Search

Focuses on the performance and future prospects of grass and livestock products in Great Britain. Methods of grassland recording; Changes in livestock prices and feed costs; Trends in grassland management.

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Abstract: Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE)., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Background: Mitapivat, an oral activator of pyruvate kinase (PK) in red blood cells (RBCs), has shown significant improvements in haemoglobin and haemolysis among patients with pyruvate kinase deficiency who were not receiving regular transfusions. We aimed to evaluate the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency receiving regular transfusions., Methods: ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20 centres across Europe, North America, and Asia. Eligible participants were adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate kinase deficiency receiving regular transfusions (at least six episodes in the previous year). Participants received oral mitapivat during a 16-week dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose period. The primary endpoint was a reduction in transfusion burden (≥33% reduction in number of RBC units transfused during the fixed-dose period, compared with the participant's individual historical transfusion burden, standardised to 24 weeks). Efficacy and safety were assessed in all participants who received at least one dose of mitapivat. This trial is registered with ClinicalTrials.gov, NCT03559699, and is complete., Findings: Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%] female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%] not reported) were enrolled and received at least one dose of mitapivat. Median duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in transfusion burden by at least 33% was found in ten (37%) participants (95% CI 19-58; p=0·0002). The most common treatment-emergent adverse events were increase in alanine aminotransferase (ten [37%] participants), headache (ten [37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five [19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events were related to study treatment: joint swelling (one participant [4%]) and an increase in aspartate aminotransferase (one participant [4%]). Three participants had serious treatment-emergent adverse events, none related to the study treatment: increased blood triglycerides, ovarian cyst, and renal colic (each in one participant [4%]). No treatment-related deaths were observed., Interpretation: Mitapivat represents a novel therapy that can reduce transfusion burden in some adults with pyruvate kinase deficiency receiving regular transfusions, and is the first disease-modifying agent approved in this disease., Funding: Agios Pharmaceuticals., Competing Interests: Declaration of interests EZ, RX, AO, PH, SG, and VB are employees and shareholders of Agios Pharmaceuticals. AG has received fees for consultancy work and as a member of advisory boards from Agios Pharmaceuticals, bluebird bio, Celgene, Novartis, and Novo Nordisk; and research grants from Alexion, Saniona, and Sanofi. EJvB has received fees as a member of advisory board from Agios Pharmaceuticals; and research funding from Agios Pharmaceuticals, Novartis, Pfizer, and RR Mechatronics. HA-S has received fees for consultancy work from Agios Pharmaceuticals, argenx, Dova–Sobi, Novartis, Rigel, Forma Therapeutics, and Moderna; and research funding from Agios Pharmaceuticals, Dova, and Amgen. VV has received fees for consultancy work, honoraria, research funding, and speakers bureau from Bristol-Myers Squibb; and fees for consultancy work and research funding from Agios Pharmaceuticals, Ionis, La Jolla Pharmaceuticals, Protagonist Therapeutics, and Vifor Pharma. KHMK has received fees for consultancy work from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio, Celgene, Pfizer, and Novartis; honoraria from Alexion and Novartis; research funding from Pfizer; and membership on an entity's Board of Directors or advisory committees from Bioverativ. FG has been on board membership or advisory committee for Addmedica. SC has received fees for consultancy work from Agios Pharmaceuticals, Alexion, Daiichi Sankyo, Novartis, and Takeda; and research funding from Agios Pharmaceuticals, Alexion, Apellis, Global Blood Therapeutics, Novartis, and Takeda. WB has received honoraria from Agios Pharmaceuticals, Alexion, and Novartis; and been on board membership or advisory committee for Bioverativ and Incyte. JP declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

There is a significant association between obesity and nocturia, which can cause a significant negative impact on quality of life. This meta-analysis aims to determine the effects of bariatric surgery on nocturia in both men and women. Studies searched via MEDLINE and Embase databases. The primary outcome was difference in nocturia scores before and after bariatric surgery. A total of 522 patients were included in the analysis of this paper. Statistically significant decreases in nocturia scores were observed post-bariatric surgery. Bariatric surgery also resulted in statistically significant reduction of BMI. Bariatric surgery can have significant improvements on nocturia symptoms in men and women with obesity. This would thereby reduce morbidity and improve quality of life following bariatric surgery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Slowly expanding lesions (SELs), a subgroup of chronic white matter lesions that gradually expand over time, have been shown to predict disability accumulation in primary progressive multiple sclerosis (MS) disease. However, the relationships between SELs, acute lesion activity (ALA), overall chronic lesion activity (CLA) and disability progression are not well understood. In this study, we examined the ASCEND phase III clinical trial, which compared natalizumab with placebo in secondary progressive MS (SPMS)., Methods: Patients with complete imaging datasets between baseline and week 108 (N=600) were analysed for SEL prevalence (the number and volume of SELs), disability progression, ALA (assessed by gadolinium-enhancing lesions and new T2-hyperintense lesions) and CLA (assessed by T1-hypointense lesion volume increase within baseline T2-non-enhancing lesions identified as SELs and non-SELs)., Results: CLA in both SELs and non-SELs was greater in patients with SPMS with confirmed disability progression than in those with no progression. In the complete absence of ALA at baseline and on study, SEL prevalence was significantly lower, while CLA within non-SELs remained associated with disability progression. Natalizumab decreased SEL prevalence and CLA in SELs and non-SELs compared with placebo., Conclusions: This study shows that CLA in patients with SPMS is decreased but persists in the absence of ALA and is associated with disability progression, highlighting the need for therapeutics targeting all mechanisms of CLA, including smouldering inflammation and neurodegeneration., Trial Registration Number: NCT01416181., Competing Interests: Competing interests: VB was an employee of Biogen (Cambridge, Massachusetts, USA) during the completion of the work related to this manuscript and remains a Biogen shareholder. She is now an employee of Agios (Cambridge, Massachusetts, USA), which was not in any way associated with this study. ICG has received fellowship support from Biogen. CE is an employee of NeuroRx Research. DLA has received grants from Biogen, Immunotec and Novartis and consulting fees from Biogen, Celgene, Frequency Therapeutics, Genentech/Roche, Med-Ex Learning, Merck, Novartis, the Population Council, Queens University and Sanofi Aventis and has an ownership interest in NeuroRx. JK, HC, MS, NC, DPB, NF, AG and SB are employees and shareholders of Biogen. LZ and CK were employees of Biogen at the time of these analyses and may hold stock and/or stock options in Biogen. GG has received speaker honoraria and consulting fees from AbbVie, Actelion, Almirall, Atara Bio, Bayer Schering, Biogen, Celgene, FivePrime, GlaxoSmithKline, GW Pharma, Ironwood, Janssen, Merck, Merck KGaA, Novartis, Pfizer, Protein Discovery Laboratories, Sanofi Genzyme, Teva Pharmaceuticals, UCB and Vertex and research support unrelated to this study from Biogen, Ironwood, Merck, Merck KGaA, Novartis, Roche and Takeda., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)