A CFTR Potentiator in Patients with Cystic Fibrosis and the G551D Mutation

BACKGROUND: Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)). RESULTS: The change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire–revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was −48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%). CONCLUSIONS: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Author Correction: Drivers of seedling establishment success in dryland restoration efforts

1 Pág. Correción errata.In the version of this Article originally published, the surname of author Tina Parkhurst was incorrectly written as Schroeder. This has now been corrected.Peer reviewe

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Seasonal priority effects : implications for invasion and restoration in California coastal sage scrub

Exotic annual grasses are invading native plant communities in many areas including the western United States, and pose a significant challenge to habitat restoration. Observations in California grasslands suggest that exotic species may become active earlier in the growing season than native species, and that this distinct phenology may contribute to invasion success. We hypothesized that flexible germination cues may allow exotic annual grasses to start annual growth early each growing season and preempt resources prior to native seedling establishment, a kind of seasonal priority effect. Flexible germination cues could incur a cost, however, if they cause seeds to germinate before the onset of favorable growing conditions. To evaluate these predictions, we compared native and exotic species performance in a coastal sage scrub community under both early (off-season) and ambient (natural) rainfall timings. Exotic annual grasses germinated substantially with off- season watering, but none of the early seedlings survived until the onset of the natural rains. Exotic annual grasses that experienced off-season watering had a depleted seedbank and lower germination following the natural rains. In contrast, native species did not germinate following the off-season watering pulse, and instead emerged with the beginning of the cold natural rains. Our results suggest that phenology is an important factor influencing invasion success and invader impact. Under some conditions, pre-growing season watering could be an important restoration strategy for native plant communities in early stages of invasion by depleting the exotic seedbank and allowing for native species to establish with reduced competitio

Lung function and energy expenditure in infants with cystic fibrosis

Lung disease is thought to occur early in children with cystic fibrosis (CF) and it is recognised that nutritional status relates to prognosis, however the natural history of lung disease and how it might relate to nutritional measures and particularly energy expenditure require further evaluation. Methods to objectively evaluate lung disease are required so that interventions may be planned and assessed. Intervention studies in infancy will also require assessment in the toddler years through to school age when spirometry may be more reliable. Therefore methods of measuring lung function, particularly non-invasive methods, need to be developed. Seventeen infants with CF diagnosed through neonatal screening and 9 healthy control infants were enrolled in a prospective, cohort study and lung function and energy expenditure were measured from shortly after birth every three months until aged two years. Lung function was measured using the SensorMedics pulmonary function cart. Respiratory system resistance was higher and specific respiratory system conductance was lower in CF infants than control infants from three months of age until 18 months and there was a trend for this to continue to two years of age. There was no difference in FRCN2 between the groups. Resting energy expenditure expressed per gram of total body potassium (REE/TBK) was higher in CF infants than controls and was highest in infants who were homozygous for F508 mutation. There was no detectable relationship between measurements of lung function and REE/TBK. Young children with CF aged between 6 months and 5 years of age had lung function measured using the same technique to assess the suitability of the methods for toddlers. The method was not found to be suitable in children over the age of two years. Tidal breathing flow-volume curves (TBFV) are non invasive and the shape of the expiratory TBFV may change with obstructive airways disease. Thirty nine subjects took part in a study to examine the stability of a new index based on the shape of the expiratory flow- volume curve called Ai compared with the widely used index of shape tPTEF/tE with change in respiratory rate (RR). Eight tidal breathing flow volume loops were stored at resting RR and then RR was increased by 10 breaths per minute and 8 loops stored at each rate until a rate of 60 breaths per minute was reached. Subjects also performed spirometry and lung volumes were measured by whole body plethysmography. Neither of the indices varied much with RR, but Ai had less than one third of the variability seen in tPTEF/tE. The correlation between FEV1 and both indices was very similar

Seasonal priority effects : implications for invasion and restoration in California coastal sage scrub

Exotic annual grasses are invading native plant communities in many areas including the western United States, and pose a significant challenge to habitat restoration. Observations in California grasslands suggest that exotic species may become active earlier in the growing season than native species, and that this distinct phenology may contribute to invasion success. We hypothesized that flexible germination cues may allow exotic annual grasses to start annual growth early each growing season and preempt resources prior to native seedling establishment, a kind of seasonal priority effect. Flexible germination cues could incur a cost, however, if they cause seeds to germinate before the onset of favorable growing conditions. To evaluate these predictions, we compared native and exotic species performance in a coastal sage scrub community under both early (off-season) and ambient (natural) rainfall timings. Exotic annual grasses germinated substantially with off- season watering, but none of the early seedlings survived until the onset of the natural rains. Exotic annual grasses that experienced off-season watering had a depleted seedbank and lower germination following the natural rains. In contrast, native species did not germinate following the off-season watering pulse, and instead emerged with the beginning of the cold natural rains. Our results suggest that phenology is an important factor influencing invasion success and invader impact. Under some conditions, pre-growing season watering could be an important restoration strategy for native plant communities in early stages of invasion by depleting the exotic seedbank and allowing for native species to establish with reduced competitio