Pragmatic strategies to address health disparities along the continuum of care in chronic liver disease.

Racial, ethnic, and socioeconomic disparities exist in the prevalence and natural history of chronic liver disease, access to care, and clinical outcomes. Solutions to improve health equity range widely, from digital health tools to policy changes. The current review outlines the disparities along the chronic liver disease health care continuum from screening and diagnosis to the management of cirrhosis and considerations of pre-liver and post-liver transplantation. Using a health equity research and implementation science framework, we offer pragmatic strategies to address barriers to implementing high-quality equitable care for patients with chronic liver disease.

aEEG in the first 3 days after extremely preterm delivery relates to neurodevelopmental outcomes.

OBJECTIVES: Investigate relationships between aEEG in the first 72 h in extremely preterm infants with 1) infant, medical, and environmental factors, and 2) infant feeding and neurobehavioral outcomes at term and school-age. METHODS: Sixty-four preterm infants (≤28 weeks gestation) were enrolled within the first 24-hours of life and had two-channel aEEG until 72 h of life. Standardized neurobehavioral and feeding assessments were conducted at term, and parent-reported outcomes were documented at 5-7 years. RESULTS: Lower aEEG Burdjalov scores (adjusted for gestational age) were related to vaginal delivery (p = 0.04), cerebral injury (p = 0.01), Black race (p < 0.01) and having unmarried parents (p = 0.02). Lower Burdjalov scores related to less NICU Network Neurobehavioral Scale arousal (p = 0.002) at term and poorer BRIEF global executive function (p = 0.004), inhibition (p = 0.007), working memory (p = 0.02), material organization (p = 0.0008), metacognition (p = 0.01), and behavioral regulation (p = 0.02) at 5-7 years. We did not observe relationships of early aEEG to feeding outcomes or sensory processing measures. CONCLUSION: Early aEEG within the first 72 h of life was related to medical and sociodemographic factors as well as cognitive outcome at 5-7 years.

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Downstaging Hepatocellular Carcinoma with Checkpoint Inhibitor Therapy Improves Access to Curative Liver Transplant.

PURPOSE: Liver transplantation is curative for hepatocellular carcinoma (HCC). Checkpoint inhibitor therapy (CPIT) has been used in unresectable HCC, but recent advances have demonstrated CPIT as an innovative method of downstaging advanced HCC with the caveat that CPIT prior to transplantation has risks including irreversible graft rejection. We report the outcomes of Mayo Clinic Arizona patients who underwent downstaging with CPIT. METHODS: This retrospective chart review was conducted for Mayo Clinic Arizona patients who were diagnosed with HCC who underwent downstaging with CPIT with the goal of meeting criteria for transplantation. RESULTS: We present nine cases with HCC outside Milan who underwent CPIT. Four received a transplant; one was delisted due to his exceptional therapeutic response. All received liver-directed therapy. Peak alpha-fetoprotein pre-CPIT ranged from 8-29,523 ng/mL, which decreased to 2.2-19.6 ng/mL on CPIT. CPIT included atezolizumab/bevacizumab, ipilimumab/nivolumab, nivolumab, and pembrolizumab; one patient received two regimens. CPIT was held prior to transplant at a median of 3 months. Three patients received methylprednisolone for immunosuppression induction; one received thymoglobulin. One patient developed acute cellular rejection at 5 weeks, 9 weeks, and 5 months post-transplant; given the late onset, these were not attributed to CPIT and were successfully treated. During an average follow-up of 16.5 months, no tumor recurrence has occurred. CONCLUSION: We describe nine patients with HCC outside Milan with inadequate response with liver-directed therapy, who achieved marked responses with CPIT, allowing for consideration of successful liver transplantation. Our case series supports the consideration of locoregional therapies and CPIT for downstaging to within transplant criteria.

Autophagy: a necessary evil in cancer and inflammation.

Autophagy, a highly regulated cellular process, assumes a dual role in the context of cancer. On the one hand, it functions as a crucial homeostatic pathway, responsible for degrading malfunctioning molecules and organelles, thereby maintaining cellular health. On the other hand, its involvement in cancer development and regression is multifaceted, contingent upon a myriad of factors. This review meticulously examines the intricacies of autophagy, from its molecular machinery orchestrated by Autophagy-Related Genes (ATG) initially discovered in yeast to the various modes of autophagy operative within cells. Beyond its foundational role in cellular maintenance, autophagy reveals context-specific functions in processes like angiogenesis and inflammation. Our analysis delves into how autophagy-related factors directly impact inflammation, underscoring their profound implications for cancer dynamics. Additionally, we extend our inquiry to explore autophagy's associations with cardiovascular conditions, neurodegenerative disorders, and autoimmune diseases, illuminating the broader medical relevance of this process. Furthermore, this review elucidates how autophagy contributes to sustaining hallmark cancer features, including stem cell maintenance, proliferation, angiogenesis, metastasis, and metabolic reprogramming. Autophagy emerges as a pivotal process that necessitates careful consideration in cancer treatment strategies. To this end, we investigate innovative approaches, ranging from enzyme-based therapies to MTOR inhibitors, lysosomal blockers, and nanoparticle-enabled interventions, all aimed at optimizing cancer treatment outcomes by targeting autophagy pathways. In summary, this comprehensive review provides a nuanced perspective on the intricate and context-dependent role of autophagy in cancer biology. Our exploration not only deepens our understanding of this fundamental process but also highlights its potential as a therapeutic target. By unraveling the complex interplay between autophagy and cancer, we pave the way for more precise and effective cancer treatments, promising better outcomes for patients.

Pro-inflammatory cerebrospinal fluid profile of neonates with intraventricular hemorrhage: clinical relevance and contrast with CNS infection.

BACKGROUND: Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters. METHODS: Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH1/2), 13 IVH grade 3/4 (IVH3/4), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4 weeks estimated gestational age. RESULTS: PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH1/2, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH3/4, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH1/2. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH3/4. CONCLUSIONS: Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.

Individual- and Community-Level Socioeconomic Status and Deceased Donor Renal Transplant Outcomes.

BACKGROUND: This study examined the relationship between socioeconomic status (SES), race, and ethnicity and clinical outcomes following deceased donor kidney transplant (DDKT) at a high-volume transplant center. METHODS: This retrospective cohort study used regression models and survival analyses to examine the relationship between individual- and community-level SES, race, and ethnicity and DDKT outcomes (i.e., delayed graft function, graft failure, mortality) adjusting for potential confounders. RESULTS: The analytic sample included 3366 patients; 40.7% (n = 1370) were female, the mean age was 54.7 (SD = 13.3) years, 49.3% were non-Hispanic White, and the median follow-up time was 39.5 months (IQR = 24.2-68.1). Patients living in the most disadvantaged communities (using the US Census data) had a higher likelihood of delayed graft function (adjusted relative risk [RR] = 1.12, p = 0.042) and a higher hazard of mortality (adjusted hazard ratio [HR] = 1.32, p = 0.025) compared to patients living in the least disadvantaged communities. Patients without a high school diploma had a higher risk of delayed graft function compared to patients with an associate degree or more (RR = 1.37, p < 0.001). Patients with public insurance coverage had a higher risk of delayed graft function (RR = 1.24, p < 0.001) and a higher hazard of mortality (HR = 1.37, p < 0.001) and graft failure (HR = 1.71, p < 0.001) compared to patients without public insurance. There were no differences in graft failure or mortality by race and ethnicity. CONCLUSIONS: SES was not consistently associated with outcomes following DDKT; however, many of the predictors were associated with delayed graft function. With a large and diverse sample size, these findings further the heterogeneity of the present renal transplant research suggesting the need for further investigation to guide implementation of innovative strategies and interventions.

Breaking Barriers and Bridging Gaps: Advancing Diversity, Equity, and Inclusion in Kidney Transplant Care for Black and Hispanic Patients in the United States.

Kidney transplantation offers better mortality and quality of life outcomes to patients with end-stage renal failure compared to dialysis. Specifically, living donor kidney transplantation is the best treatment for end-stage renal disease, since it offers the greatest survival benefit compared to deceased donor kidney transplant or dialysis. However, not all patients from all racial/ethnic backgrounds enjoy these benefits. While black and Hispanic patients bear the predominant disease burden within the United States, they represent less than half of all kidney transplants in the country. Other factors such as cultural barriers that proliferate myths about transplant, financial costs that impede altruistic donation, and even biological predispositions create a complex maze and can also perpetuate care inaccessibility. Therefore, blanket efforts to increase the overall donation pool may not extend access to vulnerable populations, who may require more targeted attention and interventions. This review uses US kidney transplantation data to substantiate accessibility differences amongst racial minorities as well as provides examples of successful institutional and national systemic level changes that have improved transplantation outcomes for all.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial.

INTRODUCTION: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. METHODS: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 - 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. RESULTS: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR 4.5 - 5.8). The incidence of injury to the deep grey nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n=414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. CONCLUSION: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Deep Learning to Optimize Magnetic Resonance Imaging Prediction of Motor Outcomes After Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for outcome prediction after hypoxic-ischemic encephalopathy (HIE). Published scoring systems contain duplicative or conflicting elements. METHODS: Infants ≥36 weeks gestational age (GA) with moderate to severe HIE, therapeutic hypothermia treatment, and T1/T2/diffusion-weighted imaging were identified. Adverse motor outcome was defined as Bayley-III motor score <85 or Alberta Infant Motor Scale <10th centile at 12 to 24 months. MRIs were scored using a published scoring system. Logistic regression (LR) and gradient-boosted deep learning (DL) models quantified the importance of clinical and imaging features. The cohort underwent 80/20 train/test split with fivefold cross validation. Feature selection eliminated low-value features. RESULTS: A total of 117 infants were identified with mean GA = 38.6 weeks, median cord pH = 7.01, and median 10-minute Apgar = 5. Adverse motor outcome was noted in 23 of 117 (20%). Putamen/globus pallidus injury on T1, GA, and cord pH were the most informative features. Feature selection improved model accuracy from 79% (48-feature MRI model) to 85% (three-feature model). The three-feature DL model had superior performance to the best LR model (area under the receiver-operator curve 0.69 versus 0.75). CONCLUSIONS: The parsimonious DL model predicted adverse HIE motor outcomes with 85% accuracy using only three features (putamen/globus pallidus injury on T1, GA, and cord pH) and outperformed LR.

Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial.

Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury scoring by radiologists. Materials and Methods In this secondary analysis, brain diffusion-weighted MRI data from neonates in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which recruited participants between January 2017 and October 2019, were analyzed. Volume of acute brain injury, defined as brain with apparent diffusion coefficient (ADC) less than 800 × 10-6 mm2/sec, was automatically computed across the whole brain and within the thalami and white matter. Outcomes of death and neurodevelopmental impairment (NDI) were recorded at 24-month follow-up. Associations between the presence and volume (in milliliters) of acute brain injury with 24-month outcomes were evaluated using multiple logistic regression. The correlation between quantitative acute brain injury volume and qualitative MRI scores was assessed using the Kendall tau-b test. Results A total of 416 neonates had available MRI data (mean gestational age, 39.1 weeks ± 1.4 [SD]; 235 male) and 113 (27%) showed evidence of acute brain injury at MRI. Of the 387 participants with 24-month follow-up data, 185 (48%) died or had any NDI. Volume of acute injury greater than 1 mL (odds ratio [OR], 13.9 [95% CI: 5.93, 32.45]; P < .001) and presence of any acute injury in the brain (OR, 4.5 [95% CI: 2.6, 7.8]; P < .001) were associated with increased odds of death or any NDI. Quantitative whole-brain acute injury volume was strongly associated with radiologists' qualitative scoring of diffusion-weighted images (Kendall tau-b = 0.56; P < .001). Conclusion Automated quantitative volume of brain injury is associated with death, moderate to severe NDI, and cerebral palsy in neonates with hypoxic ischemic encephalopathy and correlated well with qualitative MRI scoring of acute brain injury. Clinical trial registration no. NCT02811263 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

Outcomes with transplanting kidneys offered through expedited allocation.

INTRODUCTION: Expedited out-of-sequence deceased donor kidney allocation is a strategy to avoid discards after early placement attempts have been unsuccessful. Our study aimed to assess outcomes and characteristics of these transplanted kidneys. METHODS: KDPI matching was performed between expedited allocation (EA) and standard allocation (SA) deceased donor kidney transplants performed at our center. RESULTS: Between 2018 and 2021, there were 225 EA offers, and 189 (84%) were transplanted. EA recipients were older (p = .007) and had shorter dialysis vintage (p < .0001). EA kidneys were likely to be nationally allocated (p < .001), have AKI (p < .0001) and longer CIT (p < .0001). There were no differences in EA and SA time-zero kidney biopsies (ci, p = .07; ct, p = .89; cv, p = .95; ah, p = .79). EA kidneys had more DGF (p = .0006), but there were no differences in DGF duration (p = .83), hospital length of stay (p = .43), 1- and 2-year eGFR (p = .16, p = .99), patient (p = .34), or death-censored graft (p = .66) survival. CONCLUSION: During this study period, our center transplanted 189 kidneys through EA following local-regional declines. These kidneys often came from AKI donors and had more DGF but had similar outcomes to KDPI-matched SA kidneys. Although it has been suggested that EA has the potential to worsen transplant disparities, transplant center level decisions on organ acceptance contribute to these variations.

Spontaneous middle lobe torsion: An institutional case series.

Objective: Lobar torsion is a rare occurrence in which a portion of the lung is twisted on its bronchovascular pedicle. The vast majority are observed in the acute postoperative period often following right upper lobectomy. Spontaneous middle lobe torsion independent of pulmonary resection is exceptionally rarer; fewer than 15 cases have been recorded. We present an institutional case series of 2 patients postorthotopic liver transplantation who developed spontaneous middle lobe torsion due to large pleural effusions. Methods: We provide the medical course as well as intraoperative techniques for our 2 patients along with a review of the literature. Results: Both patients in this case series underwent orthotopic liver transplant complicated postoperatively by a large pulmonary effusion. Patient one developed an abdominal hematoma requiring evacuation and repair, after which he developed progressive shortness of breath. Bronchoscopy revealed a right middle lobe obstruction; upon thoracotomy, 180-degree torsion with widespread necrosis was evident and the middle lobe was removed. He is doing well to date. Patient 2 experienced postoperative pleural effusion and mucus plugging; computed tomography revealed abrupt middle lobe arterial occlusion prompting urgent operative intervention. Again, the middle lobe was grossly ischemic and dissection revealed a 360-degree torsion around the pedicle. It was resected. He is doing well to date. Conclusions: As the result of its rarity, radiographic and clinical diagnosis of spontaneous pulmonary lobar torsion is challenging; a high index of suspicion for spontaneous middle lobe torsion must be maintained to avoid delays in diagnosis. Prompt surgical intervention is essential to improve patient outcomes.

Liver transplant outcomes using late allocation grafts.

Post-cross clamp late allocation (LA) liver allografts are at increased risk for discard for many reasons including logistical complexity. Nearest neighbor propensity score matching was used to match 2 standard allocation (SA) offers to every 1 LA liver offer performed at our center between 2015 and 2021. Propensity scores were based on a logistic regression model including recipient age, recipient sex, graft type (donation after circulatory death vs. donation after brain death), Model for End-stage Liver Disease (MELD), and DRI score. During this time, 101 liver transplants (LT) were performed at our center using LA offers. In comparing LA and SA offers, there were no differences in recipient characteristics including indication for transplant ( p = 0.29), presence of PVT ( p = 0.19), TIPS ( p = 0.83), and HCC status ( p = 0.24). LA grafts came from younger donors (mean age 43.6 vs. 48.9 y, p = 0.009) and were more likely to come from regional or national Organ Procurement Organizations (OPOs) ( p < 0.001). Cold ischemia time was longer for LA grafts (median 8.5 vs 6.3 h, p < 0.001). Following LT, there were no differences between the 2 groups in intensive care unit ( p = 0.22) and hospital ( p = 0.49) lengths of stay, need for endoscopic interventions ( p = 0.55), or biliary strictures ( p = 0.21). Patient (HR 1.0, 95% CI, 0.47-2.15, p = 0.99) and graft (HR 1.23, 95% CI, 0.43-3.50, p = 0.70) survival did not vary between the LA and SA cohorts. One-year LA and SA patient survival was 95.1% and 95.0%; 1-year graft survival was 93.1% and 92.1%, respectively. Despite the additional logistical complexity and longer cold ischemia time, LT outcomes utilizing LA grafts are similar to those allocated by means of SA. Improving allocation policies specific to LA offers, as well as the sharing of best practices between transplant centers and OPOs, are opportunities to further help minimize unnecessary discards.