A polygenic risk score analysis of ASD and ADHD across emotion recognition subtypes

This study investigated the genetic components of ADHD and ASD by examining the cross-disorder trait of emotion recognition problems. The genetic burden for ADHD and ASD on previously identified emotion recognition factors (speed and accuracy of visual and auditory emotion recognition) and classes (Class 1: Average visual, impulsive auditory; Class 2: Average-strong visual & auditory; Class 3: Impulsive & imprecise visual, average auditory; Class 4: Weak visual & auditory) was assessed using ASD and ADHD polygenic risk scores (PRS). Our sample contained 552 participants: 74 with ADHD, 85 with ASD, 60 with ASD + ADHD, 177 unaffected siblings of ADHD or ASD probands, and 156 controls. ADHD- and ASD-PRS, calculated from the latest ADHD and ASD GWAS meta-analyses, were analyzed across these emotion recognition factors and classes using linear mixed models. Unexpectedly, the analysis of emotion recognition factors showed higher ASD-PRS to be associated with faster visual emotion recognition. The categorical analysis of emotion recognition classes showed ASD-PRS to be reduced in Class 3 compared to the other classes (p value threshold [pT] = 1, p = .021). A dimensional analysis identified a high ADHD-PRS reduced the probability of being assigned to the Class 1 or Class 3 (pT = .05, p = .028 and p = .044, respectively). Though these nominally significant results did not pass FDR correction, they potentially indicate different indirect causative chains from genetics via emotion recognition to ADHD and ASD, which need to be verified in future research

A systematic review to explore the effectiveness of physical health and psychosocial interventions on anxiety, depression and quality of life in people living with blood cancer

Problem identification. Anxiety and depression are more prevalent in hematological cancer patients who experience unpredictable illness trajectories and aggressive treatments compared to solid tumor patients. Efficacy of psychosocial interventions targeted at blood cancer patients is relatively unknown. This systematic review examined trials of physical health and psychosocial interventions intending to improve levels of anxiety, depression, and/or quality of life in adults with hematological cancers. Literature search. PubMed and CINAHL databases were used to perform a systematic review of literature using PRISMA guidelines. Data evaluation/synthesis. Twenty-nine randomized controlled trials of 3232 participants were included. Thirteen studies were physical therapy, nine psychological, five complementary, one nutritional and one spiritual therapy interventions. Improvements were found in all therapy types except nutritional therapy. Conclusions. Interventions that included personal contact with clinicians were more likely to be effective in improving mental health than those without. Implications for psychosocial oncology. Various psychosocial interventions can be offered but interactive components appear crucial for generating long-standing improvements in quality of life, anxiety and depression

An emotion recognition subtyping approach to studying the heterogeneity and comorbidity of autism spectrum disorders and attention-deficit/hyperactivity disorder

BackgroundEmotion recognition dysfunction has been reported in both autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). This suggests that emotion recognition is a cross-disorder trait that may be utilised to understand the heterogeneous psychopathology of ASD and ADHD. We aimed to identify emotion recognition subtypes and to examine their relation with quantitative and diagnostic measures of ASD and ADHD to gain further insight into disorder comorbidity and heterogeneity.MethodsFactor mixture modelling was used on speed and accuracy measures of auditory and visual emotion recognition tasks. These were administered to children and adolescents with ASD (N=89), comorbid ASD+ADHD (N=64), their unaffected siblings (N=122), ADHD (N=111), their unaffected siblings (N=69), and controls (N=220). Identified classes were compared on diagnostic and quantitative symptom measures.ResultsA four-class solution was revealed, with the following emotion recognition abilities: (1) average visual, impulsive auditory; (2) average-strong visual and auditory; (3) impulsive/imprecise visual, average auditory; (4) weak visual and auditory. The weakest performing class (4) contained the highest percentage of patients (66.07%) and the lowest percentage controls (10.09%), scoring the highest on ASD/ADHD measures. The best performing class (2) demonstrated the opposite: 48.98% patients, 15.26% controls with relatively low scores on ASD/ADHD measures.ConclusionsSubgroups of youths can be identified that differ both in quantitative and qualitative aspects of emotion recognition abilities. Weak emotion recognition abilities across sensory domains are linked to an increased risk for ASD as well as ADHD, although emotion recognition impairments alone are neither necessary nor sufficient parts of these disorders

A systematic review of the barriers and facilitators impacting patient enrolment in clinical trials for lung cancer

Purpose. Clinical research trials are needed to enhance the medical care and treatment for lung cancer, which remains the leading cause of cancer-related deaths worldwide. While clinical trials allow for the development of novel therapies to treat cancer, the recruitment of lung cancer patients to trials is low. This review aimed to identify and synthesise the available literature concerning barriers and facilitators affecting lung cancer patients’ decisions to enrol in clinical trials to guide future cancer research efforts. Methods. Four databases were systematically searched: Academic Search Complete, CINHAL, PubMed, and PsycINFO in August 2023. A supplemental grey literature search was also conducted alongside this. Articles were quality appraised using CASP and JMI checklists, and results were narratively synthesised. Results. Eighteen articles of varied design met the inclusion criteria, and results were mapped onto the Capability, Opportunity, and Motivation Behaviour (COM-B) Model to help structure and conceptualise review findings. Evidence suggests that the decision to enrol in a trial is multifaceted and informed by: when and how study information is presented, travel and trial eligibility, and altruistic hopes and fears. Conclusions. There is need to address the many different concerns that lung cancer patients have about participating in a clinical trial through the supply of accessible and timely trial information, and via the reduction of travel, expansion of study eligibility criteria, and recognition of a person's altruistic wishes, hopes, fears, and family-oriented concerns. Future research should aim to work alongside lung cancer patients, clinicians, and other stakeholders to increase research accessibility

The Beaker phenomenon and the genomic transformation of northwest Europe

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain’s gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Challenges and opportunities for conducting a vaccine trial during the COVID-19 pandemic in the United Kingdom

The COVID-19 pandemic has resulted in unprecedented challenges for healthcare systems worldwide. It has also stimulated research in a wide range of areas including rapid diagnostics, novel therapeutics, use of technology to track patients and vaccine development. Here, we describe our experience of rapidly setting up and delivering a novel COVID-19 vaccine trial, using clinical and research staff and facilities in three National Health Service Trusts in Cambridgeshire, United Kingdom. We encountered and overcame a number of challenges including differences in organisational structures, research facilities available, staff experience and skills, information technology and communications infrastructure, and research training and assessment procedures. We overcame these by setting up a project team that included key members from all three organisations that met at least daily by teleconference. This group together worked to identify the best practices and procedures and to harmonise and cascade these to the wider trial team. This enabled us to set up the trial within 25 days and to recruit and vaccinate the participants within a further 23 days. The lessons learned from our experiences could be used to inform the conduct of clinical trials during a future infectious disease pandemic or public health emergency