QuickStroop Predicts Time to Development of Overt Hepatic Encephalopathy and Related Hospitalizations in Patients With Cirrhosis.

Cirrhosis-related neurocognitive impairment caused by covert or minimal hepatic encephalopathy (CHE) affects psychosocial function, increases risk of overt hepatic encephalopathy (OHE) development, and worsens survival.1,2 However, detection in clinical practice is challenging.2 One modality used for screening and prediction of outcomes related to cirrhosis is the EncephalApp Stroop, but it can require up to 10 minutes. Furthermore, the assessment comprises of distinct stages of difficulty, with an easier "Off" stage and a more challenging "On" stage.3 To alleviate these concerns, QuickStroop, which takes <1 minute, was developed. This uses only the first 2 runs of the Off stage of the EncephalApp Stroop, where number signs presented in red, green, or blue need to be matched quickly to their respective colors.4 A prior study showed these versions were comparable cross-sectionally to diagnose CHE.4 However, the utility of QuickStroop to predict cirrhosis-related outcomes is unclear.5-7 Our aim was to determine the ability of QuickStroop to determine time to development of OHE and OHE-related hospitalizations, all-cause hospitalizations, and death in outpatients with cirrhosis.

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors.

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

Leadership Behaviors of Frontline Nurse Managers: A Mixed-Methods Research Study Identifying Essential Areas for Social Support.

OBJECTIVE: This study examined how frontline nurse managers (FLNMs) perceive and experience formal and informal social support and how personal factors and social support relate to their transformational leadership (TL) behaviors. BACKGROUND: Ineffective leadership by FLNMs is associated with costly outcomes. Evidence suggests that leadership development is a function of personal and social factors; however, a better understanding of this process is needed. METHODS: A convergent mixed-methods design was used. The quantitative strand included a cross-sectional survey in a sample of FLNMs. The qualitative strand used a semistructured interview and a descriptive qualitative approach with a subset of this sample. RESULTS: Formal and informal social support is positively related to the TL behaviors of FLNMs as evidenced by the convergent data. The influence of family members in the work-related decisions of FLNMs has been underreported in the literature and is an area for consideration in supporting retention and desired leadership behaviors. CONCLUSION: The findings of this study imply a need for organizations to establish systems that endorse the growth of FLNMS, create opportunities for career advancement, and integrate members of the FLNMs' personal support systems into recognition initiatives.

Describing Medication Administration and Alert Patterns Experienced by New Graduate Nurses During the First Year of Practice.

The aim of this study was to describe medication administration and alert patterns among a cohort of new graduate nurses over the first year of practice. Medical errors related to clinical decision-making, including medication administration errors, may occur more frequently among new graduate nurses. To better understand nursing workflow and documentation workload in today's clinical environment, it is important to understand patterns of medication administration and alert generation during barcode-assisted medication administration. Study objectives were addressed through a descriptive, longitudinal, observational cohort design using secondary data analysis. Set in a large, urban medical center in the United States, the study sample included 132 new graduate nurses who worked on adult, inpatient units and administered medication using barcode-assisted medication administration. Data were collected through electronic health record and administration sources. New graduate nurses in the sample experienced a total of 587 879 alert and medication administration encounters, administering 772 unique medications to 17 388 unique patients. Nurses experienced an average medication workload of 28.09 medications per shift, 3.98% of which were associated with alerts, over their first year of practice. In addition to high volume of medication administration, new graduate nurses administer many different types of medications and are exposed to numerous alerts while using barcode-assisted medication administration.

Factors Influencing Medication Administration Outcomes Among New Graduate Nurses Using Bar Code-Assisted Medication Administration.

Paramount to patient safety is the ability for nurses to make clinical decisions free from human error. Yet, the dynamic clinical environment in which nurses work is characterized by uncertainty, urgency, and high consequence, necessitating that nurses make quick and critical decisions. The aim of this study was to examine the influence of human and environmental factors on the decision to administer among new graduate nurses in response to alert generation during bar code-assisted medication administration. The design for this study was a descriptive, longitudinal, observational cohort design using EHR audit log and administrative data. The study was set at a large, urban medical center in the United States and included 132 new graduate nurses who worked on adult, inpatient units. Research variables included human and environmental factors. Data analysis included descriptive and inferential analyses. This study found that participants continued with administration of a medication in 90.75% of alert encounters. When considering the response to an alert, residency cohort, alert category, and previous exposure variables were associated with the decision to proceed with administration. It is important to continue to study factors that influence nurses' decision-making, particularly during the process of medication administration, to improve patient safety and outcomes.

Tummy Time Tracking: Examining Agreement Between Parent Recall and Direct Observation in Infants.

IMPORTANCE: Parent recall is the primary method for measuring positioning practices such as tummy time in infants. Concerns regarding the accuracy of parent recall have been raised in the literature. To date, no study has examined the agreement of tummy time recall measures with gold-standard methods. OBJECTIVE: To assess the agreement between parental recall versus direct observation of tummy time in infants, and to explore the impact of prematurity on this relationship. DESIGN: Cross-sectional observational study, spanning 1 yr. SETTING: Participants' homes Participants: Thirty-two infant-parent dyads (19 full-term, 13 preterm), with infants ages 3 to 6 mo and caregivers ages older than 18 yr. OUTCOME AND MEASURES: Home-recorded videos of infant play across 3 days were used as a proxy for direct observation of tummy time and compared with a 12-item parent recall survey. RESULTS: Parent recall had a significant moderate correlation (ρ = .54, p = .002) with direct observation in full-term infants but was not correlated (p = .23) with direct observation in preterm infants. On average, parents of preterm infants overestimated tummy time by 2.5 times per day compared with direct observation. CONCLUSIONS AND RELEVANCE: For full-term infants, parent recall measures of tummy time exhibit an acceptable level of agreement with direct observation and can be reliably used over shorter periods. Parents of preterm infants may display a bias in recalling tummy time, leading to overestimations. To accurately assess tummy time in this population, a combination of subjective and objective measures should be explored. Plain-Language Summary: Tummy time is an essential movement experience for infants, especially for preterm infants, who are at a higher risk for motor delays. The most common way to track tummy time is through parent reports, or recall, versus a practitioner directly observing tummy time in the home. Despite the widespread use of parent recall to track tummy time, no study has examined the accuracy of parent recall versus direct observation in the home. Accurately assessing tummy time is crucial for improving and supporting health outcomes for infants. This study found that prematurity may affect the accuracy of parent recall for assessing tummy time in young infants. The authors discuss the implications of this finding and provide suggestions to guide the selection of appropriate methods to measure tummy time in clinical practice and research studies.

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study.

BACKGROUND & AIMS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS: Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS: Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1ß and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION: In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION: www. CLINICALTRIALS: gov NCT03585257. IMPACT AND IMPLICATIONS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

QuickStroop, a Shortened Version of EncephalApp, Detects Covert Hepatic Encephalopathy With Similar Accuracy Within One Minute.

BACKGROUND & AIMS: Covert hepatic encephalopathy (CHE) is associated with poor outcomes but is often not diagnosed because of the time requirement. Psychometric hepatic encephalopathy score (PHES) is the gold standard against which EncephalApp Stroop has been validated. However, EncephalApp (5 runs each in "Off" and "On" state) can take up to 10 minutes. This study sought to define the smallest number of EncephalApp runs needed for comparable accuracy to the total EncephalApp using CHE on PHES as gold standard. METHODS: A derivation and a validation cohort of outpatients with cirrhosis who underwent PHES (gold standard) and total EncephalApp was recruited. Data were analyzed for individual runs versus total EncephalApp time versus PHES-CHE. The derivation cohort (n = 398) was split into training (n = 299) and test (n = 99) sets. From the training data set a regression model was created with age, gender, education, and various sums of the "Off" settings. After this, a K-fold cross-validation on the test dataset was performed for both total EncephalApp time and individual Off runs and for the validation cohort. RESULTS: In both cohorts, Off runs 1 + 2 had statistically similar area under the receiver operating curve and P value to the total EncephalApp for PHES-CHE prediction. The adjusted (age, gender, education) regression formula from the derivation cohort showed an accuracy of 84% to diagnose PHES-CHE in the validation cohort. Time for CHE diagnosis decreased from 203.7 (67.82) to 36.8 (11.25) seconds in the derivation and from 178.2 (46.19) to 32.9 (9.94) seconds in the validation cohort. CONCLUSIONS: QuickStroop, which is completed within 1 minute, gives an equivalent ability to predict CHE on the gold standard compared with the entire EncephalApp time.

Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort.

BACKGROUND & AIMS: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation. METHODS: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited. RESULTS: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity. CONCLUSIONS: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.

Role of Oral Health, Frailty, and Minimal Hepatic Encephalopathy in the Risk of Hospitalization: A Prospective Multi-Center Cohort of Outpatients With Cirrhosis.

BACKGROUND & AIMS: Hospitalizations are a sentinel event in cirrhosis; however, the changing demographics in patients with cirrhosis require updated hospitalization prediction models. Periodontitis is a risk factor for liver disease and potentially progression. The aim of this study was to determine factors, including poor oral health, associated with 3-month hospitalizations in a multi-center cohort of outpatients with cirrhosis. METHODS: North American Consortium for Study of End-stage Liver Disease (NACSELD-3), a new study cohort, recruits outpatients with cirrhosis. Cirrhosis details, demographics, minimal hepatic encephalopathy (MHE), frailty, and comorbid conditions including oral health were collected. All patients were followed for 3 months for nonelective hospitalizations. Multi-variable models were created for this outcome using demographics, cirrhosis details, oral health, MHE, frailty, and comorbid conditions with K-fold internal validation using 25%/75% split. RESULTS: A total of 442 outpatients (70% men; 37% compensated; Model for End-stage Liver Disease-Sodium, 12; 42% ascites; and 33% prior HE) were included. MHE was found in 70%, frailty in 10%; and both in 8%. In terms of oral health, 15% were edentulous and 10% had prior periodontitis. Regarding 3-month hospitalizations, 14% were admitted for mostly liver-related reasons. These patients were more likely to be decompensated with higher cirrhosis complications, MHE, frailty and periodontitis history. Multi-variable analysis showed prior periodontitis (P = .026), composite MHE + frailty score (P = .0016), ascites (P = .004), prior HE (P = .008), and hydrothorax (P = .004) were associated with admissions using the training and validation subsets. CONCLUSIONS: In a contemporaneous, prospective, multi-center cohort study in outpatients with cirrhosis, poor oral health is significantly associated with 3-month hospitalizations independent of portal hypertensive complications, MHE, and frailty. Potential strategies to reduce hospitalizations should consider oral evaluation in addition to MHE and frailty assessment in practice pathways.

A Resident-Led Firearm Curriculum for Pediatrics Residents Improves Safe Storage Counseling.

OBJECTIVE: To develop and implement a resident-led firearm safety curriculum, delivered to pediatrics residents, and to evaluate outcomes. STUDY DESIGN: A firearm safety curriculum was developed in 2019-2020 at a single academic center, using Kern's framework and cognitive load theory. The curriculum was organized using the "Be SMART" firearm safety model. Sessions were led by resident peers. The content included workshops on firearm safety counseling, advocacy training, and a gun lock program in collaboration with the local police department. Content was integrated into existing residency didactic curriculum. Impact was measured by a pre/posttest knowledge assessment and a systematic chart review. RESULTS: The curriculum was provided to 41/66 (62%) pediatrics residents. Knowledge improved (67% to 77% correct) when comparing pre-intervention with post-intervention. A total of 1477 charts were reviewed. Compared with a historical cohort, participants more often asked about presence of a firearm (27% vs 69%, P < .0001) and counseled on firearm safety (9% vs 25%, P < .0001). In the post-intervention timeframe, 25% of eligible families were provided a gun lock. CONCLUSIONS: A firearm safety curriculum designed by pediatrics residents and administered to their peers resulted in a statistically significant improvement in inquiries about firearm ownership and safety counseling in an urban tertiary care continuity clinic. These results demonstrate the promising outcomes of a firearm safety program developed by residents and delivered to peers.

Vascular injury arising from lateral skull base fractures.

PURPOSE: Although uncommon, vascular injury can be seen in patients with lateral skull base fractures (LSBF). However, little is known about this potentially life-threatening comorbidity. The objective of this study is to better characterize the vascular injuries associated with temporal and lateral sphenoid bone fractures. BASIC PROCEDURES: Retrospective review of all patients with computed tomography angiography (CTA) performed specifically to evaluate for vascular injury following LSBF. In addition to patient demographics (age, gender, race), the mechanism of injury, the location of fracture(s), and the nature of vascular injury diagnosed by CTA was recorded. Two-way ANOVA was performed to determine if any variables were predictive of vascular injury. MAIN FINDINGS: From 2011 to 2021, 143 patients with 333 subsite fractures met inclusion criteria. Of all patients, 46 (32.2 %) had CTA evidence of at least one vascular injury, the most common type being venous thrombosis/filling defect (41.7 %). Evidence of vascular injury was unclear in 14 patients (9.8 %). Fractures most associated with vascular injury ranged from 0.7 % (otic capsule fractures) to 26.7 % (mastoid, lateral sphenoid fractures). Risk of vascular injury was no different between patients with single vs multiple fractures. There were no fracture locations that could reliably predict specific vascular injury. CONCLUSIONS: Over 40 % of all CTAs ordered following LSBF identified were suspicious for associated vascular injury. Yet fracture location and number cannot reliably predict vascular injury. Until such determinants can be better identified, clinicians should have a low threshold to obtain CTA to rule out associated vascular injury.

Impact of the COVID-19 Pandemic on a Clinical Trial: A Quantitative Report on Study Engagement and Strategies.

INTRODUCTION: The COVID-19 pandemic impacted clinical research worldwide potentially altering research findings. The study purpose was to measure the effect of the pandemic on recruitment, retention, assessment, and intervention completion rates. METHODS: Enrollment and participation data from a clinical trial evaluating efficacy of a physical therapy intervention for high-risk preterm infants were compared across 3 pandemic periods (February 2019 through November 2021). RESULTS: Recruitment, retention, assessment, and intervention completion rates were lowest during the peak pandemic period. CONCLUSIONS: In compliance with the Human Subjects Review Board, and for the participants' and staff safety, transition from in-person to telehealth or hybrid visits was required to continue this longitudinal study. Despite the negative effect of the pandemic, parental resilience and commitment to the study was clear. Flexibility, quick action, dedication, and efficiency of the research team were key elements enabling study continuation with successful transition to telehealth assessments/interventions during the peak pandemic period.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57 ± 11 years; male, 66%; Child-Pugh-Turcotte score, 10 ± 2; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) were enrolled. Renal failure prevalence (28% versus 9%, P < 0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

Association of serum metabolites and gut microbiota at hospital admission with nosocomial infection development in patients with cirrhosis.

Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography-mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End-Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1-linolenoyl-glycerolphosphocholine (GPC) and 1-stearoyl-GPC and higher N-acetyltryptophan and N-acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial-metabolite correlation networks were complex and dense in patients with NIs, especially sub-networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial-metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.

A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is associated with microbial alterations that worsen with cirrhosis. Fecal microbiota transplant (FMT) could be a promising approach. APPROACH AND RESULTS: In this phase 1, double-blind, randomized clinical trial, patients with AUD-related cirrhosis with problem drinking (AUDIT-10 > 8) were randomized 1:1 into receiving one placebo or FMT enema from a donor enriched in Lachnospiraceae and Ruminococcaceae. Six-month safety was the primary outcome. Alcohol craving questionnaire, alcohol consumption (urinary ethylglucuronide/creatinine), quality of life, cognition, serum IL-6 and lipopolysaccharide-binding protein, plasma/stool short-chain fatty acids (SCFAs), and stool microbiota were tested at baseline and day 15. A 6-month follow-up with serious adverse event (SAE) analysis was performed. Twenty patients with AUD-related cirrhosis (65 ± 6.4 years, all men, Model for End-Stage Liver Disease 8.9 ± 2.7) with similar demographics, cirrhosis, and AUD severity were included. Craving reduced significantly in 90% of FMT versus 30% in placebo at day 15 (P = 0.02) with lower urinary ethylglucuronide/creatinine (P = 0.03) and improved cognition and psychosocial quality of life. There was reduction in serum IL-6 and lipopolysaccharide-binding protein and increased butyrate/isobutyrate compared with baseline in FMT but not placebo. Microbial diversity increased with higher Ruminococcaceae and other SCFAs, producing taxa following FMT but not placebo, which were linked with SCFA levels. At 6 months, patients with any SAEs (8 vs. 2, P = 0.02), AUD-related SAEs (7 vs. 1, P = 0.02), and SAEs/patient (median [interquartile range], 1.5 [1.25] vs. 0 [0.25] in FMT, P = 0.02) were higher in placebo versus FMT. CONCLUSIONS: This phase 1 trial shows that FMT is safe and associated with short-term reduction in alcohol craving and consumption with favorable microbial changes versus placebo in patients with alcohol-associated cirrhosis with alcohol misuse. There was also a reduction in AUD-related events over 6 months in patients assigned to FMT.

Admission Urinary and Serum Metabolites Predict Renal Outcomes in Hospitalized Patients With Cirrhosis.

BACKGROUND AND AIMS: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort. APPROACH AND RESULTS: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes. CONCLUSIONS: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures.

Prognosis of hospitalized patients with cirrhosis and acute kidney disease.

BACKGROUND: The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known. AIM: To study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD. METHODS: The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes. RESULTS: 1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in-hospital and 30-day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53). CONCLUSIONS: Patients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.

Managing cancer and living meaningfully (CALM) in adults with malignant glioma: a proof-of-concept phase IIa trial.

BACKGROUND: Managing Cancer and Living Meaningfully (CALM) is an evidence-based, brief, semi-structured psychotherapy designed to help patients with advanced cancer cope with the practical and profound challenges of their illness. However, no study to date has investigated its feasibility, acceptability, and preliminary effectiveness in adults with malignant glioma, despite the well-documented incidence of psychological distress in this vulnerable and underserved population. METHODS: Fourteen patients with glioma and elevated symptoms of depression and/or death anxiety enrolled in the trial: 83% glioblastoma, 75% female, Mage = 56 years (SD = 15.1; range = 27-81). Feasibility was assessed based on established metrics. Acceptability was measured by post-session surveys and post-intervention interviews. Preliminary intervention effects were explored using paired t-tests, comparing psychological distress at baseline and post-intervention. RESULTS: Of the 14 enrolled patients, 12 were evaluable. Nine completed the study (75% retention rate). Three patients withdrew due to substantial disease progression which affected their ability to participate. Participants reported high perceived benefit, and all recommended the program to others. Baseline to post-intervention assessments indicated reductions in death anxiety, generalized anxiety, and depression, and increases in spirituality. Quality of life and fear of cancer recurrence remained stable throughout the study period. CONCLUSIONS: CALM appears feasible for use with adults with malignant glioma. Enrollment and retention rates were high and comparable to psychotherapy trials for patients with advanced cancer. High perceived benefit and reductions in symptoms of death anxiety, generalized anxiety, and depression were reported by participants. These findings are extremely encouraging and support further study of CALM in neuro-oncology. TRIAL REGISTRATION NUMBER: NCT04646213 registered on 11/27/2020.