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In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of −7·1 (SD 7·0) mV (p<0·0001), and in the second, with a change of −3·7 (SD 7·3) mV (p=0·032). We recorded a response in total chloride transport (defined as a change in nasal PD of −5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0·0001) and in eight of the 21 patients in the second cycle (p<0·0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0·0003) and for nine of 21 in the second cycle (p=0·02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. PTC Therapeutics, Cystic Fibrosis Foundation Therapeutics.

One‐third of monogenic inherited diseases result from premature termination codons (PTCs). Readthrough of in‐frame PTCs enables synthesis of full‐length functional proteins. However, extended variability in the response to readthrough treatment is found among patients, which correlates with the level of nonsense transcripts. Here, we aimed to reveal cellular pathways affecting this inter‐patient variability. We show that activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts carrying PTCs. Quantitative proteomic analyses showed substantial differences in UPR activation between patients carrying PTCs, correlating with their response. We further found a significant inverse correlation between the UPR and nonsense‐mediated mRNA decay (NMD), suggesting a feedback loop between these homeostatic pathways. We uncovered and characterized the mechanism underlying this NMD‐UPR feedback loop, which augments both UPR activation and NMD attenuation. Importantly, this feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Altogether, our study demonstrates the importance of the UPR and its regulatory network for genetic diseases caused by PTCs and for cell homeostasis under normal conditions. Synopsis Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described. Proteome analyses show substantial differences in unfolded protein response (UPR) activation between patients carrying PTCs, correlated with their response to readthrough treatment. UPR activation enables CFTR and XLF function following readthrough treatment. Proteome analyses uncover inverse correlation between UPR and nonsense‐mediated mRNA decay (NMD), suggesting a feedback‐loop mechanism between these homeostatic pathways. The NMD‐UPR feedback loop augments both UPR activation and NMD attenuation. The NMD‐UPR feedback loop enhances the response to readthrough treatment, highlighting its clinical importance. Graphical Abstract Activation of the unfolded protein response (UPR) governs the response to readthrough treatment by regulating the levels of transcripts with PTCs. Furthermore, a novel nonsense‐mediated mRNA decay (NMD)‐UPR feedback loop is described.

Exceeding $2 trillion annually, health care spending in the United States is growing significantly faster than the national economy. If left unchecked, this health spending crisis will threaten Americans' ability to pay for other essential services. Driven primarily by the cost of benefits promised to seniors under Medicare and Medicaid, federal health expenditures will force lawmakers to make stark policy decisions. In this third volume of Restoring Fiscal Sanity, policy experts suggest ways to slow the growth of federal spending on health care. Unless federal health spending can be brought under control, Americans will face substantially higher taxes, sharp reductions in other government programs, and cuts in benefits to the elderly. Families, businesses, and communities will be forced to make agonizing choices between health care and other needs. Focusing on policies that do not shift costs to the states or the private sector, the authors of Restoring Fiscal Sanity 2007 suggest reforms in federal programs that have the potential to reduce the growth of spending for the entire health system, increase the efficiency and effectiveness of the care provided, and enhance health outcomes. Drawing on years of government and public policy experience, they stress the need for innovative approaches and cooperation between the private and public sectors.

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.

A small fraction of patients with cystic fibrosis have a genetic defect that introduces a premature stop codon into the CFTR gene; this results in a truncated protein that does not fulfill its normal biologic function. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that lead to dysfunction of the CFTR protein, which is an apical membrane protein regulating the transport of chloride and sodium in secretory epithelial cells. 1 Since the discovery of the CFTR gene, more than 1000 mutations have been identified, including missense, deletion or insertion, frame shift, splice site, and nonsense mutations. 2 Nonsense or stop mutations contain signals that cause a truncated or unstable protein, should result in a deficiency or absence of CFTR chloride channels, and are associated with a severe cystic fibrosis . . .

Haptoglobin (Hp), a heme-Iron chelator, has different isoforms which are associated with variable tendency toward infections: Hp 1-1, Hp 2-1, and Hp 2-2. Cystic fibrosis (CF) outcomes are variable and influenced by genetic and environmental factors. The aim of this study was to determine whether Hp phenotype influenced disease severity in CF. One hundred forty-two CF patients from two centers were analyzed for Haptoglobin phenotype using gel electrophoresis of hemoglobin enriched serum. Clinical and microbiological data including bacterial colonization status, lung function, presence of CF-related diabetes and liver disease, rate of exacerbation, and mortality were compared between Hp phenotype groups. We found a trend toward less mucoid PA among Hp 2-2 (20.4 %) compared with Hp 1-1 and Hp 2-1 individuals (33.3 %), p  = 0.317. Hp 2-2 individuals also had less antibiotic courses, and lower inflammatory markers without statistical significance. Haptoglobin phenotype is unlikely to be an important modifier of CF phenotype.

Background Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan‐population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. Methods An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next‐generation sequencing of the poly‐T/TG tracts. Results We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2‐causing mutations in the Israeli panel. Conclusions Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, a nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility. Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research. Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback. Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire. Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.

A fundamental question in learning to classify 3D shapes is how to treat the data in a way that would allow us to construct efficient and accurate geometric processing and analysis procedures. Here, we restrict ourselves to networks that operate on point clouds. There were several attempts to treat point clouds as non-structured data sets by which a neural network is trained to extract discriminative properties. The idea of using 3D coordinates as class identifiers motivated us to extend this line of thought to that of shape classification by comparing attributes that could easily account for the shape moments. Here, we propose to add polynomial functions of the coordinates allowing the network to account for higher order moments of a given shape. Experiments on two benchmarks show that the suggested network is able to provide state of the art results and at the same token learn more efficiently in terms of memory and computational complexity.