Citations

OBJECTIVE: To identify distinct phenotypes of acute respiratory distress syndrome (ARDS) developing after hematopoietic cell transplantation (HCT), using routinely available clinical data at ICU admission. DESIGN: Multicenter retrospective cohort study using latent class analysis. SETTING: ICUs across three Mayo Clinic campuses (Minnesota, Florida, and Arizona). PATIENTS: A total of 166 adult patients who developed ARDS within 120 days following HCT (96 allogeneic, 70 autologous). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Model selection was based on multiple metrics including Bayesian information criteria, entropy, and Vuong-Lo-Mendell-Rubin Likelihood Ratio testing. A two-class model optimally described the cohort. Class 1 (n = 81) was characterized by worse hypoxemia (P/F ratio 157 vs. 210, p = 0.002), higher Pco 2 (41 vs. 36 mm Hg, p < 0.001), and higher bilirubin (1.4 vs. 0.9 mg/dL, p < 0.001) compared with class 2 (n = 85). Both classes included a mix of transplant types, transcending a simple autologous/allogeneic dichotomy, although class 1 had more allogeneic recipients (70.4% vs. 45.9%, p = 0.001). Although time-from-transplant was not a class-defining variable, class 1 occurred later after transplant (30.0 vs. 11.9 d, p < 0.001) with higher frequency of idiopathic pneumonia syndrome (14.8% vs. 2.4%, p = 0.004). Class 2 had more frequent neutropenia (leukocytes 0.4 vs. 5.9 × 109, p < 0.001) and higher frequency of peri-engraftment respiratory distress syndrome (29.4% vs. 9.9%, p = 0.005). Outcomes were significantly worse for class 1 (90-d mortality: 72.8% vs. 48.2%, p = 0.001). An exploratory parsimonious model had good classification accuracy (0.90) using just six variables: leukocyte count, platelet count, bilirubin, Pco 2, body mass index, and temperature. CONCLUSIONS: ARDS after HCT comprises two distinct phenotypes with distinct clinical characteristics and outcomes. These phenotypes align with recognized post-HCT lung injury syndromes and may reflect different underlying biological processes. This framework provides a foundation for investigating targeted therapeutic approaches.

OBJECTIVE The role of amputation and myoelectric prosthetic fitting for hand function in traumatic pan–brachial plexus injury (pBPI) continues to evolve. This study evaluated the function and activity performance of patients with traumatic pBPI who underwent amputation and prosthetic fitting with a myoelectric prosthesis (MEP) for hand function. METHODS A retrospective analysis of adult patients who underwent elective amputation after sustaining a pBPI followed by MEP for hand function was performed. Demographics, mechanisms of injury, amputation details, and outcomes were collected from medical records. The Disabilities of the Arm, Shoulder and Hand (DASH) outcome measure was used to evaluate the impact of impairment, the visual analog scale (VAS) to assess pain, and the Activities Measure for Upper Limb Amputees (AM-ULA) to determine functional activity performance pre- and post-MEP usage. Follow-up time, prosthesis usage, satisfaction, and site of electrical signal used were recorded. Paired t-tests were used to compare outcomes. RESULTS Twenty-one adult patients with pBPI (90% male, mean age 32 years at the time of BPI) underwent amputations and were fitted with MEPs for hand function controlled by nonintuitive signals. Fifteen patients underwent a trans-radial amputation and 6 underwent a trans-humeral amputation. While all patients sought improved terminal grasp function, 3 patients subsequently declined prosthetic fitting after amputation. Of the 18 patients who underwent myoelectric prosthetic hand fittings, linear transducers activated by the contralateral shoulder protraction were used in 66% of patients, and traditional electrode signals from ipsilateral nonintuitive muscle were used in 33% to control MEP grasp function. Disability (DASH) and pain (VAS) scores significantly improved after amputation (p = 0.04 and p < 0.01, respectively). AM-ULA scores showed a significant improvement in activity performance after application of the MEP, with an average increase of 23 points from 0 points on a 40-point scale before amputation and prosthetic fitting (p < 0.0001). Daily users of the MEP averaged 6 hours per day and reported the prosthesis was useful during daily activities with great satisfaction at an average of 22 months of follow-up. CONCLUSIONS Amputation followed by MEP fitting in adult traumatic pBPI significantly improved function, reduced pain, and had a high prosthetic usage. The AM-ULA, a tool for quantitatively evaluating activity performance, was applied to measure the bimanual functional activity performance of patients before and after using MEPs, which revealed a significant improvement. Patients reported using their prosthetics daily with a high satisfaction rate with functional terminal grasp and release.

OBJECTIVE Open resective surgery (ORS) has become the standard of care for focal drug-resistant epilepsy (DRE). However, minimally invasive surgical alternatives, such as laser interstitial thermal therapy (LITT), have also been shown to be safe and effective. A meta-analysis comparing both treatments is warranted to assess the benefits of each modality for focal DRE. METHODS A literature search was conducted until March 14, 2024, to identify studies comparing LITT and ORS in patients with DRE. The primary outcomes included seizure freedom (SF), length of hospital stay (LHS), and complication rate (CR). Subgroup analyses were performed based on age, epilepsy etiology, and propensity score–matched (PSM) studies. RESULTS Of 558 articles, 15 cohort studies met the authors’ inclusion criteria, encompassing 3873 patients for analysis. The rate of SF in the LITT group was 52.5% (95% CI 0.453–0.597, I 2 = 47.4%) and 67.1% (95% CI 0.602–0.739, I 2 = 57.4%) for the ORS group. LITT showed a significantly lower rate of SF compared to ORS (risk ratio [RR] 0.78, 95% CI 0.70–0.88, p ≤ 0.0001). However, when PSM studies (RR 0.85, 95% CI 0.63–1.15, p = 0.30) and studies on patients with temporal lobe epilepsy (TLE) (RR 0.88, 95% CI 0.67–1.14, p = 0.34) were analyzed, the SF rates were similar. Patients who underwent LITT had a significantly shorter LHS (mean difference 2.95 days, 95% CI 1.12–4.78, p < 0.00001), lower CR (RR 0.54, 95% CI 0.37–0.79, p < 0.002, I 2 = 32%), lower rate of ischemic stroke (RR 0.15, 95% CI 0.04–0.65, p = 0.01), and lower rate of permanent neurological deficits (RR 0.13, 95% CI 0.05–0.36, p < 0.0001). CONCLUSIONS Across unmatched studies evaluating focal DRE, ORS showed a higher rate of SF. However, pooled matched-cohort analyses showed no difference between interventions in achieving SF, a trend also noted in the authors’ PSM TLE sample. LITT, however, offered significantly shorter LHS and lower CRs. Future prospective studies should match patient populations to control for confounding factors and assess key outcomes, such as postoperative neurocognitive follow-up and quality of life measurements, in order to fully evaluate the risks and benefits of each approach.

Selective inhibitors are essential for targeted therapeutics and for probing enzyme functions in various biological systems. The two main challenges in identifying such protein‐based inhibitors lie in the extensive experimental effort required, including the generation of large libraries, and in tailoring the selectivity of inhibitors to enzymes with homologous structures. To address these challenges, machine learning (ML) is being used to improve protein design by training on targeted libraries and identifying key interface mutations that enhance affinity and specificity. However, such ML‐based methods are limited by inaccurate energy calculations and difficulties in predicting the structural impacts of multiple mutations. Here, we present an ML‐based method that leverages HTS data to streamline the design of selective protease inhibitors. To demonstrate its utility, we applied our new method to find inhibitors of matrix metalloproteinases (MMPs), a family of homologous proteases involved in both physiological and pathological processes. By training ML models on binding data for three MMPs (MMP‐1, MMP‐3, and MMP‐9), we successfully designed a novel N‐TIMP2 variant with a differential specificity profile, namely, high affinity for MMP‐9, moderate affinity for MMP‐3, and low affinity for MMP‐1. Our experimental validation showed that this novel variant exhibited a significant specificity shift and enhanced selectivity compared with wild‐type N‐TIMP2. Through molecular modeling and energy minimization, we obtained structural insights into the variant's enhanced selectivity. Our findings highlight the power of ML‐based methods to reduce experimental workloads, facilitate the rational design of selective inhibitors, and advance the understanding of specific inhibitor–enzyme interactions in homologous enzyme systems.

This study presents the first in vivo intraoperative measurement of the kinetic properties of spastic human muscle. Despite slower relaxation in spastic biceps, the force-frequency relationship was similar to that of the healthy gracilis muscle. This suggests that spasticity does not substantially alter frequency-dependent force summation, possibly due to similar fiber-type compositions and limited changes in calcium handling or myosin isoforms in human spastic muscle.

IMPORTANCE: Propofol is a first-line sedative for adults receiving invasive mechanical ventilation (IMV). However, it can contribute to hemodynamic instability, especially during intubation. The magnitude, timing, risk factors, and variability of sedation-associated mean arterial pressure (MAP) changes remain poorly characterized in ICU settings. OBJECTIVES: To quantify MAP changes following propofol sedation, identify risk factors for hemodynamic instability, and characterize associated interventions. DESIGN: Retrospective cohort study. The primary outcome was MAP change within 2 hours following sedation. Secondary outcomes included vasopressor use and hypotension (MAP ≤ 60 mm Hg). Mixed-effects modeling was used to account for individual patient differences. SETTING AND PARTICIPANTS: Adults (≥ 18 yrs old) who required IMV and received greater than or equal to 6 consecutive hours of propofol infusion, between May 5th, 2018, and July 31st, 2024, in 11 ICUs across the Mayo Clinic, spanning 5 hospitals in 4 states. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in MAP within 2 hours following the initiation of propofol-based sedation. RESULTS: Across 16,418 patients, 25.2% were on vasopressors before sedation initiation. Among the remaining 12,281 patients, 40.3% required vasopressors and 7.7% experienced hypotension within 2 hours of sedation. Propofol-based sedation was associated with a MAP reduction within the first 30 minutes (–6.58 mm Hg; 95% CI, –6.85 to –6.32; p < 0.001). There was substantial interpatient variability in both baseline MAP, and MAP decline after sedation (9.5 and 40.9% between-patient differences, respectively). Higher Sequential Organ Failure Assessment (SOFA) scores (–0.31 mm Hg/point), older age (–0.04 mm Hg/yr), and male sex (–0.47 mm Hg) were associated with lower MAP. Patients with higher illness severity experienced progressively greater MAP decline over time (–0.20 mm Hg/hr/SOFA point; p < 0.001). CONCLUSIONS AND RELEVANCE: Propofol-based sedation was associated with clinically significant hemodynamic effects requiring intervention in the early post-intubation period. The marked interpatient variability in hemodynamic responses highlights the importance of personalized management approaches, including risk stratification based on age, sex, and illness severity.

Background: Although patients often aim to lose weight after total hip arthroplasty (THA) or total knee arthroplasty (TKA), long-term changes in body mass index (BMI) are unknown. We analyzed BMI at 2, 5, and 10 years after primary THA and TKA and determined predictors of BMI change. Methods: We identified patients who underwent primary THA or TKA for osteoarthritis between 2001 and 2011 and had a BMI at surgery and at 2, 5, and 10 years postoperatively. This resulted in 763 patients (310 who underwent THA and 453 who underwent TKA). The mean patient age was 66 years, and 60% of patients were female. BMI changes were analyzed with repeated-measures analysis of variance. Multinomial logistic regression determined predictors of BMI change. Results: Following THA, the mean BMI increased from 30.3 kg/m 2 at surgery to 30.9 kg/m 2 at both 2 years (p = 0.003) and 5 years (p = 0.002). Following TKA, the mean BMI increased from 32.7 kg/m 2 at surgery to 33.1 kg/m 2 at both 2 years (p = 0.053) and 5 years (p = 0.040). By 10 years, the mean BMI was 30.6 kg/m 2 (p = 0.453) for patients undergoing THA and 32.6 kg/m 2 (p = 0.947) for patients undergoing TKA, similar to the BMIs at surgery. At 10 years, 27% of patients who underwent THA and 30% of patients who underwent TKA had a BMI decrease of >5%, whereas 30% of patients who underwent THA and 32% of patients who underwent TKA had a BMI increase of >5%. Female sex among patients who underwent THA increased the odds of a >5% BMI increase at 10 years (odds ratio [OR], 2.1; p = 0.006). Older age among patients who underwent TKA decreased the odds of a >5% BMI increase at 10 years (OR per year, 0.95; p < 0.001). Conclusions: Although most patients experienced a BMI change of >5% at 10 years, the mean BMI did not meaningfully change 2, 5, or 10 years after THA or TKA. Arthroplasty should not be viewed as a gateway to BMI improvement for patients overall, but female sex and older age may predict clinically important weight changes 10 years after arthroplasty. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Subretinal injection of adeno-associated virus (AAV) is generally more efficacious and less inflammatory than intravitreal injection for retinal gene therapy. However, adverse events (e.g., chorioretinal atrophy) have been reported in many patients receiving subretinal injection of Luxturna (voretigene neparvovec-rzyl) and experimental gene therapies. Subretinal injection confines transduction to the treated area. To address this, we manufactured high-concentration fibrin hydrogels encapsulating AAV2–green fluorescent protein (AAV2- GFP ). Gels had homogeneous AAV distribution, desired mechanical properties, and retained infectivity. Epiretinal placement of fibrin–AAV2- GFP ( n = 11) was compared to subretinal ( n = 5) and intravitreal AAV2- GFP injection ( n = 3). The subretinal group exhibited inconsistent retinal pigment epithelium (RPE) transduction restricted to the injection region with severe atrophy in two cases. The intravitreal group had weak transduction and inflammation. In contrast, epiretinal hydrogels degraded within days and led to broad transduction of RPE without atrophy or inflammation. This technology could advance gene therapy for retinal degenerations and other ocular or systemic disorders.

Abstract Objectives Determine differences in quantitative stenosis severity measurements for ultra-high-resolution (UHR) photon-counting detector (PCD) coronary CT angiography (cCTA) relative to energy-integrating detector (EID) cCTA in a large patient cohort. Methods Adult participants seen between November 2022 and March 2023 underwent a clinical dual-source EID-CT cCTA and a research dual-source PCD-CT cCTA on the same day. Percent diameter stenosis (PDS) was measured, and stenosis severity was assigned based on the PDS of the most severe lesion per patient to determine a coronary artery disease reporting and data system (CAD-RADS) score. Agreement between EID-CT and PCD-CT for PDS and CAD-RADS was determined. Results A total of 112 participants were enrolled, yielding 82 subjects with at least 1 stenosis at PCD-CT (mean age, 68.0 ± 10.8 years; 69.5% [57/82] males). A total of 177 paired stenoses were quantified. The percent decrease in mean PDS from PCD-CT (24.3%) to EID-CT (29.4%) was 17.3% (median difference in PDS: −5.0%, 95% CI: −5.7% to −4.0%). The assigned CAD-RADS score changed in 31/82 subjects. In 11/31 subjects, the most severe stenosis was missed at EID-CT due to partial volume averaging of a small calcification, yet PCD clearly identified stenosis at those locations. In 20/31 subjects, the CAD-RADS score decreased at PCD-CT due to the decreased calcium blooming resulting from the improved spatial resolution. Conclusions UHR PCD cCTA decreases quantitative measures of stenosis severity when a stenosis is identified at EID, leading to decreases in CAD-RADS assignments. Advances in knowledge With its improved spatial resolution, PCD-CT identifies stenoses missed on EID-CT.