Implementing Jet Aircraft Training in a University Setting: Instructor Perceptions and Lessons Learned

This paper presents the findings of a phenomenological study of instructor pilot first-hand experiences when conducting training for collegiate flight students in a jet aircraft. While jet training has been conducted in simulators in the past, this was one of the first instances of training in an actual aircraft. A total of 22 students completed training in a very light jet aircraft during the spring semester of their junior year at the subject university. A group of four instructors conducted both simulator and flight training with the students. Surveys were used to collect data from instructors longitudinally throughout the length of the 16-week semester. At the conclusion of the training period, participants completed a structured interview. The results of those interviews suggested that students excelled in areas such as avionics programming, use of standardized operating procedures, and checklist usage. Students were challenged by the increased operating speeds of the jet aircraft, descent planning, and lesson preparedness. The instructors offered suggestions to enhance the course and provided a summary of the lessons learned

Dose finding for new vaccines: The role for immunostimulation/immunodynamic modelling.

Current methods to optimize vaccine dose are purely empirically based, whereas in the drug development field, dosing determinations use far more advanced quantitative methodology to accelerate decision-making. Applying these established methods in the field of vaccine development may reduce the currently large clinical trial sample sizes, long time frames, high costs, and ultimately have a better potential to save lives. We propose the field of immunostimulation/immunodynamic (IS/ID) modelling, which aims to translate mathematical frameworks used for drug dosing towards optimizing vaccine dose decision-making. Analogous to Pharmacokinetic/Pharmacodynamic (PK/PD) modelling, the mathematical description of drug distribution (PK) and effect (PD) in host, IS/ID modelling approaches apply mathematical models to describe the underlying mechanisms by which the immune response is stimulated by vaccination (IS) and the resulting measured immune response dynamics (ID). To move IS/ID modelling forward, existing datasets and further data on vaccine allometry and dose-dependent dynamics need to be generated and collate, requiring a collaborative environment with input from academia, industry, regulators, governmental and non-governmental agencies to share modelling expertise, and connect modellers to vaccine data

Surgeon’s and Caregivers’ Appraisals of Primary Cleft Lip Treatment with and without Nasoalveolar Molding: A Prospective Multicenter Pilot Study

Despite the increasing use of nasoalveolar molding (NAM) in early cleft treatment, questions remain about its effectiveness. This study examines clinician and caregiver appraisals of primary cleft lip and nasal reconstruction with and without NAM in a non-randomized, prospective multicenter study

Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4 we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features

Speciation, Luminescence, and Alkaline Fluorescence Quenching of 4-(2-methylbutyl)aminodipicolinic acid (H2MEBADPA)

4-(2-Methylbutyl)aminodipicolinic acid (H2MEBADPA) has been synthesized and fully characterized in terms of aqueous phase protonation constants (pKa\u27s) and photophysical measurements. The pKa\u27s were determined by spectrophotometric titrations, utilizing a fully sealed titration system. Photophysical measurements consisted of room temperature fluorescence and frozen solution phosphorescence as well as quantum yield determinations at various pH, which showed that only fully deprotonated MEBADPA2– is appreciably emissive. The fluorescence of MEBADPA2– has been determined to be quenched by hydroxide and methoxide anions, most likely through base-catalyzed excited-state tautomerism or proton transfer. This quenching phenomenon has been quantitatively explored through steady-state and time-resolved fluorescence measurements. Utilizing the determined pKas and quenching constants, the fluorescent intensity of MEBADPA2– has been successfully modeled as a function of pH

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn’s disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations)

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC