T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells ...are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8
tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8
TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8
TILs include a subpopulation of 'progenitor exhausted' cells that retain polyfunctionality, persist long term and differentiate into 'terminally exhausted' TILs. Consequently, progenitor exhausted CD8
TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8
T cells might be an important component of improving the response to checkpoint blockade.
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic ...screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
There is a robust literature of predominantly cross-sectional studies demonstrating an association between attention-deficit/hyperactivity disorder (ADHD) and sleep quality in childhood and ...adolescence, measured by subjective as well as objective measures, dimensional and categorical variables, and controlling for a wide range of confounders such as other disorders.
Moreover, ADHD symptoms and sleep problems are independently associated with adverse functional outcome and quality of life.
As a result, these are viewed as common and mutually exacerbating conditions, likely mediated by common neuropathways.
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Objective: Children with ADHD display higher rates of sleep problems, and both sleep disorders and ADHD have been shown to affect functioning in childhood. The current study examines the frequency ...and relationship between sleep problems and ADHD, and their impact on quality of life (QoL) and functional impairment. Method: Parents of 192 children with ADHD (M = 10.23 years) completed measures regarding their child’s ADHD symptoms (Swanson, Nolan and Pelham SNAP), sleep disorders (Pediatric Sleep Questionnaire PSQ), QoL (Child Health Illness Profile CHIP-PE), and functioning (Weiss Functional Impairment Rating Scale–Parent Report WFIRS-P). Results: Common sleep complaints in participants were insomnia, excessive daytime sleepiness (EDS), and variability in sleep schedule. Regression analysis indicated that sleep problems and ADHD symptoms independently predicted lower levels of QoL (ΔR2 = .12, p < .001) and social functioning (ΔR2 = .12, p < .001). Conclusion: The results suggest that ADHD may coexist with somnolence and that both conditions have a significant impact on a child’s functioning and QoL.
Objective: The Weiss Functional Impairment Rating Scale–Self-Report Form (WFIRS-S) was developed as a measure of functional impairment in adolescents and adults with ADHD. This study reports the ...psychometric properties of the Persian version of the WFIRS-S in a sample of normal Iranian adolescents. Method: Internal consistency and factor structure of the WFIRS-S were tested on a sample of 386 students (Grades 7-12). The test-retest reliability and the convergent validity of the WFIRS-S were evaluated by using two different subsamples including 50 and 100 students, respectively. Results: The Cronbach’s alpha values were between .72 and .94 for the WFIRS-S subdomains and total scale. The test-retest reliability was .80 for the total scale. The WFIRS-S subdomains had moderate to high significant correlations with the Pediatric Quality of Life total scale. Conclusion: The Persian version of the WFIRS-S has acceptable psychometric properties and could be used as a functional impairment assessment for adolescents.
The ability to maximize rewards and minimize the costs of obtaining them is vital to making advantageous explore/exploit decisions. Exploratory decisions are theorized to be greater among individuals ...with attention-deficit/hyperactivity disorder (ADHD), potentially due to deficient catecholamine transmission. Here, we examined the effects of ADHD status and methylphenidate, a common ADHD medication, on explore/exploit decisions using a 6-armed bandit task. We hypothesized that ADHD participants would make more exploratory decisions than controls, and that MPH would reduce group differences. On separate study days, adults with (n = 26) and without (n = 23) ADHD completed the bandit task at baseline, and after methylphenidate or placebo in counter-balanced order. Explore/exploit decisions were modeled using reinforcement learning algorithms. ADHD participants made more exploratory decisions (i.e., chose options without the highest expected reward value) and earned fewer points than controls in all three study days, and methylphenidate did not affect these outcomes. Baseline exploratory choices were positively associated with hyperactive ADHD symptoms across all participants. These results support several theoretical models of increased exploratory choices in ADHD and suggest the unexplained variance in ADHD decisions may be due to less value tracking. The inability to suppress actions with little to no reward value may be a key feature of hyperactive ADHD symptoms.
ObjectiveThis is a narrative review of validation and outcome studies using the Weiss Functional Impairment Rating Scale (WFIRS). The objective of the review is to establish a framework for ...understanding functional impairment and create a definition for functional response and remission.MethodsWe conducted a literature search via MEDLINE, EBSCO and Google Scholar with no date restrictions and reviewed bibliographies of selected publications. Publications found in languages other than English were translated and clarification obtained from the author(s) if needed. Inclusion criteria were any manuscript that was either a WFIRS psychometric validation study or a clinical trial using the WFIRS as an outcome. There were no exclusion criteria.ResultsThe WFIRS has been validated in multiple cultures, and in clinical, research and control populations. The WFIRS has robust psychometric properties across ages, psychiatric status and informants. Outcome studies show variable improvement, with different response patterns between domains and among different interventions.ConclusionSymptom improvement and remission needs to be complemented with evaluation of functional improvement and remission to obtain a full picture of clinical status over the course of treatment.
Purpose of the Review
The purpose of the current paper was to review and summarize the literature on ADHD and maltreatment over the past 10 years.
Recent Findings
The majority of research on ADHD and ...exposure to maltreatment focuses on the high rates of comorbidity, including international studies from Asia, South America, North America, and Europe. Longitudinal studies showed that early exposure to maltreatment is a risk factor for ADHD symptoms later in development; however, this finding was not consistent. There were some preliminary studies on the neurological and genetic mechanisms underlying the link between ADHD and exposure to maltreatment. Finally, ADHD and exposure to maltreatment were found to have an additive effect on clinically salient outcomes (e.g., aggression, suicide attempts).
Summary
Results from the review have direct clinical and future implications, including the need to understand the effect of comorbid ADHD and exposure to maltreatment in treatment studies.
This study evaluates the descriptive and psychometric properties of the Persian version of the Weiss Functional Impairment Rating Scale-Parent Report Form (WFIRS-P) in a normal sample of Iranian ...children.
Parents of 282 students (grades 1-6) completed the WFIRS-P. Means and standard deviations were computed for the total scale, each domain, and each item of the WFIRS-P. Internal consistency, interdomain correlations, and test-retest reliability were used to assess the reliability of the scale.
Among the WFIRS-P domains, life skills had the highest rated impairment (M = 0.50, SD = 0.37) and risky activities had the lowest. Internal consistency (α = .88) and test-retest reliability (r = 0.77) were strong for the WFIRS-P total scale. The correlation between the WFIRS-P domains and the total scale ranged from 0.52 to 0.81.
Results suggest that the Persian version of the WFIRS-P is a useful and psychometrically reliable measure for assessing functional skills in children.
Aim
The current study aimed at examining the ability of the Weiss Functional Impairment Rating Scale‐Parent Report (WFIRS‐P) to discriminate between children with ADHD and controls in functional ...impairment and identifying optimal cutoff scores for the WFIRS‐P subscales and total scale.
Methods
Parents of 51 children with ADHD (90.2% male; grades 1–6) and 51 gender/grade matched controls (90.2% male; grades 1–6) completed the WFIRS‐P. Receiver operating characteristic (ROC) curve analysis was used to examine the ability of the WFIRS‐P to differentiate children with ADHD from controls and to determine optimal cutoff scores of the WFIRS‐P.
Results
Area under the curve (AUC) was 0.98 for the WFIRS‐P total scale, indicating excellent ability to differentiate children with ADHD from controls. The score of 0.45 with 0.88 for sensitivity and 0.96 for specificity was determined as the optimal cutoff score for the total scale of the WFIRS‐P. AUC was 0.73 to 0.97 for the WFIRS‐P subscales, suggesting good to excellent ability for discriminating between children with ADHD and controls. Among the subscales, the family subscale score of 0.42 with 0.92 for sensitivity and 0.96 for specificity showed the highest discriminating power. The self‐concept and life skills subscales had low sensitivity, suggesting Iranian mothers do not identify problems with self‐concept or difficulty with life skills as particularly problematic in ADHD.
Conclusions
The WFIRS‐P is a sensitive and specific measure of the functional impairment associated with ADHD in Iranian children. Our sample was predominantly male, limiting the generalizability of results to females.
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