查看更多>>摘要：? 2021Cystic fibrosis (CF) was historically a disease largely afflicting children. Due to therapeutic advancements, there are now more adults with CF than children. In the past decade, medications including Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators became available that treat the underlying cause of CF and are dramatically improving lung function as well as quality and quantity of life for people with CF. As a result, more women with CF are becoming pregnant. We gathered a panel of experts in CF care, family planning, high risk obstetrics, nutrition, genetics and women with CF to review current literature on pregnancies and to provide care recommendations for this unique population.
查看更多>>摘要：? 2022CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·γ) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the simple and widely used sweat chloride test can be calibrated to provide more accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects (hereafter ‘CFTR activity’). Sweating stimulated by β-adrenergic agonists (β-sweat) is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity with carriers = 50% and CF = 0% of HC values set = 100%, but the β-sweat assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting mean sweat chloride values, taken from numerous studies and the CFTR2 database against mean β-sweat rates for CF, carriers and HC. The resulting inverse logarithmic relations indicate that sweat chloride values ≥60 mmol/L occur when CFTR activity is below 1.2% -10% of HC. These are lower than most previous estimates, which resulted from setting nasal potential difference (NPD) as linear rather than logarithmic measures of CFTR activity. Features of the sweat gland coil and duct are used to explain why readouts of CFTR activity are linear for β-sweat and logarithmic for sweat chloride. Sweat chloride values fall steeply for small increments of CFTR activity above zero—the most clinically relevant region. Thus, large health benefits can be achieved by restoring low levels of CFTR activity, especially if this is done before irreversible lung damage. Truncated Abstract: CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·γ) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the sweat chloride test can be calibrated to provide accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects. Sweating stimulated by β-adrenergic agonists is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity, but the assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting it against mean β-sweat rates for different groups. The resulting logarithmic relations indicate that CF sweat chloride values occur when CFTR activity is below 1.2% -10% of HC, and that large health benefits can be achieved by restoring low levels of CFTR activity if this is done early.
查看更多>>摘要：? 2021 European Cystic Fibrosis SocietyObjectives: Two CFTR-dependent β-adrenergic sweat rate tests applying intradermal drug injections were reported to better define diagnosis and efficacy of CFTR-directed therapies. The aim of this work was to develop and test a needle-free image-based test and to provide an accurate analysis of the responses. Methods: The modified method was conducted by applying two successive iontophoresis sessions using the Macroduct device. Efficiency of drug delivery was tested by evaporimetry. Cholinergically stimulated sweating was evoked by pilocarpine iontophoresis. β-adrenergically stimulated sweating was obtained by iontophoresis of isoproterenol and aminophylline in the presence of atropine and ascorbic acid. A nonlinear mixed-effects (NLME) approach was applied to model volumes of sweat and subject-specific effects displaying inter- and intra-subject variability. Results: Iontophoresis provided successful transdermal delivery of all drugs, including almost neutral isoproterenol and aminophylline. Pilocarpine was used at a concentration ～130-times lower than that used in the classical Gibson and Cooke sweat test. Addition of ascorbic acid lowered the pH of the solution, made it stable, prevented isoproterenol degradation and promoted drug iontophoresis. Maximal secretory capacity and kinetic rate of β-adrenergic responses were blunted in CF. A cutoff of 5.2 minutes for ET50, the time to reach the half maximal secretion, discriminated CF from controls with a 100% sensitivity and specificity. Heterozygous showed an apparently reduced kinetic rate and a preserved secretory capacity. Conclusion: We tested a safe, well-tolerated needle-free image-based sweat test potentially applicable in children. Modelling responses by NLME allowed evaluating metrics of CFTR-dependent effects reflecting secretory capacity and kinetic rate.
查看更多>>摘要：? 2021Background: The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices. Methods: A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests. Results: All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Conclusions: There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era.
查看更多>>摘要：? 2021Background: Previous studies suggest that PAP-based CF protocols are suitable for newborn screening (NBS) for cystic fibrosis (CF) when newborns designated as CFSPID should not be detected. However, there are still discussions about the performance of IRT/PAP algorithms. We present the final results of a pilot study evaluating a IRT/PAP protocol with an IRT-dependent safety net (SN) conducted from 2008 to 2016 in southwestern Germany on nearly 500,000 newborns. Methods: To achieve reliable data, all newborns were screened using both the PAP-based and a DNA-based CFNBS algorithm. PAP quantification and genetic analysis of the four most common CFTR mutations in Germany were performed in all newborns with IRT≥99.0 percentile. NBS was rated positive if either PAP was ≥1.6 μg/l and/or at least one CFTR mutation was detected. In addition, an IRT-dependent SN resulted in positive rating for both protocols if IRT was ≥99.9 percentile. To evaluate the IRT/PAP protocol, its performance was compared to that of the IRT/DNA protocol. Results: The IRT/PAP protocol with IRT-based SN used in the study achieved a sensitivity of 94%, if false-negative detected neonates with meconium ileus and those designated as CFSPID were excluded from analysis. CF/CFSPID ratio was 92. However, PPV of the IRT/PAP+SN protocol was with 10.3% very low. Conclusions: PAP-based CFNBS protocols can be used, if less detection of CFSPID is desired. The IRT/PAP protocol with IRT-dependent SN evaluated here achieved adequate sensitivity but should probably be used in combination with a third-tier test to also achieve an acceptable PPV.
查看更多>>摘要：? 2022 European Cystic Fibrosis SocietyMore than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.
查看更多>>摘要：? 2021Background: : The cystic fibrosis (CF) sweat gland is defective in β-adrenergically-stimulated sweat secretion in the coil and chloride reabsorption in the duct. Whereas chloride reabsorption is regularly assessed by quantitative pilocarpine iontophoresis (QPIT), the measurement of β-adrenergic sweat secretion is not yet established in clinical practice. Methods: : A novel sweat bubble imaging protocol was developed that determines sweat secretion rates by automatic recording, processing and quality control of the kinetics of sweat droplet formation. Results: : Treatment of CF patients with the CFTR modulators elexacaftor, tezacaftor and ivacaftor reduced the sweat chloride concentration measured in QPIT in the majority of patients to values in the intermediate or normal range. In contrast, the β-adrenergically-stimulated sweat secretion rate assayed by the automated bubble sweat test was normalized in only 3 patients, slightly increased in 12 patients and remained undetectable in 8 patients. Conclusions: : β-adrenergic sweat stimulation in the coil is apparently rather stringent in its requirements for a wild type CFTR conformation whereas chloride reabsorption in the duct tolerates residual structural and functional deficits of native or pharmacologically rescued mutant CFTR in the apical membrane.
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