Background: – Reports regarding the relationship between tacrolimus exposure and the risk of acute kidney allograft rejection are conflicting. This may be explained by the previous use of methodological approaches that disregarded important factors in the analysis of longitudinal measurements and time-to-event data. Therefore, in this study, joint models were used to investigate the relationship between repeated measurements of tacrolimus predose concentrations (C ₀) and time to acute biopsy-proven acute rejection (BPAR).Methods: – This was a post hoc analysis of a randomized controlled trial in which living-donor kidney transplant recipients (KTR) received either a standard, bodyweight-based or CYP3A5 genotype-based tacrolimus starting dose. Joint modeling was performed by coupling a mixed-effects model for tacrolimus C ₀ with a Cox proportional hazards model for the risk of rejection. Only the first episode of rejection was considered.Results: – A total of 229 KTRs were included, of whom the incidence of BPAR was 10.5% (n = 24 KTRs) in the first 3 months posttransplant. A total of 3069 tacrolimus measurements were available for the analysis. A joint model adjusted for recipient age and peak panel reactive antibodies demonstrated that tacrolimus C ₀ was associated with risk of rejection. A 1-unit increase in the time-normalized area under the curve for logarithmically (log)-transformed C ₀ represented a change of −2.65 in the log of the relative hazard (95% credible interval: −5.05 to −0.36, P = 0.022).Conclusions: – A negative association between the cumulative effect of tacrolimus C ₀ and BPAR was observed using joint modeling. This demonstrated that KTRs with lower tacrolimus exposure were at a higher risk of rejection.

Background: Essential tremor (ET) is characterized by action tremor of the arms, which can interfere substantially with daily activities. Pharmacotherapy may be ineffective or associated with side effects, and stereotactic surgery is invasive. Hence, new accessible treatment options are urgently needed. An easy-to-use and lightweight orthotic device that exerts joint damping may provide an alternative solution for reducing tremor in daily activities. Objective: Our goal was to assess the efficacy of a novel anti-tremor orthosis (STIL) in reducing clinical and accelerometry measures of distal arm tremor in ET. Methods: In a randomized crossover single-blinded trial in 24 ET patients in a hospital setting, we compared three conditions: no orthosis (baseline), a sham device, and the anti-tremor orthosis (order randomized). The orthosis, but not the sham device, passively damped joints in the forearm. Participants performed seven tasks from the Tremor Research Group Essential Tremor Rating Scale (TETRAS). The two co-primary outcome measures were: clinical tremor severity (video-scored TETRAS) and tremor power (accelerometry). Patient satisfaction was self-assessed using the Dutch Quebec User Evaluation of Satisfaction with assistive Technology. Conditions were compared using Wilcoxon signed-rank tests. Results: The anti-tremor orthosis significantly reduced TETRAS scores compared to sham and baseline (baseline: 19.0 ± 3.2, sham: 13.7 ± 3.9, orthosis: 9.9 ± 3.6; mean ± standard deviation). Similar effects were observed for tremor power, which was reduced by 87.4% (orthosis vs. baseline) and 59.5% (orthosis vs. sham) across all tasks. A total of 71% of participants were (very) satisfied and 12.5% reported minor adverse events (discomfort/redness of skin). Conclusion: The anti-tremor orthosis had a clinically relevant tremor-reducing effect in ET in a controlled setting, offering potential for a new treatment to manage ET in daily activities.