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Simple Summary: Obesity is a clear risk factor for future colorectal cancer (CRC), but its impact on mortality remains to be fully elucidated. Prior studies have had methodologic limitations, and key variables remain under-investigated. In this study of prospectively collected data from the Multiethnic Cohort, pre-diagnosis BMI trajectories were not associated with CRC-specific or all-cause mortality. Factors associated with mortality included African American race or Hawaiian ethnicity, smoking, and diabetes. Accounting for long-term BMI trajectories before diagnosis and other relevant factors demonstrates that obesity is not protective of mortality after CRC diagnosis. Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included adults aged 18–75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00–2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10–2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31–6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08–3.10], p = 0.026). Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis. [ABSTRACT FROM AUTHOR]

PURPOSE: We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. METHODS: We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. RESULTS: A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. CONCLUSION: The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs. Three (sometimes 4) rules to identify hepatic immune-related adverse events in the setting of ICI. [ABSTRACT FROM AUTHOR]

Venous collateral shunting of blood from the splanchnic to systemic venous systems due to portal hypertension increases the pressure in the ventral lingual venous bed. We hypothesized that the appearance of sublingual varices evaluated by pre-endoscopy/bedside visual inspection of ventrum of tongue (VIVOT) might predict the presence of esophageal varices (EVs). Methods: To test this hypothesis, we prospectively enrolled patients with cirrhosis (CP) referred for EV screening for assessment of lingual vasculature after informed consent. Non-cirrhosis control patients were also enrolled. Methods: VIVOT was scored based on the presence of vessels > 2 mm and/or serpiginous veins. VIVOT scores were then correlated with endoscopic findings. Results: A total of 59 patients with cirrhosis (Group 1) were enrolled, as were 62 patients without cirrhosis (Group 2). Group 1 consisted of 100% male patients with mean age 59.5 ± 5.4 years; 39.0% were African American (AA). Group 2 consisted of 86% male patients, 59.0 ± 13 years and 53% AA. Among Group 1 patients, varices were present in 29% (16 esophageal and 3 gastric). There were no demographic differences among Group 1 patients with or without varices. Positive VIVOT scores were associated with EVs on endoscopy in 11 of 16 patients (sensitivity 68.75%). Positive VIVOT findings were present in 8 of 40 patients without EVs (specificity 80%). False-positive VIVOT scores were present in 6 of 62 non-cirrhotic controls. Overall, the positive predictive value among patients with cirrhosis was 59% with a negative predictive value of 84%. Conclusions: VIVOT has modest values in predicting EVs and should not be used alone to stratify patients for endoscopic evaluation when elastography and laboratory tests are available; however, its use in resource-limited settings to identify high-risk patients may be considered. [ABSTRACT FROM AUTHOR]

In a hepatitis C virus (HCV)–controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible. [ABSTRACT FROM AUTHOR]

In a hepatitis C virus (HCV)–controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible. [ABSTRACT FROM AUTHOR]

Background and Aims: A rapid increase in the use of telemedicine for delivering healthcare has occurred since the onset of the Covid-19 pandemic. There is evidence for using telemedicine to facilitate cancer care delivery for patients with hepatocellular carcinoma (HCC). Examining how telemedicine can be used to communicate multidisciplinary tumor board (MTB) recommendations for HCC has not been studied. This study has two specific aims: (1) to evaluate the patient perspective of the MTB review process and identify best strategies for communicating treatment recommendations for HCC and (2) to pilot test a telemedicine intervention following MTB review to assess patient feasibility and satisfaction with using telemedicine to facilitate treatment decision-making and treatment referral. Methods: We conducted a mixed-methods study. First, semi-structured qualitative interviews were conducted among patients diagnosed with HCC who were discussed in MTB review at one of three VA Medical Centers (VAMC). We collected information about the MTB process from the patient perspective and identified strategies for improving communication and delivery of care. Rapid qualitative analysis was used to inform intervention development. Using our qualitative data, a MTB telemedicine pilot intervention was developed and implemented to assess the feasibility of using this approach for patients with HCC. Results: Almost all patients (94%) in the pilot study would recommend telemedicine to other patients with HCC, and half of the patients (50%) preferred telemedicine over in-person visits. Many patients (81%) found communication through telemedicine an acceptable platform to deliver difficult cancer information. Overall, patients felt they understood their treatment recommendations and found them clear and useful. Further, patients reported that they enjoyed being included in the decision-making process and appreciated being able to have family members easily join them for the telemedicine visit. Conclusions: Using telemedicine to communicate treatment recommendations following MTB review was found to be feasible and an acceptable alternative to an in-person visit for patient with HCC. Future studies could include expanding this approach for communicating MTB recommendations to patients with other types of cancers. [ABSTRACT FROM AUTHOR]

Background and aims: Studies have demonstrated that reducing farnesoid X receptor activity with ursodeoxycholic acid (UDCA) downregulates angiotensin‐converting enzyme in human lung, intestinal and cholangiocytes organoids in vitro, in human lungs and livers perfused ex situ, reducing internalization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the host cell. This offers a potential novel target against coronavirus disease 2019 (COVID‐19). The objective of our study was to compare the association between UDCA exposure and SARS‐CoV‐2 infection, as well as varying severities of COVID‐19, in a large national cohort of participants with cirrhosis. Methods: In this retrospective cohort study among participants with cirrhosis in the Veterans Outcomes and Costs Associated with Liver cohort, we compared participants with exposure to UDCA, with a propensity score (PS) matched group of participants without UDCA exposure, matched for clinical characteristics, and vaccination status. The outcomes included SARS‐CoV‐2 infection, symptomatic, at least moderate, severe, or critical COVID‐19, and COVID‐19‐related death. Results: We compared 1607 participants with cirrhosis who were on UDCA, with 1607 PS‐matched controls. On multivariable logistic regression, UDCA exposure was associated with reduced odds of developing SARS‐CoV‐2 infection (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.41–0.71, p < 0.0001). Among patients who developed COVID‐19, UDCA use was associated with reduced disease severity, including symptomatic COVID‐19 (aOR 0.54, 95% CI 0.39–0.73, p < 0.0001), at least moderate COVID‐19 (aOR 0.51, 95% CI 0.32–0.81, p = 0.005), and severe or critical COVID‐19 (aOR 0.48, 95% CI 0.25–0.94, p = 0.03). Conclusions: In participants with cirrhosis, UDCA exposure was associated with both a decrease in SARS‐CoV‐2 infection, and reduction in symptomatic, at least moderate, and severe/critical COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis. Methods: This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality. Results: A total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58–2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42–0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001). Conclusions: The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all patients with ACLF. [ABSTRACT FROM AUTHOR]

We describe the model-independent mechanism by which dark matter and dark matter structures heavier than ~ 8 × 1011 GeV form binary pairs in the early Universe that spin down and merge both in the present and throughout the Universe’s history, producing potentially observable signals. Sufficiently dense dark objects will dominantly collide through binary mergers instead of random collisions. We detail how one would estimate the merger rate accounting for finite size effects, multibody interactions, and friction with the thermal bath. We predict how mergers of dark dense objects could be detected through gravitational and electromagnetic signals, noting that such mergers could be a unique source of high frequency gravitational waves. We rule out objects whose presence would contradict observations of the CMB and diffuse gamma-rays. [ABSTRACT FROM AUTHOR]

Background: Patients with decompensated cirrhosis are excluded or underrepresented in clinical trials of systemic therapies for hepatocellular carcinoma (HCC) and comparisons of available therapies are lacking. We aimed to compare overall survival for patients with HCC and Child‐Pugh B cirrhosis treated with nivolumab or sorafenib as first systemic treatment. Methods: We performed a retrospective cohort study in patients with HCC and Child‐Pugh B cirrhosis treated at Veterans Affairs medical centers to compare overall survival, adverse events, and reason for discontinuation of therapy between patients treated with nivolumab or sorafenib as first systemic treatment. All statistical tests were 2‐sided. Results: Of those meeting inclusion criteria, 431 patients were treated with sorafenib and 79 with nivolumab. Median OS was 4.0 months (95% CI 3.5–4.8) in the sorafenib cohort and 5.0 months (95% CI 3.3–6.8) in the nivolumab cohort. In the multivariable Cox proportional hazards model, nivolumab was associated with a significantly reduced hazard of death compared to sorafenib (HR 0.69; 95% CI 0.52–0.91; p = 0.008). In a secondary analysis using propensity score methods, results did not reach statistical significance (HR 0.77; 95% CI 0.55–1.06; p = 0.11). Treatment was discontinued due to toxicity in 12% of patients receiving nivolumab compared to 36% receiving sorafenib (p = 0.001). Conclusion: In patients with HCC and Child‐Pugh B cirrhosis, nivolumab treatment may be associated with improved overall survival and improved tolerability compared to sorafenib and should be considered for the first systemic treatment in this population. [ABSTRACT FROM AUTHOR]

Background and rationale: Liver derived messenger ribonucleic acid (mRNA) transcripts were reported to be elevated in the circulation of hepatocellular carcinoma (HCC) patients. We now report the detection of high-risk mRNA variants exclusively in the circulation of HCC patients. Numerous genomic alleles such as single nucleotide polymorphisms (SNPs), nucleotide insertions and deletions (called Indels), splicing variants in many genes, have been associated with elevated risk of cancer. Our findings potentially offer a novel non-invasive platform for HCC surveillance and early detection. Approach: RNAseq analysis was carried out in the plasma of 14 individuals with a diagnosis of HCC, 8 with LC and no HCC, and 6 with no liver disease diagnosis. RNA from 6 matching tumors and 5 circulating extracellular vesicle (EV) samples from 14 of those with HCC was also analyzed. Specimens from two cholangiocarcinoma (CCA) patients were also included in our study. HCC specific SNPs and Indels referred as "variants" were identified using GATK HaplotypeCaller and annotated by SnpEff to filter out high risk variants. Results: The variant calling on all RNA samples enabled the detection of 5.2 million SNPs, 0.91 million insertions and 0.81 million deletions. RNAseq analyses in tumors, normal liver tissue, plasma, and plasma derived EVs led to the detection of 5480 high-risk tumor specific mRNA variants in the circulation of HCC patients. These variants are concurrently detected in tumors and plasma samples or tumors and EVs from HCC patients, but none of these were detected in normal liver, plasma of LC patients or normal healthy individuals. Our results demonstrate selective detection of concordant high-risk HCC-specific mRNA variants in free plasma, plasma derived EVs and tumors of HCC patients. The variants comprise of splicing, frameshift, fusion and single nucleotide alterations and correspond to cancer and tumor metabolism pathways. Detection of these high-risk variants in matching specimens from same subjects with an enrichment in circulating EVs is remarkable. Validation of these HCC selective ctmRNA variants in larger patient cohorts is likely to identify a predictive set of ctmRNA with high diagnostic performance and thus offer a novel non-invasive serology-based biomarker for HCC. [ABSTRACT FROM AUTHOR]

Purpose: Acute pancreatitis (AP) is a frequently encountered adverse drug reaction. However, the validity of diagnostic codes for AP is unknown. We aimed to determine the positive predictive value (PPV) of a diagnostic code‐based algorithm for identifying patients with AP within the US Veterans Health Administration and evaluate the value of adding readily available structured laboratory information. Methods: We identified patients with possible AP events first based on the presence of a single hospital discharge ICD‐9 or ICD‐10 diagnosis of AP (Algorithm 1). We then expanded Algorithm 1 by including relevant laboratory test results (Algorithm 2). Specifically, we considered amylase or lipase serum values obtained between 2 days before admission and the end of the hospitalization. Medical records of a random sample of patients identified by the respective algorithms were reviewed by two separate gastroenterologists to adjudicate AP events. The PPV (95% confidence interval [CI]) for the algorithms were calculated. Results: Algorithm 2, consisting of one ICD‐9 or ICD‐10 hospital discharge diagnosis of AP and the addition of lipase serum value ≥200 U/L, had a PPV 89.1% (95% CI 83.0%–95.2%), improving from the PPV of algorithm 1 (57.9% [95% CI 46.8–69.0]). Conclusions: An algorithm consisting of an ICD‐9 or ICD‐10 diagnosis of AP with a lipase value ≥200 U/L achieved high PPV. This simple algorithm can be readily implemented in any electronic health records (EHR) systems and could be useful for future pharmacoepidemiologic studies on AP. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic has disrupted health care delivery in the United States, with increased reliance on telemedicine visits as opposed to in‐person outpatient appointments. We used national data to evaluate shifts in modes of hepatology outpatient care for patients with cirrhosis during the pandemic. This was a retrospective cohort study among U.S. veterans with cirrhosis. We used linear regression to evaluate absolute and percentage changes from baseline in hepatology in‐person visits and telemedicine visits from January 1, 2020, to August 11, 2020. The proportion of in‐person and telemedicine visits were plotted geographically to demonstrate state‐level shifts in care delivery over time. Patient‐level characteristics in the pre‐COVID and during‐COVID periods were also compared. We identified 5,618 in‐person and 6,210 telemedicine hepatology visits among patients with cirrhosis. In‐person visits significantly declined (−16.0% per week; 95% confidence interval [CI] −20.7, −11.2; P < 0.001), while telemedicine visits significantly increased (61.3% per week; 95% CI 45.1, 77.5; P < 0.001) in the early during‐COVID period. At the U.S. state level, we found that nearly all states experienced a significant shift toward telemedicine over the course of several weeks. Patients over the age of 70 years and Black patients were less likely to receive telemedicine visits in the pre‐COVID period (each P < 0.05), although these differences were eliminated in the during‐COVID periods. Conclusion: Among patients with cirrhosis, hepatology outpatient care delivery has shifted heavily toward telemedicine due to COVID‐19. This occurred across the United States, and changes have been sustained through August 2020. Expanded telemedicine visits among older patients and Black patients may reflect dedicated efforts to increased access to care among these groups. [ABSTRACT FROM AUTHOR]

Background: The impact of nonalcoholic fatty liver disease (NAFLD) on overall survival (OS), treatment response and toxicity in patients with hepatocellular carcinoma (HCC) treated with sorafenib is unknown. We examined the impact of NAFLD on survival and toxicity in an international cohort of patients receiving sorafenib. Methods: Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and toxicity compared with other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed. Results: A total of 5201 patients received sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women (median age 65.8 versus 63.0 years, p < 0.01 and 10.4% versus 2.3%, < 0.01), with a median body mass index (BMI) of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.84–1.18, p = 0.98]. NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib [Barcelona Clinic Liver Class (BCLC) C/D 70.9% versus 58.9%, p < 0.01] and were more likely to be commenced on a lower starting dose of sorafenib (51.4 versus 36.4%, p < 0.01). There was no difference in sorafenib-specific survival between NAFLD and other aetiologies (HR: 0.96, 95% CI: 0.79–1.17, p = 0.96). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of greater than grade 2 hypertension (6.3% versus 5.8%, p = 1.00). Conclusion: Survival in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared with other aetiologies. [ABSTRACT FROM AUTHOR]

Background: Alcoholic hepatitis (AH) is a clinically diagnosed syndrome with high short-term mortality for which liver transplantation may be curative. A lack of validated algorithms to identify AH hospitalizations has hindered clinical epidemiology research. Methods: This was a retrospective cohort study of patients with cirrhosis using Veterans Health Administration (VHA) data from 2008 to 2015. We randomly sampled hospitalizations based upon abnormal liver tests and administrative codes for acute hepatitis or alcohol-associated liver disease (ALD). Hospitalizations were manually adjudicated for AH per society guidelines. A priori algorithms were evaluated to compute positive predicted value (PPV) and positive likelihood ratio (LR+), and were tested in an external University of Pennsylvania Health System (UPHS) cohort. Results: Of 368 hospitalizations, 142 (38.6%) were adjudicated as AH. AH patients were younger (55 vs. 58 years, p < 0.001), less likely to have prior cirrhosis decompensation (57% vs. 73.9%, p < 0.001), and had higher AST-to-ALT ratios (median 2.9 vs. 1.9 mg/dL, p < 0.001) and higher bilirubin levels (median 2.9 vs. 1.9 mg/dL, p < 0.001). Algorithms combining clinical laboratory criteria (AST > 85 U/L but < 450 U/L, AST-to-ALT ratio > 2, total bilirubin > 5 mg/dL) and administrative coding criteria yielded the highest PPV (96.4%, 95% CI 87.7–99.6) and the highest LR+ (43.0, 95% CI 10.6–173.5). Several algorithms demonstrated 100% PPV for definite AH in the UPHS external cohort. Conclusion: We have identified algorithms for AH hospitalizations with excellent PPV and LR+. These high-specificity algorithms may be used in VHA datasets to identify patients with high likelihood of AH, but should not be used to study AH incidence. [ABSTRACT FROM AUTHOR]

Background: The Freiburg index of post-TIPS survival (FIPS) score was recently demonstrated to improve prediction of post-TIPS mortality relative to existing standards. As this score was derived from a German cohort over an extended time period, it is unclear if performance will translate well to other settings. This study aimed to externally validate the FIPS score in a large Veterans Affairs (VA) cohort over two separate eras of TIPS-related care. Methods: This was a retrospective cohort study of patients with cirrhosis who underwent TIPS placement in the VA from 2008 to 2020. Cox regression models for post-TIPS survival were constructed using FIPS, MELD, MELD-Na, or CTP scores as predictors. Discrimination (Harrell's C) and calibration (joint tests of calibration curve slope and intercept) were evaluated for each score. A stratified analysis was performed for time periods between 2008–2013 and 2014–2020. Results: The cohort of 1,274 patients was 97.3% male with mean age 60.9 years and mean MELD-Na 14. The FIPS score demonstrated the highest overall discrimination versus MELD, MELD-Na, and CTP (0.634 vs. 0.585, 0.626, 0.612, respectively). However, in the modern treatment era (2014–2020), the FIPS score performed similarly to MELD-Na. Additionally, the FIPS score demonstrated poor calibration at one-month and six-month post-TIPS timepoints (joint p = 0.04 and 0.004, respectively). MELD, MELD-Na, and CTP were well-calibrated at each timepoint (each joint p > 0.05). Conclusion: The FIPS score performed similarly to MELD-Na in the modern TIPS treatment era and demonstrated regions of poor calibration. Future models derived with contemporary data may improve prediction of post-TIPS mortality. [ABSTRACT FROM AUTHOR]

Background: Little is known about use of specialty care among patients admitted with cirrhosis complications. Aims: We sought to characterize the use and impact of gastroenterology/hepatology (GI/HEP) consultations in hospitalized patients with cirrhosis. We studied two national cohorts—the Veterans Affairs Costs and Outcomes in Liver Disease (VOCAL) and a nationally representative database of commercially insured patients (Optum Clinformatics™ DataMart). Methods: Cirrhosis-related admissions were classified by ICD9/10 codes for ascites, hepatic encephalopathy, alcohol-associated hepatitis, spontaneous bacterial peritonitis, or infection related. We included 20,287/222,166 index admissions from VOCAL/Optum from 2010 to 2016. Propensity-matched analyses were conducted to balance clinical characteristics. Mortality and readmission were evaluated using competing risk regression (subhazard ratios, sHR), and length of stay (LOS) was assessed using negative binomial regression. Results: GI/HEP consultations were completed among 37% and 42% patients in VOCAL and Optum, respectively. In propensity-matched analyses for VOCAL, GI/HEP consultation was associated with adjusted estimates of increased LOS (1.55 + 1.03 additional days), 90-day mortality (sHR 1.23, 95% CI 1.14–1.36), and lower 30-day readmissions (sHR 0.82, 95% CI 0.75–0.89). In Optum, inpatient consultation was associated with higher LOS (1.13 + 1.01 additional days), higher 90-day mortality (sHR 1.57, 95% CI 1.43–1.72), and higher 30-day readmission risk (sHR 1.04, 95% CI 1.02–1.05). Post-discharge primary and specialty care was higher among admissions receiving GI/HEP consultation in both cohorts. Conclusions: Use of GI/HEP consultation for cirrhosis-related admissions was low. Patients who received consultation had higher disease severity, and consultation was not associated with lower mortality but was associated with lower 30-day readmissions in the VA cohort only. [ABSTRACT FROM AUTHOR]

Background: The Food and Drug Administration requested withdrawal of ranitidine formulations, due to a potentially carcinogenic contaminant, N-nitrosodimethylamine. Aims: We evaluate whether ranitidine use is associated with gastric cancer. Methods: This is a retrospective multicenter, nationwide cohort study within the Veterans Health Administration, among patients with Helicobacter pylori (HP) prescribed long-term acid suppression with either: (1) ranitidine, (2) other histamine type 2 receptor blocker (H2RB), or (3) proton pump inhibitor (PPI)) between May 1, 1998, and December 31, 2018. Covariates included race, ethnicity, smoking, age, HP treatment, HP eradication. Primary outcome was non-proximal gastric adenocarcinomas, using multivariable Cox proportional hazards analysis. Results: We identified 279,505 patients with HP prescribed long-term acid suppression (median 53.4 years; 92.9% male). Compared to ranitidine, non-ranitidine H2RB users were more likely to develop cancer (HR 1.83, 95%CI 1.36–2.48); PPI users had no significant difference in future cancer risk (HR 0.92, 95% CI 0.82–1.04), p < 0.001. Demographics associated with future cancer included increasing age (HR 1.18, 95% CI 1.15–1.20, p < 0.001), Hispanic/Latino ethnicity (HR 1.46, 95% CI 1.21–1.75, p < 0.001), Black race (HR 1.89, 95% CI 1.68–2.14) or Asian race (HR 2.03, 95% CI 1.17–3.52), p < 0.001, and gender (female gender HR 0.64, 95% CI 0.48–0.85, p = 0.02). Smoking was associated with future cancer (HR 1.38, 95% CI 1.23–1.54, p < 0.001). Secondary analysis demonstrated decreased cancer risk in those with confirmed HP eradication (HR 0.24, 95% CI 0.14–0.40). No association between ranitidine and increased gastric cancer was found. Conclusion: There is no demonstrable association between ranitidine use and future gastric cancer among individuals with HP on long-term acid suppression. [ABSTRACT FROM AUTHOR]

Background: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. Methods: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. Results: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22–5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15 mL/min/1.73 m2 change (p < 0.001). Conclusions: Race adjustment in eGFR equations did not enhance AKI risk estimation in patients with cirrhosis. Further study is warranted to assess the impacts of removing race from eGFR equations on clinical outcomes and policy. [ABSTRACT FROM AUTHOR]

We present current direct and astrophysical limits on the cosmological abundance of black holes with extremal magnetic charge. Such black holes do not Hawking radiate, allowing those normally too light to survive to the present to do so. The dominant constraints come from white dwarf destruction for low and intermediate masses (2 × 10−5 g – 4 × 1012 g) and Galactic gas cloud heating for heavier masses (> 4 × 1012 g). Extremal magnetic black holes may catalyze proton decay. We derive robust limits — independent of the catalysis cross section — from the effect this has on white dwarfs. We discuss other bounds from neutron star heating, solar neutrino production, binary formation and annihilation into gamma-rays, and magnetic field destruction. Stable magnetically charged black holes can assist in the formation of neutron star mass black holes. [ABSTRACT FROM AUTHOR]

Background: The natural history of patients with anti‐mitochondrial antibody (AMA)‐negative Primary Biliary Cholangitis (PBC) cirrhosis has not been well defined, with prior studies showing discordant results. Furthermore, most studies of AMA‐negative PBC have limited numbers of patients with cirrhosis and liver‐related outcomes. Methods: We investigated the association of AMA‐negative PBC and the development of death, liver‐related death, decompensation and hepatocellular carcinoma (HCC), in a large cohort of predominantly male patients with PBC cirrhosis assembled from the Veterans Health Administration. Results: In a cohort of 521 patients with PBC cirrhosis (65 AMA‐negative) with a total follow‐up of 2504.3 person‐years (PY) from cirrhosis diagnosis, patients with AMA‐negative PBC were younger and more likely to be black but had similar rates of UDCA response. AMA‐negative PBC cirrhosis was associated with similar unadjusted rates of liver‐related death (4.6 vs 5.9 per 100 PY, P =.44), overall death (7.7 vs 9.6 per 100 PY, P =.31), decompensation (7.3 vs 5.1 per 100 PY, P =.12) and HCC (0.6 vs 1.0 per 100 PY, P =.63) to AMA‐positive PBC. After adjusting for confounders, AMA‐negative PBC cirrhosis was associated with similar rates of liver‐related death (sub‐Hazard Ratio [sHR] 1.27, 95% CI 0.71‐2.28, P =.42, death [sHR] 1.24, 95% CI 0.81‐1.90, P =.32), decompensation (sHR 1.05, 95% CI 0.56‐1.98, P =.87) and HCC (sHR 0.48, 95% CI 0.11‐2.10, P =.33) to AMA‐positive patients. Conclusion: In a cohort of predominantly male patients, AMA‐negative PBC cirrhosis was associated with similar rates of overall or liver‐related death, HCC or decompensation compared with AMA‐positive disease. [ABSTRACT FROM AUTHOR]

The cosmic neutrino background is both a dramatic prediction of the hot Big Bang and a compelling target for current and future observations. The impact of relativistic neutrinos in the early universe has been observed at high significance in a number of cosmological probes. In addition, the non-zero mass of neutrinos alters the growth of structure at late times, and this signature is a target for a number of upcoming surveys. These measurements are sensitive to the physics of the neutrino and could be used to probe physics beyond the standard model in the neutrino sector. We explore an intriguing possibility where light right-handed neutrinos are coupled to all, or a fraction of, the dark matter through a mediator. In a wide range of parameter space, this interaction only becomes important at late times and is uniquely probed by late-time cosmological observables. Due to this coupling, the dark matter and neutrinos behave as a single fluid with a non-trivial sound speed, leading to a suppression of power on small scales. In current and near-term cosmological surveys, this signature is equivalent to an increase in the sum of the neutrino masses. Given current limits, we show that at most 0.5% of the dark matter could be coupled to neutrinos in this way. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Obeticholic acid (OCA) is approved for the treatment of patients with primary biliary cholangitis (PBC) who are partial responders or intolerant to ursodeoxycholic acid. Reports of serious liver injury have raised concerns about its safety in cirrhosis. We investigated the effects of treatment with OCA on hepatic decompensation and liver‐related mortality or transplantation in a cohort with compensated PBC cirrhosis. This was a retrospective cohort study using national data of US veterans with PBC and cirrhosis. We performed a propensity score model using variables associated with OCA prescription to control for baseline risk of decompensation. New OCA users were matched to nonusers. We identified 509 subjects with compensated PBC cirrhosis. We developed a propensity score model using variables associated with OCA prescription; 21 OCA users were matched with 84 nonusers. Over 569 and 3,847 person‐months, respectively, of follow‐up, 5 (23.8%) OCA users and 22 (26.2%) OCA nonusers decompensated. The C‐statistic of the propensity score model was 0.87. On multivariable analysis, after adjusting for potential confounders, OCA use was associated with an increased risk of hepatic decompensation (adjusted hazard ratio, 3.9; 95% confidence interval, 1.33‐11.57; P = 0.01). There was no association between OCA use and liver‐related mortality or transplantation (adjusted hazard ratio, 1.35; 95% confidence interval, 0.35‐5.21; P = 0.66). Conclusion: OCA use was associated with an increase in hepatic decompensation but not liver‐related mortality or transplantation in patients with compensated PBC cirrhosis. Additional studies are recommended to prospectively investigate these findings. [ABSTRACT FROM AUTHOR]