The burden of significant pain in the cirrhosis population: Risk factors, analgesic use, and impact on health care utilization and clinical outcomes.

BACKGROUND: We aimed to characterize pain and analgesic use in a large contemporary cohort of patients with cirrhosis and to associate pain with unplanned health care utilization and clinical outcomes in this population. METHODS: We included all patients with cirrhosis seen in UCSF hepatology clinics from 2013 to 2020. Pain severity and location were determined using documented pain scores at the initial visit; "significant pain" was defined as moderate or severe using established cutoffs. Demographic, clinical, and medication data were abstracted from electronic medical records. Associations between significant pain and our primary outcome of 1-year unplanned health care utilization (ie, emergency department visit or hospitalization) and our secondary outcomes of mortality and liver transplantation were explored in multivariable models. RESULTS: Among 5333 patients with cirrhosis, 32% had a nonzero pain score at their initial visit and 25% had significant (ie moderate/severe) pain. Sixty percent of patients with significant pain used ≥1 analgesic; 34% used opioids. Patients with cirrhosis with significant pain had similar Model for End-Stage Liver Disease-Sodium scores (14 vs. 13), but higher rates of decompensation (65% vs. 55%). The most common pain location was the abdomen (44%). Patients with abdominal pain, compared to pain in other locations, were more likely to have decompensation (72% vs. 56%). Significant pain was independently associated with unplanned health care utilization (adjusted odds ratio: 1.3, 95% CI: 1.1-1.5) and mortality (adjusted hazard ratio: 1.4, 95% CI: 1.2-1.6). CONCLUSIONS: Pain among patients with cirrhosis is often not well-controlled despite analgesic use, and significant pain is associated with unplanned health care utilization and mortality in this population. Effectively identifying and treating pain are essential in reducing costs and improving quality of life and outcomes among patients with cirrhosis.

Outpatient mean arterial pressure: A potentially modifiable risk for acute kidney injury and death among patients with cirrhosis.

Mean arterial blood pressure (MAP), which decreases as portal hypertension progresses, may be a modifiable risk factor among patients with cirrhosis. We included adults enrolled in the Functional Assessment in Liver Transplantation study. We completed latent class trajectory analyses to define MAP trajectories. We completed time-dependent Cox-regression analyses to test the association between outpatient MAP and 3 cirrhosis-related outcomes: (1) stage 2 acute kidney injury (AKI), defined as a ≥200% increase in serum creatinine from baseline; (2) a 5-point increase in the MELD-Na score, defined as the incidence of increase from initial MELD-Na; (3) waitlist mortality, defined as death on the waitlist. For each outcome, we defined MAP cut points by determining the maximally selected Log-rank statistic after univariable Cox-regression analyses. Among the 1786 patients included in this analysis, our latent class trajectory analyses identified 3 specific outpatient MAP trajectories: "stable-low," "stable-high," and "increasing-to-decreasing." However, >80% of patients were in a "stable-low" trajectory. We found in adjusted analyses that outpatient MAP was associated with each of our outcomes: Stage 2 AKI (adjusted hazard ratio 0.88 per 10 mm Hg increase in MAP [95% CI: 0.79-0.99]); 5-point increase in MELD-Na (adjusted hazard ratio: 0.91 [95% CI: 0.86-0.96]; waitlist mortality (adjusted hazard ratio: 0.89 [95% CI: 0.81-0.96]). For each outcome, we found that an outpatient MAP of 82 mm Hg was most associated with outcomes ( p <0.05 for all). Our study informs the association between outpatient MAP and cirrhosis-related outcomes. These findings, coupled with the identification of specific thresholds, lay the foundation for the trial of targeted outpatient MAP modulation in patients with cirrhosis.

The association between mean arterial pressure and acute kidney injury reversal among patients with decompensated cirrhosis.

BACKGROUND AND AIMS: This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology. APPROACH AND RESULTS: We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48 h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1 mm Hg, p <0.05) and a greater increase in MAP over time (0.1 mm Hg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5 mm Hg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5 mm Hg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001). DISCUSSION: Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.

Inflammatory Bowel Disease and the Risk of Anal Squamous Intraepithelial Lesions and Anal Cancer in Men Who Have Sex With Men.

BACKGROUND: The risk of anal cancer is increased in patients with human immunodeficiency virus (HIV), inflammatory bowel disease (IBD), and among men who have sex with men (MSM). High grade squamous intraepithelial lesions (HSILs) are precursor lesions to anal squamous cell carcinoma (SCC), and treatment of these lesions can decrease progression to anal SCC. This study aims to determine the prevalence of HSIL and anal cancer among MSM patients with and without IBD referred for anal cancer screening. METHODS: This is a retrospective study of all MSM patients seen at an anal squamous intraepithelial lesions (aSILs) and anal cancer screening specialty clinic. Data were manually and electronically collected from clinical documentation and pathology results for the primary outcomes of HSIL and anal cancer. Demographics, HIV status, IBD disease status, disease phenotype, and immunosuppressive medication use were collected through the electronic health record. Descriptive statistics were used. RESULTS: In all, 4623 patients were included for analysis. Among 57 MSM patients with IBD, 25 (43.9%) had a history of HSIL, and 2 (3.5%) had a history of anal cancer. Among 4618 MSM patients without IBD, 2417 (52.3%) had a history of HSIL, and 139 (3.0%) had a history of anal cancer (P = .744). Rates of HIV were 49.1% among MSM patients with IBD and 69.8% among MSM patients without IBD (P = .001). There remained no difference in prevalence of HSIL and anal cancer between groups when adjusting for HIV status. Among IBD patients, only 21.6% were referred for screening by their gastroenterologist. CONCLUSIONS: Among MSM with and without IBD, both groups had an equally high prevalence of HSIL and anal SCC. Awareness of appropriate surveillance to identify aSIL in MSM patients with IBD is needed among gastroenterologists.

This retrospective study of MSM patients with IBD referred for anal screening compared with those without IBD found equally high prevalence of anal squamous cell cancer and its precursor, HSIL, with a low rate of referral from gastroenterologists.

Nonselective beta-blockers may lead to stage 2 acute kidney injury and waitlist mortality in child class C cirrhosis.

BACKGROUND AND AIMS: Nonselective beta-blockers (NSBB) protect patients with compensated cirrhosis; however, it is unclear if NSBB is associated with acute kidney injury (AKI) in patients with decompensated cirrhosis. We aimed to determine if the use of NSBB was associated with an increased risk of stage II AKI or greater and waitlist mortality (WLM) among patients with decompensated cirrhosis awaiting liver transplant stratified by cirrhosis severity. METHODS: Included were 1816 outpatients listed for liver transplantation at UCSF from June 2012 to April 2022. Our primary outcome was stage 2 AKI (>200% increase in serum creatinine). Our secondary outcome was WLM (all-cause mortality). Our primary exposure was the use of any NSBB derived using natural language processing of clinical notes. Multivariable Cox proportional hazards models with time-dependent variables were used to determine the HR of NSBB use on stage 2 AKI and WLM, stratified by Child-Pugh Score. RESULTS: The average age of the cohort was 58 years old, with 35% identifying as female. In multivariable time-dependent models, NSBB use was associated with 1.53 × (95 CI 1.19-1.97) the hazard of stage 2 AKI in the cohort overall and 1.80 × (95 CI 1.26-2.57) among those with Child C cirrhosis, respectively. Similarly, NSBB use was associated with 1.30 × (95 CI 1.07-1.59) and 1.45 × (95 CI 1.03-2.03) the hazard of WLM, overall and in Child C, respectively. NSBB use was not significantly associated with AKI nor WLM among those with Child A. CONCLUSION: NSBB use is associated with Stage 2 AKI and WLM in patients awaiting liver transplantation and Child C cirrhosis. These data suggest cautious use of NSBBs in patients in this population.

Predicting post-liver transplant outcomes in patients with acute-on-chronic liver failure using Expert-Augmented Machine Learning.

Liver transplantation (LT) is a treatment for acute-on-chronic liver failure (ACLF), but high post-LT mortality has been reported. Existing post-LT models in ACLF have been limited. We developed an Expert-Augmented Machine Learning (EAML) model to predict post-LT outcomes. We identified ACLF patients who underwent LT in the University of California Health Data Warehouse. We applied the RuleFit machine learning (ML) algorithm to extract rules from decision trees and create intermediate models. We asked human experts to rate the rules generated by RuleFit and incorporated these ratings to generate final EAML models. We identified 1384 ACLF patients. For death at 1 year, areas under the receiver-operating characteristic curve were 0.707 (confidence interval [CI] 0.625-0.793) for EAML and 0.719 (CI 0.640-0.800) for RuleFit. For death at 90 days, areas under the receiver-operating characteristic curve were 0.678 (CI 0.581-0.776) for EAML and 0.707 (CI 0.615-0.800) for RuleFit. In pairwise comparisons, both EAML and RuleFit models outperformed cross-sectional models. Significant discrepancies between experts and ML occurred in rankings of biomarkers used in clinical practice. EAML may serve as a method for ML-guided hypothesis generation in further ACLF research.

Prevalence and Causes of Diagnostic Errors in Hospitalized Patients Under Investigation for COVID-19.

BACKGROUND: The COVID-19 pandemic required clinicians to care for a disease with evolving characteristics while also adhering to care changes (e.g., physical distancing practices) that might lead to diagnostic errors (DEs). OBJECTIVE: To determine the frequency of DEs and their causes among patients hospitalized under investigation (PUI) for COVID-19. DESIGN: Retrospective cohort. SETTING: Eight medical centers affiliated with the Hospital Medicine ReEngineering Network (HOMERuN). TARGET POPULATION: Adults hospitalized under investigation (PUI) for COVID-19 infection between February and July 2020. MEASUREMENTS: We randomly selected up to 8 cases per site per month for review, with each case reviewed by two clinicians to determine whether a DE (defined as a missed or delayed diagnosis) occurred, and whether any diagnostic process faults took place. We used bivariable statistics to compare patients with and without DE and multivariable models to determine which process faults or patient factors were associated with DEs. RESULTS: Two hundred and fifty-seven patient charts underwent review, of which 36 (14%) had a diagnostic error. Patients with and without DE were statistically similar in terms of socioeconomic factors, comorbidities, risk factors for COVID-19, and COVID-19 test turnaround time and eventual positivity. Most common diagnostic process faults contributing to DE were problems with clinical assessment, testing choices, history taking, and physical examination (all p < 0.01). Diagnostic process faults associated with policies and procedures related to COVID-19 were not associated with DE risk. Fourteen patients (35.9% of patients with errors and 5.4% overall) suffered harm or death due to diagnostic error. LIMITATIONS: Results are limited by available documentation and do not capture communication between providers and patients. CONCLUSION: Among PUI patients, DEs were common and not associated with pandemic-related care changes, suggesting the importance of more general diagnostic process gaps in error propagation.

Relation of statin nonadherence and treatment intensification.

Failure to intensify medication and failure to adhere to medication have been shown to contribute to suboptimal low-density lipoprotein cholesterol goal attainment. To examine whether nonadherence to statins in 126,903 patients on stable statin therapy is associated with subsequent treatment intensification, we conducted a retrospective analysis using an integrated pharmacy and medical claims database. Pharmacy claims were analyzed to determine whether nonadherence, as measured by proportion of days covered on statins <80%, was associated with intensification of statin treatment over a 360-day follow-up. Of 11,361 patients who had treatment intensification, 44% were previously nonadherent to statins. Patients whose treatment was intensified had slightly lower adherence to statin therapy than those without intensification (76% vs 78%, p <0.0001) and were more likely to be nonadherent as defined by proportion of days covered <80% (44% vs 37%, p <0.0001). After controlling for confounding factors, patients nonadherent to statins were 30% more likely to have treatment intensification compared to adherent patients (odds ratio 1.30, 95% confidence interval 1.25 to 1.36). In addition, patients with statin intensification were more likely to be younger, women, and have coronary artery disease, diabetes, hypertension, dyslipidemia, stroke, peripheral arterial disease, heart failure, or depression. Primary care physicians were more likely to escalate therapy than cardiologists. In conclusion, nearly 1/2 of patients with therapy escalation were nonadherent to statins. Clinicians should inquire about adherence and consider adherence before escalating statin therapy.

A strategy to standardize the learning of core clerkship objectives.

BACKGROUND: Consistent and effective implementation of clinical clerkship objectives remains elusive. Using the behavioral principles of self assessment, active learning and learner differences, we designed an objectives checklist to ensure that all students mastered a core body of internal medicine (IM) knowledge and to facilitate self-directed learning. METHODS: We developed a 54-item learning objectives checklist card in the IM clerkship. In a randomized controlled trial by clerkship site and block, students in the intervention group received the checklist card and were instructed to obtain sign off on objectives by faculty and housestaff and to seek teaching, literature, and clinical experiences to satisfy objectives unmet through routine activities. Intervention group faculty and housestaff were oriented to the use of the checklist. Both intervention and control groups received the course syllabus. We assessed learning with faculty and housestaff evaluations, student knowledge self-assessment, and a written examination. Satisfaction with the cards was assessed with written evaluations. RESULTS: There were no significant differences in ward evaluations, examination scores or self-assessed knowledge between students using the learning objectives cards and control groups. Faculty were more likely than students to agree that objectives cards improved education. CONCLUSIONS: An intervention designed to guide students in the use of a learning objectives card did not enhance learning as assessed by ward evaluations, a written examination, and satisfaction surveys. It is possible that more sensitive outcome measures could detect differences in knowledge for students using learning objectives checklist cards.

Intersessions: covering the bases in the clinical year.

OBJECTIVE: At most medical schools students spend the core clerkship year entirely in clinical settings, geographically dispersed, and assigned to separate teams. Because of the immediacy of experiential learning in the clinical environment, this year is often the highlight of medical school. However, the intensity of the experience and the dispersion of students poses serious challenges to student well being and professional development, and to meeting important educational objectives best taught in the clinical year but difficult to implement in competition with direct patient care. To address these challenges in a way that does not interfere with the clinical experiences, we developed and are implementing three one-week intersessions. These are designated weeks between clerkship rotations when all third-year students are "off rotations" and studying together in an integrative, collaborative and reflective manner. DESCRIPTION: We identified themes for the intersession course from several sources. In response to strong documentation by past students of isolation and insufficient opportunity to reflect on their experiences during the core clerkships we placed a high priority on students gathering together as a class and on professional development. Additionally, based on knowledge gaps identified in the AAMC Graduation Questionnaire and our commitment to integrating basic science teaching into the clinical year, we developed the following five themes: evidence-based medicine, ethics, health systems (quality; resource allocation), advances in science (recent advances that fundamentally shift clinical practice), and professional development. Each intersession week consists of 20 hours of structured contact time; 75% is devoted to small-group learning. The weeks rely heavily on student directed and collaborative learning to complete required readings and assignments. All sessions build on the clinical experiences students have had during clerkships and enhance the students' skills for upcoming rotations. DISCUSSION: In 1999-2000, we restructured the clinical core year into eight-week modules allowing us to gather the entire class, in between clerkships, for intersessions. We phased in two intersession weeks in 2000-2001 and are implementing three intersession weeks in 2001-2002 (October, February, and June). In the evaluations of the first year's intersessions students valued the opportunity to gather together, to process their clinical experience, and to utilize their clinical experience to drive learning in important, clinically relevant areas that are not consistently taught in the clerkships. Evaluations from the first intersession of the second cycle further underscore the preference for learning experiences that are highly relevant to the clinical year (e.g., practicing efficient search strategies to quickly answer clinical questions, utilizing systematic reviews, discussing ethics cases from the students' experiences) and the benefits of faculty facilitated small-group discussions over lecture time. The advances in science sessions are most effective when they focus on advances in diseases that students are likely to have encountered. In our next phase, we will use Web-based interfaces to collect cases from students on clerkships and to promote discussion of topics in anticipation of the next intersession. As we continue to refine intersessions, our experience so far provides good evidence to support intersessions as a successful curricular innovation.