In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial

Background The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population. Methods This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25–65 years (BCR-ABL1-negative) or 18–65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days –6 to –2, melphalan 140 mg/m2 on day –2, and alemtuzumab 30 mg on day –1 [sibling donor] and days –2 and –1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617. Findings From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36–70), 4-year event-free survival was 46·8% (95% CI 40·1–53·2) and 4-year overall survival was 54·8% (48·0–61·2). 4-year cumulative incidence of relapse was 33·6% (27·9–40·2) and 4-year TRM was 19·6% (15·1–25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2–4 occurred in 29 (12%) of 247 patients and grade 3–4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46–3·93]) and time-to-relapse (HR 2·41 [1·29–4·48]). Interpretation FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. Funding Cancer Research UK

Inelastic photoproduction of J/Psi mesons at HERA

An analysis of inelastic photoproduction of J/Psi mesons is presented using data collected at the ep collider HERA corresponding to an integrated luminosity of above 80pb-1. Differential and double differential cross sections are measured in a wide kinematic region: 6

Charmonium Production in Deep Inelastic Scattering at HERA

The electroproduction of J/psi and psi(2S) mesons is studied in elastic, quasi-elastic and inclusive reactions for four momentum transfers 2 Q^2 80 GeV^2 and photon-proton centre of mass energies 25 W 180 GeV. The data were taken with the H1 detector at the electron proton collider HERA in the years 1995 to 1997. The total virtual photon-proton cross section for elastic J/psi production is measured as a function of Q^2 and W. The dependence of the production rates on the square of the momentum transfer from the proton (t) is extracted. Decay angular distributions are analysed and the ratio of the longitudinal and transverse cross sections is derived. The ratio of the cross sections for quasi-elastic psi(2S) and J/psi meson production is measured as a function of Q^2. The results are discussed in terms of theoretical models based upon perturbative QCD. Differential cross sections for inclusive and inelastic production of J/psi mesons are determined and predictions within two theoretical frameworks are compared with the data, the non-relativistic QCD factorization approach including colour octet and colour singlet contributions, and the model of Soft Colour Interactions

Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016

The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Vascular Remodeling in Health and Disease

The term vascular remodeling is commonly used to define the structural changes in blood vessel geometry that occur in response to long-term physiologic alterations in blood flow or in response to vessel wall injury brought about by trauma or underlying cardiovascular diseases.1, 2, 3, 4 The process of remodeling, which begins as an adaptive response to long-term hemodynamic alterations such as elevated shear stress or increased intravascular pressure, may eventually become maladaptive, leading to impaired vascular function. The vascular endothelium, owing to its location lining the lumen of blood vessels, plays a pivotal role in regulation of all aspects of vascular function and homeostasis.5 Thus, not surprisingly, endothelial dysfunction has been recognized as the harbinger of all major cardiovascular diseases such as hypertension, atherosclerosis, and diabetes.6, 7, 8 The endothelium elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation.8, 9, 10 Among the primary biologic mediators emanating from the endothelium is nitric oxide (NO) and the arachidonic acid metabolite prostacyclin [prostaglandin I2 (PGI2)], which exert powerful vasodilatory, antiadhesive, and antiproliferative effects in the vessel wall