Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 ...deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome.
Patients (aged 1–23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low <0·0001 and high ≥0·0001) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls, and the secondary outcomes were comparison of long-term outcomes (event-free survival, overall survival, relapse, and treatment-related mortality TRM) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls. Two matched cohorts were formed: for MRD analyses and for long-term outcome analyses. For both cohorts, matching was based on induction regimen; for the long-term outcome cohort, matching also included MRD-guided treatment group. We used mixed-effect models, Cox models, and competing risk for statistical analyses.
Of 251 children and adolescents with Down syndrome and acute lymphocytic leukaemia, 136 were eligible for analyses and matched to 407 (of 8426) non-Down syndrome patients with acute lymphocytic leukaemia (matched controls). 113 patients with Down syndrome and acute lymphocytic leukaemia were excluded from matching in accordance with predefined rules, no match was available for two patients with Down syndrome and acute lymphocytic leukaemia. The proportion of patients with high MRD at the end of induction treatment was similar for patients with Down syndrome and acute lymphocytic leukaemia (52 38% of 136) and matched controls (157 39% of 403; OR 0·97 95% CI 0·64–1·46; p=0·88). Patients with Down syndrome and acute lymphocytic leukaemia had a higher relapse risk than did matched controls in the IKZF1 deleted group (relapse at 5 years 37·1% 17·1–57·2 vs 13·2% 6·1–23·1; cause-specific hazard ratio HRcs 4·3 1·6–11·0; p=0·0028), but not in the IKZF1 wild-type group (relapse at 5 years 5·8% 2·1–12·2 vs 8·1% 5·1–12·0; HRcs 1·0 0·5–2·1; p=0·99). In addition to increased induction deaths (15 6% of 251 vs 69 0·8% of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12·2% 7·0–18·9 vs 2·7% 1·3–4·9; HRcs 5·0 2·3–10·8; p<0·0001).
Induction treatment is equivalently effective for patients with Down syndrome and acute lymphocytic leukaemia and for matched patients without Down syndrome. Down syndrome itself provides an additional risk in individuals with IKZF1 deletions, suggesting an interplay between the germline environment and this poor risk somatic aberration. Different treatment strategies are warranted considering both inherent risk of relapse and high risk of TRM.
Stichting Kinder Oncologisch Centrum Rotterdam and the Princess Máxima Center Foundation, NHMRC Australia, The Cancer Council NSW, Tour de Cure, Blood Cancer UK, UK Medical Research Council, Children with Cancer, Swedish Society for Pediatric Cancer, Swedish Childhood Cancer Fund, Danish Cancer Society and the Danish Childhood Cancer Foundation.
Charged-particle production was studied in proton-proton collisions collected at the LHC with the ALICE detector at centre-of-mass energies 0.9 TeV and 2.36 TeV in the pseudorapidity range |{eta}| < ...1.4. In the central region (|{eta}| < 0.5), at 0.9 TeV, we measure charged-particle pseudorapidity density d N{sub ch}/d{eta} = 3.02 {+-} 0.01(stat.){sub -0.05}{sup +0.08}(syst.) for inelastic interactions, and d N{sub ch}/d{eta} = 3.58 {+-} 0.01(stat.){sub -0.12}{sup +0.12}(syst.) for non-single-diffractive interactions. At 2.36 TeV, we find d N{sub ch}/d{eta} = 3.77 {+-} 0.01(stat.){sub -0.12}{sup +0.25}(syst.) for inelastic, and d N{sub ch}/d{eta} = 4.43 {+-} 0.01(stat.){sub -0.12}{sup +0.37}(syst.) for non-single-diffractive collisions. The relative increase in charged-particle multiplicity from the lower to higher energy is 24.7% {+-} 0.5%(stat.){sub -2.8}{sup +5.7}%(syst.) for inelastic and 23.7% {+-} 0.5%(stat.){sub -1.1}{sup +4.6}%(syst.) for non-single-diffractive interactions. This increase is consistent with that reported by the CMS collaboration for non-single-diffractive events and larger than that found by a number of commonly used models. The multiplicity distribution was measured in different pseudorapidity intervals and studied in terms of KNO variables at both energies. The results are compared to proton-antiproton data and to model predictions.
The patterns of direct oral anticoagulant (DOAC) selection and switching to a different oral anticoagulant (OAC) in patients with atrial fibrillation (AF) are unknown.
To describe temporal patterns ...in first DOAC prescriptions, estimate the incidence, and identify predictors of switching to a different OAC within 1 year in OAC-naive AF patients.
In this retrospective cohort study, using a near-nationwide prescription registry (IQVIA, the Netherlands), we determined the number of patients per month initiated on each DOAC and identified predictors of switching within 1 year with robust Poisson regression.
We included 94,874 patients. From November 2015 to November 2019, the monthly use of apixaban (n = 366 to n = 1066, +191%), rivaroxaban (n = 379 to n = 868, +129%), and edoxaban (n = 2 to n = 305, +15,150%) increased, whereas that of dabigatran decreased (n = 317 to n = 179, −44%). In the 66,090 patients with ≥1 year of available calendar time, 7% switched to a different OAC within 1 year. Strong predictors of switching to a different DOAC were using dabigatran (adjusted risk ratio aRR, 3.33; 95% CI, 3.02-3.66) or edoxaban (aRR, 1.56; 95% CI, 1.34-1.82) rather than apixaban and using a standard DOAC dose (aRR, 2.54; 95% CI, 2.23-2.88). Strong predictors of switching to a vitamin K antagonist were using rivaroxaban (aRR, 1.36; 95% CI, 1.19-1.54 vs apixaban) and using a standard DOAC dose (aRR, 1.49; 95% CI, 1.26-1.77).
In the Netherlands, factor Xa inhibitors are increasingly being selected for OAC-naive AF patients. Seven percent of patients switch to a different OAC within 1 year, and the initial DOAC type and dose are strong predictors of switching.
Display omitted
•Prescription and switching patterns of oral anticoagulants for atrial fibrillation are unknown.•We performed a retrospective cohort study using a near-nationwide pharmacy database.•The use of the factor Xa inhibitors is increasing steadily.•Direct oral anticoagulant type and dose predict switching to another oral anticoagulant.
Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological ...immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro. We showed that incubation of peripheral blood mononuclear cells with these epitopes triggers proliferation of CD4+CD25+FoxP3+ T cells that suppress killing of target cells loaded with MHC class I antigens in an antigen-specific fashion, through a mechanism that seems to require cell-to-cell contact. Expression of a construct encoding for the AAV capsid structural protein fused to Tregitopes resulted in reduction of CD8+ T cell reactivity against the AAV capsid following immunization with an adenoviral vector expressing capsid. This was accompanied by an increase in frequency of CD4+CD25+FoxP3+ T cells in spleens and lower levels of inflammatory infiltrates in injected tissues. This proof-of-concept study demonstrates modulation of CD8+ T cell reactivity to an antigen using regulatory T cell epitopes is possible.
HCV has emerged as a sexually transmitted infection (STI) among HIV-positive men who have sex with men (MSM). We evaluated HCV incidence and its risk factors among HIV-negative MSM using HIV ...pre-exposure prophylaxis (PrEP).
Participants of the Amsterdam PrEP project were tested for HCV antibodies or HCV-RNA every 6 months. Participants used daily or event-driven PrEP and could switch regimens during follow-up. We calculated incidence rates (IRs) for overall HCV infection and separately for primary and re-infection. A univariable Bayesian exponential survival model was used to identify risk factors associated with incident HCV infection. The HCV NS5B gene fragment (709 bp) was sequenced and compared to HCV isolates from HIV-positive MSM and other risk groups (n = 419) using phylogenetic analysis.
Among 350 participants contributing 653.6 person-years (PYs), we detected 15 HCV infections in 14 participants (IR = 2.30/100PY). There were 8 primary infections (IR = 1.27/100PY) and 7 re-infections (IR = 27.8/100PY). IR was 2.71/100PY in daily and 1.15/100PY in event-driven PrEP users. Factors associated with incident HCV infection were higher number of receptive condomless anal sex acts with casual partners (posterior hazard ratio HR 1.57 per ln increase; 95% credibility interval CrI 1.09–2.20), anal STI (posterior HR 2.93; 95% CrI 1.24–7.13), injecting drug use (posterior HR 4.69; 95% CrI 1.61–12.09) and sharing straws when snorting drugs (posterior HR 2.62; 95% CrI 1.09–6.02). We identified robust MSM-specific HCV clusters of subtypes 1a, 4d, 2b and 3a, which included MSM with and without HIV.
HIV-negative MSM using PrEP are at risk of incident HCV infection, while identified risk factors are similar to those in HIV-positive MSM. Regular HCV testing is needed, especially for those with a previous HCV infection and those reporting risk factors.
We report that hepatitis C virus infections are frequently acquired among HIV-negative men who have sex with men (MSM) using pre-exposure prophylaxis to prevent HIV infection. New infections occurred more frequently in those reporting receptive anal sex without using condoms, having an anal sexually transmitted infection, injecting drugs, and sharing straws when snorting drugs. The viruses found in HIV-negative men using pre-exposure prophylaxis are genetically similar to those in HIV-positive men, but not in other hepatitis C risk groups, suggesting that (sexual) transmission is occurring between HIV-positive MSM and HIV-negative MSM using pre-exposure prophylaxis.
Dutch trial registration number NTR5411.
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•HIV-negative men who have sex with men while on pre-exposure prophylaxis are at risk of incident HCV infection.•High incidence rates of both HCV primary and re-infection were observed.•Identified HCV risk-factors were similar to those in HIV-positive men who have sex with men.•Specific clusters of HCV strains were identified in men who have sex with men, with and without HIV.•HCV-testing for HIV-negative men who have sex with men while on pre-exposure prophylaxis is recommended.
Summary
Objective
Insulin resistance develops prior to the onset of overt type 2 diabetes, making its early detection vital. Direct accurate evaluation is currently only possible with complex ...examinations like the stable isotope‐based hyperinsulinemic euglycemic clamp (HIEC). Metabolomic profiling enables the detection of thousands of plasma metabolites, providing a tool to identify novel biomarkers in human obesity.
Design
Liquid chromatography mass spectrometry–based untargeted plasma metabolomics was applied in 60 participants with obesity with a large range of peripheral insulin sensitivity as determined via a two‐step HIEC with stable isotopes 6,6‐2H2glucose and 1,1,2,3,3‐2H5glycerol. This additionally enabled measuring insulin‐regulated lipolysis, which combined with metabolomics, to the knowledge of this research group, has not been reported on before.
Results
Several plasma metabolites were identified that significantly correlated with glucose and lipid fluxes, led by plasma (gamma‐glutamyl)citrulline, followed by betaine, beta‐cryptoxanthin, fructosyllysine, octanylcarnitine, sphingomyelin (d18:0/18:0, d19:0/17:0) and thyroxine. Subsequent machine learning analysis showed that a panel of these metabolites derived from a number of metabolic pathways may be used to predict insulin resistance, dominated by non‐essential amino acid citrulline and its metabolite gamma‐glutamylcitrulline.
Conclusion
This approach revealed a number of plasma metabolites that correlated reasonably well with glycemic and lipolytic flux parameters, measured using gold standard techniques. These metabolites may be used to predict the rate of glucose disposal in humans with obesity to a similar extend as HOMA, thus providing potential novel biomarkers for insulin resistance.
Semiconducting transition metal dichalcogenides have gained increased interest as potential alternatives to graphene due to their tunable electronic bandgaps. In this study, we present the deposition ...of stoichiometric WS
2
x
Se
2−2
x
(0 ≤
x
≤ 1) binary and ternary thin films using the single source precursors, WECl
4
(E′
n
Bu
2
) (E = S or Se; E′ = S or Se),
via
low-pressure chemical vapour deposition. Compositional and structural characterisations of the deposits have been performed by grazing-incidence X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy, confirming the phase purity and stoichiometry. Electrical characterisation
via
Hall measurements reveals high electrical conductivities for those films. Such high conductivity is likely related to Se and S vacancies in the films and can be tuned through an annealing process. The thermoelectric capabilities of the WS
2
x
Se
2−2
x
have been characterised with the use of variable-temperature Seebeck measurements, showing a peak power factor of 6 μW m
−1
K
−2
for the as-deposited WS
2
film at 553 K.
A series of novel single source precursors, WECl
4
(E′
n
Bu
2
) (E = S or Se; E′ = S or Se), are developed in this work to deposit stoichiometric WS
2
x
Se
2−2
x
(0 ≤
x
≤ 1) binary and ternary thin films.
Semiconducting transition metal dichalcogenides have gained increased interest as potential alternatives to graphene due to their tunable electronic bandgaps. In this study, we present the deposition ...of stoichiometric WS
2
x
Se
2−2
x
(0 ≤
x
≤ 1) binary and ternary thin films using the single source precursors, WECl
4
(E′
n
Bu
2
) (E = S or Se; E′ = S or Se),
via
low-pressure chemical vapour deposition. Compositional and structural characterisations of the deposits have been performed by grazing-incidence X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy, confirming the phase purity and stoichiometry. Electrical characterisation
via
Hall measurements reveals high electrical conductivities for those films. Such high conductivity is likely related to Se and S vacancies in the films and can be tuned through an annealing process. The thermoelectric capabilities of the WS
2
x
Se
2−2
x
have been characterised with the use of variable-temperature Seebeck measurements, showing a peak power factor of 6 μW m
−1
K
−2
for the as-deposited WS
2
film at 553 K.
Aim
To develop a patient‐reported outcome measure (PROM) assessing upper limb function related to activities of daily living (ADL) that cannot be observed in a clinical setting, specifically for ...patients with Duchenne muscular dystrophy (DMD) across a wide age range, applicable in the different stages of the disease.
Method
The developmental process was based on US Food and Drug Administration guidelines. This included item generation from a systematic review of existing tools and expert opinion on task difficulty and relevance, involving individuals with DMD. Cultural aspects affecting ADL were taken into consideration to make this tool applicable to the broad DMD community. Items were selected in relation to a conceptual framework reflecting disease progression covering the full range of upper limb function across different ADL domains.
Results
After pilot testing and iterative Rasch analyses, redundant or clinically irrelevant items were removed. The final questionnaire consists of 32 items covering four domains of ADL (food, self‐care, household and environment, leisure and communication). Test–retest reliability was excellent.
Interpretation
A DMD‐specific upper limb PROM was developed on the basis of clinical relevance and psychometric robustness. Its main purpose is to document the patient self‐reported natural history of DMD and assess the efficacy of interventions.
What this paper adds
A new patient‐reported outcome measure (PROM) for Duchenne muscular dystrophy (DMD) has been developed.
The DMD Upper Limb PROM targets upper limb function in daily life.
Psychometric techniques confirmed its unidimensionality, internal consistency, and test–retest reliability.
Involvement of different stakeholders guaranteed the clinical relevance of the tool.
This article is commented on by Pangalila on pages 123–124 of this issue.
Part One: https://youtu.be/Xllfkotw7Dg
Part Two: https://youtu.be/BuEwCLG_l1E
The associations of circulating 25-hydroxyvitamin D 25(OH)D concentrations with total and sitespecific cancer incidence have been examined in several epidemiological studies with overall inconclusive ...findings. Very little is known about the association of vitamin D with cancer incidence in older populations. We assessed the association of pre-diagnostic serum 25(OH)D levels with incidence of all cancers combined and incidence of lung, colorectal, breast, prostate and lymphoid malignancies among older adults. Pre-diagnostic 25(OH)D concentrations and cancer incidence were available in total for 15,486 older adults (mean age 63, range 50-84 years) participating in two cohort studies: ESTHER (Germany) and TROMSØ (Norway); and a subset of previously published nested-case control data from a another cohort study: EPIC-Elderly (Greece, Denmark, Netherlands, Spain and Sweden) from the CHANCES consortium on health and aging. Cox proportional hazards or logistic regression were used to derive multivariable adjusted hazard and odds ratios, respectively, and their 95 % confidence intervals across 25(OH)D categories. Meta-analyses with random effects models were used to pool study-specific risk estimates. Overall, lower 25(OH)D concentrations were not significantly associated with increased incidence of most of the cancers assessed. However, there was some evidence of increased breast cancer and decreased lymphoma risk with higher 25(OH)D concentrations. Our meta-analyses with individual participant data from three large European population-based cohort studies provide at best limited support for the hypothesis that vitamin D may have a major role in cancer development and prevention among European older adults.
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