Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

Assessment of chest rise during mask ventilation of preterm infants in the delivery room.

BACKGROUND: Current neonatal resuscitation guidelines recommend using visual assessment of chest wall movements to guide the choice of inflating pressure during positive pressure ventilation (PPV) in the delivery room. The accuracy of this assessment has not been tested. We compared the assessment of chest rise made by observers standing at the infants' head and at the infants' side with measurements of tidal volume. METHODS: Airway pressures and expiratory tidal volume (V(Te)) were measured during neonatal resuscitation using a respiratory function monitor. After 60s of PPV, resuscitators standing at the infants' head (head view) and at the side of the infant (side view) were asked to assess chest rise and estimate V(Te). These estimates were compared with V(Te) measurements taken during the previous 30s. RESULT: We studied 20 infants who received a mean (SD) of 23 (4) inflations during the 30s. Some observer felt unable to assess chest rise both from the head view (6/20) and from the side view (3/20). Observers from both head and side tended to underestimate tidal volume by 3.5mL and 3.3mL respectively. Agreement between clinical assessment and measured V(Te) was generally poor. CONCLUSION: During mask ventilation, resuscitators were unable to accurately assess chest wall movement visually from either head or side view.

Assessment of flow waves and colorimetric CO2 detector for endotracheal tube placement during neonatal resuscitation.

AIM: Clinical assessment and end-tidal CO(2) (ETCO(2)) detectors are routinely used to verify endotracheal tube (ETT) placement. However, ETCO(2) detectors may mislead clinicians by failing to identify correct placement under a variety of conditions. A flow sensor measures gas flow in and out of an ETT. We reviewed video recordings of neonatal resuscitations to compare a colorimetric CO(2) detector (Pedi-Cap®) with flow sensor recordings for assessing ETT placement. METHODS: We reviewed recordings of infants <32 weeks gestation born between February 2007 and January 2010. Airway pressures and gas flow were recorded with a respiratory function monitor. Video recording were used (i) to identify infants who were intubated in the delivery room and (ii) to observe colour change of the ETCO(2) detector. Flow sensor recordings were used to confirm whether the tube was in the trachea or not. RESULTS: Of the 210 infants recorded, 44 infants were intubated in the delivery room. Data from 77 intubation attempts were analysed. In 35 intubations of 20 infants both a PediCap® and flow sensor were available for analysis. In 21 (60%) intubations, both methods correctly identified successful ETT placement and in 3 (9%) both indicated the ETT was not in the trachea. In the remaining 11 (31%) intubations the PediCap® failed to change colour despite the flow wave indicating correct ETT placement. CONCLUSION: Colorimetric CO(2) detectors may mislead clinicians intubating very preterm infants in the delivery room. They may fail to change colour in spite of correct tube placement in up to one third of the cases.