Renalase Levels are Decreased in Maternal Blood and Placental Tissues in Pregnancies Associated with Preterm Preeclampsia.

Preeclampsia (PEC) is a complication of pregnancy associated with hypertension and the risk of eclampsia. The pathophysiology of PEC is unknown and identifying factors associated with PEC during pregnancy is crucial for placental, fetal, and maternal health. Renalase (RNLS) is an anti-inflammatory secretory flavoprotein associated with hypertension. Recent data demonstrated a correlation between maternal serum RNLS and PEC, and work from our group identified RNLS expression in the placenta. However, it remains unknown whether RNLS levels in placenta are altered by preeclampsia. Additionally, it is unclear if there is a differential effect of preterm and term PEC on RNLS. We demonstrate that serum RNLS was reduced in preterm cases of PEC. Similarly, placental RNLS was diminished in the chorion of preterm cases of PEC. However, a reduction of RNLS in the decidua was observed with all cases of PEC, while the levels of RNLS within the placental villi were similar in all cases. Overall, we demonstrate that RNLS correlates with PEC both systemically in maternal serum and locally within the placenta, with variable effects on the different layers of the placenta and more pronounced in preterm cases.

Alcohol-Related Care Among Veterans With Unhealthy Alcohol Use: The Role of Long-term Opioid Therapy Receipt.

OBJECTIVES: Long-term opioid therapy (LTOT) is potentially dangerous among patients with unhealthy alcohol use because of possible adverse interactions. We examined receipt of alcohol-related care among patients with unhealthy alcohol use receiving LTOT and without opioid receipt. METHODS: We use data collected from 2009 to 2017 in the Women Veterans Cohort Study, a national cohort of Veterans engaged in Veterans Health Administration care. We included patients who screened positive for unhealthy alcohol use (score ≥5) using the Alcohol Use Disorder Identification Consumption questionnaire. Our primary exposure was LTOT (receipt of prescribed opioids for ≥90 days) versus no opioid receipt at the time of the first positive Alcohol Use Disorder Identification Consumption. Our primary outcome was receipt of brief intervention within 14 days of positive alcohol screen. Unadjusted and 4 adjusted modified Poisson regression models assessed prevalence and relative rates (RRs) of outcomes. RESULTS: Among eligible veterans, 6222 of 113,628 (5.5%) received LTOT at screening. Among patients receiving LTOT, 67.5% (95% confidence interval [CI], 66.3%-68.6%) had a documented brief intervention within 14 days of positive screen, compared with 70.1% (95% CI, 69.8%-70.4%) among patients without opioid receipt (RR, 0.96; 95% CI, 0.95-0.98; P < 0.001). Within adjusted models, the rate of brief intervention among patients receiving LTOT remained lower than patients without opioid receipt. CONCLUSIONS: Among patients with unhealthy alcohol use, patients receiving LTOT had significantly lower rates of brief intervention receipt compared with those without opioid receipt, and they should be a focus for interventions to improve alcohol-related care and safer opioid prescribing.

The impact of a blood-culture diagnostic stewardship intervention on utilization rates and antimicrobial stewardship.

Blood-culture overutilization is associated with increased cost and excessive antimicrobial use. We implemented an intervention in the adult intensive care unit (ICU), combining education based on the DISTRIBUTE algorithm and restriction to infectious diseases and ICU providers. Our intervention led to reduced blood-culture utilization without affecting safety metrics.

The liver frailty index is a predictor of healthcare utilization after liver transplantation in older adults.

BACKGROUND: Older adults have higher healthcare utilization after liver transplantation (LT), yet objective risk stratification tools in this population are lacking. We evaluated the Liver Frailty Index (LFI) as one potential tool. METHODS: Ambulatory LT candidates ≥65 years without hepatocellular carcinoma (HCC) who underwent LT from 1/2012 to 6/2022 at 8 U.S. centers were included. Estimates of the difference in median using quantile regression were used to assess the adjusted association between LFI and hospitalized days within 90 days post-LT. RESULTS: Of 131 LT recipients, median (interquartile range [IQR]) (1st -3rd quartiles) age was 68 years (66-70); median pre-LT MELD-Na was 19 (15-24). Median LFI was 4.1 (3.6-4.7); 27% were frail (LFI≥4.5). Median hospitalized days within 90 days post-LT was 11 (7-20). Compared with non-frail patients, frail patients were hospitalized for a median of 5 days longer post-LT (95% CI .30-9.7, p = .04). Each .5 unit increase in pre-LT LFI was associated with an increase of 1.16 days (95%CI .42-2.69, p = .02) in hospitalized days post-LT. CONCLUSION: Among older adults undergoing LT, frailty was associated with more hospitalized days within 90 days after LT. The LFI can identify older adults who might benefit from pre-LT or early post-LT programs which may reduce post-LT healthcare utilization, such as early rehabilitation or post-hospital discharge programs.

Clinical Characteristics Associated With Posttransplant Survival Among Adults 70 Years Old or Older Undergoing Liver Transplantation.

GOALS: We sought to identify pre-liver transplantation (LT) characteristics among older adults associated with post-LT survival. BACKGROUND: The proportion of older patients undergoing deceased-donor liver transplantation (DDLT) has increased over time. STUDY: We analyzed adult DDLT recipients in the United Network for Organ Sharing registry from 2016 through 2020, excluding patients listed as status 1 or with a model of end-stage liver disease exceptions for hepatocellular carcinoma. Kaplan-Meier methods were used to estimate post-LT survival probabilities among older recipients (age ≥70 y). Associations between clinical covariates and post-LT mortality were assessed using Cox regressions. RESULTS: Of 22,862 DDLT recipients, 897 (4%) were 70 years old or older. Compared with younger recipients, older recipients had worse overall survival ( P < 0.01) (1 y: 88% vs 92%, 3 y: 77% vs 86%, and 5 y: 67% vs 78%). Among older adults, in univariate Cox regressions, dialysis [hazards ratio (HR): 1.96, 95% CI: 1.38-2.77] and poor functional status [defined as Karnofsky Performance Score (KPS) <40] (HR: 1.82, 95% CI: 1.31-2.53) were each associated with mortality, remaining significant on multivariable Cox regressions. The effect of dialysis and KPS <40 at LT on post-LT survival (HR: 2.67, 95% CI: 1.77-4.01) was worse than the effects of either KPS <40 (HR: 1.52, 95% CI: 1.03-2.23) or dialysis alone (HR: 1.44, 95% CI: 0.62-3.36). Older recipients with KPS >40 without dialysis had comparable survival rates compared with younger recipients ( P = 0.30). CONCLUSIONS: While older DDLT recipients had worse overall post-LT survival compared with younger recipients, favorable survival rates were observed among older adults who did not require dialysis and had poor functional status. Poor functional status and dialysis at LT may be useful to stratify older adults at higher risk for poor post-LT outcomes.

The tele-liver frailty index (TeLeFI): development of a novel frailty tool in patients with cirrhosis via telemedicine.

Frailty is a critical determinant of outcomes in cirrhosis patients. The increasing use of telemedicine has created an unmet need for virtual frailty assessment. We aimed to develop a telemedicine-enabled frailty tool (tele-liver frailty index). Adults with cirrhosis in the liver transplant setting underwent ambulatory frailty testing with the liver frailty index (LFI) in-person, then virtual administration of (1) validated surveys (eg, SARC-F and Duke Activity Status Index [DASI]), (2) chair stands, and (3) balance. Two models were selected and internally validated for predicting LFI ≥4.4 using: (1) Bayesian information criterion (BIC), (2) C-statistics, and (3) ease of use. Of 145 patients, the median (interquartile range) LFI was 3.7 (3.3-4.2); 15% were frail. Frail (vs not frail) patients reported significantly greater impairment on all virtually assessed instruments. We selected 2 parsimonious models: (1) DASI + chair/bed transfer (SARC-F) (BIC 255, C-statistics 0.78), and (2) DASI + chair/bed transfer (SARC-F) + virtually assessed chair stands (BIC 244, C-statistics 0.79). Both models had high C-statistics (0.76-0.78) for predicting frailty. In conclusion, the tele-liver frailty index is a novel tool to screen frailty in liver transplant patients via telemedicine pragmatically and may be used to identify patients who require in-person frailty assessment, more frequent follow-up, or frailty intervention.

Women with cirrhosis have lower self-rated health than men.

BACKGROUND: Women systematically experience lower rates of liver transplantation (LT) and higher rates of waitlist mortality than men. Self-rated health has been associated with patient outcomes in the global population. We, therefore, assessed gender differences in self-rated and clinician-rated health among LT candidates. METHODS: Ambulatory LT candidates without hepatocellular carcinoma were enrolled from 2012 to 2018. Participants and their hepatologists were asked separately to rate the participant's overall general health on a 6-point scale (0="excellent" to 5="very poor"). Logistic regression was used to assess the associations between covariates and superior self-assessment, defined as 1 SD above the mean self-assessment score. RESULTS: Of 855 participants, the median (interquartile range) self-rated health score was 2 (1-3); 156 (18%) were categorized as superior self-rated health. The correlation between self-rated and clinician-rated health was positive (Spearman's rho 0.3, P<0.001). In univariate analysis, being a woman was associated with lower odds of superior self-rated health (OR 0.7, 95% CI 0.5-1.0, P=0.04), which persisted on multivariable analysis (aOR 0.7, 95% CI 0.4-1.0, P=0.05), controlling for race, frailty, work status, comorbidities, Model for End-Stage Liver Disease-Na, hepatic encephalopathy, and ascites. CONCLUSION: These findings highlight the need for well-designed quality-based research to determine how our patients perceive health to highlight opportunities to offer more comprehensive, quality-based care.

Plasma renalase levels are associated with the development of acute pancreatitis.

BACKGROUND/OBJECTIVES: Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans. METHODS: Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis. RESULTS: Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 µg/ml, Mild 5.1 µg/ml, Severe 6.0 µg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 µg/ml, Mild 0.9 µg g/ml, Severe 1.2 µg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = -0.31, p = 0.023). CONCLUSION: Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes.

Racial and Ethnic Disparities Among Patients Hospitalized for Acute Cholangitis in the United States.

GOALS: We sought to determine whether race/ethnicity is associated with hospitalization outcomes among patients admitted with acute cholangitis. BACKGROUND: Few studies have evaluated the association between race and outcomes in patients with acute cholangitis. STUDY: We analyzed United States hospitalizations from 2009 to 2018 using the Nationwide Inpatient Sample (NIS). We included patients 18 years old or above admitted with an ICD9/10 diagnosis of cholangitis. Race/ethnicity was categorized as White, Black, Hispanic, or Other. We used multivariable regression to determine the association between race/ethnicity and in-hospital outcomes of interest, including endoscopic retrograde cholangiopancreatography (ERCP), early ERCP (<48 h from admission), length of stay (LOS), and in-hospital mortality. RESULTS: Of 116,889 hospitalizations for acute cholangitis, 70% identified as White, 10% identified as Black, 11% identified as Hispanic, and 9% identified as Other. The proportion of non-White patients increased over time. On multivariate analysis controlling for clinical and sociodemographic variables, compared with White patients, Black patients had higher in-hospital mortality (adjusted odds ratio: 1.4, 95% confidence interval: 1.2-1.6, P <0.001). Black patients were also less likely to undergo ERCP, more likely to undergo delayed ERCP, and had longer LOS ( P <0.001 for all). CONCLUSIONS: In this contemporary cohort of hospitalized patients with cholangitis, Black race was independently associated with fewer and delayed ERCP procedures, longer LOS, and higher mortality rates. Future studies with more granular social determinants of health data should further explore the underlying reasons for these disparities to develop interventions aimed at reducing racial disparities in outcomes among patients with acute cholangitis.

Targeted gut microbiota manipulation attenuates seizures in a model of infantile spasms syndrome.

Infantile spasms syndrome (IS) is a devastating early-onset epileptic encephalopathy associated with poor neurodevelopmental outcomes. When first-line treatment options, including adrenocorticotropic hormone and vigabatrin, are ineffective, the ketogenic diet (KD) is often employed to control seizures. Since the therapeutic impact of the KD is influenced by the gut microbiota, we examined whether targeted microbiota manipulation, mimicking changes induced by the KD, would be valuable in mitigating seizures. Employing a rodent model of symptomatic IS, we show that both the KD and antibiotic administration reduce spasm frequency and are associated with improved developmental outcomes. Spasm reductions were accompanied by specific gut microbial alterations, including increases in Streptococcus thermophilus and Lactococcus lactis. Mimicking the fecal microbial alterations in a targeted probiotic, we administered these species in a 5:1 ratio. Targeted probiotic administration reduced seizures and improved locomotor activities in control diet-fed animals, similar to KD-fed animals, while a negative control (Ligilactobacillus salivarius) had no impact. Probiotic administration also increased antioxidant status and decreased proinflammatory cytokines. Results suggest that a targeted probiotic reduces seizure frequency, improves locomotor activity in a rodent model of IS, and provides insights into microbiota manipulation as a potential therapeutic avenue for pediatric epileptic encephalopathies.

Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome.

The ketogenic diet (KD) is an effective treatment for infantile spasms syndrome (IS). However, the KD has implications for somatic growth, development, and the gut microbiota. The impact of incorporating a prebiotic fiber (PRE, oligofructose-enriched inulin, 0.8 g/dL) into a KD diet on spasms, developmental milestones, fecal gut microbiota, metabolites, and hippocampal mitochondrial metabolism were examined. Following IS induction, animals were randomized to KD or KD + PRE diets. A third group without IS and suckled by dams was included as a normally developing reference group (R). PRE inclusion decreased ketones and increased circulating glucose levels but had no impact on spasms. In the liver, PRE increased triglyceride concentrations, decreased carnitine levels, and downregulated genes encoding enzymes responsible for ketogenesis. In the hippocampus, PRE increased glutathione levels but did not affect the maximal respiratory capacity of mitochondria. Analysis of the gut microbiota showed that KD + PRE increased microbial richness and the relative abundance of Bifidobacterium pseudolongum and Lactobacillus johnsonii. No differences in developmental milestones (i.e., surface righting, negative geotaxis, and open field behavior) were observed between KD and KD + PRE, except for ultrasonic vocalizations that were more frequent in KD + PRE. In summary, PRE did not impact spasms or developmental outcomes, but was effective in improving both metabolic parameters and gut microbiota diversity.

Room of Hazards: A Comparison of Differences in Safety Hazard Recognition Among Various Hospital-Based Healthcare Professionals and Trainees in a Simulated Patient Room.

OBJECTIVES: Adverse events in hospitals are common. While studies have used simulated patient rooms to assess healthcare trainees' skills in detecting safety hazards, few have explored the characteristics of safety hazards that make them more or less identifiable to healthcare workers. We sought to determine differences in hospital-based safety hazard identification among physicians, nurses, and other staff members. METHODS: Healthcare workers were invited to identify safety hazards in a simulated patient room with intentionally placed hazards. Responses were transcribed and compared between physicians (MD), nurses (RN), and other hospital-based healthcare professionals and trainees (other). Data were analyzed using nonparametric statistical analysis. RESULTS: Twelve physicians, 29 nurses, and 26 other staff members participated in this study. Different professions identified different numbers of total hazards with nurses identifying more hazards than other professions (RN: 9.59, MD: 9.17, other: 6.35; P = 0.001). All professions had difficulty identifying hazards associated with omission (e.g., no precaution sign: MD: 8.3%, RN: 3.4%, other: 0%) or hazards requiring 2-step logical thinking (e.g., intravenous heparin for patient with head laceration: MD: 0%, RN: 6.9%, other: 0%). CONCLUSIONS: Physicians, nurses, and others identified different numbers of total hazards, and few participants identified hazards associated with omission or 2-step logical thinking. While previous studies have found differences in types of hazards identified among different healthcare members, we identified hazards that were collectively challenging for all participants to identify. Future studies should target identification of these types of hazards, using human factor engineering to decrease risk of patient harm.

Availability of medical cannabis services by racial, social, and geographic characteristics of neighborhoods in New York: a cross-sectional study.

BACKGROUND: Within the United States (US), because racial/ethnic disparities in cannabis arrests continue, and cannabis legalization is expanding, understanding disparities in availability of legal cannabis services is important. Few studies report mixed findings regarding disparities in availability of legal cannabis services; none examined New York. We examined disparities in availability of medical cannabis services in New York. We hypothesized that New York census tracts with few Black or Hispanic residents, high incomes, high education levels, and greater urbanicity would have more medical cannabis services. METHODS: In this cross-sectional study, we used data from the 2018 US Census Bureau 5-year American Community Survey and New York Medical Marijuana Program. Main exposures were census tract characteristics, including urban-rural classification, percentage of Black and Hispanic residents, percentage of residents with bachelor's degrees or higher, and median household income. Main outcomes were presence of at least one medical cannabis certifying provider and dispensary in each census tract. To compare census tracts' characteristics with (vs. without) certifying providers and dispensaries, we used chi-square tests and t-tests. To examine characteristics independently associated with (vs. without) certifying providers, we used multivariable logistic regression. RESULTS: Of 4858 New York census tracts, 1073 (22.1%) had medical cannabis certifying providers and 37 (0.8%) had dispensaries. Compared to urban census tracts, suburban census tracts were 62% less likely to have at least one certifying provider (aOR = 0.38; 95% CI = 0.25-0.57). For every 10% increase in the proportion of Black residents, a census tract was 5% less likely to have at least one certifying provider (aOR = 0.95; 95% CI = 0.92-0.99). For every 10% increase in the proportion of residents with bachelor's degrees or higher, a census tract was 30% more likely to have at least one certifying provider (aOR = 1.30; 95% CI = 1.21-1.38). Census tracts with (vs. without) dispensaries were more likely to have a higher percentage of residents with bachelor's degrees or higher (43.7% vs. 34.1%, p < 0.005). CONCLUSIONS: In New York, medical cannabis services are least available in neighborhoods with Black residents and most available in urban neighborhoods with highly educated residents. Benefits of legal cannabis must be shared by communities disproportionately harmed by illegal cannabis.

Renalase and its receptor, PMCA4b, are expressed in the placenta throughout the human gestation.

Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase's role in normal and diseased human placenta.