Changes in Ascitic Fluid Polymorphonuclear Cell Count After Antibiotics Are Associated With Mortality in Spontaneous Bacterial Peritonitis.

Spontaneous bacterial peritonitis (SBP) is a feared complication of ascites that affects 10%-30% of hospitalized patients with cirrhosis with an associated mortality rate of approximately 20%.1-3 Although efforts have been undertaken to encourage prompt evaluation and treatment of SBP, outcomes have generally remained dismal.3 There is significant interest in identifying factors that can reliably predict mortality among individuals with SBP.

Impact of Neoadjuvant Chemotherapy and Pretreatment Biliary Drainage for Pancreatic Head Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in the USA. Although management strategies have evolved, there are continued controversies about the use of neoadjuvant chemotherapy (NAC) and pretreatment biliary drainage (PBD) in patients with resectable and potentially resectable disease. AIMS: We aimed to characterize the practice trends and outcomes for NAC and PBD. METHODS: A single-center cohort study was performed. Electronic medical records were reviewed between 2011 and 2019, and 140 patients who had pancreaticoduodenectomy for PDAC were included. Diagnosis, treatment, and outcome data were captured. RESULTS: There were no statistically significant temporal trends relating to the use of chemotherapy and PBD. Overall, 41% of patients received NAC and had improved survival, independent of other factors. Of the 71% who received PBD, only 40% had appropriate indications; 30% experienced postprocedure complications, and 34% required reintervention. Factors associated with the application of PBD included preoperative jaundice (OR 70.5, 95% CI 21.4-306.6) and evaluation by non-tertiary therapeutic endoscopists (OR 3.9, 95% CI 1.3-13.6). PBD was associated with a 12-day delay in surgery among those who did not receive NAC (p = 0.005), but there were no differences in surgical complications or mortality. CONCLUSIONS: Our findings suggest that (1) NAC may confer a survival benefit and (2) PBD should be reserved for individuals with jaundice requiring NAC. Implementation of guidelines by North American gastroenterology societies, multidisciplinary treatment models, and delivery of care at high-volume tertiary centers may help optimize management.

Utilization of an Internal Medicine Triaging Resident in the Emergency Department Reduces Preventable Admissions and Improves Trainee Experiences.

OBJECTIVE: Increasing patient care requirements and suboptimal communication between emergency department (ED) and Internal Medicine (IM) services may lead to inefficient hospital utilization, lapses in transitions of care, and reduced trainee satisfaction in the inpatient setting. Furthermore, a lack of triaging roles for IM trainees has been a common limitation in graduate medical education. We aimed to demonstrate that the addition of an IM triaging resident (TR) in the ED may represent an innovative solution to these problems. METHODS: A single-center pilot study was performed. An IM trainee served as the TR at a tertiary Veterans Affairs hospital for 2 weeks. The TR evaluated medical patients in a parallel manner with ED physicians and assisted in the initial management, disposition, and transitions of care under the supervision of an IM attending physician. Hospital utilization and patient safety were tracked using electronic records, and trainee satisfaction was measured using daily surveys administered to IM resident teams. RESULTS: Of the 62 cases evaluated by the TR for medical admission, 26 (42%) represented preventable admissions; 12 (46%) of those patients were discharged from the ED, representing a 19% overall reduction. There were statistically significant improvements in trainee experiences relating to patient flow (P < 0.01) and initial patient management (P < 0.02), and our intervention did not have a negative impact on ED performance metrics or patient safety. CONCLUSIONS: Expansion of this model in select integrated health systems may improve graduate medical education and healthcare system performance. Future iterations of this study can aim to improve transitions of care between ambulatory and inpatient providers and limit the overuse of antimicrobial agents, radiography, and consultative services.

Impact of SGLT2 inhibitors in comparison with DPP4 inhibitors on ascites and death in veterans with cirrhosis on metformin.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have favourable neurohumoral and metabolic effects in patients with chronic liver disease. However, studies examining SGLT2i in this population have been limited to patients with non-alcoholic fatty liver disease and have focused on surrogate biomarkers. Our aim was to evaluate whether SGLT2i can reduce the incidence of ascites and death over a period of 36 months in patients with cirrhosis and diabetes mellitus. Using electronic health data from Veterans Affairs hospitals in the United States, we conducted a propensity score matched intention-to-treat analysis among veterans on metformin who subsequently received either SGLT2i or dipeptidyl peptidase-4 inhibitors. Among 423 matched pairs (in total, 846 patients), we found no significant difference in the risk for ascites (hazard ratio 0.68 for SGLT2i, 95% confidence interval 0.37-1.25; p = .22) but did find that SGLT2i users had a reduced risk for death (adjusted hazard ratio 0.33, 95% confidence interval 0.11-0.99; p < .05). In comparison with dipeptidyl peptidase-4 inhibitors, SGLT2i may improve survival for patients with cirrhosis who require additional pharmacotherapy for diabetes mellitus beyond metformin, but confirmatory studies are necessary.

CD40 in Endothelial Cells Restricts Neural Tissue Invasion by Toxoplasma gondii.

Little is known about whether pathogen invasion of neural tissue is affected by immune-based mechanisms in endothelial cells. We examined the effects of endothelial cell CD40 on Toxoplasma gondii invasion of the retina and brain, organs seeded hematogenously. T. gondii circulates in the bloodstream within infected leukocytes (including monocytes and dendritic cells) and as extracellular tachyzoites. After T. gondii infection, mice that expressed CD40 restricted to endothelial cells exhibited diminished parasite loads and histopathology in the retina and brain. These mice also had lower parasite loads in the retina and brain after intravenous (i.v.) injection of infected monocytes or dendritic cells. The protective effect of endothelial cell CD40 was not explained by changes in cellular or humoral immunity, reduced transmigration of leukocytes into neural tissue, or reduced invasion by extracellular parasites. Circulating T. gondii-infected leukocytes (dendritic cells used as a model) led to infection of neural endothelial cells. The number of foci of infection in these cells were reduced if endothelial cells expressed CD40. Infected dendritic cells and macrophages expressed membrane-associated inducible Hsp70. Infected leukocytes triggered Hsp70-dependent autophagy in CD40+ endothelial cells and anti-T. gondii activity dependent on ULK1 and beclin 1. Reduced parasite load in the retina and brain not only required CD40 expression in endothelial cells but was also dependent on beclin 1 and the expression of inducible Hsp70 in dendritic cells. These studies suggest that during endothelial cell-leukocyte interaction, CD40 restricts T. gondii invasion of neural tissue through a mechanism that appears mediated by endothelial cell anti-parasitic activity stimulated by Hsp70.

Systemic Management for Advanced Hepatocellular Carcinoma: A Review of the Molecular Pathways of Carcinogenesis, Current and Emerging Therapies, and Novel Treatment Strategies.

Hepatocellular carcinoma (HCC) arises from a number of cirrhosis-related and non-cirrhosis-related exposures and is one of the leading causes of cancer-related deaths worldwide. Achieving a durable cure currently relies on either resection or transplantation, but since most patients will be diagnosed with inoperable disease, there is great interest in achieving more effective systemic therapies. At a molecular level, HCC is heterogeneous, but initial treatment strategies, including the use of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, have been fairly homogenous, depending on general host factors and overall tumor burden rather than specific molecular signatures. Over the past 2 decades, however, there has been significant success in identifying key molecular targets, including driver mutations involving the telomerase reverse transcriptase, p53, and beta-catenin genes, and significant work is now being devoted to translating these discoveries into the development of robust and well-tolerated targeted therapies. Furthermore, multi-modal therapies have also begun to emerge, harnessing possible synergism amongst a variety of different treatment classes. As the findings of these landmark trials become available over the next several years, the landscape of the systemic management of advanced HCC will change significantly.

Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy.

Cirrhosis is a leading cause of morbidity and mortality, impacting more than 120 million people worldwide. Although geographic differences exist, etiologic factors such as alcohol use disorder, chronic viral hepatitis infections, and non-alcoholic fatty liver disease are prevalent in nearly every region. Historically, significant effort has been devoted to modifying these risks to prevent disease progression. Nevertheless, more than 11% of patients with compensated cirrhosis experience hepatic decompensation each year. This transition signifies the most important prognostic factor in the natural history of the disease, corresponding to a decline in median survival to below 2 years. Over the past decade, the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized, and non-selective beta-blockers have emerged as the most effective option to date. However, a critical therapeutic gap still exists, and additional therapies have been proposed, including statins, rifaximin, and sodium-glucose cotransporter-2 inhibitors. Based on the results of innovative retrospective analyses and small-scale prospective trials, these pharmacotherapies represent promising options, but further studies, including randomized controlled trials, are necessary before they can be incorporated into clinical use. This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.

Emerging concepts in the care of patients with cirrhosis and septic shock.

Septic shock impacts approximately 6% of hospitalized patients with cirrhosis and is associated with high rates of morbidity and mortality. Although a number of landmark clinical trials have paved the way for incremental improvements in the diagnosis and management of septic shock in the general population, patients with cirrhosis have largely been excluded from these studies and critical knowledge gaps continue to impact the care of these individuals. In this review, we discuss nuances in the care of patients with cirrhosis and septic shock using a pathophysiology-based approach. We illustrate that septic shock may be challenging to diagnose in this population in the context of factors such as chronic hypotension, impaired lactate metabolism, and concomitant hepatic encephalopathy. Furthermore, we demonstrate that the application of routine interventions such as intravenous fluids, vasopressors, antibiotics, and steroids should be carefully considered among those with decompensated cirrhosis in light of hemodynamic, metabolic, hormonal, and immunologic disturbances. We propose that future research should include and characterize patients with cirrhosis in a systematic manner, and clinical practice guidelines may need to be refined accordingly.

Clinical Phenotyping and the Application of Precision Medicine in MAFLD.

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Impact of epinephrine volume on further bleeding due to high-risk peptic ulcer disease in the combination therapy era.

BACKGROUND: In monotherapy studies for bleeding peptic ulcers, large volumes of epinephrine were associated with a reduction in rebleeding. However, the impact of epinephrine volume in patients treated with combination endoscopic therapy remains unclear. AIM: To assess whether epinephrine volume was associated with bleeding outcomes in individuals who also received endoscopic thermal therapy and/or clipping. METHODS: Data from 132 patients with Forrest class Ia, Ib, and IIa peptic ulcers were reviewed. The primary outcome was further bleeding at 7 d; secondary outcomes included further bleeding at 30 d, need for additional therapeutic interventions, post-endoscopy blood transfusions, and 30-day mortality. Logistic and linear regression and Cox proportional hazards analyses were performed. RESULTS: There was no association between epinephrine volume and all primary and secondary outcomes in multivariable analyses. Increased odds for further bleeding at 7 d occurred in patients with elevated creatinine values (aOR 1.96, 95%CI 1.30-3.20; P < 0.01) or hypotension requiring vasopressors (aOR 6.34, 95%CI 1.87-25.52; P < 0.01). Both factors were also associated with all secondary outcomes. CONCLUSION: Epinephrine maintains an important role in the management of bleeding ulcers, but large volumes up to a range of 10-20 mL are not associated with improved bleeding outcomes among individuals receiving combination endoscopic therapy. Further bleeding is primarily associated with patient factors that likely cannot be overcome by increased volumes of epinephrine. However, in carefully-selected cases where ulcer location or size pose therapeutic challenges or when additional modalities are unavailable, it is conceivable that increased volumes of epinephrine may still be beneficial.

Early mechanical ventilation for grade IV hepatic encephalopathy is associated with increased mortality among patients with cirrhosis: an exploratory study.

BACKGROUND: Unresponsive patients with toxic-metabolic encephalopathies often undergo endotracheal intubation for the primary purpose of preventing aspiration events. However, among patients with pre-existing systemic comorbidities, mechanical ventilation itself may be associated with numerous risks such as hypotension, aspiration, delirium, and infection. Our primary aim was to determine whether early mechanical ventilation for airway protection was associated with increased mortality in patients with cirrhosis and grade IV hepatic encephalopathy. METHODS: The National Inpatient Sample was queried for hospital stays due to grade IV hepatic encephalopathy among patients with cirrhosis between 2016 and 2019. After applying our exclusion criteria, including cardiopulmonary failure, data from 1,975 inpatient stays were analyzed. Patients who received mechanical ventilation within 2 days of admission were compared to those who did not. Univariable and multivariable logistic regression analyses were performed to identify clinical factors associated with in-hospital mortality. RESULTS: Of 162 patients who received endotracheal intubation during the first 2 hospital days, 64 (40%) died during their hospitalization, in comparison to 336 (19%) of 1,813 patients in the comparator group. In multivariable logistic regression analysis, mechanical ventilation was the strongest predictor of in-hospital mortality in our primary analysis (adjusted odds ratio, 3.00; 95% confidence interval, 2.14-4.20; P<0.001) and in all sensitivity analyses. CONCLUSIONS: Mechanical ventilation for the sole purpose of airway protection among patients with cirrhosis and grade IV hepatic encephalopathy may be associated with increased in-hospital mortality. Future studies are necessary to confirm and further characterize our findings.

Circumferential esophageal perforation resulting in tension hydropneumothorax in a patient with septic shock.

Esophageal perforations occur traumatically or spontaneously and are typically associated with high mortality rates. Early recognition and prompt management are essential. We present the case of a 76-year-old man who was admitted to the medical intensive care unit with fulminant Clostridium difficile colitis, shock, and multi-organ failure. After an initial period of improvement, his condition rapidly deteriorated despite aggressive medical management, and he required mechanical ventilation. Radiography after endotracheal intubation showed interval development of pneumomediastinum and bilateral hydropneumothorax with tension physiology. Chest tube placement resulted in the drainage of multiple liters of dark fluid, and pleural fluid analysis was notable for polymicrobial empyemas. Despite the unusual presentation, esophageal perforation was suspected. Endoscopy ultimately confirmed circumferential separation of the distal esophagus from the stomach, and bedside endoscopic stenting was performed with transient improvement. Two weeks after admission, he developed mediastinitis complicated by recurrent respiratory failure and passed away. This report further characterizes our patient's unique presentation and briefly highlights the clinical manifestations, management options, and outcomes of esophageal perforations.

SGLT2 inhibitors in patients with cirrhosis and diabetes mellitus: A tertiary center cohort study and insights about a potential therapeutic target for portal hypertension.

Highlights Sodium glucose cotransporter 2 (SGLT2) inhibitors have favorable pleiotropic effects in patients with diabetes mellitus and cardiovascular or renal disease. The benefits of SGLT2 inhibitors may extend to portal hypertension, but they have not been formally evaluated in patients with cirrhosis. Our study is the first to provide clinical data for SGLT2 inhibitors in a cohort of patients with cirrhosis, and our findings support ongoing evaluation in the form of a clinical trial.

Liver Pathologic Changes After Direct-Acting Antiviral Agent Therapy and Sustained Virologic Response in the Setting of Chronic Hepatitis C Virus Infection.

CONTEXT.­: Treatment of chronic viral hepatitis C (HCV) infection with direct-acting antiviral agents (DAAs) results in cure, or sustained viral response (SVR), in more than 90% of patients. However, there are subsets of patients who have persistent liver inflammation and fibrosis and develop hepatocellular carcinoma (HCC) despite achieving SVR. A possible reason for these phenomena may be the presence of virus particles in liver tissue but not blood, otherwise defined as occult infection. OBJECTIVE.­: To describe liver histologic findings following successful DAA therapy, test HCV RNA by (liver) tissue polymerase chain reaction in treated cases, and identify predictive markers for HCC development in treated cases. DESIGN.­: A total of 96 identified patients were divided into 4 groups, each differentiated by the presence or absence of SVR and HCC. Groups were compared for several clinicopathologic variables, including degree of inflammation and fibrosis, and the 'directionality' of fibrosis in cirrhotic livers using the novel progressive-indeterminate-regressive scoring system. RESULTS.­: Overall, we found a significant decrease in inflammation in SVR patients. None of the patients showed regression of their cirrhosis following treatment. No evidence of occult HCV infection was seen in 40 livers tested, including 21 with HCC. The number of patients who developed HCC was similar in the SVR and non-SVR groups, and increased inflammation and fibrosis were associated with HCC development. CONCLUSIONS.­: Following DAA-SVR there appears to be an overall decrease in inflammation, but the fibrosis tends to persist, at least in the short term (median follow-up of 20.2 months).

Where does TIPS fit in the management of patients with cirrhosis?

In this review, we summarise the current knowledge on the indications and contraindications of transjugular intrahepatic portosystemic shunt (TIPS) placement for the treatment of the complications of portal hypertension in cirrhosis, specifically variceal haemorrhage and ascites. Moreover, we discuss the role of TIPS for the treatment of portal vein thrombosis (PVT) and the prevention of complications after extrahepatic surgery ('preoperative TIPS') in patients with cirrhosis. The position of TIPS in the treatment hierarchy depends on the clinical setting and on patient characteristics. In acute variceal haemorrhage, preemptive TIPS is indicated in patients at a high risk of failing standard therapy, that is those with a Child-Pugh score of 10-13 points or Child-Pugh B with active bleeding at endoscopy, although the survival benefit in the latter group still remains to be established. Non-preemptive TIPS is a second-line therapy for the prevention of recurrent variceal haemorrhage and for the treatment of ascites. Of note, TIPS may also improve sarcopenia. Contraindications to TIPS placement, independent of clinical setting, include very advanced disease (Child-Pugh >13 points), episodes of recurrent overt hepatic encephalopathy without an identifiable precipitating factor, heart failure, and pulmonary hypertension. In patients with PVT, TIPS placement not only controls complications of portal hypertension, but also promotes portal vein recanalisation. Although the severity of portal hypertension correlates with poor outcomes after extrahepatic surgery, there is no evidence to recommend preoperative TIPS placement.

Graft-Versus-Host Disease After Pancreatic Transplantation.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.