Indeterminate etiology of acute liver failure in North America: Less common, still grave prognosis.

BACKGROUND: The etiology of acute liver failure (ALF) remains one of the most important factors in determining prognosis and predicting outcomes. In a significant proportion of ALF cases, however, the etiology remains unknown and is categorized as indeterminate ALF (IND-ALF). In this study, we summarize findings from patients with IND-ALF from 32 transplant centers across the United States, and we compare laboratory, prognostic, and outcome data for patients with IND-ALF. METHODS: Between 1998 and 2019, 3364 adult patients with ALF or acute liver injury (ALI) from 32 liver transplant centers were enrolled in the ALFSG registry. The primary clinical outcome of interest was 21-day transplant-free survival (TFS). RESULTS: Of the 3364 patients enrolled in the ALFSG registry, 3.4 % (n = 114) were adjudicated as true indeterminate. On multivariate analysis, patients with a lower bilirubin, lower INR, lack of use of mechanical ventilation and no clinical features of coma at baseline had a higher odds ratio of transplant free survival. The number of deaths were similar between patients with true-IND ALF versus patients with indeterminable ALF (29.8% vs. 27.2%), with almost half of the patients requiring liver transplant (42.1% vs. 45.7%). CONCLUSION: We illustrate the poor prognoses that true-IND-ALF and indeterminable ALF carry and the need for emergency liver transplantation in most cases.

Alcohol-Related Liver Disease Including New Developments.

The prevalence of alcohol consumption, alcohol use disorder (AUD), and alcohol-related liver disease (ALD) has exponentially increased over the last several years and rates continue to increase. Significant alcohol use can cause progression from steatosis in the liver to inflammation, fibrosis, and eventually cirrhosis. Additional risk factors for the progression of ALD disease include gender, race, and genetic predisposition. As such, it is essential for clinicians to understand and implement screening tools for early diagnosis of both AUD and ALD and be aware of emerging novel treatment options.

Screening, Diagnosis, and Treatment of Alcohol-Related Liver Disease and Alcohol-Associated Hepatitis.

Alcohol-related liver disease is a spectrum of disease in which continued, significant alcohol use can cause progression from fatty changes in the liver to inflammation, fibrosis, and eventually cirrhosis. The rates of alcohol consumption, alcohol use disorder, and alcoholrelated liver disease have increased substantially during the past several years. However, the amount of alcohol consumption may not be the only risk factor for such progression of disease. Studies have found several other risk factors, including sex, race, and genetic predisposition, as possible culprits of worsening disease. As a result, clinicians must understand and implement screening tools for early diagnosis and remain up-to-date with the evolving nature of treatment options. This article reviews the diagnosis and treatment of alcohol use disorder as well as the pathophysiology, clinical presentation, and treatment of alcohol-related liver disease, including alcohol-associated hepatitis.

Liver Transplantation Services During the Time of COVID-19.

The coronavirus disease 2019 (COVID-19) is associated with high morbidity and mortality, prompting overwhelmed hospital systems to reallocate resources to those stricken with the disease. In response, many liver transplantation programs unexpectedly came to an abrupt halt, significantly affecting the lives of living donors and recipients around the world. As the risk-benefit scale of liver transplantation has changed in the era of COVID-19, it is prudent to understand the impact of COVID-19 on those with underlying liver disease and those in need of a liver transplant. In this review, we discuss recommendations put forth by hepatology and transplant societies, summarize results from emerging studies, and propose strategies to appropriately risk stratify patients prior to transplantation.

Amniotic membrane transplant in acute ocular surface burns in Western India: A tertiary eye care center study.

Purpose: To evaluate the outcomes of early amniotic membrane transplant (AMT) in acute ocular surface burns using Dua's classification. Methods: In this retrospective analysis conducted at a tertiary eye care center in Western India. We included 27 eyes of 24 patients from May 2014 to May 2019 who underwent AMT within 2 weeks post insult along with medical treatment for acute ocular surface burns using Dua's classification for grading on presentation. Post-operative assessment for ocular surface epithelization, corneal vascularization, symblepharon formation, and visual outcome at the time of complete epithelization was done. Results: Eight, seven, three, and nine eyes with grade III, IV, V, and VI, respectively, were included in the study. The mean duration of the presentation was 5.5 ± 3.6 days, with the mean follow-up of 4.83 ± 2.2 months. Alkali burn (62.96%, 17/27 eyes) was the commonest. The mean epithelization time was 5.80 ± 2.92 weeks. Corneal vascularization for >6 clock hours was seen in 52.38% (11/21 eyes with vascularization). Symblepharon was seen in 55.55% (15/27 eyes). Vision improvement and corneal vascularization to a lesser extent (<6 clock hours) was observed in Group A (grades III and IV) as compared to group B (grades V and VI) and found to be significant (P-value = 0.031, P value = 0.007, respectively). Conclusion: Amniotic membrane grafting is a useful aid in moderate grades of acute ocular surface burns with an important adjunct role in severe cases.

Daily Aspirin Use Does Not Impact Clinical Outcomes in Patients With Inflammatory Bowel Disease.

BACKGROUND: Although several studies have associated the use of nonsteroidal anti-inflammatory drugs with disease flares in patients with inflammatory bowel disease (IBD), little is known about the impact of daily aspirin use on clinical outcomes in patients with IBD. METHODS: We conducted a retrospective analysis of a prospectively collected registry of patients with IBD from May 2008 to June 2015. Patients with any disease activity with daily aspirin use were matched 1:4 to controls by age, sex, disease, disease location, and presence of cardiac comorbidity. Patients with at least 18 months of follow-up were included in the final analysis. The primary outcomes of interest were having an IBD-related hospitalization, IBD-related surgery, and requiring corticosteroids during the follow-up period. RESULTS: A total of 764 patients with IBD were included in the analysis, of which 174 patients were taking aspirin. There was no statistical difference in age, gender, diagnosis (Crohn's disease vs ulcerative colitis), disease duration, Charlson Comorbidity Index, smoking status, medication usage, or baseline C-reactive protein between groups. After controlling for covariables and length of follow-up in the entire population, aspirin use was not associated with a risk of being hospitalized for an IBD-related complication (odds ratio [OR], 1.46; P = 0.10), corticosteroid use (OR, 0.99; P = 0.70), or having an IBD-related surgery (OR, 0.99; P = 0.96). CONCLUSION: In this single-center analysis, aspirin use did not impact major clinical outcomes in patients with IBD. Although the effect of aspirin use on mucosal inflammation was not directly assessed in this study, these findings support the safety of daily aspirin use in this population.

Racial disparities in nonalcoholic fatty liver disease clinical trial enrollment: A systematic review and meta-analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a heterogeneous distribution across racial and ethnic groups, with a disproportionate burden among Hispanics. Although there are currently no approved therapies for treatment of NAFLD, several therapies have been investigated in clinical trials. AIM: To analyze the inclusion of racial and ethnic minority groups in clinical trials for NAFLD. METHODS: We performed a systematic review of North American, English-language, prospective studies for NAFLD therapies published from 2005 to 2019. Racial and ethnic enrollment data were recorded for each eligible study. Meta-analysis was performed to compute pooled prevalence of different racial and ethnic groups, followed by further subgroup analyses. These analyses were based on diagnosis of non-alcoholic steatohepatitis (NASH) and timing of study on enrollment by ethnicity. Descriptive statistics were performed to compare racial and ethnic study enrollment to previously reported NAFLD population prevalence. RESULTS: Thirty-eight studies met criteria for inclusion in the systematic review. When reported, median age of enrolled subjects was 49 years (range 41.5-58) with 56% female participants. NAFLD was defined through biopsy findings in 79% (n = 30) of the studies. Of the included articles, treatment modalities ranged from medications (n = 28, 74%), lifestyle interventions (n = 5, 13%), bariatric surgery (n = 4, 11%) and phlebotomy (n = 1, 2%). Twenty-eight studies (73%) included racial and/or ethnic demographic information, while only 17 (45%) included information regarding Hispanic participation. Of the 2983 patients enrolled in all eligible trials, a total of only 346 (11.6%) Hispanic participants was reported. Meta-analysis revealed a pooled Hispanic prevalence of 24.3% (95% confidence interval 16.6-32.0, I 2 94.6%) among studies documenting Hispanic enrollment. Hispanic enrollment increased over time from 15% from 2005-2014 to 37% from 2015-2019. CONCLUSION: In a meta-analysis of NAFLD trials, documentation of racial/ethnic demographic data occurred in less than half of studies. Standardization of reporting of race/ethnicity and targeted interventions toward minority recruitment are needed to improve diversity of enrollment.

Reactivation of Epstein-Barr Virus by HIF-1α Requires p53.

We previously reported that the cellular transcription factor hypoxia-inducible factor 1α (HIF-1α) binds a hypoxia response element (HRE) located within the promoter of Epstein-Barr virus's (EBV's) latent-lytic switch BZLF1 gene, Zp, inducing viral reactivation. In this study, EBV-infected cell lines derived from gastric cancers and Burkitt lymphomas were incubated with HIF-1α-stabilizing drugs: the iron chelator deferoxamine (Desferal [DFO]), a neddylation inhibitor (pevonedistat [MLN-4924]), and a prolyl hydroxylase inhibitor (roxadustat [FG-4592]). DFO and MLN-4924, but not FG-4592, induced accumulation of both lytic EBV proteins and phosphorylated p53 in cell lines that contain a wild-type p53 gene. FG-4592 also failed to activate transcription from Zp in a reporter assay despite inducing accumulation of HIF-1α and transcription from another HRE-containing promoter. Unexpectedly, DFO failed to induce EBV reactivation in cell lines that express mutant or no p53 or when p53 expression was knocked down with short hairpin RNAs (shRNAs). Likewise, HIF-1α failed to activate transcription from Zp when p53 was knocked out by CRISPR-Cas9. Importantly, DFO induced binding of p53 as well as HIF-1α to Zp in chromatin immunoprecipitation (ChIP) assays, but only when the HRE was present. Nutlin-3, a drug known to induce accumulation of phosphorylated p53, synergized with DFO and MLN-4924 in inducing EBV reactivation. Conversely, KU-55933, a drug that inhibits ataxia telangiectasia mutated, thereby preventing p53 phosphorylation, inhibited DFO-induced EBV reactivation. Lastly, activation of Zp transcription by DFO and MLN-4924 mapped to its HRE. Thus, we conclude that induction of BZLF1 gene expression by HIF-1α requires phosphorylated, wild-type p53 as a coactivator, with HIF-1α binding recruiting p53 to Zp.IMPORTANCE EBV, a human herpesvirus, is latently present in most nasopharyngeal carcinomas, Burkitt lymphomas, and some gastric cancers. To develop a lytic-induction therapy for treating patients with EBV-associated cancers, we need a way to efficiently reactivate EBV into lytic replication. EBV's BZLF1 gene product, Zta, usually controls this reactivation switch. We previously showed that HIF-1α binds the BZLF1 gene promoter, inducing Zta synthesis, and HIF-1α-stabilizing drugs can induce EBV reactivation. In this study, we determined which EBV-positive cell lines are reactivated by classes of HIF-1α-stabilizing drugs. We found, unexpectedly, that HIF-1α-stabilizing drugs only induce reactivation when they also induce accumulation of phosphorylated, wild-type p53. Fortunately, p53 phosphorylation can also be provided by drugs such as nutlin-3, leading to synergistic reactivation of EBV. These findings indicate that some HIF-1α-stabilizing drugs may be helpful as part of a lytic-induction therapy for treating patients with EBV-positive malignancies that contain wild-type p53.

PPIs and Beyond: A Framework for Managing Anticoagulation-Related Gastrointestinal Bleeding in the Era of COVID-19.

Coronavirus disease of 2019 (COVID-19) can be associated with high morbidity and mortality; patients with severe clinical manifestations may develop significant coagulopathy as well as unexpected thromboembolic complications. In response, centers are increasingly treating selected patients with intermediate-dose prophylactic or even therapeutic dose anticoagulation in order to prevent potentially catastrophic thrombotic complications. With this changing practice, the authors suspect that inpatient gastrointestinal consult teams across the country will be frequently managing COVID-19 patients with gastrointestinal bleeding (GIB). In order to reduce potentially avoidable hospital readmissions for GIB while improving patient outcomes, it is imperative to appropriately risk-stratify patients prior to initiation of anticoagulation. In this review, we discuss how to appropriately identify high-risk patients for GIB and how to mitigate GIB risk with proton-pump inhibitor co-therapy, medication reconciliation, and Helicobacter pylori testing and treating in this complex and morbid population.

An Outcome-Based Follow-up Study of Cured Category I Pulmonary Tuberculosis Adult Cases from Various Tuberculosis Units under Revised National Tuberculosis Control Program from a Western Indian City.

CONTEXT: Despite the nationwide implementation of the Revised National Tuberculosis Control Program in India, adverse outcome after treatment is on rise. Program guidelines propose follow-up of cured patients for 2 years which is rarely done. OBJECTIVES: The main objectives of this study is (1) To find the response of treatment in terms of failure and drug resistance (recurrence of symptoms and mortality experience) and (2) Collect client perspective about the program and suggest the same to program managers. SUBJECTS AND METHODS: Community-based tracking of 365 cured adult Category I pulmonary tuberculosis (TB) cases drawn from three nearby TB units was done with a structured designed questionnaire. It was done to record the adverse events after 1-3 years of completion of treatment and also to record the client perspective about the program. In case of nonsurvivors, verbal autopsy was conducted by interviewing the next available relative. RESULTS: A total of 365, only 226 (60%) could be covered mainly due to wrong/incomplete address and 35 cases did not survive. Of 191 survivors who were tracked, 94.7% had sputum microscopy at the completion of treatment. Total 54 (23.9%) cases had adverse outcomes, including 31 with symptoms suggestive of TB and 23 died directly/indirectly due to TB. This cohort of cured cases, posttreatment, observed 15 times (annualized) high mortality than their counterparts. Clients or relatives largely rated the program as good/very good. CONCLUSIONS: Post-treatment tracking is must to detect an adverse outcome which is high. Most survivors and relatives of expired cases rated the program as good to very good.

Clinical Response and Complications are not Associated with Drug Levels in Patients with Severe Ulcerative Colitis on IV Cyclosporine Induction Therapy.

Background: IV ciclosporin therapy is effective in steroid-refractory ulcerative colitis. The optimal drug level to achieve response and minimize complications during induction therapy is not known. Aim: The primary aim was to evaluate if serum ciclosporin drug levels are associated with increased risk of colectomy within 90 days of hospitalization. Secondary aims were to determine if ciclosporin levels are associated with avoidance of colectomy at 7 and 30 days, if ciclosporin levels are associated with drug-related and postoperative complications, and if patient-specific factors are associated with response to ciclosporin. Methods: We conducted a retrospective analysis of 81 hospitalized patients with steroid-refractory ulcerative colitis treated with ciclosporin. Risk factors for colectomy within 7, 30, and 90 days, medication-specific and postoperative complications were compared by first, mean, and peak ciclosporin level during IV induction therapy. Results: There were 47 patients (58%) who underwent surgery. There were no differences between initial, mean, and peak ciclosporin levels among responders and nonresponders and treatment-related or postoperative complications. Responders within 90 days had lower C-reactive-protein levels (20mg/L vs. 38mg/L, P = 0.01), lower serum albumin concentrations (3.4g/dL vs. 3.7g/dL, P = 0.03), and higher rates of kidney injury (50% vs 17%, P = 0.002). Conclusion: Initial, mean, and peak serum levels of ciclosporin did not correlate with response or toxicity. However, C-reactive-protein levels levels and kidney injury may be helpful in predicting clinical response to ciclosporin.

Outcomes of Early Versus Delayed Colonoscopy in Lower Gastrointestinal Bleeding Using a Hospital Administrative Database.

BACKGROUND: Limited data exist on whether early colonoscopy for lower gastrointestinal bleeding (LGIB) alters 30-day mortality, performance of endoscopic intervention, or need for blood transfusion. Our primary objective was to determine whether early colonoscopy in LGIB is associated with decreased 30-day mortality using a large hospital administrative database. METHODS: Patients hospitalized between January 2008 and September 2015 were identified using a validated, machine learning algorithm for identifying patients with LGIB. "Early" colonoscopy occurred by day 2 of admission and "late" colonoscopy between days 3 and 5. A propensity score for early colonoscopy was constructed using plausible confounders. Univariable and multivariable logistic regression were used to determine factors associated with 30-day mortality, endoscopic intervention, and transfusion need. The propensity score was included as a confounding factor for mortality analysis in the multivariable model. RESULTS: In total, 1204 patients underwent colonoscopy for LGIB. Of these, 295 patients (25%) underwent early colonoscopy, and these patients had a lower Charlson Comorbidity Index (P=0.001) and shorter length of stay (3 vs. 5 d, P=0.0001). Early colonoscopy was not associated with decreased 30-day mortality [odds ratio (OR), 0.73; confidence interval (CI), 0.27-1.69], but was associated with increased endoscopic intervention (OR, 2.62; CI, 1.37-4.95) and decreased need for transfusion (OR, 0.65; CI, 0.49-0.87). On multivariable analysis adjusting for timing of colonoscopy, age, and propensity score for early colonoscopy, early colonoscopy was not associated with a decrease in 30-day mortality (OR, 1.37; CI, 0.50-3.79). CONCLUSIONS: Early colonoscopy does not affect 30-day mortality but may allow for earlier endoscopic intervention and decreased transfusion need.

Lower gastrointestinal bleeding in patients with coronary artery disease on antithrombotics and subsequent mortality risk.

BACKGROUND: Lower gastrointestinal bleeding (LGIB) is a common complication for patients with coronary artery disease (CAD) due to the use of antithrombotic medications. Limited data exist describing which patients are at increased risk for mortality. AIM: This study aims to (i) determine whether patients on dual antiplatelet therapy (DAPT) or triple therapy are at higher risk of 90-day and 6-month mortality compared with patients on aspirin alone and (ii) evaluate risk factors for mortality in patients with CAD on antithrombotics hospitalized with LGIB. METHODS: We conducted a retrospective cohort study of patients hospitalized with LGIB and CAD while on aspirin at a single academic medical center from 2007 to 2015. Patients were identified using a validated, machine-learning algorithm and classified by use of aspirin, DAPT, or triple therapy. Univariate and multivariate Cox proportional hazards were used to determine mortality associated risk factors. RESULTS: Seven hundred sixteen patients were identified with LGIB and CAD. Four hundred seventy-two (65.9%) patients were on aspirin monotherapy, 179 (25%) on aspirin and thienopyridine (DAPT), and 65 (9.1%) on aspirin, thienopyridine, and systemic anticoagulant (triple therapy). On univariate analysis, triple therapy use was associated with increased risk of 90-day (hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.52-5.92, P = 0.003) and 6-month (HR 2.46, 95%CI 1.29-4.35, P = 0.008) mortality. Holding anticoagulation was associated with higher mortality at 90 days (HR 2.30, 95%CI 1.27-4.07, P = 0.007). On multivariate analysis, after adjusting for confounding variables, the use of triple therapy remained associated with higher 90-day mortality (HR 3.23, 95%CI 1.56-6.16, P = 0.003). CONCLUSION: Triple therapy is associated with mortality at 90 days and at 6 months post discharge.

Resumption of Warfarin After Hospitalization for Lower Gastrointestinal Bleeding and Mortality Benefits.

GOALS: To evaluate whether resumption of warfarin after hospitalization for lower gastrointestinal bleeding (LGIB) is associated with improved 90-day and 6-month survival. BACKGROUND: LGIB is a common complication for patients on warfarin. There is limited data to guide clinicians on the optimal management of warfarin following hospitalization for LGIB. STUDY: We identified patients hospitalized with LGIB while on warfarin using a validated, machine-learning algorithm. Patients were classified as those who had warfarin resumed at discharge and those who did not. Univariate and multivariate Cox proportional hazards were used to determine whether resuming warfarin was associated with improved 90-day and 6-month mortality. RESULTS: In total, 607 patients were admitted with warfarin-associated LGIB. A total of 403 (66.4%) patients had warfarin held at discharge. Discontinuation of warfarin was associated with an increased 90-day and 6-month mortality on univariate analysis [hazard ratio (HR), 2.07, 95% confidence interval (CI), 1.04-4.58, P=0.04; HR, 1.78, 95% CI, 1.02-3.27, P=0.04]. On multivariate regression adjusting for age, comorbidities, and transfusion requirement, only a higher Charlson Index was associated with increased 90-day mortality (HR, 1.18, 95% CI, 1.07-1.29, P=<0.001). At 6 months, only older age was associated with an increased mortality on multivariate regression (HR, 1.02, 95% CI, 1.00-1.05, P=0.02), with no significantly increased mortality risk with holding warfarin (HR, 1.48, 95% CI, 0.84-2.78, P=0.18) CONCLUSIONS:: There was no association between resumption of warfarin at discharge following hospitalization for LGIB and either 90-day or 6-month mortality on multivariate analysis. Mortality in LGIB was largely driven by age and comorbidities.

Evaluation of antibiotic pressurized pulse lavage for contaminated retromuscular abdominal wall reconstruction.

BACKGROUND: Despite patient risk factors such as diabetes and obesity, contamination during surgery remains a significant cause of infections and subsequent wound morbidity. Pressurized pulse lavage (PPL) has been utilized as a method to reduce bacterial bioburden with promising results in many fields. Although existing methods of lavage have been utilized during abdominal operations, no studies have examined the use of PPL during complex hernia repair. METHODS: Patients undergoing abdominal wall reconstruction (AWR) in clean-contaminated or contaminated fields with antibiotic PPL, from January 2012 to May 2013, were prospectively evaluated. Primary outcome measures studied were conversion of retrorectus space culture from positive to negative after PPL and 30-day surgical site infection (SSI) rate. RESULTS: A total of 56 patients underwent AWR, with 44 patients (78.6 %) having clean-contaminated fields and 12 patients (21.4 %) having contaminated ones. Twenty-two patients (39.3 %) had positive pre-PPL cultures, 18 of which (81.8 %) converted to negative cultures after PPL. Eleven patients (19.6 %) developed SSIs. Those with persistently positive cultures after PPL had the highest rate of SSI, where two out of four patients (50.0 %) developed an SSI. Contrastingly, only 5 of 18 patients (27.8 %) who converted from a positive to negative culture after PPL developed an SSI. CONCLUSION: Our findings demonstrate that antibiotic PPL is an effective method to reduce bacterial bioburden during AWR in clean-contaminated and contaminated fields. While complete conversion and eradication of SSI were not achieved, we believe that PPL may be a useful adjunct to standard operative asepsis in preventing prosthetic contamination during contaminated AWR.