Tracking patient outcomes using cystic fibrosis (CF) national data registries, we have seen a dramatic improvement in patient survival. As there are multiple ways to measure survival, it is important ...for readers to understand these different metrics in order to clearly translate this information to patients and their families. The aims of this review were to describe measures of survival and to review the recent literature pertaining to survival in CF to capture the changing epidemiology.
Although survival has improved on a population level, several individual factors continue to impact survival such as sex, age of diagnosis, ethnic background and lung function. Survival estimates, conditional on surviving to a specified age, are more relevant to individuals living with CF today and are higher than the reported overall median age of survival. There is some evidence to suggest that newborn screening (NBS) has resulted in prolonged survival in CF.
Prognosis in CF is often described by reporting the median age of survival, the median age of death, the median survival conditional on living to a certain age and the survival by birth cohort. Each of these metrics provide useful information depending on an individual's personal disease trajectory. The median age of survival continues to increase in CF in many countries while mortality rates are decreasing. Several factors have been associated with worse survival such as female sex, ethnicity, worse nutritional status, lower lung function and microbiology. When comparing survival between countries, one needs to ensure that similar data collection and processing techniques are used to ensure valid and robust comparisons.
In neurons, the proper distribution of mitochondria is essential because of a requirement for high energy and calcium buffering during synaptic neurotransmission. The efficient, regulated transport ...of mitochondria along axons to synapses is therefore crucial for maintaining function. The trafficking kinesin protein (TRAK)/Milton family of proteins comprises kinesin adaptors that have been implicated in the neuronal trafficking of mitochondria via their association with the mitochondrial protein Miro and kinesin motors. In this study, we used gene silencing by targeted shRNAi and dominant negative approaches in conjunction with live imaging to investigate the contribution of endogenous TRAKs, TRAK1 and TRAK2, to the transport of mitochondria in axons of hippocampal pyramidal neurons. We report that both strategies resulted in impairing mitochondrial mobility in axonal processes. Differences were apparent in terms of the contribution of TRAK1 and TRAK2 to this transport because knockdown of TRAK1 but not TRAK2 impaired mitochondrial mobility, yet both TRAK1 and TRAK2 were shown to rescue transport impaired by TRAK1 gene knock-out. Thus, we demonstrate for the first time the pivotal contribution of the endogenous TRAK family of kinesin adaptors to the regulation of mitochondrial mobility.
•Microsimulation can evaluate the potential impact of interventions.•By 2030, elexacaftor/tezacaftor/ivacaftor could improve survival by 9.2 years.•Delayed access to elexacaftor/tezacaftor/ivacaftor ...will mitigate the impact.
Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access.
A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 (‘early’) or 3) availability in 2025 (‘delayed’). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states.
Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths.
Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population.
Abstract
Despite hope that a cure was imminent when the causative gene was cloned nearly 30 years ago, cystic fibrosis (CF MIM: 219700) remains a life-shortening disease affecting more than 70 000 ...individuals worldwide. However, within the last 6 years the Food and Drug Administration's approval of Ivacaftor, the first drug that corrects the defective cystic fibrosis transmembrane conductance regulator protein CFTR (MIM: 602421) in patients with the G551D mutation, marks a watershed in the development of novel therapeutics for this devastating disease. Here we review recent progress in diverse research areas, which all focus on curing CF at the genetic, biochemical or physiological level. In the near future it seems probable that development of mutation-specific therapies will be the focus, since it is unlikely that any one approach will be efficient in correcting the more than 2000 disease-associated variants. We discuss the new drugs and combinations of drugs that either enhance delivery of misfolded CFTR protein to the cell membrane, where it functions as an ion channel, or that activate channel opening. Next we consider approaches to correct the causative genetic lesion at the DNA or RNA level, through repressing stop mutations and nonsense-mediated decay, modulating splice mutations, fixing errors by gene editing or using novel routes to gene replacement. Finally, we explore how modifier genes, loci elsewhere in the genome that modify CF disease severity, may be used to restore a normal phenotype. Progress in all of these areas has been dramatic, generating enthusiasm that CF may soon become a broadly treatable disease.
Fluoroquinolone antibiotics are commonly used to treat infections and are prescribed by general practitioners, medical specialists and surgeons. Tendon injury has been associated with the use of ...these medications but the risk associated with newer fluoroquinolones has not been established.
The aim of this systematic review was to evaluate the evidence from observational studies to determine the strength of the association between fluoroquinolone use and tendinopathy, and to identify risk factors for this complication.
We searched MEDLINE, EMBASE and the Cochrane Collaboration from inception through May 2013 to identify observational studies focused on tendon injury and fluoroquinolones. Studies with original data were selected for inclusion following the PRISMA guidelines. Of the 560 abstracts screened, 16 relevant studies were independently rated by three authors (WW, AS, DC) using the Newcastle-Ottawa Quality Assessment Scale, and assigned a quality score out of 9. High-quality studies (i.e. scored 4.5 or higher) are summarized in detail in this article. Data were independently extracted by two authors (WW, AS).
Overall, 16 studies were included in our study. Eight were deemed to be of high quality and five specifically evaluated Achilles tendon rupture. In addition, three studies examined Achilles tendinitis, and three included tendon disorders (including any tendon rupture) as an outcome. Results from these studies suggest that individuals exposed to fluoroquinolones are at increased risk for Achilles tendon rupture, particularly within the first month following exposure to the drug (odds ratios ranged from 1.1 to 7.1). One study showed an increased risk of tendon rupture in those over 60 years of age. Five studies stated that individuals taking fluoroquinolones and oral corticosteroids are at increased risk for tendon injury compared with those taking fluoroquinolones alone. Four studies examined the differential effect of a limited number of fluoroquinolones. Ofloxacin had the highest risk of tendon injury in three of the studies.
Included studies are observational in nature and rely on self-report, which may lead to misclassification or underestimation of tendon injury.
Observational studies showed an increased risk of tendon injury, including tendon rupture and tendinitis, with exposure to fluoroquinolone antibiotic therapy. Although this complication appears to be rare, concomitant corticosteroids increase the risk for tendon injury, which varies depending on the fluoroquinolone used.
In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between ...national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias.
To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States.
Population-based study.
42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers.
Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013.
Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival.
Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 95% CI, 0.54 to 0.81). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively standardized difference, 13.7). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status.
Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results.
Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage.
U.S. Cystic Fibrosis Foundation.
Previously established predictors of survival may no longer apply in the current era of cystic fibrosis (CF) care. Our objective was to identify risk factors associated with survival in a ...contemporary CF population. We used the Canadian CF Registry, a population-based cohort, to calculate median age of survival and summarise patient characteristics from 1990 to 2012. Clinical, demographic and geographical factors, and survival were estimated for a contemporary cohort (2000-2012) using Cox proportional hazards models. There were 5787 individuals in the registry between 1990 and 2012. Median survival age increased from 31.9 years (95% CI 28.3-35.2 years) in 1990 to 49.7 years (95% CI 46.1-52.2 years) in the most current 5-year window ending in 2012. Median forced expiratory volume in 1 s improved (p=0.04) and fewer subjects were malnourished (p<0.001) over time. Malnourished patients (hazard ratio (HR) 2.1, 95% CI 1.6-2.8), those with multiple exacerbations (HR 4.5, 95% CI 3.2-6.4) and women with CF-related diabetes (HR 1.8, 95% CI 1.2-2.7) were at increased risk of death. Life expectancy in Canadians with CF is increasing. Modifiable risk factors such as malnutrition and pulmonary exacerbations are associated with an increased risk of death. The sex gap in CF survival may be explained by an increased hazard for death in women with CF-related diabetes.
Contemporary studies evaluating post-transplant survival are limited and often include data from single centers or selected sub-groups. The purpose of this study was to evaluate overall transplant ...survival and to identify risk factors associated with death after transplant.
The Canadian Cystic Fibrosis Registry, a population-based cohort, was used to describe survival after lung transplant. Pre-transplant factors associated with post-transplant survival were estimated using Cox proportional hazards models.
Between 1988 and 2012, 580 patients received a lung transplant. In the entire cohort, post-lung transplant 1-year survival was 87.8%, 5-year survival was 66.7%, and 10-year survival was 50.2%. Median post-transplant survival was 3.3 years (95% confidence interval CI = 2.13-6.56) in patients infected with Burkholderia cepacia complex compared with 12.36 years (95% CI = 10.34-17.96) in patients without B cepacia infection (hazard ratio HR = 2.63, 95% CI = 2.0-3.44). After adjustment, there was a non-significant trend toward better post-transplant survival with increasing year of transplant (HR = 0.98, 95% CI = 0.96-1.00). Pancreatic sufficiency (HR = 2.13, 95% CI = 1.41-3.20) and age at transplant such that youngest and oldest had the poorest survival (p < 0.001) were significant negative predictors of survival. The risk of death after transplant for patients infected with B cepacia was highest within the first year (HR = 6.29, 95% CI = 3.87-10.21) but remained elevated >1 year after transplant (HR = 1.92, 95% CI = 1.33-2.77) compared with patients without B cepacia infection.
After lung transplantation, 5-year survival in Canadians with CF is 67%, and 50% of patients live >10 years. Despite these impressive probabilities, age at transplant, pancreatic sufficiency and B cepacia infection remain important determinants of survival after lung transplantation.
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