Real-world evidence for factors associated with maintenance treatment practices among U.S. adults with autoimmune hepatitis.

BACKGROUND AIMS: While avoidance of long-term corticosteroids is a common objective in the management of autoimmune hepatitis (AIH), prolonged immunosuppression is usually required to prevent disease progression. This study investigates the patient and provider factors associated with treatment patterns in U.S. patients with AIH. APPROACH RESULTS: A retrospective cohort of adults with incident and prevalent AIH was identified from Optum's de-identified Clinformatics® Data Mart Database. All patients were followed for at least 2 years, with exposures assessed during the first year and treatment patterns during the second. Patient and provider factors associated with corticosteroid-sparing monotherapy and cumulative prednisone use were identified using multivariable logistic and linear regression, respectively.The cohort was 81.2% female, 66.3% White, 11.3% Black, 11.2% Hispanic and with median age 61 years. Among 2,203 patients with ≥1 AIH prescription fill, 83.1% received a single regimen for >6 months of the observation year, which included 52.2% azathioprine monotherapy, 16.9% azathioprine/prednisone and 13.3% prednisone monotherapy. Budesonide use was uncommon (2.1% combination, 1.9% monotherapy). Hispanic ethnicity (aOR 0.56; p=0.006), cirrhosis (aOR 0.73; p=0.019), osteoporosis (aOR 0.54; p=0.001) and top quintile of provider AIH experience (aOR 0.66; p=0.005) were independently associated with lower use of corticosteroid-sparing monotherapy. Cumulative prednisone use was greater with diabetes (+441 mg/year; p=0.004), osteoporosis (+749 mg/year; p<0.001) and highly experienced providers (+556 mg/year; p<0.001). CONCLUSIONS: Long-term prednisone therapy remains common, and unexpectedly higher among patients with comorbidities potentially aggravated by corticosteroids. The greater use of corticosteroid-based therapy with highly experienced providers may reflect more treatment-refractory disease.

Center expansion of liver transplants using donation after circulatory death organs is associated with reduced overall waitlist mortality.

INTRODUCTION: Waitlist outcomes in liver transplantation (LT) for individual recipients are improved by use of allografts procured through donation after circulatory death (DCD). However, the impact of increased DCD acceptance on overall center outcomes is unknown. METHODS: Using the United Network for Organ Sharing database, 88 centers performing an average of ≥10 LTs/year between 1/2004 and 12/2019 were compared by percent DCD use quartile and categorized into four phenotypes according to temporal usage trends. Overall center median Model for End-stage Liver Disease at LT (MMaT), waitlist mortality, and waiting time were evaluated. RESULTS: The overall DCD rate was 6.1% (N = 4906/80,709), ranging from 0% to 25.5%. Centers in the top DCD use quartile had lower MMaT (24 vs. 26; p < .001) and shorter overall waiting times (median 66 days vs. 90 days; p < .001) compared to bottom quartile centers. MMaT increased less over time at centers with increasing DCD use and was lower than at centers with declining DCD use (27 vs. 32; p = .017). Overall waitlist mortality between 2016 and 2019 was lower at increasing DCD use centers (17.8% vs. 22.5%, p = .034), yet did not affect 1-year mortality (p = .747). CONCLUSIONS: The improved waitlist outcomes at centers with expanded DCD use extend beyond DCD recipients alone without negative consequences to overall post-LT center metrics.

Utilization and outcomes of rescue hepatectomy among U.S. liver retransplant candidates.

INTRODUCTION: The frequency and outcomes of anhepatic patients listed for transplantation in the United States have not been studied. The United Network for Organ Sharing (UNOS) records anhepatic status for patients listed as Status 1A for hepatic artery thrombosis (HAT) or primary non-function (PNF). METHODS: Using the UNOS database from 2005 to 2020, demographics and waitlist outcomes of anhepatic candidates relisted as Status 1A for HAT or PNF were assessed. RESULTS: Among 1364 adult Status 1A patients relisted for PNF or HAT across 120 distinct transplant centres, 75 (5.5%) patients were anhepatic and 1289 (94.5%) were non-anhepatic. A substantial number of centres (n = 51) had experience with ≥1 anhepatic patient relisted for either PNF or HAT, with individual centre rates ranging from 0% to 11.4%. Waitlist mortality was more than twice as high for anhepatic patients: 42.5% versus 17.0% non-anhepatic patients (p < .001). The post-transplant outcomes of anhepatic patients were markedly inferior to non-anhepatic patients. For example, 41.9% of anhepatic patients died during the index admission versus 23.4% of the non-anhepatic group (p = .006). Patient survival for the anhepatic and non-anhepatic groups was 48.3% versus 66.2% at 1-year and 29.3% versus 46.2% at 5-years, respectively (log-rank test for overall survival p = .014). CONCLUSIONS: Rescue hepatectomy after initial liver transplantation is not only associated with high waitlist mortality, but also markedly worse post-transplant outcomes. With less than half of anhepatic patients surviving to the first year post-LT, further research is warranted to better delineate which patients should be considered for rescue hepatectomy.

Higher Long-term Quality of Life Metrics After Video-Assisted Thoracoscopic Surgery Lobectomy Compared With Robotic-Assisted Lobectomy.

BACKGROUND: Robotic-assisted thoracic surgery (RATS) lung lobectomy has emerged as an alternative approach to video-assisted thoracoscopic surgery (VATS). Patient-reported outcomes comparing these approaches have been limited. METHODS: At a single, high-volume academic center, patients undergoing VATS and RATS lobectomies for stage I and II non-small cell lung cancer from 2014 to 2018 were evaluated. The European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire (QLQ-C30) and Quality of Life Questionnaire in Lung Cancer (QLQ-LC13), along with the Fear of Recurrence (FoR) survey, were administered preoperatively and at 1, 6, and 12 months postoperatively. Raw scores underwent linear transformation (0-100 scale). Linear mixed-effects models were used for quality of life and FoR score comparisons. RESULTS: The study included 219 patients (139 VATS and 80 RATS). RATS patients had longer (P < .05) operative times and a higher incidence (P < .05) of postoperative myocardial infarction compared to VATS patients. VATS patients reported higher (P < .05) QLQ-C30 summary scores postoperatively and at 12 months, including higher (P < .05) Social Functioning and Cognitive scores, and less (P < .05) appetite loss. VATS patients reported decreased (P < .05) QLQ-LC13 symptom summary scores at 6 months postoperatively, including decreased (P < .05) dyspnea, neuropathy, and pain compared with RATS patients. VATS patients also reported lower (P < .05) FoR summary scores at 6 months postoperatively. CONCLUSIONS: VATS patients report improvement in select quality of life and FoR measures after lobectomy. Further study comparing these 2 approaches is required.

Similar Quality of Life After Conventional and Robotic Transhiatal Esophagectomy.

BACKGROUND: Patient-reported outcomes (PROs) for minimally invasive esophagectomy (MIE) have demonstrated benefits compared with open transthoracic or 3-hole esophagectomy. PROs, including quality of life (QoL) and fear of recurrence (FoR), comparing open transhiatal esophagectomy (THE) and transhiatal robotic-assisted MIE (Th-RAMIE) have been limited. METHODS: At a single, high-volume academic center, patients undergoing THE and Th-RAMIE with gastric conduit for clinical stage I to III esophageal cancer from 2013 to 2018 were evaluated. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), the EORTC Quality of Life Questionnaire in Esophageal Cancer (QLQ-OES18), and the FoR survey were administered preoperatively and at 1, 6, and 12 months postoperatively. Linear mixed-effects models were used for QoL and FoR score comparisons. Perioperative outcomes were also compared. RESULTS: A total of 309 patients (212 in the group and 97 in the Th-RAMIE group) were included. The Th-RAMIE cohort had a significantly higher number of lymph nodes harvested (14 ± 0.8 vs 11.2 ± 0.4; P = .01), a shorter length of stay (days, 10.0 ± 6.7 vs 12.1 ± 7.0; P = .03), lower rates of postoperative ileus (5% vs 15%; P = .02), and fewer opioids prescribed at discharge (71% vs 85%; P = .03). After adjustment, there were no significant differences in QLQ-C30, QLQ-OES18, and FoR scores between the groups out to 1 year postoperatively. CONCLUSIONS: There were no clear patient-reported benefits of Th-RAMIE over THE for esophageal cancer. However, Th-RAMIE conferred several perioperative benefits.

Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices.

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.

Early treatment with exosomes following traumatic brain injury and hemorrhagic shock in a swine model promotes transcriptional changes associated with neuroprotection.

BACKGROUND: We have shown that administration of mesenchymal stem cell-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy. METHODS: Yorkshire swine (40-45 kg) were subjected to a severe TBI (12-mm cortical impact) and hemorrhagic shock (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or exosomes suspended in LR (LR + EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Periinjured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA sequencing data analysis, and results compared between control and experimental groups. RESULTS: Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation, and nonneuronal cell proliferation contributing to reactive gliosis. Exosome treatment also significantly increased (p < 0.005) the genes that are associated with stability of blood-brain barrier. CONCLUSIONS: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment for TBI is promising and requires further investigation for human translation.

Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock.

BACKGROUND: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity. METHODS: Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or LR + exosomes (1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the perilesion BBB. RESULTS: Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens 1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p < 0.05) in the exosome-treated cohort at the end of the experiment. CONCLUSION: In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity.

Variable Benefits of Antibody Induction by Kidney Allograft Type.

BACKGROUND: Kidneys from acute renal failure (ARF), expanded criteria donors (ECD), and donation after cardiac death (DCD) donors are often discarded due to concerns for delayed graft function (DGF) and graft failure. Induction immunosuppression may be used to minimize these risks, but practices vary widely. Furthermore, little is known regarding national outcomes of transplant recipients receiving induction immunosuppression for receipt of high-risk kidneys. MATERIALS AND METHODS: Using a center-level retrospective study, deceased donor transplants (115,485) from the Scientific Registry of Transplant Recipients from January 2003 to June 2016 were evaluated. Patients who received induction immunosuppression, including lymphocyte immune globulin, muromonab CD-3, IL-1 receptor antagonist, anti-thymocyte globulin, daclizumab, basiliximab, alemtuzumab, and rituximab, were included. Associations of center-level induction use with acute rejection in the first post-transplant year, graft failure, and patient mortality were evaluated using multivariable Cox and logistic regression. RESULTS: Among all kidneys, increasing percentage of center-level induction was associated with lower risk of graft failure, acute rejection, and patient mortality. In recipients of ARF kidneys, the beneficial association of induction on graft failure and acute rejection was greater than in those that received non-ARF kidneys. Marginally greater benefit of induction was seen for acute rejection in ECD compared to standard criteria donor (SCD) recipients and for graft failure in DCD compared to donors after brain death (DBD). No benefit of induction was detected for patient and graft survival in ECD recipients, acute rejection in DCD recipients, and patient survival in DGF recipients. No difference in the benefit of induction was detected in any other comparisons. CONCLUSIONS: While seemingly beneficial for recipients of all kidneys, induction has more robust associations with lower graft failure and acute rejection probability for recipients of ARF kidneys. Given the lack of observed benefit for ECD recipients, induction policies should be carefully considered in these patients.

Comparative analysis of isoform-specific and non-selective histone deacetylase inhibitors in attenuating the intestinal damage after hemorrhagic shock.

BACKGROUND: Isoform-specific histone deacetylase inhibitors (HDACIs) MC1568 and ACY1083 are comparable to the non-selective HDACI valproic acid (VPA) in improving survival in rodents undergoing lethal hemorrhage. However, the organ-specific properties of isoform-specific HDACIs have not been fully evaluated. Also, whether they can act synergistically is not known. We hypothesized that isoform-specific HDACIs are superior to VPA in attenuating intestinal injury and act synergistically when coadministered. METHODS: Sprague Dawley rats were hemorrhaged (40% of total blood volume) and randomized to receive (n=4 per group) (1) MC1568 (5 mg/kg), (2) ACY1083 (30 mg/kg), (3) MC1568+ACY1083 (combination: 5 mg/kg + 30 mg/kg, respectively), (4) VPA (250 mg/kg), or (5) normal saline (NS; vehicle; 250 µL). Animals were observed for 3 hours, after which blood samples were collected and samples of the ileum were harvested. Expression of interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) was assessed in the tissues using enzyme-linked immunosorbent assay. Intestinal cleaved caspase 3 (c-caspase 3) levels were assessed as a marker of apoptosis, and histologic sections of the ileum were examined for signs of bowel injury. Levels of IL-1ß and TNF-α were also measured in the serum as global markers of inflammation. RESULTS: Treatments with MC1568, ACY1083, MC1568+ACY1083, and VPA were associated with decreased IL-1ß levels in the intestine and serum compared with NS. IL-1ß and TNF-α levels were significantly lower in the ACY1083 group compared with the VPA group. CINC-1 levels were significantly lower in the isoform-specific HDACI groups compared with the NS; however, no significant differences were seen with VPA. All treatment groups had a lower expression of intestinal c-caspase 3 compared with NS. Furthermore, MC1568 and ACY1083 groups had lower apoptosis compared with the VPA group. Bowel injury scores were significantly lower in the isoform-specific HDACI groups compared with the NS group; however, the attenuation in the VPA-treated animals did not reach statistical significance. DISCUSSION: Isoform-specific HDACIs provide superior intestinal protection compared with VPA in a rodent model of hemorrhagic shock. LEVEL OF EVIDENCE: Preclinical study.

Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

BACKGROUND: Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes. METHODS: Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes. RESULTS: This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels. CONCLUSION: VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.

The impact of intraoperative fluid management during laparoscopic donor nephrectomy on donor and recipient outcomes.

BACKGROUND: Intraoperative fluid management during laparoscopic donor nephrectomy (LDN) may have a significant effect on donor and recipient outcomes. We sought to quantify variability in fluid management and investigate its impact on donor and recipient outcomes. METHODS: A retrospective review of patients who underwent LDN from July 2011 to January 2016 with paired kidney recipients at a single center was performed. Patients were divided into tertiles of intraoperative fluid management (standard, high, and aggressive). Donor and recipient demographics, intraoperative data, and postoperative outcomes were analyzed. RESULTS: Overall, 413 paired kidney donors and recipients were identified. Intraoperative fluid management (mL/h) was highly variable with no correlation to donor weight (kg) (R = 0.017). The aggressive fluid management group had significantly lower recipient creatinine levels on postoperative day 1. However, no significant differences were noted in creatinine levels out to 6 months between groups. No significant differences were noted in recipient postoperative complications, graft loss, and death. There was a significant increase (P < 0.01) in the number of total donor complications in the aggressive fluid management group. CONCLUSIONS: Aggressive fluid management during LDN does not improve recipient outcomes and may worsen donor outcomes compared to standard fluid management.