Citations

OBJECTIVES: Nosocomial infections (NIs) can be a major cause of morbidity and mortality in cirrhosis. This study aims to define the determinants of NI development and its impact on 30-day outcomes among hospitalized patients with cirrhosis. METHODS: North American Consortium for the Study of End-Stage Liver Disease enrolled patients with cirrhosis who were admitted nonelectively. Admission variables and 30-day outcomes were compared between patients with and without NI. These were also compared based on whether there was an isolated admission infection, NI, or both. Models were created for NI development using admission variables and for 30-day mortality. RESULTS: The study included 2,864 patients; of which, 15% (n = 436) developed NI. When comparing NI vs no NI, 1,866 patients were found to be infection free, whereas 562 had admission infections only, 228 had only NI, and 208 had both infections. At admission, patients with NI were more likely to be infected and have advanced cirrhosis. NIs were associated with higher rates of acute-on-chronic liver failure, death, and transplant regardless of admission infections. Patients with NI had higher respiratory infection, urinary tract infection, Clostridium difficile infection, fungal infections, and infection with vancomycin-resistant enterococci compared with patients without NI. Risk factors for NIs were admission infections, model for end-stage liver disease (MELD) > 20, systemic inflammatory response syndrome criteria, proton pump inhibitor, rifaximin, and lactulose use, but the regression model (sensitivity, 0.67; specificity, 0.63) was not robust. Age, alcohol etiology, admission MELD score, lactulose use, acute-on-chronic liver failure, acute kidney injury, intensive care unit, and NI increased the risk of death, whereas rifaximin decreased the risk of death. DISCUSSION: NIs are prevalent in hospitalized patients with cirrhosis and are associated with poor outcomes. Although higher MELD scores and systemic inflammatory response syndrome are associated with NI, all hospitalized patients with cirrhosis require vigilance and preventive strategies.

Purpose: We aimed to determine whether clinical EEG reports obtained from children in the intensive care unit with refractory status epilepticus could provide data for comparative effectiveness research studies. Methods: We conducted a retrospective descriptive study to assess the documentation of key variables within clinical continuous EEG monitoring reports based on the American Clinical Neurophysiology Society's standardized EEG terminology for children with refractory status epilepticus from 10 academic centers. Two pediatric electroencephalographers reviewed the EEG reports. We compared reports generated using free text or templates. Results: We reviewed 191 EEG reports. Agreement between the electroencephalographers regarding whether a variable was described in the report ranged from fair to very good. The presence of electrographic seizures (ES) was documented in 46% (87/191) of reports, and these reports documented the time of first ES in 64% (56/87), ES duration in 72% (63/85), and ES frequency in 68% (59/87). Reactivity was documented in 16% (31/191) of reports, and it was more often documented in template than in free-text reports (40% vs. 14%, P = 0.006). Other variables were not differentially reported in template versus free-text reports. Conclusions: Many key EEG features are not documented consistently in clinical continuous EEG monitoring reports, including ES characteristics and reactivity assessment. Standardization may be needed for clinical EEG reports to provide informative data for large multicenter observational studies.

AbstractPatients with phosphoglucomutase (PGM1) deficiency, a congenital disorder of glycosylation (CDG) suffer from multiple disease phenotypes. Midline cleft defects are present at birth. Overtime, additional clinical phenotypes, which include severe hypoglycemia, hepatopathy, growth retardation, hormonal deficiencies, hemostatic anomalies, frequently lethal, early‐onset of dilated cardiomyopathy and myopathy emerge, reflecting the central roles of the enzyme in (glycogen) metabolism and glycosylation. To delineate the pathophysiology of the tissue‐specific disease phenotypes, we constructed a constitutive Pgm2 (mouse ortholog of human PGM1)‐knockout (KO) mouse model using CRISPR‐Cas9 technology. After multiple crosses between heterozygous parents, we were unable to identify homozygous life births in 78 newborn pups (P = 1.59897E‐06), suggesting an embryonic lethality phenotype in the homozygotes. Ultrasound studies of the course of pregnancy confirmed Pgm2‐deficient pups succumb before E9.5. Oral galactose supplementation (9 mg/mL drinking water) did not rescue the lethality. Biochemical studies of tissues and skin fibroblasts harvested from heterozygous animals confirmed reduced Pgm2 enzyme activity and abundance, but no change in glycogen content. However, glycomics analyses in serum revealed an abnormal glycosylation pattern in the Pgm2+/− animals, similar to that seen in PGM1‐CDG.

Background. We examined the association between sarcopenia and post-transplant mortality in acutely ill inpatients with cirrhosis who underwent urgent liver transplantation. Methods. Included were inpatients at 4 centers who were urgently listed as nonstatus 1 and transplanted from 2005 to 2017 with an abdominal computed tomography scan <90 days before transplantation. Skeletal muscle index (SMI) = total skeletal muscle cross-sectional area at the L3 vertebral level, normalized to height. Cox regression associated SMI with post-transplant mortality. Optimal search identified SMI cutoffs to detect survival. Results. Of 126 inpatients, 63% were male patients, model for end-stage liver disease (MELDNa) was 32, and follow up was 5.1 years. Among men, 23% died. Median SMI was lower in men who died versus survived (45 versus 51 cm2/m2). SMI was associated with post-transplant mortality (hazard ratio [HR] = 0.96 per cm2/m2, 95% CI 0.92-0.99). Patients with SMI ≤ 48 cm2/m2 versus >48 cm2/m2 experienced higher rates of death at 1 year (86% versus 95%) and 3 years (73% versus 95%) (Log-rank P = 0.01). In MELD-adjusted analysis, sarcopenia was strongly associated with post-transplant mortality (HR = 4.39, 95% CI 1.49-12.97). Among women, 35% died. Median SMI was similar in women who died versus survived (45 versus 44 cm2/m2). SMI was not associated with post-transplant mortality (HR = 1.02, 95% CI 0.96-1.09). Optimal search did not identify any SMI cutoff that predicted post-transplant mortality. Conclusions. Among patients who underwent urgent inpatient evaluation and liver transplantation, we identified an SMI cutoff value of 48 cm2/m2 to predict post-transplant mortality in men. Our data support the use of SMI as a tool to capture the impact of muscle depletion on post-transplant mortality in acutely ill men with cirrhosis undergoing urgent liver transplantation.

Glioma incidence is highest in non‐Hispanic Whites, and to date, glioma genome‐wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case–Control Study and GliomaSE Case–Control Study previously estimated to have <80% EA, or self‐identify as non‐White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome‐wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 −4 ; 11p11.12, p = 7.0 × 10 −4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 ( p = 4.36 × 10 −6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 −4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 −4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

We hypothesize that the prevalence of chronic kidney disease (CKD) among patients with cirrhosis has increased due to the increased prevalence of CKD‐associated comorbidities, such as diabetes. We aimed to assess the characteristics of hospitalized patients with cirrhosis with CKD and its impact on renal and patient outcomes. The North American Consortium for the Study of End‐Stage Liver Disease (NACSELD) prospectively enrolled nonelectively admitted patients with cirrhosis and collected data on demographics, laboratory results, in‐hospital clinical course, and postdischarge 3‐month outcomes. CKD positive (CKD+) patients, defined as having an estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease–4 variable formula) of ≤60 mL/minute for >3 months, were compared with chronic kidney disease negative (CKD–) patients for development of organ failures, hospital course, and survival. There were 1099 CKD+ patients (46.8% of 2346 enrolled patients) who had significantly higher serum creatinine (2.21 ± 1.33 versus 0.83 ± 0.21 mg/dL in the CKD– group) on admission, higher prevalence of nonalcoholic steatohepatitis cirrhosis etiology, diabetes, refractory ascites, and hospital admissions in the previous 6 months compared with the CKD– group (all P < 0.001). Propensity matching (n = 922 in each group) by Child‐Pugh scores (9.78 ± 2.05 versus 9.74 ± 2.04, P = 0.70) showed that CKD+ patients had significantly higher rates of superimposed acute kidney injury (AKI; 68% versus 21%; P < 0.001) and eventual need for dialysis (11% versus 2%; P < 0.001) than CKD– patients. CKD+ patients also had more cases of acute‐on‐chronic liver failure as defined by the NACSELD group, which was associated with reduced 30‐ and 90‐day overall survival ( P < 0.001 for both). A 10 mL/minute drop in eGFR was associated with a 13.1% increase in the risk of 30‐day mortality. In conclusion, patients with CKD should be treated as a high‐risk group among hospitalized patients with cirrhosis due to their poor survival, and they should be monitored carefully for the development of superimposed AKI.

Abstract Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

ABSTRACT Normal vitamin D homeostasis is critical for optimal health; nevertheless, vitamin D deficiency is a worldwide public health problem. Vitamin D insufficiency is most commonly due to inadequate cutaneous synthesis of cholecalciferol and/or insufficient intake of vitamin D, but can also arise as a consequence of pathological states such as obesity. Serum concentrations of 25(OH)D (calcidiol) are low in obesity, and fail to increase appropriately after vitamin D supplementation. Although sequestration of vitamin D in adipose tissues or dilution of ingested or cutaneously synthesized vitamin D in the large fat mass of obese patients has been proposed to explain these findings, here we investigate the alternative mechanism that reduced capacity to convert parent vitamin D to 25(OH)D due to decreased expression of CYP2R1, the principal hepatic vitamin D 25-hydroxylase. To test this hypothesis, we isolated livers from female mice of 6 to 24 weeks of age, weaned onto either a normal chow diet or a high-fat diet, and determined the abundance of Cyp2r1 mRNA using digital droplet-quantitative PCR. We observed a significant (p &lt; 0.001) decrease in Cyp2r1 mRNA in the liver of high-fat diet–fed mice relative to lean-chow–fed female mice. Moreover, there was a significant (p &lt; 0.01) relationship between levels of Cyp2r1 mRNA and serum 25(OH)D concentrations as well as between Cyp2R1 mRNA and the ratio of circulating 25(OH)D3 to cholecalciferol (p &lt; 0.0001). Using linear regression we determined a curve with 25(OH)D3/cholecalciferol versus normalized Cyp2R1 mRNA abundance with an R2 value of 0.85. Finally, we performed ex vivo activity assays of isolated livers and found that obese mice generated significantly less 25(OH)D3 than lean mice (p &lt; 0.05). Our findings indicate that expression of CYP2R1 is reduced in obesity and accounts in part for the decreased circulating 25(OH)D. © 2019 American Society for Bone and Mineral Research.

Abstract Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.