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This reflective article was drafted in November 2020. Since this time, the authors have worked with the counter-slavery sector to co-develop a refined public health framework to address modern slavery (Such et al, 2021). Significant knowledge mobilisation has also occurred with a range of stakeholders, and the Independent Anti-Slavery Commissioner has encouraged the UK Home Office and the Home Secretary to embed a public health approach within the UK’s response to modern slavery (IASC/Home Secretary, 2021). Key references and insights from research in 2021 are available as a collection.

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBXI) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBXI showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBXI had a significantly higher cumulative incidence of relapse, especially among patients aged >= 35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).

In myelodysplastic syndromes (MDS), the 20q deletion [del(20q)] may cause deletion of the ASXL1 gene. We studied 153 patients with MDS and del(20q) to assess the incidence, prognostic value and impact on response to azacitidine (AZA) of ASXL1 chromosomal alterations and genetic mutations. Additionally, in vitro assay of the response to AZA in HAP1 (HAP1(WT)) and HAP1 ASXL1 knockout (HAP1(KN)) cells was performed. ASXL1 chromosomal alterations were detected in 44 patients (28 center dot 5%): 34 patients (22%) with a gene deletion (ASXL1(DEL)) and 10 patients (6 center dot 5%) with additional gene copies. ASXL1(DEL) was associated with a lower platelet count. The most frequently mutated genes were U2AF1 (16%), ASXL1 (14%), SF3B1 (11%), TP53 (7%) and SRSF2 (6%). ASXL1 alteration due to chromosomal deletion or genetic mutation (ASXL1(DEL)/ASXL1(MUT)) was linked by multivariable analysis with shorter overall survival [hazard ratio, (HR) 1 center dot 84; 95% confidence interval, (CI): 1 center dot 11-3 center dot 04; P = 0 center dot 018] and a higher rate for acute myeloid leukaemia progression (HR 2 center dot 47; 95% CI: 1 center dot 07-5 center dot 70, P = 0 center dot 034). ASXL1(DEL)/ASXL1(MUT) patients were correlated by univariable analysis with a worse response to AZA. HAP1(KN) cells showed more resistance to AZA compared to HAP1(WT) cells. In conclusion, ASXL1 alteration exerts a negative impact on MDS with del(20q) and could become useful for prognostic risk stratification and treatment decisions.

Background\ud Globally, international migration is increasing. Population growth, along with other demographic changes, may be expected to put new pressures on healthcare systems. Some studies across Europe suggest that emergency departments (EDs) are used more, and differently, by migrants compared to non-migrant populations, which may be a result of unfamiliarity with the healthcare systems and difficulties accessing primary healthcare. However, little evidence exists to understand how migrant parents, who are typically young and of childbearing age, utilise EDs for their children. This study aimed to examine the association between paediatric ED utilisation in the first 5 years of life and maternal migration status in the Born in Bradford (BiB) cohort study.\ud \ud Methods and findings\ud We analysed linked data from the BiB study—an ongoing, multi-ethnic prospective birth cohort study in Bradford. Bradford is a large, ethnically diverse city in the north of England. In 2017, more than a third of births in Bradford were to mothers who were born outside the UK. Between March 2007 and December 2010, pregnant women were recruited to BiB during routine antenatal care, and the children born to these mothers have been, and continue to be, followed over time to assess how social, genetic, environmental, and behavioural factors impact on health from childhood to adulthood. Data analysed in this study included baseline questionnaire data from BiB mothers, and Bradford Royal Infirmary ED episode data for their children. Main outcomes were likelihood of paediatric ED use (no visits versus at least 1 ED visit in the first 5 years of life) and ED utilisation rates (number and frequency of ED visits) for children who have accessed the ED. The main explanatory variable was mother’s migrant status (foreign-born versus UK/Irish-born). Multivariable analyses (logistic and zero-truncated negative binomial regression) were conducted adjusting for socio-demographic and socio-economic factors. The final dataset included 10,168 children born between April 2007 and June 2011, of whom 35.6% were born to migrant mothers. Foreign-born mothers originated from South Asia (28.6%), Europe/Central Asia (3.2%), Africa (2.1%), East Asia/Pacific (1.1%), and the Middle East (0.6%). At recruitment the mothers ranged in age from 15 to 49 years old. Overall, 3,104 (30.5%) children had at least 1 ED visit in the first 5 years of life, with the highest proportion of visits being in the first year of life (36.7%). The proportion of children who visited the ED at least once was lower for children of migrant mothers as compared to children of non-migrant mothers (29.4% versus 31.2%). Children of migrant mothers were found to be less likely to visit the ED (odds ratio 0.88 [95% CI 0.80 to 0.97], p = 0.012). However, among children who visited the ED, the utilisation rate was significantly higher for children of migrant mothers (incidence rate ratio [IRR] 1.19 [95% CI 1.01 to 1.40], p = 0.040). Utilisation rates were higher for children born to mothers from Europe (IRR 1.71 [95% CI 1.07 to 2.71], p = 0.024) and established migrants (≥5 years living in UK) (IRR 1.24 [95% CI 1.02 to 1.51], p = 0.032) compared to UK/Irish-born mothers. Important limitations include being unable to measure children’s underlying health status and the urgency of ED attendance, as well as the analysis being limited by missing data.\ud \ud Conclusions\ud In this study we observed that there is no higher likelihood of first paediatric ED attendance in the first 5 years of life for children in the BiB cohort for migrant mothers. However, among ED users, children of migrant mothers attend the service more frequently than children of UK/Irish-born mothers. Our findings show that patterns of ED utilisation differ by mother’s region of origin and time since arrival in the UK.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring =2 mutations had a worse outcome than patients with

This article has a companion Point by Thol and Platzbecker.

The platelet-derived growth factor receptor beta (PDGFRB) gene translocations lead to a spectrum of chronic myeloid neoplasms, frequently associated with eosinophilia. Clinical heterogeneity is associated with a molecular one. Here, we report a novel case of a patient harboring a t(5;8)(q33;p22) translocation, resulting in the PCM1/PDGFRB fusion. Conventional cytogenetics and RNA sequencing were performed to identify the chromosomes and the genes involved in the rearrangement, respectively. This study shows that the combination of different strategies is pivotal to fine-tune the diagnosis and the clinical management of the patient. After 1 year of treatment with imatinib, the patient achieves hematological and molecular remission. We present an attractive strategy to identify novel and/or cryptic fusions, which will be relevant for clinicians dealing with the diagnosis of the patients with myelodysplastic syndrome/myeloproliferative diseases with atypical manifestations.

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p 0.001), correlated with a worse and a better outcome, respectively. TP53 mutations also demonstrated impact on the cumulative incidence of relapse (CIR) (1year CIR 47.1% vs. 9.8%, p = 0.006) and were related with complex karyotype (p = 0.003). cGVHD improved the outcome even among patients with more than 2 mutated genes (1-year OS 88.9% at 1year vs. 31.3%, p = 0.02) and patients with TP53 mutations (1-year CIR 20% vs. 42.9%, p = 0.553). These results confirm that cGVHD could ameliorate the adverse impact of somatic mutations in patients with MDS with HSCT.

High rates of immigration in recent years in the United Kingdom presents service design and delivery challenges to primary care. At a time when resources are stretched, services must be both efficient and equitable for patients. Migrants are often healthy on arrival but some groups, such as refugees and asylum seekers, may have many healthcare needs. This study sought to explore how primary care is managing demand on its services by new migrants and how it addresses need in provision.APPROACHThe research was exploratory and formative. It looked at the services delivered in primary care organisations. The study took place between November 2015 and March 2016. Its methods were:Survey and contact form: Non-probability sampleof GPs, other health professionals, practice managers and third sector providers who hadserved new migrant populations in the last fiveyears (n=70); Responses were sifted for contact details and selected for case studies.In-depth case studies: Documentary analysis andin-depth interviews and focus groups with eightcase study primary care organisations.University of Sheffield’s School of Health and Related Research ethics committee (ref no 006009)The report was produced by the School of Health and Related Research (ScHARR) and the Academic Unit of Primary Medical Care (AUMPC), University of Sheffield. ISBN 978-0-9571207-3-0

The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1mutDNMT3Amut). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1mutDNMT3Amut patients showed a higher RBC transfusion dependency (92% versus 48%, p =.007), a shorter overall survival (OS) (median, 30 versus 97 months, p =.034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p =.023) than SF3B1mutDNMT3Awt patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1mut patients with a negative clinical impact. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for similar to 80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (>= 1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients. (C) 2015 Wiley Periodicals, Inc.

Dysregulation of MYBL2 has been associated to tumorigenesis and the S427G polymorphism could induce partial inactivation of MYBL2, associating it with cancer risk. It has previously been shown that MYBL2 was over-expressed in some acute myeloid leukemias (AML), portending poor prognosis. However, to date no studies have investigated the S427G or other genetic variants of MYBL2 in AML. This study analyzed the S427G in 197 AML patients and 179 controls and screened the MYBL2 sequence in patients. In contrast to other studies in solid tumors, the S427G was not associated with the incidence of AML. This study detected four unannotated genetic alterations, of which the Q67X could be involved in MYBL2 dysfunction. Eight polymorphisms were identified, among which the rs73116571, located in a splicing region, was associated with higher incidence in AML and weaker MYBL2 expression, suggesting pre-disposition to AML. Additional functional studies should be performed to verify these genetic variations as possible targets in AML.