New Insights in Adherence and Survival in Myotonic Dystrophy Patients Using Home Mechanical Ventilation

BACKGROUND: Non-invasive home mechanical ventilation (HMV) is a complex treatment in myotonic dystrophy type 1 (DM1) patients, due to a presumed poor adherence, variable symptom improvement, and uncertainty regarding survival benefits. OBJECTIVES: We aimed to investigate indications, adherence to HMV and its effects on mortality in a large cohort of DM1 patients. METHODS: In this retrospective cohort study, we evaluated 224 DM1 patients. Different groups based on hypercapnia and HMV treatment were compared. Cox regression analyses were performed to compare mortality between different defined groups. RESULTS: 224 patients were analysed of whom 111 started non-invasive HMV. Indications were daytime hypercapnia (n = 75), only nocturnal hypercapnia (n = 33), or other reasons (n = 3). Adequate adherence (≥4 h/night) was found in 84.9% of patients. Adequate ventilation was reached in 86.5% of patients. In 33 patients (29.7%), HMV was stopped prematurely due to not reaching patients' expectations on symptom relief or treatment burden (n = 22), or intolerance (n = 8), or other reasons (n = 3). HMV did not improve survival in daytime hypercapnic patients (p = 0.61) nor in nocturnal hypercapnia patients compared to daytime hypercapnia (p = 0.21). Significant survival benefits after starting HMV were found for patients with HMV adherence ≥5 h/24 h compared to patients who used HMV less. CONCLUSION: In this large cohort, daytime hypercapnia is the main reason for starting HMV, which is well tolerated and used. Mortality is not associated with the reason why HMV was started, but once started, patients with ≥5 h/24 h adherence have significantly better survival compared to patients who use it less

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation

Contains fulltext : 229853.pdf (Publisher’s version ) (Closed access)BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed

Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia

Cystic fibrosis is caused by genetic defects that impair the CFTR channel in airway epithelial cells. These defects may be overcome by specific CFTR modulating drugs, for which the efficacy can be predicted in a personalized manner using 3D nasal-brushing-derived airway organoids in a forskolin-induced swelling assay. Despite of this, previously described CFTR function assays in 3D airway organoids were not fully optimal, because of inefficient organoid differentiation and limited scalability. In this report, we therefore describe an alternative method of culturing nasal-brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture. In addition, we have defined organoid culture conditions, with the growth factor/cytokine combination neuregulin-1<i>β</i> and interleukin-1<i>β</i>, which enabled consistent detection of CFTR modulator responses in nasal-airway organoid cultures from subjects with cystic fibrosis

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolininduced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-toexcellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner

European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre

A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries

ECFS best practice guidelines: the 2018 revision

Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field. In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe

The optimal approach to nutrition and cystic fibrosis : latest evidence and recommendations

PURPOSE OF REVIEW: Cystic fibrosis (CF) is a progressive genetic disease that affects multiple organ systems. Therapy is directed to maintain and optimize nutritional status and pulmonary function, as these are key factors in survival. In this review, the most recent findings regarding nutritional management associated with pulmonary function and outcome will be explored. RECENT FINDINGS: Evidence-based and expert-based guidelines emphasize the need for adequate nutritional intake to improve nutritional status. For infants and young children, the aim is to achieve the 50th percentile of weight and length for a healthy same-age population up to age 2 years. For older children and adolescents 2-18 years, the target is a BMI of at or above the 50th percentile for healthy children. For CF adults of at least 18 years, the target is a BMI of at or above 22 kg/m for women and at or above 23 kg/m for men. Recently, new drugs are developed with the aim to treat the malfunction of the cystic fibrosis transmembrane conductance regulator gene. This potentiator/corrector therapy improves lung function and nutritional status and decreases the number of infective exacerbations. As survival is improving and the CF population is aging, it is important to focus on micronutrient and macronutrient intake of CF patients in different age and disease stages. SUMMARY: Recent evidence-based nutritional guidelines and improved medical treatment support the nutritional monitoring and interventions in CF patients. Nutritional care should be personalized and provided by a specialized CF dietitian because patients' care needs may change dramatically during their disease progress

The optimal approach to nutrition and cystic fibrosis : latest evidence and recommendations

PURPOSE OF REVIEW: Cystic fibrosis (CF) is a progressive genetic disease that affects multiple organ systems. Therapy is directed to maintain and optimize nutritional status and pulmonary function, as these are key factors in survival. In this review, the most recent findings regarding nutritional management associated with pulmonary function and outcome will be explored. RECENT FINDINGS: Evidence-based and expert-based guidelines emphasize the need for adequate nutritional intake to improve nutritional status. For infants and young children, the aim is to achieve the 50th percentile of weight and length for a healthy same-age population up to age 2 years. For older children and adolescents 2-18 years, the target is a BMI of at or above the 50th percentile for healthy children. For CF adults of at least 18 years, the target is a BMI of at or above 22 kg/m for women and at or above 23 kg/m for men. Recently, new drugs are developed with the aim to treat the malfunction of the cystic fibrosis transmembrane conductance regulator gene. This potentiator/corrector therapy improves lung function and nutritional status and decreases the number of infective exacerbations. As survival is improving and the CF population is aging, it is important to focus on micronutrient and macronutrient intake of CF patients in different age and disease stages. SUMMARY: Recent evidence-based nutritional guidelines and improved medical treatment support the nutritional monitoring and interventions in CF patients. Nutritional care should be personalized and provided by a specialized CF dietitian because patients' care needs may change dramatically during their disease progress