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Lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines have proven to be very successful in the fight against the coronavirus disease 2019 (COVID-19) pandemic. They are effective, safe, and can be produced in large quantities. However, the long-term storage of mRNA-LNP vaccines without freezing is still a challenge. Here, we demonstrate that nucleoside-modified mRNA-LNPs can be lyophilized, and the physicochemical properties of the lyophilized material do not significantly change for 12 weeks after storage at room temperature and for at least 24 weeks after storage at 4°C. Importantly, we show in comparative mouse studies that lyophilized firefly luciferase-encoding mRNA-LNPs maintain their high expression, and no decrease in the immunogenicity of a lyophilized influenza virus hemagglutinin-encoding mRNA-LNP vaccine was observed after 12 weeks of storage at room temperature or for at least 24 weeks after storage at 4°C. Our studies offer a potential solution to overcome the long-term storage-related limitations of nucleoside-modified mRNA-LNP vaccines.
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COVID-19 , Vacinas contra Influenza , Nanopartículas , Animais , COVID-19/prevenção & controle , Liofilização , Lipossomos , Camundongos , Nanopartículas/química , Nucleosídeos , RNA Mensageiro/genética , Vacinas Sintéticas , Vacinas de mRNARESUMO
Water-responsive materials undergo reversible shape changes upon varying humidity levels. These mechanically robust yet flexible structures can exert substantial forces and hold promise as efficient actuators for energy harvesting, adaptive materials and soft robotics. Here we demonstrate that energy transfer during evaporation-induced actuation of nanoporous tripeptide crystals results from the strengthening of water hydrogen bonding that drives the contraction of the pores. The seamless integration of mobile and structurally bound water inside these pores with a supramolecular network that contains readily deformable aromatic domains translates dehydration-induced mechanical stresses through the crystal lattice, suggesting a general mechanism of efficient water-responsive actuation. The observed strengthening of water bonding complements the accepted understanding of capillary-force-induced reversible contraction for this class of materials. These minimalistic peptide crystals are much simpler in composition compared to natural water-responsive materials, and the insights provided here can be applied more generally for the design of high-energy molecular actuators.
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N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.
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Acetilgalactosamina/química , Receptor de Asialoglicoproteína/metabolismo , RNA Interferente Pequeno/administração & dosagem , Animais , Feminino , Células Hep G2 , Humanos , Injeções Subcutâneas , Ligantes , Lipossomos , Masculino , Camundongos , Nanopartículas , Primatas , RNA Interferente Pequeno/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: SARS-CoV-2 has disproportionately affected nursing homes (NH). In Ireland, the first NH case COVID-19 occurred on 16 March 2020. A national point-prevalence testing programme of all NH residents and staff took place (18 April 2020 to 5 May 2020). AIMS: to examine characteristics of NHs across three Irish Community Health Organisations, proportions with COVID-19 outbreaks, staff and resident infection rates symptom profile and resident case fatality. METHODS: in total, 45 NHs surveyed, requesting details on occupancy, size, COVID-19 outbreak, outbreak timing, total symptomatic/asymptomatic cases and outcomes for residents from 29 February 2020 to 22 May 2020. RESULTS: surveys were returned from 62.2% (28/45) of NHs (2,043 residents, 2,303 beds). Three-quarters (21/28) had COVID-19 outbreaks (1,741 residents, 1,972 beds). Median time from first COVID-19 case in Ireland to first case in these NHs was 27.0 days. Resident incidence was 43.9% (764/1,741)-40.8% (710/1,741) laboratory confirmed, with 27.2% (193/710) asymptomatic and 3.1% (54/1,741) clinically suspected. Resident case fatality was 27.6% (211/764) for combined laboratory-confirmed/clinically suspected COVID-19. Similar proportions of residents in NHs with 'early-stage' (<28 days) versus 'later-stage' outbreaks developed COVID-19. Lower proportions of residents in 'early' outbreak NHs had recovered compared with those with 'late' outbreaks (37.4 versus 61.7%; χ2 = 56.9, P < 0.001). Of 395 NH staff across 12 sites with confirmed COVID-19, 24.7% (99/398) were asymptomatic. There was a significant correlation between the proportion of staff with symptomatic COVID-19 and resident numbers with confirmed/suspected COVID-19 (Spearman's rho = 0.81, P < 0.001). CONCLUSION: this study demonstrates the significant impact of COVID-19 on the NH sector. Systematic point-prevalence testing is necessary to reduce risk of transmission from asymptomatic carriers and manage outbreaks in this setting.
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Infecções Assintomáticas/mortalidade , Teste para COVID-19/métodos , COVID-19 , Portador Sadio/diagnóstico , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , Casas de Saúde/estatística & dados numéricos , Idoso , COVID-19/diagnóstico , COVID-19/mortalidade , Transmissão de Doença Infecciosa/prevenção & controle , Feminino , Humanos , Irlanda/epidemiologia , Masculino , Serviços Preventivos de Saúde/métodos , Gestão de Riscos/métodos , Gestão de Riscos/organização & administração , SARS-CoV-2/isolamento & purificação , Avaliação de Sintomas/estatística & dados numéricosRESUMO
BACKGROUND: Omphalitis is an important contributor to neonatal mortality in Kenya. Chlorhexidine digluconate 7.1 % w/w (CHX; equivalent to 4 % w/w chlorhexidine) was identified as a life-saving commodity for newborn cord care by the United Nations and is included on World Health Organization and Kenyan Essential Medicines Lists. This pilot study assessed the potential resource savings and breakeven price of implementing CHX for neonatal umbilical cord care versus dry cord care (DCC) in Kenya. METHODS: We employed a cost-consequence model in a Kenyan birth cohort. Firstly, the number of omphalitis cases and cases avoided by healthcare sector were estimated. Incidence rates and treatment effect inputs were calculated from a Cochrane meta-analysis of randomised clinical trials (RCTs) (base case) and 2 other RCTs. Economic outcomes associated with omphalitis cases avoided were determined, including direct, indirect and total cost of care associated with omphalitis, resource use (outpatient visits and bed days) and societal impact (caregiver workdays lost). Costs and other inputs were sourced from literature and supplemented by expert clinical opinion/informed inputs, making necessary assumptions. RESULTS: The model estimated that, over 1 year, ~ 23,000 omphalitis cases per 500,000 births could be avoided through CHX application versus DCC, circumventing ~ 13,000 outpatient visits, ~ 43,000 bed days and preserving ~ 114,000 workdays. CHX was associated with annual direct cost savings of ~ 590,000 US dollars (USD) versus DCC (not including drug-acquisition cost), increasing to ~ 2.5 million USD after including indirect costs (productivity, notional salary loss). The most-influential model parameter was relative risk of omphalitis with CHX versus DCC. Breakeven analysis identified a budget-neutral price for CHX use of 1.18 USD/course when accounting for direct cost savings only, and 5.43 USD/course when including indirect cost savings. The estimated breakeven price was robust to parameter input changes. DCC does not necessarily represent standard of care in Kenya; other, potentially harmful, approaches may be used, meaning cost savings may be understated. CONCLUSIONS: Estimated healthcare cost savings and potential health benefits provide compelling evidence to implement CHX for umbilical cord care in Kenya. We encourage comprehensive data collection to make future models and estimates of impacts of upscaling CHX use more robust.
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Anti-Infecciosos Locais , Clorexidina , Humanos , Mortalidade Infantil , Recém-Nascido , Quênia/epidemiologia , Cordão UmbilicalRESUMO
Fluticasone furoate and fluticasone propionate are recommended options for prophylactic maintenance treatment of persistent asthma. Using data from two previous clinical studies (GSK studies: FFA109685/NCT00603278, FFA112059/NCT01159912), this meta-analysis compared change from baseline in clinic visit mean trough forced expiratory volume in 1 s (FEV1) with fluticasone furoate 100 µg once-daily (FF100) versus fluticasone propionate 250 µg twice-daily (FP250) in adolescents and adults with persistent asthma. Using a DerSimonian-Laird random-effects model (primary meta-analysis), there was no statistically significant difference between FF100 and FP250 in change from baseline in trough FEV1 (-1.7 mL [95% CI -80.4, +77.0], p = 0.9664) and FF100 was non-inferior to FP250. Supporting analyses using least squares mean and fixed-effects model approaches produced similar findings. In this analysis, FF100 and FP250 demonstrated a comparable treatment effect on trough FEV1 in patients aged ≥12 years with persistent asthma; however, results interpretation should consider study design and methodological limitations.
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Androstadienos/administração & dosagem , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Asma/fisiopatologia , Esquema de Medicação , Volume Expiratório Forçado , Humanos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). METHODS: This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6â months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4â weeks (8 or 10â mg/kg for body weight (BW) <30â kg; 8â mg/kg for BW ≥30â kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. RESULTS: In part 1, 188 patients received tocilizumab (<30â kg: 10â mg/kg (n=35) or 8â mg/kg (n=34); ≥30â kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). CONCLUSIONS: Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. TRIAL REGISTRATION NUMBER: NCT00988221.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Receptores de Interleucina-6/antagonistas & inibidores , Adolescente , Corticosteroides/uso terapêutico , Bronquite/induzido quimicamente , Celulite (Flegmão)/induzido quimicamente , Criança , Pré-Escolar , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Pneumonia/induzido quimicamente , Indução de Remissão/métodos , Resultado do TratamentoRESUMO
BACKGROUND: This cost-utility analysis assessed the long-term clinical and economic benefits of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy vs FF/VI or UMEC/VI from a Quebec societal perspective in patients with chronic obstructive pulmonary disease (COPD) with ≥1 moderate/severe exacerbation in the previous year. METHODS: The validated GALAXY disease progression model was utilized, with parameters set to baseline and efficacy data from IMPACT. Treatment costs (2017 Canadian dollars [C$]) were estimated using Quebec-specific unit costs. Costs and health outcomes were discounted at 1.5 %/year. A willingness-to-pay threshold of C$50,000/quality-adjusted life year (QALY) was considered cost-effective. Outcomes modeled were exacerbation rates, QALYs, life years (LYs), costs and incremental cost-effectiveness ratios (ICERs). Subgroup analyses were performed according to prior treatment, exacerbation history in the previous year, and baseline lung function. RESULTS: Over a lifetime horizon, FF/UMEC/VI resulted in more QALYs and LYs gained, at a small incremental cost compared with FF/VI and UMEC/VI. From a societal perspective, the estimated ICER for the base case was C$18,152/QALY vs FF/VI, and C$15,847/QALY vs UMEC/VI. For the subgroup analyses (FF/UMEC/VI compared with FF/VI and UMEC/VI), ICERs ranged from: C$17,412-25,664/QALY and C$16,493-18,663/QALY (prior treatment); C$15,247-19,924/QALY and C$15,444-28,859/QALY (exacerbation history); C$14,025-34,154/QALY and C$16,083-17,509/QALY (baseline lung function). INTERPRETATION: FF/UMEC/VI was predicted to improve outcomes and be cost-effective vs both comparators in the base case and all subgroup analyses, and based on this analysis would be an appropriate investment of health service funds in Quebec. CLINICAL TRIAL REGISTRATION NUMBER: IMPACT trial NCT02164513.
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Androstadienos , Álcoois Benzílicos , Clorobenzenos , Análise Custo-Benefício , Doença Pulmonar Obstrutiva Crônica , Anos de Vida Ajustados por Qualidade de Vida , Quinuclidinas , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/economia , Quebeque , Álcoois Benzílicos/economia , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/uso terapêutico , Quinuclidinas/economia , Quinuclidinas/administração & dosagem , Quinuclidinas/uso terapêutico , Masculino , Feminino , Clorobenzenos/economia , Clorobenzenos/administração & dosagem , Clorobenzenos/uso terapêutico , Androstadienos/economia , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Pessoa de Meia-Idade , Combinação de Medicamentos , Nebulizadores e Vaporizadores/economia , Administração por Inalação , Idoso , Pirrolidinas/economia , Pirrolidinas/uso terapêutico , Pirrolidinas/administração & dosagem , Broncodilatadores/economia , Broncodilatadores/administração & dosagem , Broncodilatadores/uso terapêutico , Progressão da Doença , Quimioterapia Combinada , Resultado do TratamentoRESUMO
We investigate the nanometrology of sub-nanometre particle sizes in industrially manufactured sodium silicate liquors at high pH using time-resolved fluorescence anisotropy. Rather than the previous approach of using a single dye label, we investigate and quantify the advantages and limitations of multiplexing two fluorescent dye labels. Rotational times of the non-binding rhodamine B and adsorbing rhodamine 6G dyes are used to independently determine the medium microviscosity and the silicate particle radius, respectively. The anisotropy measurements were performed on the range of samples prepared by diluting the stock solution of silicate to concentrations ranging between 0.2 M and 2 M of NaOH and on the stock solution at different temperatures. Additionally, it was shown that the particle size can also be measured using a single excitation wavelength when both dyes are present in the sample. The recovered average particle size has an upper limit of 7.0 ± 1.2 Å. The obtained results were further verified using small-angle X-ray scattering, with the recovered particle size equal to 6.50 ± 0.08 Å. To disclose the impact of the dye label on the measured complex size, we further investigated the adsorption state of rhodamine 6G on silica nanoparticles using molecular dynamics simulations, which showed that the size contribution is strongly impacted by the size of the nanoparticle of interest. In the case of the higher radius of curvature (less curved) of larger particles, the size contribution of the dye label is below 10%, while in the case of smaller and more curved particles, the contribution increases significantly, which also suggests that the particles of interest might not be perfectly spherical.
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BACKGROUND: Demographic changes are leading to an increase in the number of older drivers: as dementia is an age-related disease, there is also an increase in the numbers of drivers with dementia. Dementia can impact on both the mobility and safety of drivers, and the impact of formal assessment of driving is unknown in terms of either mobility or safety. Those involved in assessment of older drivers need to be aware of the evidence of positive and negative effects of driving assessment. Cognitive tests are felt by some authors to have poor face and construct validity for assessing driving performance; extrapolating from values in one large-scale prospective cohort study, the cognitive test that most strongly predicted future crashes would, if used as a screening tool, potentially prevent six crashes per 1000 people over 65 years of age screened, but at the price of stopping the driving of 121 people who would not have had a crash. PRIMARY OBJECTIVES: 1. to assess whether driving assessment facilitates continued driving in people with dementia; 2. to assess whether driving assessment reduces accidents in people with dementia. SECONDARY OBJECTIVE: 1. to assess the quality of research on assessment of drivers with dementia. SEARCH METHODS: ALOIS, the Cochrane Dementia Group's Specialized Register was searched on 13 September 2012 using the terms: driving or driver* or "motor vehicle*" or "car accident*" or "traffic accident*" or automobile* or traffic. This register contains records from major healthcare databases, ongoing trial databases and grey literature sources and is updated regularly. SELECTION CRITERIA: We sought randomised controlled trials prospectively evaluating drivers with dementia for outcomes such as transport mobility, driving cessation or motor vehicle accidents following driving assessment. DATA COLLECTION AND ANALYSIS: Each review author retrieved studies and assessed for primary and secondary outcomes, study design and study quality. MAIN RESULTS: No studies were found that met the inclusion criteria. A description and discussion of the driving literature relating to assessment of drivers with dementia relating to the primary objectives is presented. AUTHORS' CONCLUSIONS: In an area with considerable public health impact for drivers with dementia and other road users, the available literature fails to demonstrate the benefit of driver assessment for either preserving transport mobility or reducing motor vehicle accidents. Driving legislation and recommendations from medical practitioners requires further research that addresses these outcomes in order to provide the best outcomes for both drivers with dementia and the general public.
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Acidentes de Trânsito/prevenção & controle , Exame para Habilitação de Motoristas/psicologia , Demência/psicologia , Segurança , Idoso , HumanosRESUMO
BACKGROUND: Demographic changes are leading to an increase in the number of older drivers: as dementia is an age-related disease, there is also an increase in the numbers of drivers with dementia. Dementia can impact on both the mobility and safety of drivers, and the impact of formal assessment of driving is unknown in terms of either mobility or safety. Those involved in assessment of older drivers need to be aware of the evidence of positive and negative effects of driving assessment. Cognitive tests are felt by some authors to have poor face and construct validity for assessing driving performance; extrapolating from values in one large-scale prospective cohort study, the cognitive test that most strongly predicted future crashes would, if used as a screening tool, potentially prevent six crashes per 1000 people over 65 years of age screened, but at the price of stopping the driving of 121 people who would not have had a crash. PRIMARY OBJECTIVES: 1. to assess whether driving assessment facilitates continued driving in people with dementia;2. to assess whether driving assessment reduces accidents in people with dementia. SECONDARY OBJECTIVE: 1. to assess the quality of research on assessment of drivers with dementia. SEARCH METHODS: ALOIS, the Cochrane Dementia Group's Specialized Register was searched on 13 September 2012 using the terms: driving or driver* or "motor vehicle*" or "car accident*" or "traffic accident*" or automobile* or traffic. This register contains records from major healthcare databases, ongoing trial databases and grey literature sources and is updated regularly. SELECTION CRITERIA: We sought randomised controlled trials prospectively evaluating drivers with dementia for outcomes such as transport mobility, driving cessation or motor vehicle accidents following driving assessment. DATA COLLECTION AND ANALYSIS: Each review author retrieved studies and assessed for primary and secondary outcomes, study design and study quality. MAIN RESULTS: No studies were found that met the inclusion criteria. A description and discussion of the driving literature relating to assessment of drivers with dementia relating to the primary objectives is presented. AUTHORS' CONCLUSIONS: In an area with considerable public health impact for drivers with dementia and other road users, the available literature fails to demonstrate the benefit of driver assessment for either preserving transport mobility or reducing motor vehicle accidents. Driving legislation and recommendations from medical practitioners requires further research that addresses these outcomes in order to provide the best outcomes for both drivers with dementia and the general public.
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Acidentes de Trânsito/prevenção & controle , Exame para Habilitação de Motoristas/psicologia , Demência/psicologia , Segurança , Idoso , Humanos , Meios de TransporteRESUMO
Purpose: For patients with chronic obstructive pulmonary disease (COPD) who remain symptomatic despite maintenance treatment, clinical management guidelines recommend a stepwise escalation from monotherapy to dual therapy, and from dual therapy to triple therapy. However, in clinical practice, patients are often escalated directly from monotherapy to triple therapy based on disease severity. This study evaluated the cost-effectiveness of once-daily, single-inhaler fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) triple therapy compared with long-acting muscarinic antagonist monotherapy with once-daily tiotropium (TIO) in patients with symptomatic moderate-to-very severe COPD, from a UK National Health Service perspective. Patients and Methods: The validated GALAXY-COPD disease progression model was populated with patient baseline characteristics and treatment effect data from the 12-week GSK Study 207626 comparing FF/UMEC/VI with TIO in patients with moderate-to-very severe COPD. UK unit costs and drug costs (British Pound, 2021) were applied to healthcare resource utilization and treatments. The base case analysis was conducted over a lifetime horizon, and costs and health outcomes (except for life years [LYs]) were discounted at 3.5% per year. Model outputs included exacerbation rates, healthcare costs, LYs, quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios. Results: Overall, treatment with FF/UMEC/VI resulted in increased clinical benefit (reduction in total exacerbations and increased overall survival and QALYs), coupled with cost savings (derived from lower maintenance and exacerbation healthcare costs) compared with TIO monotherapy. In the base case analysis, FF/UMEC/VI provided an additional 0.393 LYs (95% range: 0.176, 0.655) and 0.443 QALYs (0.246, 0.648), at a cost saving of £880 (£54, £1608) versus TIO. FF/UMEC/VI remained the cost-effective (dominant) treatment option across sensitivity and scenario analyses. Conclusion: FF/UMEC/VI offers greater clinical benefits and is a cost-effective treatment option compared with TIO for the treatment of adult patients with COPD with persistent symptoms and/or who are at risk of exacerbation in the UK.
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Doença Pulmonar Obstrutiva Crônica , Medicina Estatal , Adulto , Humanos , Brometo de Tiotrópio/efeitos adversos , Análise Custo-Benefício , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Nebulizadores e Vaporizadores , Reino UnidoRESUMO
Lipid nanoparticles (LNPs) have proven a successful platform for the delivery of nucleic acid (NA)-based therapeutics and vaccines, with the ionizable lipid component playing a key role in modulating potency and tolerability. Here, a library of 16 novel ionizable lipids is screened hypothesizing that short, branched trialkyl hydrophobic domains can improve LNP fusogenicity or endosomal escape, and potency. LNPs formulated with the top-performing trialkyl lipid (Lipid 10) encapsulating transthyretin siRNA elicit significantly greater gene silencing and are better tolerated than those with the benchmark Onpattro lipid DLin-MC3-DMA. Lipid 10 also demonstrates superior liver delivery of mRNA when compared to other literature ionizable lipids, is well tolerated, and successfully repeat-doses in nonhuman primates. In a prime-boost hemagglutinin rodent vaccine model, intramuscular administration of Lipid-10 LNP elicits comparable or better antibody titers to the SM-102 and ALC-0315 lipid compositions used in the U.S. Food and Drug Administration approved mRNA COVID vaccines. These data suggest that Lipid 10 is a particularly versatile ionizable lipid, well-suited for both systemic therapeutic and intramuscular vaccine applications and able to successfully deliver diverse NA payloads.
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COVID-19 , Nanopartículas , Animais , RNA Interferente Pequeno/química , Nanopartículas/química , Lipídeos/química , RNA MensageiroRESUMO
The controls governing the availability of reduced selenium (Se) species, namely selenite (Se[IV]) and dissolved organo-Se (DOSe), to primary producers at the sediment-water interface in depositional environments (i.e., lentic systems) were assessed through consideration of theoretical principles and field data. Selenite is generated in suboxic sediment porewater via the microbially mediated reduction of selenate (Se[IV]) and/or reductive dissolution of Se-bearing iron oxides. Field data for lentic environments demonstrate that the production of DOSe in sediment porewaters can also be redox- and depth-dependent. In this manner, the remobilization depths of Se(IV) and DOSe in depositional environments are dependent on the vertical redox gradient (dEh/dz), where deeper depths of remobilization are observed in less reducing sedimentary environments (lower dEh/dz). In turn, remobilization depth has a direct bearing on the concentration of dissolved Se(IV) and DOSe that may be realized at the sediment-water interface because the depth of reaction governs the diffusive path length, concentration gradient, and rate of diffusional transport toward the sediment-water interface. The principles that link sediment redox gradients, depth of remobilization, diffusive transport processes, and concentration of reduced Se species at the sediment-water interface have a direct bearing on the potential for Se uptake by primary producers in lentic food chains (e.g., phytoplankton, biofilms, bacteria). Overall, these processes complement the current conceptual "benthic detrital food chain" model that describes the accumulation of Se in lentic systems. Environ Toxicol Chem 2022;41:2859-2869. © 2022 SETAC.
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Selênio , Ácido Selenioso , Cadeia Alimentar , Ácido Selênico , Oxirredução , Água , FerroRESUMO
BACKGROUND: The IMPACT trial demonstrated superior outcomes following 52â weeks of once-daily single-inhaler treatment with fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) (100/62.5/25â µg) compared with once-daily FF/VI (100/25â µg) or UMEC/VI (62.5/25â µg). This study evaluated the cost-effectiveness of FF/UMEC/VI compared with FF/VI or UMEC/VI for the treatment of chronic obstructive pulmonary disease (COPD) from a UK National Health Service perspective. METHODS: Patient characteristics and treatment effects from IMPACT were populated into a hybrid decision tree/Markov economic model. Costs (GB£ inflated to 2018 equivalents) and health outcomes were modelled over a lifetime horizon, with a discount rate of 3.5% per annum applied to both. Sensitivity analyses were performed to test the robustness of key assumptions and input parameters. RESULTS: Compared with FF/VI and UMEC/VI, FF/UMEC/VI provided an additional 0.296 and 0.145 life years (LYs) (discounted) and 0.275 and 0.118 quality-adjusted life years (QALYs), at an additional cost of £1129 and £760, respectively. Incremental cost-effectiveness ratios (ICERs) for FF/UMEC/VI were £4104/QALY and £3809/LY gained versus FF/VI and £6418/QALY and £5225/LY gained versus UMEC/VI. At a willingness-to-pay threshold of £20â000/QALY, the probability that FF/UMEC/VI was cost-effective was 96% versus FF/VI and 74% versus UMEC/VI. Results were similar in a subgroup of patients recommended triple therapy in the 2019 National Institute for Health and Care Excellence COPD guideline. CONCLUSIONS: FF/UMEC/VI single-inhaler triple therapy improved health outcomes and was a cost-effective option compared with FF/VI or UMEC/VI for patients with symptomatic COPD and a history of exacerbations in the UK at recognised cost-effectiveness threshold levels.
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Purpose: Given between-country differences in healthcare systems, treatment costs, and disease management guidelines, country-specific cost-effectiveness analyses are important. This study evaluated the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI among patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations from a Spanish healthcare system perspective. Patients and Methods: Baseline data and treatment effects from the IMPACT trial were populated into the validated GALAXY COPD progression model. Utilities were estimated using Spanish observational data. Direct healthcare costs (2019 ) were informed by Spanish public sources. A 3% discount rate for costs and benefits was applied. The time horizon and treatment duration were 3 years (base case). One-way sensitivity, scenario, and probabilistic sensitivity analyses were performed. Results: FF/UMEC/VI treatment resulted in fewer exacerbations over 3 years (4.130 vs 3.648) versus FF/VI, with a mean (95% confidence interval [CI]) incremental cost of 444 (149, 713) per patient and benefit of 0.064 (0.053, 0.076) quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of 6887 per QALY gained. FF/UMEC/VI was a dominant treatment strategy versus UMEC/VI, resulting in fewer exacerbations (4.130 vs 3.360), with a mean (95% CI) incremental cost of -450 (-844, -149) and benefit of 0.054 (0.043, 0.064) QALYs. FF/UMEC/VI was cost-effective versus FF/VI and UMEC/VI across all analyses. Conclusion: FF/UMEC/VI was predicted to be a cost-effective treatment option versus FF/VI or UMEC/VI in symptomatic COPD patients at risk of exacerbations in Spain, across all scenarios and sensitivity analyses.
Assuntos
Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Administração por Inalação , Álcoois Benzílicos , Clorobenzenos , Análise Custo-Benefício , Combinação de Medicamentos , Fluticasona/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , EspanhaRESUMO
Purpose: The 24-week INTREPID trial demonstrated the clinical benefits of once-daily single-inhaler triple therapy (SITT) with fluticasone furoate, umeclidinium, and vilanterol (FF/UMEC/VI) versus non-ELLIPTA multiple-inhaler triple therapy (MITT) in patients with symptomatic chronic obstructive pulmonary disease (COPD). This analysis assessed the cost-effectiveness of FF/UMEC/VI versus non-ELLIPTA MITT for the treatment of symptomatic COPD from a United Kingdom (UK) National Health Service (NHS) perspective. Patients and Methods: The analysis was conducted using the validated GALAXY COPD disease progression model. Baseline characteristics, treatment effect parameters (forced expiratory volume in 1 second and St. George's Respiratory Questionnaire score [derived from exploratory COPD Assessment Test score mapping]), and discontinuation data from INTREPID were used to populate the model. UK healthcare resource and drug costs (2020 British pounds) were applied, and costs and outcomes were discounted at 3.5%. Analyses were conducted over a lifetime horizon from a UK NHS perspective. Model outputs included exacerbation rates, total costs, life years (LYs), quality-adjusted LYs (QALYs) and incremental cost-effectiveness ratio per QALY. Sensitivity analyses were conducted to assess the robustness of the results by varying parameter values and assumptions. Results: Over a lifetime horizon, FF/UMEC/VI provided an additional 0.174 (95% confidence interval [CI]: 0.024, 0.344) LYs (approximately 2 months), and 0.253 (95% CI: 0.167, 0.346) QALYs (approximately 3 months), at a cost saving of £1764 (95% CI: -£2600, -£678) per patient, compared with non-ELLIPTA MITT. FF/UMEC/VI remained the dominant treatment option, meaning greater benefits at lower costs, across all scenario and sensitivity analyses. Conclusion: Based on this analysis, in a UK setting, FF/UMEC/VI would improve health outcomes and reduce costs compared with non-ELLIPTA MITT for the treatment of patients with symptomatic COPD. SITT may help to reduce the clinical and economic burden of COPD and should be considered by physicians as a preferred treatment option.
Assuntos
Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica , Humanos , Administração por Inalação , Androstadienos , Álcoois Benzílicos , Broncodilatadores , Clorobenzenos , Análise Custo-Benefício , Método Duplo-Cego , Combinação de Medicamentos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas , Medicina EstatalRESUMO
Objectives: In the IMPACT trial (NCT02164513), triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) showed clinical benefit compared with dual therapy with either FF/VI or UMEC/VI in the treatment of chronic obstructive pulmonary disease (COPD). We used data from IMPACT to determine whether this translated into differences in COPD-related healthcare resource utilization (HRU) costs in a United Kingdom (UK) setting. Methods: In a within-trial analysis, individual patient data from the IMPACT intention-to-treat (ITT) population were analyzed to estimate rates of COPD-related HRU with FF/UMEC/VI, FF/VI, or UMEC/VI. A Bayesian approach was applied to address issues typically encountered with this kind of data, namely data missing due to early study withdrawal, subjects with zero reported HRU, and skewness. Rates of HRU were estimated under alternate assumptions of data being missing at random (MAR) or missing not at random (MNAR). UK-specific unit costs were then applied to estimated HRU rates to calculate treatment-specific costs. Results: Under each MNAR scenario, per patient per year (PPPY) rates of COPD-related HRU were lowest amongst those patients who received treatment with FF/UMEC/VI compared with those receiving either FF/VI or UMEC/VI. Although absolute HRU rates and costs were typically higher for all treatment groups under MNAR scenarios versus MAR, final economic conclusions were robust to patient withdrawals. Conclusions: PPPY rates were typically lower with FF/UMEC/VI versus FF/VI or UMEC/VI.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Androstadienos/efeitos adversos , Teorema de Bayes , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Atenção à Saúde , Método Duplo-Cego , Combinação de Medicamentos , Fluticasona/uso terapêutico , Humanos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/efeitos adversosRESUMO
BACKGROUND: Antimicrobial use is recognized as a risk factor for Clostridium difficile infection (CDI) and outbreaks. We studied the relationship between PCR ribotype, antimicrobial susceptibility and the genetic basis of resistance in response to exposure to antimicrobial agents. METHODS: C. difficile isolates were cultured from 133 CDI patients for whom recent antimicrobial drug exposure had been recorded. Isolates were ribotyped by PCR and assessed for their susceptibility to the macrolide-lincosamide-streptogramin B (MLS(B)) group of compounds (erythromycin and clindamycin) and fluoroquinolone antimicrobials (ciprofloxacin, levofloxacin and moxifloxacin). Where relevant, the genetic basis of resistance was determined. RESULTS: Prevalent ribotypes (including 027, 001 and 106) exhibited significantly greater antimicrobial resistance compared with ribotypes 078 and 014, among others. Clindamycin-resistant ribotype 078 was detected for the first time. Ribotypes 027 and 001 were more likely to exhibit MLS(B) resistance, a feature that was associated with the erm(B) gene. Exposure to MLS(B) or fluoroquinolone antimicrobial compounds in the 8 weeks prior to the onset of infection was not associated with specific genetic markers of resistance. Single amino acid substitutions in the A and B subunits of DNA gyrase were noted and were ribotype specific and linked to resistance to moxifloxacin. CONCLUSIONS: Resistance to MLS(B) and fluoroquinolone antimicrobial compounds is common among prevalent ribotypes of C. difficile. The genetic basis for antimicrobial resistance appears to be ribotype specific and conserved in the absence of recent antimicrobial selection pressure.