Hyperactivity, impulsivity, and inattention in boys with cleft lip and palate: relationship to ventromedial prefrontal cortex morphology

The purpose of this study is to evaluate quantitative structural measures of the ventromedial prefrontal cortex (vmPFC) in boys with isolated clefts of the lip and/or palate (ICLP) relative to a comparison group and to associate measures of brain structure with quantitative measures of hyperactivity, impulsivity, and inattentiveness. A total of 50 boys with ICLP were compared to 60 healthy boys without clefts. Magnetic resonance imaging brain scans were used to evaluate vmPFC structure. Parents and teachers provided quantitative measures of hyperactivity, impulsivity, and inattentiveness using the Pediatric Behavior Scale. Boys with ICLP had significantly higher ratings of hyperactivity/impulsivity/inattention (HII) and significantly increased volume of the right vmPFC relative to the comparison group. There was a direct relationship between HII score and vmPFC volume in both the ICLP group and control group, but the relationship was in the opposite direction: in ICLP, the higher the vmPFC volume, the higher the HII score; for the comparison group, the lower the vmPFC volume, the greater the HII score. The vmPFC is a region of the brain that governs behaviors of hyperactivity, impulsivity and inattention (HII). In boys with ICLP, there are higher levels of HII compared to the controls and this is directly related to a significantly enlarged volume of the right vmPFC. Enlargement of this region of the brain is therefore considered to be pathological in the ICLP group and supports the notion that abnormal brain structure (from abnormal brain development) is the underlying etiology for the abnormal behaviors seen in this population

Psychological impact of visible differences in patients with congenital craniofacial anomalies

© 2015, Singh and Moss; licensee Springer. Background: Patients with craniofacial anomalies often have appearance concerns and related social anxiety which can affect their quality of life. This study assessed the psychological impact of facial and dental appearance in patients with craniofacial anomalies in comparison to a general population control group. Methods: The study involved 102 adult patients (51% male) with congenital craniofacial anomalies and 102 controls (49% male). Both groups completed the Nepali version of Derriford Appearance Scale (DAS) and the Psychological Impact of Dental Aesthetic Questionnaire (PIDAQ) in a clinical setting to assess appearance-related distress, avoidance, and anxiety. Results: There was a significant difference between patients and controls on both PIDAQ (mean score for patients 33.25 ± 9.45 while for controls 27.52 ± 5.67, p < 0.001) and DAS59 scores (mean score for patients 159.16 ± 31.54 while for controls 77.64 ± 6.57, p < 0.001), indicating that patients experienced greater negative psychological impact of living with their appearance (PIDAQ) and more appearance-related distress (DAS) than controls. DAS scores were not associated with gender. There was no association of the place of residence (rural vs. urban) with PIDAQ or DAS59 scores. Conclusions: There is a significant psychological impact of altered facial and dental appearance in patients with craniofacial anomalies compared to controls. There was no effect of locality (rural/urban) on the psychological impact of facial and dental appearance in patients

FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing

Aims FOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients’ formalin-fixed, paraffin-embedded tumour blocks was undertaken at two centralised biomarker laboratories (Leeds and Cardiff), and the results fed directly to the Medical Research Council Clinical Trials Unit, and used for subsequent randomisation. Here the laboratories discuss their experiences. Methods Following successful tumour content assessment, blocks were sectioned for DNA extraction and immunohistochemistry (IHC). Pyrosequencing was initially used to determine tumour mutation status (KRAS, NRAS, BRAF and PIK3CA), then from 2018 onwards, next-generation sequencing was employed to allow the inclusion of TP53. Protein expression of MLH1, MSH2, MSH6, PMS2 and pTEN was determined by IHC. An interlaboratory comparison programme was initiated, allowing sample exchanges, to ensure continued assay robustness. Results 1291 tumour samples were successfully analysed. Assay failure rates were very low; 1.9%–3.3% for DNA sequencing and 0.9%–1.3% for IHC. Concordance rates of >98% were seen for the interlaboratory comparisons, where a result was obtained by both laboratories. Conclusions Practical and logistical problems were identified, including poor sample quality and difficulties with sample anonymisation. The often last-minute receipt of a sample for testing and a lack of integration with National Health Service mutation analysis services were challenging. The laboratories benefitted from both pretrial validations and interlaboratory comparisons, resulting in robust assay development and provided confidence during the implementation of new sequencing technologies. We conclude that our centralised approach to biomarker testing in FOCUS4 was effective and successful

Psychopharmacological and Other Treatments in Preschool Children with Attention-Deficit/Hyperactivity Disorder: Current Evidence and Practice

Objective: This article reviews rational approaches to treating attention-deficit/hyperactivity disorder (ADHD) in preschool children, including pharmacological and nonpharmacological treatments. Implications for clinical practice are discussed. Data Sources: We searched MEDLINE, PsychINFO, Cumulative Index to Nursing & Allied Health, Educational Resources Information Center, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects for relevant literature published in English from 1967 to 2007 on preschool ADHD. We also reviewed the references cited in identified reports. Study Selection: Studies were reviewed if the sample included at least some children younger than 6 years of age or attending kindergarten, the study participants had a diagnosis of ADHD or equivalent symptoms, received intervention aimed at ADHD symptoms, and included a relevant outcome measure. Data Extraction: Studies were reviewed for type of intervention and outcome relevant to ADHD and were rated for the level of evidence for adequacy of the data to inform clinical practice. Conclusions: The current level of evidence for adequacy of empirical data to inform clinical practice for shortterm treatment of ADHD in preschool children is Level A for methylphenidate and Level B for parent behavior training, child training, and additive-free elimination diet

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.

Background: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. Methods: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. Results: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. Conclusion: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate

Contesting the psychiatric framing of ME / CFS

ME/CFS is a medically contested illness and its understanding, framing and treatment has been the subject of heated debate. This paper examines why framing the condition as a psychiatric issue—what we refer to as ‘psychiatrisation’—has been so heavily contested by patients and activists. We argue that this contestation is not simply about stigmatising mental health conditions, as some have suggested, but relates to how people diagnosed with mental illness are treated in society, psychiatry and the law. We highlight the potentially harmful consequences of psychiatrisation which can lead to people’s experiential knowledge being discredited. This stems, in part, from a psychiatric-specific form of ‘epistemic injustice’ which can result in unhelpful, unwanted and forced treatments. This understanding helps explain why the psychiatrisation of ME/CFS has become the focus of such bitter debate and why psychiatry itself has become such a significant field of contention, for both ME/CFS patients and mental health service users/survivors. Notwithstanding important differences, both reject the way psychiatry denies patient explanations and understandings, and therefore share a collective struggle for justice and legitimation. Reasons why this shared struggle has not resulted in alliances between ME and mental health activists are noted

Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

PURPOSE Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition. METHODS Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level. RESULTS FOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%). CONCLUSION In this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10-5). While the association was not genome-wide significant (p<1×10-7), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10-6). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al