Calculations of binding affinity between C8-substituted GTP analogs and the bacterial cell-division protein FtsZ

The FtsZ protein is a self-polymerizing GTPase that plays a central role in bacterial cell division. Several C8-substituted GTP analogs are known to inhibit the polymerization of FtsZ by competing for the same binding site as its endogenous activating ligand GTP. Free energy calculations of the relative binding affinities to FtsZ for a set of five C8-substituted GTP analogs were performed. The calculated values agree well with the available experimental data, and the main contribution to the free energy differences is determined to be the conformational restriction of the ligands. The dihedral angle distributions around the glycosidic bond of these compounds in water are known to vary considerably depending on the physicochemical properties of the substituent at C8. However, within the FtsZ protein, this substitution has a negligible influence on the dihedral angle distributions, which fall within the narrow range of −140° to −90° for all investigated compounds. The corresponding ensemble average of the coupling constants 3J(C4,H1′) is calculated to be 2.95 ± 0.1 Hz. The contribution of the conformational selection of the GTP analogs upon binding was quantified from the corresponding populations. The obtained restraining free energy values follow the same trend as the relative binding affinities to FtsZ, indicating their dominant contribution

Free energies of binding of R- and S-propranolol to wild-type and F483A mutant cytochrome P450 2D6 from molecular dynamics simulations

Detailed molecular dynamics (MD) simulations have been performed to reproduce and rationalize the experimental finding that the F483A mutant of CYP2D6 has lower affinity for R-propranolol than for S-propranolol. Wild-type (WT) CYP2D6 does not show this stereospecificity. Four different approaches to calculate the free energy differences have been investigated and were compared to the experimental binding data. From the differences between calculations based on forward and backward processes and the closure of thermodynamic cycles, it was clear that not all simulations converged sufficiently. The approach that calculates the free energies of exchanging R-propranolol with S-propranolol in the F483A mutant relative to the exchange free energy in WT CYP2D6 accurately reproduced the experimental binding data. Careful inspection of the end-points of the MD simulations involved in this approach, allowed for a molecular interpretation of the observed differences

Molecular dynamics simulations of the interactions of DMSO, mono- and polyhydroxylated cryosolvents with a hydrated phospholipid bilayer

AbstractMolecular dynamics (MD) simulations have been used to investigate the interactions of a variety of hydroxylated cryosolvents (glycerol, propylene glycol and ethylene glycol), methanol and dimethyl sulfoxide (DMSO) in aqueous solution with a 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) bilayer in its fluid phase at 323K. Each cryosolvent induced lateral expansion of the membrane leading to thinning of the bilayer and resulting in disordering of the lipid hydrocarbon chains. Propylene glycol and DMSO were observed to exhibit a greater disordering effect on the structure of the membrane than the other three alcohols. Closer examination exposed a number of effects on the lipid bilayer as a function of the molecular size and hydrogen bonding capacity of the cryosolvents. Analyses of hydrogen bonds revealed that increased concentrations of the polyhydroxylated cryosolvents induced the formation of a cross-linked cryosolvent layer across the surface of the membrane bilayer. This effect was most pronounced for glycerol at sufficiently high concentrations, which displayed a comparatively enhanced capacity to induce cross-linking of lipid headgroups resulting in the formation of extensive hydrogen bonding bridges and the promotion of a dense cryosolvent layer across the phospholipid bilayer

Robot-assisted Versus Open Radical Cystectomy in Bladder Cancer:An Economic Evaluation Alongside a Multicentre Comparative Effectiveness Study

Background: Open radical cystectomy (ORC) is regarded as the standard treatment for muscle-invasive bladder cancer, but robot-assisted radical cystectomy (RARC) is increasingly used in practice. A recent study showed that RARC resulted in slightly fewer minor but slightly more major complications, although the difference was not statistically significant. Some differences were found in secondary outcomes favouring either RARC or ORC. RARC use is expected to increase in coming years, which fuels the debate about whether RARC provides value for money.Objective: To assess the cost-effectiveness of RARC compared to ORC in bladder cancer. Design, setting, and participants: This economic evaluation was performed alongside a prospective multicentre comparative effectiveness study. We included 348 bladder cancer patients (ORC, n = 168; RARC, n = 180) from 19 Dutch hospitals. Outcome measurements and statistical analysis: Over 1 yr, we assessed the incremental cost per quality-adjusted life year (QALY) gained from both healthcare and societal perspectives. We used single imputation nested in the bootstrap percentile method to assess missing data and uncertainty, and inverse probability of treatment weighting to control for potential bias. Deterministic sensitivity analyses were performed to explore the impact of various parameters on the cost difference. Results and limitations: The mean healthcare cost per patient was €17 141 (95% confidence interval [CI] €15 791–€18 720) for ORC and €21 266 (95% CI €19 163–€23 650) for RARC. The mean societal cost per patient was €18 926 (95% CI €17 431–€22 642) for ORC and €24 896 (95% CI €21 925–€31 888) for RARC. On average, RARC patients gained 0.79 QALYs (95% CI 0.74–0.85) compared to 0.81 QALYs (95% CI 0.77–0.85) for ORC patients, resulting in a mean QALY difference of −0.02 (95% CI −0.05 to 0.02). Using a cost-effectiveness threshold of €80 000, RARC was cost-effective in 0.6% and 0.2% of the replications for the healthcare and societal perspectives, respectively. Conclusions: RARC shows no difference in terms of QALYs, but is more expensive than ORC. Hence, RARC does not seem to provide value for money in comparison to ORC. Patient summary: This study assessed the relation between costs and effects of robot-assisted surgery compared to open surgery for removal of the bladder in 348 Dutch patients with bladder cancer. We found that after 1 year, the two approaches were similarly effective according to a measure called quality-adjusted life years, but robot-assisted surgery was much more expensive. This trial was prospectively registered in the Netherlands Trial Register as NTR5362 (https://www.trialregister.nl/trial/5214).</p

Robot-assisted Radical Cystectomy Versus Open Radical Cystectomy in Bladder Cancer Patients: A Multicentre Comparative Effectiveness Study

Background: Radical cystectomy with pelvic lymph node dissection (PLND) and urinary diversion in patients with bladder cancer is known for its high risk of complications. Although open radical cystectomy (ORC) is regarded as the standard treatment, robot-assisted radical cystectomy (RARC) is increasingly used in practice, despite the fact that high-quality evidence comparing the effectiveness of both techniques is lacking. Objective: To study the effectiveness of RARC compared with that of ORC, in terms of 90 d complications (Clavien-Dindo), health-related quality of life (HRQOL), and clinical outcomes. Design, setting, and participants: A prospective comparative effectiveness study was conducted in 19 Dutch centres, expert in either ORC or RARC. Follow-up visits were scheduled at 30, 90, and 365 d. Intervention: Standard ORC or RARC with PLND, using a standardised perioperative protocol. Outcome measurements and statistical analysis: The primary outcome was any-grade complications after 90 d. Secondary outcomes included HRQOL, complications (minor, major, 30 d, and 365 d), and clinical outcomes. Differences were calculated as risk differences (RDs) between the groups with 95% confidence intervals (CIs), adjusted for potential baseline differences by means of propensity score–based inverse probability of treatment weighting. Results and limitations: Between March 2016 and November 2018, 348 patients were included (n = 168 for ORC, n = 180 for RARC). At 90 d, any-grade complication rates were 63% for ORC and 56% for RARC (RD –6.4%, 95% CI –17 to 4.5). Major complication rates were 15% for ORC and 16% for RARC (RD 0.9%, 95% CI –7.0 to 8.8). Total minor complication rates were 57% for ORC and 49% for RARC (RD –7.6%, 95% CI –19 to 3.6). Analyses showed no statistically significant differences in HRQOL between ORC and RARC. Some differences were found in the secondary outcomes in favour of either RARC or ORC. The major drawback inherent to the design comprises residual confounding. Conclusions: This multicentre comparative effectiveness study showed no statistically significant differences between ORC and RARC in terms of complications and HRQOL. Patient summary: This multicentre study did not show differences in overall complication rates, health-related quality of life, mortality, and clinical and oncological outcomes between open and robot-assisted radical cystectomy in bladder cancer patients

Robot-assisted Versus Open Radical Cystectomy in Bladder Cancer:An Economic Evaluation Alongside a Multicentre Comparative Effectiveness Study

Background: Open radical cystectomy (ORC) is regarded as the standard treatment for muscle-invasive bladder cancer, but robot-assisted radical cystectomy (RARC) is increasingly used in practice. A recent study showed that RARC resulted in slightly fewer minor but slightly more major complications, although the difference was not statistically significant. Some differences were found in secondary outcomes favouring either RARC or ORC. RARC use is expected to increase in coming years, which fuels the debate about whether RARC provides value for money.Objective: To assess the cost-effectiveness of RARC compared to ORC in bladder cancer. Design, setting, and participants: This economic evaluation was performed alongside a prospective multicentre comparative effectiveness study. We included 348 bladder cancer patients (ORC, n = 168; RARC, n = 180) from 19 Dutch hospitals. Outcome measurements and statistical analysis: Over 1 yr, we assessed the incremental cost per quality-adjusted life year (QALY) gained from both healthcare and societal perspectives. We used single imputation nested in the bootstrap percentile method to assess missing data and uncertainty, and inverse probability of treatment weighting to control for potential bias. Deterministic sensitivity analyses were performed to explore the impact of various parameters on the cost difference. Results and limitations: The mean healthcare cost per patient was €17 141 (95% confidence interval [CI] €15 791–€18 720) for ORC and €21 266 (95% CI €19 163–€23 650) for RARC. The mean societal cost per patient was €18 926 (95% CI €17 431–€22 642) for ORC and €24 896 (95% CI €21 925–€31 888) for RARC. On average, RARC patients gained 0.79 QALYs (95% CI 0.74–0.85) compared to 0.81 QALYs (95% CI 0.77–0.85) for ORC patients, resulting in a mean QALY difference of −0.02 (95% CI −0.05 to 0.02). Using a cost-effectiveness threshold of €80 000, RARC was cost-effective in 0.6% and 0.2% of the replications for the healthcare and societal perspectives, respectively. Conclusions: RARC shows no difference in terms of QALYs, but is more expensive than ORC. Hence, RARC does not seem to provide value for money in comparison to ORC. Patient summary: This study assessed the relation between costs and effects of robot-assisted surgery compared to open surgery for removal of the bladder in 348 Dutch patients with bladder cancer. We found that after 1 year, the two approaches were similarly effective according to a measure called quality-adjusted life years, but robot-assisted surgery was much more expensive. This trial was prospectively registered in the Netherlands Trial Register as NTR5362 (https://www.trialregister.nl/trial/5214).</p

Robot-assisted Versus Open Radical Cystectomy in Bladder Cancer: An Economic Evaluation Alongside a Multicentre Comparative Effectiveness Study

Background: Open radical cystectomy (ORC) is regarded as the standard treatment for muscle-invasive bladder cancer, but robot-assisted radical cystectomy (RARC) is increasingly used in practice. A recent study showed that RARC resulted in slightly fewer minor but slightly more major complications, although the difference was not statistically significant. Some differences were found in secondary outcomes favouring either RARC or ORC. RARC use is expected to increase in coming years, which fuels the debate about whether RARC provides value for money. Objective: To assess the cost-effectiveness of RARC compared to ORC in bladder cancer. Design, setting, and participants: This economic evaluation was performed alongside a prospective multicentre comparative effectiveness study. We included 348 bladder cancer patients (ORC, n = 168; RARC, n = 180) from 19 Dutch hospitals. Outcome measurements and statistical analysis: Over 1 yr, we assessed the incremental cost per quality-adjusted life year (QALY) gained from both healthcare and societal perspectives. We used single imputation nested in the bootstrap percentile method to assess missing data and uncertainty, and inverse probability of treatment weighting to control for potential bias. Deterministic sensitivity analyses were performed to explore the impact of various parameters on the cost difference. Results and limitations: The mean healthcare cost per patient was €17 141 (95% confidence interval [CI] €15 791–€18 720) for ORC and €21 266 (95% CI €19 163–€23 650) for RARC. The mean societal cost per patient was €18 926 (95% CI €17 431–€22 642) for ORC and €24 896 (95% CI €21 925–€31 888) for RARC. On average, RARC patients gained 0.79 QALYs (95% CI 0.74–0.85) compared to 0.81 QALYs (95% CI 0.77–0.85) for ORC patients, resulting in a mean QALY difference of −0.02 (95% CI −0.05 to 0.02). Using a cost-effectiveness threshold of €80 000, RARC was cost-effective in 0.6% and 0.2% of the replications for the healthcare and societal perspectives, respectively. Conclusions: RARC shows no difference in terms of QALYs, but is more expensive than ORC. Hence, RARC does not seem to provide value for money in comparison to ORC. Patient summary: This study assessed the relation between costs and effects of robot-assisted surgery compared to open surgery for removal of the bladder in 348 Dutch patients with bladder cancer. We found that after 1 year, the two approaches were similarly effective according to a measure called quality-adjusted life years, but robot-assisted surgery was much more expensive. This trial was prospectively registered in the Netherlands Trial Register as NTR5362 (https://www.trialregister.nl/trial/5214)