13 research outputs found
An epitaxial model for heterogeneous nucleation on potent substrates
© The Minerals, Metals & Materials Society and ASM International 2012In this article, we present an epitaxial model for heterogeneous nucleation on potent substrates. It is proposed that heterogeneous nucleation of the solid phase (S) on a potent substrate (N) occurs by epitaxial growth of a pseudomorphic solid (PS) layer on the substrate surface under a critical undercooling (ÎT ). The PS layer with a coherent PS/N interface mimics the atomic arrangement of the substrate, giving rise to a linear increase of misfit strain energy with layer thickness. At a critical thickness (h ), elastic strain energy reaches a critical level, at which point, misfit dislocations are created to release the elastic strain energy in the PS layer. This converts the strained PS layer to a strainless solid (S), and changes the initial coherent PS/N interface into a semicoherent S/N interface. Beyond this critical thickness, further growth will be strainless, and solidification enters the growth stage. It is shown analytically that the lattice misfit (f) between the solid and the substrate has a strong influence on both h and ÎT ; h decreases; and ÎT increases with increasing lattice misfit. This epitaxial nucleation model will be used to explain qualitatively the generally accepted experimental findings on grain refinement in the literature and to analyze the general approaches to effective grain refinement.EPSRC Centre for Innovative Manufacturing in Liquid Metal Engineerin
Safety and efficacy of vanzacaftorâtezacaftorâdeutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials
Background
Elexacaftorâtezacaftorâivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing.
Methods
We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftorâtezacaftorâdeutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftorâtezacaftorâdeutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftorâdeutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)âtezacaftorâdeutivacaftor or tezacaftorâivacaftor active control for 4 weeks, following a 4-week tezacaftorâivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete.
Findings
In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI â0·8 to 7·0) and 2·7 percentage points (â1·0 to 6·5) from baseline at week 12, respectively, versus â0·8 percentage points (â6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)âtezacaftorâdeutivacaftor (n=9), vanzacaftor (10 mg)âtezacaftorâdeutivacaftor (n=19), vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (â1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (â4·1 to 8·0), respectively, in sweat chloride concentration of â42·8 mmol/L (â51·7 to â34·0), â45·8 mmol/L (95% CI â51·9 to â39·7), â49·5 mmol/L (â55·9 to â43·1), and 2·3 mmol/L (â7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (â10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=18) and tezacaftorâivacaftor (n=10) had mean changes relative to baseline (taking tezacaftorâivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and â0·1 percentage points (â6·4 to 6·1), respectively, in sweat chloride concentration of â45·5 mmol/L (â49·7 to â41·3) and â2·6 mmol/L (â8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and â5·0 points (â16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftorâtezacaftorâdeutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity.
Interpretation
Once-daily dosing with vanzacaftorâtezacaftorâdeutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftorâtezacaftorâdeutivacaftor in phase 3 clinical trials compared with elexacaftorâtezacaftorâivacaftor.
Funding
Vertex Pharmaceuticals
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Delivering pediatric HIV care in resource-limited settings: cost considerations in an expanded response
If children are to be protected from HIV, the expansion of PMTCT programs must be complemented by increased provision of paediatric treatment. This is expensive, yet there are humanitarian, equity and children's rights arguments to justify the prioritization
of treating HIV-infected children. In the context of limited budgets, inefficiencies cost lives, either through lower coverage or less effective services. With the goal of informing the design and expansion of efficient paediatric treatment programs able to utilize to greatest effect the available resources allocated to the treatment of HIV-infected children, this article reviews what is known about cost drivers in paediatric HIV interventions, and makes suggestions for improving efficiency in paediatric HIV programming. High-impact interventions known to deliver disproportional returns on investment are highlighted and targeted for immediate scale-up.
Progress will carry a cost-increased funding, as well as additional data on intervention costs and outcomes, will be required if universal access of HIV-infected children to treatment is to be achieved and sustained.