BACKGROUND The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted ...represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown. METHODS Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype. RESULTS Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted ( P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg ( P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y ( P = .001) and median total IV treatment days decreased from 74 to 38 d/y ( P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects. CONCLUSIONS Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.
Pulmonary exacerbations (PExs) are significant life events in people with cystic fibrosis (CF), associated with declining lung function, reduced quality of life, hospitalizations, and decreased ...survival. The adult CF population is increasing worldwide, with many patients surviving prolonged periods with severe multimorbid disease. In many countries, the number of adults with CF exceeds the number of children, and PExs are particularly burdensome for adults as they tend to require longer courses and more IV treatment than children. The approach to managing PExs is multifactorial and needs to evolve to reflect this changing adult population. This review discusses PEx definitions, precipitants, treatments, and the wider implications to health-care resources. It reviews current management strategies, their relevance in particular to adults with CF, and highlights some of the gaps in our knowledge. A number of studies are underway to try to answer some of the unmet needs, such as the optimal length of treatment and the use of nonantimicrobial agents alongside antibiotics. An overview of these issues is provided, concluding that with the changing landscape of adult CF care, the definitions and management of PExs may need to evolve to enable continued improvements in outcomes across the age spectrum of CF.
Diagnosing Cystic Fibrosis in Adults Barry, Peter J; Simmonds, Nicholas J
Seminars in respiratory and critical care medicine,
04/2023, Volume:
44, Issue:
2
Journal Article
Peer reviewed
Open access
Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn ...screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the
gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.
Scientific studies of Aloe vera have tentatively explained therapeutic claims from a mechanistic perspective. Furthermore, in vitro outcomes demonstrate that the breakage of acemannan chains into ...smaller fragments enhances biological effects. These fragments can intravenously boost vaccine efficacy or entrain the immune system to attack cancer cells by mannose receptor agonism of macrophage or dendritic cells. With oral consumption, epithelialisation also occurs at injured sites in the small intestine or colon. The main advantage of dietary acemannan is the attenuation of the digestive process, increasing satiety, and slowing the release of sugars from starches. In the colon, acemannan is digested by microbes into short‐chain fatty acids that are absorbed and augment the sensation of satiety and confer a host of other health benefits. In topical applications, an acemannan/chitosan combination accelerates the closure of wounds by promoting granular tissue formation, which creates a barrier between macrophages or neutrophils and the wound dressing. This causes M2 polarisation, reversal of inflammation, and acceleration of the re‐epithelialisation process. This review summarises and explains the current pharmacodynamic paradigm in the context of acemannan in topical, oral, and intravenous applications. However, due to contradictory results in the literature, further research is required to provide scientific evidence to confirm or nullify these claims.
Advanced lung disease in adult cystic fibrosis (CF) drives most clinical care requirements. The aim was to evaluate outcome (time to death while in the study) in a cohort of adult CF patients with ...severe lung disease, and to determine the association among baseline patient characteristics and outcome.
A retrospective cohort study was performed and clinical records between 2000 and 2015 were reviewed. Severe lung disease was defined as forced expiratory volume in the first second (FEV
) < 30% of predicted. Outcomes of all patients, including their date of death or transplantation, were determined till January 1st, 2016. Clinical data were recorded at the entry date.
Among 39 subjects included in the study, 20 (51.3%) died, 16 (41.0%) underwent bilateral lung transplantation, and 3 were alive at the end of the study period. Two variables were independently associated with death: body mass index (BMI ≥ 18.5 kg/m
) (HR = 0.78, 95% CI = 0.64-0.96 and p = 0.017) and use of tobramycin inhalation therapy (HR = 3.82, 95% CI = 1.38-10.6 and p = 0.010). Median survival was 37 (95% CI = 16.4-57.6) months. The best cut-off point for BMI was 18.5 kg/m
. Median survival in patients with BMI < 18.5 kg/m
was 36 months (95% CI = 18.7-53.3).
Median survival of CF subjects with FEV
< 30% was 37 months. BMI and tobramycin inhalation therapy were independently associated with death. Median survival in patients with BMI < 18.5 kg/m
was significantly lower than in patients with BMI ≥ 18.5 kg/m
. The association of tobramycin inhalation with death was interpreted as confounding by severity (use was reserved for advanced lung disease).
Grape seeds are a rich source of flavan-3-ol monomers, oligomers, and polymers. The diverse profile of compounds includes mainly B-type procyanidins (especially C4→C8 linked molecules) and the key ...monomers, catechin, and epicatechin that are positively implicated in the 'French Paradox'. Today grape seed nutraceuticals have become a multi-million-dollar industry. This has created incentives to elucidate the variations in chemistry across cultivars, to identify signs of adulteration, and to understand the intrinsic and extrinsic factors controlling the expression of metabolites in the seeds' metabolome. This review provides a critical overview of the existing literature on grape seed chemistry. Although the biosynthetic pathways for polymeric procyanidins in seeds have not yet been explained, abiotic factors have been shown to modulate associated genes. Research of extrinsic factors has demonstrated that the control of procyanidin expression is strongly influenced, in order of importance, by genotype (species first, then variety) and environment, as claimed anecdotally. Unfortunately, research outcomes on the effects of abiotic factors have low certainty, because effects can be specific to genotype or variety, and there is limited control over physical metrics in the field. Thus, to gain a fuller understanding of the effects of abiotic factors and biosynthetic pathways, and realise potential for optimisation, a more fundamental research approach is needed. Nevertheless, the current synthesis offers insight into the selection of species or varieties according to the profile of polyphenols, as well as for optimisation of horticultural practices, with a view to produce products that contain the compounds that support health claims.
Hemp (
Cannabis sativa
L.) is a widely researched industrial crop with a variety of applications in the pharmaceutical, nutraceutical, food, cosmetic, textile, and materials industries. Although many ...of these applications are related to its chemical composition, the chemical diversity of the hemp metabolome has not been explored in detail and new metabolites with unknown properties are likely to be discovered. In the current study, we explored the chemical diversity of the hemp seed metabolome through an untargeted metabolomic study of 52 germplasm accessions to 1) identify new metabolites and 2) link the presence of biologically important molecules to specific accessions on which to focus on in future studies. Multivariate analysis of mass spectral data demonstrated large variability of the polar chemistry profile between accessions. Five main groups were annotated based on their similar metabolic fingerprints. The investigation also led to the discovery of a new compound and four structural analogues, belonging to a previously unknown chemical class in hemp seeds: cinnamic acid glycosyl sulphates. Although variability in the fatty acid profiles was not as marked as the polar components, some accessions had a higher yield of fatty acids, and variation in the ratio of linoleic acid to α-linolenic acid was also observed, with some varieties closer to 3:1 (reported as optimal for human nutrition). We found that that cinnamic acid amides and lignanamides, the main chemical classes of bioactive metabolites in hemp seed, were more concentrated in the Spanish accession Kongo Hanf (CAN58) and the French accession CAN37, while the Italian cultivar Eletta Campana (CAN48) demonstrated the greatest yield of fatty acids. Our results indicate that the high variability of bioactive and novel metabolites across the studied hemp seed accessions may influence claims associated with their commercialization and inform breeding programs in cultivar development.
There is a growing consensus that the perspective of the patient should be considered in the evaluation of novel interventions.
What treatment outcomes matter to people with cystic fibrosis (CF), and ...what trade-offs would they make to realize these outcomes?
Adults attending a specialist CF center were invited to complete an online discrete choice experiment (DCE). The DCE required participants to evaluate hypothetical CF treatment profiles, defined by impact on lung function, pulmonary exacerbations, abdominal symptoms, life expectancy, quality of life, inhaled medicine usage, and physiotherapy requirement. Choice data were analyzed, using multinomial logit and latent class models.
One hundred and three people with CF completed the survey (median age, 35 years; range, 18-76 years); 52% were female; mean FEV
% predicted, 69% SD, 22%). On average, an improvement in life expectancy by 10 years or more had the greatest impact on treatment preference, followed by a 15% increase in lung function. However, it was shown that people would trade substantial reductions in these key outcomes to reduce treatment time or burden. Preference profiles were not uniform across the sample: three distinct subgroups were identified, each placing markedly different importance on the relative importance of both life expectancy and lung function compared with other attributes.
The relative importance of treatment burden to people with CF, compared with life expectancy and lung function, suggests it should be routinely captured in clinical trials as an important secondary outcome measure. When considering the patient perspective, it is important that decision-makers recognize that the values of people with CF are not homogeneous.
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