Cost-effectiveness of carotid endarterectomy in symptomatic patients

Background: Medical therapy for stroke prevention has improved significantly over the past 30 years. Recent analyses of medically treated cohorts have suggested that early rates of stroke may have reduced, and reports of the safety of carotid surgery have also shown improvements. Since the effectiveness of carotid surgery versus medical therapy was established in the 1990s, there is an urgent need to evaluate whether surgery remains cost-effective in the UK.  Methods: A decision model was developed to estimate the lifetime costs and utilities of modern medical therapy with and without carotid endarterectomy in patients with symptomatic stenosis from the perspective of the UK National Health Service. The base-case population consisted of adults aged 70 years with 70–99 per cent stenosis. Model data were obtained from clinical studies and wider literature. Univariate and probabilistic sensitivity analyses were carried out.  Results: In the base-case scenario, the 5-year absolute risk reduction with carotid endarterectomy was 5 per cent, and the incremental cost-effectiveness ratio was €12 021 (exchange rate £1 GBP = €1.1125 (Tuesday 1 January 2019)) per quality-adjusted life-year. Surgery was more cost-effective if performed rapidly after presentation. In patients with 50–69 per cent carotid stenosis, surgery appeared less clinically effective. However, there was considerable uncertainty.  Conclusion: Surgery may not now be clinically effective and cost-effective in those with moderate carotid stenosis. However, these results are uncertain because of the limited data on modern medical therapy and an RCT may be justified.</p

Additional file 1 of Robust normalization protocols for multiplexed fluorescence bioimage analysis

Appendix. Figure A-1: Column 1 to 4 represent four different cases: first two columns are from histologically normal tissue and the last two are from cancerous tissue of the same patient. Rows 1 to 4 represent pseudo-color images obtained after applying low rank normalization protocols as marked by the experts. Figure A-2: Within class KL-divergence for Patient 2. Within class KL-divergence for second patient after performing phenotyping using different normalization protocols. Figure A-3: Between class KL-divergence for Patient 2. Between class KL-divergence for second patient after performing phenotyping using different normalization protocols. (PDF 341 kb

Intraperitoneal glucose tolerance test.

<p>Islet functional study was performed by taking IP glucose tolerance test (IPGTT). Mice were starved overnight before intraperitoneal injection of glucose at 1.5 mg/g of animal body weight. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043623#s2" target="_blank">Results</a> of IPGTT showed both stains did not recover 3 weeks after Myc deactivation, comparing to their wildtype litter mates (A). After 3 month recovery both strains were able to maintain normal blood glucose (B).</p

Loss of IGF-II impedes recovery of beta cell mass following beta cell ablation.

<p>For each individual, beta cell mass was calculated as cross sectional area of insulin immunoreactivity divided by total sectional area for at least 5 levels (n = 3). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043623#s2" target="_blank">Results</a> showed in MIG mice beta cell mass increased 2-fold at 4 days Myc deactivation (p = 0.0106), whereas in MIGKO mice the beta cell mass was largely unchanged. After 3 months recovery the beta cell mass increased 6-fold in MIG mice and in MIGKO mice the increase was 5-fold.</p

IGF-II re-expression in MIG mice after brief Myc activation.

<p>Total pancreas RNA was extracted from pIns-c-MycER^TAM/IGF-II^+/+ (MIG) and pIns-c-MycER^TAM/IGF-II^+/− (MIGKO) mice at 24 hr and 48 hr following Myc activation to induce beta cell ablation (n = 3). RT-PCR data (A) shows the amplified products in MIG mice after 24 hr (1) and 48 hr (3) of Myc activation in the target size of 357 bp. No amplified product was found in MIGKO mice at 24 hr (2) and 48 hr (4) of Myc activation by comparing to the positive control (WT mouse E17.5 placenta RNA) (0). Quantitative RT-PCR was performed and validated the RT-PCR results. IGF-II mRNA was expressed 5-fold higher in MIG mice after brief Myc activation but not in MIGKO mice nor in negative controls (B).</p

Glucagon positive cell cluster in MIG mice after 3 months Myc deactivation.

<p>In MIG mice after 3 months of recovery, clusters of glucagon positive cells separate from islets were observed. This might be new islets forming or possible clusters of alpha cells which might then further differentiate into beta cells. Such clusters were not seen in MIGKO mice or control mice pre-ablation.</p

Blood glucose homeostasis.

<p>Myc activation was induced for 11 days in mice following which Myc was deactivated for up to 3 months. Blood glucose levels (Mean ± SEM) were measured in MIG mice n = 3 and MIGKO mice n = 3 during this period (A). Both strains developed hyperglyceamia after Myc activation and MIGKO mice showed a delay of recovery from hyperglycemia at day 4 following Myc deactivation. After 3 months both strains were able to return to normal blood glucose level.</p

Loss of IGF-II affects recovery of beta cell numbers following beta cell ablation.

<p>Beta cell number was counted in up to 200 islets from five pancreas levels per mouse (n = 3) by software co-developed with our collaborators <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043623#pone.0043623-Herold1" target="_blank">[30]</a>. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0043623#s2" target="_blank">Results</a> showed in MIG mice beta cell number increased by 60% at 4 days Myc deactivation, whereas in MIGKO mice the beta cell mass was barely changed. Consistently with our previous observation in beta cell mass after 3 months recovery, both MIG and MIGKO mice achieved 3- to 4-fold increase of beta cell numbers.</p

Discovery of Novel Insulin-Like Growth Factor‑1 Receptor Inhibitors with Unique Time-Dependent Binding Kinetics

This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure–activity and structure–kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound <b>2</b>. With an IGF-1R dissociative half-life (<i>t</i>_1/2) of >100 h, compound <b>2</b> demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties