Profile of plecanatide in the treatment of chronic idiopathic constipation: design, development, and place in therapy

Amol Sharma, Anam Asif Herekar, Jigar Bhagatwala, Satish SC Rao  Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA  Abstract: Constipation is a multifactorial disorder that can cause significant psychological distress to patients and economic burden on the health care system. Many patients are not satisfied with their current established treatment, highlighting the need for new and improved therapeutic options. Guanylate cyclase-C (GC-C)/cyclic guanosine monophosphate agonists have emerged as a safe and efficacious class of drugs for the treatment of chronic idiopathic constipation (CIC). Plecanatide, a second-in-class, US FDA-approved, synthetic GC-C agonist, has recently been approved in the US for the treatment of irritable bowel syndrome with constipation at doses of 3 and 6 mg and CIC at the 3 mg dosage. In this study, we summarize the design of this novel 16-amino acid uroguanylin analog, drug development through Phase I, II, and III clinical studies, and its role in the treatment of CIC.  Keywords: plecanatide, uroguanylin, constipatio

Correction: Race/Ethnicity-Specific Association of Vitamin D and Global DNA Methylation: Cross-Sectional and Interventional Findings.

[This corrects the article DOI: 10.1371/journal.pone.0152849.]

Optimal Compressed Sensing and Reconstruction of Unstructured Mesh Datasets

Abstract Exascale computing promises quantities of data too large to efficiently store and transfer across networks in order to be able to analyze and visualize the results. We investigate compressed sensing (CS) as an in situ method to reduce the size of the data as it is being generated during a large-scale simulation. CS works by sampling the data on the computational cluster within an alternative function space such as wavelet bases and then reconstructing back to the original space on visualization platforms. While much work has gone into exploring CS on structured datasets, such as image data, we investigate its usefulness for point clouds such as unstructured mesh datasets often found in finite element simulations. We sample using a technique that exhibits low coherence with tree wavelets found to be suitable for point clouds. We reconstruct using the stagewise orthogonal matching pursuit algorithm that we improved to facilitate automated use in batch jobs. We analyze the achievable compression ratios and the quality and accuracy of reconstructed results at each compression ratio. In the considered case studies, we are able to achieve compression ratios up to two orders of magnitude with reasonable reconstruction accuracy and minimal visual deterioration in the data. Our results suggest that, compared to other compression techniques, CS is attractive in cases where the compression overhead has to be minimized and where the reconstruction cost is not a significant concern

Race/Ethnicity-Specific Association of Vitamin D and Global DNA Methylation: Cross-Sectional and Interventional Findings

<div><p>Objectives</p><p>Understanding of the influence of vitamin D deficiency on epigenome will provide novel insights into the chronic disease risk. We tested our hypotheses that 1) vitamin D deficiency is associated with global hypomethylation and this association may be race/ethnicity dependent; and 2) vitamin D supplementation will increase global DNA methylation level.</p><p>Methods</p><p>A two-stage design, cross-sectional observation followed by a 16 week randomized, double- blinded, placebo-controlled trial (RCT) of vitamin D3 supplementation, was undertaken. Global DNA methylation level (percentage of 5-methylcytosine, %5-mC) was quantified using leukocyte DNA with the MethylFlash^TM Methylated DNA Quantification kit (Epigentek). Global methylation data was obtained from 454 Caucasians and African Americans (42%) in the observation cohort and 58 African Americans with vitamin D deficiency in the dose responsive RCT.</p><p>Results</p><p>In the cross-sectional study, African Americans had lower %5-mC than Caucasians (<i>P</i> = 0.04). A significant interaction was detected between plasma 25(OH)D and race on %5-mC (<i>P</i> = 0.05), as a positive association was observed between plasma 25(OH)D and %5-mC in African Americans (β = 0.20, <i>p</i><0.01), but not in Caucasians (β = 0.03, <i>p</i> = 0.62). In the 16-week RCT, a dose-response benefit of vitamin D₃ supplementation was observed for %5-mC, as indicated by a significant linear upward trend (-0.01 ± 0.01%, placebo; 0.11 ± 0.01%, ~600 IU/day; 0.30 ± 0.01%, ~2,000 IU/day; and 0.65 ± 0.01%, ~4,000 IU/day group; <i>P</i>-trend = 0.04).</p><p>Conclusions</p><p>Vitamin D deficiency is associated with global hypomethylation in African Americans. Vitamin D3 supplementation increases global DNA methylation in a dose-response manner in African Americans with vitamin D deficiency.</p></div

General characteristics of LACHY study participants.

<p>General characteristics of LACHY study participants.</p

Changes in global methylation in response to 16 week vitamin D3 supplementation (placebo, 600 IU/d, 2,000 IU/d, or 4,000 IU/d).

<p>Data represent mean ± SE. <i>p</i> trend <0.01.</p