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• Children who initiated LUM/IVA treatment between 2 and 5 years of age in real-world settings had: ○ Increases in BMI, height, and weight percentiles relative to modulator-naïve comparators. ○ Reductions in pulmonary exacerbations and hospitalizations relative to baseline. • Data suggest early initiation of LUM/IVA could have a beneficial impact on CF disease progression. Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR). The LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F /MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort). The LUM/IVA cohort matched to the F /MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F /MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F /MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021. This interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation. [ABSTRACT FROM AUTHOR]

Context: Changes to surgical training programmes in the UK has led to a reduction in theatre time for trainees, and an increasing reliance on simulation to provide procedural experience. Whilst simulation offers opportunity for repetitive practice, the effectiveness of simulation as an educational intervention for developing procedural surgical skills is unclear.Methods: A systematic literature review was undertaken to retrieve all studies describing simulation-based medical education (SBME) interventions for the development of procedural surgical skills using the MEDLINE, PsycINFO, CINAHL, EMBASE and PUBMED databases. Studies measuring skill retention or demonstrating transferability of skills for improving patient outcomes were included in the review.Results: SBME is superior to no training and can lead to improvement in procedural surgical skills, such that skills transfer from simulated environments into theatre. SBME results in minimal skill degradation after 2 weeks, although more significant decay results after >90 days. Many studies recruited <10 participants, used a variety of methods and were restricted to endoscopic surgical techniques. All studies did not compare interventions with non-SBME teaching methods for developing procedural surgical skills. No studies compared the curriculum design of different surgical training programmes.Conclusions: SBME interventions are effective for developing procedural skills in surgery. SBME interventions are also effective for preventing the decay of procedural surgical skills. Although no studies demonstrate non-inferiority of SBME interventions compared to time in theatre developing skills, SBME interventions do enable the transfer of skills into theatre, and the potential for improving patient outcomes. [ABSTRACT FROM AUTHOR]

Landsat and Shuttle Radar Topography Mission (SRTM) imagery have recently been used to identify broad-scale floristic units in Neotropical rain forests, corresponding to geological formations and their edaphic properties. Little is known about the structural and functional variation between these floristic units, however, and Landsat and SRTM data lack the spectral and spatial resolution needed to provide this information. Imaging spectroscopy and LiDAR (Light Detection and Ranging) have been used to measure canopy structure and function in a variety of ecosystems, but the ability of these technologies to measure differences between compositionally-distinct but otherwise uniform tropical forest types remains unknown. We combined 16 tree inventories from central Panama with imaging spectroscopy and LiDAR elevation data from the Carnegie Airborne Observatory to test our ability to identify patterns in plant species composition, and to measure the spectral and structural differences between adjacent closed-canopy tropical forest types. We found that variations in spectroscopic imagery and LiDAR data were strong predictors of spatial turnover in plant species composition. We also found that these compositional, chemical, and structural patterns corresponded to underlying geological formations and their geomorphological properties. We conclude that imaging spectroscopy and LiDAR data can be used to interpret patterns identified in lower resolution sensors, to provide new information on forest function and structure, and to identify underlying determinants of these patterns. [ABSTRACT FROM AUTHOR]

Summary: Background: Indacaterol is a novel, inhaled once-daily ultra-long-acting beta-2 agonist under development as a fixed-dose combination with an inhaled corticosteroid (ICS) for asthma treatment. This study evaluated the 24-h bronchodilator efficacy of indacaterol in Japanese patients with asthma. Methods: Randomised, placebo-controlled, 5-period crossover study. Patients with persistent asthma (18–75 years, FEV1 50–85% predicted, ≥12% and 200 mL FEV1 reversibility) receiving ICS were randomised to double-blind single dose indacaterol 150, 300, or 600 μg or placebo, with open-label salmeterol 50 μg twice-daily for one day in the 5th period. Primary endpoint was FEV1AUC22–24h. Results: Of 41 randomised patients (48.8% male; mean age: 47.8 years), 39 completed. All indacaterol doses showed significantly higher FEV1AUC22–24h than placebo (P <0.001), with treatment–placebo differences of 180, 220, and 260mL for indacaterol 150, 300, and 600 μg, respectively (salmeterol–placebo difference 170mL; P < 0.001). For individual time-point FEV1, all indacaterol doses were superior to placebo from 5min to 24h post-dose (P < 0.001). Compared with salmeterol, all indacaterol doses were superior from 5 to 30min (P < 0.05); in addition indacaterol 300 μg and 600 μg were superior at a number of subsequent time points. Changes in safety parameters with indacaterol were similar to placebo. All indacaterol doses were well tolerated. Conclusion: Single dose indacaterol provided sustained 24-h bronchodilation with a faster onset of action than salmeterol and a good overall safety and tolerability profile in Japanese patients with asthma. These results are consistent with data from Caucasian populations. [ABSTRACT FROM AUTHOR]

Summary: This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled β 2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV1⩾40% of predicted and ⩾1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400μg or placebo via multi-dose dry powder inhaler, or indacaterol 400μg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18μg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC22–24h) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC22–24h were seen for 400 and 200μg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200μg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled β 2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile. [Copyright &y& Elsevier]

Summary: The safety and tolerability of indacaterol, a novel once-daily β 2-agonist bronchodilator with a fast onset of action, were assessed in 156 asthma patients in a multicentre, randomized, double-blind, placebo-controlled study. Patients received indacaterol 200, 400 or 600μg or placebo once daily for 28 days. Adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, spirometry and physical examinations were monitored. Indacaterol pharmacokinetics were assessed. There was no evidence of dose-related increases in AE incidence or clinically significant hypokalaemia or hyperglycaemia in indacaterol-treated patients. Mean pulse rate changes were minor in any group, with maximum 1-h post-dose changes from baseline of −3.7, −3.3 and −2.2bpm for indacaterol 200, 400 and 600μg, respectively, and −2.9bpm for placebo. Mean QTc interval was similar between groups; change from baseline >60ms occurred in only two patients. Mean FEV1 increased after the first indacaterol dose; baseline-adjusted pre-dose (trough) values remained ⩾166mL higher than placebo at all subsequent visits, supporting a 24-h bronchodilator effect. Pre-dose (but not post-dose) serum indacaterol concentrations indicated a slight trend for accumulation. Once-daily indacaterol 200–600μg has a favourable therapeutic index. It is well tolerated, and is not associated with any adverse cardiac or metabolic effects, while providing effective 24-h bronchodilation. [Copyright &y& Elsevier]

There are many possible scenarios for the future of electric utility consolidation, but experiences in banking and telecommunications deregulation and consolidation suggest one as the most likely: larger players will continue to consolidate, smaller players will be acquired or focus on niche markets, and new, non-utility investors will enter utility markets, with varying degrees of success. [Copyright &y& Elsevier]

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity. [Display omitted] • The hepatic vagal nerve affects glucose clearance and insulin sensitivity • Hepatocyte membrane potential regulates serum insulin and insulin sensitivity • GABA transport into and out of the hepatocyte relies on electrogenic transporters • Hepatic vagal nerve activity is inhibited by GABA A receptor stimulation Geisler et al. show that obesity depolarizes hepatocytes, favoring transport-mediated GABA release. Hyperpolarizing hepatocytes limits transporter-mediated GABA release. GABA released by the liver decreases vagal afferent nerve activity, causing an increase in serum insulin and insulin resistance. Thus, electrogenic GABA transporters can be modulated to affect glucose homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: Background: A light-porous-particle, dry-powder formulation of tobramycin was developed, using PulmoSphere® technology, to improve airway delivery efficiency, substantially reduce delivery time, and improve patient convenience and satisfaction. We evaluated the safety, efficacy and convenience of tobramycin inhalation powder (TIP™) versus tobramycin inhalation solution (TIS, TOBI®) for treating Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients aged ≥6years. Methods: In this open-label study, 553 patients were randomized 3:2 to TIP (total 112mg tobramycin) via the Novartis T-326 Inhaler or TIS 300mg/5mL via PARI LC® PLUS nebulizer twice daily for three treatment cycles (28days on-drug, 28days off-drug). Safety, efficacy, and treatment satisfaction outcomes were evaluated. Results: TIP was generally well-tolerated; adverse events were similar in both groups. The rate of cough suspected to be study drug related was higher in TIP-treated patients (TIP: 25.3%; TIS: 4.3%), as was the overall discontinuation rate (TIP: 26.9%; TIS: 18.2%). Increases in FEV1% predicted from baseline to Day 28 of Cycle 3 were similar between groups; the mean reduction in sputum P. aeruginosa density (log10 CFU/g) on Day 28 of Cycle 3 was also comparable between groups. Administration time was significantly less for TIP (mean: 5.6 versus 19.7min, p <0.0001). Treatment satisfaction was significantly higher for TIP for effectiveness, convenience, and global satisfaction. Conclusions: TIP has a safety and efficacy profile comparable with TIS, and offers a far more convenient treatment option for pseudomonas lung infection in CF. [ABSTRACT FROM AUTHOR]

Olfactory systems serve as excellent model systems for the study of numerous widespread aspects of neural development and also for the elucidation of features peculiar to the formation of neural circuits specialized to process odor inputs. Accumulated research reveals a fine balance between developmental autonomy of olfactory structures and intercellular interactions essential for their normal development. Recent findings have uncovered evidence for more autonomy than previously realized, but simultaneously have begun to reveal the complex cellular and molecular underpinnings of key interactions among neurons and glial cells at several important steps in olfactory development. Striking similarities in the functional organization of olfactory systems across vertebrate and invertebrate species allow the advantages of different species to be used to address common issues. Our own work in the moth Manduca sexta has demonstrated reciprocal neuron-glia interactions that have key importance in two aspects of development, the sorting of olfactory receptor axons into fascicles targeted for specific glomeruli and the creation of glomeruli. Studies in vertebrate species suggest that similar neuron-glia interactions may underlie olfactory development, although here the roles have not been tested so directly. Similar cellular interactions also are likely to play roles in development of some other systems in which axons of intermixed neurons must sort according to target specificity and systems in which reiterated modules of synaptic neuropil develop. [Copyright &y& Elsevier]