Search

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Genetic variants that introduce premature termination codons (PTCs) have remained difficult to therapeutically target due to lack of protein product. Nonsense mediated mRNA decay (NMD) targets PTC-bearing transcripts to reduce the potentially damaging effects of truncated proteins. Readthrough compounds have been tested on PTC-generating variants in attempt to permit translation through a premature stop. However, readthrough compounds have not proved efficacious in a clinical setting due to lack of stable mRNA. Here, we investigate N-terminal variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which have been shown to escape NMD, potentially through a mechanism of alternative translation initiation at downstream AUG codons. We hypothesized that N-terminal variants in CFTR that evade NMD will produce stable transcript, allowing CFTR function to be restored by a combination of readthrough and protein modulator therapy. We investigate this using two cell line models expressing CFTR-expression minigenes (EMG; HEK293s and CFBEs) and primary human nasal epithelial (NE) cells, and we test readthrough compounds G418 and ELX-02 in combination with CFTR protein modulators. HEK293 cells expressing the variants E60X and L88X generate CFTR-specific core glycosylated products that are consistent with downstream translation initiation. Mutation of downstream methionines at codons 150 and 152 does not result in changes in CFTR protein processing in cells expressing L88X-CFTR-EMG. However, mutation of methionine at 265 results in loss of detectable CFTR protein in cells expressing E60X, L88X, and Y122X CFTR-EMGs, indicating that downstream translation initiation is occurring at the AUG codon at position M265. In HEK293 stable cells harboring L88X, treatment with readthrough compounds alone allows for formation of full-length, but misfolded CFTR protein. Upon addition of protein modulators in combination with readthrough, we observe formation of mature, complex-glycosylated CFTR. In CFBE and NE cells, addition of readthrough ELX-02 and modulator therapy results in substantial recovery of CFTR function. Our work indicates that N-terminal variants generate stable CFTR transcript due to translation initiation at a downstream AUG codon. Thus, individuals with CF bearing 5′ nonsense variants that evade NMD are ideal candidates for treatment with clinically safe readthrough compounds and modulator therapy.

This study explored the French horn and its various properties that contribute to its unique timbre. With an emphasis on the role of the right hand, the variables studied were: type of material, manufacturer, right hand position with respect to the bell, the range of notes, and player. The project mainly included experiments at Loyola University Chicago and was supported using Northwestern University’s anechoic chamber. Horns are cylindrical-conical hybrids and are able to produce many harmonics, creating a rich sound. The right hand in the bell can be used for quick intonation adjustments and its placement has large effects on the timbre. Our analysis determined the variable that most contributed to the unique sound was the right hand position, while the type of horn (a combination of material and manufacturer) and the range of notes played also had moderate effects on timbre. We will present the theory surrounding the horn's shape and various components, experimental procedure and analysis of our results. The significance of the results to the horn player will be discussed.

This study explored the French horn and its various properties that contribute to its unique timbre. With an emphasis on the role of the right hand, the variables studied were: type of material, manufacturer, right hand position with respect to the bell, the range of notes, and player. The project mainly included experiments at Loyola University Chicago and was supported using Northwestern University's anechoic chamber. Horns are cylindrical-conical hybrids and are able to produce many harmonics, creating a rich sound. The right hand in the bell can be used for quick intonation adjustments and its placement has large effects on the timbre. Our analysis determined the variable that most contributed to the unique sound was the right hand position, while the type of horn (a combination of material and manufacturer) and the range of notes played also had moderate effects on timbre. We will present the theory surrounding the horn's shape and various components, experimental procedure, and analysis of our results. The significance of the results to the horn player will be discussed.

The impact of endoscopic sinus surgery (ESS) on pulmonary function in cystic fibrosis (CF) patients with chronic rhinosinusitis remains unclear, as studies have demonstrated conflicting results. To date, no study has looked specifically at the impact of CF genotype on lung function after ESS. In this study, we reviewed changes in pulmonary function test (PFT) results after ESS in F508del homozygotes and heterozygotes.The charts of 25 patients with CF without prior lung transplant, who underwent ESS performed by the same surgeon between the period of July 2005 to July 2015, were retrospectively reviewed. Data including genotype and PFT results were collected. Patients were grouped based on genotype. Pre- and postoperative PFTs were compared.Some differences in PFT outcomes after ESS could be seen on subgroup analyses. For example, when considered as a whole group, the overall cohort showed a significant improvement from preoperative FEVPrior studies investigating the impact of ESS on pulmonary function in CF patients have shown conflicting results. To our knowledge, those earlier udies did not separate and compare different genotypes, which may have introduced heterogeneity in their patient populations. Our study suggests that grouping CF patients more strictly according to genotype or disease severity when investigating outcomes may reveal differences among various subgroups.

The increase in the population level, followed by a subsequent expansion in national and international markets, has resulted in a rampant exploitation of public and common resources. Primarily, the paper addresses and analyses examples of the 'land grabbing' cases in Noida and West Bengal, 'Kaveri river water dispute' between Karnataka and Tamil Nadu and the 'Bhopal gas tragedy' in Madhya Pradesh. The paper also emphasises the regulation and governance of the legitimate right of citizens over their own commons resources, using the methodology and concepts of the classical contributions of Garret Hardin's important work, the "Tragedy of Commons". The paper will suggest alternative ideas which might help to reduce the tragedy of commons by introducing Elinor Ostrom's conflict resolving mechanisms. Furthermore, the paper would facilitate the design of strategies to promote and ensure more environmental justice and a more sustainable and reliable pattern of the development of the environment.

The paper begins with the present scenario of the world economy. The paper explains the concept of a new branch of economics, green economics, which focuses on both value-in-use and value-in-exchange and gives importance to the regeneration of individuals, communities and ecosystems. The paper reflects the practical application of green economics, which is broader than environmental economics and may be able to provide an answer to our future problems. In a world where value is expressed in terms of money, assigning a monetary value to externalities is a significant contribution. Hence, the paper emphasises the importance of sustainability funding. First, it explains the need for ecology pricing and its feasibility. Furthermore, the paper stresses the need to create a separate pool of funds for sustainability by imposing an ecology cess much like the Swachh Bharat Cess (Clean India Collection) introduced in India recently for certain services to clean up the environment. The paper concludes with empirical evidence, suggesting a separate legislation to raise necessary funds for the purpose of enriching biodiversity and maintaining ecological balance.