Recent advances in pathophysiology, diagnosis and management of hepatorenal syndrome: A review.

Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a form of rapidly progressive kidney dysfunction in patients with decompensated cirrhosis and/or acute severe liver injury such as acute liver failure. Current data suggest that HRS-AKI occurs secondary to circulatory dysfunction characterized by marked splanchnic vasodilation, leading to reduction of effective arterial blood volume and glomerular filtration rate. Thus, volume expansion and splanchnic vasoconstriction constitute the mainstay of medical therapy. However, a significant proportion of patients do not respond to medical management. These patients often require renal replacement therapy and may be eligible for liver or combined liver-kidney transplantation. Although there have been advances in the management of patients with HRS-AKI including novel biomarkers and medications, better-calibrated studies, more widely available biomarkers, and improved prognostic models are sorely needed to further improve diagnosis and treatment of HRS-AKI.

A 26-Year-Old Woman With Retinal Telangiectasias, Onychodystrophy, and Persistent Dyspnea.

CASE PRESENTATION: A 26-year-old woman with no significant past medical history sought treatment for worsening dyspnea and hypoxia. The exertional dyspnea began 2 years prior and was associated with substernal chest discomfort. She did not report myalgia, edema, or worsening of dyspnea on supine or upright position. The patient reported no personal history of tobacco or illicit drug use. Family history was unremarkable. She was started on supplemental oxygen at 3 L/min. Initial workup included CT scan angiography of the chest, which showed no pulmonary embolism and normal lung parenchyma. Transthoracic echocardiography showed unremarkable results. She was not given a clear diagnosis for hypoxia and was treated empirically with antibiotics and bronchodilators without improvement. Over the course of 2 years, her condition progressed to requiring 6 L/min nasal canula at rest and associated dyspnea with minimal exertion and a 30-pound unintentional weight loss. During this time, pulmonary function tests noted normal spirometry results and lung volumes, but a decreased diffusing capacity for carbon monoxide of 33%. She also was discovered incidentally to be leukopenic and thrombocytopenic, with subsequent bone marrow biopsy revealing hypocellularity of 30% to 40%. The patient concurrently demonstrated bilateral visual impairment secondary to retinal telangiectasias with increased severity of deficit in the right eye. She subsequently was referred to our institution for further evaluation.

Advances in the management of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a primary malignancy of the bile ducts with three anatomically and molecularly distinct entities: Intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. As a result of phenotypic and anatomic differences they differ significantly with respect to management. For each type of CCA there have been significant changes in management over the last several years which will be discussed in this review. Although resection remains the standard of care for all types of CCA, liver transplantation has been established as curative treatment for selected patients with pCCA and is being evaluated for iCCA with early success. With respect to systemic therapy capecitabine is now first line adjuvant therapy for all biliary tract malignancies after curative intent resection. Progress in exploiting the pathologic mutations and molecular abnormalities has also yielded regulatory approval of targeted therapy for CCA in patients with acquired alterations in the fibroblast growth factor receptor. There is also increased consensus in managing malignant biliary obstruction associated with CCA where pre-operative biliary stenting is not beneficial while self-expanding metal stents have been shown to be superior to plastic stents in patients who are not surgical candidates.

Adaptive staffing can mitigate essential worker disease and absenteeism in an emerging epidemic.

Essential worker absenteeism has been a pressing problem in the COVID-19 pandemic. Nearly 20% of US hospitals experienced staff shortages, exhausting replacement pools and at times requiring COVID-positive healthcare workers to remain at work. To our knowledge there are no data-informed models examining how different staffing strategies affect epidemic dynamics on a network in the context of rising worker absenteeism. Here we develop a susceptible-infected-quarantined-recovered adaptive network model using pair approximations to gauge the effects of worker replacement versus redistribution of work among remaining healthy workers in the early epidemic phase. Parameterized with hospital data, the model exhibits a time-varying trade-off: Worker replacement minimizes peak prevalence in the early phase, while redistribution minimizes final outbreak size. Any "ideal" strategy requires balancing the need to maintain a baseline number of workers against the desire to decrease total number infected. We show that one adaptive strategy-switching from replacement to redistribution at epidemic peak-decreases disease burden by 9.7% and nearly doubles the final fraction of healthy workers compared to pure replacement.

Locoregional Therapy Protocols With and Without Radioembolization for Hepatocellular Carcinoma as Bridge to Liver Transplantation.

OBJECTIVE: The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). MATERIALS AND METHODS: Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. RESULTS: One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. CONCLUSIONS: Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

Utility of clinical suspicion and endoscopic re-examination for detection of esophagogastric perforation after pneumatic dilation for achalasia.

BACKGROUND AND STUDY AIMS: Esophagrams are often obtained routinely after pneumatic balloon dilation for achalasia, even in asymptomatic patients, as there is a risk of postprocedure esophagogastric perforation, which is a potentially life-threatening complication. The aim of this study was to determine whether the combination of a clinical suspicion of perforation and endoscopic re-examination after pneumatic dilation for achalasia can detect esophagogastric perforation, and thereby preclude the need for routine esophagrams in all patients. PATIENTS AND METHODS: All patients who underwent pneumatic dilation between January 2002 and June 2012 at our single tertiary referral center were identified retrospectively. Procedures were categorized into two groups: Group 1 underwent routine esophagograms after pneumatic dilation, and Group 2 underwent esophagograms only if there was a clinical suspicion of perforation. The detection rate of esophageal perforation after pneumatic dilation was compared between the two groups. RESULTS: A total of 119 achalasia dilation procedures were performed in 70 patients. Group 1 included 49/119 procedures (41.2 %), all of which were followed by routine esophagograms. Group 2 included 70/119 procedures (58.8 %), 12 of which were followed by esophagograms based on a clinical suspicion of perforation. No esophageal perforations were found in Group 1, whereas three were found in Group 2. No perforations occurred in the 58 procedures that were not followed by esophagograms. The overall rate of perforation was 3/119 (2.5 %). CONCLUSIONS: Esophagrams obtained routinely after pneumatic dilation for achalasia did not reveal unsuspected esophagogastric perforations. No esophageal perforations were missed after procedures that were not followed by esophagograms. Obtaining an esophagram only in cases of clinical suspicion of perforation and endoscopic evaluation may be an alternative to routine esophagograms in patients undergoing pneumatic dilation for achalasia.

PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice.

Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah(enu2) mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah(enu2) mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah(enu2) mice and corresponded to rapid reduction of serum Phe levels.