Mercury biomagnification in the food chain of a piscivorous turtle species (Testudines: Chelidae: Chelus fimbriata) in the Central Amazon, Brazil.

Due to their natural history and ecological attributes, turtles are excellent organisms for studies of heavy metal contamination. Turtles have a large geographical distribution, occupy different aquatic habitats, and occupy various trophic levels. The present study investigated mercury bioaccumulation in the carnivorous chelonian Chelus fimbriata (Matamata turtle) and Hg biomagnification in relation to its aquatic food chain in the middle Rio Negro, AM-Brazil. Tissue samples of muscle, carapace and claws were collected from 26 C. fimbriata individuals, as well as collections of autotrophic energy sources found in the turtle's aquatic habitat area. The samples were collected in February-March/2014 and analyzed for THg concentrations and carbon (δ13C) and nitrogen (δ15N) stable isotopes. The highest THg levels were found in claws (3780 ng.g-1), carapace (3622 ng.g-1) and muscle (403 ng.g-1), which were found to be significantly different [F(2.73) = 49.02 p < 0.01]. However, THg concentrations in muscle tissue were below the consumption threshold indicated by the WHO and Brazilian Health Ministry. The average δ13C and δ15N values in Matamata samples were -31.7‰ and 11.9‰, respectively. The principal energy source sustaining the food chain of C. fimbriata was found to be terrestrial shrubs, with smaller contributions from emergent aquatic herbaceous plants and algae, while δ15N values showed its trophic position to be two levels above the autotrophic energy sources. There was a positive correlation between THg and turtle size, while a significant relationship was found between THg and δ15N, showing strong biomagnification in the food chain of C. fimbriata: y = 0.21x + 0.46; r2 = 0.45; p < 0.001, for which the slope presented a value of 0.21.

Lung function decline is mitigated following liver transplantation in people with cystic fibrosis: A retrospective cohort study.

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from -2.2% to -0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations.

Incidence of fibrosing colonopathy with pancreatic enzyme replacement therapy in patients with cystic fibrosis.

BACKGROUND: High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures. METHODS: This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication. RESULTS: Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC. CONCLUSIONS: The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products.

The Cystic Fibrosis Learning Network: A mixed methods evaluation of program goals, attributes, and impact.

Introduction: The Cystic Fibrosis (CF) Foundation sponsored the design, pilot testing, and implementation of the CF Learning Network (CFLN) to explore how the Foundation's Care Center Network (CCN) could become a learning health system. Six years after the design, the Foundation commissioned a formative mixed methods evaluation of the CFLN to assess: CFLN participants' understanding of program goals, attributes, and perceptions of current and future impact. Methods: We performed semi-structured interviews with CFLN participants to identify perceived goals, attributes, and impact of the network. Following thematic analyses, we developed and distributed a survey to CFLN members and a matched sample of CCN programs to understand whether the themes were unique to the CFLN. Results: Interviews with 24 CFLN participants were conducted. Interviewees identified the primary CFLN goal as improving outcomes for people living with CF, with secondary goals of providing training in quality improvement (QI), creating a learning community, engaging all stakeholders in improvement, and spreading best practices to the CCN. Project management, use of data, common QI methods, and the learning community were seen as critical to success. Survey responses were collected from 103 CFLN members and 25 CCN members. The data revealed that CFLN respondents were more likely than CCN respondents to connect with other CF programs, routinely use data for QI, and engage patient and family partners in QI. Conclusions: Our study suggests that the CFLN provides value beyond that achieved by the CCN. Key questions remain about whether spread of the CFLN could improve outcomes for more people living with CF.

Cystic fibrosis survival outcomes following second lung transplant: The north American experience.

INTRODUCTION: Re-transplant is an option for those who develop end-stage lung disease due to rejection; however, little data exist following re-transplantation in cystic fibrosis (CF). METHODS: Data from the Canadian CF Registry and US CF Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. Individuals who underwent a 2nd lung transplant between 2005 and 2019 were included. The Kaplan-Meier method was used to estimate the probability of survival post-second transplant at 1, 3, and 5-years. RESULTS: Of those people who were waitlisted for a second transplant (N = 818), a total of 254 (31%) died waiting, 395 (48%) were transplanted and 169 (21%) people were alive on the waitlist. Median survival time after 2nd lung transplant was 3.3 years (95% CI: 2.8-4.1). The 1-, 3- and 5-year survival rates were 77.4% (95% CI: 73.1-82%), 52% (95% CI: 46.7-58%) and 39.4% (95% CI: 34.1-45.6%). CONCLUSIONS: Survival following second lung transplant in CF patients is lower than estimates following the first transplant. Over half of subjects who are potentially eligible for a second transplant die without receiving a second organ. This warrants further investigation.

Impact of loss to follow-up on survival estimation for cystic fibrosis.

PURPOSE: Deaths among those lost to follow-up (LTFU) in the Cystic Fibrosis Foundation Patient Registry (CFFPR) are critically important to the epidemiology of cystic fibrosis (CF). Unreported deaths could impact estimates of survival if LTFU is associated with disease trajectory. METHODS: We characterized the LTFU population (1986-2017) from the CFFPR and identified deaths via linkage with the National Death Index (NDI). Median predicted survival age and conditional survival were estimated with and without additional deaths and person-time from the NDI. RESULTS: Of the 10,582 individuals LTFU in the CFFPR, 2,460 (23.2%) matched to an NDI death record. Individuals who died after LTFU with a CF diagnosis were 43% female, 91% White/non-Hispanic, 59% had advanced CF lung disease based on last CFFPR recorded forced expiratory volume in one second (FEV1) %predicted <40 and 18% were post-lung transplant. Median predicted survival age during the most recent period available, 2013-2017, increased from 44.3 years (95% CI: 43.2, 45.7) to 45.8 years (95% CI 44.5, 47.1) with the inclusion of NDI data. CONCLUSIONS: Inclusion of deaths and additional person-time among those LTFU changed the point estimate of median predicted survival for most time periods and increased the point estimate from 2009 onwards.

Acute ecotoxicological effects of Hg(CN)2 in Danio rerio (zebrafish).

Artisanal and small-scale gold mining (ASGM) is the largest source of anthropogenic Hg emissions on the planet. In addition, Hg-contaminated tailings are often reprocessed with sodium cyanide (NaCN) to extract the residual gold remaining in the material. This leads to the formation of mercury cyanide (Hg(CN)2) complexes, which are often discharged in untreated form into local drainages, leading to large amounts of free cyanide being released. However, data on mercury-cyanide interactions are scarce. In this study, we investigated the impact of cyanide and Hg bioavailability in zebrafish when added as Hg(CN)2. Different concentrations of Hg(CN)2 and NaCN were used, leading to an LC50 of 0.53 mg.L-1 for NaCN and 0.16 mg.L-1 for Hg(CN)2. Analyzing free cyanide concentrations in aquarium water, >40% dissociation was observed for NaCN and about 5% for Hg(CN)2. The accumulation of total Hg (THg) in the brain, gills, muscle and kidney was quantified. All fish exposed to Hg(CN)2 had higher THg levels than their controls and kidney was the tissue with higher Hg(CN)2 accumulation. Histological effects on the kidney and gills of both cyanides in D. rerio tissues were investigated, suggesting renal alterations in fish exposed to Hg(CN)2 and showing hyperplasia in the gills of animals exposed to NaCN and Hg(CN)2. The results alert to the risks of the presence of these complexes in aquatic environments.

Lung Function Decline in Cystic Fibrosis: Impact of Data Availability and Modeling Strategies on Clinical Interpretations.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Cystic fibrosis prevalence in the United States and participation in the Cystic Fibrosis Foundation Patient Registry in 2020.

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation. METHODS: In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968. RESULTS: We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later. CONCLUSIONS: We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data.

Contemporary cystic fibrosis incidence rates in Canada and the United States.

BACKGROUND: The availability of new diagnostic algorithms for cystic fibrosis (CF), changing population demographics and programs that impact family planning decisions can influence incidence rates. Thus, previously reported incidence rates in Canada and the United States (US) may be outdated. The objectives of this study were to estimate contemporary CF incidence rates in Canada and the US and to determine if the incidence rate has changed over time. METHOD: This population-based cohort study utilized data between 1995-2019 from the Canadian CF Registry (CCFR), Statistics Canada, US CF Foundation Patient Registry (CFFPR) data, and US Center for Disease Control (CDC) National Vital Statistics System. Incidence was estimated using the number of live CF births by year, sex, and geographic region using Poisson regression, with the number of live births used as the denominator. To account for delayed diagnoses, we imputed the proportion of diagnoses expected given historical trends, and varying rates of newborn screening (NBS) implementation by region. RESULTS: After accounting for implementation of NBS and delayed diagnoses, the estimated incidence rate for CF in 2019 was 1:3848 (95% CI: 1:3574, 1:4143) live births in Canada compared to 1:5130 (95% CI:1:4996, 1:5267) in the US. There was substantial regional variation in incidence rates within both Canada and the US. Since 1995, incidence rates have decreased at a rate of 1.6% per year in both countries (p<0.001). CONCLUSION: Contemporary CF incidence rates suggest CF incidence is lower than previously reported and varies widely within North America. This information is important for resource planning and for tracking how programs (e.g., genetic counselling, modulator availability etc.) may impact the incidence of CF moving forward.

Application of palaeogenetic techniques to historic mollusc shells reveals phylogeographic structure in a New Zealand abalone.

Natural history collections worldwide contain a plethora of mollusc shells. Recent studies have detailed the sequencing of DNA extracted from shells up to thousands of years old and from various taphonomic and preservational contexts. However, previous approaches have largely addressed methodological rather than evolutionary research questions. Here, we report the generation of DNA sequence data from mollusc shells using such techniques, applied to Haliotis virginea Gmelin, 1791, a New Zealand abalone, in which morphological variation has led to the recognition of several forms and subspecies. We successfully recovered near-complete mitogenomes from 22 specimens including 12 dry-preserved shells up to 60 years old. We used a combination of palaeogenetic techniques that have not previously been applied to shell, including DNA extraction optimized for ultra-short fragments and hybridization-capture of single-stranded DNA libraries. Phylogenetic analyses revealed three major, well-supported clades comprising samples from: (1) The Three Kings Islands; (2) the Auckland, Chatham and Antipodes Islands; and (3) mainland New Zealand and Campbell Island. This phylogeographic structure does not correspond to the currently recognized forms. Critically, our nonreliance on freshly collected or ethanol-preserved samples enabled inclusion of topotypes of all recognized subspecies as well as additional difficult-to-sample populations. Broader application of these comparatively cost-effective and reliable methods to modern, historical, archaeological and palaeontological shell samples has the potential to revolutionize invertebrate genetic research.

Telehealth and CFTR modulators: Accelerating innovative models of cystic fibrosis care.

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study.

BACKGROUND: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. RESULTS: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). CONCLUSIONS: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.

The Impact of COVID-19 in Cystic Fibrosis

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Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data.

RATIONALE: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results. OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences. METHODS: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics). RESULTS: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK. CONCLUSIONS: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

Impact of the COVID-19 pandemic: How our response is shaping the future of cystic fibrosis care.

The findings of this body of work are presented in the eight articles included in this supplement. The impact and perspectives of adult and pediatric care teams and patient/families are covered with special attention to mental health care, the financial and personnel impacts within care programs, the experiences of vulnerable and underrepresented patient populations, and implementation of remoting monitoring. Commentaries from colleagues provide a broader perspective, offering reflections on the findings and their implications regarding the future CF care model.

Cystic Fibrosis Foundation Nebulizer and Compressor Accessibility Survey.

BACKGROUND: Although guidelines for inhaled therapies for individuals with cystic fibrosis (CF) are available, recommendations for compressors/nebulizers to optimize care are lacking. The CF Foundation (CFF) convened a multidisciplinary task force to assess the use, durability, accessibility, and cost burden of compressors/nebulizers. METHODS: Online surveys were developed and distributed to 287 CFF programs and adults with CF and parents of children with CF (adults with CF/parents). RESULTS: Health care providers from 38 states completed the survey (59% response rate). Respiratory therapists were mostly responsible to coordinate ordering nebulizers and compressors. Durable medical equipment companies were the most common source of acquisition of compressors (71.8%) and nebulizers (45.9%). A majority of health care providers did not feel the compressors were durable (51.1%) or that they could get enough nebulizers to their patients (69.2%). Barriers to procure compressors were reported. The survey was completed by 734 adults with CF/parents from 48 states. Most adults with CF/parents rated their compressor as durable (65.8%); however, 85.5% of respondents reported some user-experience problem(s). "Hoses popping off" and "increased nebulization time" were most commonly reported. Almost 20% of respondents did not have access to a compressor at some point in the previous year. Most adults with CF/parents did not change compressor filters per manufacturer's recommendation (40% never). Adults with CF/parents reported performing a median of 4 inhaled treatments per day. Median use of nebulizers was 6 months. Most adults with CF/parents thought they had enough nebulizers (53.7%). Individuals with CF doing more inhaled treatments reported more compressor malfunctions. The median out-of-pocket expense was $75-99 and $50-74 for compressors and nebulizers, respectively. CONCLUSIONS: Although the perceptions of health care providers and adults with CF/parents differed to a certain extent, the surveys uncovered several significant issues that may compromise quality of care. Improvement in access to devices and education are needed.