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Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Background Arising in blood and lymph-forming tissues, haematological malignancies (leukaemias, lymphomas and myelomas) are the fifth most common group of cancers. Around 60% are currently incurable and follow a chronic, remitting–relapsing pathway often initially managed by ‘watch & wait’. This involves hospital-based monitoring, followed by treatment if the cancer progresses (which not all do) and then further observation, in a process that may continually repeat. New treatments are constantly emerging, survival is improving and prevalence is rising, but population-based data documenting entire care pathway are sparse. Hence, empirically-based incidence and prevalence estimates about various treatment states (watch and wait, first-line treatment, observation, second-line treatment, etc.) and patterns of healthcare activity are lacking. Likewise, despite complex trajectories, anxiety-provoking watch and wait, and therapies that impede quality of life and incur marked healthcare costs, evidence about patient preferences for information sharing and treatment decisions is scant. Objectives Primary – to generate high-quality, evidence-based information about the care pathways of the general population of patients with chronic haematological malignancies. Secondary – to produce information resources suitable for testing in routine National Health Service practice. Design Population-based cohort of ≈ 8000 patients with chronic haematological malignancies, incorporating five nested work packages, each with its own individual design: (1) exploration of patient experiences: information and treatment decisions; (2) population-based analyses; (3) health economics; (4) development of information resources to support decision-making; and (5) patient well-being and decision-making survey. Setting This programme is predicated on the infrastructure of the United Kingdom’s Haematological Malignancy Research Network (www.hmrn.org); which provides ‘real-world’, robust, generalisable data to inform research and clinical practice, nationally and internationally. Set in Yorkshire and Humberside, the Haematological Malignancy Research Network’s catchment population of ≈ 4 million has a comparable sex, age, urban/rural, and area-based deprivation (Index of Multiple Deprivation, income domain) distribution to the United Kingdom as a whole; and in terms of ethnic diversity the region is centrally ranked, with around 80% of residents identifying as White British, 9% as Asian and 2% as black. Within the Haematological Malignancy Research Network, clinical practice adheres to national guidelines, and all patients with blood cancers are centrally diagnosed (≈ 2500 each year), tracked through their treatment pathways and linked to national databases (deaths, cancer registrations and Hospital Episode Statistics). Linked to the same national databases, the Haematological Malignancy Research Network also contains an age- and sex-matched general-population cohort. Participants Patients aged ≥ 18 years, resident in the study region, and diagnosed with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Methods Core Haematological Malignancy Research Network data were used to compare the hospital activity of patients with chronic lymphocytic leukaemia, follicular lymphoma and myeloma with that of the general population. Following additional linkages to genetic and clinical data, follicular lymphoma prognostic factors were examined. Two self-administered questionnaires addressing (1) quality of life and well-being and (2) decision-making were iteratively developed, piloted and deployed. Linkage to quality of life, clinical information and Hospital Episode Statistics enabled economic (myeloma) model development. In-depth interviews were conducted with 35 patients (10 alongside relatives). Results Trajectories of ≈ 8000 patients were mapped, and patient-pathway visualisations summarising individual and aggregate information were developed. As expected, patients with chronic blood cancers experienced higher levels of hospital activity than their general population counterparts, the largest effects being for myeloma. Following survey deployment, 3153 patients were recruited across 14 hospitals, 1282 with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Over half of the questionnaires were completed by patients on watch and wait; the remainder were completed during treatment or post-chemotherapy monitoring. Information gathered, coupled with in-depth interviews, demonstrated patients’ marked anxiety and fluctuating preferences for information sharing and decision-making, contingent on complex, inter-related factors. In turn, prognostic and microsimulation economic models were used to predict individual-level trajectories across multiple treatment lines, examining associated overall survival, costs and quality-adjusted life-years. Limitations Survey mapping to individual care pathways could not be completed because the COVID-19 pandemic delayed clinical data collection. Patients who attended clinics and participated in the survey were more likely than non-attenders to have had first-line chemotherapy, be slightly younger and live in more affluent areas. Conclusions This programme collated high-quality, population-based evidence. Previously lacking, this, coupled with new findings on preferences for information sharing and treatment decisions, provides the foundation for future research. Future work The translation of information accrued into resources suitable for testing in routine NHS practice is key. In this regard, COVID-19 has changed the communication landscape. The visualisations developed by this programme require further refinement/testing using participatory co-design with stakeholder groups. Underpinned by a suitable protocol applied within a single multidisciplinary team setting, prior to further evaluation within/outside the region, such outputs require testing in a cluster-randomised trial. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0613-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 5. See the NIHR Funding and Awards website for further award information. Plain language summary Around half of all blood cancers (leukaemias, lymphomas and myeloma) are chronic and incurable. Management often involves ‘watch and wait’, which begins with hospital-based monitoring and is followed by treatment if the cancer progresses. This typically leads to further observation and treatment in an ongoing process over time. Patients often experience anxiety and distress about not being treated at diagnosis and also because of uncertainty about ‘if’ and ‘when’ chemotherapy might be needed. Information is critical if patients are to (1) understand what may happen to them in the future and (2) be involved treatment decisions. However, evidence about the care pathways most patients follow is lacking. This programme was designed to fill this gap, tracking all patients with chronic blood cancers through their care pathways. We collected information about diagnosis, treatment and outcome on approximately 8000 patients. These data were used to develop models that could be used to examine outcomes and costs. When compared with the general population, patients with blood cancer were confirmed to have more healthcare activity (e.g. hospital appointments and admissions). Computer programs were developed to electronically generate visual care-pathway ‘maps’ that revealed key similarities and differences between patient groups. Two questionnaires exploring quality of life and involvement in treatment decisions were developed and completed by 3153 patients in 14 hospitals. Thirty-five patients were interviewed about their preferences for information sharing and decision-making; needs were found to differ between patients and over time, and treatment recommendations from clinical staff were generally preferred. Emotional difficulties associated with uncertain trajectories were also clearly described. Yielding new information about the pathways of patients with chronic haematological malignancies, findings from this programme can be built on to improve future care. Final information resources could not be developed or tested in practice due to COVID-19, which continues to impact how health care is delivered. Scientific summary Background Population-based data are required to inform aetiological hypotheses, plan healthcare services and monitor the impact of therapeutic change in the general patient population. This need for data is particularly pertinent in fast-moving areas such as haemato-oncology, where treatments change rapidly and ‘gold-standard’ randomised controlled trials are absent or restricted to specific subgroups (often younger patients with fewer comorbidities), to specific time points (commonly first-line treatment) or by factors such as socioeconomic status, gender or ethnicity. Arising in blood and lymph-forming tissues, haematological malignancies (leukaemias, lymphomas and myelomas) are, collectively, the fifth most common cancer. With diverse aetiologies, treatments and outcomes, more than 100 subtypes are currently recognised by the World Health Organization. Although the incidence of these cancers is stable in high-income countries such as the UK, prevalence is increasing due to population ageing and the development of new multifaceted regimens (e.g. chemotherapies, radiotherapy, stem cell transplants, novel targeted agents). However, around 60% of blood cancers remain incurable, with management often beginning with regular hospital-based monitoring, known as ‘watch & wait’ (W&W). While some patients may never need treatment, others often experience a remitting–relapsing care pathway, requiring treatment at progression interspersed with further monitoring. As with many chronic conditions, there are often uncertainties regarding how individual trajectories will progress, and variations are evident in the need for (and response to) treatment; the most effective regimen; the time when treatment is required (if ever); and the impact of treatment (and non-treatment) on quality of life. Despite such complex trajectories, many of which are associated with anxiety-provoking W&W, and therapies that impede quality of life and incur marked healthcare costs, empirically-based incidence and prevalence estimates relating to treatment states (W&W, first-line treatment, second-line treatment, etc.) are lacking, and granular population-based evidence to guide treatment decisions is sparse. Importantly, new data-gathering measures to redress this deficit have been introduced in the UK but are presently insufficiently mature to guide decisions, and the rapidly evolving nature of haemato-oncology means that generic sources may never be adequate for assessing particular therapies and their impact on individuals. Furthermore, most health economic models have been developed to reflect specific (often static) decision problems, despite effective clinical management being dynamic, involving treatment, monitoring and therapy switching, and depending on treatment response and disease evolution. To summarise, there is a dearth of accessible, reliable information to guide clinicians and patients about treatment and associated healthcare activities, physical health (e.g. disruption to daily life), psychosocial well-being, quality of life and life expectancy. This situation, which is particularly difficult for patients who face uncertain pathways and unresolved anxiety about the future, is compounded by the fact that little is known about preferences for information sharing and the desire to engage in treatment decisions. Objectives This programme sought to address the deficits described above, the premise being that the provision of personalised evidence-based information at key decision points would facilitate treatment decisions, support clinical practice and improve patient experiences. The objectives were as follows: primary – to generate high-quality, longitudinal, real-world information about the care pathways of the general population of patients with chronic haematological malignancies, incorporating data on healthcare costs, and patient preferences for information sharing and engagement in treatment decisions secondary – to produce accessible information resources suitable for testing in routine NHS practice. Design This was a population-based cohort of ≈ 8000 patients with chronic haematological malignancies, incorporating 5 distinct, but inter-related, nested work packages with individual designs, including longitudinal studies, cross-sectional surveys, data linkage and qualitative investigation of patient experiences, as follows: in-depth exploration of patient experiences: information and decision-making population-based analyses health economics development of information resources to support decision-making patient well-being and decision-making survey. Setting This programme is predicated on the established expertise and infrastructure of the UK’s Haematological Malignancy Research Network (HMRN; www.hmrn.org), which was initiated in 2004 to provide robust, generalisable data to inform research and clinical practice. Set in Yorkshire and Humberside, HMRN’s population of ≈ 4 million people has a comparable sex, age, urban/rural and area-based deprivation (Index of Multiple Deprivation, income domain) distribution to that of the UK. Within HMRN, clinical practice adheres to national guidelines, and all patients are centrally diagnosed (≈ 2500 each year), tracked through their care pathways and linked to nationwide health administrative databases (deaths, cancer registrations and Hospital Episode Statistics). HMRN also contains a general-population cohort linked to the same nationwide administrative databases as the patient cohort. HMRN has ethics approval (Leeds West Research Ethics Committee 04/Q1205/69) and Section 251 support [NHS Act 2006: Patient Information and Advisory Group 1-05(h)2007], which provides the legal basis for data collection/linkage. Research building on HMRN’s infrastructure requires supplementary approvals, granted for this programme by the London, City and East Committee (Research Ethics Committee 16/LO/0740). Participants Participants were patients aged ≥ 18 years resident in the study area and diagnosed with one of the three commonest chronic haematological malignancies: chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Patient public involvement and engagement Patient and public involvement and engagement is integral to HMRN, and lay individuals are routinely involved in all research activities via the Patient Partnership, which was established in 2009 and is overseen by a Partnership Committee comprising patients, relatives/carers and researchers. The Partnership includes several hundred people who have agreed to further contact for research purposes, including directing HMRN’s activities and participating in surveys and individual/group discussions. HMRN also benefits from a group that act as a ‘sounding board’, ensuring that all our research is patient-centred and relevant. Patients and relatives were involved in the current programme as applicants and participants. Discussions preceding our application identified issues for investigation, based on patient experiences. Information was considered an area requiring improvement because of widespread concern about W&W and the anxiety and distress that this was said to instil due to uncertainty about ‘if’ and ‘when’ treatment may be required, and its likely impact. Such stories underpinned this programme, alongside our ability (via HMRN) to provide information, mapped to pathways. Changes to programme Following piloting, the survey instrument was split and the content expanded. Questionnaire 1 focused on quality of life and was to be completed pre appointment, and questionnaire 2 targeted treatment decisions and was to be completed post appointment. The number of in-depth interviews was finalised at 35 as the purposeful sampling strategy identified ‘information-rich’ sources and high-quality data. Finally, the secondary objective was curtailed by the COVID-19 pandemic (see Conclusions). Results Patient characteristics and treatment pathways With a median diagnostic age of 71 years, chronic lymphocytic leukaemia and myeloma occur more frequently in men than in women. By contrast, with a younger median age of 65.5 years, follicular lymphoma has a slight preponderance among female patients. First-line management varied markedly by subtype; 84.7% of chronic lymphocytic leukaemia patients were monitored via W&W, compared with 40.9% with follicular lymphoma and 20.2% with myeloma. Furthermore, with a 5-year relative survival of 47.7%, patients with myeloma fared less well than those with chronic lymphocytic leukaemia (5-year relative survival 84.1%) or follicular lymphoma (5-year relative survival 88.1%). To quantify/visualise the data, two software applications were developed. First, a tree-based approach aggregated patients into pathway subgroups, beginning with the initial management or event (chemotherapy, observation or death) and ending with the last. Diversity by cancer subtype was clearly evident: among those diagnosed between 2004 and 2010 who were initially managed by W&W, 40.6% (419/1031) with chronic lymphocytic leukaemia, 38.4% (93/242) with follicular lymphoma and 26.5% (90/339) with myeloma were still on W&W at the end of follow-up (5–11 years later). Second, a patient pathway generator was developed in-house from a Data-Driven Documents (D3) JavaScript library (https://d3js.org/), followed by an iterative graphical restructuring algorithm that displayed visualisations of entire pathways that included all diagnoses, investigations, treatments/responses and hospital activity in real time (generation < 1 second). Population-based analysis and prognostic model Facilitating the identification of patients requiring alternative treatment strategies and separating those at high-risk of disease progression and/or transformation from those who are not is important for clinicians and patients. With a view to incorporating genetic data into conventional prognostic models and the future development of novel targeted treatments, we examined the mutational data of patients newly diagnosed with follicular lymphoma. The molecular investigations undertaken determined that aberrant somatic hypermutations played a leading role in the genetic substructure of follicular lymphoma, with a small number of key genetic mutations, including STAT6, having a marked impact on prognosis. These clusters have implications both for understanding pathogenesis and for potential future treatment strategies. However, separation of follicular lymphoma according to mutational status despite being linked to apparent underlying mechanistic differences provides only limited prognostic information in conventionally treated patients. Hospital activity patterns Patients often question the difference their disease, or treatment, is likely to have on their survival, future healthcare needs and quality of life. As expected, inpatient and outpatient Hospital Episode Statistics activity post diagnosis was considerably higher among patients with chronic haematological malignancies than in the general population, the largest differences being for myeloma. For all three diagnoses, hospital activity peaks around the time of diagnosis, outpatient activity remaining high but levelling around 12 months after diagnosis, and inpatient activity around 8 months post diagnosis for chronic lymphocytic leukaemia and 36 months for follicular lymphoma. Health economics A microsimulation model was developed for myeloma to reflect multiple lines of treatment, post-treatment surveillance and overall survival. The model was used to predict long-term costs, and quality-adjusted life-years to enable future assessment of the expected impact of new treatments and policies. Input parameters were estimated by analysing individual-level time-to-event data (to represent patients’ trajectories), the EuroQol-5 Dimensions, five-level version (to derive quality-adjusted life-years), and HMRN treatment data (to model treatment sequences). Healthcare costs were estimated from Hospital Episode Statistics, based on national tariffs. The model is flexible enough to incorporate evidence from other sources, including clinical trials. Results were based on 2687 patients with myeloma, diagnosed 2004–15 and followed up until December 2017. Patient survey Two questionnaires for use in haemato-oncology outpatient clinics were developed in-house and piloted: questionnaire 1 (health-related quality of life) was to be completed before the clinic appointment, and questionnaire 2 (treatment decisions) was to be completed after. The survey was successfully implemented in all 14 HMRN hospitals, 2016–8, with 3153 patients participating, 1282 with chronic lymphocytic leukaemia, follicular lymphoma or myeloma. Providing information across the pathway, over half of patients completed questionnaires while on W&W; the remainder either received chemotherapy or were monitored post treatment. Survey distribution and data collection were found to be simple and effective, and patients said that they appreciated the opportunity to ‘give back’ via taking part in research. Patient preferences for information sharing and engagement in treatment decisions Interviews were conducted with 35 patients who had experienced varying treatment pathways, and 10 relatives. A large, rich data set generated multifaceted findings. The unpredictable nature of chronic haematological malignancies was confirmed, as were the challenges of coping with uncertain pathways. This caused prolonged anxiety, which could be more distressing than any physical symptoms and difficult to resolve because of infrequent clinic visits and an absence of definitive information. Preferences for information (timing, content, depth and format) varied markedly, both between patients and across individual pathways over time. Regarding treatment decisions, most interviewees said that they preferred a discussion about options, but did not wish, or felt ill-equipped, to make choices themselves. Finally, individual access to a support network (e.g. family, friends or clinical staff) was found to impact positively on experiences and preferences. Conclusions Enhancing understanding about the pathways of the general population of patients with chronic haematological malignancies, this programme has accrued an abundance of new evidence. Data collection instruments have been developed, pathway visualisation programmes have been written, and detailed quantitative and qualitative information, to an extent not previously captured, are now available. We have demonstrated that it is possible to distribute questionnaires and collect longitudinal data in hospital settings, and assemble, summarise and visualise longitudinal pathways, including data on diagnostics, prognostics, treatments, transformations/progressions, hospital episodes, outcomes and costs. Regarding health economics, we have shown the utility of using longitudinal data to estimate how many patients are on each treatment line, post treatment after each line, receiving palliative care, and so on, thereby facilitating cost calculations and resource planning. Such models could potentially be used by commissioners and healthcare managers to simulate the impact of novel policies, treatments and pathway changes prior to their introduction. The marked, ongoing anxiety experienced by some patients due to uncertain pathways suggests that benefits could be accrued from increased awareness about the extent and impact of this, alongside interventions to counteract such difficulties. Addressing varied preferences for information (content, depth, format and timing) would require a broad range and depth of material (from a basic overview to detailed options), complexity (from simple terminology to more complicated graphs) and methods for sharing (verbal, written or electronic), thereby enabling patients to access what they want to know, when they want to know it. As most (but not all) people reported a preference for clinicians to make treatment recommendations, this should also be considered. Changing preferences means that strategies for patient engagement with information-sharing and treatment decisions may need to be tailored to individual needs over time, assessed by routine clinician monitoring. Clinicians might also explore the social infrastructure and support network available to patients, so that they are aware of gaps that could be addressed. Based on several thousand patients, and exceeding any evidence previously generated, this programme collated, assessed and successfully mapped high-quality evidence-based information about the pathways of the general population of patients with chronic haematological malignancies. Previously lacking, these data, coupled with new evidence on preferences for information-sharing and treatment decisions garnered directly from patients, provide the foundation to improve clinical practice. Unfortunately, the final part of the programme could not be completed due to the COVID-19 pandemic; hence, the key future priority is the translation of the data accrued into accessible information resources suitable for testing in routine NHS practice. These would need to be responsive to both the rapidly changing haemato-oncology landscape and the varying needs of clinicians and patients at different points on the pathway. Building on the foundations of the present programme, future research, in collaboration with clinicians and patients, could include: co-refinement of electronic visualisations for use in multidisciplinary team settings co-design of resources for use in clinician–patient consultations development of cluster randomised trial protocols to test resources developed in (1) and (2) across a single multidisciplinary team area using the data collection instruments developed, prior to further evaluation within/outside the region. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-0613-20002) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 5. See the NIHR Funding and Awards website for further award information.

(1) Background: In a metabolomics analysis conducted to investigate the mechanisms behind the growth-promoting effects of probiotics in broilers, β-alanine was found to be significantly elevated. This led to the hypothesis that β-alanine could also contribute to growth-promoting effects in infected broilers. (2) Methods: An in vitro culture system was developed to assess β-alanine’s impact on proinflammatory cytokine response in chicken macrophage cells, gut integrity in chicken intestinal epithelial cells, and muscle differentiation in quail muscle cells and primary chicken embryonic muscle cells. In vivo animal feeding studies were then conducted to investigate the effects of dietary β-alanine on various disease parameters in Eimeria maxima-infected broiler chickens. (3) Results: In vitro, β-alanine treatment significantly decreased the gene expression of cytokines in chicken macrophage cells and increased occuldin expression in chicken intestinal epithelial cells. Dietary β-alanine increased the body weight of chickens following Eimeria maxima infection in the H-ALA group. Dietary β-alanine also suppressed cytokines and increased JAM-2 and occludin expression in the H-ALA group compared to the infected group without β-alanine supplementation. (4) Conclusions: These results strongly support the positive effects of dietary β-alanine on intestinal immune responses and gut barrier function in broiler chickens infected with Eimeria maxima.

Introduction Glioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of 7 months. The aim of treatment at recurrence is to prolong survival and maintain health-related quality of life (HRQoL). Chemotherapy is typically employed for recurrent GBM, often using nitrosourea-based regimens. However, efficacy is limited, with reported median survivals between 5 and 9 months from recurrence. Although less commonly used in the UK, there is growing evidence that re-irradiation may produce survival outcomes at least similar to nitrosourea-based chemotherapy. However, there remains uncertainty as to the optimum approach and there is a paucity of available data, especially with regards to HRQoL. Brain Re-Irradiation Or Chemotherapy (BRIOChe) aims to assess re-irradiation, as an acceptable treatment option for recurrent IDH-wild-type GBM.Methods and analysis BRIOChe is a phase II, multi-centre, open-label, randomised trial in patients with recurrent GBM. The trial uses Sargent’s three-outcome design and will recruit approximately 55 participants from 10 to 15 UK radiotherapy sites, allocated (2:1) to receive re-irradiation (35 Gy in 10 daily fractions) or nitrosourea-based chemotherapy (up to six, 6-weekly cycles). The primary endpoint is overall survival rate for re-irradiation patients at 9 months. There will be no formal statistical comparison between treatment arms for the decision-making primary analysis. The chemotherapy arm will be used for calibration purposes, to collect concurrent data to aid interpretation of results. Secondary outcomes include HRQoL, dexamethasone requirement, anti-epileptic drug requirement, radiological response, treatment compliance, acute and late toxicities, progression-free survival.Ethics and dissemination BRIOChe obtained ethical approval from Office for Research Ethics Committees Northern Ireland (reference no. 20/NI/0070). Final trial results will be published in peer-reviewed journals and adhere to the ICMJE guidelines.Trial registration number ISRCTN60524.

Coastal ecosystems and human communities are threatened worldwide by climate change, and shocks from social, market and political change. There is an urgent global need to promote resilient food production and livelihoods in the face of these shocks. Small-scale fisheries (SSF) in rural settings can be particularly vulnerable as they frequently lack the resources, rights and infrastructure to respond to shocks originating outside the focal systems. We examined ecological and social outcomes of environmental extremes in a SSF socio-ecological system (SES) by using long-term oceanographic (between 2010-2019) and ecological (2006-2018) data tracking change in a kelp forest ecosystem of Baja California, Mexico, and concurrent documentation of proactive and reactive actions of a fishing community organized in a cooperative. Results indicate a complex landscape of ‘winners’ and ‘losers’ among species and fisheries exposed to unprecedented environmental extremes, including marine heat waves and prolonged hypoxia, and a suite of adaptive actions by the local fishing cooperative, and others in the region, that have helped confront these rapid and drastic changes. Cooperatives have established voluntary marine reserves to promote recovery of affected populations and have invested in diversification of activities enabled by access rights, collective decision-making, and participatory science programs. Results indicate that local actions can support social and ecological resilience in the face of shocks, and that enabling locally-driven adaptation pathways is critical to resilience. This case study highlights the crucial importance of strengthening and supporting rights, governance, capacity, flexibility, learning, and agency for coastal communities to respond to change and sustain their livelihoods and ecosystems in the long run.

Students are often apprehensive about group work and about learning research methods. Challenges such as group work ‘free-riders’, and high anxiety about methods, dominate the literature on teaching within these complex learning domains. Drawing on both reflexive and emotional turns in sociological theory, we explore the potential of a group research project on students' experiences of group work for fostering reflexive learning of skills in group work and research methods. Guided by a socio-personal pedagogical theory, which prioritises students reflecting on and integrating experiences within their identities and values, the group project featured an individual reflexive journal assessment on students' socio-emotional experiences of group work. The findings highlight the merits of taking such a ‘metalogic’ approach that prompts learning about learning itself. Students showed experience-based understanding of the socio-emotional complexities of qualitative research practices, and insight into their emerging group work skills – identifying how they, not just others, can develop skills to improve reflexive practice and group work, and to better grapple with the complexities of learning and applying research methods.

Purpose The United Kingdom Childhood Cancer Study’s (UKCCS’s) matched cohort was established to examine the longer term morbidity and mortality of individuals previously diagnosed with cancer before 15 years of age, comparing future healthcare patterns in 5-year cancer survivors to baseline activity seen in age- and sex-matched individuals from the general population.Participants Predicated on a national childhood cancer case-control study conducted in the early 1990s (4430 cases, 9753 controls) in England, Scotland and Wales, the case population comprises 3125 cancer survivors (>5 years), and the control population 7156 age- and sex-matched individuals from the general population who did not have cancer as a child. Participants are now being followed up via linkage to national administrative healthcare databases (deaths, cancers and secondary care hospital activity).Findings to date Enabling the creation of cohorts with minimal selection bias and loss to follow-up, the original case-control study registered all newly diagnosed cases of childhood cancer and their corresponding controls, regardless of their family’s participation. Early findings based on the registered case population found marked survival variations with age and sex across subtypes and differences with deprivation among acute lymphoblastic leukaemia (ALL) survivors. More recently, comparing the health-activity patterns of the case and control populations revealed that survivors of childhood ALL experienced excess outpatient and inpatient activity across their teenage/young adult years. Adding to increased risks of cancer and death and involving most clinical specialties, excesses were not related to routine follow-up monitoring and showed no signs of diminishing over time.Future plans With annual linkage updates, the UKCCS’s maturing population-based matched cohorts provide the foundation for tracking the health of individuals through their lifetime. Comparing the experience of childhood cancer survivors to that of unaffected general-population counterparts, this will include examining subsequent morbidity and mortality, secondary care hospital activity and the impact of deprivation on longer term outcomes.

Abstract Background Clinical decision‐making for patients with myelodysplastic syndromes (MDS) is challenging, and both disease and treatment effects heavily impact health‐related quality of life (HRQoL) of these patients. Therefore, disease‐specific HRQoL measures can be critical to harness the patient voice in MDS research. Methods We report a prospective international validation study of the Quality of Life in Myelodysplasia Scale (QUALMS) with a main focus on providing information on the psychometric characteristics of its three subscales: physical burden (QUALMS‐P), emotional burden (QUALMS‐E), and benefit finding (QUALMS‐BF). The analysis is based on patients enrolled from three European countries and Israel, participating to the MDS‐RIGHT Project. The scale structure and psychometric properties of the QUALMS were assessed. Results Overall, 270 patients with a median age of 74 years were analyzed and the majority of them (60.3%) had a low MDS‐Comorbidity Index score. Results of the confirmatory factor analysis supported the underlying scale structure of the QUALMS, which, in addition to a total score, includes three subscales: QUALMS‐P, QUALMS‐E, and the QUALMS‐BF. The QUALMS‐P exhibited the highest Cronbach's alpha coefficients. Discriminant validity analysis indicated good results with the QUALMS‐P and QUALMS‐E distinguishing between patients with different performance status, comorbidity, anemia, and transfusion dependency status. No floor and ceiling effects were observed. Responsiveness to change analysis supported the validity of the measure. Patients with a hemoglobin (Hb) level of

Abstract Introduction Following 2016 legislation permitting limited access to cannabis for research and medicinal purposes, the number of randomized clinical trials (RCTs) investigating the effectiveness of medicinal cannabis (MC) on symptom burden relief in cancer contexts has increased in Australia. This study aimed to understand the perceptions, hopes and concerns of people with advanced cancer regarding the future availability and regulation of MC in Australia. Methods This qualitative study draws on semistructured interviews conducted between February 2019 and October 2020 in Brisbane, Australia, as part of an MC RCT substudy. Interviews were undertaken on 48 patients with advanced cancer in palliative care eligible to participate in an MC trial (n = 26 participated in an RCT; n = 2 participated in a pilot study; n = 20 declined). Interviews included a discussion of patients' decision‐making regarding trial participation, concerns about MC and perceptions of future availability, including cost. Transcribed interviews were analysed inductively and abductively, informed by constructivist thematic analysis conventions. Results Overall, participants supported making MC legally accessible as a prescription‐only medication. Fear of financial toxicity, however, compromised this pathway. Steep posttrial costs of accessing MC prompted several people to decline trial participation, and others to predict—if found effective—that many would either access MC through alternative pathways or reduce their prescribed dosage to enable affordable access. Conclusions These findings suggest that—despite a relatively robust universal healthcare system—Australians are potentially vulnerable to and fearful of financial toxicity. Prevalent in the United States, financial toxicity occurs when disadvantaged cancer patients access necessary but expensive medications with lasting consequences: bankruptcy, ongoing anxiety and cancer worry. Interview transcripts indicate that financial fears—and the systems sustaining them—may pose a threat to RCT completion and to equitable access to legal MC. Such findings support calls for embedding qualitative substudies and community partnerships within RCTs, while also suggesting the importance of subsidisation to overcoming injustices. Patient or Public Contribution A patient advisory committee informed RCT design. This qualitative substudy foregrounds patients' decision‐making, perceptions and experiences.

Objectives Patients with chronic haematological cancers are often treated on a relapsing-remitting pathway, which may extend for many years. Such diagnoses are associated with uncertainties that often cause anxiety and distress, meaning patients (and families) are susceptible to potentially prolonged emotional difficulties, across the cancer journey. Experiences and preferences regarding psychosocial needs and support over time are relatively unexplored, which this study aimed to address.Setting and design Set within the UK’s Haematological Malignancy Research Network (an ongoing population-based cohort that generates evidence to underpin improved clinical practice) a qualitative, exploratory study was conducted, using semistructured interviews. Reflexive thematic analysis was used to assess the interview data via an exploratory, inductive approach, underpinned by the research questions.Participants Thirty-five patients were included with chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma or myeloma; 10 of whom were interviewed alongside a relative.Results Five themes were identified from the data: (1) accessing support, (2) individual coping behaviour affecting support preferences, (3) divergent and fluctuating thoughts on patient support forums, (4) the role, influence and needs of family and friends and (5) other sources of support and outstanding needs. Findings suggest that patients’ individual attitudes towards support varied over time. This also influenced whether support was perceived to be available, and if it was then used.Conclusion This study highlighted the variation in preferences towards psychosocial support among patients with chronic haematological cancers. As patients can live for many years with significant emotional difficulties, they may benefit from frequent monitoring of their psychosocial well-being, as well as signposting to holistic support, if this is needed.

Abstract Background Recruitment for randomised controlled trials in palliative care can be challenging; disease progression and terminal illness underpin high rates of attrition. Research into participant decision-making in medicinal cannabis randomised controlled trials (RCTs) is very limited. Nesting qualitative sub-studies within RCTs can identify further challenges to participation, informing revisions to study designs and recruitment practices. This paper reports on findings from a qualitative sub-study supporting RCTs of medicinal cannabis for symptom burden relief in patients with advanced cancer in one Australian city. Methods Semi-structured qualitative interviews were conducted with 48 patients with advanced cancer, eligible to participate in a medicinal cannabis RCT (n=28 who consented to participate in an RCT; n=20 who declined). An iterative and abductive approach to thematic analysis and data collection fostered exploration of barriers and enablers to participation. Results Key enablers included participants’ enthusiasm and expectations of medicinal cannabis as beneficial (to themselves and future patients) for symptom management, especially after exhausting currently approved options, and a safer alternative to opioids. Some believed medicinal cannabis to have anti-cancer effects. Barriers to participation were the logistical challenges of participating (especially due to driving restrictions and fatigue), reluctance to interfere with an existing care plan, cost, and concerns about receiving the placebo and the uncertainty of the benefit. Some declined due to concerns about side-effects or a desire to continue accessing cannabis independent of the study. Conclusions The findings support revisions to subsequent medicinal cannabis RCT study designs, namely, omitting a requirement that participants attend weekly hospital appointments. These findings highlight the value of embedding qualitative sub-studies into RCTs. While some challenges to RCT recruitment are universal, others are context (population, intervention, location) specific. A barrier to participation found in research conducted elsewhere—stigma—was not identified in the current study. Thus, findings have important implications for those undertaking RCTs in the rapidly developing context of medical cannabis.

Background ST elevation myocardial infarction (STEMI) represents a cardiac emergency. Time to diagnosis, identification of culprit lesion, and intervention are important. Inferior STEMI represents a dilemma for cardiologists. The territory can be supplied by the right coronary artery (RCA) or the left circumflex coronary artery (LCx). Diagnostic algorithms have been proposed to predict the culprit artery.Methods We performed a single-centre retrospective cohort analysis of all patients admitted to our hospital from 2008 to 2020 with a diagnosis of inferior STEMI. We examined the diagnostic 12 lead ECG for quantification of ST elevation in leads II and III and compared this to culprit lesion found on angiography.Results There were 304 patients identified with STEMI in our database; 105 were found to have an inferior myocardial infarction by ECG criteria. Ninety-nine were included in our study with either RCA or LCx culprit lesions on angiography (82 males, 17 females). The average age of these patients was 64.9 years old. Sensitivity, specificity, positive predictive value and negative predictive value for ST elevation in lead II exceeding lead III predicting LCx culprit lesion was 0.32 (95% CI 0.13 to 0.57), 0.94 (95% CI 0.86 to 0.98), 0.55 (95% CI 0.29 to 0.78), 0.85 (95% CI 0.81 to 0.89), respectively. Sensitivity, specificity, positive predictive value and negative predictive value for ST elevation in lead III exceeding lead II predicting RCA culprit lesion was 0.94 (95% CI 0.86 to 0.98), 0.32 (95% CI 0.13 to 0.57), 0.85 (95% CI 0.81 to 0.89), 0.55 (95% CI 0.29 to 0.78), respectively.Conclusions In inferior STEMI, comparison of ST elevation in leads II and III can reliably predict culprit lesion artery and guide intervention.Subject indexing Culprit artery localisation, inferior stemi, ECG.

Summary: Previously, we found that amyloid-beta (Aβ) competitively inhibits the kinesin motor protein KIF11 (Kinesin-5/Eg5), leading to defects in the microtubule network and in neurotransmitter and neurotrophin receptor localization and function. These biochemical and cell biological mechanisms for Aβ-induced neuronal dysfunction may underlie learning and memory defects in Alzheimer’s disease (AD). Here, we show that KIF11 overexpression rescues Aβ-mediated decreases in dendritic spine density in cultured neurons and in long-term potentiation in hippocampal slices. Furthermore, Kif11 overexpression from a transgene prevented spatial learning deficits in the 5xFAD mouse model of AD. Finally, increased KIF11 expression in neuritic plaque-positive AD patients’ brains was associated with better cognitive performance and higher expression of synaptic protein mRNAs. Taken together, these mechanistic biochemical, cell biological, electrophysiological, animal model, and human data identify KIF11 as a key target of Aβ-mediated toxicity in AD, which damages synaptic structures and functions critical for learning and memory in AD.

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Abstract Background Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration ISRCTN15837212 , 31 July 2018.

Introduction The standard of care for patients with localised rectal cancer is radical surgery, often combined with preoperative neoadjuvant (chemo)radiotherapy. While oncologically effective, this treatment strategy is associated with operative mortality risks, significant morbidity and stoma formation. An alternative approach is chemoradiotherapy to try to achieve a sustained clinical complete response (cCR). This non-surgical management can be attractive, particularly for patients at high risk of surgical complications. Modern radiotherapy techniques allow increased treatment conformality, enabling increased radiation dose to the tumour while reducing dose to normal tissue. The objective of this trial is to assess if radiotherapy dose escalation increases the cCR rate, with acceptable toxicity, for treatment of patients with early rectal cancer unsuitable for radical surgery.Methods and analysis APHRODITE (A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer) is a multicentre, open-label randomised controlled phase II trial aiming to recruit 104 participants from 10 to 12 UK sites. Participants will be allocated with a 2:1 ratio of intervention:control. The intervention is escalated dose radiotherapy (62 Gy to primary tumour, 50.4 Gy to surrounding mesorectum in 28 fractions) using simultaneous integrated boost. The control arm will receive 50.4 Gy to the primary tumour and surrounding mesorectum. Both arms will use intensity-modulated radiotherapy and daily image guidance, combined with concurrent chemotherapy (capecitabine, 5-fluorouracil/leucovorin or omitted). The primary endpoint is the proportion of participants with cCR at 6 months after start of treatment. Secondary outcomes include early and late toxicities, time to stoma formation, overall survival and patient-reported outcomes (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR29, low anterior resection syndrome (LARS) questionnaire).Ethics and dissemination The trial obtained ethical approval from North West Greater Manchester East Research Ethics Committee (reference number 19/NW/0565) and is funded by Yorkshire Cancer Research. The final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines.Trial registration number ISRCTN16158514.

mRNAs export from the nucleus is thought to be regulated in part by three nucleoporins that comprise the nuclear basket, but whether and how distinct basket nucleoporins interact with the RNA export machinery is unclear. Here, the authors use rapid auxin-mediated degradation of basket nucleoporins Nup153, Nup50, and Tpr, and see that Tpr interacts with the TREX-2 mRNA export complex.

Objectives Haematological malignancies are the fifth most common cancer in the UK, with chronic subtypes comprising around a third of all new diagnoses. These complex diseases have some similarities with other cancers, but often require different management. Surgical resection is not possible, and while some are curable with intensive chemotherapy, most indolent subtypes are managed with non-aggressive intermittent or continuous treatment, often over many years. Little is known about the views of patients with chronic haematological cancers regarding treatment decision making (TDM), a deficit our study aimed to address.Setting and design Set within the Haematological Malignancy Research Network (HMRN: www.hmrn.org), an ongoing population-based cohort that provides infrastructure to support evidence-based research, HMRN data were augmented by qualitative information from in-depth interviews. Data were analysed for thematic content, combining inductive and deductive approaches. Interpretation involved seeking meaning, salience and connections within data.Participants Thirty-five patients with four chronic subtypes: chronic lymphocytic leukaemia, follicular lymphoma, marginal zone lymphoma, and myeloma. Ten relatives were present and contributed to varying extents.Results Five themes were discerned: (1) Preference for clinician recommendations; (2) Factors implicated in patient involvement in TDM; (3) Perceptions of proactive/non-proactive approaches to TDM; (4) Experiences of TDM at various points in the disease trajectory; (5) Support from others. Our principal finding relates to a strong preference among interviewees for treatment recommendations from haematologists, based on trust in their expertise and perceptions of empathetic patient–clinician relationships.Conclusion Interviewees wanted to be involved in TDM to varying extents, contingent on complex, inter-related factors, that are dynamic and subject to change according to differing clinical and personal contexts. Patients may benefit from clinicians assessing their shifting preferences for involvement on multiple occasions. Strong preferences for acceptance of recommendations was associated with cancer complexity, trust in clinician expertise and positive perceptions of patient–clinician relationships.

Objectives To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population.Design National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases.Setting The study population comprised all children (0–14 years) registered for primary care with the National Health Service (NHS) in England 1992–1996.Participants 1082 5-year survivors of ALL diagnosed

Abstract In the last decades, many marine invertebrates have experienced dramatic declines throughout many coastal marine ecosystems worldwide due to overfishing, disease outbreaks, and climate vulnerability. Despite extensive conservation and restoration effort, evidence of successful population recovery is rare. In this work, we document mass mortality events of pink and green abalone (Haliotis corrugata and Haliotis fulgens) in 2009–2010, and their subsequent rapid recovery following the continued enforcement and monitoring of two voluntary no‐take reserves by the local fishing cooperative (2006–present) and a 6‐year fishing closure (2012–2017) around Isla Natividad, Baja California Sur, Mexico. Age data collected from harvested abalone in 2019 suggest recruitment was maintained throughout the years when abundance was lowest following mass mortalities. The observed 6 to 8‐year time frame for recovery is consistent with scenarios presented in previous modeling studies, where marine reserves and other measures aimed at protecting large spawners predicted the potential for rapid recovery of abalone populations. This case study supports the effectiveness of a portfolio of resilience strategies, which include combining climate refugia and marine reserves, adherence to conservative annual fishing quotas, fishing closures, minimum size limitations, and ecological monitoring. Importantly, this example showcases how close collaboration between fishers, resource managers, scientists, and non‐governmental organization (NGOs) is critical for designing, implementing, and learning from conservation and management interventions to reverse marine population and ecosystem decline, reinforcing the legacy of Dr. Pete Peterson's life work on fully integrating ecology with marine management and restoration.

BackgroundCancer is one of the predominant causes of morbidity and mortality in older adult populations worldwide. Among a range of barriers, comorbidity particularly poses a clinical challenge in cancer diagnosis, prognosis, and treatment owing to its heterogeneous nature. While accurate comorbidity assessments and appropriate treatment administration can result in better patient outcomes, evidence related to older adult cancer populations is limited as these individuals are often excluded from regular clinical trials due to age and comorbid conditions. ObjectiveTo determine the prevalence of physical comorbidity and the impact of physical comorbidities and rurality on treatment and its outcomes in older adult cancer populations. MethodsScientific databases Embase and PubMed were searched for published scientific literature on physical comorbidity and older adult cancer patients. Google Scholar was searched for scholarly literature published in nonindexed journals. Snowballing was utilized to identify research papers missed in the above searches. Included studies : (1) reported on original research involving cancer patients; (2) included patients aged 65 years or older; (3) had patients receiving cancer-related treatment and (4) cancer survivors; (5) reported on physical comorbidity as a variable; (6) were published in English; and (7) conducted from any geographical location. ResultsIn total, 29 studies were selected for data extraction, evidence synthesis, and quality assessment. In these, comorbidities ranged from 37.9%-74.3% in colorectal cancer, 74%-81% in head and neck cancer, and 12.6%-49% in breast cancer. Moderate comorbidities ranged from 13%-72.9%, and severe comorbidities from 2.5%-68.2%. Comorbidity increased with age, with comorbidity affecting both treatment choice and process. Physical comorbidities significantly affected treatment initiation, causing delay, toxicity, and discontinuation. Older adult cancer patients were given less vigorous and nonstandard treatments and were also less likely to be offered treatment. Where patients are given more vigorous treatment, several studies showed better survival outcomes. Appropriate treatment in older adult cancer patients increased both overall and disease-related survival rates. None of the studies noted rurality as a distinct variable. ConclusionsThis systematic review concludes that there is evidence to substantiate the adverse effect of comorbidity on treatment and survival outcomes. However, the mechanism by which comorbidity impedes or impacts treatment is unknown in many cases. Some low-quality evidence is available for considering the functional status and biological age in treatment decisions. Future studies that substantiate the value of comprehensive older adult assessments before treatment initiation in cancer patients, including assessing the nature and severity of comorbidities, and additional consideration of rurality as a factor, could lessen the effect of comorbidities on the treatment process.

Anti-arrhythmic drugs (AADs) uniquely affect the various electrolyte channels in the heart and can slow conduction, increase refractoriness, and/or decrease automaticity with the goal of preventing tachyarrhythmias. Due to these properties, these same drugs are by nature pro-arrhythmic. Vaughan-Williams classification Ic AADs belong to a class of medications that inhibit sodium channels, leading to decreased conduction velocity of myocytes and Purkinje fibers as well as to decreased automaticity of pacemaker cells. When present in toxic amounts, this leads to classic changes on the electrocardiogram (ECG) that are harbingers of potentially lethal arrhythmias. Presented is a clinical series of ECGs that occurred in a patient who presented with flecainide toxicity. Keywords: Flecainide, Antiarrhythmic drugs, Toxicity, Atrial fibrillation

Objective To examine mortality and morbidity patterns before and after premalignancy diagnosis in individuals with monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL) and compare their secondary healthcare activity to that of the general population.Design Population-based patient cohort, within which each patient is matched at diagnosis to 10 age-matched and sex-matched individuals from the general population. Both cohorts are linked to nationwide information on deaths, cancer registrations and Hospital Episode Statistics.Setting The UK’s Haematological Malignancy Research Network, which has a catchment population of around 4 million served by 14 hospitals and a central diagnostic laboratory.Participants All patients newly diagnosed during 2009–2015 with MGUS (n=2193) or MBL (n=561) and their age and sex-matched comparators (n=27 538).Main outcome measures Mortality and hospital inpatient and outpatient activity in the 5 years before and 3 years after diagnosis.Results Individuals with MGUS experienced excess morbidity in the 5 years before diagnosis and excess mortality and morbidity in the 3 years after diagnosis. Increased rate ratios (RRs) were evident for nearly all clinical specialties, the largest, both before and after diagnosis, being for nephrology (before RR=4.29, 95% CI 3.90 to 4.71; after RR=13.8, 95% CI 12.8 to 15.0) and rheumatology (before RR=3.40, 95% CI 3.18 to 3.63; after RR=5.44, 95% CI 5.08 to 5.83). Strong effects were also evident for endocrinology, neurology, dermatology and respiratory medicine. Conversely, only marginal increases in mortality and morbidity were evident for MBL.Conclusions MGUS and MBL are generally considered to be relatively benign, since most individuals with monoclonal immunoglobulins never develop a B-cell malignancy or any other monoclonal protein-related organ/tissue-related disorder. Nonetheless, our findings offer strong support for the view that in some individuals, monoclonal gammopathy has the potential to cause systemic disease resulting in wide-ranging organ/tissue damage and excess mortality.

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS.Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated “autoinflammatory disease” (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups.Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p < 0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02–4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22–6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080).Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis.

ObjectivesTo explore alignment of experiences before lymphoma and myeloma diagnosis with the appraisal, help seeking and diagnostic intervals in the Model of Pathways to Treatment (MPT).DesignA qualitative study using in-depth semistructured interviews with patients and relatives. Interviews were transcribed verbatim, anonymised and analysed using qualitative description.SettingA UK population-based haematological malignancy patient cohort.ParticipantsFifty-five patients (35 lymphoma, 20 myeloma: diagnosed 2014–2016) and 28 relatives participated, within around a year of the patient’s diagnosis. Patients were selected from those in the cohort who had returned a questionnaire about their symptoms and help seeking, and consented to contact for further research. Sampling was purposive, to achieve maximum variation in age, sex and time to diagnosis.ResultsParticipants described time from symptom onset to diagnosis as ranging from several weeks to years. Pathways largely aligned with MPT components and help seeking could lead to the rapid investigations and identification of abnormalities. However, symptoms could be vague and/or inadvertently interpreted as other conditions, which if perpetuated, could cause diagnostic delay. The latter was associated with chaotic pathways, with activities rarely occurring only once or in a linear sequence. Rather, intermittent or ongoing processes were described, moving forward and backwards through intervals. This is ‘unpacked’ within five themes: (1) appraisal and reappraisal; (2) patient-initiated self-management/treatment; (3) initial help seeking; (4) re-presentation; and (5) patient-initiated actions, decisions and emotions during re-presentation. Within these themes, various healthcare professionals were consulted, often many times, as symptoms persisted/progressed. Input from family/friends was described as substantial, as was the extent to which information seeking occurred.ConclusionLymphoma and myeloma pathways align with the MPT, but do not fully capture the repetition and complexity described by participants. Time to diagnosis was often prolonged, despite the best efforts of patients, relatives and healthcare professionals. The impact of National Health Service England’s Multi-diagnostic Disciplinary Centres on time to haematological cancer diagnosis remains to be seen.

Abstract: Most studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.

Background: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera®, Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2–6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. Objectives: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non-inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. Design: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. Results: The DMEC’s interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM-miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months’ follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of –£7723, a quality-adjusted life-year loss of –0.73 and a resulting incremental net monetary loss of –£6780. Conclusions: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. Future work: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. Trial registration: Current Controlled Trials ISRCTN16544962. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information.

Offshore aquaculture is increasingly viewed as a mechanism to meet growing protein demand for seafood, while minimizing adverse consequences on the environment and other uses in the oceans. However, despite growing interest in offshore aquaculture, there appears to be no consensus as to what measures commonly define an offshore site or how effects of offshore aquaculture—relative to more nearshore practices—are assessed. This lack of agreement on what constitutes offshore aquaculture has the potential to convolute communication, create uncertainty in regulatory processes, and impede understanding of the ecological implications of offshore farming. To begin addressing these issues, we reviewed and analyzed biologically-focused primary and gray literature (Ntotal = 70) that categorize and quantify characteristics of offshore aquaculture from around the world. We found that many “offshore” descriptions are relatively close to shore (

BackgroundMarfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin‐1 (FBN1); however, the mechanisms through which fibrillin‐1 deficiency causes MFS‐associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS‐associated aortopathy is caused by increased transforming growth factor‐β (TGF‐β) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF‐β signaling drives MFS‐associated aortopathy. We used a mouse model to test whether SMC TGF‐β signaling is perturbed by a fibrillin‐1 variant that causes MFS and whether blockade of SMC TGF‐β signaling prevents MFS‐associated aortopathy. Methods and ResultsMFS mice (Fbn1C1039G/+ genotype) were genetically modified to allow postnatal SMC‐specific deletion of the type II TGF‐β receptor (TBRII; essential for physiologic TGF‐β signaling). In young MFS mice with and without superimposed deletion of SMC‐TBRII, we measured aortic dimensions, histopathology, activation of aortic SMC TGF‐β signaling pathways, and changes in aortic SMC gene expression. Young Fbn1C1039G/+ mice had ascending aortic dilation and significant disruption of aortic medial architecture. Both aortic dilation and disrupted medial architecture were exacerbated by superimposed deletion of TBRII. TGF‐β signaling was unaltered in aortic SMC of young MFS mice; however, SMC‐specific deletion of TBRII in Fbn1C1039G/+ mice significantly decreased activation of SMC TGF‐β signaling pathways. ConclusionsIn young Fbn1C1039G/+ mice, aortopathy develops in the absence of detectable alterations in SMC TGF‐β signaling. Loss of physiologic SMC TGF‐β signaling exacerbates MFS‐associated aortopathy. Our data support a protective role for SMC TGF‐β signaling during early development of MFS‐associated aortopathy.

This article discusses Joseph Brodsky’s 1985 autobiographical essay In a Room and a Half. It argues that the use of the exilic discourse in the essay enables Brodsky to subvert the genre of autobiography as it was defined during the Enlightenment. His life story does not aspire to universalise. It attempts to reconcile the truth-­telling mnemonic writing with the attainment of a new identity that recognises his place within the Russian and the English speaking traditions, and takes account of postmodernist theories related to historicity, ethnic identity and the decentred subject.

The present paper discusses Marina Tsvetaeva’s essay about Maksimilian Voloshin The Living about the Living (1932) in the light of Tsvetaeva’s views on the legacy of the Silver Age in the early 1930s and her responses to the emergence of Socialist Realism in the Soviet Union. The essay demonstrates that Tsvetaeva presents herself as a strong advocate of modernist aesthetic principles that enable the reader both to experience the sense of estrangement and to reinvent classical themes in new contexts, so the notions of reading and transgression become entwined. It juxtaposes Tsvetaeva’s views on the use of myth in literature to several important trends related to the revival of ancient ritual and folk performance that occured in the 1910s-20s in Europe and in Russia (discussed in the works of Viacheslav Ivanov, Voloshin, Jane Harrison and Walter Benjamin).

Growth factors play an important role in nerve regeneration and repair. An attractive drug delivery strategy, termed “magnetic targeting”, aims to enhance therapeutic efficiency by directing magnetic drug carriers specifically to selected cell populations that are suitable for the nervous tissues. Here, we covalently conjugated nerve growth factor to iron oxide nanoparticles (NGF-MNPs) and used controlled magnetic fields to deliver the NGF–MNP complexes to target sites. In order to actuate the magnetic fields a modular magnetic device was designed and fabricated. PC12 cells that were plated homogenously in culture were differentiated selectively only in targeted sites out of the entire dish, restricted to areas above the magnetic “hot spots”. To examine the ability to guide the NGF-MNPs towards specific targets in vivo, we examined two model systems. First, we injected and directed magnetic carriers within the sciatic nerve. Second, we injected the MNPs intravenously and showed a significant accumulation of MNPs in mouse retina while using an external magnet that was placed next to one of the eyes. We propose a novel approach to deliver drugs selectively to injured sites, thus, to promote an effective repair with minimal systemic side effects, overcoming current challenges in regenerative therapeutics.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson's disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning. In the social transmission of food preference test, mice showed a significant decrease in preference for familiar food 30 days post-MPTP compared to controls. Mice at both 7 and 30 days post-MPTP lesioning had increased fear extinction compared to controls. High Performance Liquid Chromatography analysis of tissues homogenates showed dopamine and serotonin were depleted in the striatum, frontal cortex, and amygdala. No changes in anxiety or depression were detected by the tail suspension, sucrose preference, light–dark preference, or hole-board tests. In conclusion, acute MPTP lesioning regimen in mice causes impairments in associative memory and conditioned fear, no mood changes, and depletion of dopamine and serotonin throughout the brain.

Ольга Симонова-Партан, Ты права, Филумена! Вахтанговцы за кулисами театра, Прозаик, М., 2012, c. 320.