Citations

Context.— Clinical testing for Wilson disease (WD) is potentially challenging. Measuring the fraction of labile bound copper (LBC) to total copper may be a promising alternative diagnostic tool with better sensitivity and specificity than some current biomarker approaches. A dual filtration–based inductively coupled mass spectrometry (ICP-MS) assay to measure LBC in serum was developed. Objective.— To establish a reference interval for LBC and LBC to total copper (LBC fraction) in a healthy adult population, and to examine associations between total copper, LBC, and LBC fraction with age, sex, menopausal status, hormone replacement therapy, and supplement use. Design.— Serum samples were collected from healthy male (n = 110) and female (n = 104) patients between the ages of 19 and 80 years. Total copper and LBC were analyzed using ICP-MS. Results were used to calculate the LBC fraction. Reference intervals were calculated for the 2.5th and 97.5th percentiles for both LBC and LBC fraction. Results.— The reference intervals for LBC were determined to be 13 to 105 ng/mL and 12 to 107 ng/mL for female and male patients, respectively. The reference intervals for the LBC fraction were 1.0% to 8.1% and 1.2% to 10.5% for female and male patients, respectively. No significant associations were found regarding age, menopausal status, hormone replacement therapy, or vitamin and supplement use. Conclusions.— Sex-specific reference intervals have now been established for LBC and LBC fraction. These data in conjunction with further testing of WD populations can be used to assess the sensitivity and specificity of LBC fraction in screening, monitoring, and diagnosis.

Objective and Background: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an aspartate aminotransferase to platelet ratio combined with an albumin-bilirubin grade (APRI+ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). Methods: A total of 12,056 patients from the National Surgical Quality Improvement Program database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. The performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2525 patients. In 620 patients, the APRI+ALBI MVM, trained in the National Surgical Quality Improvement Program cohort, was compared with the MVM’s based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). Results: A MVM including APRI+ALBI, age, sex, tumor type, and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC: 0.74). In direct comparison with other MVM’s based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for the calculation of the APRI+ALBI MVM was designed. Conclusion: Risk assessment through the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents a universally available and cost-effective risk assessment before hepatectomy, facilitated by a freely available smartphone app.

Objective To develop an individualized method for detecting cognitive adverse events (CAEs) in the context of an ongoing trial of electroconvulsive therapy for refractory agitation and aggression for advanced dementia (ECT-AD study). Methods Literature search aimed at identifying (a) cognitive measures appropriate for patients with advanced dementia, (b) functional scales to use as a proxy for cognitive status in patients with floor effects on baseline cognitive testing, and (c) statistical approaches for defining a CAE, to develop CAEs monitoring plan specifically for the ECT-AD study. Results Using the Severe Impairment Battery-8 (SIB-8), baseline floor effects are defined as a score of ≤5/16. For patients without floor effects, a decline of ≥6 points is considered a CAE. For patients with floor effects, a decline of ≥30 points from baseline on the Barthel Index is considered a CAE. These values were derived using the standard deviation index (SDI) approach to measuring reliable change. Conclusions The proposed plan accounts for practical and statistical challenges in detecting CAEs in patients with advanced dementia. While this protocol was developed in the context of the ECT-AD study, the general approach can potentially be applied to other interventional neuropsychiatric studies that carry the risk of CAEs in patients with advanced dementia.

Purpose To describe the patient‐reported clinical outcomes following medial meniscus root repair with meniscus centralization and to identify common complications and detail provisional results. Methods Patients undergoing medial meniscus root repair with meniscus centralization from 2020 to 2022 were identified using an institutional database. Patients were followed prospectively using postoperative Tegner Activity Scale, visual analog scale (VAS) for pain, Knee Injury and Osteoarthritis Outcome Score, Joint Replacement, International Knee Documentation Committee score, and a Likert score for improvement, surgery satisfaction, and subsequent surgeries at minimum 1‐year follow‐up with mean 2‐year follow‐up. Demographics, injury characteristics, and surgical details were also collected. Results Twenty‐five patients (age: 50 ± 11 years; sex: 76% female; body mass index: 33 ± 8) were included in this study. Postoperative Tegner score was maintained at preoperative levels ( P = .233), and VAS at rest, VAS with use, Knee Injury and Osteoarthritis Outcome Score, Joint Replacement, and International Knee Documentation Committee improved significantly postoperatively ( P = .003; P < .001, P < .001, P = .023, respectively). Eighty‐eight percent of patients reported subjective improvement in their knee at final follow‐up. Postoperative radiographs did not show any significant osteoarthritis progression, and no patients had undergone a revision meniscus surgery or total knee arthroplasty at the time of follow‐up. Conclusions At minimum 1‐year follow‐up and mean 2‐year follow‐up, patients undergoing medial meniscus root repair with meniscus centralization demonstrated significant postoperative improvements in pain, function, and quality of life and reported high rates of surgery satisfaction. There was no evidence of significant arthritic progression on postoperative imaging, and no patients underwent revision meniscus surgery or total knee arthroplasty. Level of Evidence Level IV, case series.

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle–specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0–1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m2, Days 1 and 8), and docetaxel (75 mg/m2, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64−1.40), p = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39−1.16), p = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.

BACKGROUND: Kidney transplant is the most common transplant operation performed in the United States. Although various approaches to pain management have been described, the optimal analgesic strategy remains undefined. Specifically, the role of intrathecal opioids in this patient population has not been comprehensively evaluated. METHODS: Using a retrospective cohort design, data from kidney transplant operations at a single tertiary care medical center between August 1, 2017, and July 31, 2022, were extracted. Inverse probability of treatment weighting (IPTW) was used to assess differences in clinical outcomes based on the presence or absence of intrathecal opioid administration before surgical incision. The primary outcome was total opioid exposure expressed in milligram morphine equivalents (MME) in the first 72 hours postoperatively, with secondary outcomes including total MME (intraoperative plus postoperative MME, postoperative pain scores, and the presence of postoperative nausea/vomiting [PONV], pruritus, or adverse events). RESULTS: A total of 1014 kidney transplants in 1012 unique patients were included, with 411 (41%) receiving intrathecal opioids preoperatively. Hydromorphone was the intrathecal opioid used in all cases with median dose of 100 µg (interquartile range [IQR], 100, 100; range 50–200). Subjects receiving intrathecal opioids had significantly lower postoperative opioid requirements at 72 hours (30 [0–68] vs 64 [22, 120] MME), with ratio of geometric means in the IPTW analysis (ratio of geometric means 0.34, 95% confidence interval [CI], 0.26–0.43; P < .001). Similar findings were observed for total opioids (45 [30–75] vs 75 [60–90] MME; ratio of geometric means 0.58, 95% CI, 0.54–0.63; P < .001). Maximum reported pain scores in the intrathecal group were lower at 24 hours (4 [2–7] vs 7 [5, 8]; OR, 0.28; 95% CI, 0.21–0.37 for experiencing a higher pain score with intrathecal opioids, P < .001) and 72 hours (6 [4–7] vs 7 [5–8]; OR, 0.41; 95% CI, 0.31–0.54; P < .001). Patients receiving intrathecal opioids were more likely to experience PONV (225 of 411 [55%] vs 232 of 603 [38%]; OR, 2.16; 95% CI, 1.63–2.86; P < .001). CONCLUSIONS: Intrathecal opioid administration was associated with improved pain outcomes in patients undergoing kidney transplantation, including lower opioid requirements and pain scores through 72 hours. However, this was accompanied by an increased risk of PONV.