or without recent physical measurements; awareness of specific pandemic-related guidelines for ADHD management; forms of telemedicine or digital technology being used for patient consultation; other modifications or flexibilities introduced to usual clinical practice; use of non-pharmacologic support strategies, and involvement of other staff in supporting ADHD management. Each closed question was followed by an open-ended question which invited participants to provide free-text qualitative comments to contextualise their responses to the closed question. The survey was approved by the Executive committee of the George-Still Forum (GSF), which is a UK-wide ADHD Clinical Network whose membership consists of mainly Neurodevelopmental Paediatricians. Links to the survey were emailed to all the delegates who attended the GSF annual scientific meeting in 2019 and provided consent to be contacted. The survey ran between June and July 2020. Responses to structured questions are presented in the results as proportions. We applied reflexive thematic content analysis 3.A total of 62 responses were received out of 115 delegates who attended the last GSF annual scientific conference in 2019 who were sent the survey link by email. This represents 54% response rate. Most of the respondents (62%) were not redeployed from their main clinical roles to support Covid-19 patients. Consistent with the prevailing pandemic-induced change in service delivery, all respondents had adopted remote service provision, of which the most common was by telephone (98%). Report of service disruption was most pronounced for new ADHD referrals as almost half of respondents (47%) ceased service provision for this cohort and only 28% were able to maintain services for most of their new referrals. Conversely, service provision remained high for existing patients requiring non-physical ADHD follow-up appointments. For the latter cohort, 65% of respondents were still offering services to most patients, and only 16% interrupted their service provision.The respondents' qualitative comments provided further insights into these altered service arrangements. For example, some respondents pointed out that they ceased new ADHD assessments because the simultaneous closure of schools meant that the collateral information required for completion of new ADHD assessments was not available. Others noted that where the collateral information was already available, they were able to proceed with new ADHD assessment through remote sessions. Similarly, some respondents felt able to remotely initiate medications for patients newly diagnosed with ADHD if the patient had already had normal physical exam prior to the lockdown.th centile, those on the upper ceiling of the normal range of medications , patients who had had home measurements that were outside normal limits, or those with other presentations considered to require urgent face to face clinical review.The physical monitoring required for ADHD management was severely interrupted such that only 5% of respondents reported being able to obtain measurements for most of their patients. Where physical monitoring occurred, most still occurred in specialist centres (25%), while others took place at home (13%), or in primary care (10%). Qualitative comments indicated that clinicians used risk stratification strategy to determine the patients most likely to benefit from the limited available face to face appointments for physical monitoring. In this context, respondents prioritised face-to-face monitoring for: patients with pre-existing concern about their physical well-being such as weight already below 9The disruption of face-to-face clinical contact and difficulty with obtaining physical measurements led some respondents to adopt more cautionary approaches to ADHD clinical work. Qualitative comments highlighted two such cautions: not to initiate new medications especially when baseline physical investigation was not possible, and avoiding changes to the dose of existing medication unless the patient was well known and had a trend from past physical measurements that was in the normal range.Some of the participants were aware of the European ADHD Guidelines Group Covid-19 recommendation The respondents reported how the alterations in clinical service provision during the pandemic led to promotion of self-reliance among families. The respondents indicated that at the beginning of the pandemic, many families were not able to check weight, height, blood pressure and height at home but the proportion increased during the lockdown. In some cases, specialist services sourced the equipment for families while clinicians provided written or live guidance on their appropriate use. Many families preferred home measurements due to worry about exposure to Covid-19 if they came to the clinic. Some respondents rationalised which measurements families needed to focus on. For example, some advised less focus on height because, in their experience, once yearly height measurements can be adequate.Similarly, some respondents reported some helpful cross-service collaborations to support CYP with ADHD during the first Covid-19 pandemic lockdown in the UK. Respondents mentioned the support of Specialist Nurses who provided more than a quarter (26%) of the required face to face appointments. Some services set up specific nurse-led clinics for physical monitoring for patients who needed to be seen in person. Collaboration with clinicians in Child and Adolescent Mental health services (CAMHS) was also reported to have provided 19% of the required face to face appointments. Some schools supported CYP with ADHD by offering physical monitoring for the few more vulnerable children who were allowed to be in school during the lockdown.4.The Covid-19 pandemic caused significant challenges for CYP with ADHD and their families, and for the services that support them. This survey of Paediatricians providing ADHD assessment and treatment during the first Covid-19 lockdown in the UK between March and June 2020 noted huge service disruptions such that almost half of the respondents ceased the assessment of new patients with ADHD, and only 5% were able to offer physical monitoring for most patients. However, all respondents had adopted telemedicine, which allowed them to maintain high levels of non-physical service provision for existing patients. The Paediatricians used risk stratification strategies to determine which patients were more likely to benefit from the limited available face to face appointments for physical monitoring. The Paediatricians demonstrated clinical pragmatism to meet the needs of their patients such as starting medication without physical exam especially if the patient's behaviour was so challenging that it was presenting a crisis at home, and setting aside monthly limits for stimulant medications. Some respondents reported helpful cross-service collaborations to support CYP with ADHD and their families.These findings are consistent with other studies from different parts of the world such as summarised in a recent review Some CYP with ADHD have experienced increased ADHD symptoms and related difficulties during the ongoing Covid-19 pandemic Telemedicine has been crucial in maintaining ADHD Service provision while limiting face-to-face contact to reduce the risk of Covid-19 transmission. There is increasing evidence that tele-medicine is effective in the diagnosis and treatment of ADHD https://www.bhf.org.uk/informationsupport/support/manage-your-blood-pressure-at-home). One advantage of home Blood Pressure monitoring is reduced potential for “white coat syndrome”. For example, one study showed that CYP with ADHD seen face to face during the first Covid-19 lockdown in the UK tended to have higher Blood Pressure compared with their re-pandemic readings but improved after the lockdown without further intervention One of the challenges for telemedicine-based ADHD treatment is the need for physical examination. The current study and others show that some parents were able to check weight, height, Blood Pressure, and Pulse at home. Some ADHD services are providing the equipment for families that do not already have them. Some clinicians in the current study were able to provide live guidance for parents to use the equipment. Also there are easy to access online instructions on how to check Blood Pressure , patients who had had home measurements that were outside normal limits, or those with other presentations considered to require urgent face to face clinical review.While acknowledging the important contribution of telemedicine, the nature of ADHD service provision is such that some face to face meetings would still be required. In this case, the current study suggests some triaging strategies to identify and prioritise the CYP who would most benefit from a face to face appointment. These include: patients with pre-existing concern about their physical well-being such as weight already below 9The strengths of this study include the use of both quantitative and qualitative comments to explore the experiences of the Paediatricians who are supporting CYP with ADHD. Another strength is the UK wide membership of GSF, which provides some support for the external validity in relation to neurodevelopmental paediatricians' practice during the period of the survey. Some implications for practice include rapid adoption of telemedicine, pragmatic application of clinical guidelines, maintaining some face to face treatment based on clinically triaged needs, and cross-service collaborations. The study's limitations include the relative small sample size, the absence of comparative pre-pandemic data on ADHD-related telemedicine, lack of data on non-ADHD paediatric practices, lack of location-specific data, and the cross-sectional and self-report nature of the survey.5.The Covid-19 pandemic has had adverse effect on many CYP with ADHD and caused huge disruption to the ADHD services that support them. The pandemic continues to be a challenge through the emergence of new variants such as Omicron that was causing the re-introduction of restrictions at the time of writing this paper. Thus, it is possible that disruptions to ADHD services are likely for some time. This shows the need to continue to learn from helpful service adaptions that can be maximised to provide more stable and sustainable ADHD services during this pandemic. Also, ADHD services need to consider continuing positive pandemic-engendered ADHD service changes that are now emerging from the literature where such changes can help to improve effective and efficient care delivery even after the current pandemic. These positive changes that are now emerging from the literature could also serve as blue prints in the event of a future pandemic.


The association of ADHD with mental health and medical conditions is commonly encountered in clinical practice. Interestingly there are patients with congenital conditions who present with features of ADHD and little is known about their association and neurological basis. There is no strong literature but anecdotal reports that indicate children with congenital heart disease are more likely to suffer from mental health conditions including ADHD. The clinic however is unable to analyze such hypothesis and instead decided to evaluate cases related to Neurofibromatosis (NF1), Arnold Chiari Malformation, Transposition of great arteries, Di George syndrome to understand the longitudinal history, symptom persistence and functional impact of ADHD.Index patient aged 45 years referred for possible association of ADHD and Neurofibromatosis with issues related to long-standing trouble with sleep and movement disorder.Index patient aged 41 years received a surgical repair for a Chiari malformation hoping it would improve the cognitive functioning but still suffers lot of symptoms that are consistent with clinical picture of ADHD.Index patient aged 19 years referred for ADHD assessment reported history of transposition of great arteries and VSD that warranted emergency operative procedure before age 3. The behavioural symptoms that were suspected as related to physical illness and frequent attendance to hospital however did not resolve and were noted to be in line with possible ADHD.Index patient aged 40 years admitted to general psychiatry following episode of psychosis and during examination presented history of Di George syndrome with brief input from Cardiology. It was apparent that patient struggled with poor understanding, lack of consistency, disorganization, distractibility, learning difficulties and the features suggested a pattern of Attention deficit disorder.The qualitative analysis of developmental history, childhood rating scale, symptom comorbidity and functional impairment of such cases.It studied the family history of physical and mental illness including predisposition to ADHD or neurodevelopmental conditions.It also evaluated the treatment response to stimulant/non-stimulant therapy.Focused onClinically there was no typical co-relation of increased mental illness or genetic predisposition for ADHD in the family history and qualitatively the presentation did not differ from other ADHD patients and the treatment response was not variable, however it still draws attention towards the need for regular screening of all nervous and cardiac origin congenital conditions for an early intervention.


In this article, we critically review the changes made to the DSM-5 Text Revision published in 2022 regarding the diagnostic entity of Attention Deficit/Hyperactivity Disorder (ADHD). We structure our critique around three points. The first discusses the acknowledgment of ADHD as a neurodevelopmental disorder. The second examines the definition of ADHD provided in the updated edition of the manual. The third scrutinizes the changes in the diagnostic criteria for ADHD and assesses whether these changes make the diagnosis more accurate. We conclude that DSM's latest edition does not escape the logical and scientific pitfalls of its predecessor. DSM-5-TR keeps the faith in the neo-Kraepelinian paradigm by explicitly and implicitly cultivating the essentialist medical scientific metaphor of disorder, creating the illusion that it represents scientific progress that validates ADHD as a neurodevelopmental disorder. From the publication of the third edition in 1980 and on, the Diagnostic and Statistical Manual of Mental Disorders (DSM) has embraced psychiatry as a branch of medicine by committing to a “neo-Kraepelinian” cause-effect biomedical framework with the assumption that biological discoveries will eventually establish the somatic etiology of separate and independent mental diseases , 3]. By In this opinion paper, we critically review the changes made to the DSM-5 Text Revision published in 2022 regarding the diagnostic entity of Attention Deficit/Hyperactivity Disorder (ADHD). We structure our critique around three points. The first discusses the acknowledgment of ADHD as a neurodevelopmental disorder. The second examines the definition of ADHD provided in the updated edition of the manual. The third scrutinizes the changes in the diagnostic criteria for ADHD and assesses whether these changes make the diagnosis more accurate. We point out how DSM-5-TR keeps the faith in the neo-Kraepelinian paradigm by explicitly and implicitly cultivating the essentialist medical scientific metaphor of disorder.As in its predecessor, ADHD is placed within the manual's chapter “Neurodevelopmental Disorders”. According to the DSM-5-TR neurodevelopmental disorders “are characterized by developmental deficits or differences in brain processes that produce impairments of personal, social, academic, or occupational functioning” p. 36). The authors of the manual assert that issues relevant to the placement of ADHD have been resolved by the available data “with the preponderance of evidence supporting placement in the “Neurodevelopmental Disorders” chapter” . GWAS ovia electronic screens), or is interacting in one-on-one situations ” .Moreover, the DSM-5-TR includes a new and very interesting statement in the “Prevalence” section: “prevalence is higher in special populations such as foster children or correctional settings” .Leaving these factors out of the manual does not weaken the neurodevelopmental hypothesis of behaviors and functioning associated with the diagnostic category, as brain is a plastic organ which development is affected by adverse life experiences. However, silence about the complexity of the role of psychosocial factors for the development of inattentive, compulsive and hyperkinetic behaviors throughout the manual, and particularly in connection with ADHD and foster or correctional setting, implies essentialism. This bias toward biopsychological factors is strengthened in section “Risk and Prognostic Factors”, where psychosocial factors are vaguely referred to by noting that “[f]amily interaction patterns in early childhood are unlikely to cause ADHD but may influence its course or contribute to secondary development of conduct problems” .Essentialist neuropathological premise are also assumed in the section “Diagnostic Features”, in which it is stated that the “essential feature of attention-deficit/hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development” .The definition of ADHD remains the same in DSM-5-TR in comparison to DSM-5. More specifically, it is stated that “ADHD is a neurodevelopmental disorder defined by impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity. Inattention and disorganization entail inability to stay on task, seeming not to listen, and losing materials necessary for tasks, at levels that are inconsistent with age or developmental level. Hyperactivity-impulsivity entails overactivity, fidgeting, inability to stay seated, intruding into other people's activities, and inability to wait— symptoms that are excessive for age or developmental level” . This definition retains the circular logic of the previous edition, that is “if A then B, and if B then A.” . For theexplains behaviors associated with ADHD diagnosis. ADHD as a diagnostic entity remains a descriptive classification of behaviors, not an explanation for them. When behaviors are explained by using a descriptive classification, adhering to circular reasoning is inescapable. Tautology is thus inevitably disguised as scientific explanation  and the presentation of primarily inattentive features  were briefly discussed under section “Gender-related Diagnostic Issues”. No explicit or implicit reference to potential causes or factors leading to these differences were made. DSM-5-TR presents two changes in this section. The tittle is changed to “Sex- and Gender- Related Diagnostic Issues”, making a conceptual distinction between biological notion of sex and psychological, social, historical, and cultural aspects related to biological sex . Also, one sentence is added, stating that differences in “ADHD symptom severity may be due to differing genetic and cognitive liabilities between sexes” .Thus, in contrast to the previous edition, the authors of DSM-5-TR explicitly imply the connection between inherent features and the manifestation of so-called symptoms according to sex. This attribution is strengthened by making a distinction between sex and gender yet saying nothing about gender-related factors . Instead, diagnostic issues related to sex and gender are reduced to biopsychological aspects and assumptions related to female/male binary  . This isCulture-related normative assumptions regarding behaviors are discussed in the section about “Culture-Related Diagnostic Issues” in similar fashion to the previous version of the manual, that is, cultural bias in diagnostic practices is acknowledged. Some apparent improvements have also taken place, suggesting the need for “culturally competent diagnostic practices […] in assessing ADHD” .In line with the previous version, ADHD is portrayed as a neurodevelopmental condition within an individual caused by natural development processes over which etiology psychosocial, societal or cultural factors have no power. Instead, these factors seem to be portrayed as hindering the adequate detection and diagnosis of the condition, as evidenced in the following statement: “Underdetection may result from mislabeling of ADHD symptoms as oppositional or disruptive in socially oppressed ethnic or racialized groups because of explicit or implicit clinician bias)” .This essentialist framework of Western psychiatry guided by the DSM has long been criticized by feminist scholars within and outside psychiatry, emphasizing the intersecting links between psychological hardships and the broad social, economic and political context . While As expected, DSM's latest edition does not escape the logical and scientific pitfalls of its predecessor . What is also pervasive in the DSM-5-TR is an attempt to further solidify ADHD as a neurodevelopmental disorder. Explicitly and implicitly, DSM-5-TR creates the illusion that it represents real scientific progress that validates ADHD as a neurodevelopmental disorder. In contrast, scientific research on etiology and pathophysiology of people diagnosed with ADHD rather questions the current operationalization of ADHD as a categorical diagnosis in line with the “neo-Kraepelinian” view of discrete boundaries between health and disorder . Given DSM's multifaceted influence in organizing institutional , academic , and social and psychological lives , e.g., , 29–31],–31,29–31Finally, we would like to underline the importance of the influence of the DSM since an ADHD diagnosis can expose those diagnosed to potential harm. We will briefly illustrate two examples here through the lens of the relative age effect phenomenon. First, research clearly shows an international, cross-cultural pattern of a relative-age effect in the diagnosis of ADHD . ChildrOn top of that, Panther et al.  found thAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Patients with Attention Deficit/Hyperactivity Disorder (ADHD) have shown an increased risk of developing a DSM Cluster B  and DSM Avoidant Personality Disorder . Although different comorbidities affect males and females with ADHD , gender differences in personality traits and disorders have not yet been investigated.To describe gender differences in personality traits and disorders among a sample of adult outpatients with ADHD.A consecutive sample of DSM-5 ADHD outpatients was recruited at the Adult ADHD Center of the “San Luigi” University Hospital (Orbassano (TO), Italy) between Jan 2017 and Jan 2018. Patients’ personality was assessed by Millon Clinical Multiaxial Inventory .The study sample consisted of 82 males and 31 females. Sixty percent of men vs. 77% of women had a personality disorder  when compared with men. Further studies on larger samples should be conducted to confirm more severe personality profiles in women than in men.No significant relationships.


TheB-site ordered CaCu3Fe2Os2O12 is a system with a very high ferrimagnetic ordering temperatureof 580 K having the Cu2+(↑)Fe3+(↑)Os5+(↓) charge and spin arrangement. In comparison, thehighly disordered CaCu3Fe2Os2O12 has a reduced magnetic transition temperature of about 350K. The Cu2+Fe3+Os5+ charge combinationremains the same without any sign of changes in the valence stateof the constituent ions. Although the average net moments of eachsublattice are reduced, the average ferrimagnetic spin arrangementis unaltered. The robustness of the basic magnetic properties of CaCu3Fe2Os2O12 against site disordermay be taken as an indication of the tendency to maintain the short-rangeorder of the atomic constituents.The B-site Fe/Os ordered and disordered quadruple perovskiteoxidesCaCu 3Fe2Os2O12 weresynthesized at different high-pressure and high-temperature conditions.Both compounds form the Cu2+(↑)Fe3+(↑)Os5+(↓) valence and magnetic arrangement. The orderedperovskite experiences a long-range ferrimagnetic transition at 580K on account of the strong Cu−Os coupling. However, the disorderedone undergoes a spin-glass transition at 350 K because the Cu−Oscoupling is disturbed by the disorder. The relative robustness ofthe magnetic properties against disorder may be taken as an indicationof the presence of short-range order of the B-site cations.TheB-site Fe/Os ordered and disordered quadruple perovskiteoxides CaCu For such a simple ABO3 perovskite, when three-quarters of the A-sites are replaced by transitionmetals and, simultaneously, half of the B-sites are substituted byanother kind of transition metal, one may obtain a peculiar quadrupleperovskite oxide with the chemical formula of AA′3B2B′2O12. Since the A′-siteis occupied by a transition metal that is coordinated with four oxygensand forms a square-planar unit, the Jahn–Teller ions such asCu2+ and Mn3+ are appropriate choices. The drasticdistortion of the structure gives rise to an orderly distributionof the A- and A′-sites with a 1:3 ratio. However, because bothB- and B′-sites accommodate transition metals and form an octahedronwith six coordinated oxygens, these two sites can either be disordered with B-siteordered Fe/Osdistribution was successfully synthesized.11 It possesses a very high ferrimagnetic Curie temperature TC of 580 K and a considerable magnetic momentof 5.0 μB/fu. The charge and spin configuration isCu2+(↑)Fe3+(↑)Os5+(↓),11 quite analogous to some other isostructuralsystems12 and with alsosigns for the presence of orbital moments.13 Itis worth noting that CCFOO was synthesized under the high-pressureand high-temperature (HPHT) method, which is able to stabilize themetastable phase at ambient pressure.17Recently, a new quadruple perovskite oxide CaCu2MnCoO6, for example, the Mn–Codisorder leads not only to a lower magnetic ordering temperature butalso to changes in the Mn and Co valence states.18 Such an order–disorder study for the quadruple perovskitesis, however, not so straightforward. Ordering of the B- and B′-sitesrequires remarkable differences in ionic radii and valence statesbetween the two different elements, and high pressures up to severalGPa and a relatively lower temperature are required during the synthesis.However, the requirements for the disordered B-sites are almost theopposite, i.e., similar B/B′ ionic radii, relatively lowerpressures, and higher temperatures are needed. Thus one has to carefullyselect the combination of B/B′ elements and adjust the synthesizingconditions to obtain both the B-site ordered and disordered perovskites.We now would like to knowwhat effect disorder could have on themagnetic properties of such a complex system as the quadruple perovskites.In La21 to determine the magnitude and orientation of the magnetic momentson each atomic  constituent separately.In this study, we have successfully synthesized both the B-site(Fe/Os) ordered and disordered CCFOO, using different HPHT conditions.We have performed the element-specific X-ray absorption spectroscopy(XAS) and X-ray magnetic circular dichroism (XMCD) measurements22O3, and Os with a moleratio of 1:3:1:2 were used as starting materials.CaO was produced by sintering CaCO3 at 1273 K for 10 hin an atmosphere of Ar gas. An appropriate amount of KClO4 was added as the oxidizing agent. The raw materials were thoroughlymixed and ground using an agate mortar in a glove box filled withAr gas. Then, the mixture was pressed into a platinum capsule forHPHT synthesis. A cubic-anvil-type high-pressure apparatus was adoptedfor the HPHT experiment. For the CCFOO-ordered compound, the pressurewas slowly increased to 8 GPa, and the reactants were heated at 1373K for 30 min. Then, the heating power was cut off, and the temperaturewas quickly dropped to room temperature in several seconds. Afterthat, the pressure was slowly decreased to ambient within 8 h. Forthe CCFOO-disordered compound, the reactants were pressed to 6 GPaand heated at 1673 K for 20 min. Then, the heating power was cut off,and the pressure was slowly released to ambient within 6 h. Finally,the CCFOO-ordered and CCFOO-disordered products were grained and thenrinsed with deionized water to wipe off the residual KCl.High purity (>99.9%)powders of CaO, CuO, FeKα1 radiation. The scanning 2θ angle range was from 10 to 100°,with a step size of 0.005°. The crystallographic parameters wererefined using the GSAS package.22 A smallamount of impurities (∼3% in weight) was excluded in the refinement.The XAS spectra at the Cu-L3 and Fe-L2,3 edges were measured at beamline TLS11A ofNSRRC, and the XAS spectrum at the Os-L3 edge was measured at beamline TLS17C of NSRRC. The XMCD patternsat the Cu-L2,3 and Fe-L2,3 edges were collected under 4.2 K and 6 T at beamlineDEIMOS of synchrotron SOLEIL. The XMCD patterns at the Os-L2,3 edge were collected under 300 K and 7 Tat beamline ID12 of the European synchrotron radiation facility (ESRF).Both the direction of the applied magnetic field and the helicityof X-rays (∼97%) were alternately flipped after each energyscan to obtain the μ+  and μ–  spectra.PowderX-ray diffraction (XRD) was carried out on a Huber X-raydiffractometer  with Cu-3 by a standard four-probemethod on a Quantum Design physical property measurement system (PPMS-7).The heat capacity was measured using a bulk with a size of about 2× 2 × 0.4 mm3 on PPMS-7.The magnetic susceptibilityand isothermal magnetization were measuredusing a Quantum Design superconducting quantum interference devicemagnetometer (MPMS-3). Both zero-field-cooling (ZFC) and field-cooling(FC) modes were adopted for magnetic susceptibility measurements at0.1 T. The resistivity was measured using a pellet with a size ofabout 2 × 1 × 1 mm3h + k + l = odd, such as (111) and(311), can be clearly found in the XRD pattern of CCFOO-ordered (Pn3̅ space group (No. 201),indicating the 1:3 ordered distribution of Ca and Cu at the A- andA′-site and the rock-salt-type distribution of Fe and Os atthe B- and B′-sites, respectively. Note that during the refinement,a 9% antisite occupation was found for the B-site Fe and B′-siteOs, similar to a previous study (11%).11 In comparison, CCFOO-disordered crystallizes to an Im3̅ space group (No. 204), indicating the disordered distributionof Fe and Os at the B-site. It is worth noting that if we refine CCFOO-disorderedusing a B-site ordered Pn3̅ space group, anearly 50% antisite of Fe and Os is found to occur, suggesting a totallydisordered B-site distribution. Thus, using the same reactants underdifferent HPHT procedures, two kinds of quadruple perovskite oxidesCCFOO with B-site ordering and disordering can be obtained. The refinedparameters for CCFOO-ordered and CCFOO-disordered are listed in 24 give the valence states of Ca2+ and Cu2+ forboth CCFOO compounds. For CCFOO-ordered, the valence states of Fe3+ and Os5+ can also be determined using BVS calculations.For CCFOO-disordered, BVS calculations cannot be meaningfully applieddue to the uncertainties in the bond lengths.-ordered 2a, stron-ordered 2b. Via tL2,3 edges ishighly sensitive to the valence state. For an open 3d shell system, an increase in the valence of the transition metalion by one leads to a shift of the L2,3 XAS spectrum to the higher energies by one eV or more, accompaniedby remarkable changes in the spectral feature.27 On accountof its element-selective feature, XAS is especially appropriate forstudying complex, multielement, and disordered systems such as ourCCFOO. As shown in L3 XAS peaks of bothCCFOO compounds locate at the same energy position (930.8 eV), indicatingCu2+ in both compounds. One should note that both of theCu-L3 peaks locate at 0.5 eV lower inenergy than that of CuO (931.3 eV).29 This energyshift comes from the modest crystal field of Cu in CCFOO (CuO4 square-planar) compared with that of CuO (CuO6 octahedron). The Fe-L2,3 XAS spectraare displayed in 3+ valence state,whereas the disorder leads mainly to somewhat broader spectral features. L3 XAS spectra. The Os-L3 XAS peaks for both CCFOO compounds also locate at the identicalenergy position, also indicating the same valence state of Os5+ in both CCFOO compounds. Hereto, we can conclude that thevalence states scheme of both CCFOO-ordered and CCFOO-disordered tobe Cu2+Fe3+Os5+. This result forCCFOO-ordered is in accordance with the BVS analysis, while for CCFOO-disordered,as explained above, BVS was not capable of providing the numbers.To directly obtain the valence states of the transitionmetal ions,especially of the CCFOO-disordered compound, we performed XAS measurementson both CCFOO compounds. It is well known that element-selective XASat the transition metal TC (580 K) and the sharp transitionof CCFOO-ordered (inset of B/fu) is still reluctantto saturate and increases monotonically with increasing field, alsoindicating a strongly frustrated magnetic structure in CCFOO-disordered.For comparison, the magnetization of CCFOO-ordered behaves as a canonicallong-range ferro-/ferrimagnet, with a much smaller coercive field(0.25 T) and a much larger saturated magnetization (5.0 μB/fu), as shown in the inset of 11inset of ), the ma2MnCoO6, the Mn/Co disorder leads to a lowering of the ordering temperaturefrom 225 to 150 K.18 Interestingly, thevalence states of both the Mn and Co ions are different between theordered and disordered materials, and the presence of nonmagneticlow-spin Co3+ in the disordered sample is the main reasonfor the reduced magnetic ordering temperature. For the quadruple perovskiteCaCu3Fe2Nb2O12, with Cuand Fe forming a FiM structure, the magnetic transition temperatureof the disordered sample decreases as a result of the presence ofantiphase boundaries.13 Our CCFOO systemis different. The valence configuration remains the same for CCFOO-orderedand CCFOO-disordered.It can be expected that disorder decreases themagnetic orderingtemperature. For the double perovskite LaL2,3 and the Fe-L2,3 XMCD spectra of CCFOO-ordered, respectively, from ref /(μ+ + μ–)] at the Os-L2 edge reaches 24%, which is the largest valueat room temperature for Os5+ compounds reported so far.36 One can observe that the L3 (L2) edges of Cu and Fe are negative (positive),opposite to that of the Os. Thus, our XMCD measurements experimentallyconfirm the Cu2+(↑)Fe3+(↑)Os5+(↓) magnetic arrangement.11To get a deeper insight into the magneticproperties, we performedXMCD measurements of both CCFOO-ordered and CCFOO-disordered compounds. from ref . Figure 2+(↑)Fe3+(↑)Os5+(↓)magnetic arrangement as CCFOO-ordered. Here, we note that the Os XMCDsignal in CCFOO-disordered has decreased significantly as comparedto that in CCFOO-ordered. This is due to the fact that the Os XMCDhas been performed at 300 K, which is only 50 K below the magneticordering temperature of CCFOO-disordered (350 K) but 280 K below theordering temperature of CCFOO-ordered (580 K); see also The XMCD spectra of CCFOO-disordered are shownin 11 From this pointof view, for CCFOO-disordered, with the Fe and Os randomly distributedat the B-sites, one may expect to find a more conductive behavior. R–T behavior can be observed inmore metallic perovskite oxides.38 We further measured the heatcapacity for CCFOO-disordered, as shown in CP = αT3 +βT3/2 + γT below 20 K with α = 5.1 × 10–4 J mol–1 K–4, β = 1.4 × 10–2 J mol–1 K–5/2, and γ = 8.1 × 10–3 J mol–1 K–2. Obviously, the presence of the γ termindicates the conductive nature of CCFOO-disordered.Finally,we investigated the electric properties. CCFOO-orderedhas been reported to be an insulator with a band gap of 1.0 eV. Theinsulating behavior is stabilized by the ordering of the B-site Feand B′-site Os.43Fe2Os2O12. CCFOO-orderedcrystallizes to a Pn3̅ space group, in whichthe B-site Fe and Os are orderly distributed in a rock-salt-type fashion.Using XAS and XMCD, we confirmed the Cu2+(↑)Fe3+(↑)Os5+(↓) valence and magneticarrangement. CCFOO-disordered, on the other hand, crystallizes intoan Im3̅ space group, where Fe and Os disorderlyoccupy the B-site. XAS revealed the Cu2+, Fe3+, and Os5+ valence states, which are the same as thoseof the B-site ordered counterpart. Although XMCD showed smaller effectivelocal moments, which is consistent with the lower magnetic orderingtemperature, the average spin arrangement is still that of the orderedcompound. The relative robustness of the magnetic properties againstdisorder may be taken as an indication of the presence of short-rangeorder of the B-site cations.In summary, under differentHPHT conditions, we successfully synthesizedthe B-site Fe/Os ordered and disordered quadruple perovskite oxidesCaCu


Secale cereale L.), a naturally cross-pollinating relative of wheat, is a tertiary gene donor and of substantial value in wheat improvement. Wheat powdery mildew is caused by Blumeria graminis f. sp. tritici (Bgt), which seriously affects yield and quality worldwide. Identifying and transferring new, effective resistance genes against powdery mildew from rye is important for wheat breeding. The current study developed a wheat-rye line YT2 resistant to powdery mildew by crossing, backcrossing, and self-pollination for multiple generations between octoploid triticale 09R2-100 and common wheat cultivar Shixin 616. YT2 was confirmed to be a 6R disomic addition and T1RS⋅1BL translocation line by genomic in situ hybridization (GISH), multicolor fluorescence in situ hybridization (mc-FISH), multicolor-GISH (mc-GISH), and molecular marker analyses. Disease responses to different Bgt isolates and genetic analysis showed that the powdery mildew resistance gene of YT2 was derived from the rye chromosome 6R of 09R2-100, which differed from the previously reported Pm genes from rye including Pm20 on 6RL. Resistance phenotype of different translocation lines and deletion lines derived from YT2 combined with newly developed 6RL-specific markers analysis suggested that the powdery mildew resistance gene of YT2 was localized to the region in chromosome 6RL: 890.09–967.51 Mb and flanked by markers XM189 and X4M19, corresponding to the reference genome of Weining rye. Therefore, YT2 could be used as a promising bridging parent for wheat disease resistance improvement.Rye ( Triticum aestivum L.) is one of the most important grain crops worldwide ensuring national food security. Powdery mildew, caused by Blumeria graminis (DC.) Speer f. sp. tritici emend. É. J. Marchal (Bgt), can significantly decrease wheat yield and quality worldwide by 5–40% and, in severe cases, up to 62% (Pm) resistance genes/alleles continue to be explored, with more than a hundred Pm genes  reported so far  is a naturally cross-pollinating relative of common wheat, which possesses huge diversity for using as a gene donor in wheat improvement  resistance  is synthesized artificially through distant hybridization between common wheat and rye. It possesses multiple resistance genes to wheat disease and can be more easily crossed with wheat than rye, thus can be used as an alternative source in wheat improvement  were used as controls, including TAM104/Thatcher with Pm20 from 6RL, Kavkaz with Pm8, and Amigo with Pm17 that both located on 1RS, and CI14189 with Pm7 from 2RL. Each genotype was tested with 22 single-pustule-derived powdery mildew isolates in the same way to compare their reaction patterns. A population of 97 F2 plants from a cross of YT2 and susceptible commercial cultivar Gao 8901 was used to determine the resistance source of powdery mildew resistance.A wheat-rye derivative line, designated as YT2, was produced by crossing octoploid triticale 09R2-100  with wheat cultivar Shixin 616, with self-pollination for multiple generations. Wheat cultivar Mingxian 169 susceptible to all the Wheat cultivars Chinese Spring (CS) and Holdfast, rye cultivars Weining and King II, 6R disomic addition line of Holdfast × King II (DA 6R), 6RS ditelosomic addition line (DtA 6RS), and 6RL ditelosomic addition line (DtA 6RL) were used to verify the specificity of molecular markers.The complete set of disomic addition lines (DA 1R to 7R) of CS × Imperial, two hexaploid triticale lines 10R2-193-2 and 10R2-194-2 (AABBRR), and two T1BL⋅1RS wheat-rye translocation lines Lovrin 10 and Lovrin 13  were usein situ hybridization and FISH were performed to determine the chromosomal composition of YT2. The mitotic metaphase chromosomes from root tips of YT2 were prepared and observed as previously described  labeled with fluorescein-12-dUTP combined with probe pAs1 (red) labeled with Texas-red-5-dCTP was used in mc-FISH detection. For ND-FISH detection, Oligo-pSc119.2-2 and Oligo-pTa535-2 were 5′-end-labeled with 6-carboxyfluorescein (6-FAM) producing green signals and 6-carboxytetramethylrhodamine (TAMRA) producing red signals, respectively. The FISH patterns were referred to Triticum urartu , Aegilops speltoides , and Aegilops tauschii . The total genomic DNA of rye and T. urartu was labeled with fluorescein-12-dUTP, and the total genomic DNA of Ae. tauschii was labeled with Texas-red-5-dCTP, while total genomic DNA of Ae. speltoides was used for blocking , SW22063 , and SW5284  were used to detect rye chromosome arms 6RS, 6RL, and 1RS, respectively . The marPm gene(s) were used as controls  from rye, TAM104/Thatcher with Pm20 from 6RL of Prolific rye was resistant to 15 but susceptible to seven Bgt isolates. CI14189 with Pm7 derived from 2RL of Rosen rye was highly susceptible to all the 22 isolates; Kavkaz with Pm8 from 1RS of Petkus rye was resistant to isolates E50 and E60; Amigo with Pm17 from 1RS of Insave rye was resistant to E06 and E13. In addition, compared with WR49-1, a wheat-rye 6R disomic addition line derived from wheat cultivar Xiaoyan 6 and rye cultivar German white that was previously identified by our laboratory, YT2 had a narrower response spectrum but was resistant to the four Bgt isolates E18, E19, E20, and E49, while WR49-1 was susceptible  can be found in the article/DA, GH, and HY conceived the research. GH, HY, JW, LC, and SL performed the experiments. LL and XL contributed to the development of the materials. YZ and JF performed phenotypic assessments. GH and HY wrote the manuscript. DA and LL supervised the research. All authors read and approved the final 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.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.


To evaluate and compare the effects of three courses of different structural patterns of electroencephalography neurofeedback on predominantly inattentive attention deficit hyperactivity disorder (ADHD‐PI) and combined ADHD (ADHD‐CT).θ, β, α, SMR and their ratios , and eighteen integrated visual and auditory continuous performance test (IVA/CPT) quotients were obtained and compared. Data were analyzed by SPSS software, and p < .05 was considered statistically significant.Thirty‐eight ADHD‐PI and ADHD‐CT children were selected and completed three courses of different structural patterns of electroencephalography neurofeedback according to their ADHD type. Before and after each course, relative power value of electroencephalography, including θ, three IVA/CPT quotients in both types and two comprehensive quotients in ADHD‐CT changed significantly . After two courses, θ/α, θ/β and five IVA/CPT quotients in both types, θ and α in ADHD‐PI, four comprehensive quotients, and four respond control quotients in ADHD‐CT varied significantly compared to before treatment and after one course . After three courses, α, β, θ, θ/α, θ/β and ten IVA/CPT quotients in both types changed significantly compared to before treatment and after one course . In addition, six IVA/CPT quotients in both types after three courses were significantly higher than those after two courses .After one course, Different structural patterns of electroencephalography neurofeedback targeted for ADHD‐CT and ADHD‐PI were both effective and feasible. Three courses of EEG neurofeedback were most effective.   The structural patterns of EEG neurofeedback for ADHD‐PI and ADHD‐CT patients were 1st–5th of “2.3According to the literature . Numerical variables were expressed as mean ± standard deviation. Age, IQ, and the sex ratio of children between ADHD‐PI and ADHD‐CT groups were compared by the independent sample t test and Chi‐square test, respectively. The changes or differences in IVA/CPT quotients and brain waves among each treatment course or between two groups were analyzed by repeated measures analysis . The Greenhouse–Geisser corrected F test  was used when the data did not conform to Mauchly's test of sphericity. The Bonferroni test was used for comparisons of the confidence interval of main effect, and the F test was used for interactions between two groups and indexes among each course of treatment. All tests were two‐tailed, and 33.1t = .664, p = .511). There were 32 boys and six girls, the sex ratio was 16:3, and there was no significant difference in the sex ratio between ADHD‐PI (15:4) and ADHD‐CT  groups. The mean IQ of all subjects was 101.81 ± 12.79, and there was no significant difference in the IQ of subjects between ADHD‐PI (101.74 ± 14.76) and ADHD‐CT  groups.Before treatment, age, gender and IQ of children between two groups were balanced and comparable. All subjects were aged from 6.02 to 11.78 years, with a mean of 8.29 ± 1.46 years, and there was no significant difference between ADHD‐PI (8.06 ± 1.28) and ADHD‐CT .After one treatment course of EEG neurofeedback, θ/α and θ/β in both types, θ in ADHD‐CT decreased significantly, whereas α in ADHD‐PI increased after two treatment courses of EEG neurofeedback . Similarly, after two treatment courses of EEG neurofeedback, θ in ADHD‐PI decreased significantly and α in ADHD‐CT increased significantly compared to before treatment . The data are presented in Table Compared to before treatment and after one treatment course, θ/α, θ/β, and θ in both types decreased significantly, whereas α and β in both types increased . In addition, SMR in ADHD‐PI was significantly higher than that before treatment . The data are presented in Table After one treatment course of EEG neurofeedback, VAQ, VIGA, FOCA, and FOCV in both types, as well as FAQ and AAQ in ADHD‐CT increased significantly . PRUA and PRUV in ADHD‐CT, as well as ARCQ, VRCQ, FAQ, AAQ, STAA, and STAV in ADHD‐PI after two treatment courses of EEG neurofeedback were significantly higher than those before treatment . The data are presented in Table VAQ, VIGA, VIGV, FOCA, FOCV, SPDA, and SPDV in both types, as well as ARCQ, VRCQ, FAQ, AAQ, CONA, CONV, STAA, and STAV in ADHD‐CT after two treatment courses of EEG neurofeedback were significantly higher than those before treatment and after one treatment course . FAQ, AAQ, VAQ, STAV, VIGA, VIGV, FOCA, FOCV, SPDA, and SPDV in both types, as well as ARCQ, VRCQ, PRUV, CONA, CONV, and STAA in ADHD‐CT after three treatment courses of EEG neurofeedback were significantly higher than those before treatment and after one treatment course . FRCQ and PRUA in ADHD‐CT, as well as FRCQ, ARCQ, VRCQ, CONA, and STAA in ADHD‐PI after three treatment courses of EEG neurofeedback were significantly higher than those before treatment .As shown in Table 4α wave increased. In our study, during whole three‐course structural paradigm treatment of EEG neurofeedback, θ in both types decreased gradually with the extension of treatment time. In addition, θ/β and θ/α in both types showed a downward trend after two and three treatment courses. By contrast, α and β in both types increased significantly after two and three treatment courses. These results indicated that both structural patterns of EEG neurofeedback for ADHD‐PI and ADHD‐CT patients were effective. In addition, changes in EEG were observed after two treatment courses, and the curative effect showed an obviously increasing trend with the prolongation of treatment course, suggesting that at least two consecutive treatment courses are required so as to achieve relatively satisfactory therapeutic effects.In the connective process of brain function, neural resource allocation is different when attention is used for task control  in both types increased gradually. Namely, subjects’ attention improved significantly after two treatment courses, and further improved and stabilized after three treatment courses. The results also indicated that different structural patterns of the EEG neurofeedback targeted for different ADHD types could improve the attention retention ability and concentration of patients with different ADHD types, and the therapeutic effects are basically same.Six control quotients, namely prudence, consistency and stamina quotients of visual and auditory signals, were used to measure the ability to stop, think, recognize, respond correctly to disturbances, maintain the response consistency over time, and remain stable throughout the test, respectively. They jointly reflect the overall coordination and volitional control abilities of the subjects. In ADHD‐CT, prudence, consistency, and the stamina quotients of children increased significantly after two treatment courses, revealing that the ability to deal with disturbance and attention control of these children improved dramatically. And further improvement and stabilization of these two abilities were achieved after three treatment courses. In ADHD‐PI, only the stamina quotients of children increased after two treatment courses. This was reasonable because the ability to deal with disturbance of external stimuli or information and attention control of ADHD‐PI patients was still within normal range. And after each treatment course, the corresponding quotients reflecting these two abilities did not change significantly. Above results together suggested that different structural patterns of EEG neurofeedback targeted for characteristics of brain function of different ADHD types was necessary and feasible. In the other hand, three comprehensive quotients reflecting the respond control ability  in both types improved, except these changes were more obvious in ADHD‐CT. Taken collectively, these results indicate that different structural patterns of EEG neurofeedback targeted for different ADHD types adopted in this study can effectively improve the cognitive and executive functions of different types of ADHD patients. And the more treatment courses, the better treatment effect.This study had some limitations. The sample size of this study was comparatively small and only met the basic statistical requirements. The statistical efficiency would have improved if blind grouping was used and/or the sample size was increased appropriately. Furthermore, all subjects were from Jiaxing City. As a medium‐sized city, although Jiaxing City has a good representative, there might have regional limitations. Therefore, further studies are needed to verify the results of this study.5In summary, the results of this study indicated that different structural patterns of EEG neurofeedback targeted for ADHD‐CT and ADHD‐PI were both effective and feasible, especially in cognitive and executive functions, including attention and respond control abilities. Two treatment courses of EEG neurofeedback had a good therapeutic effect in ADHD patients, but three treatment courses were most effective. In the future, this targeted and different structural pattern multi‐course treatment of EEG neurofeedback deserves to be applied in the treatment of ADHD to achieve a better therapeutic effect.No financial or non‐financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.Concept and design: Tong‐kun Shi. Methodology: Xiao‐mei Cui and He‐dan Zhao. Data curation: Ling‐fei Yang and Zheng Wang. Writing—original draft: Feng‐hua Wang and Li‐yan Sun. Writing‐review and editing: Feng‐hua Wang and Li‐yan Sun. Project Administration: Tong‐kun Shi. Funding acquisition: Tong‐kun Shi. All authors have read and agreed to the published version of the manuscript.https://publons.com/publon/10.1002/brb3.2572The peer review history for this article is available at