Delving into the Latest Updates on Sheffield Children's NHS Foundation Trust with Synapse

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疾病领域	数量

神经系统疾病	1

排名前五的药物类型	数量

小分子化药	1

排名前五的靶点	数量

Kv3.1(电压门控性钾通道蛋白亚型Kv3.1)	1

关联

1

项与 Sheffield Children's NHS Foundation Trust 相关的药物

AUT-00063

靶点

Kv3.1

作用机制

Kv3.1调节剂

在研机构

NIHR Manchester Biomedical Research Centre初创企业 [+2]

原研机构

Autifony Therapeutics Ltd.

在研适应症

耳鸣

非在研适应症

听力损失 [+2]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期-

100 项与 Sheffield Children's NHS Foundation Trust 相关的临床结果

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0 项与 Sheffield Children's NHS Foundation Trust 相关的专利（医药）

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524

项与 Sheffield Children's NHS Foundation Trust 相关的文献（医药）

2024-12-01·Genetics in Medicine

Persistent growth-promoting effects of vosoritide in children with achondroplasia are accompanied by improvements in physical and social aspects of health-related quality of life

Article

作者: Leiva-Gea, Antonio ; Low, Andrea ; Mohnike, Klaus ; Arundel, Paul ; Hoover-Fong, Julie E. ; Harmatz, Paul ; Kubota, Takuo ; Huntsman-Labed, Alice ; Bacino, Carlos A. ; Polgreen, Lynda E ; Prada, Carlos E ; Sabir, Ian ; Wilcox, William R ; Hoover-Fong, Julie E ; Wilcox, William R. ; Bacino, Carlos A ; Day, Jonathan ; Rowell, Richard ; Polgreen, Lynda E. ; Irving, Melita ; Prada, Carlos E. ; Savarirayan, Ravi

PURPOSEEvaluate the impact of vosoritide on health-related quality of life in children with achondroplasia.METHODSParticipants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766).RESULTSThe population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the QoLISSY physical score (5.99 [19.41], caregiver-reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 (22.64), respectively). Changes were greatest in participants with ≥1 SD increase in height Z-score (physical: 11.36 [19.51], caregiver-reported [n=38]; 8.48 [21.83], self-reported [n=28]) (social: 5.84 [15.45] and 9.79 [22.80], respectively). To determine how domain scores may change with age in untreated persons, models were produced using observational/untreated-person data. A 1-year increase in age was associated with a change of 0.16 (SE, 0.55) and 0.16 (0.50), for caregiver-reported physical and social domain scores, respectively. Self-reported scores changed by 1.45 (0.71) and 1.92 (0.77), respectively.CONCLUSIONThese data suggest that after 3 years of treatment vosoritide demonstrates a positive effect on physical and social functioning among children with achondroplasia, particularly in children with a more pronounced change in height Z-score.

2024-10-01·Journal of Medical Genetics

The PS4-likelihood ratio calculator: flexible allocation of evidence weighting for case-control data in variant classification

Article

作者: Hanson, Helen ; Callaway, Alison ; McDevitt, Trudi ; Allen, Sophie ; Rowlands, Charlie F ; Grant, Jonathan ; Palmer-Smith, Sheila ; Jones, Michael ; Robinson, Rachel ; Turnbull, Clare ; Whiffin, Nicola ; Pagan, Judith ; Durkie, Miranda ; Frugtniet, Bethan ; Field, Joanne ; Garrett, Alice ; McVeigh, Terri P ; Burghel, George J

BackgroundThe 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework specifies that case-control observations can be scored as ‘strong’ evidence (PS4) towards pathogenicity.MethodsWe developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non-association (eg, OR≤1).ResultsPS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation.ConclusionPS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.

2024-09-01·Bone Reports

Losartan alters osteoblast differentiation and increases bone mass through inhibition of TGFB signalling in vitro and in an OIM mouse model

Article

作者: Kalajzic, Ivo ; Ottewell, Penelope D. ; Morita, Mai ; Lefley, Diane V. ; Reilly, Gwen ; Cebe, Tugba ; Arshad, Fawaz ; Lefley, Diane V ; Bishop, Nicolas J ; Quayle, Lewis A. ; Quayle, Lewis A ; George, Christopher N. ; Ottewell, Penelope D ; Balsubramanian, Meena ; George, Christopher N ; Bishop, Nicolas J.

Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFβ-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFβ is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFβ signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFβ from 79.2 g/L in the control to 60.0 ng/ml following losartan (p < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness (P < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae (P < 0.05) and the vertebrae (P < 0.01), increased cortical bone thickness (P < 0.001) reduced the trabecular pattern factor (P < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast (P < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFβ signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects.

100 项与 Sheffield Children's NHS Foundation Trust 相关的药物交易

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100 项与 Sheffield Children's NHS Foundation Trust 相关的转化医学

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