Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

Temporal Requirement for Pulmonary Resident and Circulating T Cells during Virulent Francisella tularensis Infection.

The lung is a complex organ with anatomically distinct pools of T cells that play specific roles in combating infection. Our knowledge regarding the generation and/or maintenance of immunity by parenchymal or circulating T cells has been gathered from either persistent (>60 d) or rapidly cleared (<10 d) infections. However, the roles of these distinct T cell pools in infections that are cleared over the course of several weeks are not understood. Clearance of the highly virulent intracellular bacterium Francisella tularensis subspecies tularensis (Ftt) following pulmonary infection of immune animals is a protracted T cell-dependent process requiring ∼30-40 d and serves as a model for infections that are not acutely controlled. Using this model, we found that intranasal vaccination increased the number of tissue-resident CD4+ effector T cells, and subsequent challenge of immune mice with Ftt led to a significant expansion of polyfunctional parenchymal CD4+ effector T cells compared with the circulating pool. Despite the dominant in vivo response by parenchymal CD4+ T cells after vaccination and challenge, circulating CD4+ T cells were superior at controlling intracellular Ftt replication in vitro. Further examination in vivo revealed temporal requirements for resident and circulating T cells during Ftt infection. These requirements were in direct contrast to other pulmonary infections that are cleared rapidly in immune animals. The data in this study provide important insights into the role of specific T cell populations that will be essential for the design of novel effective vaccines against tularemia and potentially other agents of pulmonary infection.

Commercial determinants of health: advertising of alcohol and unhealthy foods during sporting events.

Tobacco, alcohol and foods that are high in fat, salt and sugar generate much of the global burden of noncommunicable diseases. We therefore need a better understanding of how these products are promoted.The promotion of tobacco products through sporting events has largely disappeared over the last two decades, but advertising and sponsorship continues bycompanies selling alcohol, unhealthy food and sugar-sweetened beverage. The sponsorship of sporting events such as the Olympic Games, the men's FIFA World Cup and the men's European Football Championships in 2016, has received some attention in recent years in the public health literature. Meanwhile, British football and the English Premier League have become global events with which transnational companies are keen to be associated, to promote their brands to international markets. Despite its reach, the English Premier League marketing and sponsorship portfolio has received very little scrutiny from public health advocates. We call for policy-makers and the public health community to formulate an approach to the sponsorship of sporting events, one that accounts for public health concerns.

Le tabac, l'alcool et les aliments riches en graisse, en sel et en sucre génèrent la plus large partie de la charge mondiale des maladies non transmissibles. Il est donc nécessaire de mieux comprendre la manière dont ces produits sont promus. La promotion des produits du tabac dans le cadre d'événements sportifs a largement disparu au cours des vingt dernières années, mais la publicité et le sponsoring par des entreprises qui vendent de l'alcool, des produits alimentaires peu sains et des boissons sucrées sont encore d'actualité. Depuis quelques années, la littérature sur la santé publique commence à porter son attention sur le sponsoring d'événements sportifs, tels que les Jeux olympiques, la Coupe du monde masculine de la FIFA ou encore le Championnat d'Europe de football masculin de 2016. Mais dans le même temps, le football britannique et la Premier League anglaise sont devenus des événements mondiaux auxquels les multinationales aiment être associées pour promouvoir leurs marques auprès de marchés internationaux. Malgré leur portée, le marketing et le sponsoring de la Premier League anglaise semblent négligés par les défenseurs de la santé publique. Nous appelons les décideurs politiques et la communauté de santé publique à élaborer une approche pour le sponsoring d'événements sportifs qui réponde aux enjeux de santé publique.

El tabaco, el alcohol y los alimentos que son ricos en grasa, como la sal y el azúcar, generan gran parte de la carga mundial de enfermedades no contagiosas. Por tanto, necesitamos una mejor comprensión de la forma en que se promueven estos productos. La promoción de los productos del tabaco a través de eventos deportivos ha desaparecido en gran medida en las últimas dos décadas, pero la publicidad y el patrocinio continúan por parte de las empresas que venden alcohol, alimentos poco saludables y bebidas azucaradas. El patrocinio de eventos deportivos como los Juegos Olímpicos, la Copa Mundial de la FIFA masculina y el Campeonato de Fútbol Europeo del 2016 ha recibido cierta atención en los últimos años en la bibliografía sobre salud pública. Mientras tanto, el fútbol británico y la Premier League inglesa se han convertido en eventos globales con los que las empresas transnacionales están dispuestas a asociarse, para promocionar sus marcas ante los mercados internacionales. A pesar de su alcance, la cartera de comercialización y patrocinio de la Premier League inglesa apenas han sido objeto de escrutinio por parte de los defensores de la salud pública. Pedimos a los responsables de la formulación de políticas y a la comunidad de la salud pública que formulen un enfoque para el patrocinio de eventos deportivos, que tenga en cuenta estas preocupaciones sobre la salud pública.

Exploring the relationship between Big Food corporations and professional sports clubs: a scoping review.

OBJECTIVE: Professional sport occupies a prominent cultural position in societies across the globe and commercial organisations make use of this to promote their products. The present scoping review explores existing academic literature on the relationship between professional sports clubs and food and drink marketing and considers how this relationship may impact upon the public's health. DESIGN: The scoping review searched six databases. Experts were also consulted. Records written in languages other than English were excluded. We also excluded records relating to mega events (e.g. Olympics, Football World Cup) and alcohol marketing, because of the attention already given to these. SETTING: Professional sports clubs. RESULTS: We identified 18 166 titles, reviewed 163 abstracts and read twenty-six full texts. We included six papers in the review. Four were from Australia and New Zealand. The Australasian literature focused largely on the marketing of foods and beverages to children and the potential impact on consumption. Single papers from researchers in Turkey and the USA were identified. The Turkish paper analysed shirt sponsorship in football leagues internationally and showed food and beverage (including alcohol) companies were the most common sponsors. The US paper examined a mixed reaction to a football team named after an energy drink. CONCLUSIONS: Commercial relationships between professional sports clubs and Big Food corporations have largely eluded scrutiny in much of the world. The current review highlights the lack of public health research on these relationships. Research exploring the interdependent commercial practices of food and drink companies and professional sports clubs is urgently needed.

Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group.

Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84-94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage.

Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

BACKGROUND: The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. METHODS: We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. RESULTS: The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L and was below 1 mg·L in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). CONCLUSIONS: Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.

Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8.

Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity constitute a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. In this article, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated live vaccine strain, inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα-independent inhibition of NF-κBp65 activation and selective inhibition of activation of IFN regulatory factors. Interference with NF-κBp65 and IFN regulatory factors is also observed following infection with viable SchuS4. Together these data provide novel insight into how highly virulent bacteria selectively modulate the host to interfere with innate immune responses required for survival of infection.

Associations between e-cigarette access and smoking and drinking behaviours in teenagers.

BACKGROUND: Public health concerns regarding e-cigarettes and debate on appropriate regulatory responses are focusing on the need to prevent child access to these devices. However, little is currently known about the characteristics of those young people that are accessing e-cigarettes. METHODS: Using a cross-sectional survey of 14-17 year old school students in North West England (n = 16,193) we examined associations between e-cigarette access and demographics, conventional smoking behaviours, alcohol consumption, and methods of accessing cigarettes and alcohol. Access to e-cigarettes was identified through a question asking students if they had ever tried or purchased e-cigarettes. RESULTS: One in five participants reported having accessed e-cigarettes (19.2%). Prevalence was highest among smokers (rising to 75.8% in those smoking >5 per day), although 15.8% of teenagers that had accessed e-cigarettes had never smoked conventional cigarettes (v.13.6% being ex-smokers). E-cigarette access was independently associated with male gender, having parents/guardians that smoke and students' alcohol use. Compared with non-drinkers, teenagers that drank alcohol at least weekly and binge drank were more likely to have accessed e-cigarettes (adjusted odds ratio [AOR] 1.89, P < 0.001), with this association particularly strong among never-smokers (AOR 4.59, P < 0.001). Among drinkers, e-cigarette access was related to: drinking to get drunk, alcohol-related violence, consumption of spirits; self-purchase of alcohol from shops or supermarkets; and accessing alcohol by recruiting adult proxy purchasers outside shops. CONCLUSIONS: There is an urgent need for controls on the promotion and sale of e-cigarettes to children. Findings suggest that e-cigarettes are being accessed by teenagers more for experimentation than smoking cessation. Those most likely to access e-cigarettes may already be familiar with illicit methods of accessing age-restricted substances.

Long-term outcomes of alemtuzumab-based reduced-intensity conditioned hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myelogenous leukemia secondary to myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) offers a potential cure for patients with myelodysplastic syndrome (MDS) who are ineligible for standard-intensity regimens. Previously published data from our institution suggest excellent outcomes at 1 yr using a uniform fludarabine, busulfan, and alemtuzumab-based regimen. Here we report long-term follow-up of 192 patients with MDS and acute myelogenous leukemia (AML) secondary to MDS (MDS-AML) transplanted with this protocol, using sibling (n = 45) or matched unrelated (n = 147) donors. The median age of the cohort was 57 yr (range, 21 to 72 yr), and median follow-up was 4.5 yr (range, 0.1 to 10.6 yr). The 5-yr overall survival (OS), event-free survival, and nonrelapse mortality were 44%, 33%, and 26% respectively. The incidence of de novo chronic graft-versus-host disease (GVHD) was low at 19%, illustrating the efficacy of alemtuzumab for GVHD prophylaxis. Conversely, the 5-yr relapse rate was 51%. For younger patients (age <50 yr), the 5-yr OS and relapse rates were 58% and 39%, respectively. On multivariate analysis, advanced age predicted significantly worse outcomes, with patients age >60 yr having a 5-yr OS of 15% and relapse rate of 66%. Patients receiving preemptive donor lymphocyte infusions had an impressive 5-yr OS of 67%, suggesting that this protocol may lend itself to the incorporation of immunotherapeutic strategies. Overall, these data demonstrate good 5-yr OS for patients with MDS and MDS-AML undergoing alemtuzumab-based RIC-HSCT. The low rate of chronic GVHD is encouraging, and comparative studies with other RIC protocols are warranted.

Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes.

Relapse occurs in 30%-50% of recipients of T cell-depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis.

This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17-89 years) and median follow-up was 45 months [95% confidence interval (CI) 27-62 months]. TP53 mutations occurred in 30 (9.4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with -5/5q-(72%), correlated with International Prognostic Scoring System intermediate-2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild-type (9 versus 66 months, P < 0.001) and it retained significance in multivariable model (Hazard Ratio 3.8, 95%CI 2.3-6.3,P < 0.001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5-azacitidine, however clones increased in non-responders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q- and CK with -5/5q-, possibly implies two different mechanistic roles for TP53 protein.