Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors

Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket‐1 (TP‐1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A‐ and B‐rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC₅₀ values between 17 and 63 μm . Of these, the newly synthesized 6,8‐diallyl‐5,7‐dihydroxycoumarin ( 8a ) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB‐ 34 . The binding site of 8a was mapped to TP‐1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP‐1 site binders. NS5B‐TP‐1‐ 8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.     

Methods of Retaining the Suture in a Sub-Cuticular Stitch Using Non Absorbable Suture – Innovations and Diversity of Techniques

Subcuticular sutures have been extensively used for closure of wounds, particularly when good cosmesis is required. Both absorbable and nonabsorbable sutures are used in subcuticular sutures. Nonabsorbable sutures have some distinct advantages over absorbable sutures from cosmetic point of view, when used in subcuticular sutures. The challenge remains in keeping the nonabsorbable suture secure and in situ. We present six different methods of securing the suture in position while closing the wound with a nonabsorbable suture (2-0/3-0 polypropylene, polyamide, or polyethylene).     

Can we increase the cervical cancer screening interval with an HPV test for women living with HIV? Results of a cohort study from Maharashtra,India

We are reporting (a) updated incidence of cervical intraepithelial neoplasia (CIN) among women who did not have colposcopic or histopathological disease at baseline and (b) disease outcomes among women treated for CIN and their follow-up HPV status; in a cohort of women living with HIV (WHIV). The median overall follow-up was 3.5 years (IQR 2.8-4.3). The incidence of any CIN and that of CIN 2 or worse disease was 16.7 and 7.0 per 1000 person-years of observation (PYO), respectively. Compared with women who were HPV negative at baseline, women who cleared HPV infection had 23.95 times increased risk of incident CIN 2 or worse lesions (95% CI 2.40-661.07). Women with persistent HPV infection had 138.18 times increased risk of CIN 2 or worse lesions (95% CI 20.30-3300.22). Complete disease regression was observed in 65.6% of the HPV positive women with high-grade CIN and were treated with thermal ablation but HPV persistence was seen in 44.8% of those with high-grade disease. Among those who did not have any disease at baseline and were also HPV negative, about 87% (95% CI 83.79-89.48) women remained HPV negative during consecutive HPV test/s with the median interval of 3.5 years. Long-term surveillance of WHIV treated for any CIN is necessary for the prevention of cervical cancer among them. Our study provides an early indication that the currently recommended screening interval of 3 to 5 years among WHIV may be extended to at least 5 years among HPV negative women. Increasing the screening interval can be cost saving and improve scalability among WHIV to support WHO's cervical cancer elimination initiative.     

Medicare's hospital readmissions reduction program and the rise in observation stays

Objective

To evaluate whether Medicare's Hospital Readmissions Reduction Program (HRRP) is associated with increased observation stay use.

Data Sources and Study Setting

A nationally representative sample of fee-for-service Medicare claims, January 2009–September 2016.

Study Design

Using a difference-in-difference (DID) design, we modeled changes in observation stays as a proportion of total hospitalizations, separately comparing the initial (acute myocardial infarction, pneumonia, heart failure) and subsequent (chronic obstructive pulmonary disease) target conditions with a control group of nontarget conditions. Each model used 3 time periods: baseline (15 months before program announcement), an intervening period between announcement and implementation, and a 2-year post-implementation period, with specific dates defined by HRRP policies.

Data Collection/Extraction Methods

We derived a 20% random sample of all hospitalizations for beneficiaries continuously enrolled for 12 months before hospitalization (N = 7,162,189).

Principal Findings

Observation stays increased similarly for the initial HRRP target and nontarget conditions in the intervening period (0.01% points per month [95% CI −0.01, 0.3]). Post-implementation, observation stays increased significantly more for target versus nontarget conditions, but the difference is quite small (0.02% points per month [95% CI 0.002, 0.04]). Results for the COPD analysis were statistically insignificant in both policy periods.

Conclusions

The increase in observation stays is likely due to other factors, including audit activity and clinical advances.     

Compound library development guided by protein structure similarity clustering and natural product structure

To identify biologically relevant and drug-like protein ligands for medicinal chemistry and chemical biology research the grouping of proteins according to evolutionary relationships and conservation of molecular recognition is an established method. We propose to employ structure similarity clustering of the ligand-sensing cores of protein domains (PSSC) in conjunction with natural product guided compound library development as a synergistic approach for the identification of biologically prevalidated ligands with high fidelity. This is supported by the concepts that (i) in nature spatial structure is more conserved than amino acid sequence, (ii) the number of fold types characteristic for all protein domains is limited, and (iii) the underlying frameworks of natural product classes with multiple biological activities provide evolutionarily selected starting points in structural space. On the basis of domain core similarity considerations and irrespective of sequence similarity, Cdc25A phosphatase, acetylcholinesterase, and 11beta-hydroxysteroid dehydrogenases type 1 and type 2 were grouped into a similarity cluster. A 147-member compound collection derived from the naturally occurring Cdc25A inhibitor dysidiolide yielded potent and selective inhibitors of the other members of the similarity cluster with a hit rate of 2-3%. Protein structure similarity clustering may provide an experimental opportunity to identify supersites in proteins.