A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis.

In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. PURPOSE/INTRODUCTION: In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. METHODS: We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. RESULTS: Patients experienced a ~ 5-22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. CONCLUSIONS: A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

Osteoclast Recycling and the Rebound Phenomenon Following Denosumab Discontinuation.

PURPOSE OF REVIEW: Inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) with denosumab is an effective treatment in a number of conditions including osteoporosis where suppression of bone resorption is desired. However, denosumab discontinuation is associated with rebound increase in bone resorption and subsequent loss in bone mass and a rapid return to baseline fracture risk. We review recent data on the rebound increase in bone resorption following denosumab discontinuation and the potential mechanisms behind this phenomenon. RECENT FINDINGS: Osteoclasts have been considered to be highly specialised cells that undergo apoptosis after fulfilling their function of bone resorption. However, recent studies suggest that osteoclasts are longer lived cells which migrate through vasculature and are capable of undergoing fission into a novel cell type (the osteomorph) and re-fusion in a process termed osteoclast recycling. The life cycle of the osteoclast is more complex than previously appreciated. Osteoclast recycling provides a novel mechanistic framework to examine changes in osteoclast biology in response to treatment of bone diseases and provides an exciting new avenue towards personalised medicine.

Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.

A novel design for biodiesel production from methanol + mutton bone fat mixture.

Bioenergy plays a significant role in the green transition. In this work, the conversion of methanol and mutton bone fat oil (as a low-cost feedstock) for bioenergy production was studied. The five-level, three-factor response surface methodology (RSM) was used to optimize the transesterification reaction conditions for produced biodiesel. Twenty ultrasonic-assisted experiments at the frequency of 25 kHz were conducted to investigate the effects of methanol/oil molar ratio (M/O) and concentrations of KOH and NaOH as catalysts on biodiesel yield. A second-order polynomial equation was developed by fitting the RSM experimental data using Design-Expert software. Results showed that the optimum biodiesel yield of 90.087% could be achieved by the KOH catalyst with 2.5 wt% concentration and 15:1 M/O during 3 h of the reaction. Furthermore, the biofuel analyses showed that methanol and mutton bone fat oil can be used as a proper feedstock for biofuel production. In the following, a membrane filtration package system is proposed and modeled. The reaction kinetics was determined based on experimental data. The results of the mathematical modeling showed the reaction time appears to be 6 times shorter in a membrane setup (30 min). Consequently, membrane application is highly recommended for biodiesel production from mutton bone fat oil.

Complete analytic solutions for convection-diffusion-reaction-source equations without using an inverse Laplace transform.

Transient mass-transfer phenomena occurring in natural and engineered systems consist of convection, diffusion, and reaction processes. The coupled phenomena can be described by using the unsteady convection-diffusion-reaction (CDR) equation, which is classified in mathematics as a linear, parabolic partial-differential equation. The availability of analytic solutions is limited to simple cases, e.g., unsteady diffusion and steady convective diffusion. The CDR equation has been considered analytically intractable, depending on the initial and boundary conditions. If spatial adsorption and desorption of matter are super-positioned in the CDR equation as sink and source functions, respectively, then the governing equation becomes an unsteady convection-diffusion-reaction-source (CDRS) equation, of which general solutions are unknown. In this study, a general 1D analytic solution of the CDRS equation is obtained by using a one-sided Laplace transform, by assuming constant diffusivity, velocity, and reactivity. This paper also provides a general formalism to derive 1D analytic solutions for Dirichlet/Dirichlet and Dirichlet/Neumann boundary conditions. Derivations of the analytic solutions are found to be straightforward if a combination of the source function and the initial concentration provide a non-zero singularity pole of inverse Laplace transform.

Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation.

SUMMARY: A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered. LEARNING POINTS: Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

Monte Carlo simulation of colloidal membrane filtration: principal issues for modeling.

The principal issues involved in developing a Monte Carlo simulation model of colloidal membrane filtration are investigated in this study. An important object for modeling is the physical dynamics responsible for causing particle deposition and accumulation when encountering an open system with continuous outflow. A periodic boundary condition offers a solution to the problem by recirculating continuous flow back through the system. Scaling to full physical dimensions will allow for release of the model from flawed assumptions such as constant cake layer volume fraction and thickness throughout the system. Furthermore, rigorous modeling on a precise scale extends the model to account for random particle collisions with acute accuracy. A major finding of this study proves that forces within the colloidal filtration system are summed and transferred cumulatively through the inter-particle interactions. The force summation and transfer phenomenon only realizes its true value when the model is scaled to full dimensions. The overall strategy for model development, therefore, entails three stages: first, rigorous modeling on a microscopic scale; next, comprehensive inclusion of relevant physical dynamics; and finally, scaling to full physical dimensions.

EPS biofouling in membrane filtration: an analytic modeling study.

Biofouling is theoretically investigated by modeling solute transport within a biofilm, defined in this study as a swarm of solid biocolloids surrounded by liquid-like exopolymeric substances (EPS). A mathematical approach is employed to map the biofilm to an equivalent, simple spherical cell using a self-consistent method. It is found that the physical presence of EPS and their reaction with solute ions reduce the mass transfer coefficient, which significantly contributes to permeate flux decline in reverse osmosis and nanofiltration membrane processes.

Hydrodynamics of an ideal aggregate with quadratically increasing permeability.

In this study, we consider the ideal aggregate with quadratically increasing permeability kappa = k2r2 and derive the analytical expression of the stream function within the porous aggregate by incorporating the Brinkman and continuity equations. The hydrodynamic properties of the aggregate are investigated by taking account of the hydrodynamic radius, settling velocity, and fluid collection efficiency, which are found to be solely dependent on the permeability prefactor k2. The fractal dimension Df and prefactor k2 of the ideal aggregate are found to be 5/3 (=1.67) and 0.20, respectively, and well describe the hydrodynamics of aggregates formed in the diffusion-limited-cluster-aggregation (DLCA) regime. More important, hydrodynamic similarity between the ideal aggregate and impermeable solid sphere is discovered in terms of variations of the hydrodynamic radius, settling velocity, and fluid collection efficiency with respect to the aggregate radius.

Brownian Dynamics, Molecular Dynamics, and Monte Carlo modeling of colloidal systems.

This paper serves as an introductory review of Brownian Dynamics (BD), Molecular Dynamics (MD), and Monte Carlo (MC) modeling techniques. These three simulation methods have proven to be exceptional investigative solutions for probing discrete molecular, ionic, and colloidal motions at their basic microscopic levels. The review offers a general study of the classical theories and algorithms that are foundational to Brownian Dynamics, Molecular Dynamics, and Monte Carlo simulations. Important topics of interest include fundamental theories that govern Brownian motion, the Langevin equation, the Verlet algorithm, and the Metropolis method. Brownian Dynamics demonstrates advantages over Molecular Dynamics as pertaining to the issue of time-scale separation. Monte Carlo methods exhibit strengths in terms of ease of implementation. Hybrid techniques that combine these methods and draw from these efficacies are also presented. With their rigorous microscopic approach, Brownian Dynamics, Molecular Dynamics, and Monte Carlo methods prove to be especially viable modeling methods for problems with challenging complexities such as high-level particle concentration and multiple particle interactions. These methods hold promising potential for effective modeling of transport in colloidal systems.

Aggregate formation and collision efficiency in differential settling.

A new method of application of Stokesian dynamics, which can efficiently simulate movements of up to 500 particles with interparticle interactions in reasonable computational times, has been developed for the purpose of investigating particle-cluster aggregation in aqueous systems. The method is applied to monodisperse non-Brownian spherical particles aggregating in differential settling, while repulsive colloidal interaction is presumed to be negligible, so that a minimum separation distance can represent the attractive van der Waals force. The final aggregates formed by this algorithm, composed of 300 primary particles, have a common fractal dimension of approximately 2.0. The computed collision efficiency, defined as the product of a global and a capture efficiency, is about 5.77x10(-3). This value is significantly larger than the collision efficiency of primary particles colliding with an impermeable solid sphere of the same size as the aggregate, illustrating the important interplay between the permeability and the formation of aggregates.

The permeability of synthetic fractal aggregates with realistic three-dimensional structure.

The permeability of fractal porous aggregates with realistic three-dimensional structure is investigated theoretically using model aggregates composed of identical spherical primary particles. Synthetic aggregates are generated by several techniques, including a lattice-based method, simulation of aggregation by differential settling and turbulent shear, and the specification of simple cubic structures, resulting in aggregates characterized by the number of primary particles, solid fraction, characteristic radius, and fractal dimension. Stokesian dynamics is used to determine the total hydrodynamic force on and the distribution of velocity within an aggregate exposed to a uniform flow. The aggregate permeability is calculated by comparing these values with the total force and velocity distribution calculated from the Brinkman equation applied locally and to the entire aggregate using permeability expressions from the literature. The relationship between the aggregate permeability and solid fraction is found to be best predicted by permeability expressions based on cylindrical rather than spherical geometrical elements, the latter tending to underestimate the aggregate permeability significantly. The permeability expressions of Jackson and James or Davies provide good estimates of the force on and flow through porous aggregates of known structure. These relationships are used to identify a number of general characteristics of fractal aggregates.

Simulation of colloidal fouling by coupling a dynamically updating velocity profile and electric field interactions with Force Bias Monte Carlo methods for membrane filtration.

Pressure-driven flow through a channel with membrane walls is modeled for high particulate volume fractions of 10%. Particle transport is influenced by Brownian diffusion, shear-induced diffusion, and convection due to the axial crossflow. The particles are also subject to electrostatic double layer repulsion and van der Waals attraction, from both particle-particle and particle-membrane interactions. Force Bias Monte Carlo (FBMC) simulations predict the deposition of the particles onto the membranes, where both hydrodynamics and the change in particle potentials determine the probability that a proposed move is accepted. The particle volume fraction is used to determine an apparent local viscosity observed by the continuum flow. As particles migrate, the crossflow velocity field evolves in quasi-steady fashion with each time instance appearing fully developed in the downstream direction. Particles subject to combined hydrodynamic and electric effects (electrostatic double layer repulsion and van der Waals attraction) reach a more stable steady-state as compared to systems with only hydrodynamic effects considered. As expected, at higher crossflow Reynolds numbers more particles remain in the crossflow free stream.

Fundamental mechanisms of three-component combined fouling with experimental verification.

The present article describes a novel fundamental theory for investigating combined fouling by colloids (STXL), macromolecules, and solute ions (NaCl). Three macromolecules were used for the combined fouling study, bovine serum albumin (BSA), alginate, and dextran. The presented theory unifies singlet, doublet, and triplet fouling phenomena, including cake-enhanced osmotic pressure and binary colloidal fouling models, giving rise to the combined flux equation for three-component fouling assuming a completely mixed fouling layer. The predicted combined flux was compared to two equivalent fluxes calculated from individual foulant contributions. The strong form of the equivalent flux, known as the additive flux, was based on a linear superposition of flux decline due to individual foulants. The weak form of equivalent flux assumed stratification of individual foulant layers and hence a linear superposition of the individual fouling resistance. A comparison of experimental data and theoretical calculations revealed that the weak form of equivalent flux and the combined flux that was predicted by the novel theory provided the upper and lower limits, respectively, of the observed permeate flux. Furthermore, the model simulation results suggested a structural compression of the BSA gel layer, whereas such a compression did not occur in cases of alginate and dextran. The gel concentrations of alginate and dextran in the combined fouling layer seemed to be less than those in the macromolecular gel layer.