Genotype-guided prescribing predictors in CYP2C19 intermediate metabolizers receiving percutaneous coronary intervention.

Background: Previous differences in guideline recommendation strength for CYP2C19 intermediate metabolizers may have limited genotype (PGx)-optimal post-percutaneous coronary intervention antiplatelet prescribing. Results: In this single-center retrospective observational cohort study of CYP2C19 intermediate metabolizers, patients prescribed PGx-optimal therapy were younger and less likely on anticoagulation (2 vs 12%; p = 0.006). More patients prescribed PGx-optimal therapy possessed commercial insurance (36 vs 7%; p < 0.001), which was a predictor for PGx-optimal selection (OR: 6.464; 95% CI: 2.386-17.516; p < 0.001). Conclusion: Anticoagulation use was significantly associated with clopidogrel use (OR: 0.138; 95% CI: 0.026-0.730; p = 0.020). No statistical difference in composite major adverse cardiovascular events (5 vs 14%; p = 0.173) or bleeding (8 vs 6%; Not significant) was observed between PGx-optimal and PGx-suboptimal therapy.

Not all CYP2C19 intermediate metabolizers undergoing PCI are prescribed genotype-optimal P2Y12 antiplatelet therapy. Commercial insurance and no anticoagulant were found to be associated with ticagrelor and prasugrel prescribing in this population.

Trismus therapy devices: A systematic review.

BACKGROUND: There is a wide range of commercial and custom-made devices available for the treatment of trismus (restricted jaw opening). They are used often in conjunction with a prescribed exercise program with the aim of improving maximal inter-incisal opening (MIO). This study compared the efficacy (MIO and patient reported outcome results), adverse events, consumer experience and cost of the different types of devices available. METHODS: Four databases were searched between the years 2001-2021 using the terms 'trismus' and 'device'. Two independent authors assessed each paper for inclusion, then conducted a quality analysis. RESULTS: Thirty-two studies met the criterion required for inclusion. The majority (n = 27) were in the context of established trismus, where the remaining five used the device preventatively. The trismus device improved MIO in 23 of the rehabilitation programs (pooled mean MIO increased by 9.5 mm in the intervention arm compared to 2.4 mm for controls; p = 0.0001). Improved MIO was not observed in the prevention studies. The Therabite ® was the most common trismus device investigated and with a mean increase in MIO of 10.0 mm and cost of $499AUD. Forces applied by trismus devices were regulated by the perception of pain experienced by the patient, rather than a prescribed force by the treating health professional. Despite this guidance, several adverse events occurred (n = 8), including mandibular and molar fractures. Barriers experienced by consumers included pain, ill-fitting mouthpiece, adverse events, exercise adherence and cost. CONCLUSION: Trismus devices which use the application of force to the jaw can improve the MIO of patients with established trismus. However, their role is unproven in the setting of trismus prevention during radiotherapy and several significant barriers such as cost, exercise adherence and safety concerns have been demonstrated for the intervention setting.

The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.

SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.

Failure of stimulated skeletal muscle mainly contributed by passive force: an in vivo rabbit model.

OBJECTIVE: To evaluate the role of active and passive muscle forces in the failure mechanism of stimulated muscle. DESIGN: An in vivo rabbit model. BACKGROUND: Eccentric contractions can result in a greater incidence of muscle injury. However, the relative role of the active and passive muscle force in the failure mechanism of the activated muscle is not well elucidated. METHODS: After anaesthesia, New Zealand white rabbits were fixed in a frame on a materials testing machine. The triceps surae muscle-tendon units were passively stretched to rupture with our without continuous nerve stimulation. The force and muscle length were simultaneously recorded. Active muscle force, passive muscle force, and ratio of the active to passive muscle were calculated and depicted against strain. RESULTS: The results showed that the mean maximal passive force of triceps surae muscle was 293.1 N at a strain of 38%. The mean peak active muscle force was 21.5 N at a strain of 21%. The ratio of active to passive muscle force reached its peak first, followed by the active muscle force, and then the passive muscle force. The ratio of active to passive muscle force at the peak total force was only 3.3%. CONCLUSIONS: The stimulated muscle can exert its maximal response at extreme physiological extension. Injury of the stimulated muscle is caused mainly by passive muscle force.

Influences of configuration changes of the patella on the knee extensor mechanism.

Biomechanical analysis of the configuration changes of the patella was studied. Normal patellar tracking in the sagittal plane was obtained by recording and digitizing knee extension of six healthy adults with fluoroscopy. Based on the digitized data, the changes of patellar thickness were simulated by translating its axis and its forward and backward tilting by rotation in the sagittal plane. We assumed that the extensor moment remained constant before and after the patellar configuration was changed. Therefore, using a balance beam, model equilibrium was reached, after each simulated change of patellar configuration, of the forces involved in the extensor mechanism: the quadriceps muscle force, tension of patella tendon and patellofemoral joint reaction force. The results revealed that when the patellar thickness decreased, quadriceps force increased but patellofemoral joint reaction force decreased and the reverse was seen when the patella thickened. Backward tilting of the patella decreased quadriceps force and patellofemoral joint reaction force and increased the patella tendon/quadriceps force ratio, which produced a better mechanical advantage of force transmission of patella. The reverse was seen in forward tilting. These results suggest that the patella could be tilted backward for the older patient undergoing total knee replacement. For younger patients with relatively strong quadriceps musculature, we suggest that the patellar thickness could be decreased to reduce the patellofemoral joint reaction force so as to reduce the chance of failure of the patella prosthesis.