Journal of Cystic Fibrosis最新文献_第5页

Development of metabolic syndrome in people with Cystic Fibrosis one year after exposure to elexacaftor-tezacaftor-ivacaftor 囊性纤维化患者在使用 elexacaftor-tezacaftor-ivacaftor 一年后出现代谢综合征。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.09.022

Gregory A. Ratti , Hannah Smith , Sasan Mirfakhraee , Joan Reisch , Leah Cohen , Raksha Jain , James D. Finklea

Background

The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF.

Methods

A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period.

Results

After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130–139/90–99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001.

Conclusions

Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

背景：高血压、躯干肥胖、空腹血糖受损、低高密度脂蛋白和高甘油三酯血症被称为代谢综合征（MetSyn），与心血管疾病和其他疾病相关。囊性纤维化患者（pwCF）服用 Elexacaftor-tezacaftor-ivacaftor (ETI) 会导致体重增加，但对心血管风险的影响尚不清楚。本研究旨在调查囊性纤维化患者的 ETI 暴露和 MetSyn 的发病风险：方法：进行了一项前瞻性队列研究，研究对象包括暴露于 ETI 的年龄≥ 18 岁的 pwCF。用于计算 MetSyn 的所有数据均来自开始使用 ETI 和使用 ETI 1 年 ± 3 个月后的电子病历。共有 152 名接触过 ETI 的儿童和 34 名从未接触过 CF 跨膜电导调节剂的儿童被纳入分析。在此期间，还对高血压分类的变化进行了研究：使用 ETI 1 年后，MetSyn 从 13 例增加到 30 例，p < 0.0001。未接触过 ETI 的人群中没有出现新的 MetSyn 病例。使用 ETI 1 年后，更多的人达到了 1 级高血压（血压 130-139/90-99 mm Hg）或 2 级高血压（血压≥140/≥90 mm Hg）标准，无论之前是否接触过调节剂，P < 0.0001：暴露于 ETI 1 年会导致 MetSyn 病例增加。高血压发病率的增加与暴露于 ETI 有关。需要进行更多的研究来进一步研究这一趋势，并确定这些变化是否会随着时间的推移转化为心血管并发症。

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引用次数: 0

Exogenous insulin does not reduce protein catabolism in pre-diabetic cystic fibrosis patients: A randomized clinical trial 外源性胰岛素不会减少糖尿病前期囊性纤维化患者的蛋白质分解：随机临床试验。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.10.005

Michele Schiavon , Claudio Cobelli , K. Sreekumaran Nair , Katherine Klaus , Gianna Toffolo , Lin Zhang , Antoinette Moran

Background

Cystic Fibrosis (CF) patients historically suffered from undernutrition, infection and inflammation. Insulin insufficiency-related protein catabolism further compromised health. We aimed to determine whether insulin improves protein catabolism in CF youth with abnormal glucose tolerance (AGT).

Methods

This double-masked, placebo-controlled trial in CF youth age 10–25 with AGT who were in their usual state of health used triple-tracer stable-isotope methodology to measure protein turnover during a baseline test meal and after four weeks of insulin/placebo treatment. Healthy controls were assessed once. CF patients were randomized 1:1:1 to once-daily long-acting insulin (0.25 U/kg/d), three-times daily rapid-acting insulin (0.5 U/15gr carbohydrate), or injectable placebo.

Results

Thirty CF patients completed the study. There were no differences in any measure of protein turnover between insulin- and placebo-treated subjects, including endogenous protein breakdown (primary study endpoint). In contrast to earlier studies, protein turnover in the 37 CF patients who completed the baseline meal was normal compared to 20 healthy controls. Meal isotope appeared in plasma earlier in CF than controls, suggesting more rapid gut emptying. The study was interrupted by the pandemic; futility analysis led to study discontinuation before the planned remaining 15 CF patients were studied.

Conclusions

Recent advances in CF have led to remarkable clinical improvements. In this study, CF youth with AGT had normal protein catabolism at baseline. Pre-meal or daily basal insulin therapy, while safe and well tolerated, did not significantly enhance protein turnover and does not appear to be necessary in clinically stable patients prior to development of CFRD.

背景：囊性纤维化（CF）患者历来饱受营养不良、感染和炎症之苦。与胰岛素不足有关的蛋白质分解进一步损害了患者的健康。我们旨在确定胰岛素是否能改善糖耐量异常（AGT）的 CF 青少年的蛋白质分解代谢：这项双掩蔽、安慰剂对照试验以 10-25 岁、患有 AGT 且处于正常健康状态的 CF 青少年为对象，采用三重示踪剂稳定同位素方法，测量基线测试餐期间和胰岛素/安慰剂治疗四周后的蛋白质代谢情况。健康对照组接受一次评估。CF患者按1:1:1的比例随机接受每日一次的长效胰岛素（0.25 U/kg/d）、每日三次的速效胰岛素（0.5 U/15gr碳水化合物）或注射安慰剂治疗：30名CF患者完成了研究。胰岛素治疗和安慰剂治疗的受试者在蛋白质周转的任何指标上都没有差异，包括内源性蛋白质分解（主要研究终点）。与之前的研究相比，37 名完成基线餐的 CF 患者与 20 名健康对照组相比，蛋白质周转率正常。与对照组相比，CF 患者血浆中出现膳食同位素的时间更早，这表明肠道排空更快。这项研究因大流行病而中断；无用性分析导致在对计划中剩余的 15 名 CF 患者进行研究之前中止了研究：结论：CF 的最新研究进展已使临床症状得到显著改善。在这项研究中，患有 AGT 的 CF 青少年基线蛋白质分解代谢正常。餐前或每日基础胰岛素治疗虽然安全且耐受性良好，但并不能显著提高蛋白质的转化率，因此临床稳定的患者在出现 CFRD 之前似乎没有必要接受这种治疗。

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引用次数: 0

Learning from the CFTR modulator baby boom 从CFTR调制器婴儿潮中学习。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.12.003

Raksha Jain , Jennifer L. Goralski

引用次数: 0

Differential times of submission and approval of CFTR modulators for the treatment of Cystic Fibrosis in the United States and the European Union 美国和欧盟提交和批准用于治疗囊性纤维化的 CFTR 调节剂的时间不同。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.08.002

Enrico Costa , Silvia Girotti , Clément Mathieu , Carlo Castellani , Joseph S. Ross , Jennifer L. Taylor-Cousar , Hubert G.M. Leufkens

Background

The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU).

Methods

By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023.

Results

Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications.

Conclusion

We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US

背景：本研究旨在评估 CFTR 调节剂在美国（US）和欧盟（EU）申请和批准的不同时间：本研究的目的是评估 CFTR 调节剂在美国和欧盟的提交和批准时间差异：通过从美国食品药品管理局和欧洲药品管理局的网站上收集公开数据，我们量化了截至 2023 年 12 月 31 日美国和欧盟 CFTR 调节剂首次上市授权和适应症变更的提交时间、审查持续时间和批准时间的差异：结果：4种CFTR调节剂的上市申请在欧盟的提交时间比美国晚103（SD ±143）天：首次批准晚 31 天（标准差 ±39 天），补充适应症晚 124 天（标准差 ±155 天）。美国的监管审查过程在 181 天[IQR，179 - 182]内完成，欧盟的监管审查过程在 325 天[IQR，276 - 382]内完成：首次批准用时美国为 167 天[IQR，102 - 232]，欧盟为 346 天[IQR，302 - 400]；补充适应症批准用时美国为 181 天[IQR，181 - 182]，欧盟为 324 天[IQR，264 - 382]。欧盟批准 CFTR 调节剂的时间比美国晚 267 天（SD 143）：首次批准 220 天（SD ±76），补充适应症批准 280 天（SD ±157）：我们发现，美国和欧盟在 CFTR 调节剂的提交和批准时间上存在明显差异，美国总是最先获得首次批准和后续适应症批准。

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引用次数: 0

Insights into epithelial-mesenchymal transition from cystic fibrosis rat models 从囊性纤维化大鼠模型中了解上皮-间质转化。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.09.003

Nathan Rout-Pitt , Bernadette Boog , Alexandra McCarron , Nicole Reyne , David Parsons , Martin Donnelley

Background

Molecular pathways contributing to Cystic Fibrosis pathogenesis remain poorly understood. Epithelial-mesenchymal transition (EMT) has been recently observed in CF lungs and certain CFTR mutation classes may be more susceptible than others. No investigations of EMT processes in CF animal models have been reported.

Aim

The aim of this study was to assess the expression of EMT-related markers in Phe508del and knockout (CFTR-KO) rat lung tissue and tracheal-derived basal epithelial stem cells, to determine whether CFTR dysfunction can produce an EMT state.

Method

The expression of EMT-related markers in lung tissue and cultured tracheal basal epithelial stem cells from wildtype (WT), Phe508del, and CFTR-KO rats were assessed using qPCR and Western blots. Cell responses were evaluated in the presence of Rho-associated protein kinase (ROCK) inhibitor Y27632, which blocks EMT-pathways, or after treatment with TGFβ1 to stimulate EMT.

Results

Different gene expression profiles were observed between Phe508del and CFTR-KO rat models compared to wild type. There was lower expression of type 1 collagen in KO lungs and primary cell cultures, while Phe508del lungs and cells had higher expression, particularly when treated with TGFβ1. The addition of Y27632 rescued changes in EMT related genes in Phe508del cells but not in KO cells.

Conclusion

Our findings show the first evidence of upregulated EMT pathways in the lungs and airway cells of any CF animal model. Differences in the regulation of the EMT genes and proteins in the Phe508del and CFTR-KO cells suggest that the signalling pathways underlying EMT are CFTR mutation dependent.

背景：导致囊性纤维化发病机制的分子途径仍然鲜为人知。最近在 CF 肺中观察到上皮-间质转化（EMT），某些 CFTR 突变类别可能比其他类别更易受影响。目的：本研究旨在评估 Phe508del 和基因敲除（CFTR-KO）大鼠肺组织和气管源性基底上皮干细胞中 EMT 相关标记物的表达，以确定 CFTR 功能障碍是否会产生 EMT 状态：方法：使用 qPCR 和 Western 印迹法评估野生型（WT）、Phe508del 和 CFTR-KO 大鼠肺组织和培养的气管基底上皮干细胞中 EMT 相关标记物的表达。在有阻断 EMT 通路的 Rho- 相关蛋白激酶（ROCK）抑制剂 Y27632 存在的情况下，或用刺激 EMT 的 TGFβ1 处理后，对细胞反应进行了评估：与野生型相比，Phe508del 和 CFTR-KO 大鼠模型的基因表达谱不同。在 KO 肺和原代细胞培养物中，1 型胶原的表达量较低，而 Phe508del 肺和细胞的表达量较高，尤其是在用 TGFβ1 处理时。加入 Y27632 后，Phe508del 细胞中 EMT 相关基因的变化得到了缓解，而 KO 细胞中的变化则没有缓解：我们的研究结果首次证明了在任何 CF 动物模型的肺和气道细胞中 EMT 通路的上调。Phe508del细胞和CFTR-KO细胞中EMT基因和蛋白的调控差异表明，EMT的信号通路依赖于CFTR突变。

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引用次数: 0

Linkage of the CF Foundation Patient Registry with the Scientific Registry of Transplant Recipients database 将 CF 基金会患者登记处与移植受者科学登记处数据库连接起来。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.09.015

Elizabeth A. Cromwell , Yoon Son Ahn , Patrick J. Johnson , Kathleen J. Ramos , A. Jay Freeman , Albert Faro , Jon J. Snyder

Background

The Cystic Fibrosis Foundation Patient Registry (CFFPR) maintains clinical data, including history of solid organ transplant, on people with cystic fibrosis (CF) who obtain care at CF Foundation-accredited care centers. The Scientific Registry of Transplant Recipients (SRTR) database is a collection of national data related to organ transplantation that supports research to evaluate solid organ transplant candidate and recipient outcomes.

Methods

Individuals in the CFFPR were matched to SRTR records using an algorithm that compared names, last four digits of social security numbers, date of birth and date of death. We evaluated match quality by summarizing the extent to which transplant status agreed between the two data sources by organ and year of listing or transplant. We summarized CFFPR-reported characteristics for lung and liver transplants in the year prior to transplant.

Results

A total of 7,594 individuals who participated in the CFFPR matched SRTR records with approximately 75% having at least one transplant record in SRTR. Over 97% of the matched population had a CF diagnosis reported to SRTR. In total, 5,253 people were identified as lung transplant recipients and 499 as liver transplant recipients in SRTR. Clinical characteristics for lung and liver transplants were consistent with the epidemiology of transplantation for people with CF.

Conclusions

Linkage of the two data sources was successful, with high agreement between them supporting the use of the matched population as a valid resource to study transplantation in CF, particularly leveraging pre-transplant characteristics (collected in CFFPR) with detailed transplant data (collected in SRTR).

背景：囊性纤维化基金会患者登记处（CFFPR）保存了在囊性纤维化基金会认可的护理中心接受治疗的囊性纤维化（CF）患者的临床数据，包括实体器官移植史。移植受者科学登记（SRTR）数据库收集了与器官移植相关的全国性数据，为评估实体器官移植候选者和受者结果的研究提供支持：使用一种比较姓名、社会保障号最后四位数字、出生日期和死亡日期的算法将 CFFPR 中的个人与 SRTR 记录进行匹配。我们按器官和上市或移植年份总结了两个数据源之间移植状态的一致程度，以此评估匹配质量。我们总结了 CFFPR 报告的移植前一年肺移植和肝移植的特征：共有 7594 名参与 CFFPR 的个人与 SRTR 记录相匹配，其中约 75% 在 SRTR 中至少有一项移植记录。超过 97% 的匹配人群向 SRTR 报告了 CF 诊断。在 SRTR 中，共有 5,253 人被确认为肺移植受者，499 人被确认为肝移植受者。肺移植和肝移植的临床特征与CF患者的移植流行病学一致：这两个数据源的链接是成功的，它们之间的高度一致支持将匹配人群作为研究 CF 移植的有效资源，特别是利用移植前特征（在 CFFPR 中收集）和详细的移植数据（在 SRTR 中收集）。

{"title":"Linkage of the CF Foundation Patient Registry with the Scientific Registry of Transplant Recipients database","authors":"Elizabeth A. Cromwell , Yoon Son Ahn , Patrick J. Johnson , Kathleen J. Ramos , A. Jay Freeman , Albert Faro , Jon J. Snyder","doi":"10.1016/j.jcf.2024.09.015","DOIUrl":"10.1016/j.jcf.2024.09.015","url":null,"abstract":"<div><h3>Background</h3><div>The Cystic Fibrosis Foundation Patient Registry (CFFPR) maintains clinical data, including history of solid organ transplant, on people with cystic fibrosis (CF) who obtain care at CF Foundation-accredited care centers. The Scientific Registry of Transplant Recipients (SRTR) database is a collection of national data related to organ transplantation that supports research to evaluate solid organ transplant candidate and recipient outcomes.</div></div><div><h3>Methods</h3><div>Individuals in the CFFPR were matched to SRTR records using an algorithm that compared names, last four digits of social security numbers, date of birth and date of death. We evaluated match quality by summarizing the extent to which transplant status agreed between the two data sources by organ and year of listing or transplant. We summarized CFFPR-reported characteristics for lung and liver transplants in the year prior to transplant.</div></div><div><h3>Results</h3><div>A total of 7,594 individuals who participated in the CFFPR matched SRTR records with approximately 75% having at least one transplant record in SRTR. Over 97% of the matched population had a CF diagnosis reported to SRTR. In total, 5,253 people were identified as lung transplant recipients and 499 as liver transplant recipients in SRTR. Clinical characteristics for lung and liver transplants were consistent with the epidemiology of transplantation for people with CF.</div></div><div><h3>Conclusions</h3><div>Linkage of the two data sources was successful, with high agreement between them supporting the use of the matched population as a valid resource to study transplantation in CF, particularly leveraging pre-transplant characteristics (collected in CFFPR) with detailed transplant data (collected in SRTR).</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 1","pages":"Pages 112-117"},"PeriodicalIF":5.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evidence for secondary ciliary dyskinesia in patients with cystic fibrosis 囊性纤维化患者继发性睫状肌运动障碍的证据。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.10.003

Romane Bonhiver , Noemie Bricmont , Maud Pirotte , Marc-Antoine Wuidart , Justine Monseur , Lionel Benchimol , Anne-Lise Poirrier , Catherine Moermans , Doriane Calmés , Florence Schleich , Renaud Louis , Marie-Christine Seghaye , Céline Kempeneers

Background

Mucociliary clearance (MCC) impairment can be due to mucus abnormalities or to a ciliary dysfunction, which can be innate, or secondary to infection and/or inflammation. In cystic fibrosis (CF), it is well documented that MCC is impaired due to mucus abnormalities, but little is known concerning ciliary beating. This study aimed to confirm that ciliary dyskinesia is present in CF, and if this might be innate or secondary to the chronic infection and/or inflammation.

Methods

Ciliated epithelial samples were obtained by nasal brushing from 51 CF patients, and from 30 healthy subjects. Ciliary beating was evaluated using digital high-speed videomicroscopy at 37 °C, allowing to evaluate ciliary beat frequency (CBF) and the percentage of abnormal beat pattern (CBP); this was repeated after air-liquid interface (ALI) cell culture.

Results

Ciliary dyskinesia was higher in CF patients than in healthy subjects, with a lower CBF and a higher percentage of abnormal CBP. Ciliary dyskinesia, already present in childhood, normalized after ALI cell culture. A chronic airway colonization did not worsen ciliary dyskinesia.

Conclusions

We showed that, in CF, a ciliary dyskinesia, present from childhood, might contribute to the impaired MCC. Our results also found that the abnormal ciliary beating was not associated with a chronic infection, and resolved after ALI cell culture, suggesting that ciliary dyskinesia in CF is not innate, and might be secondary to chronic inflammation.

背景：粘液纤毛清除（MCC）障碍可由粘液异常或纤毛功能障碍引起，纤毛功能障碍可能是先天性的，也可能是继发于感染和/或炎症。在囊性纤维化（CF）患者中，粘液异常是导致粘液纤毛清除障碍的主要原因，但有关纤毛跳动的情况却鲜为人知。本研究旨在证实纤毛运动障碍存在于囊性纤维化患者中，以及这可能是先天性的，还是继发于慢性感染和/或炎症：方法：通过刷鼻获得 51 名 CF 患者和 30 名健康受试者的纤毛上皮样本。在 37 °C下使用数字高速视频显微镜评估纤毛跳动，从而评估纤毛跳动频率（CBF）和异常跳动模式百分比（CBP）；在气液界面（ALI）细胞培养后重复这一过程：结果：与健康人相比，CF 患者的睫状肌运动障碍程度更高，CBF 更低，CBP 异常比例更高。睫状肌运动障碍在儿童时期就已存在，经过 ALI 细胞培养后趋于正常。慢性气道定植并不会加重睫状肌运动障碍：我们的研究结果表明，在 CF 患者中，睫状肌运动障碍从小就存在，可能是导致 MCC 受损的原因之一。我们的研究结果还发现，睫状肌异常跳动与慢性感染无关，在 ALI 细胞培养后即可缓解，这表明 CF 中的睫状肌运动障碍不是先天性的，可能是继发于慢性炎症。

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引用次数: 0

Aging with CF: Characteristics of people with CF aged 40 and older in the United States 老年 CF 患者：美国 40 岁及以上 CF 患者的特征。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.10.009

Joshua S. Ostrenga , Kristina Robinson , A. Whitney Brown , Christopher H. Goss , Elizabeth A. Cromwell

We conducted a descriptive analysis of people with CF 40 years of age and older using CF Foundation Patient Registry data from 2022 to provide a current estimate of the population size and characteristics. We summarized demographic details including biological sex, race, ethnicity, insurance and employment status. Clinical data including body mass index, lung function, respiratory infections, hospitalization rates, prevalence of CF-related complications and CF therapy prescriptions were collated. A total of 5,243 individuals aged 40 years or older contributed data to the CFFPR: 2,687 (51 %) people aged 40–49 years; 1,410 (27 %) people aged 50–59 years; and 1,146 (22 %) people aged 60 years or older. The ≥60 year old group have unique characteristics compared to younger individuals, with later diagnosis of CF and greater proportion of females (58 %). These results highlight heterogeneity in the older CF adult population and the need to develop and individualize CF care practices.

我们利用 2022 年 CF 基金会患者登记数据，对 40 岁及以上的 CF 患者进行了描述性分析，以提供对人口规模和特征的最新估计。我们总结了人口统计学细节，包括生理性别、种族、民族、保险和就业状况。我们还整理了临床数据，包括体重指数、肺功能、呼吸道感染、住院率、CF 相关并发症发病率和 CF 治疗处方。共有 5,243 名 40 岁或以上的人向 CFFPR 提供了数据：2,687 人（51%）年龄在 40-49 岁之间；1,410 人（27%）年龄在 50-59 岁之间；1,146 人（22%）年龄在 60 岁或以上。与年轻人相比，≥60 岁的人群有其独特的特点，即 CF 诊断较晚，女性比例更高（58%）。这些结果凸显了老年 CF 成年人群的异质性，以及发展和个性化 CF 护理实践的必要性。

引用次数: 0

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.11.014

Yimin Zhu , Mengliang Wu , Danni Li , Mark Habgood , Holly R Chinnery , Elena K. Schneider-Futschik

Background and Objective

Elexacaftor-tezacaftor-ivacaftor (ETI) is a drug treatment for cystic fibrosis that is debatable for use in pregnant women. Fetal ocular changes following prenatal exposure and while breastfeeding to ETI have been reported. The aim of this study was to assess eye development in rat fetuses following in-utero exposure to ETI.

Design and Methods

Eyes from Sprague Dawley rats born to dams given clinically relevant ETI or sham treatment from embryonic day 12–19 (E12-E19) were investigated using histology and optical coherence tomography (OCT).

Results

Lens thickness was higher in the ETI-exposure group, as measured by OCT (p = 0.0003). Lens cavities were observed in both groups, but the median individual lens cavities area was higher in the ETI-exposed eyes (p < 0.0001), as measured by histology.

Conclusion

In-utero exposure to ETI during E12-E19 was associated with subtle changes to lens anatomy, however the mechanism and clinical significance of this observation requires further investigation.

背景和目的：elexaftor - tezactor -ivacaftor （ETI）是一种治疗囊性纤维化的药物，在孕妇中使用尚存争议。胎儿在产前和母乳喂养时暴露于ETI后的眼部变化已有报道。本研究的目的是评估大鼠胎儿在子宫内暴露于ETI后的眼睛发育。设计和方法：采用组织学和光学相干断层扫描（OCT）技术，对胚胎12-19天（E12-E19）给予临床相关ETI或假治疗的母鼠所生的Sprague Dawley大鼠的眼睛进行观察。结果：通过OCT测量，eti暴露组的晶状体厚度更高（p = 0.0003）。两组均观察到晶状体空洞，但经组织学测量，暴露于eti的眼睛中位个体晶状体空洞面积更高（p < 0.0001）。结论：E12-E19期宫内接触ETI与晶状体解剖结构的细微变化有关，但这一观察的机制和临床意义有待进一步研究。

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引用次数: 0

Next generation triplex-forming PNAs for site-specific genome editing of the F508del CFTR mutation 用于 F508del CFTR 突变位点特异性基因组编辑的下一代三重形成 PNA。

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis

Pub Date : 2025-01-01 DOI: 10.1016/j.jcf.2024.07.009

Anisha Gupta , Christina Barone , Elias Quijano , Alexandra S. Piotrowski-Daspit , J. Dinithi Perera , Adele Riccardi , Haya Jamali , Audrey Turchick , Weixi Zao , W. Mark Saltzman , Peter M. Glazer , Marie E. Egan

Background

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein for which there is no cure. One approach to cure CF is to correct the underlying mutations in the CFTR gene. We have used triplex-forming peptide nucleic acids (PNAs) loaded into biodegradable nanoparticles (NPs) in combination with donor DNAs as reagents for correcting mutations associated with genetic diseases including CF. Previously, we demonstrated that PNAs induce recombination between a donor DNA and the CFTR gene, correcting the F508del CFTR mutation in human cystic fibrosis bronchial epithelial cells (CFBE cells) and in a CF murine model leading to improved CFTR function with low off-target effects, however the level of correction was still below the threshold for therapeutic cure.

Methods

Here, we report the use of next generation, chemically modified gamma PNAs (γPNAs) containing a diethylene glycol substitution at the gamma position for enhanced DNA binding. These modified γPNAs yield enhanced gene correction of F508del mutation in human bronchial epithelial cells (CFBE cells) and in primary nasal epithelial cells from CF mice (NECF cells).

Results

Treatment of CFBE cells and NECF cells grown at air-liquid interface (ALI) by NPs containing γtcPNAs and donor DNA resulted in increased CFTR function measured by short circuit current and improved gene editing (up to 32 %) on analysis of genomic DNA.

Conclusions

These findings provide the basis for further development of PNA and NP technology for editing of the CFTR gene.

背景：囊性纤维化（CF）是一种常染色体隐性遗传病，由囊性纤维化跨膜传导调节器（CFTR）蛋白的编码基因突变引起，目前尚无法治愈。治疗 CF 的一种方法是纠正 CFTR 基因的潜在突变。我们将装入生物可降解纳米颗粒（NPs）的三重肽核酸（PNAs）与供体 DNA 结合使用，作为纠正与 CF 等遗传疾病有关的基因突变的试剂。此前，我们证明了 PNAs 可诱导供体 DNA 与 CFTR 基因之间的重组，从而纠正人类囊性纤维化支气管上皮细胞（CFBE 细胞）和 CF 小鼠模型中的 F508del CFTR 突变，从而改善 CFTR 功能，且脱靶效应较低，但纠正水平仍低于治疗治愈的阈值。方法：在此，我们报告了新一代化学修饰γPNAs（γPNAs）的使用情况，其γ位含有二甘醇取代物，可增强 DNA 结合力。这些经过修饰的γPNAs能增强人类支气管上皮细胞（CFBE细胞）和CF小鼠原代鼻上皮细胞（NECF细胞）中F508del突变的基因校正：结果：用含有γtcPNAs和供体DNA的NPs处理在气液界面（ALI）生长的CFBE细胞和NECF细胞，通过短路电流测量，CFTR功能增强，基因组DNA分析显示基因编辑率提高（达32%）：这些发现为进一步开发用于编辑 CFTR 基因的 PNA 和 NP 技术奠定了基础。

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引用次数: 0