Exploring anhedonia in adolescents with Chronic Fatigue Syndrome (CFS):A mixed-methods study

BACKGROUND: Chronic Fatigue Syndrome (CFS/ME) may get in the way of enjoying activities. A substantial minority of adolescents with CFS/ME are depressed. Anhedonia is a core symptom of depression. Anhedonia in adolescents with CFS/ME has not been previously investigated. METHOD: One hundred and sixty-four adolescents, age 12 to 18, with CFS/ME completed a diagnostic interview (K-SADS) and questionnaires (HADS, RCADS). We used a mixed-methods approach to explore the experience of anhedonia and examine how common it is, comparing those with clinically significant anhedonia to those without. RESULTS: Forty-two percent of adolescents with CFS/ME reported subclinical or clinical levels of anhedonia. Fifteen percent had clinically significant anhedonia. Thematic analysis generated two themes: (1) stopping activities that they previously enjoyed and (2) CFS/ME obstructs enjoyment. Most (72%) of those who reported clinically significant anhedonia met the depression diagnostic criteria. Those who were depressed used more negative language to describe their experience of activities than in those who were not depressed, although the themes were broadly similar. CONCLUSIONS: Experiencing pleasure from activities may be affected in CFS/ME, particularly in those who are depressed. Anhedonia may get in the way of behavioural strategies used within CFS/ME treatments

Benefits of a Multi-institutional, Hybrid Approach to Teaching Course Design for Graduate Students, Postdoctoral Scholars, and Leaders

In this study, graduate students and postdoctoral scholars participated in a hybrid, multi-institutional workshop series about course design. Trainees developed college courses based on their research expertise, posting works-in-progress to a shared, online drive for peer review and collaboration. Learners also met weekly with local facilitators at their institution. The program led to similar learning outcomes as when the program was previously run in a face-to-face only format at one institution. However, the multi-institutional design led to additional benefits, especially for leaders at each institution, who described a rich learning community in their collaborative work

Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair

Canonical roles for macrophages in mediating the fibrotic response after a heart attack include extracellular matrix turnover and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal that macrophages directly contribute collagen to the forming post-injury scar. Unbiased transcriptomics shows an upregulation of collagens in both zebrafish and mouse macrophages following heart injury. Adoptive transfer of macrophages, from either collagen-tagged zebrafish or adult mouse GFPtpz-collagen donors, enhances scar formation via cell autonomous production of collagen. In zebrafish, the majority of tagged collagen localises proximal to the injury, within the overlying epicardial region, suggesting a possible distinction between macrophage-deposited collagen and that predominantly laid-down by myofibroblasts. Macrophage-specific targeting of col4a3bpa and cognate col4a1 in zebrafish significantly reduces scarring in cryoinjured hosts. Our findings contrast with the current model of scarring, whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair

Experimental neck muscle pain impairs standing balance in humans

Impaired postural control has been reported in patients with chronic neck pain of both traumatic and non-traumatic etiologies, but whether painful stimulation of neck muscle per se can affect balance control during quiet standing in humans remains unclear. The purpose of the present experiment was thus to investigate the effect of experimental neck muscle pain on standing balance in young healthy adults. To achieve this goal, 16 male university students were asked to stand upright as still as possible on a force platform with their eyes closed in two conditions of No pain and Pain of the neck muscles elicited by experimental painful electrical stimulation. Postural control and postural performance were assessed by the displacements of the center of foot pressure (CoP) and of the center of mass (CoM), respectively. The results showed increased CoP and CoM displacements variance, range, mean velocity, and mean and median frequencies in the Pain relative to the No pain condition. The present findings emphasize the destabilizing effect of experimental neck muscle pain per se, and more largely stress the importance of intact neck neuromuscular function on standing balance

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Funding Information: D.B. has consulted for NanoString, reports honoraria from AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. J.R. and M.A.B. have consulted for Achilles Therapeutics. N.M. has stock options in and has consulted for Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004) and predicting survival rates of patients with cancer (PCT/GB2020/050221). A.H. attended one advisory board for Abbvie, Roche and GRAIL, and reports personal fees from Abbvie, Boehringer Ingelheim, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, Merck/MSD, UCB and Roche for delivering general education/training in clinical trials. A.H. owned shares in Illumina and Thermo Fisher Scientific (sold in 2020) and receives fees for membership of Independent Data Monitoring Committees for Roche-sponsored clinical trials. S.A.Q. is co-founder and Chief Scientific Officer of Achilles Therapeutics. A.C.H. is a board member and equity holder in ImmunoQure, AG and Gamma Delta Therapeutics, and is an equity holder in Adaptate Biotherapeutics and chair of the scientific advisory board. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer Ingelheim, Archer Dx Inc (collaboration in minimal residual disease-sequencing technologies) and Ono Pharmaceuticals, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial. C.S has consulted for Amgen, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, GRAIL, Illumina, Medixci, Metabomed, MSD, Novartis, Pfizer, Roche-Ventana and Sarah Cannon Research Institute. C.S. has stock options in Apogen Biotechnologies, Epic Biosciences and GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds patents relating: to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221); to treating cancer by targeting Insertion/deletion (indel) mutations (PCT/GB2018/051893); to identifying indel mutation targets (PCT/GB2018/051892); to methods for lung cancer detection (PCT/US2017/028013); and to identifying responders to cancer treatment (PCT/GB2018/051912). The remaining authors declare no competing interests. Funding Information: We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant no. 203141/Z/16/Z) for the generation and initial processing of the RNA-seq data from sorted TILs. We thank S. Bola for technical support and S. Vanloo for administrative support. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Y.W. was supported by a Wellcome Trust Clinical Research Career Development Fellowship (no. 220589/Z/20/Z), an Academy of Medical Sciences Starter Grant for Clinical Lecturers, a National Institute for Health Research (NIHR) Academic Clinical Lectureship and the NIHR University College London Hospitals Biomedical Research Centre. D.B. was supported by funding from the NIHR University College London Hospitals Biomedical Research Centre, the ideas 2 innovation translation scheme at the Francis Crick Institute, the Breast Cancer Research Foundation (BCRF) and a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award. M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from CRUK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the NIHR Biomedical Research Centre at University College London Hospitals, the CRUK–University College London Centre, Experimental Cancer Medicine Centre and the BCRF. This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (no. FP7/2007-2013) Consolidator Grant (no. FP7-THESEUS-617844), European Commission ITN (no. FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant no. 665233). Publisher Copyright: © 2022, The Author(s).Peer reviewedPublisher PD

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations