Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation ...pathways continues to evolve.
Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation.
Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.
CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers ...with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
IMPORTANCE: A growing body of literature has been developed with the goal of attempting to understand the experiences of female surgeons. While it has helped to address inequities and promote ...important programmatic improvements, work remains to be done. OBJECTIVE: To explore how practicing male and female surgeons’ experiences with gender compare across 5 qualitative/quantitative domains: career aspirations, gender-based discrimination, mentor-mentee relationships, perceived barriers, and recommendations for change. DESIGN, SETTING, AND PARTICIPANTS: This national concurrent mixed-methods survey of Fellows of the American College of Surgeons (FACS) compared differences between male and female FACS. Differences between female FACS and female members of the Association of Women Surgeons (AWS) were also explored. A randomly selected 3:1 sample of US-based male and female FACS was surveyed between January and June 2020. Female AWS members were surveyed in May 2020. EXPOSURE: Self-reported gender. MAIN OUTCOMES AND MEASURES: Self-reported experiences with career aspirations (quantitative), gender-based discrimination (quantitative), mentor-mentee relationships (quantitative), perceived barriers (qualitative), and recommendations for change (qualitative). RESULTS: A total of 2860 male FACS (response rate: 38.1% 2860 of 7500) and 1070 female FACS (response rate: 42.8% 1070 of 2500) were included, in addition to 536 female AWS members. Demographic characteristics were similar between randomly selected male and female FACS, with the notable exception that female FACS were less likely to be married (720 67.3% vs 2561 89.5%; nonresponse-weighted P < .001) and have children (660 61.7% vs 2600 90.9%; P < .001). Compared with female FACS, female AWS members were more likely to be younger and hold additional graduate degrees (320 59.7% were married; 238 44.4% had children). FACS of both genders acknowledged positive and negative aspects of dealing with gender in a professional setting, including shared experiences of gender-based harassment, discrimination, and blame. Female FACS were less likely to have had gender-concordant mentors. They were more likely to emphasize the importance of gender when determining career aspirations and prioritizing future mentor-mentee relationships. Moving forward, female FACS emphasized the importance of avoiding competition among female surgeons. They encouraged male surgeons to acknowledge gender bias and admit their potential role. Male FACS encouraged male and female surgeons to treat everyone the same. CONCLUSIONS AND RELEVANCE: Experiences with gender are not limited to supportive female surgeons. The results of this study emphasize the importance of recognizing the voices of all stakeholders involved when striving to promote workforce diversity and the related need to develop quality improvement/surgical education initiatives that enhance inclusion through open, honest discourse.
Right heart failure occurs in 9% to 44% of left ventricular assist device (LVAD) implants, of which less than 10% require right ventricular assist device (RVAD) support either concurrently with the ...LVAD or staged, as a delayed procedure. We have reported our outcomes based on whether the RVAD was placed concurrently or staged.
Clinical data were obtained from the Duke University Medical Center database. The study focused on all consecutive adult patients who received continuous flow LVAD with either concurrent or staged (within 7 days) extracorporeal, temporary RVAD, between October 2007 and October 2017. Adverse event profiles and ability to wean from RVAD were compared between these two groups.
Overall, 43 patients required an extracorporeal RVAD; 67% (n = 29) were implanted concurrently and 33% (n = 14) were implanted as staged after the LVAD. In all, 67% of patients (n = 29) could be weaned to an isolated LVAD. The 30-day, inhospital, and total mortality rates for our cohort were 14%, 28%, and 51% respectively. The mortality rate in the study period for the staged implants was 71% versus 45% for the concurrent implants (p = 0.101). In addition, staged RVAD implantation carried a significantly higher rate of postoperative renal failure (64% versus 28%, p = 0.044).
There was a low incidence of need for RVAD in our cohort. The majority could be weaned to an isolated LVAD. Morbidity and mortality rates of this mode of biventricular support remain high. Early institution of RVAD support was associated with reduced rates of post-LVAD renal failure rates.
Mutagenesis is integral for bacterial evolution and the development of antibiotic resistance. Environmental toxins and stressors are known to elevate the rate of mutagenesis through direct DNA ...toxicity, known as stress-associated mutagenesis, or via a more general stress-induced process that relies on intrinsic bacterial pathways. Here, we characterize the spectra of mutations induced by an array of different stressors using high-throughput sequencing to profile thousands of spectinomycin-resistant colonies of Bacillus subtilis. We found 69 unique mutations in the
and
genes, and that each stressor leads to a unique and specific spectrum of antibiotic-resistance mutations. While some mutations clearly reflected the DNA damage mechanism of the stress, others were likely the result of a more general stress-induced mechanism. To determine the relative fitness of these mutants under a range of antibiotic selection pressures, we used multistrain competitive fitness experiments and found an additional landscape of fitness and resistance. The data presented here support the idea that the environment in which the selection is applied (mutagenic stressors that are present), as well as changes in local drug concentration, can significantly alter the path to spectinomycin resistance in B. subtilis.
Donor brain death duration (BDD) may impact posttransplant graft function and survival in lung transplant.
We queried the 2007 to 2018 United Network for Organ Sharing Registry for adult recipients ...undergoing first-time isolated lung transplant. Cox proportional hazard modeling with splines enabled identification of 3 donor brain death intervals for subsequent analysis: short (<24 hours), reference (24-60 hours), and long (>60 hours). The primary outcome was posttransplant survival.
In total, 19,721 donors and recipients met inclusion criteria. Median time from donor brain death until cross-clamp was 36.6 hours (interquartile range, 19.5). Unadjusted overall survival between cohorts was equivalent (log-rank P = .42); however, longer BDD was associated with improved bronchiolitis obliterans syndrome (BOS)-free survival (log-rank P < .001). On multivariable Cox proportional hazards regression, BDD was not associated with recipient survival (P > .05). Similarly, logistic regression did not identify an independent association between BDD and primary graft dysfunction (P > .05). Increased BDD was, however, associated with a decreased risk of acute rejection (long vs reference; adjusted odds ratio, 0.78; 95% confidence interval, 0.64-0.94) and improved BOS-free survival (long vs reference; adjusted hazard ratio, 0.88; 95% confidence interval, 0.81-0.96).
Donor BDD is not associated with posttransplant survival or primary graft dysfunction. Long donor BDD, however, is associated with a decreased risk for acute rejection and improved BOS-free survival. Therefore, lung allografts from donors with a prolonged length of time from brain death until explant should not be viewed less favorably by donor selection centers.
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Lung transplantation offers a survival benefit for patients with end-stage lung disease. When suitable donors are identified, centers must accept or decline the offer for a matched candidate on their ...waitlist. The degree to which variability in per-center offer acceptance practices impacts candidate survival is not established. The purpose of this study was to determine the degree of variability in per-center rates of lung transplantation offer acceptance and to ascertain the associated contribution to observed differences in per-center waitlist mortality.
We performed a retrospective cohort study of candidates waitlisted for lung transplantation in the US using registry data. Logistic regression was fit to assess the relationship of offer acceptance with donor, candidate, and geographic factors. Listing center was evaluated as a fixed effect to determine the adjusted per-center acceptance rate. Competing risks analysis employing the Fine-Gray model was undertaken to establish the relationship between adjusted per-center acceptance and waitlist mortality.
Of 15,847 unique organ offers, 4,735 (29.9%) were accepted for first-ranked candidates. After adjustment for important covariates, transplant centers varied markedly in acceptance rate (9%-67%). Higher cumulative incidence of 1-year waitlist mortality was associated with lower acceptance rate. For every 10% increase in adjusted center acceptance rate, the risk of waitlist mortality decreased by 36.3% (sub-distribution hazard ratio 0.637; 95% confidence interval 0.592-0.685).
Variability in center-level behavior represents a modifiable risk factor for waitlist mortality in lung transplantation. Further intervention is needed to standardize center-level offer acceptance practices and minimize waitlist mortality.
Lungs from “nonideal,” but acceptable donors are underutilized; however, organ procurement organization (OPO) metrics do not reflect the extent to which OPO‐specific practices contribute to these ...trends. We developed a comprehensive system to evaluate nonideal lung donor avoidance, or risk aversion among OPOs. Adult donors in the UNOS registry who donated ≥1 organ for transplantation between 2007 and 2018 were included. Nonideal donors had any of age>50, smoking history ≥20 pack‐years, PaO2/FiO2 ratio ≤350, donation after circulatory death, or increased risk status. OPO‐level risk aversion in donor pursuit, consent attainment, lung recovery, and transplantation was assessed. Among 83916 donors, 70372 (83.9%) were nonideal. Unadjusted OPO‐level rates of nonideal donor pursuit ranged from 81 to 100%. In a three‐tier system of overall risk aversion, tier 3 OPOs (least risk‐averse) had the highest rates of nonideal donor pursuit, consent attainment, lung recovery, and transplantation. Tier 1 OPOs (most risk‐averse) had the lowest rates of donor pursuit, consent attainment, and lung recovery, but higher rates of transplantation compared to tier 2 OPOs (moderately risk‐averse). Risk aversion varies among OPOs and across the donation process. OPO evaluations should reflect early donation process stages to best differentiate over‐ and underperforming OPOs and encourage optimal OPO‐specific performance.
The authors characterize variability in the pursuit and use of nonideal donor lungs among US organ procurement organizations and propose a 3‐tier evaluation system for OPOs that provides a detailed performance breakdown for each stage of the donation process and actionable information to guide improvement.
Background
Organ procurement organizations (OPOs) vary in willingness to pursue and utilize non‐ideal donor lungs; implications of these practices for lung transplant (LTx) recipients remain unclear. ...We examined associations between OPO‐level behavior toward non‐ideal donors and post‐LTx outcomes.
Methods
Adult lung donors and corresponding adult first‐time LTx recipients in the 2008–2019 UNOS registry were included. Non‐ideal donors had any of age > 50, smoking history ≥20 pack‐years, PaO2/FiO2 ratio ≤350, donation after circulatory death, or increased risk status. OPOs were classified as least, moderately, or most aggressive based on non‐ideal donor pursuit, consent attainment, lung recovery, and transplantation. Post‐transplant outcomes were compared among aggressiveness strata.
Results
Of 22,795 recipients, 6229 (27.3%), 8256 (36.2%), and 8310 (36.5%) received lungs from least, moderately, and most aggressive OPOs, respectively. Moderately aggressive OPOs had the highest recipient rates of pre‐discharge acute rejection, grade 3 primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and longest lengths of stay. After adjustment, moderately and most aggressive OPOs had similar risks of recipient mortality as least aggressive OPOs.
Conclusions
The most and least aggressive OPOs achieve similar patient survival and short‐term post‐LTx outcomes. Aggressive pursuit and utilization of non‐ideal donor lungs by less aggressive OPOs would likely expand the donor pool, without compromising recipient outcomes.
Abstract
BACKGROUND
Patient-reported assessments of the clinic experience are increasingly important for improving the delivery of care. The Clinician and Group Consumer Assessment of Healthcare ...Providers and Systems (CG-CAHPS) survey is the current standard for evaluating patients’ clinic experience, but its format gives 2-mo delayed feedback on a small proportion of patients in clinic. Furthermore, it fails to give specific actionable results on individual encounters.
OBJECTIVE
To develop and assess the impact of a single-page Clinic Satisfaction Tool (CST) to demonstrate real-time feedback, individualized responses, interpretable and actionable feedback, improved patient satisfaction and communication scores, increased physician buy-in, and overall feasibility.
METHODS
We assessed CST use for 12 mo and compared patient-reported outcomes to the year prior. We assessed all clinic encounters for patient satisfaction, all physicians for CG-CAHPS global rating, and physician communication scores, and evaluated the physician experience 1 yr after implementation.
RESULTS
During implementation, 14 690 patients were seen by 12 physicians, with a 96% overall CST utilization rate. Physicians considered the CST superior to CG-CAHPS in providing immediate feedback. CG-CAHPS global scores trended toward improvement and were predicted by CST satisfaction scores (P < .05). CG-CAHPS physician communication scores were also predicted by CST satisfaction scores (P < .01). High CST satisfaction scores were predicted by high utilization (P < .05). Negative feedback dropped significantly over the course of the study (P < .05).
CONCLUSION
The CST is a low-cost, high-yield improvement to the current method of capturing the clinic experience, improves communication and satisfaction between physicians and patients, and provides real-time feedback to physicians.
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