The obesity paradox: association of obesity with improved survival in medically managed severe aortic stenosis

INTRODUCTIONThe obesity paradox, where obesity is associated with improved survival, has been described in patients undergoing haemodialysis and in those with heart failure. It was also demonstrated in patients undergoing valve replacement for aortic stenosis (AS). We explored this phenomenon in medically managed severe AS.METHODS154 patients with medically managed severe AS (aortic valve area index [AVAi] < 0.6 cm²/m²; mean pressure gradient > 40 mmHg and peak velocity > 400 cm/s) and preserved left ventricular ejection fraction (> 50%) were categorised into the obese (body mass index [BMI] Asian cut-off ≥ 27.5 kg/m²) and non-obese groups. Their clinical and echocardiographic profiles were compared.RESULTS24 (15.6%) patients were obese. Obese patients were similar to non-obese patients in age (68.5 ± 11.6 years vs. 68.9 ± 13.1 years) but had higher prevalence of cardiovascular risk factors. Left atrial diameter (43.7 ± 6.7 mm vs. 38.5 ± 10.2 mm) was larger in obese patients, while left ventricular outflow tract diameter (19.5 ± 1.7 mm vs. 20.4 ± 2.1 mm) was smaller. Despite lower AVAi in obese patients (0.36 ± 0.10 cm²/m² vs. 0.43 ± 0.11 cm²/m²), there was lower mortality (37.5% vs. 41.0%, log-rank 4.06, p = 0.045) on follow-up (8.0 ± 5.7 years). After adjusting for age and AVAi, higher BMI ≥ 27.5 kg/m² remained protective for mortality (hazard ratio 0.38, 95% confidence interval 0.15 to 0.98, p = 0.046).CONCLUSIONWe demonstrated that obesity was associated with improved survival in severe AS despite lower AVAi and increased prevalence of cardiovascular risk factors.     

Retrospective first-in-human use of the LithoVue™ Elite ureteroscope to measure intrarenal pressure

Objective

To report on our first-in-human experience using the LithoVue Elite™ ureteroscope (Boston Scientific Corp., Marlborough, MA, USA) to measure intrarenal pressure (IRP) during flexible ureteroscopy.

Patients and Methods

A single-arm retrospective observational analysis was performed in 50 consecutive patients undergoing ureteroscopic lithotripsy using the LithoVue Elite™ system with pressure sensing capability between April 2022 and February 2023 at two centres. A pressure bag set at 150 mmHg or hand irrigation with a 60-mL syringe was used for irrigation and a ureteric access sheath (UAS) was placed at the physician's discretion. Median and maximum IRPs, and relative cumulative time exceeding 20, 40, 60, 80, 100, 120, 140, 160, and 200 mmHg per total procedure time were analysed. The two-sample Mann–Whitney U-test was used, with statistical significance set at P < 0.05.

Results

The median (interquartile range [IQR]) patient age and body mass index (BMI) was 62.5 (46.7–68.2) years and 27.6 (23.3–32.1) kg/m², respectively. During the median (IQR) total procedure time of 31.9 (17.4–44.9) min, the median and maximum IRPs were 28.5 (20.0–47.5) and 174.0 (133.5–266.0) mmHg, respectively. IRP remained at <60 mmHg during 92% of the procedure times. Patients with Asian ethnicity, and those without pre-stenting or UAS use exhibited longer cumulative/total durations exceeding pre-defined IRP cut-off values. The smaller 10/12-F UAS did not lower pressures as much as the 11/13-F or 12/14-F UAS (P < 0.001). Age, diabetes, hypertension, preoperative α-blockade, stone size, and BMI did not show any statistically significant associations with IRP.

Conclusions

The IRP can now be routinely measured during ureteroscopy. Patients had a median IRP of 28.5 mmHg and a maximum of 174 mmHg. Using a smaller UAS (10/12 F), Asian ethnicity, and tight ureters were found to have higher IRPs.     

Design and biological characterization of a series of dual mechanism ERK1/2 inhibitors with a Triazolopyridinone core

Oncology clinical development programs have targeted the RAS/RAF/MEK/ERK signaling pathway with small molecule inhibitors for a variety of cancers during the past decades, and most therapies have shown limited or minimal success. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, most cancers have shown treatment resistance after several months of inhibitor usage, and reports indicate resistance is often associated with the reactivation of the MAPK signaling pathway. It is widely accepted that an effective MAPK therapy will have a significant impact on curtailing cancer growth and improving patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, an FDA-approved, effective anti-cancer ERK inhibitor has yet to be developed. Here, we present the design, optimization, and biological characterization of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate the phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. Our series of dual mechanism ERK1/2 inhibitors, in which we incorporated a triazolopyridinone core, may present potential benefits for enhancing efficacy and addressing the emergence of treatment resistance.