Biomarker-Directed Therapy in Black and White Men With Metastatic Castration-Resistant Prostate Cancer.

Importance: Black men have higher incidence and mortality from prostate cancer. Whether precision oncology disparities affect Black men with metastatic castration-resistant prostate cancer (mCRPC) is unknown. Objective: To compare precision medicine data and outcomes between Black and White men with mCRPC. Design, Setting, and Participants: This retrospective cohort study used data collected by the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) consortium, a multi-institutional registry with linked clinicogenomic data, from April 2020 to December 2021. Participants included Black and White patients with mCRPC with molecular data. Data were analyzed from December 2021 to May 2023. Exposures: Database-reported race and ethnicity. Main Outcomes and Measures: The primary outcome was the frequency of actionable molecular data, defined as the presence of mismatch repair deficiency (MMRD) or high microsatellite instability (MSI-H), homologous recombination repair deficiency, or tumor mutational burden of 10 mutations per megabase or greater. Secondary outcomes included the frequency of other alterations, the type and timing of genomic testing performed, and use of targeted therapy. Efficacy outcomes were prostate-specific antigen response rate, site-reported radiographic response, and overall survival. Results: A total of 962 eligible patients with mCRPC were identified, including 204 Black patients (21.2%; median [IQR] age at diagnosis, 61 [55-67] years; 131 patients [64.2%] with Gleason scores 8-10; 92 patients [45.1%] with de novo metastatic disease) and 758 White patients (78.8%; median [IQR] age, 63 [57-69] years; 445 patients [58.7%] with Gleason scores 8-10; 310 patients [40.9%] with de novo metastatic disease). Median (IQR) follow-up from mCRPC was 26.6 (14.2-44.7) months. Blood-based molecular testing was more common in Black men (111 men [48.7%]) than White men (317 men [36.4%]; P < .001). Rates of actionable alterations were similar between groups (65 Black men [32.8%]; 215 White men [29.1%]; P = .35), but MMRD or MSI-H was more common in Black men (18 men [9.1]) than White men (36 men [4.9%]; P = .04). PTEN alterations were less frequent in Black men than White men (31 men [15.7%] vs 194 men [26.3%]; P = .003), as were TMPRSS alterations (14 men [7.1%] vs 155 men [21.0%]; P < .001). No other differences were seen in the 15 most frequently altered genes, including TP53, AR, CDK12, RB1, and PIK3CA. Matched targeted therapy was given less frequently in Black men than White men (22 men [33.5%] vs 115 men [53.5%]; P = .008). There were no differences in response to targeted therapy or survival between the two cohorts. Conclusions and Relevance: This cohort study of men with mCRPC found higher frequency of MMRD or MSI-H and lower frequency of PTEN and TMPRSS alterations in Black men compared with White men. Although Black men received targeted therapy less frequently than White men, no differences were observed in clinical outcomes.

A novel method of transapical ProtekDuo rapid deployment cannula as temporary left ventricular assist device.

Peripheral extracorporeal membrane oxygenation (ECMO) is one of the most common strategies for cardiogenic shock. ECMO cannulation is associated with an increased risk of complications. We describe a minimally invasive, off-pump technique to provide adequate hemodynamic support and left ventricular unloading. A 54-year-old male with nonischemic cardiomyopathy and severe peripheral vascular disease with cardiogenic shock was initially supported with inotropes and an intra-aortic balloon pump. Despite continued support, he continued to deteriorate, and we escalated to a temporary left ventricular support with a CentriMag, using a transapical ProtekDuo Rapid Deployment cannula via mini left-thoracotomy. This approach provides adequate hemodynamic support, left ventricular unloading and early ambulation. After 9 days, the patient's functional status was improved and was medically optimized. The patient received a left ventricular assist device as destination therapy. He was discharged home, resumed his normal activities and has been doing well for more than 27 months.

HLA Sensitization in Patients Bridged to Lung Transplantation With Extracorporeal Membrane Oxygenation.

Lung transplantation is a definitive therapy for many end-stage lung pathologies. Extracorporeal membrane oxygenation (ECMO) is increasingly being used as a bridge to lung transplantation (BTT). HLA sensitization is a major barrier to lung transplantation. The development of HLA sensitization while undergoing ECMO support as a BTT has recently been reported in a 2-patient series. Methods: We performed a retrospective analysis of patients undergoing ECMO as a BTT at a single large academic medical center from January 2016 to April 2022. The study was approved by the institutional review board. We selected patients who had undergone ECMO support for at least 7 d with either negative HLA before cannulation or initial negative HLA on ECMO (3 patients). Results: We identified 27 patients bridged to lung transplantation with available HLA data. Of this group, 8 patients (29.6%) developed significant HLA sensitization (>10%). We did not identify any factors predisposing to sensitization, including infection episodes or blood product transfusion. Sensitized patients demonstrated a trend toward an increased primary graft dysfunction rate, a need for posttransplant ECMO support, and a decreased 1-y survival; however, these did not meet statistical significance. Conclusions: Our study is the largest series today describing the association between HLA sensitization and ECMO therapy. We suggest that interaction between the immune system and ECMO circuit contributes to allosensitization pretransplant, similar to that occurring with ventricular assist device. Further work is needed to better characterize the incidence of HLA sensitization in a multicenter cohort and to identify potentially modifiable factors associated with HLA sensitization.

Bilateral Lung Transplantation With Donor Positive for COVID-19 Infection on Bronchoalveolar Lavage: A Case Report.

Initial experience with lung transplant of COVID-19-positive donors was marked by disappointing results, including a reported case of mortality through donor to recipient transmission of infection. However, since that time a number of improvements in preventative and therapeutic measures against COVID-19 have been developed. We present the case of a 51-year-old woman with scleroderma-associated interstitial lung disease who was awaiting lung transplant. A potential donor with excellent lung physiology was located; however, initial testing on bronchoalveolar lavage (BAL) was positive for COVID-19. The donor had tested positive 2 weeks prior and had symptomatically recovered. Our patient had been fully vaccinated but not seroconverted. Given the history of a donor with recovering COVID infection and a fully immunized recipient, our multidisciplinary team elected to proceed with the transplant. The patient successfully underwent bilateral lung transplant with standard induction immunosuppression. Bebtelovimab was given post-transplant day 1 because the recipient remained seronegative to COVID-19. Serial bronchoalveolar lavages post transplant have been negative for COVID-19. The patient has done well after transplant. She was seen in the clinic 2 months post transplant and is ambulatory without supplemental oxygen requirements. To our knowledge, this represents the first reported successful case of lung transplant with a donor positive for COVID-19 on lower respiratory tract sampling.

Repair of Tracheal Dehiscence After Heart-Lung Transplant Complicated by SARS-CoV-2 Infection.

Airway complications are a major cause of morbidity after thoracic transplantation. Airway ischemia, necrosis, and tracheobronchial anastomotic dehiscence are associated with early mortality. We describe a case of tracheal anastomotic dehiscence after en bloc heart-lung transplant complicated by severe acute respiratory syndrome coronavirus 2 infection. Timely surgical management and reconstruction with a bovine pericardial patch and double muscle flap were performed. After 8 months of follow-up, there are no airway complications and normalized allograft function.

State of the art - Extracorporeal membrane oxygenation as a bridge to thoracic transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has revolutionized the treatment of refractory cardiac and respiratory failure, and its use continues to increase, particularly in adults. However, ECMO-related morbidity and mortality remain high. MAIN TEXT: In this review, we investigate and expand upon the current state of the art in thoracic transplant and extracorporeal life support (ELS). In particular, we examine recent increase in incidence of heart transplant in patients supported by ECMO; the potential changes in patient care and selection for transplant in the years prior to updated United Network for Organ Sharing (UNOS) organ allocation guidelines versus those in the years following, particularly where these guidelines pertain to ECMO; and the newly revived practice of heart-lung block transplants (HLT) and the prevalence and utility of ECMO support in patients listed for HLT. CONCLUSIONS: Our findings highlight encouraging outcomes in patients bridged to transplant with ECMO, considerable changes in treatment surrounding the updated UNOS guidelines, and complex, diverse outcomes among different centers in their care for increasingly ill patients listed for thoracic transplant.

A learning health system approach to the COVID-19 pandemic: System-wide changes in clinical practice and 30-day mortality among hospitalized patients.

Introduction: Rapid, continuous implementation of credible scientific findings and regulatory approvals is often slow in large, diverse health systems. The coronavirus disease 2019 (COVID-19) pandemic created a new threat to this common "slow to learn and adapt" model in healthcare. We describe how the University of Pittsburgh Medical Center (UPMC) committed to a rapid learning health system (LHS) model to respond to the COVID-19 pandemic. Methods: A treatment cohort study was conducted among 11 429 hospitalized patients (pediatric/adult) from 22 hospitals (PA, NY) with a primary diagnosis of COVID-19 infection (March 19, 2020 - June 6, 2021). Sociodemographic and clinical data were captured from UPMC electronic medical record (EMR) systems. Patients were grouped into four time-defined patient "waves" based on nadir of daily hospital admissions, with wave 3 (September 20, 2020 - March 10, 2021) split at its zenith due to high volume with steep acceleration and deceleration. Outcomes included changes in clinical practice (eg, use of corticosteroids, antivirals, and other therapies) in relation to timing of internal system analyses, scientific publications, and regulatory approvals, along with 30-day rate of mortality over time. Results: The mean (SD) daily number of admissions across hospitals was 26 (29) with a maximum 7-day moving average of 107 patients. System-wide implementation of the use of dexamethasone, remdesivir, and tocilizumab occurred within days of release of corresponding seminal publications and regulatory actions. After adjustment for differences in patient clinical profiles over time, each month of hospital admission was associated with an estimated 5% lower odds of 30-day mortality (adjusted odds ratio [OR] = 0.95, 95% confidence interval: 0.93-0.97, P < .001). Conclusions: In our large LHS, near real-time changes in clinical management of COVID-19 patients happened promptly as scientific publications and regulatory approvals occurred throughout the pandemic. Alongside these changes, patients with COVID-19 experienced lower adjusted 30-day mortality following hospital admission over time.

Analysis of the movements generated by a multi-field functional electrical stimulation device for upper extremity rehabilitation.

BACKGROUND: The most common chronic sequela after stroke is the loss of arm function, and functional electrical stimulation (FES) applied to the forearm muscles is one of the options to treat it. Surface multi-field electrodes have emerged, showing a great potential to improve the selectivity of the stimulation, delay muscle fatigue, and provide easier donning and doffing. The muscular selectivity takes on special relevance in the rehabilitation of the upper extremity as hand dexterity requires a wide diversity of specific muscle actions. METHODS: This pilot study analyses the movements generated in the wrist and fingers using a commercial multi-field technology-based FES device (Fesia Grasp). The study included five patients with hemiplegic subacute stroke, in which scanning of all cathodes of the electrode was carried out daily for 5 days, in two different forearm positions, with the resulting movements being labeled by experienced therapists. RESULTS: The aim of this pilot study was to determine if there were differences between subjects and between forearm positions in terms of produced movements. Movements of the wrist (two movements) and the fingers (six movements) could be achieved in two different forearm positions. CONCLUSIONS: The multi-field electrode of Fesia Grasp enables to generate a wide range of movements of the hand in different positions. This fact could allow to produce more physiological movement patterns during the rehabilitation process with FES, which could have a beneficial effect on the recovery of patients with neurological diseases.

Optimal multi-field functional electrical stimulation parameters for the "drinking task - reaching phase" and related upper limb kinematics repeatability in post stroke subjects.

BACKGROUND: No specific guidelines for the management of functional electrical stimulation (FES) parameters in post stroke patients have been defined yet, despite its frequent use. The purpose of this study is to characterize the optimal FES parameters that assist the reaching phase of drinking task ("drinking task - reaching phase") on post stroke subjects and to analyze the related upper limb (UL) movement quality indicators repeatability. METHODS: An observational study with a test and re-test design involving ten post stroke subjects with UL dysfunction was performed. End-point and joint kinematics of contralesional UL were assessed during the "drinking task - reaching phase" with FES through a test and retest design. FES parameters were adjusted to improve UL function according to a consensus between physiotherapists and patients' perspective. FINDINGS: It was possible to establish reliable FES parameters that assisted the "drinking task - reaching phase". All FES parameters presented high to very high repeatability and led to moderate to very high repeatability in almost UL movement quality indicators during the "drinking task - reaching phase". INTERPRETATION: These findings show that the main characteristics of FES parameters that improves patient perception of change are quite stable, which facilitate its implementation in clinical practice by allowing consistence between intervention sessions.

BeatWalk: Personalized Music-Based Gait Rehabilitation in Parkinson's Disease.

Taking regular walks when living with Parkinson's disease (PD) has beneficial effects on movement and quality of life. Yet, patients usually show reduced physical activity compared to healthy older adults. Using auditory stimulation such as music can facilitate walking but patients vary significantly in their response. An individualized approach adapting musical tempo to patients' gait cadence, and capitalizing on these individual differences, is likely to provide a rewarding experience, increasing motivation for walk-in PD. We aim to evaluate the observance, safety, tolerance, usability, and enjoyment of a new smartphone application. It was coupled with wearable sensors (BeatWalk) and delivered individualized musical stimulation for gait auto-rehabilitation at home. Forty-five patients with PD underwent a 1-month, outdoor, uncontrolled gait rehabilitation program, using the BeatWalk application (30 min/day, 5 days/week). The music tempo was being aligned in real-time to patients' gait cadence in a way that could foster an increase up to +10% of their spontaneous cadence. Open-label evaluation was based on BeatWalk use measures, questionnaires, and a six-minute walk test. Patients used the application 78.8% (±28.2) of the prescribed duration and enjoyed it throughout the program. The application was considered "easy to use" by 75% of the patients. Pain, fatigue, and falls did not increase. Fear of falling decreased and quality of life improved. After the program, patients improved their gait parameters in the six-minute walk test without musical stimulation. BeatWalk is an easy to use, safe, and enjoyable musical application for individualized gait rehabilitation in PD. It increases "walk for exercise" duration thanks to high observance. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02647242.

Optimal Multifield Functional Electrical Stimulation Parameters for the "Turn on the Light" Task and Related Upper Limb Kinematics Repeatability in Poststroke Subjects.

OBJECTIVE: To characterize the optimal functional electrical stimulation (FES) parameters that assist the turn on the light task (TOTL) on poststroke participants and to analyze the related upper limb (UL) kinematics repeatability. DESIGN: Cross-sectional study. SETTING: Human movement research center. PARTICIPANTS: Poststroke individuals (N=11) with history of a single unilateral stroke that resulted in a motor control dysfunction of the contralesional UL. INTERVENTIONS: FES based on surface multifield technology applied to the contralesional wrist and finger extensors during the TOTL. MAIN OUTCOME MEASURES: FES outcome metrics (virtual electrodes, stimulation duration, intensity) and kinematic metrics (end-point kinematics [absolute and relative duration, mean and peak velocities, relative instant of peak velocity, index of curvature, number of movement units] and joint kinematics [shoulder, elbow, wrist end position and range of movement]). Outcome measures were assessed 2 times with a 72-hour maximum time interval. CONCLUSION: It was possible to establish reliable FES parameters that assisted the TOTL on poststroke participants. These stimulation parameters led to high to very high repeatability in terms of UL kinematics for most of the cases.

Femoral venoarterial extracorporeal membrane oxygenation using a novel biatrial cannula for venous drainage and left ventricular venting.

Extracorporeal life support (ECLS) is an expanding technology for patients in cardiogenic shock. The majority of patients requiring ECLS can be managed with percutaneous venoarterial (VA) femoral cannulation. Despite sufficient extracorporeal circulatory support, a unclear number of patients develop left ventricular distension which can result in increased wall tension and stress as well as worsening pulmonary edema. Indications to vent the left ventricle can be controversial. When venting is indicated, a number of additional procedures may be considered including inotropic support, intra-aortic balloon pump, impella, balloon atrial septostomy, or placement of a transseptal cannula. We present a unique case of a femoral VA extracorporeal membrane oxygenation as a bridge to transplant with left-sided venting using a Bio-Medicus NextGen cannula (Medtronic) with a transseptal approach.

Pedicle flap coverage for infected ventricular assist device augmented with dissolving antibiotic beads: Creation of an antibacterial pocket.

Infectious complications following left ventricular assist device implantation can carry significant morbidity and mortality. The main tenet of treatment is source control which entails local wound care, intravenous antimicrobial therapy, surgical debridement, and at times, soft tissue flap coverage. The mode of therapy depends on the severity, etiology, and location of infection as well as the clinical status of the patient. We describe a case of a 46-year-old male who underwent left ventricular assist device placement complicated by pump thrombosis, recurrent infection, and hardware exposure who was successfully treated with a novel method of staged, soft tissue reconstruction.

Peripheral femoral venoarterial extracorporeal membrane oxygenation as bridge to heart-lung transplant omne iter incipit primus.

Heart-lung transplant (HLT) is a widely accepted modality for certain patients with advanced and refractory cardiopulmonary disease. Some of these patients are critically ill on the transplant waiting list, and venoarterial extracorporeal membrane oxygenation (VA-ECMO) can be used as a bridge to transplantation. Although the experience with ECMO as a bridge to lung transplant is promising, there is limited evidence to use ECMO as a bridge to HLT. Femoral cannulation remains a concern for ambulation given the risk of bleeding and cannula complications despite studies reporting its safety. We present a case of a 56-year-old male with interstitial lung disease and severe secondary pulmonary hypertension, who was successfully bridged to HLT with ambulatory femoral VA-ECMO.

Left ventricular myxoma: A contractile mass causing intracavitary obstruction and severe pulmonary hypertension.

Cardiac myxomas can be fatal and left ventricular (LV) myxomas with papillary muscle and mitral valve (MV) involvement are rare. The following case is that of a 55-year-old woman who developed signs and symptoms of pulmonary hypertension. Imaging revealed a contractile mass in the LV that was in continuum with the papillary muscles and affected MV function. Her clinical course, radiologic, and hemodynamic findings are discussed. Finally, her surgical extraction technique is described in addition to potential complications encountered.

Sortase-mediated fluorescent labeling of CRISPR complexes.

Fluorescent labeling of proteins is a critical requirement for single-molecule imaging studies. Many protein labeling strategies require harsh conditions or large epitopes that can inactivate the target protein, either by decreasing the protein's enzymatic activity or by blocking protein-protein interactions. Here, we provide a detailed protocol to efficiently label CRISPR-Cas complexes with a small fluorescent peptide via sortase-mediated transpeptidation. The sortase tag consists of just a few amino acids that are specifically recognized at either the N- or the C-terminus, making this strategy advantageous when the protein is part of a larger complex. Sortase is active at high ionic strength, 4°C, and with a broad range of organic fluorophores. We discuss the design, optimization, and single-molecule fluorescent imaging of CRISPR-Cas complexes on DNA curtains. Sortase-mediated transpeptidation is a versatile addition to the protein labeling toolkit.