IMPORTANCE: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). OBJECTIVE: To ...determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. DESIGN, SETTING, AND PARTICIPANTS: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. INTERVENTIONS: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. MAIN OUTCOMES AND MEASURES: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. RESULTS: Among 167 randomized patients (mean SD age, 54.8 years 16.7; 90 men 54%), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group 3 points and from 10.3 to 6.8 in the placebo group 3.5 points; difference, −0.10; 95% CI, −1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, −8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, −2.8 to 4.2; P = .70) at 168 hours. CONCLUSIONS AND RELEVANCE: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02106975
Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve ...dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open‐label, randomized clinical trial with a 5‐month follow‐up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT‐randomized patients received 5 days of broad‐spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow‐up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT‐related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End‐Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post‐FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727–1738)
Adverse childhood experiences (ACEs) are linked to multiple adverse health outcomes. This study examined the association between ACEs and cancer diagnosis.
Data from the 2010 Behavioral Risk Factor ...Surveillance System (BRFSS) survey were used. The BRFSS is the largest ongoing telephone health survey, conducted in all US states, the District of Columbia, Puerto Rico, Guam and the U.S. Virgin Islands, and provides data on a variety of health issues among the non-institutionalized adult population. Principal component analysis (PCA) was used to derive components for ACEs. Multivariable logistic regression models were used to provide adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between ACE components and overall, childhood and adulthood cancer, adjusting for confounders such as age, gender, race/ethnicity, income, educational status, marital status, and insurance status.
Approximately 62% of respondents reported being exposed to ACEs and about one in ten respondents reported ever having been diagnosed with cancer. Component 1, which had the sexual abuse variables with the highest weights, was significantly associated with adulthood cancer (adjusted OR: 1.21; 95% CI: 1.03-1.43).
The association between ACEs and adulthood cancer may be attributable to disease progression through association of ACEs with risk factors for other chronic diseases. More research should focus on the impact of sexual abuse ACEs and adverse health outcomes.
Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain ...circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing-activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.
It is well-documented that the mental health of pregnant and postpartum women is essential for maternal, child, and family well-being. Of major public health concern is the perinatal mental health ...impacts that may occur during the ongoing coronavirus disease 2019 (COVID-19) pandemic. It is essential to explore the symptom experience and predictors of mental health status, including the relationship between media use and mental health.
The purpose of this study is to evaluate the experiences of pregnant and postpartum women (
= 524) in the United States in the early phase of the COVID-19 pandemic. This cross-sectional online observational study collected psychosocial quantitative and qualitative survey data in adult pregnant and postpartum (up to 6 months postdelivery) women in April-June 2020.
Multivariable linear regression models were used to evaluate predictors of depressive symptoms, anxiety, and post-traumatic stress disorder. The most common predictors were job insecurity, family concerns, eating comfort foods, resilience/adaptability score, sleep, and use of social and news media. Qualitative themes centered on pervasive uncertainty and anxiety; grief about losses; gratitude for shifting priorities; and use of self-care methods including changing media use.
This study provides information to identify risk for anxiety, depression, and PTSD symptoms in perinatal women during acute public health situations. Women with family and job concerns and low resilience/adaptability scores seem to be at high risk of psychological sequelae. Although use of social media is thought to improve social connectedness, our results indicate that increased media consumption is related to increased anxiety symptoms.
Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to ...improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus HCV, 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)
Background & Aims The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key ...function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression. Methods Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC–MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin. Results Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics ( p <0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae , Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r = 0.57, p <0.008) while Ruminococcaceae were positively correlated with DCA (r = 0.4, p <0.05). A positive correlation between Ruminococcaceae and DCA/CA (r = 0.82, p <0.012) and Blautia with LCA/CDCA (r = 0.61, p <0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios. Conclusions Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa.
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.
Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of ...the study was to validate EncephalApp for MHE diagnosis in a multicenter study.
Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort.
A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with >70% sensitivity.
In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development.
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