The Chalcidoidea bush of life: evolutionary history of a massive radiation of minute wasps.

Chalcidoidea are mostly parasitoid wasps that include as many as 500 000 estimated species. Capturing phylogenetic signal from such a massive radiation can be daunting. Chalcidoidea is an excellent example of a hyperdiverse group that has remained recalcitrant to phylogenetic resolution. We combined 1007 exons obtained with Anchored Hybrid Enrichment with 1048 ultra-conserved elements (UCEs) for 433 taxa including all extant families, >95% of all subfamilies, and 356 genera chosen to represent the vast diversity of the superfamily. Going back and forth between the molecular results and our collective knowledge of morphology and biology, we detected bias in the analyses that was driven by the saturation of nucleotide data. Our final results are based on a concatenated analysis of the least saturated exons and UCE datasets (2054 loci, 284 106 sites). Our analyses support an expected sister relationship with Mymarommatoidea. Seven previously recognized families were not monophyletic, so support for a new classification is discussed. Natural history in some cases would appear to be more informative than morphology, as illustrated by the elucidation of a clade of plant gall associates and a clade of taxa with planidial first-instar larvae. The phylogeny suggests a transition from smaller soft-bodied wasps to larger and more heavily sclerotized wasps, with egg parasitism as potentially ancestral for the entire superfamily. Deep divergences in Chalcidoidea coincide with an increase in insect families in the fossil record, and an early shift to phytophagy corresponds with the beginning of the "Angiosperm Terrestrial Revolution". Our dating analyses suggest a middle Jurassic origin of 174 Ma (167.3-180.5 Ma) and a crown age of 162.2 Ma (153.9-169.8 Ma) for Chalcidoidea. During the Cretaceous, Chalcidoidea may have undergone a rapid radiation in southern Gondwana with subsequent dispersals to the Northern Hemisphere. This scenario is discussed with regard to knowledge about the host taxa of chalcid wasps, their fossil record and Earth's palaeogeographic history.

Outcomes reported in randomised trials of surgical prehabilitation: a scoping review.

BACKGROUND: Heterogeneity of reported outcomes can impact the certainty of evidence for prehabilitation. The objective of this scoping review was to systematically map outcomes and assessment tools used in trials of surgical prehabilitation. METHODS: MEDLINE, EMBASE, PsychInfo, Web of Science, CINAHL, and Cochrane were searched in February 2023. Randomised controlled trials of unimodal or multimodal prehabilitation interventions (nutrition, exercise, psychological support) lasting at least 7 days in adults undergoing elective surgery were included. Reported outcomes were classified according to the International Society for Pharmacoeconomics and Outcomes Research framework. RESULTS: We included 76 trials, mostly focused on abdominal or orthopaedic surgeries. A total of 50 different outcomes were identified, measured using 184 outcome assessment tools. Observer-reported outcomes were collected in 86% of trials (n=65), with hospital length of stay being most common. Performance outcomes were reported in 80% of trials (n=61), most commonly as exercise capacity assessed by cardiopulmonary exercise testing. Clinician-reported outcomes were included in 78% (n=59) of trials and most frequently included postoperative complications with Clavien-Dindo classification. Patient-reported outcomes were reported in 76% (n=58) of trials, with health-related quality of life using the 36- or 12-Item Short Form Survey being most prevalent. Biomarker outcomes were reported in 16% of trials (n=12) most commonly using inflammatory markers assessed with C-reactive protein. CONCLUSIONS: There is substantial heterogeneity in the reporting of outcomes and assessment tools across surgical prehabilitation trials. Identification of meaningful outcomes, and agreement on appropriate assessment tools, could inform the development of a prehabilitation core outcomes set to harmonise outcome reporting and facilitate meta-analyses.

Towards a common definition of surgical prehabilitation: a scoping review of randomised trials.

BACKGROUND: There is no universally accepted definition for surgical prehabilitation. The objectives of this scoping review were to (1) identify how surgical prehabilitation is defined across randomised controlled trials and (2) propose a common definition. METHODS: The final search was conducted in February 2023 using MEDLINE, Embase, PsycINFO, Web of Science, CINAHL, and Cochrane. We included randomised controlled trials (RCTs) of unimodal or multimodal prehabilitation interventions (nutrition, exercise, and psychological support) lasting at least 7 days in adults undergoing elective surgery. Qualitative data were analysed using summative content analysis. RESULTS: We identified 76 prehabilitation trials of patients undergoing abdominal (n=26, 34%), orthopaedic (n=20, 26%), thoracic (n=14, 18%), cardiac (n=7, 9%), spinal (n=4, 5%), and other (n=5, 7%) surgeries. Surgical prehabilitation was explicitly defined in more than half of these RCTs (n=42, 55%). Our findings consolidated the following definition: 'Prehabilitation is a process from diagnosis to surgery, consisting of one or more preoperative interventions of exercise, nutrition, psychological strategies and respiratory training, that aims to enhance functional capacity and physiological reserve to allow patients to withstand surgical stressors, improve postoperative outcomes, and facilitate recovery.' CONCLUSIONS: A common definition is the first step towards standardisation, which is needed to guide future high-quality research and advance the field of prehabilitation. The proposed definition should be further evaluated by international stakeholders to ensure that it is comprehensive and globally accepted.

International consensus is needed on a core outcome set to advance the evidence of best practice in cancer prehabilitation services and research.

Prehabilitation aims to optimise patients' physical and psychological status before treatment. The types of outcomes measured to assess the impact of prehabilitation interventions vary across clinical research and service evaluation, limiting the ability to compare between studies and services and to pool data. An international workshop involving academic and clinical experts in cancer prehabilitation was convened in May 2022 at Sheffield Hallam University's Advanced Wellbeing Research Centre, England. The workshop substantiated calls for a core outcome set to advance knowledge and understanding of best practice in cancer prehabilitation and to develop national and international databases to assess outcomes at a population level.

A longitudinal study combining the Double Diamond framework and Behavior Change Wheel to co-create a sedentary behavior intervention in police control rooms.

BACKGROUND: Police work can be sedentary and stressful, negatively impacting health and wellbeing. In a novel co-creation approach, we used the Behavior Change Wheel (BCW) and Double Diamond (DD) design framework to guide the collaborative design and development of a sedentary behavior intervention in the control rooms of two British police forces. METHODS: Multiple stakeholders participated in four phases of research. In Phase 1, a literature review, focus groups (n = 20) and interviews (n = 10) were conducted to 'discover' the relationship between physical activity and wellbeing in the police. In Phase 2, a steering group consolidated Phase 1 findings to 'define' a specific behavior for intervention. Phases 3 and 4 'developed' the intervention across six workshops with control room workers and six steering group workshops. RESULTS: The co-creation process identified contextual sedentary behavior as the target behavior, driven by behavioral regulation, social influence and social norms. The sedentary behavior intervention targeted these drivers and aimed to engage control room workers in short bursts of physical activity throughout their shifts. Key intervention features targeted involvement of staff in decision-making and embedding physical activity into work practices. CONCLUSIONS: The BCW and DD can be combined to co-create evidence-based and participant-informed interventions and translate science into action.

Tackling physical inactivity and inequalities: implementing a whole systems approach to transform community provision for disabled people and people with long-term health conditions.

BACKGROUND: Physical inactivity is a global public health priority. There are known health and well-being consequences of being inactive, and the benefits of being physically active are well established. However, there are persistent inequalities when it comes to how physically active people are, with disabled people, people living with long-term health conditions, and people residing in areas of socio-economic deprivation being particularly affected. Methods such as whole system approaches (WSAs), which are dynamic, multifaceted, and engage all relevant stakeholders, have gained momentum as an approach to address such complex public health problems. However, evidence relating to the implementation of WSAs to address physical inactivity is lacking. The aim of the Prevention and Enablement Model (PEM) was to take a whole system approach in Essex to encourage and support disabled people and/or individuals living with long-term health conditions to be more active, happier, and to live more independently. METHODS: The aim of this study was to explore the enablers, challenges, and reflections associated with the process of designing and implementing the PEM. Semi-structured interviews (n = 12) were used to collect data from people involved in the PEM's design, implementation and/or delivery. Data was analysed using Braun and Clarke's reflexive thematic analysis. RESULTS: Four themes were identified: (1) Working collaboratively: Specific enablers of time and space were identified as important in the planning and implementation of a WSA (2) Leadership and planning: Distributed and flexible leadership was identified as central to successful implementation (3) Re-orientating practice: Highlighted the transformative potential of a whole system approach and how it contrasts with conventional work practices, and (4) Reflection and learning: Informing ongoing refinements and further implementation of successful system change. CONCLUSIONS: These findings highlight the challenge and complexity of implementing a WSA that involves diverse stakeholders from across adult social care, the NHS, and the third sector. Several important enablers are identified, such as leadership and planning, and the challenges and discomfort that can arise whilst changing systems. Ongoing efforts are required to ensure that different elements of the system collaborate effectively to address inequalities in physical activity participation, through the implementation of a WSA.

Deregulated miRNA Expression in Triple-Negative Breast Cancer of Ancestral Genomic-Characterized Latina Patients.

Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, high p53 expression, increased cancer recurrence, presence of distant metastasis, and deceased status. This study reinforces the importance of integration analysis of CNAs and miRNAs in TNBC, allowing for the identification of interactions among molecular mechanisms. Additionally, this study emphasizes the significance of considering the patients ancestral background when examining TNBC, as it can influence the relationship between intrinsic tumor molecular characteristics and clinical manifestations of the disease.

Use of the behaviour change wheel to improve everyday person-centred conversations on physical activity across healthcare.

BACKGROUND: An implementation gap exists between the evidence supporting physical activity in the prevention and management of long-term medical conditions and clinical practice. Person-centred conversations, i.e. focussing on the values, preferences and aspirations of each individual, are required from healthcare professionals. However, many currently lack the capability, opportunity, and motivation to have these conversations. This study uses the Behaviour Change Wheel (BCW) to inform the development of practical and educational resources to help bridge this gap. METHODS: The BCW provides a theoretical approach to enable the systematic development of behaviour change interventions. Authors followed the described eight-step process, considered results from a scoping review, consulted clinical working groups, tested and developed ideas across clinical pathways, and agreed on solutions to each stage by consensus. RESULTS: The behavioural diagnosis identified healthcare professionals' initiation of person-centred conversations on physical activity at all appropriate opportunities in routine medical care as a suitable primary target for interventions. Six intervention functions and five policy categories met the APEASE criteria. We mapped 17 Behavioural Change Techniques onto BCW intervention functions to define intervention strategies. CONCLUSIONS: This study uses the BCW to outline a coherent approach for intervention development to improve healthcare professionals' frequency and quality of conversations on physical activity across clinical practice. Time-sensitive and role-specific resources might help healthcare professionals understand the focus of their intervention. Educational resources aimed at healthcare professionals and patients could have mutual benefit, should fit into existing care pathways and support professional development. A trusted information source with single-point access via the internet is likely to improve accessibility. Future evaluation of resources built and coded using this framework is required to establish the effectiveness of this approach and help improve understanding of what works to change conversations around physical activity in clinical practice.

The relationship between physical activity and severity of COVID-19 symptoms in non-hospitalized individuals.

BACKGROUND: The study explored the relationship between physical activity (PA) behaviour and severity of symptoms in people infected by coronavirus disease 2019 (COVID-19). METHODS: Five hundred and thirty-three people [16% males, mean age: 45 ± 11 years, body mass index (BMI): 23.3 ± 20] took part in the study. All participants were post-COVID-19 infection. An online questionnaire was used to gather data on; participants demographics, comorbidities and treatment, symptomatology of COVID-19, quality of life (QoL) and pre- and post-COVID-19 infection PA. RESULTS: Logistic regression revealed that only a high BMI (>25) increased the severity of (odds ratio 1.01; 95% confidence interval, 0.99-1.03) symptoms from none to mild-to-moderate. Weekly PA behaviour (min/week) did not affect the primary outcome (symptom severity) as a predictor variable and neither differ (P > 0.05) between symptomatology for both moderate (no symptoms: 181.3 ± 202.1 vs. mild-to-moderate symptoms: 173 ± 210.3) and vigorous (no symptoms: 89.2 ± 147 vs. mild-to-moderate symptoms: 88.9 ± 148.3) PA. QoL (i.e. mobility, self-care, usual activities, pain/discomfort, anxiety/depression and perceived health) was significantly (P < 0.05) worse post-COVID-19 infection. CONCLUSIONS: Our findings did not present an association between PA levels and mild-to-moderate COVID-19 symptoms. However, all participants exceeded the lower limit of the World Health Organization recommended, adult PA dose. This might explain the lack of PA effect, on mild-to-moderate symptoms post-COVID-19 infection. Future studies should explore the effects of PA levels in more severe cases (e.g. hospitalizations) and assess the effectiveness of PA to reduce hospitalizations, and mortality rates as a result of COVID-19 infection.

Chance Favors the Perplexed Mind: The Critical Role of Mechanistic Biochemistry in Drug Discovery.

Scientific discoveries often start with an observation that does not quite make sense, within the framework of a well-established hypothesis. It is when researchers delve deeply to understand such perplexing data that established hypotheses are modified or replaced, and new and expanded knowledge of the system can be gained. This is often the case in the field of drug discovery. In this Perspective, case studies demonstrate how an understanding of perplexing data can lead to novel discoveries regarding the biological function of drug targets, or the mechanisms of compound-target interactions, that can ultimately result in new drugs entering the clinic. These case studies reinforce two interdependent themes: (1) that understanding the pathophysiological context in which drug targets function and the mechanistic details of drug-target interactions are critical to efficient and effective drug discovery and (2) that investing time and energy into following up on perplexing data can lead to novel discoveries that can drive the development of new and improved medicines.

A panel of miRNAs as prognostic markers for African-American patients with triple negative breast cancer.

BACKGROUND: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways, and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC). METHODS: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions. RESULTS: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seven (let-7f-5p, miR-1255b-5p, miR-1268b, miR-200c-3p, miR-520d, miR-527, and miR-518a-5p), and three (miR-1200, miR-1249-3p, and miR-1271-3p) miRNAs showed a robust discriminatory power based on tumor size (AUC = 0.917), LN (AUC = 0.945) and REC (AUC = 0.981) status, respectively. Enrichment pathway analysis revealed their involvement in proteoglycans and glycan and cancer-associated pathways. Eight miRNAs with deregulated expressions in patients with large tumor size, positive LN metastasis, and recurrence were significantly associated with lower survival rates. Finally, the construction of miRNA/mRNA networks based in experimentally validated mRNA targets, revealed nodes of critical cancer genes, such as AKT1, BCL2, CDKN1A, EZR and PTEN. CONCLUSIONS: Altogether, our data indicate that miRNA deregulated expression is a relevant biological factor that can be associated with the poor prognosis in TNBC of AA patients, by conferring to their TNBC cells aggressive phenotypes that are reflected in the clinical characteristics evaluated in this study.

High-intensity exercise to improve cardiorespiratory fitness in cancer patients and survivors: A systematic review and meta-analysis.

Improving cardiorespiratory fitness (CRFit) in cancer patients is crucial to increase survivorship, promote health, and improve quality of life. High-intensity training (HIT) has the potential to increase CRFit, perhaps better than other exercise modalities, but the extant evidence has yet to be fully explored. This systematic review and meta-analysis aimed to evaluate the effects of HIT on CRFit in cancer patients and survivors and to identify the optimal characteristics of the interventions (eg, cancer type, intervention timing, exercise modality, intervention's duration, and the number of minutes of high-intensity exercise in each session). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. A total of 31 articles (2515 participants) were included in the systematic review and 25 in the meta-analyses. CRFit significantly improved with HIT in comparison with a control group (P < .00001, SMD = 0.44 and a 95% confidence interval from 0.25 to 0.64). The results obtained in the sub-analysis were statistically significant except the comparison with the active group CRFit (P = .13). The results showed that higher effects could be achieved in: patients starting to exercise before treatment, interventions longer than eight weeks, programs including exclusively cardiovascular training and with a high-intensity part of session duration of at least 20 minutes.

Exploring the benefits of participation in community-based running and walking events: a cross-sectional survey of parkrun participants.

BACKGROUND: Whilst the benefits of physical activity for health and wellbeing are recognised, population levels of activity remain low. Significant inequalities exist, with socioeconomically disadvantaged populations being less physically active and less likely to participate in community events. We investigated the perceived benefits from participation in a weekly running/walking event called parkrun by those living in the most socioeconomically deprived areas and doing the least physical activity. METHODS: A cross-sectional online survey was emailed to 2,318,135 parkrun participants in the UK. Demographic and self-reported data was collected on life satisfaction, happiness, health status, physical activity, motives, and the perceived benefits of parkrun. Motivation, health status and benefits were compared for sub-groups defined by physical activity level at parkrun registration and residential Index of Multiple Deprivation. RESULTS: 60,000 completed surveys were received (2.7% of those contacted). Respondents were more recently registered with parkrun (3.1 v. 3.5 years) than the parkrun population and had a higher frequency of parkrun participation (14.5 v. 3.7 parkruns per year). Those inactive at registration and from deprived areas reported lower happiness, lower life satisfaction and poorer health compared to the full sample. They were more likely to want to improve their physical health, rather than get fit or for competition. Of those reporting less than one bout of activity per week at registration, 88% (87% in the most deprived areas) increased their physical activity level and 52% (65% in the most deprived areas) reported improvements to overall health behaviours. When compared to the full sample, a greater proportion of previously inactive respondents from the most deprived areas reported improvements to fitness (92% v. 89%), physical health (90% v. 85%), happiness (84% v. 79%) and mental health (76% v. 69%). CONCLUSION: The least active respondents from the most socioeconomically deprived areas reported increases to their activity levels and benefits to health and wellbeing since participating in parkrun. Whilst the challenge of identifying how community initiatives like parkrun can better engage with underrepresented populations remains, if this can be achieved they could have a critical public health role in addressing inequalities in benefits associated with recreational physical activity.

"The balloon was just the kick start, I had to do the rest myself": Adolescents living with severe obesity experiences of an intra-gastric balloon alongside a lifestyle support programme.

BACKGROUND: Few treatments exist for adolescents living with severe obesity. This qualitative study explored the experiences of severely obese adolescents and their families who participated in the BOB study. METHODS: Twelve adolescents (5 males;7 females; mean age 15 years; BMI > 3.5 s.d; puberty stage 4 +) who were engaged with the research study BOB (a non-randomised, pilot novel obesity treatment programme that involved the insertion of an intra-gastric balloon coupled with a family lifestyle behavioural support programme). Adolescents attended weekly lifestyle sessions before, during and post balloon insertion. All participants were interviewed at 3 months, (halfway through intra-gastric balloon insertion) and at 12 months follow-up (6 months post intra-gastric balloon removal, 3 months post lifestyle intervention). RESULTS: All BOB participants had exhausted all treatment options deeming this study their final option. Many alluded to feelings of desperation and referred to a sense of hope that this intervention would be effective. Family involvement and attendance within the structured sessions differed significantly. Adolescents and parents perceived support from the research study ceased when the intra-gastric balloon was removed at 6-months despite attendance post balloon removal being poor. All participants emphasised a need for further support longer term with the integration of the family a critical factor. CONCLUSIONS: Further research is needed to explore the specific role families play within treatment to optimise health and wellbeing outcomes. Adolescents perspectives should be integrated within treatment to inform and improve the effectiveness of future treatment programmes for severely obese adolescents and their families.

Developing a theory-driven framework for a football intervention for men with severe, moderate or enduring mental health problems: a participatory realist synthesis.

Background: Physical activity interventions are an important adjunct therapy for people with severe to moderate and/or enduring mental health problems. Football is particularly popular for men in this group. Several interventions have emerged over the past decade and there is a need to clearly articulate how they are intended to work, for whom and in what circumstances.Aims: To develop a theory-driven framework for a football intervention for men with severe, moderate and/or enduring mental health problems using a participatory realist approach.Methods: A participatory literature review on playing football as a means of promoting mental health recovery with a realist synthesis. It included the accounts and input of 12 mental health service users and the contributions of other stakeholders including football coaches and occupational therapists.Results: Fourteen papers were included in the review. Analysis revealed that interventional mechanisms were social connectedness, identity security, normalising experiences and positive affectivity. These supported mental health recovery. Outcomes were moderated by social stigma and several interventional factors such as over-competitiveness.Conclusions: The context mechanism outcome configuration framework for these interventions map well onto social models of mental health recovery and provide insight into how they work. This now requires testing.

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.

BACKGROUND: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2. METHODS: We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing. FINDINGS: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. INTERPRETATION: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. FUNDING: Epizyme and Eisai.

Barriers and facilitators to implementing workplace health and wellbeing services in the NHS from the perspective of senior leaders and wellbeing practitioners: a qualitative study.

BACKGROUND: The National Health Service (NHS) seems appropriately placed to be an exemplar employer in providing effective and proactive workplace health and wellbeing services for its staff. However, NHS staff sickness absence costs an estimated £2.4 billion. Evidence suggests staff health and wellbeing services delivered in the NHS can improve health, productivity and sickness absence and yet the adoption of these services remains a challenge, with few examples nationally. This research aimed to explore the perceptions of NHS senior leaders and health and wellbeing practitioners regarding barriers and facilitators to implementing workplace health and wellbeing services for staff in the NHS. METHODS: Semi-structured interviews were conducted with NHS staff, consisting of four senior leaders, four heads of department and three health and wellbeing practitioners in one region of the UK. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Themes describe the experience of delivering workplace health and wellbeing services in the NHS, and barriers and facilitators to implementation from senior decision makers. Barriers to implementation of services include; a busy and pressurised environment, financial constraints and reluctance to invest in staff health and wellbeing. Barriers to staff engagement were also reported and include difficulty of access to health and wellbeing services and lack of time. Initiating services were facilitated by financial incentives, a supportive organisational structure and culture that takes a preventative, rather than reactive, approach to staff health and wellbeing. Facilitators to implementing health and wellbeing services include a coherent, strategic approach to implementation, effective communication and advertisement, being creative and innovative with resources and conducting a needs analysis and evaluation before, during and after implementation. CONCLUSIONS: Barriers to the successful initiation and implementation of health and wellbeing services in the NHS are numerous and range from front-line logistical issues with implementation to high-level strategic and financial constraints. Adopting a strategic and needs-led approach to implementation and ensuring thorough staff engagement are amongst a number of factors that facilitate implementation and help overcome barriers to initiation of wellbeing programmes in the NHS. There is a need for a culture that supports staff health and wellbeing in the NHS.

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

PRC2 and SWI/SNF Chromatin Remodeling Complexes in Health and Disease.

The dynamic structure of histones and DNA, also known as chromatin, is regulated by two classes of enzymes: those that mediate covalent modifications on either histone proteins or DNA and those that use the energy generated by ATP hydrolysis to mechanically alter chromatic structure. Both classes of enzymes are often found in large protein complexes. In this review, we describe two such complexes: polycomb repressive complex 2 (PRC2), with the protein methyltransferase EZH2 as its catalytic subunit, and the ATP-dependent chromatin remodeler switch/sucrose non-fermentable (SWI/SNF). EZH2 catalyzes the methylation of lysine 27 on histone H3, a covalent chromatin modification that is associated with repressed heterochromatin. The catalytic activity of SWI/SNF, in contrast, leads to a state of open chromatin associated with active transcription. In this review, we discuss the biochemical properties of both complexes, outline the principles of their regulation, and describe their opposing roles in normal development, which can be perturbed in disease settings such as cancer.