Kirkpatrickboje1979

able models (HR 3·72 [1·56-8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49-6·39]; p=0·0025).

Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum.

National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.

Patients with essential thrombocythaemia or polycythaemia vera have several symptoms that can worsen their quality of life. Guggulsterone E&Z We aimed to assess how symptom burden changes over time with cytoreductive therapy.

We performed a post-hoc analysis of data from MPN-RC 111-a single-arm, open-label, phase 2, multicentre trial at 17 hospitals and cancer centres in Italy and the USA, evaluating the clinical-haematological response to pegylated interferon alfa-2a in patients who were resistant or intolerant to hydroxyurea (NCT01259817)-and MPN-RC 112-a randomised, open-label, phase 3, multicentre trial at 25 hospitals and cancer centres in France, Germany, Israel, Italy, the UK, and the USA, comparing the clinical-haematological response to pegylated interferon alfa-2a versus hydroxyurea in therapy-naive patients with either high-risk essential thrombocythaemia or polycythaemia vera (NCT01258856). Patients completed the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organisation for thealfa-2a (mean total symptom score change -10·2, 95% CI -13·2 to -7·2) and those treated with hydroxyurea (-6·8, -11·2 to -2·4). However, symptom burden worsened between 3 and 12 months in patients with low baseline symptom burden (patients treated with pegylated interferon alfa-2a mean total symptom score change 3·2, 95% CI 0·9 to 5·4; patients treated with hydroxyurea 3·4, 0·6 to 6·2).

Results can inform treatment decisions, including treatment timing and goals in managing essential thrombocythaemia and polycythaemia vera, because measuring symptom burden from the patient perspective is crucial to understanding treatment efficacy and tolerability.

US National Cancer Institute of the National Institutes of Health, and Roche Genentech.

US National Cancer Institute of the National Institutes of Health, and Roche Genentech.

In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities.

SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 11 ratio to low-dose (10 mg/kg per day) or moderate-dose (e hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression.

Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke.

National Institute of Neurological Disorders and Stroke.

National Institute of Neurological Disorders and Stroke.

Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD.

GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (11), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was oonse 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group.

The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD.

Incyte.

Incyte.Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here, we elucidate the structural basis and mode of action for two potent SARS-CoV-2 spike (S)-neutralizing monoclonal antibodies, CV3-1 and CV3-25, which remain effective against emerging variants of concern in vitro and in vivo. CV3-1 binds to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the "RBD-up" position and triggers potent shedding of the S1 subunit. In contrast, CV3-25 inhibits membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among β-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in the RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.The detection of BCR-ABL1 mRNA transcripts is essential to molecular chronic myeloid leukemia (CML) diagnosis. In most cases, the RT-qPCR technique is performed as the gold standard diagnosis tool for clinical cases. However, this method requires expensive reagents and equipment, such as a real-time thermal cycler, probes and master mix. Consequently, the development and validation of simple and low-cost methods are essential for a rapid CML diagnosis in less specialized and equipped centers. In this study, we develop and demonstrate an accessible, rapid, and low-cost method using RT-LAMP for BCR-ABL1 detection in both cell lines and CML clinical samples, using fluorescent and colorimetric assays. Both methods demonstrated diagnostic specificity of 100% and while diagnostic sensitivity reaches more than 90% in samples with RT-qPCR cycle threshold above 31. The obtained data indicates that the proposed method here described is robust, specific and rapid approach for CML diagnosis with outstanding performance, especially for CML diagnostic procedure where present high BCR-ABL1 expression.

Recent studies have indicated that N-acetyl-leucine (N-Ac-Leu) is a potential biomarker of diabetes. This study aimed to measure the levels of enantiomers of the chiral molecule N-Ac-DL-Leu in the saliva of patients with type 2 diabetes and further determine the potential association between them.

A novel validated method was established using ultra-performance liquid chromatography (UPLC) with fluorescence (FL) detection, in which precolumn derivatization of (R)-(-)-4-(N, N-dimethylaminosulfonyl)-7-(3-aminopyrrolidin-l-yl)-2,1,3-benzoxadiazole [(R)-(-)-DBD-APy] was used for the simultaneous determination and chiral separation of N-Ac-DL-Leu in human saliva.

The labeled N-Ac-DL-Leu diastereomers were completely separated, with a resolution value of 1.93. Additionally, excellent linearity for N-Ac-DL-Leu was observed, with high coefficients of correlation (r

≥0.9999) in the range of 10-300μM; the limit of quantitation (signal-to-noise ratio=10) was 40-120pmol/mL, and the mean recoveries of N-Ac-L-Leu and N-Ac-D-Leu were 102.48% and 104.68%, respectively. The levels of N-Ac-Leu in the saliva of diabetic patients and healthy volunteers were determined, and it was found that the levels of N-Ac-DL-Leu in the saliva of diabetic patients were significantly lower than those in healthy volunteers. (p<0.01).

The proposed method was successfully applied for the measurement of N-Ac-DL-Leu enantiomers in the saliva of diabetic patients and healthy volunteers.

The proposed method was successfully applied for the measurement of N-Ac-DL-Leu enantiomers in the saliva of diabetic patients and healthy volunteers.

Triglyceride-rich lipoproteins (TRL chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity.

This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as metabolically healthy lean (MHL, n=30), metabolically unhealthy lean (MUL, n=25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n=42).

As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C

, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant.

Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).