Quantifying cardiovascular disease risk and heart age predictions for men in the prison environment.

OBJECTIVES: Cardiovascular disease (CVD) and associated risk factors within the prison population often present at a younger age in this cohort. Given CVD is largely preventable, it warrants investigation to fully quantify this risk. This study explored the relative predicted 10-year CVD risk and examined the calculated heart age in a representative sample of male individuals aged 25-84 years within the prison environment. STUDY DESIGN: This was a cross-sectional study. METHODS: Data were collected on 299 men who underwent a cardiometabolic risk assessment in HMP Parc, Bridgend. The QRISK2 algorithm was used to calculate 10-year CVD risk, relative risk (to general population) and the predicted heart age of an individual. Between-group differences (prison population vs general community) in cardiovascular risk predictions (10-year CVD risk and heart age) were assessed. RESULTS: We observed that at all age groups, the relative risk of predicted 10-year CVD scores in the prison population was double that of the community risk (2.1 ± 0.6), and this was most apparent in the oldest age group (≥50 years: 17.0% compared to 8.8%; P < 0.001). Overall, the heart age of the sample was 7.5 (6.7-8.2) years higher than their own chronological age, and this difference increased to above 9 years in those aged ≥40 years. CONCLUSIONS: This study provides quantifiable evidence to the elevated CVD risk in prison. Heart age predictions were almost a decade higher in those aged ≥40 years. Lowering the screening age for CVD by around 5 years in the prison population should be considered.

What features of a nutrition resource are important to adolescents of a low socioeconomic status?

OBJECTIVE: To identify the key features of a nutrition resource that are important to adolescents of a low socioeconomic status (SES). DESIGN: Structured interviews were conducted to explore participants' preferences relating to the features of a nutrition resource. Thematic framework analysis was used to determine key themes, subthemes and concepts from the data. SETTING: Streetsport activity sessions, north-east of Scotland. PARTICIPANTS: Eighteen adolescents aged 12-17 years from a low socioeconomic background. RESULTS: The overarching themes identified were barriers and facilitators to engagement with a nutrition resource. Adolescents expressed a preference for an app, and this was mainly attributed to convenience and low cost. There was also an emphasis on the integral role social media has in their lives. Aesthetics was a facilitator for both male and female participants, with a particular focus on weight loss. Behaviour change support, including reminders, access to simple recipes and adopting a 'small change approach', were identified as possible facilitators, whereas cost, environmental influences, and existing eating habits were identified as possible barriers to engaging with a nutrition resource. CONCLUSIONS: A number of subthemes, including aesthetics, cost and convenience, which have previously been reported in adolescents with a higher SES, were prominent in our research. The present study contributes to insights relating to behaviour change tools that should be considered when developing a nutrition resource targeting disadvantaged adolescents. Further research focusing on how mobile phone technology and social media can be utilised to support dietary behaviour change in low SES adolescents is recommended.

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia.

Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO's licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto's odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84-0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90-1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.

Transfusion in CMV seronegative T-depleted allogeneic stem cell transplant recipients with CMV-unselected blood components results in zero CMV transmissions in the era of universal leukocyte reduction: a U.K. dual centre experience.

OBJECTIVES: To establish rates of cytomegalovirus (CMV) transmission with use of CMV-unselected (CMV-U), leukocyte-reduced blood components transfused to CMV-seronegative patient/CMV-seronegative donor (CMV neg/neg) allogeneic stem cell transplantation (SCT) recipients including those receiving T-depleted grafts. BACKGROUND: CMV infection remains a major cause of morbidity following SCT. CMV-seronegative SCT recipients are particularly at risk of transfusion transmitted CMV (TT-CMV) and until recently they have received blood components from CMV-seronegative donors with significant resource implications. Although leukocyte reduction of blood components is reported to minimise risk of TT-CMV, its efficacy in high-risk situations, such as in T-depleted transplant recipients, is unknown. METHODS: We retrospectively analysed the incidence of TT-CMV in CMV neg/neg allogeneic SCT recipients transfused with CMV-U, leukocyte-reduced blood components in two transplantation centres in the UK. Patients were monitored for CMV infection by weekly CMV polymerase chain reaction testing. Leukocyte reduction of blood components was in accordance with current UK standards. RESULTS: Among 76 patients, including 59 receiving in vivo T-depletion, no episodes of CMV infection were detected. Patients were transfused with 1442 CMV-unselected, leukocyte-reduced components, equating to 1862 donor exposures. CONCLUSIONS: Our findings confirm the safety of leukocyte reduction as a strategy in preventing TT-CMV in high-risk allogeneic SCT recipients.

Dying whilst on probation: a scoping review of mortality amongst those under community justice supervision.

AIM: Data suggest mortality rates of those under community justice services such as probation or parole have been increasing year on year. Little is known about why and how these individuals are dying. This scoping review explores the causes and contributing factors of mortality in those under community justice supervision. METHODS: Studies published between 2011 and 2021 were identified across CINAHL, Embase, Global Health, Ovid Medline and PsycINFO. Articles were included if they presented original data on either mortality rates among those under community justice supervision or risk factors associated with the mortality of those under community justice supervision. RESULTS: Searches identified 101 unique articles of which 13 were included in the review. Articles were representative of five countries. All articles were either retrospective reviews or retrospective cohort studies. The studies fell into the categories of all-cause mortality, self-inflicted deaths or drug-related deaths. CONCLUSION: Mortality rates of those under community justice supervision were found to be consistently higher than mortality rates for the general population regardless of cause of death. Factors identified as affecting mortality included history of drug use, history of self-harm and previous imprisonment including length of time in custody and experience of hospitalisation or solitary confinement while in custody.

Artificial intelligence methods to estimate overall mortality and non-relapse mortality following allogeneic HCT in the modern era: an EBMT-TCWP study.

Allogeneic haematopoietic cell transplantation (alloHCT) has curative potential counterbalanced by its toxicity. Prognostic scores fail to include current era patients and alternative donors. We examined adult patients from the EBMT registry who underwent alloHCT between 2010 and 2019 for oncohaematological disease. Our primary objective was to develop a new prognostic score for overall mortality (OM), with a secondary objective of predicting non-relapse mortality (NRM) using the OM score. AI techniques were employed. The model for OM was trained, optimized, and validated using 70%, 15%, and 15% of the data set, respectively. The top models, "gradient boosting" for OM (AUC = 0.64) and "elasticnet" for NRM (AUC = 0.62), were selected. The analysis included 33,927 patients. In the final prognostic model, patients with the lowest score had a 2-year OM and NRM of 18 and 13%, respectively, while those with the highest score had a 2-year OM and NRM of 82 and 93%, respectively. The results were consistent in the subset of the haploidentical cohort (n = 4386). Our score effectively stratifies the risk of OM and NRM in the current era but do not significantly improve mortality prediction. Future prognostic scores can benefit from identifying biological or dynamic markers post alloHCT.

Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT.

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

The immune response to foreign red blood cells and the participation of short-lived lymphocytes.

The sequence of morphological changes in the rat spleen following SRBC injection associated with hemolysin production has been correlated with estimates of proliferative activity by splenic lymphatic tissue. Formation of new, reactive germinal centers containing macrophages which engulf nuclear debris is a prominent feature of the response. This is prevented by pretreatment of the animal with cortisol. Indirect evidence is provided that short-lived lymphocytes produced in germinal centers may be a necessary component in the induction of other cells to proliferate and differentiate into hemolysin-producing cells. The reasons are discussed for considering short-lived lymphocytes, such as those produced in the thymus, bone marrow, and germinal centers, as differing from long-lived lymphocytes capable of antibody synthesis.

A Comparison of Inpatient and Outpatient-Based Chemotherapy Regimens for the Treatment of Acute Myeloid Leukaemia In The Elderly.

INTRODUCTION: Acute myeloid leukaemia (AML) is an aggressive haematological malignancy which is more common in the elderly and has a poor 5-year survival. There are no established beneficial interventions to treat AML in elderly patients. It is unclear whether outpatient delivery of palliative chemotherapies could reduce the burden of disease and hospitalisation for this group. AIMS: To compare overall survival, response to treatment and supportive care needs between inpatient and outpatient-based treatments for AML in elderly patients. MATERIALS & METHODS: We undertook a retrospective cohort study in the Haematology Department at Belfast City Hospital comparing overall survival (OS), treatment responses and supportive care needs between inpatient and outpatient treatments for AML in elderly patients. Consecutive entrants to outpatient and inpatient based clinical trials between February 2013 and January 2017 were included. Case notes, chemotherapy charts, clinic letters, blood bank and electronic care records were analysed. RESULTS: OS and rates of CR (complete remission), CRi (CR with incomplete count recovery) and PR (partial response) was not significantly different between inpatient and outpatient regimens with a median OS of 201 vs. 124 days, respectively. No response was observed in 35% of patients in the inpatient group compared with 65% of the outpatient group, however this did not reach significance. Of patients who achieved CR/CRi in the outpatient group, 75% relapsed at a median of 271 days, compared with 60% of the inpatient group at a median of 209 days. At least one grade 3-4 toxicity was experienced by 90% and 83.3% of inpatient and outpatient groups, respectively. There was no difference in six common grade 3-4 toxicities. Patients on the outpatient regimen spent fewer days in hospital but had a median packed red cell use of more than twice that of the inpatient group. No difference was noted in infections, days on antibiotics or platelet use. DISCUSSION: Our data suggests that outpatient chemotherapy is safe and can reduce hospitalisation for elderly patients with AML, without a decline in OS or response rates. These results provide an important rationale to test the comparative efficacy of outpatient chemotherapy. Chemotherapy related toxicities remain a significant source of morbidity in this population and highlight the need to develop novel, targeted therapies for this age group.

Full-intensity and reduced-intensity allogeneic stem cell transplantation in AML.

Allogeneic stem cell transplantation represents the most active form of anti-leukaemic therapy in acute myeloid leukaemia (AML). Advances in transplant technology and supportive care have resulted in improved outcomes in patients allografted using a myeloablative conditioning regimen. At the same time the use of reduced-intensity conditioning regimens has allowed an immunologically mediated graft-versus-leukaemia effect to be exploited in older patients who were previously ineligible for transplantation on the grounds of age or comorbidity. This coupled with the increased availability of alternative stem cell sources, in the form of either unrelated or cord blood donations, has established allogeneic transplantation as a key therapeutic strategy in the treatment of both younger and older adults with AML.

A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia.

BACKGROUND: In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT) from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo) versus matched (MUD 10/10) or mismatched unrelated donor at a single HLA-locus (MMUD 9/10) for patients with acute leukemia in remission. METHODS: Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. RESULTS: The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS) and overall survival (OS) were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. CONCLUSIONS: Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. KEY POINT 1: Better outcomes using fully (10/10) matched unrelated donor for allo-SCT in acute leukemia in remission. KEY POINT 2: Similar outcomes after allo-SCT from unmanipulated haploidentical graft or mismatched (9/10) unrelated donor in acute leukemia in remission.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

This corrects the article DOI: 10.1038/bmt.2016.266.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P<0.0001, marrow and CR: HR: 3.17, P=0.027). Independent risk factors for OS were disease status at time of transplant and the use of in vivo T-cell depletion (TCD). Patients who did not receive TCD and were transplanted from an unrelated donor had worse OS (HR: 4.08, P<0.0001). In conclusion, 'lower' risk MDS patients have better outcome than those with 'higher risk' after haematopoietic stem cell transplant (HSCT). Selecting the right source of stem cells, a CMV-positive donor for CMV-positive patients and using in vivo TCD results in the best outcome in these patients. More studies are needed to evaluate the role of HSCT in these patients as compared with conventional treatment.

Optimizing the use of cyclosporin in allogeneic stem cell transplantation.

Cyclosporin remains the most widely used immunosuppressive agent in patients undergoing allogeneic stem cell transplantation (SCT). The increased awareness of the impact of the intensity of post-transplant immunosuppression on determining outcome after allogeneic SCT has resulted in a re-examination of whether cyclosporin is currently being optimally used in this population of patients. Recent studies in solid organ transplantation have questioned whether the use of trough levels provides the most accurate reflection of the immunosuppressive actions of cyclosporin and alternative strategies to monitor cyclosporin dosage after liver and kidney transplantation are increasingly being used. As a result there is now interest in examining whether there is scope for translating these advances into the arena of haematopoietic transplantation. In this paper, we will review the rationale underlying the current schedules for dosing and monitoring cyclosporin after allogeneic SCT and identify specific areas in which the use of cyclosporin requires re-evaluation. These include evaluation of whether patient outcome would be improved by using peak cyclosporin levels to determine dosing schedules, analysis of optimal cyclosporin dosing schedules in patients undergoing reduced intensity allografts and investigation of surrogate markers of cyclosporin's immunosuppressive activity.

Increased acute GvHD and higher transplant-related mortality in non-caucasians undergoing standard sibling allogeneic stem cell transplantation.

We conducted a retrospective study to compare outcome in Caucasians and non-Caucasians undergoing standard sibling allogeneic SCT. End points of the study were to compare graft-versus-host disease (GvHD) occurrence and transplant-related mortality (TRM). There were 251 patients, 43 non-Caucasian and 208 Caucasian. A higher proportion of non-Caucasian patients developed acute GvHD (aGvHD) grade 2 or greater as compared to the Caucasian group (48 vs 26%, respectively) P = 0.02. With a median follow-up of 27 months, 26% (11/43) of non-Caucasians and 14% (29/208) of Caucasian patients had died from TRM, which accounted for 55% of all deaths in the non-Caucasian group compared to 33% in Caucasians, P = 0.02. Overall survival 12 months post transplant was 64 vs 69% in the non-Caucasian and Caucasian groups, respectively (P = 0.43). Although there were higher numbers of CMV-positive patients in the non-Caucasian group, there were no deaths from CMV reactivation in this subgroup. We conclude that there is increased TRM and aGvHD following standard sibling allograft in the non-Caucasian population and this could be due to either differences in tumour biology or extrinsic factors such as socio-economic factors, nutritional status, post transplant care or presenting with late stage disease.

Topical issues in unrelated donor haematopoietic stem cell transplants: a report from a workshop convened by the Anthony Nolan Trust in London - 2005.

Over more than three decades, The Anthony Nolan Trust (ANT) has provided an unrelated donor (UD) for over 4000 children and adults lacking a suitable family member donor, and has remained at the forefront of developments in haematopoietic stem cell transplantation (HSCT) and bone marrow register management. These three decades have seen major changes in clinical practice of UD-HSCT, including new indications, increased use of alternative haematopoietic cell sources, significant improvement of the outcome as a result of better support care, less-toxic conditioning regimens, and better donor selection, and expansion to older patients with higher comorbidities. In order to foster our goal of improving UD-HSCT availability and outcome in a progressively more complex clinical scenario, a new initiative from ANT was launched in 2005 to convene an experts workshop to address the topical issues in this field. Four consecutive panels addressed factors influencing donor selection and transplant outcome, the use of cord blood, regulatory and accreditation issues, and future developments in this field. This report summarizes the discussions held in this workshop, which will likely develop into a periodic event where transplant clinicians, scientists and registry members will meet to share their experience and vision in the field of UD-HSCT.

Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors.

Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34+ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34+ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.