Influence of Dominance and Drift on Lethal Mutations in Human Populations.

Front Genet. 2020;11:267

Authors: Waxman D, Overall ADJ

Abstract
We consider disease-causing mutations that are lethal when homozygous. Lethality involves the very strongest form of negative selection, with the selection coefficient against the disease-carrying homozygote having its maximum value of unity. We determine results for the behavior of the frequency of a lethal allele in an effectively infinite population. This includes an estimate of the time it takes to achieve equilibrium, and a description of transient behavior associated with a sudden change in the fitness of the heterozygote. We determine analogous results for a finite population, showing that a lethal disease-causing allele needs to be described by a modified Wright-Fisher model, which deviates from the standard model, where selection coefficients are assumed small compared with 1. We show that a by-product of the dynamics, resulting from the absence of the disease-allele carrying homozygote in adults, is the general constraint that the frequency of the disease-causing allele cannot exceed 1 2 . The results presented in this work should prove useful to a number of areas including analysis of lethal/near lethal mutations in Mendelian disorders and, in particular, for exploring how mutation-selection-drift balance explains the current spectrum of mutation frequencies in humans. While the number of empirical examples of overdominance in lethal genetic disorders is not large, relatively high observed heterozygote frequencies may be a hint of transient heterozygous advantage in nature. For lethal disorders with anomalous frequencies, such as cystic fibrosis and Tay-Sachs, our analysis lends further support to the role that transitory episodes of weak overdominance may play in the evolution of lethal mutations.

PMID: 32300356 [PubMed]

Getting neural about airway gland secretion.

Eur Respir J. 2020 Apr;55(4):

Authors: Amatngalim GD, Ribeiro CMP

PMID: 32300022 [PubMed - in process]

Lung transplantation as standard of care for advanced cystic fibrosis lung disease.

J Heart Lung Transplant. 2020 Apr 08;:

Authors: Benden C

PMID: 32299651 [PubMed - as supplied by publisher]

Susceptibility of Staphylococcus aureus (MSSA & MRSA) to drying: Implications for nebuliser hygiene in patients with cystic fibrosis (CF).

J Hosp Infect. 2020 Apr 13;:

Authors: Moore JE, Cherie Millar B

PMID: 32298736 [PubMed - as supplied by publisher]

[Mycobacterium abscessus complex representatives in patients with bronchopulmonary pathology: prevalence, peculiarities of cultivation and identification.]

Klin Lab Diagn. 2020;65(5):316-320

Authors: Kalimulina KR, Ismatullin DD, Lyamin AV, Kondratenko OV, Kozlov AV, Zhestkov AV

Abstract
More and more publications appear in the modern literature on the increase in the prevalence of non-tuberculous mycobacteria (NTMs), in particular, representatives of M. chelonae / Mycobacterium abscessus complex (MABSc). The paper presents data on the current classification of M. chelonae / Mycobacterium abscessus complex and its main representatives. The main data on the possible sources and ways of infection of MABSc patients in hospital are presented. The main features of cultivation on various nutrient media and their possible identification using modern methods are also indicated. The main risk factors for the development of mycobacteriosis in patients and the possible clinical picture are described. The prevalence of MABSc representatives in the structure of non-tuberculous mycobacteria isolated from clinical material from 483 patients from the Samara region was assessed for examination for tuberculosis, and the prevalence from 933 patients with cystic fibrosis (CF) from 55 regions of the Russian Federation from 2016 to 2019 was estimated. In total, as a result of the study, 316 NTM strains (65.4%) were isolated and identified in the first group of patients. M.abscessus was isolated and identified 10 strains and 5 strains - M.chelonae, which amounted to 3.2% and 1.6%, respectively, of all NTMs. In general, MABSc representatives were isolated in 3.1% of the examined patients. As a result of a screening study of patients with CF, 14194 microorganism strains from 933 patients were isolated and identified. Altogether M. abscessus was isolated and confirmed from 14 patients of different ages. Thus, the prevalence of MABSc among the examined patients with CF in the Russian Federation was 1.5%.

PMID: 32298549 [PubMed - as supplied by publisher]

Thalidomide for de novo Crohn's disease after ileal pouch anal anastomosis for ulcerative colitis.

J Clin Pharm Ther. 2020 Apr 16;:

Authors: Dipasquale V, Tropeano A, Caime F, Romano C

Abstract
WHAT IS KNOWN AND THE OBJECTIVE: De novo Crohn's disease (CD) is an increasingly reported diagnosis after ileal pouch anal anastomosis (IPAA). Currently, no consensus exists on the best treatment strategy.
CASE SUMMARY: This report details the case of a 5-year-old child with early-onset ulcerative colitis (UC) who developed findings compatible with CD 12 months after IPAA. Thalidomide therapy led to clinical and endoscopic remission without side effects at 6 months.
WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first report of thalidomide for treatment of de novo CD. Thalidomide therapy could be considered in patients with de novo CD, with similar indications of CD.

PMID: 32298484 [PubMed - as supplied by publisher]

Lung compartment analysis assessed from N2 multiple-breath washout in children with cystic fibrosis.

Pediatr Pulmonol. 2020 Apr 16;:

Authors: Skov L, Green K, Stanojevic S, Jensen R, Buchvald F, Ratjen F, Nielsen KG

Abstract
BACKGROUND: Compartment analysis (CA) based on nitrogen multiple-breath washout (N2 MBW) has been shown to allow the assessment of specific volume and ventilation of faster- and slower-ventilating lung compartments of the lung in adults with cystic fibrosis (CF). The aim of this study was to extend previous findings into the pediatric age range.
METHODS: Cross-sectional multicenter observational study in children with CF and healthy controls (HC) was done with the assessment of N2 MBW and spirometry. A two-lung compartment model-based analysis (CA) was used to estimate size and function of faster- and slower-ventilating lung compartments from N2 MBW.
RESULTS: A total of 125 children with CF and 177 HC, median age 10.8 (range, 2.8-18.9) years, were included in the analysis. CA could be calculated in 66 (53%) children with CF compared with 48 (27%) HC (P < .0001). The proportion of the slower-ventilating lung compartment was significantly smaller in children with CF (53.5%; 95% confidence interval [CI]: 51.9%-55.7%) compared with HC (62.2%; 95% CI: 59.0%-65.0%) The regional specific ventilation of the slower compartment (rVT ,slow/rFRC,slow, %) was significantly lower in children with CF (4.9%; 95% CI: 4.5-5.9) compared with HC (9.7%, 95% CI: 9.2-10.9), and showed inverse correlation to lung clearance index (r2  = -.65; P < .0001), Sacin  × VT (r2  = -.36; P = .003) and Scond  × VT (r2  = -.51; P < .0001). There was no significant difference in pulmonary parameters between children with CF with and without feasible CA.
CONCLUSION: CA is less feasible in children than in adults and correlated to other MBW parameters. The clinical value of CA is still unclear and is yet to be established.

PMID: 32297698 [PubMed - as supplied by publisher]

Prenatal diagnosis of rare genetic conditions at a tertiary care hospital in Karachi.

J Pak Med Assoc. 2020 Apr;70(4):724-727

Authors: Karim K, Dileep D, Munim S

Abstract
This study aims to observe the spectrum of Prenatal Diagnosis of Rare Genetic conditions at a Tertiary care hospital in Karachi. This is a retrospective review conducted at the Aga Khan University Hospital, Karachi from January 2016 to July 2018. All cases undergoing invasive testing by Chorionic villus sampling for indications other than Thalassemia were included. Forty percent of patients in our cohort underwent invasive testing for muscular dystrophies particularly survival motor neuron (SMN) gene deletion and 32% for Cystic Fibrosis. Other rare disorders like JAM 3 mutation, PEX 1 gene, Barters Syndrome, Wardenberg, Bardet-Beidl Syndrome and Lissencephaly accounted for 28%. Sophistication in laboratory technology and DNA banking has improved the prenatal diagnosis of rare genetic disorders particularly SMN gene deletion. Integrated care involving foetal medicine specialist, Paediatric geneticist, and dedicated Laboratory personnel improves Counseling and Diagnosis of rare genetic conditions. Provision of dedicated nursing staff along with strengthening of welfare facility for non-affording patients would improve the uptake of invasive testing.

PMID: 32296222 [PubMed - in process]

Electronic health record phenotypes associated with genetically regulated expression of CFTR and application to cystic fibrosis.

Genet Med. 2020 Apr 16;:

Authors: Zhong X, Yin Z, Jia G, Zhou D, Wei Q, Faucon A, Evans P, Gamazon ER, Li B, Tao R, Rzhetsky A, Bastarache L, Cox NJ

Abstract
PURPOSE: The increasing use of electronic health records (EHRs) and biobanks offers unique opportunities to study Mendelian diseases. We described a novel approach to summarize clinical manifestations from patient EHRs into phenotypic evidence for cystic fibrosis (CF) with potential to alert unrecognized patients of the disease.
METHODS: We estimated genetically predicted expression (GReX) of cystic fibrosis transmembrane conductance regulator (CFTR) and tested for association with clinical diagnoses in the Vanderbilt University biobank (N = 9142 persons of European descent with 71 cases of CF). The top associated EHR phenotypes were assessed in combination as a phenotype risk score (PheRS) for discriminating CF case status in an additional 2.8 million patients from Vanderbilt University Medical Center (VUMC) and 125,305 adult patients including 25,314 CF cases from MarketScan, an independent external cohort.
RESULTS: GReX of CFTR was associated with EHR phenotypes consistent with CF. PheRS constructed using the EHR phenotypes and weights discovered by the genetic associations improved discriminative power for CF over the initially proposed PheRS in both VUMC and MarketScan.
CONCLUSION: Our study demonstrates the power of EHRs for clinical description of CF and the benefits of using a genetics-informed weighing scheme in construction of a phenotype risk score. This research may find broad applications for phenomic studies of Mendelian disease genes.

PMID: 32296164 [PubMed - as supplied by publisher]

Genomic analysis of an Irish population of Mycobacterium abscessus complex collected between 2006 and 2017.

J Clin Microbiol. 2020 Apr 15;:

Authors: Redondo N, Mok S, Montgomery L, Flanagan PR, McNamara E, Smyth EG, Sullivan NO, Schaffer K, Rogers TR, Fitzgibbon MM

Abstract
Mycobacterium abscessus complex (MABC) are multidrug resistant nontuberculous mycobacteria and cause opportunistic pulmonary infections in individuals with cystic fibrosis (CF). In this study, genomic analysis of MABC was performed to gain greater insights into the epidemiology of circulating strains in Ireland.Whole genome sequencing (WGS) was performed on 70 MABC isolates that had been referred to the Irish Mycobacteria Reference Laboratory between 2006 and 2017 across nine Irish healthcare centres. MABC comprised of 52 isolates from 27 CF patients and 18 isolates from 10 non-CF patients.WGS identified 57 (81.4%) as M. abscessus subsp. abscessus (MAB), 10 (14.3%) as M. abscessus subsp. massiliense (MMAS) and 3 (4.3%) as M. abscessus subsp. bolletii (MBOL). Forty-nine isolates (94%) from 25 CF patients were identified as MAB whereas 3 (6%) isolates from 2 CF patients were identified as MMAS. Among non-CF patients, 44% (8/18) were identified as MAB, 39% (7/18) as MMAS and 17% (3/18) as MBOL. WGS detected two clusters of closely related MAB that included isolates from different CF centres.There was greater genomic diversity of MABC among non-CF compared to CF patients. Although WGS failed to show direct evidence of patient to patient transmission among CF patients, there was a predominance of two different strains of MAB. Furthermore, some MABC were closely related to global strains suggesting their international spread. Future prospective real-time epidemiological and clinical data along with contemporary MABC sequence analysis may elucidate sources and routes of transmission among patients infected with MABC.

PMID: 32295892 [PubMed - as supplied by publisher]

Evaluating the Alimentary and Respiratory Tracts in Health and disease (EARTH) research programme: a protocol for prospective, longitudinal, controlled, observational studies in children with chronic disease at an Australian tertiary paediatric hospital.

BMJ Open. 2020 Apr 14;10(4):e033916

Authors: Coffey MJ, McKay IR, Doumit M, Chuang S, Adams S, Stelzer-Braid S, Waters SA, Kasparian NA, Thomas T, Jaffe A, Katz T, Ooi CY

Abstract
INTRODUCTION: Chronic gastrointestinal and respiratory conditions of childhood can have long-lasting physical, psychosocial and economic effects on children and their families. Alterations in diet and intestinal and respiratory microbiomes may have important implications for physical and psychosocial health. Diet influences the intestinal microbiome and should be considered when exploring disease-specific alterations. The concepts of gut-brain and gut-lung axes provide novel perspectives for examining chronic childhood disease(s). We established the 'Evaluating the Alimentary and Respiratory Tracts in Health and disease' (EARTH) research programme to provide a structured, holistic evaluation of children with chronic gastrointestinal and/or respiratory conditions.
METHODS AND ANALYSIS: The EARTH programme provides a framework for a series of prospective, longitudinal, controlled, observational studies (comprised of individual substudies), conducted at an Australian tertiary paediatric hospital (the methodology is applicable to other settings). Children with a chronic gastrointestinal and/or respiratory condition will be compared with age and gender matched healthy controls (HC) across a 12-month period. The following will be collected at baseline, 6 and 12 months: (i) stool, (ii) oropharyngeal swab/sputum, (iii) semi-quantitative food frequency questionnaire, (iv) details of disease symptomatology, (v) health-related quality of life and (vi) psychosocial factors. Data on the intestinal and respiratory microbiomes and diet will be compared between children with a condition and HC. Correlations between dietary intake (energy, macro-nutrients and micro-nutrients), intestinal and respiratory microbiomes within each group will be explored. Data on disease symptomatology, quality of life and psychosocial factors will be compared between condition and HC cohorts.Results will be hypothesis-generating and direct future focussed studies. There is future potential for direct translation into clinical care, as diet is a highly modifiable factor.
ETHICS AND DISSEMINATION: Ethics approval: Sydney Children's Hospitals Network Human Research Ethics Committee (HREC/18/SCHN/26). Results will be presented at international conferences and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER: NCT04071314.

PMID: 32295774 [PubMed - in process]

Burkholderia cepacia Complex Bacteria: a Feared Contamination Risk in Water-Based Pharmaceutical Products.

Clin Microbiol Rev. 2020 Jun 17;33(3):

Authors: Tavares M, Kozak M, Balola A, Sá-Correia I

Abstract
SUMMARYBurkholderia cepacia (formerly Pseudomonas cepacia) was once thought to be a single bacterial species but has expanded to the Burkholderia cepacia complex (Bcc), comprising 24 closely related opportunistic pathogenic species. These bacteria have a widespread environmental distribution, an extraordinary metabolic versatility, a complex genome with three chromosomes, and a high capacity for rapid mutation and adaptation. Additionally, they present an inherent resistance to antibiotics and antiseptics, as well as the abilities to survive under nutrient-limited conditions and to metabolize the organic matter present in oligotrophic aquatic environments, even using certain antimicrobials as carbon sources. These traits constitute the reason that Bcc bacteria are considered feared contaminants of aqueous pharmaceutical and personal care products and the frequent reason behind nonsterile product recalls. Contamination with Bcc has caused numerous nosocomial outbreaks in health care facilities, presenting a health threat, particularly for patients with cystic fibrosis and chronic granulomatous disease and for immunocompromised individuals. This review addresses the role of Bcc bacteria as a potential public health problem, the mechanisms behind their success as contaminants of pharmaceutical products, particularly in the presence of biocides, the difficulties encountered in their detection, and the preventive measures applied during manufacturing processes to control contamination with these objectionable microorganisms. A summary of Bcc-related outbreaks in different clinical settings, due to contamination of diverse types of pharmaceutical products, is provided.

PMID: 32295766 [PubMed - in process]

Spectrum of chronic lung allograft pathology in a mouse minor-mismatched orthotopic lung transplant model.

Am J Transplant. 2019 01;19(1):247-258

Authors: Martinu T, Oishi H, Juvet SC, Cypel M, Liu M, Berry GJ, Hwang DM, Keshavjee S

Abstract
Chronic lung allograft dysfunction (CLAD) is a fatal condition that limits survival after lung transplantation (LTx). The pathological hallmark of CLAD is obliterative bronchiolitis (OB). A subset of patients present with a more aggressive CLAD phenotype, called restrictive allograft syndrome (RAS), characterized by lung parenchymal fibrosis (PF). The mouse orthotopic single LTx model has proven relevant to the mechanistic study of allograft injury. The minor-alloantigen-mismatched strain combination using C57BL/10(B10) donors and C57BL/6(B6) recipients reportedly leads to OB. Recognizing that OB severity is a spectrum that may coexist with other pathologies, including PF, we aimed to characterize and quantify pathologic features of CLAD in this model. Left LTx was performed in the following combinations: B10→B6, B6→B10, B6→B6. Four weeks posttransplant, blinded pathologic semi-quantitative assessment showed that OB was present in 66% of B10→B6 and 30% of B6→B10 grafts. Most mice with OB also had PF with a pattern of pleuroparenchymal fibroelastosis, reminiscent of human RAS-related pathology. Grading of pathologic changes demonstrated variable severity of airway fibrosis, PF, acute rejection, vascular fibrosis, and epithelial changes, similar to those seen in human CLAD. These assessments can make the murine LTx model a more useful tool for further mechanistic studies of CLAD pathogenesis.

PMID: 30378739 [PubMed - indexed for MEDLINE]

Thinking inside the box: nebulizer care, safe storage, and risk of infection in cystic fibrosis.

J Bras Pneumol. 2020 Apr 09;46(2):e20190226

Authors: Alexander L, Carson J, McCaughan J, Moore JE, Millar BC

PMID: 32294716 [PubMed - as supplied by publisher]

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

J Antimicrob Chemother. 2020 Apr 15;:

Authors: Pearce C, Ruth MM, Pennings LJ, Wertheim HFL, Walz A, Hoefsloot W, Ruesen C, Muñoz Gutiérrez J, Gonzalez-Juarrero M, van Ingen J

Abstract
BACKGROUND: Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use.
OBJECTIVES: To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients.
METHODS: We infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5 mg doses, by inhalation, or untreated, for 28 days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time-kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients.
RESULTS: Inhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients.
CONCLUSIONS: Inhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.

PMID: 32294173 [PubMed - as supplied by publisher]

Cooperation or Tension? Dyadic Coping in Cystic Fibrosis.

Fam Process. 2020 Apr 15;:

Authors: Werner S, Hochman Y, Rosenne H, Kurtz S

Abstract
Following a rise in the life expectancy of cystic fibrosis (CF) patients, many adults with CF form couple relationships. Yet, dyadic coping has not been previously examined in people with CF. This study examined how adults with CF and their partners cope as a couple with the illness, and what meanings each partner and the couple as a unit attribute to the experience. Seventeen adult CF patients and their partners participated in separate semi-structured in-depth interviews. Two main patterns of dyadic coping with CF were identified as follows: cooperation and tension. For couples in cooperation, the marital relationship served as a resource for adaptive coping. These couples were characterized by similarities in their perception of the place of CF in their lives and of their roles in the marital relationship. Couples in tension described the couple relationship as strained by difficulty of accepting the disease, proliferation of negative emotions, and a sense of burden and loneliness in the process of coping. Findings point to the importance of mutual empathy, clear and accepted division of roles between the partners, and open communication for facilitating coping as a couple.

PMID: 32293718 [PubMed - as supplied by publisher]

The prevalence of viral infections in children with cystic fibrosis in a tertiary care center in Saudi Arabia.

Int J Pediatr Adolesc Med. 2019 Sep 12;:

Authors: Banjar H, Chaballout M, Karkour K, Al-Ghamdi H, Al-Mogarri I, Al-Haider S, Nizami I, Raja R, AlNakhli A

Abstract
Introduction: Studies have shown that pulmonary exacerbations in cystic fibrosis (CF) patients are associated with respiratory viruses. The most common agent causing viral infections in patients with CF before the age of 3 years is respiratory syncytial virus.
Objectives: To obtain the prevalence of the different types of viral infection in CF patients and to identify its relation with the type of bacterial infection, (CFTR) mutations and pulmonary function test (PFT).
Methodology: A retrospective charts review of 387 patients with CF of all age groups who were screened for the detection of viruses during respiratory exacerbation from the period of January 1, 1984 to June 1, 2016.
Results: A total of 159 CF patients had pulmonary exacerbation and had viral PCR obtained. Fifty-eight patients (36%) had positive viral PCR. Males were more commonly infected in 30/58 patients (52%) compared to females in 28 patients (48%). Forty-five of 58 patients (78%) were alive and 13 patients (22%) died. Rhinovirus was the most frequently reported viral PCR in 33/74 sample (45%). Out of 74 viral PCR, 41 (55.4%) were during the colder seasons (October-February) and 33 (44.5%) during the warmer seasons (March-September). During viral infection and viral recurrence, there was an increase in bacterial colonization specifically of H. influenza and staphylococcus aureus. The most common CFTR mutation for the CF viral infection is: 3120+1G>A in Intron 16 in 11/57 patients (19%). The Eastern Province had the highest viral infection of 24 out of 57 patients (42%). Follow-up PFT post viral infection showed no significant difference in the type and the severity of PFT compared to the initial PFT during the viral illness.
Conclusion: Viral infections contributed to the increase in morbidity and mortality of CF patients in our population, and rhinovirus was the most common causative agent. Viral infections and viral recurrence increased the prevalence of bacterial infection of specific pathogens such as H. influenza and S. aureus. Physicians should be aware to prevent progressive lung damage in CF patients by treating the concomitant viral and bacterial infections. Viral infection may be associated with some common CFTR mutations.

PMID: 32292813 [PubMed - as supplied by publisher]

Resting energy expenditure in cystic fibrosis patients decreases after lung transplantation, which improves applicability of prediction equations for energy requirement.

J Cyst Fibros. 2020 Apr 11;:

Authors: Hollander-Kraaijeveld FM, van Lanen AS, de Roos NM, van de Graaf EA, Heijerman HGM

PMID: 32291160 [PubMed - as supplied by publisher]

Real-world evidence in cystic fibrosis modulator development: Establishing a path forward.

J Cyst Fibros. 2020 Apr 11;:

Authors: Magaret A, Warden M, Simon N, Heltshe S, Mayer-Hamblett N

PMID: 32291159 [PubMed - as supplied by publisher]

The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis.

Expert Opin Drug Discov. 2020 Apr 15;:1-19

Authors: Guerra L, Favia M, Di Gioia S, Laselva O, Bisogno A, Casavola V, Colombo C, Conese M

Abstract
Introduction: Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, F508del, induces protein misprocessing and loss of CFTR function. The discovery through in vitro studies of the CFTR correctors (i.e. lumacaftor, tezacaftor) that partially rescue the misprocessing of F508del-CFTR with the potentiator ivacaftor is promising in giving an unprecedented clinical benefit in affected patients.Areas covered: Online databases were searched using key phrases for CF and CFTR modulators. Tezacaftor-ivacaftor treatment has proved to be safer than lumacaftor-ivacaftor, although clinical efficacy is similar. Further clinical efficacy has ensued with the introduction of triple therapy, i.e. applying second-generation correctors, such as VX-569 and VX-445 (elexacaftor) to tezacaftor-ivacaftor. The triple combinations will herald the availability of etiologic therapies for patients for whom no CFTR modulators are currently applied (i.e. F508del/minimal function mutations) and enhance CFTR modulator therapy for patients homozygous for F508del.Expert opinion: CF patient-derived tissue models are being explored to determine donor-specific response to current approved and future novel CFTR modulators for F508del and other rare mutations. The discovery and validation of biomarkers of CFTR modulation will complement these studies in the long term and in real-life world.

PMID: 32290721 [PubMed - as supplied by publisher]