Citations

Abstract: Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C 0 ) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration–time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells–regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C 0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

Background: Elbow flexion after upper brachial plexus injury may be restored by a nerve transfer from the ulnar nerve to the biceps motor branch with an optional nerve transfer from the median nerve to the brachialis motor branch (single and double fascicular nerve transfer). This meta-analysis assesses the effectiveness of both techniques and the added value of additional reinnervation of the brachialis muscle. Methods: Comprehensive searches were performed identifying studies concerning restoration of elbow flexion through single and double fascicular nerve transfers. Only C5 to C6 lesion patients were included in quantitative analysis to prevent confounding by indication. Primary outcome was the proportion of patients reaching British Medical Research Council elbow flexion grade 3 or greater. Meta-analysis was performed with random effects models. Results: Thirty-five studies were included (n = 688). In quantitative analysis, 29 studies were included (n = 341). After single fascicular nerve transfer, 190 of 207 patients reached Medical Research Council grade 3 or higher (random effects model, 95.6 percent; 95 percent CI, 92.9 to 98.2 percent); and after double fascicular nerve transfer, 128 of 134 patients reached grade 3 or higher (random effects model, 97.5 percent; 95 percent CI, 95.0 to 100 percent; p = 0.301). Significantly more double nerve transfer patients reached grade 4 or greater if preoperative delay was 6 months or less (84 of 101 versus 49 of 51; p = 0.035). Conclusions: Additional reinnervation of the brachialis muscle did not result in significantly more patients reaching Medical Research Council grade 3 or higher for elbow flexion. Double fascicular nerve transfer may result in more patients reaching grade 4 or higher in patients with a preoperative delay less than 6 months. The median nerve may be preserved or used for another nerve transfer without substantially impairing elbow flexion restoration.

ABSTRACT Musculoskeletal infections (MSKI) remain the bane of orthopedic surgery, and result in grievous illness and inordinate costs that threaten healthcare systems. As prevention, diagnosis, and treatment has remained largely unchanged over the last 50 years, a 2nd International Consensus Meeting on Musculoskeletal Infection (ICM 2018, https://icmphilly.com ) was completed. Questions pertaining to all areas of MSKI were extensively researched to prepare recommendations, which were discussed and voted on by the delegates using the Delphi methodology. The questions, including the General Assembly (GA) results, have been published ( GA questions ). However, as critical outcomes include: (i) incidence and cost data that substantiate the problems, and (ii) establishment of research priorities; an ICM 2018 research workgroup (RW) was assembled to accomplish these tasks. Here, we present the result of the RW consensus on the current and projected incidence of infection, and the costs per patient, for all orthopedic subspecialties, which range from 0.1% to 30%, and $17,000 to $150,000. The RW also identified the most important research questions. The Delphi methodology was utilized to initially derive four objective criteria to define a subset of the 164 GA questions that are high priority for future research. Thirty‐eight questions (23% of all GA questions) achieved the requisite > 70% agreement vote, and are highlighted in this Consensus article within six thematic categories: acute versus chronic infection, host immunity, antibiotics, diagnosis, research caveats, and modifiable factors. Finally, the RW emphasizes that without appropriate funding to address these high priority research questions, a 3rd ICM on MSKI to address similar issues at greater cost is inevitable.

Efforts to characterize stakeholder attitudes about the implementation of genomic medicine would benefit from a validated instrument for measuring public views of the potential benefits and harms of genomic technologies, which would facilitate comparison across populations and clinical settings. We sought to develop a scale to evaluate attitudes about the future of genomic medicine. We developed a 21‐item scale that examined the likelihood of various outcomes of genomic medicine. The scale was administered to participants in a genomic sequencing study. Exploratory factor analysis was conducted and bivariate correlations were calculated. The genomic orientation (GO) scale was completed by 2895 participants. A two‐factor structure was identified, corresponding to an optimism subscale (16 items, α = 0.89) and a pessimism subscale (5 items, α = 0.63). Genomic optimism was positively associated with a perceived value of genetic test results, higher health literacy, and decreased decisional conflict about participation in a genomic research study. Genomic pessimism was associated with concerns about genetic testing, lower health literacy, and increased decisional conflict about the decision to participate in the study. The GO scale is a promising tool for measuring both positive and negative views regarding the future of genomic medicine and deserves further validation.

525 Background: Exposure to cytotoxic chemotherapy (CC) has been observed to be associated with significant changes in body composition, namely marked lean muscle mass losses, with implications for treatment-related toxicity and oncologic outcomes. However, prior studies predominately include elderly patients who, a priori, are at risk for sarcopenia or severe skeletal muscle deficiency. To date, the impact of CC on body composition in young men with testicular cancer remains undefined. Methods: A retrospective analysis of 19 patients with metastatic testicular cancer treated with CC was performed (2015-17). Lumbar skeletal muscle index (SMI), visceral (VAI), subcutaneous (SCAI), and intramuscular adipose (IMAI) indices (cm2/m2), as well as fat-free mass (FFM, kg) and fat mass (FM, kg) were calculated using cross-sectional soft tissue area measurements on pre- and post-CC computed tomography (CT) axial scans and compared using paired Wilcoxon Signed Rank Tests. Results: Median age was 29 years. According to the NHANES FMI-based classification, 5 (26.3%), 9 (47.4%), 4 (21.1%), and 1 (5.3%) patients had normal, excess, class I, and class II obesity, respectively. Median pre- and post-CC BMI was 27.7 vs. 29.6 kg/m2(p = 0.03). Median pre- and post-CC SMI, VAI, SAI, and IAI were 63.5 vs 57.8 (p = 0.14), 19.9 vs 30.8 (p = 0.01), 47.9 vs 58.2 (p = 0.03), and 3.0 vs 5.2 (p = 0.002), respectively. Median muscle density pre- and post-CC were 47.0 vs 43.6 HU (p = 0.002). Pre- and post-chemotherapy FFM were 21.5 vs 19.5 kg, representing an overall median loss of 2.8%, (IQR -10.1, +4.7; Range -49.5 - +16.3; p = 0.14). Conversely, pre- and post-CC FM were 6.6 vs 7.5 kg, representing an overall median gain of 13.3% (IQR -3.3, +17.0; -24.9 - +50; p = 0.01). Median time between imaging assessments was 121 days. Specific median measures of adiposity each increased significantly, such that VIA increased by 29% (p = 0.01), SCAI increased by 39.7% (p = 0.03), and IMIA increased by 39.7% (p = 0.002). Conclusions: While lean muscularity remained stable, we observed significant increases in total body adipose mass with decreased muscle density in this consecutive case series of testicular cancer patients following CC.