Modern-Day Practice of DCD Liver Transplantation: Controversies, Innovations, and Future Directions.

PURPOSE OF REVIEW: Over the past decade, donation after circulatory death (DCD) liver transplantation has expanded in the United States due to improved surgical experience and perioperative management. Despite these advances, there remains a reluctance towards broader utilization of DCD liver allografts due to lack of standardized donation process, concern for inferior graft survival, and risk of ischemic cholangiopathy associated with temporary lack of oxygenated perfusion during withdrawal of life-supporting treatment during procurement. RECENT FINDINGS: New perfusion technologies offer potential therapeutic options to mitigate biliary complications and expand utilization of marginal DCD grafts. As these modalities enter routine clinical practice, DCD utilization will continue to increase, and liver allocation policies in turn will evolve to reflect this growing practice. This review describes recent progress in DCD LT, current challenges with utilization of DCD liver allografts, and how novel technologies and policies could impact the future of the field.

Development of a rat forelimb vascularized composite allograft (VCA) perfusion protocol.

Vascularized composite allografts (VCAs) refer to en bloc heterogenous tissue that is transplanted to restore form and function after amputation or tissue loss. Rat limb VCA has emerged as a robust translational model to study the pathophysiology of these transplants. However, these models have predominately focused on hindlimb VCAs which does not translate anatomically to upper extremity transplantation, whereas the majority of clinical VCAs are upper extremity and hand transplants. This work details our optimization of rat forelimb VCA procurement and sub-normothermic machine perfusion (SNMP) protocols, with results in comparison to hindlimb perfusion with the same perfusion modality. Results indicate that compared to hindlimbs, rat forelimbs on machine perfusion mandate lower flow rates and higher acceptable maximum pressures. Additionally, low-flow forelimbs have less cellular damage than high-flow forelimbs based on oxygen uptake, edema, potassium levels, and histology through 2 hours of machine perfusion. These results are expected to inform future upper extremity VCA preservation studies.

Robotic vs. Laparoscopic Metabolic and Bariatric Surgery, Outcomes over 5 Years in Nearly 800,000 Patients.

INTRODUCTION: Studies assessing outcomes between laparoscopic and robotic bariatric metabolic surgery (BMS) have been limited by the relatively small percentage of robotic cases. However, in recent years, the number of robotic BMS cases has doubled. We report the largest US study comparing robotic versus laparoscopic outcomes in BMS over the longest time period (5 years). METHODS: Analysis of the MBSAQIP database was undertaken. This included information on 791,423 patients from 2015-2019 in the USA. Within this retrospective case-control study, 13.7% of SG and 16.6% of RYGB cases were done robotically. SETTING: USA, MBSAQIP database. RESULTS: Robotic BMS increased mean operative time by 26 min for SG and 40 min for RYGB. However, this did not increase the 30-day venous thromboembolism (VTE) or organ dysfunction complications between the 2 groups. Robotic SG had slightly higher risks of multiple infectious complications (OR 1.26 to 1.76). Robotic RYGB had slightly lower infectious complications and transfusion requirements. Robotic BMS had higher 30-day readmission rates and 30-day reoperative rates for both SG and RYGB. CONCLUSIONS: Both robotic SG and RYGB were found to have significantly longer operative times than laparoscopic SG and RYGB. Potential outcome benefits from robotic BMS can include a reduction in infectious complications and transfusion requirements with robotic RYGB cases. SGs were found to have slightly higher infectious complications.

Heterogeneity in transplant center responses to the minimum acceptance criteria across UNOS regions.

Transplantation of organs from increased risk donors for infection transmission (IRDs) is increasing. These organs confer survival benefit to recipients. This study examined transplant center acceptance policies for IRD kidneys across United Network for Organ Sharing (UNOS) regions, based on transplant centers' annual responses to the Minimum Acceptance Criteria (MAC) for acceptance of IRD kidneys, and the association with national and regional IRD kidney utilization. De-identified MAC responses from all transplant centers in the United States from 2007 to 2019 were obtained. Implementation of MAC responses into practice was evaluated based on annual rates of recovery and transplantation of IRD kidneys, by MAC and UNOS region. Nationally, the number of transplant centers willing to accept IRD kidneys across all criteria increased from 22% in 2007 to 64% in 2019. Acceptance rates increased markedly from donors with intravenous drug use and other potential HIV exposures. However, significant heterogeneity exists in transplant center willingness to accept IRD kidneys, both regionally and between criteria. Trends towards increasing acceptance are strongly associated with higher rates of recovery and transplantation of IRD kidneys. Further research on provider- and center-based refusal to consider IRD kidneys for waitlisted patients is needed to improve utilization of this organ pool.

The role of antifreeze glycoprotein (AFGP) and polyvinyl alcohol/polyglycerol (X/Z-1000) as ice modulators during partial freezing of rat livers.

Introduction: The current liver organ shortage has pushed the field of transplantation to develop new methods to prolong the preservation time of livers from the current clinical standard of static cold storage. Our approach, termed partial freezing, aims to induce a thermodynamically stable frozen state at high subzero storage temperatures (-10°C to -15°C), while simultaneously maintaining a sufficient unfrozen fraction to limit ice-mediated injury. Methods and results: Using glycerol as the main permeating cryoprotectant agent, this research first demonstrated that partially frozen rat livers showed similar outcomes after thawing from either -10°C or -15°C with respect to subnormothermic machine perfusion metrics. Next, we assessed the effect of adding ice modulators, including antifreeze glycoprotein (AFGP) or a polyvinyl alcohol/polyglycerol combination (X/Z-1000), on the viability and structural integrity of partially frozen rat livers compared to glycerol-only control livers. Results showed that AFGP livers had high levels of ATP and the least edema but suffered from significant endothelial cell damage. X/Z-1000 livers had the highest levels of ATP and energy charge (EC) but also demonstrated endothelial damage and post-thaw edema. Glycerol-only control livers exhibited the least DNA damage on Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining but also had the lowest levels of ATP and EC. Discussion: Further research is necessary to optimize the ideal ice modulator cocktail for our partial-freezing protocol. Modifications to cryoprotective agent (CPA) combinations, including testing additional ice modulators, can help improve the viability of these partially frozen organs.

Ethical and Public Health Considerations for Integrating Physicians with Mental Disability into the Physician Workforce.

Stigma against mental disability within the medical field continues to impose significant barriers on physicians and trainees. Here, we examine several implications of this stigma and propose steps toward greater inclusion of persons with mental disabilities in the physician workforce.

The effect of blood cells retained in rat livers during static cold storage on viability outcomes during normothermic machine perfusion.

In transplantation, livers are transported to recipients using static cold storage (SCS), whereby livers are exposed to cold ischemic injury that contribute to post-transplant risk factors. We hypothesized that flushing organs during procurement with cold preservation solutions could influence the number of donor blood cells retained in the allograft thereby exacerbating cold ischemic injury. We present the results of rat livers that underwent 24 h SCS after being flushed with a cold University of Wisconsin (UW) solution versus room temperature (RT) lactated ringers (LR) solution. These results were compared to livers that were not flushed prior to SCS and thoroughly flushed livers without SCS. We used viability and injury metrics collected during normothermic machine perfusion (NMP) and the number of retained peripheral cells (RPCs) measured by histology to compare outcomes. Compared to the cold UW flush group, livers flushed with RT LR had lower resistance, lactate, AST, and ALT at 6 h of NMP. The number of RPCs also had significant positive correlations with resistance, lactate, and potassium levels and a negative correlation with energy charge. In conclusion, livers exposed to cold UW flush prior to SCS appear to perform worse during NMP, compared to RT LR flush.

The impact of race and comorbid conditions on adult liver transplant outcomes in obese recipients.

Many prior studies comparing liver transplant outcomes between obese and nonobese recipients found no significant differences in survival. However, obesity is intrinsically associated with demographic factors such as race and comorbidities. Thus, this work aimed to analyze the effects of obesity, in conjunction with these factors, on liver transplant outcomes. OPTN data was analyzed to identify adult-only, first-time liver transplants between 1995 and 2019. Obesity was defined by the CDC obesity classification. Race, insurance status, age, and comorbidities were analyzed together with patient survival and graft survival using a multivariable Cox Proportional-Hazards model and long-term survival with Kaplan-Meier curves. The multivariable models found that being black, older than 50 years, having diabetes, or having nonprivate insurance were all risk factors for both patient survival and graft survival after liver transplant. Adjusting for obesity class, black recipients had a 20% lower patient survival and 23% lower graft survival compared with nonblack recipients. Survival curves verified that obese black liver transplant recipients had poorer long-term patient survival and graft survival compared with both obese nonblack and nonobese recipients. In conclusion, obesity compounds known factors associated with poor outcomes after liver transplantation. Further work is critical to understand why these discrepancies persist.

Influence of donor and recipient hepatitis B virus infection on long-term outcomes after kidney transplantation.

BACKGROUND: The demand for transplantable kidneys continues to outstrip supply, and the risk of donor-derived infection limits utilization. The effect of donor or recipient HBV status, defined by surface antigen (HBsAg) positivity, on long-term survival outcomes of kidney transplant (KT) is unknown. METHODS: We conducted a retrospective cohort study based on Organ Procurement and Transplantation Network (OPTN) data from 2000 to 2019. We identified three cohorts based on donor (D) or recipient (R) HBsAg status: D-R, D-R+, and D+R-. Pairwise comparisons of patient survival (PS) and all-cause graft survival (GS) after propensity score matching were performed to assess the effect of HBV infection in KT recipients. RESULTS: Our findings showed that there were no statistically significant differences in PS and GS among D-R, D-R+, and D+R-groups, nor was the patient or GS different between donor and recipient HBsAg+ status. Finally, in 2019 kidney discard rates were 15% higher for HBsAg+ deceased donors compared to HBsAg- donors. CONCLUSIONS: HBsAg+ status was not associated with worse PS or GS after KT. Prior to broadly advocating utilization of HbsAg+ kidneys, further studies assessing KT recipient morbidity and safety are necessary.

Thrombolytic Therapy During ex-vivo Normothermic Machine Perfusion of Human Livers Reduces Peribiliary Vascular Plexus Injury.

Background: A major limitation in expanding the use of donation after circulatory death (DCD) livers in transplantation is the increased risk of graft failure secondary to ischemic cholangiopathy. Warm ischemia causes thrombosis and injury to the peribiliary vascular plexus (PVP), which is supplied by branches of the hepatic artery, causing higher rates of biliary complications in DCD allografts. Aims/Objectives: We aimed to recondition discarded DCD livers with tissue plasminogen activator (tPA) while on normothermic machine perfusion (NMP) to improve PVP blood flow and reduce biliary injury. Methods: Five discarded DCD human livers underwent 12 h of NMP. Plasminogen was circulated in the base perfusate prior to initiation of perfusion and 1 mg/kg of tPA was administered through the hepatic artery at T = 0.5 h. Two livers were split prior to perfusion (S1, S2), with tPA administered in one lobe, while the other served as a control. The remaining three whole livers (W1-W3) were compared to seven DCD control liver perfusions (C1-C7) with similar hepatocellular and biliary viability criteria. D-dimer levels were measured at T = 1 h to verify efficacy of tPA. Lactate, total bile production, bile pH, and difference in biliary injury scores before and after perfusion were compared between tPA and non-tPA groups using unpaired, Mann-Whitney tests. Results: Average weight-adjusted D-dimer levels were higher in tPA livers in the split and whole-liver model, verifying drug function. There were no differences in perfusion hepatic artery resistance, portal vein resistance, and arterial lactate between tPA livers and non-tPA livers in both the split and whole-liver model. However, when comparing biliary injury between hepatocellular and biliary non-viable whole livers, tPA livers had significantly lower PVP injury scores (0.67 vs. 2.0) and mural stroma (MS) injury scores (1.3 vs. 2.7). Conclusion: This study demonstrates that administration of tPA into DCD livers during NMP can reduce PVP and MS injury. Further studies are necessary to assess the effect of tPA administration on long term biliary complications.

The Heterogenous Effect of COVID-19 on Liver Transplantation Activity and Waitlist Mortality in the United States.

Background: The COVID-19 pandemic curtailed the practice of liver transplantation (LT), which lacks a temporizing life-saving measure for candidates on the waitlist. Aims/Objectives: The objective of this research was to (1) determine the effect of decreased LT activity on waitlist mortality in the United States and (2) assess if this effect was homogenous across the country. Methods: We conducted a retrospective, cross-sectional analysis utilizing United Network for Organ Sharing (UNOS) data assessing 3,600 liver transplants from January 1, 2020 to June 2, 2020. COVID-19 incidence data was taken directly from the New York Times case count. Results: During weeks 10 to 15 of 2020, there was a 38% reduction in the number of LTs performed nationally, which was temporally associated with a transient 97% increase in waitlist mortality. When stratified by UNOS region, waitlist mortality was inversely correlated with the number of LTs performed in all 11 regions. However, the range of the association strength (r) was large (Pearson correlation coefficient range: -0.73 to -0.01). Conclusion: Interruptions in LT activity due to COVID-19 were associated with rapid increases in waitlist mortality, and these effects were unevenly distributed among candidates across the United States. The transplant community can utilize these results to mitigate inequalities in transplant allocation between UNOS regions and advocate for the uninterrupted practice of LT should another pandemic surge or COVID-19 variant arise.

Long-Term Outcomes of Early Experience in Donation After Circulatory Death Liver Transplantation: Outcomes at 10 Years.

BACKGROUND Donation after circulatory death (DCD) livers remain an underutilized pool of transplantable organs due to concerns of inferior long-term patient survival (PS) and graft survival (GS), which factors greatly into clinician decision-making and patient expectations. MATERIAL AND METHODS This retrospective study used SRTR data to assess 33 429 deceased-donor liver transplants (LT) and compared outcomes between DCD and donation after brain death (DBD) LT recipients in the United States. Data were collected from 2002 to 2008 to obtain 10 years of follow-up (2012-2018) in the era of MELD implementation. Propensity scores for donor type (DCD vs DBD) were estimated using logistic regression, and the association of donor type with 10-year outcomes was evaluated after adjustment using stabilized inverse probability of treatment weights. RESULTS After adjusting for confounders, patient survival for DBD recipients at 10 years was 60.7% versus 57.5% for DCD recipients (P=0.24). Incorporating retransplants, 10-year adjusted patient survival was 60.2% for DBD recipients versus 55.5% for DCD recipients (P=0.07). Adjusted 10-year graft survival for DBD recipients was 56.4% versus 45.4% for DCD recipients (P<0.001). Surprisingly, however, 1 year after LT, DBD and DCD graft failure rates converged to 7.5% over the remaining 9 years. CONCLUSIONS These data reveal inferior 10-year DCD graft survival, but only in the first year after LT, and similar 10-year patient survival in DCD LT recipients compared to DBD recipients. Our results show the stability and longevity of DCD grafts, which should encourage the increased utilization of these livers for transplantation.

Evolving utilization of donation after circulatory death livers in liver transplantation: The day of DCD has come.

Compared to donation after brain death (DBD), livers procured for transplantation from donation after circulatory death (DCD) donors experience more ischemia-reperfusion injury and higher rates of ischemic cholangiopathy due to the period of warm ischemic time (WIT) following withdrawal of life support. As a result, utilization of DCD livers for liver transplant (LT) has generally been limited to short WITs and younger aged donor grafts, causing many recovered DCD organs to be discarded without consideration for transplant. This study assesses how DCD liver utilization and outcomes have changed over time, using OPTN data from adult, first-time, deceased donor, whole-organ LTs between January 1995 and December 2019. Results show that increased clinical experience with DCD LT has translated into increased use of livers from DCD donors, shorter ischemic times, shorter lengths of hospitalization after transplant, and lower rates of retransplantation. The data also reveal that over the past decade, the rate of increase in DCD LTs conducted in the United States has outpaced that of DBD. Together, these trends signal an opportunity for the field of liver transplantation to mitigate the organ shortage by capitalizing on DCD liver allografts that are currently not being utilized.

Biases in the evaluation of self-harm in patients with disability due to spinal cord injury.

INTRODUCTION: Suicide is a global problem and accurate assessment of risk for self-harm is critical. Even morally principled clinicians can manifest bias when assessing self-harm in patients with physical disabilities such as spinal cord injury (SCI). Assessment of self-harm is an obligation for health care clinicians and overestimating or underestimating risk may undermine a patient's trust in their care, possibly leading to less engagement, increased apathy about having an interest in living, and less adherence to healthy treatment options. CASE PRESENTATION: Introduces readers to three biases that can impact decision-making regarding a patient with a disability when assessing the patient's risk for self-harm: (1) ineffectual bias, (2) fragile friendliness bias, and (3) catastrophe bias. These preconceptions are derived from a mix of paternalism, projection, low expectations, pity, and infantilization. In this paper, we explain how each bias can affect clinical decision-making regarding diagnosis, treatment, prognosis, and prevention for patients with SCI within a common case scenario. Readers can employ personal reflection and potential self-application when they encounter individuals with SCI in and outside clinical settings. DISCUSSION: Unchecked biases toward the disabled and patients with SCI can undermine ethical caregiving. Biases are habits of mind and thoughtful clinical and education interventions can improve clinical practice. The literature on health care bias with other minority groups is instructive for investigating biases related to patients with disabilities, and especially for clinicians outside of rehabilitation medicine.

Twenty-four hour ex-vivo normothermic machine perfusion in rat livers.

Ex-vivo liver perfusion (EVLP) is an ideal platform to study liver disease, therapeutic interventions, and pharmacokinetic properties of drugs without any patient risk. Rat livers are an ideal model for EVLP due to less organ quality variability, ease of hepatectomy, well-defined molecular pathways, and relatively low costs compared to large animal or human perfusions. However, the major limitation with rat liver normothermic machine perfusion (NMP) is maintaining physiologic liver function on an ex-vivo machine perfusion system. To address this need, our research demonstrates 24-hour EVLP in rats under normothermic conditions. Early (6 hour) perfusate transaminase levels and oxygen consumption of the liver graft are shown to be good markers of perfusion success and correlate with viable 24-hour post-perfusion histology. Finally, we address overcoming challenges in long-term rat liver perfusions such as rising intrahepatic pressures and contamination, and offer future directions necessary to build upon our work.

From disability to human flourishing: how fourth wave psychotherapies can help to reimagine rehabilitation and medicine as a whole.

Aim: With disabled patients, clinicians are often mechanistically oriented, limiting goals to bodily improvements of perceived deficits back to species-typical functioning. Psychological goals, when present at all, are often pessimistically narrow, or phenomenologically shallow. Recent research on fourth wave psychotherapies helps broaden clinical concepts of healing and treatment beyond mere deficit remediation, and helps match clinical goals with the richness of human flourishing and the layered complexity of the patient's evolving experience of meaning.Method: This article draws from first-hand accounts of the experience of disability and adjustment to impairment, along with a synthesis of recent theoretical and experimental work in clinical psychology and psychotherapy, to present recommendations for more accurate and ethical notions of rehabilitation for clinical practice.Results: We explain the clinical value of "flourishing": the psychological, social, cultural, existential, moral, spiritual and religious dimensions of the patient in the context of their dynamic narrative existence in meaningful relationship and ritual formation. This approach allows clinicians to personalize and humanize caregiving in line with human strengths, move beyond an aim of mere recovery, more accurately characterize perceived impairments, goals of care, and successful treatment outcomes. These more capacious and experientially-attuned clinical concepts and aims help the clinician accompany and empower patients by understanding what is at stake throughout the illness experience.Conclusions: This flourishing model helps to reimagine the clinician-patient relationship, and the methods and entire purpose of rehabilitation medicine, and clinical medicine more broadly. The condition of blindness is presented as an illustrative case.Implications for rehabilitationAmidst vast medical and technological advances in diagnosis and treatment of disabilities, modern health systems often still approach rehabilitation of disability via species-typical standards of bodily or mental homeostasis as the standard of sound health, without considering the perspectives and experiences of flourishing that are unique to the individual who is sufferingPsychological, social scientific, and religious traditions uniquely explore the inner experiences of individuals and their relationships, and can be used to help patients find individualized paths to recovery, healing, and flourishingFourth-wave psychotherapies, utilizing existential, humanistic, and spiritual/religious philosophies, have resources clinicians can use to help patients aim beyond mere recovery, and allow for the possibility of "ultrabilitation"Attention to the psychological, social, cultural, existential, moral, spiritual, and religious dimensions of the patient in the context of their dynamic existence can promote ultrabilitationDedicated focus on compassion, virtue, dignity, gratitude, contemplative wisdom, and transcendence can enable one to conceptualize flourishing in a way independent or complementary to bodily outcomes in recovery, and sometimes even when illness or disability persists.

Biomarkers for Barrett's esophagus - a contemporary review.

INTRODUCTION: Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate (10%-18%), and incidence has increased dramatically in the past three decades. Barrett's esophagus (BE) is the precursor lesion to EAC and is the replacement of the normally squamous lined esophagus with columnar cells that develop an intestinal phenotype characterized by the presence of goblet cells. Given the known precursor state, EAC is amenable to screening and surveillance strategies (analogous to colon cancer). However, unlike from colon cancer screening, BE poses challenges that make effective screening difficult. Robust and concerted effort is under way to find biomarkers of BE. Areas covered: This review summarizes current known biomarkers for BE. These include dysplasia, genomic markers, and gene expression alterations that occur early in the dysplasia/carcinoma sequence. Expert commentary: Despite the tremendous breadth of work in studying molecular advances, the ideal biomarker for BE has not yet been discerned. This review comments on innovations in the field of BE research that combine state-of-the-art molecular advances with simple technologies.