Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Identification of a Patient Suitable for CAR-T Cell Therapy in the Outpatient Setting: A Vodcast and Case Example.

Chimeric antigen receptor T cell (CAR-T) therapies targeting the CD19 antigen have been associated with high and durable response rates in patients with diffuse large B cell lymphoma (DLBCL). CAR-T cell therapies are commonly administered in the inpatient setting due to the average onset of cytokine release syndrome within the first 3 days post infusion, but there has been growing interest in delivering CAR-T cell therapies in the outpatient setting to overcome frequent hospital bed shortages and the high cost of inpatient care. Although this approach could improve access whilst catering to patient preference, it requires a multidisciplinary approach as well as careful patient selection. Herein, Dr. Foley and Dr. Kuruvilla discuss the case of a patient presenting with the ideal profile for CAR-T cell therapy referral whilst also determining the key attributes for eligibility from a clinician's perspective. Solutions for successful outpatient management include proper education, caregiver support, and early referral to ensure a timely infusion. In conclusion, outpatient administration of CAR-T cell therapy in patients with DLBCLs should be assessed on a case-by-case basis.A vodcast feature is available for this article.

A spatial examination of alcohol availability and the level of disadvantage of schools in Ireland.

BACKGROUND: The availability of alcohol is a major factor in underage drinking and according to the alcohol harm paradox, those living in more deprived communities are more susceptible to the negative consequences of alcohol use, despite drinking the same or less than those from more affluent areas. Alcohol availability within the vicinity of the home or school normalises alcohol for schoolchildren. For the first time in the Republic of Ireland, this study examines the number of premises licensed to sell alcohol within 300 m of all schools in Ireland and differences in this number between disadvantaged and non-disadvantaged schools. METHODS: Using publicly available data from the Department of Education and Revenue, the addresses of all schools (n = 3,958) and all premises with at least one liquor licence (n = 14,840) were geocoded and analysed using the Geographic Information System software, Quantum GIS (QGIS). Schools were identified by their disadvantaged classification using the HP Pobal Deprivation Index and the number of liquor licences within 300 m of each school type was examined. To test for significant differences between schools' level of disadvantage, a combination of Mann-Whitney U tests, Kruskal-Wallis tests and Dunn-Bonferroni tests were used. RESULTS: There was a mean of two licenced premises within 300 m of all schools in Ireland, but when disadvantaged schools were compared to non-disadvantaged schools, there was a significantly higher number of licenced premises around disadvantaged schools (p < .001). Primary schools are further classified according to their level of disadvantage and the results indicated that those schools classified as the most disadvantaged had a significantly greater number of liquor licences within 300 meters (p < .001). There was no significant difference in density of licenced premises when comparing disadvantaged secondary schools with non-disadvantaged secondary schools (p = .705). CONCLUSION: Ireland is considering increasing alcohol availability through the Sale of Alcohol Bill, 2022. However, this analysis indicates already problematic numbers of licenced premises within close proximity of schools in Ireland. It is essential that the harms associated with alcohol availability are considered, especially for those living and attending school in disadvantaged communities, where higher numbers of licenced premises were identified.

Treatment Pattern, Healthcare Resource Utilization and Symptom Burden Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study.

PURPOSE: This study aims to describe the treatment patterns, outcomes, health care utilization and symptom burden of triple class exposed (TCE) relapsed/refractory patents with multiple myeloma (MM) receiving a subsequent line of treatment (LOT). METHODS: This is a retrospective observational cohort study using administrative databases in Ontario, Canada. Outcomes were captured for TCE patients receiving a subsequent LOT and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), health care utilization, palliative care referral, and patient reported symptoms. RESULTS: Of the 16,777 patients diagnosed with MM between 2007-2021 in Ontario, 1358 (8%) patients were classified as TCE. Among the TCE MM patients, 489 (36%) received a subsequent LOT. The two most commonly administered therapies post TCE were carfilzomib/dexamethasone (n = 111, 22%) and pomalidomide/dexamethasone(n = 95, 19%). Median TTNT was 1.7 months (95%CI 1.2-2.4 months) and median OS 12.8 months (95%CI 10.8-16.5). Healthcare utilization was high with 276 (56%) of patients evaluated in an emergency department (ED) or admitted to hospital. There was high symptom burden as reported by patients with moderate-severe impairment in well-being, fatigue, pain and drowsiness noted in greater than 25% of the cohort. Palliative care referrals rates were low with only 10% (n = 48) patients referred to palliative care. Among the patients that died during study follow up, the majority died in hospital (n = 147,44%). CONCLUSION: Our study reports one of the largest series of real-world TCE patients published and demonstrates the poor outcomes of TCE patients receiving a subsequent LOT.

A health data led approach for assessing potential health benefits of green and blue spaces: Lessons from an Irish case study.

Research producing evidence-based information on the health benefits of green and blue spaces often has within its design, the potential for inherent or implicit bias which can unconsciously orient the outcomes of such studies towards preconceived hypothesis. Many studies are situated in proximity to specific or generic green and blue spaces (hence, constituting a green or blue space led approach), others are conducted due to availability of green and blue space data (hence, applying a green or blue space data led approach), while other studies are shaped by particular interests in the association of particular health conditions with presence of, or engagements with green or blue spaces (hence, adopting a health or health status led approach). In order to tackle this bias and develop a more objective research design for studying associations between human health outcomes and green and blue spaces, this paper discussed the features of a methodological framework suitable for that purpose after an initial, year-long, exploratory Irish study. The innovative approach explored by this study (i.e., the health-data led approach) first identifies sample sites with good and poor health outcomes from available health data (using data clustering techniques) before examining the potential role of the presence of, or engagement with green and blue spaces in creating such health outcomes. By doing so, we argue that some of the bias associated with the other three listed methods can be reduced and even eliminated. Finally, we infer that the principles and paradigm adopted by the health data led approach can be applicable and effective in analyzing other sustainability problems beyond associations between human health outcomes and green and blue spaces (e.g., health, energy, food, income, environment and climate inequality and justice etc.). The possibility of this is also discussed within this paper.

Leukemic progenitor compartment serves as a prognostic measure of cancer stemness in patients with acute myeloid leukemia.

We systematically investigate functional and molecular measures of stemness in patients with acute myeloid leukemia (AML) using a cohort of 121 individuals. We confirm that the presence of leukemic stem cells (LSCs) detected through in vivo xenograft transplantation is associated with poor survival. However, the measurement of leukemic progenitor cells (LPCs) through in vitro colony-forming assays provides an even stronger predictor of overall and event-free survival. LPCs not only capture patient-specific mutations but also retain serial re-plating ability, demonstrating their biological relevance. Notably, LPC content represents an independent prognostic factor in multivariate analyses including clinical guidelines of risk stratification. Our findings suggest that LPCs provide a robust functional measure of AML, enabling quantitative and rapid assessment of a wide range of patients. This highlights the potential of LPCs as a valuable prognostic factor in AML management.

Socio-ecological determinants of older people's mental health and well-being during COVID-19: A qualitative analysis within the Irish context.

Background: Evidence indicates that older people with biological and social vulnerabilities are at high risk of short- and long-term consequences related to the COVID-19 pandemic. However, studies have also highlighted that the crisis may present opportunities for personal growth if older individuals are met with appropriate resources and support. Objective: The aim of this study was to explore the perceptions of older people regarding how individual, social, and environmental factors have supported or hindered their well-being and health during COVID-19. Methods: We analyzed data collected between April-May and October-November 2021 from the Well-being, Interventions and Support during Epidemics (WISE) study, a qualitative investigation of community-dwellers based in Ireland and aged 65 years or over. Participants (n = 57) completed written submissions, narrative interviews and/or go-along interviews detailing their experiences during the pandemic. Framework analysis was carried out in NVivo 12 to identify determinants, linkages, and explanations within Bronfenbrenner's socio-ecological model. Results: The mean age of participants was 74.9 years, 53% were female, 45% lived alone, and 86% lived in areas with high urban influence. Our findings highlight the heterogeneous effect of COVID-19 across diverse older individuals who held distinct concerns, capabilities, and roles in society before and during the pandemic. Multi-scalar contextual characteristics such as individual's living arrangements, neighborhood social and built environments, as well as social expectations about aging and help seeking, had an influential role in participants' well-being and available supports. We identified mixed views regarding public health restrictions, but a consensus emerged questioning the suitability of one-size-fits-all approaches based on chronological age. Conclusions: Our results suggest that some negative pandemic consequences could have been avoided by increasing collaboration with older people and with the provision of clearer communications. The interdependencies identified between individual characteristics and socio-ecological factors that influenced participants' availability of supports and development of adaptive strategies represent areas of opportunity for the development of age-friendly interventions during and beyond public health crises.

Persistent hematopoietic polyclonality after lentivirus-mediated gene therapy for Fabry disease.

The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gene therapy trials, we conducted a comprehensive DNA insertion site analysis of peripheral blood samples from the five patients in our gene therapy trial. We found that patients had a polyclonal integration site spectrum and did not find evidence of a dominant clone in any patient. Although we identified vector integrations near proto-oncogenes, these had low percentages of contributions to the overall pool of integrations and did not persist over time. Overall, we show that our trial of lentivirus-mediated gene therapy for Fabry disease did not lead to hematopoietic clonal dominance and likely did not elevate the risk of leukemogenic transformation.

Can Views and Contact with Nature at Home Help Combat Anxiety and Depression during the Pandemic? Results of the GreenCOVID study.

BACKGROUND: The COVID-19 pandemic and the lockdown measures have had important consequences on the mental health of the population, although little is known about the role played by nature and its benefits. OBJECTIVES: The present study aims to evaluate the risk of anxiety and depression during the first wave of the COVID-19 pandemic in Spain and to identify the factors most strongly associated with anxiety and depression, including sociodemographic, household characteristics, and access to or contact with natural environment. METHODS: GreenCOVID is an online cross-sectional study promoted by the Health & Territory Research (HTR) of the University of Seville in Spain, Maynooth University in Ireland, and the University of Winchester in the United Kingdom. This study includes only data from Spain which were collected between April 8, 2020 and April 27, 2020. Binary logistic regression was conducted to identify the factors associated with anxiety and depression through the HADS scale. RESULTS: Of the total of 2,464 adults who participated in GreenCOVID Spain, mean age was 38.1 years, 72.6% were female, 58.1% were at risk of anxiety, and 32.3% of depression. In the multivariable logistic regression, the factors associated with risk of anxiety were female: gender, being a student and problems at home. Regarding the risk of depression, the factors most associated were being a student, female gender, problems at home, worse evaluation of views from home and less help from outside views to cope with lockdown. CONCLUSIONS: Our findings show that during COVID-19 pandemic, in addition to sociodemographic factors female gender and being a student, problems at home, lack of natural elements in the home, and worse appreciation of views from home were associated with mental health problems. Thus, housing conditions and access to the natural environment were important for mental health during COVID-19 lockdown.

Urban Blue Spaces as Therapeutic Landscapes: "A Slice of Nature in the City".

Urban blue spaces are defined as all natural and manmade surface water in urban environments. This paper draws on how the concepts of experienced, symbolic, social, and activity space combine to position urban blue spaces as therapeutic landscapes. We conducted 203 intercept interviews between 12 October 2019 and 10 November 2019. Although safety concerns had health-limiting impacts, interacting with the Glasgow Canal and surrounding landscape was predominantly perceived as health-enhancing. Our findings build on current evidence, which has suggested that urban blue spaces, particularly canals, may foster therapeutic properties, contributing to healthier city environments. Further research is required to understand better the interconnectedness of urban blue spaces and health and how such spaces can be best developed and managed to improve the health outcomes of local populations.

The importance for wellbeing of having views of nature from and in the home during the COVID-19 pandemic. Results from the GreenCOVID study.

Introduction: The COVID-19 pandemic has influenced the daily lives of people and may affect their well-being. The aim of the present study is to assess well-being and associated factors during the first wave of the COVID-19 pandemic in the general population in three European countries. Methods: GreenCOVID was an observational cross-sectional study using an online survey (7 April 2020 to 24 July 2020) promoted by the Health & Territory Research (HTR) of the University of Seville in Spain, Maynooth University in Ireland, and the University of Winchester in England, which included a sample of 3109 unselected adults. Well-being was measured using the World Health Organization-Five Well-Being Index (WHO-5) scale. Seven aspects, related to the natural environment of the home, were evaluated (role of outdoor views in coping with lockdown, importance of blue spaces during lockdown, importance of green spaces during lockdown, quality of view from home, use of outdoor spaces or window views, elements of nature in the home, and views of green or blue spaces from home). Binary logistic regression was conducted to identify the parameters associated with poor well-being. Results: Mean age was 39.7 years and 79.3% lived in Spain, the majority in urban areas (92.8%). 73.0% were female and 72.0% had undertaken university studies. Poor well-being was reported by 59.0%, while 26.6% indicated the possible presence of clinical depression. The factors most associated with poor well-being were students (OR = 1.541), those who had no engagement in physical activity (OR = 1.389), those who reported 'living in Spain' compared to Ireland (OR = 0.724), being female (OR = 1.256), poor quality views from home (OR = 0.887), less benefit from views of the natural environment to cope with lockdown (OR = 0.964), and those younger in age (OR = 0.990). Conclusions: More than half of participants reported poor well-being and one in four indicated the possible presence of clinical depression during the first wave of the COVID-19 pandemic. We identified that belonging to a younger age cohort, being a student, being female, not being able to continue with daily pursuits such as physical activity, and having poorer quality of views from home led to poor well-being among participants. Our study highlights the importance of continued physical activity and views of nature to improve the well-being of individuals during times of crisis such as the COVID-19 pandemic.

Automated bone marrow cytology using deep learning to generate a histogram of cell types.

Background: Bone marrow cytology is required to make a hematological diagnosis, influencing critical clinical decision points in hematology. However, bone marrow cytology is tedious, limited to experienced reference centers and associated with inter-observer variability. This may lead to a delayed or incorrect diagnosis, leaving an unmet need for innovative supporting technologies. Methods: We develop an end-to-end deep learning-based system for automated bone marrow cytology. Starting with a bone marrow aspirate digital whole slide image, our system rapidly and automatically detects suitable regions for cytology, and subsequently identifies and classifies all bone marrow cells in each region. This collective cytomorphological information is captured in a representation called Histogram of Cell Types (HCT) quantifying bone marrow cell class probability distribution and acting as a cytological patient fingerprint. Results: Our system achieves high accuracy in region detection (0.97 accuracy and 0.99 ROC AUC), and cell detection and cell classification (0.75 mean average precision, 0.78 average F1-score, Log-average miss rate of 0.31). Conclusions: HCT has potential to eventually support more efficient and accurate diagnosis in hematology, supporting AI-enabled computational pathology.

A scoping review protocol of age-friendly practices during the COVID-19 pandemic.

Background: Actions focused on age-friendly environments contribute to promote and maintain older people's functional ability and may enable them to contribute to their communities and enjoy life. As such, age-friendly practices require collaboration between diverse stakeholders across multiple sectors responsible for natural, built, and social environments, which can be particularly relevant during public health emergencies when socio-ecological vulnerabilities become more salient and may disproportionally affect older people. This paper presents a protocol for a scoping review aiming to investigate the breadth of evidence concerning the development, implementation, and evaluation of age-friendly practices during the COVID-19 pandemic. The protocol sets out the objectives, methods, and dissemination plans for the review. Methods: The scoping review will be conducted in line with the Joanna Briggs Institute (JBI) scoping review methodology. We will search databases (PubMed, Web of Science, Embase, CINAHL, Scopus, PsychNet) and grey literature sources. Publications relating to practices across the 8 domains of the World Health Organization's age-friendly cities and communities' framework will be included. A tabular data extraction tool will be used to facilitate a narrative synthesis of results. Ethics and dissemination: Ethical approval is not required as the methods proposed for this scoping review consist of collecting publicly available data. Findings will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) and submitted to a journal for academic dissemination. Lay dissemination plans include an infographic and a blog-style article presenting our core results. Conclusion: The publication of this protocol allows for transparency in the systematic process of a scoping review focused on age-friendly practices during COVID-19. Findings emerging from the scoping review will provide insights into the evidence available regarding age-friendly activities during COVID-19 and may inform future age-friendly practices during public health emergencies and beyond.

Perceptions of Change in the Natural Environment produced by the First Wave of the COVID-19 Pandemic across Three European countries. Results from the GreenCOVID study.

Although different studies have evaluated the positive impacts of the COVID-19 pandemic and lockdown measures on reducing noise pollution and traffic levels and improving air quality, how populations have perceived such changes in the natural environment has not been adequately evaluated. The present study provides a more in-depth exploration of human population perception of enhanced natural exposure (to animal life and nature sounds) and reduced harmful exposure (by improved air quality and reduced traffic volume) as a result of the COVID-19 pandemic lockdown. The data is drawn from 3,109 unselected adults who participated in the GreenCOVID survey from April to July 2020 in England, Ireland, and Spain. The findings suggest that the positive impacts to the natural environment as a result of the lockdown have been better received by the population in Spain and Ireland, in comparison to England. Participants who resided in urban areas had better perceived improvements in nature sounds, air quality, and traffic volume compared to those in rural areas. Older populations and those with lower smoking and alcohol consumption were found to perceive this improvement the most. Furthermore, the greater perception of improvements in environmental elements was also associated with better self-perceived health and improved wellbeing. In the binary logistic regression, living in Ireland or Spain, urban areas, female gender, older age, and good overall wellbeing were associated with a greater perception of improvements in the natural environment, while the factors most associated with a greater perception of reduced harmful exposure were living in Spain, had a good self-perceived health status and older age.

Well-being, Interventions and Support during Epidemics (WISE): Protocol for a qualitative longitudinal study of older adults' experiences during COVID-19.

Background: The coronavirus disease 2019 (COVID-19) pandemic has the potential to trigger multiple stress domains and lead to long-term repercussions in an individual's quality of life, health, and well-being. Stressors from the pandemic are likely to be experienced in many ways by older adults with heterogeneous life experiences and supports available. In this context, it is necessary to tease out the underlying mechanisms leading to positive and negative well-being and mental health across interdependent individual, social and environmental factors. The aim of the present study is to explore community-dwelling older adults' experiences during the COVID-19 pandemic, with a particular focus on mental health and psychosocial well-being. Methods: An exploratory longitudinal qualitative study will be conducted with data collected through written submissions, narrative interviews and go-along interviews with older adults living in Irish community settings. To enable the exploration of participants' responses to the evolving social, economic and environmental circumstances, data collection will take during the implementation of public health restrictions and once these are eased and the vaccination program is rolled out. Framework analysis will be carried out to identify data themes, linkages, and explanations within Bronfenbrenner's socio-ecological model. Ethics and dissemination:  Ethical approval has been granted by the Royal College of Surgeons in Ireland, Research Ethics Committee (REC202011028). Findings will be disseminated through peer-reviewed journal publications, presentations at relevant conferences, and in consultation with Public and Patient Involvement (PPI) contributors. A lay summary of findings and infographic will be distributed to multiple stakeholders including our PPI panel, older people, caregivers, community organizations, charities, and media.

Abnormal dopamine receptor signaling allows selective therapeutic targeting of neoplastic progenitors in AML patients.

The aberrant expression of dopamine receptors (DRDs) in acute myeloid leukemia (AML) cells has encouraged the repurposing of DRD antagonists such as thioridazine (TDZ) as anti-leukemic agents. Here, we access patient cells from a Phase I dose escalation trial to resolve the cellular and molecular bases of response to TDZ, and we extend these findings to an additional independent cohort of AML patient samples tested preclinically. We reveal that in DRD2+ AML patients, DRD signaling in leukemic progenitors provides leukemia-exclusive networks of sensitivity that spare healthy hematopoiesis. AML progenitor cell suppression can be increased by the isolation of the positive enantiomer from the racemic TDZ mixture (TDZ+), and this is accompanied by reduced cardiac liability. Our study indicates that the development of DRD-directed therapies provides a targeting strategy for a subset of AML patients and potentially other cancers that acquire DRD expression upon transformation from healthy tissue.

A(nother) time for nature? Situating non-human nature experiences within the emotional transitions of sight loss.

Sight impairment is experienced by approximately 253 million people worldwide, including people of all generations, at all life course stages. Caught between past and present embodiments of the world, people often express feelings of loss with the onset of sight impairment. This paper examines the role of nonhuman nature encounters as a contingent resource amongst individuals navigating these emotional transitions. It responds to recent calls to attend to the life course in both critical disability studies and the growing body of work linking nonhuman nature relations to human wellbeing. The paper draws on findings from a qualitative study that combined in-depth narrative interviews with in situ go-along interviews to explore how 31 people with sight impairment in England describe and experience a sense of wellbeing (or otherwise) with nature across their everyday lives and life trajectories. The data were analysed using inductive narrative thematic analysis. While nonhuman nature encounters were valued by many participants in promoting a sense of freedom, relatedness, pleasurable sensory immersion, opportunities for exploration and 'skilling up', this paper cautions against generalised or overly Romantic tropes of what nonhuman nature can 'do' through key sight loss junctures, and for whom. It highlights the value of providing timely and sensitive social scaffolding and nurturing creativity to open up meaningful opportunities to engage with nonhuman nature and to counter feelings of loss exacerbated by identity-limiting life course narratives and disability stereotypes. Informed by the stories shared by participants to chart and situate their experiences of sight loss, we call for a new identity politics within and beyond the growing movement to 'connect' people to nonhuman nature for wellbeing; a politics that affirms diverse forms of more-than-human embodiment, recognising how and why such relations may weave into - and indeed out of - people's varied, interdependent life course trajectories.

Lentivirus-mediated gene therapy for Fabry disease.

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy.

Is a View of Green Spaces from Home Associated with a Lower Risk of Anxiety and Depression?

Although a large body of research supports the theory that exposure to nature results in mental health benefits, research evidence on the effects of having a view of green space from home is still scarce. The aim of the present study is to assess the impact that access to a green space view from home has on anxiety and depression. This is a cross-sectional study extracting data from the "2018 Green Spaces, Daily Habits and Urban Health Survey" conducted in Carmona (Spain). The study included variables on sociodemographic and lifestyle, view of green spaces from home, self-perceived health status, and risk of anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). Chi-square tests were used to assess variable's associations and a multiple linear regression models used to identify the variables explaining the risk of anxiety and depression, taking into account sociodemographic characteristics, frequency of visits and view of green spaces from home. According to our results, adults who enjoy a view of green spaces from home have a lower risk of anxiety and depression.

Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60­7·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9­23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9­25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2­29·2) versus 31·3% (21·9­40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5­35·1) in the anti-thymocyte globulin group and 41·3% (31·3­51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·6­78·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·8­62·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35­0·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.