Citations

Abstract Objective To identify potential diagnostic and prognostic biomarkers for clinical management and clinical trials in amyotrophic lateral sclerosis. Methods We analysed proteomics data of ALS patient‐induced pluripotent stem cell‐derived motor neurons available through the AnswerALS consortium. After stratifying patients using clinical ALSFRS‐R and ALS‐CBS scales, we identified differentially expressed proteins indicative of ALS disease severity and progression rate as candidate ALS‐related and prognostic biomarkers. Pathway analysis for identified proteins was performed using STITCH. Protein sets were correlated with the effects of drugs using the Connectivity Map tool to identify compounds likely to affect similar pathways. RNAi screening was performed in a Drosophila TDP‐43 ALS model to validate pathological relevance. A statistical classification machine learning model was constructed using ridge regression that uses proteomics data to differentiate ALS patients from controls. Results We identified 76, 21, 71 and 1 candidate ALS‐related biomarkers and 22, 41, 27 and 64 candidate prognostic biomarkers from patients stratified by ALSFRS‐R baseline, ALSFRS‐R progression slope, ALS‐CBS baseline and ALS‐CBS progression slope, respectively. Nineteen proteins enhanced or suppressed pathogenic eye phenotypes in the ALS fly model. Nutraceuticals, dopamine pathway modulators, statins, anti‐inflammatories and antimicrobials were predicted starting points for drug repurposing using the connectivity map tool. Ten diagnostic biomarker proteins were predicted by machine learning to identify ALS patients with high accuracy and sensitivity. Interpretation This study showcases the powerful approach of iPSC‐motor neuron proteomics combined with machine learning and biological confirmation in the prediction of novel mechanisms and diagnostic and predictive biomarkers in ALS.

AbstractPurposeVancomycin area under the concentration-time curve (AUC) can be calculated using steady-state serum peak and trough concentrations; however, compared to traditional trough-only monitoring, this approach requires an additional blood sample. Recently published data demonstrated vancomycin AUC estimations using trough-only data with a volume of distribution (Vd) model incorporating age and actual body weight were reasonably accurate and precise in a veteran population. This study sought to extend these methods to a Mayo Clinic adult population.MethodsA retrospective, observational cohort of adult patients with documented steady-state vancomycin peak and trough concentrations was evaluated. Vancomycin AUCs were estimated using trough-only data, and 4 Vd models were assessed for accuracy and precision. Estimated AUCs were compared to AUCs calculated using 1-compartment intermittent infusion equations and steady-state peak and trough (“peak-trough”) data.ResultsThe study population (N = 95) was 46% female, with a median age of 59 years and a median weight of 97 kg. Using the VancoPK equation Vd = 0.29 (age in y) + 0.33 (actual weight in kg) + 11, the mean peak-trough and estimated trough-only AUC were 533 and 534, respectively, with a correlation of 0.936. The root mean square error was 47.7, meaning about 95% of AUCs were within 95 mg · h/L of peak-trough AUCs.ConclusionsAccuracy and precision of Vancomycin AUC estimations using trough-only data and the described Vd model were demonstrated in a Mayo Clinic cohort. Targeting an estimated AUC of 500 mg · h/L using the VancoPK model would likely result in an actual AUC within 400 to 600 mg · h/L.

Abstract Background Sexual assault survivors are at increased risk for sexually transmitted infections. Due to patient vulnerability, institutions have implemented Sexual Assault Nurse Examiner (SANE) protocols to care for these patients. These protocols guide evidence collection, testing, treatment, and medical follow-up to ensure optimization of sexually transmitted infections (STIs) treatment, monitoring and follow-up. Previous gap analyses have identified decreased prescribing of prophylactic STI medications and scheduling follow-up appointments compared to guideline recommendations. The purpose of this study was to assess adherence of medication prescribing and follow-up scheduling practices to Centers for Disease Control (CDC) guidelines. Methods This study was a single-center, retrospective, observational, descriptive assessment which evaluated adherence rates to CDC guidelines, to scheduling medical follow-up, and patient attendance at scheduled appointments. Pediatric and adult patients who presented to the emergency department at Mayo Clinic Health System in La Crosse, WI from January 2018 through December 2021 were included. Data collected through chart review included demographics and laboratory data necessary for prescribing prophylactic HIV medications, antibiotics for STIs, emergency contraception, and vaccine administration. Descriptive statistics were used to evaluate results. Results One hundred three patients were evaluated. Majority of patients were female and presented within 3 days of assault. Medication adherence to CDC guidelines was ≥ 80% for chlamydia and gonorrhea whereas < 80% was noted for trichomoniasis and HIV prophylaxis. Adherence to post-ED discharge follow-up was 40%. Conclusion Opportunities to improve adherence of ED-SANE protocols for medication prescribing and medical follow-up for trichomoniasis and HIV prophylaxis exist. Disclosures All Authors: No reported disclosures.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

AbstractSince the publication of AAPM Task Group (TG) 148 on quality assurance (QA) for helical tomotherapy, there have been many new developments on the tomotherapy platform involving treatment delivery, on‐board imaging options, motion management, and treatment planning systems (TPSs). In response to a need for guidance on quality control (QC) and QA for these technologies, the AAPM Therapy Physics Committee commissioned TG 306 to review these changes and make recommendations related to these technology updates. The specific objectives of this TG were (1) to update, as needed, recommendations on tolerance limits, frequencies and QC/QA testing methodology in TG 148, (2) address the commissioning and necessary QA checks, as a supplement to Medical Physics Practice Guidelines (MPPG) with respect to tomotherapy TPS and (3) to provide risk‐based recommendations on the new technology implemented clinically and treatment delivery workflow. Detailed recommendations on QA tests and their tolerance levels are provided for dynamic jaws, binary multileaf collimators, and Synchrony motion management. A subset of TPS commissioning and QA checks in MPPG 5.a. applicable to tomotherapy are recommended. In addition, failure mode and effects analysis has been conducted among TG members to obtain multi‐institutional analysis on tomotherapy‐related failure modes and their effect ranking.

ImportanceRacial and ethnic minority and socioeconomically disadvantaged patients have been underrepresented in randomized clinical trials. Efforts have focused on enhancing inclusion of minority groups at sites participating at clinical trials; however, there may be differences in the patient populations of the sites that participate in clinical trials.ObjectiveTo identify any differences in the racial, ethnic, and socioeconomic composition of patient populations among candidate sites in the US that did vs did not participate in trials for novel transcatheter therapies.Design, Setting, and ParticipantsThis cross-sectional analysis used Medicare Provider Claims from 2019 for patients admitted to hospitals in the US. All clinical trials for transcatheter mitral and tricuspid valve therapies and the hospitals participating in each of the trials were identified using ClinicalTrials.gov. Hospitals with active cardiac surgical programs that did not participate in the trials were also identified. Data analysis was performed between July 2021 and July 2022.ExposuresMultivariable linear regression models were used to identify differences in racial, ethnic, and socioeconomic characteristics among patients undergoing cardiac surgery or transcatheter aortic valve replacement at trial vs nontrial hospitals.Main Outcome and MeasuresThe main outcome of the study was participation in a clinical trial for novel transcatheter mitral or tricuspid valve therapies.ResultsA total of 1050 hospitals with cardiac surgery programs were identified, of which 121 (11.5%) participated in trials for transcatheter mitral or tricuspid therapies. Patients treated in trial hospitals had a higher median zip code–based household income (difference of $5261; 95% CI, $2986-$7537), a lower Distressed Communities Index score (difference of 5.37; 95% CI, 2.59-8.15), and no significant difference in the proportion of patients dual eligible for Medicaid (difference of 0.86; 95% CI, −2.38 to 0.66). After adjusting for each of the socioeconomic indicators separately, there was less than 1% difference in the proportion of Black and Hispanic patients cared for at hospitals participating vs not participating in clinical trials.Conclusions and RelevanceIn this cohort study among candidate hospitals for clinical trials for transcatheter mitral or tricuspid valve therapies, trial hospitals took care of a more socioeconomically advantaged population than nontrial hospitals, with a similar proportion of Black and Hispanic patients. These data suggest that site selection efforts may improve enrollment of socioeconomically disadvantaged patients but may not improve the enrollment of Black and Hispanic patients.

Background Previous literature has postulated a relationship between greater hamstring stiffness and a higher risk of sustaining injury. Shear wave elastography (SWE) presents a relatively new means for non-invasive evaluation of soft tissue elasticity pre- and post- injury or intervention. Purpose 1. (1) To establish baseline hamstring stiffness measures for young competitive athletes and (2) determine effect of targeted neuromuscular training (TNMT) on shear wave stiffness of the hamstring. Study Design Un-blinded, prospective, non-randomized, cohort study. Methods Six-hundred forty-two lower extremities from 321 high school and collegiate basketball athletes (177 F: 139 M) were examined for hamstring stiffness prior to the start of their competitive basketball season. Teams were cluster assigned to either the control or intervention (TNMT) group. Subjects in the control group underwent regular season activities as directed, with no influence from the research team. For the TNMT group, the research team introduced a hamstring targeted dynamic warm-up program as an intervention focused on activating the hamstring musculature. Results Collegiate status was significant to hamstring stiffness for both sexes (p ≤ 0.02), but hamstring stiffness did not correlate to age or sex (r 2 ≤ 0.08). Intervention was a significant factor to hamstring stiffness when the hip was positioned in extension (p ≤ 0.01), but not in deeper flexion (p = 0.12). This effect was sex-specific as TNMT influenced hamstring stiffness in females (p = 0.03), but not in males (p ≥ 0.13). Control athletes suffered three HAM injuries; TNMT athletes suffered 0 hamstring injuries. Conclusion Higher SWE measurements correlated with increased risk of injury, male sex, and collegiate athletics. TNMT intervention can lessen muscle stiffness which may reduce relate to injury incidence. Intervention effectiveness may be sex specific. Level of Evidence II

This study is the first to examine the applicability of BCL-2 inhibition in the setting of active HIV infectionin vivo. Furthermore, this study demonstrates that venetoclax significantly enhances target cell killing induced by Fas ligand, TRAIL, and perforin/granzyme B and synergistically enhances autologous NK and CD8 cells’ killing of target cells.

Background Coronavirus disease 2019 (COVID-19) is associated with a prothrombotic state; leading to multiple sequelae. We sought to detect whether thromboelastography (TEG) parameters would be able to detect thromboembolic events in patients hospitalized with COVID-19. Methods We performed a retrospective multicenter case–control study of the Collaborative Research to Understand the Sequelae of Harm in COVID (CRUSH COVID) registry of 8 tertiary care level hospitals in the United States (US). This registry contains adult patients with COVID-19 hospitalized between March 2020 and September 2020. Results A total of 277 hospitalized COVID-19 patients were analyzed to determine whether conventional coagulation TEG parameters were associated with venous thromboembolic (VTE) and thrombotic events during hospitalization. A clotting index (CI) >3 was present in 45.8% of the population, consistent with a hypercoagulable state. Eighty-three percent of the patients had clot lysis at 30 min (LY30) = 0, consistent with fibrinolysis shutdown, with a median of 0.1%. We did not find TEG parameters (LY30 area under the receiver operating characteristic [ROC] curve [AUC] = 0.55, 95% CI: 0.44-0.65, P value = .32; alpha angle [α] AUC = 0.58, 95% CI: 0.47-0.69, P value = .17; K time AUC = 0.58, 95% CI: 0.46-0.69, P value = .67; maximum amplitude (MA) AUC = 0.54, 95% CI: 0.44-0.64, P value = .47; reaction time [R time] AUC = 0.53, 95% CI: 0.42-0.65, P value = .70) to be a good discriminator for VTE. We also did not find TEG parameters (LY30 AUC = 0.51, 95% CI: 0.42-0.60, P value = .84; R time AUC = 0.57, 95%CI: 0.48-0.67, P value .07; α AUC = 0.59, 95%CI: 0.51-0.68, P value = .02; K time AUC = 0.62, 95% CI: 0.53-0.70, P value = .07; MA AUC = 0.65, 95% CI: 0.57-0.74, P value < .01) to be a good discriminator for thrombotic events. Conclusions In this retrospective multicenter cohort study, TEG in COVID-19 hospitalized patients may indicate a hypercoagulable state, however, its use in detecting VTE or thrombotic events is limited in this population.