Direct pharmacologic and osmolal effects of contrast media on the mechanics of heart muscle isolated from cats

We studied 56 right ventricular papillary muscles isolated from cats to determine whether the direct mechanical effects of contrast media are due to their pharmacologic action or to the hyperosmolality caused by them. A 10% solution of Renografin-76 abruptly decreased force 22% below control, then slowly increased it to 22% above control. To elucidate these changes we also studied: (1) Renografin-60 (lower concentration of diatrizoate); (2) meglumine and diatrizoate; (3) meglumine alone; (4) diatrizoate sodium; (5) ethylene diamine tetra-acetic acid (EDTA) (same concentration as in Renografin-76); (6) sucrose to increase osmolality; and (7) Amipaque (metrizamide), a contrast medium without meglumine or diatrizoate. All solutions containing meglumine, and EDTA alone decreased force. Diatrizoate sodium also decreased force initially, presumably due to the high sodium concentration. Meglumine alone decreased force abruptly and substantially. In contrast, metrizamide and 100 mmol sucrose only increased force. Thus, the abrupt decrease in force was caused by the pharmacologic action of meglumine, EDTA, or high sodium in the contrast media, whereas the slow increase in force was caused by hyperosmolality.     

Cost effectiveness of enzyme immunoassay and immunoblot testing for the diagnosis of syphilis

The burden of disease and associated health-care costs of syphilis are significant despite widespread screening and treatment. Our objective was to conduct an economic evaluation using a simulation model when comparing enzyme immunoassay (EIA) initial testing and Inno-Lia (IL) confirmatory testing (EIA + IL) with rapid plasma reagin (RPR) initial testing and Treponema pallidum particle agglutination assay (TPPA) and fluorescent treponemal antibody absorption assay (FTA-ABS) confirmatory testing (RPR + TPPA/FTA). Estimates of prevalence, test costs and utilization of services for 2006 were derived from Alberta databases. Estimates of test characteristics were derived from the available literature. The incremental cost-effectiveness ratio was Canadian $461 per additional correct diagnosis (less costly and more effective). EIA + IL is cost-effective when compared with RPR + TPPA/FTA for screening and diagnosis of syphilis.     

H1.0 induces paclitaxel‐resistance genes expression in ovarian cancer cells by recruiting GCN5 and androgen receptor

More than 90% of ovarian cancer deaths are due to relapse following development of chemoresistance. Our main objective is to better understand the molecular mechanism underlying paclitaxel resistance (taxol resistance, Txr) in ovarian cancer. Here, we observed that the linker histone H1.0 is upregulated in paclitaxel‐resistant ovarian cancer cells. Knockdown of H1.0 significantly downregulates the androgen receptor (AR) and sensitizes paclitaxel‐resistant SKOV3/Txr and 2774/Txr cell lines to paclitaxel. Conversely, ectopic expression of H1.0 upregulates AR and increases Txr in parental SKOV3 and MDAH2774 cells. Notably, H1.0 upregulation is associated with disease recurrence and poor survival in a subset of ovarian cancer subjects. Inhibition of PI3K significantly reduces H1.0 mRNA and protein levels in paclitaxel‐resistant cells, suggesting the involvement of the PI3K/AKT signaling pathway. Knockdown of H1.0 and AR also downregulates the Txr genes ABCB1 and ABCG2 in paclitaxel‐resistant cells. Our data show that H1.0 induces GCN5 expression and histone acetylation, thereby enhancing Txr gene transactivation. These findings suggest that Txr in ovarian cancer involves the PI3K/AKT pathway and leads to upregulation of histone H1.0, recruitment of GCN5 and AR, followed by upregulation of a subgroup of Txr genes that include ABCB1 and ABCG2. This study is the first report describing the relationship between histone H1.0 and GCN5 that cooperate to induce AR‐dependent Txr in ovarian cancer cells.     

Bictegravir/emtricitabine/tenofovir alafenamide in older individuals with HIV: Results of a 96-week,phase 3b,open-label,switch trial in virologically suppressed people ≥65 years of age

Objectives

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is an effective treatment for HIV-1 infection; however, clinical trial data in older people living with HIV (PLWH) are lacking. The primary 24-week and secondary 48-week analyses of study GS-US-380-4449 (NCT03405935), which assessed the efficacy and safety of switching to B/F/TAF in older PLWH, have been published. Here we report the results of the final 96-week analyses from the study.

Methods

In this 96-week, phase 3b, open-label, single-arm trial, virologically suppressed PLWH aged ≥65 years switched from elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen to B/F/TAF. Viral suppression, resistance, immune response, safety, tolerability and adherence were evaluated through week 96.

Results

Of 90 participants screened, 86 were enrolled and switched to B/F/TAF. No participants had HIV-1 RNA ≥50 copies/ml (by FDA Snapshot algorithm) at weeks 72 or 96; virologic suppression rates were 94.2% (81/86; 95% CI 87.0–98.1) and 74.4% (64/86; 95% CI 63.9–83.2), respectively. No treatment-emergent resistance was observed, and CD4 counts remained stable. There were no study drug-related serious adverse events. Three participants experienced drug-related treatment-emergent adverse events that led to premature drug discontinuation. There were no clinically relevant changes from baseline to week 96 in fasting lipid parameters, and the median change in body weight at week 96 was 0.0 kg (IQR −2.3, 2.0). Median self-reported adherence was 100% (IQR 100–100%).

Conclusions

Switching to B/F/TAF is an effective long-term option for virologically suppressed adults ≥65 years of age, with favourable safety and tolerability profiles in this population.     

Bringing the Workforce Shortage into Focus

The Journal of Behavioral Health Services & Research -