Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders.

OBJECTIVE: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.

An Update on Laboratory-Based Diagnostic Biomarkers for Multiple Sclerosis and Beyond.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. CONTENT: This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands. Biomarkers discovered in the past 2 decades, such as aquaporin-4 (AQP4) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies, have been incorporated into clinical practice in the diagnosis of disorders referred to as MS mimics. The importance of test selection, assay methodology, optimal sample for testing, and diagnostic utility of these biomarkers is reviewed. Other laboratory testing that can aid in the differentiation between MS and these biomarker-defined CNS demyelinating diseases is described. There is a focus on emerging biomarkers such as the use of kappa immunoglobulin free light chain concentration in CSF and kappa CSF index measurement as an alternative to oligoclonal bands which has a potential for an improvement in laboratory workflows. Finally, the role of biomarkers of disease activity and prognosis are discussed, including neurofilament light chain, glial fibrillary acidic protein, and myelin basic protein. Future perspectives with improved laboratory testing tools and discovery of additional biomarkers are provided. SUMMARY: Laboratory testing for demyelinating disorders using CSF and serum are routine practices that can benefit from an update, as novel biomarker-defined entities have reduced the potential for MS misdiagnosis, and CSF/serum biomarkers reinstated in the diagnostic criteria of MS.

Parkland's 12-Minute Tracheotomy: Is It Reproducible?

Tracheotomy is a procedure in which an incision is made on the anterior aspect of the neck to access the trachea, where a stoma is created to serve as either independent airway or as a site of insertion for a cannula. Surgeons must be proficient in this technique. The purpose of this paper is to reproduce, with slight modifications, the Parkland 12-minute checklist tracheotomy. A quality-improvement initiative was designed. The primary outcome variable was the time required by a resident to perform a tracheotomy. Time was recorded from incision to presence of a capnography wave. Sixteen patients (11 males, 5 females; mean age, 60.87; age range, 38-89) were included. The average time was 11.50 minutes. Factors related to prolonged time included bleeding and thyroid gland in the midway. The employment of the Parkland checklist proved to be reliable, efficient, and a safe guide to perform a tracheotomy in a teaching setting.

Metabo- and mechanoreceptor expression in human heart failure: Relationships with the locomotor muscle afferent influence on exercise responses.

NEW FINDINGS: What is the central question of this study? How do locomotor muscle metabo- and mechanoreceptor expression compare in heart failure patients and controls? Do relationships exist between the protein expression and cardiopulmonary responses during exercise with locomotor muscle neural afferent feedback inhibition? What is the main finding and its importance? Heart failure patients exhibited greater protein expression of transient receptor potential vanilloid type 1 and cyclooxygenase-2 than controls. These findings are important as they identify receptors that may underlie the augmented locomotor muscle neural afferent feedback in heart failure. ABSTRACT: Heart failure patients with reduced ejection fraction (HFrEF) exhibit abnormal locomotor group III/IV afferent feedback during exercise; however, the underlying mechanisms are unclear. Therefore, the purpose of this study was to determine (1) metabo- and mechanoreceptor expression in HFrEF and controls and (2) relationships between receptor expression and changes in cardiopulmonary responses with afferent inhibition. Ten controls and six HFrEF performed 5 min of cycling exercise at 65% peak workload with lumbar intrathecal fentanyl (FENT) or placebo (PLA). Arterial blood pressure and catecholamines were measured via radial artery catheter. A vastus lateralis muscle biopsy was performed to quantify cyclooxygenase-2 (COX-2), purinergic 2X3 (P2X3 ), transient receptor potential vanilloid type 1 (TRPV 1), acid-sensing ion channel 3 (ASIC3 ), Piezo 1 and Piezo 2 protein expression. TRPV 1 and COX-2 protein expression was greater in HFrEF than controls (both P < 0.04), while P2X3 , ASIC3 , and Piezo 1 and 2 were not different between groups (all P > 0.16). In all participants, COX-2 protein expression was related to the percentage change in ventilation (r = -0.66) and mean arterial pressure (MAP) (r = -0.82) (both P < 0.01) with FENT (relative to PLA) during exercise. In controls, TRPV 1 protein expression was related to the percentage change in systolic blood pressure (r = -0.77, P = 0.02) and MAP (r = -0.72, P = 0.03) with FENT (relative to PLA) during exercise. TRPV 1 and COX-2 protein levels are elevated in HFrEF compared to controls. These findings suggest that the elevated TRPV 1 and COX-2 expression may contribute to the exaggerated locomotor muscle afferent feedback during cycling exercise in HFrEF.

Telemedicine, drug-resistant epilepsy, and ketogenic dietary therapies: A patient survey of a pediatric remote-care program during the COVID-19 pandemic.

OBJECTIVE: The purpose of this study was to assess parent satisfaction with the management of ketogenic diet therapies (KDTs) through telemedicine using WhatsApp as the main tool. METHODS: Parent satisfaction was longitudinally evaluated through questionnaires. The survey was developed with Google Questionnaire forms and sent via WhatsApp. The questionnaire consisted of 13 items concerning the management of KDTs using telemedicine in the context of the coronavirus disease 2019 (COVID-19) pandemic. Our population of patients has limited financial resources and low levels of education. Given that many families did not have either computers or WIFI, or any other access to information or communication technology, WhatsApp was chosen as a tool as it was available on the cell phones of all families and the professionals. RESULTS: Our survey showed that 96.3% of the parents were satisfied with the management of KDTs through telemedicine. The main benefits observed were the possibility of continuing treatment during the COVID-19 pandemic and the ease of accessing the professional team from the comfort of their home. Overall, 72.2% of the families would recommend using telemedicine for KDTs in any situation regardless of the pandemic. None of the families reported that they would recommend against treatment by telemedicine. The availability of a social support network (parents WhatsApp group) coordinated by professionals from the KDT team was considered to be useful by most respondents (90%). CONCLUSIONS: Our study suggests that management of children with DRE on KDTs through telemedicine is feasible, well accepted by the families, and probably as safe as conventional medicine. WhatsApp may be an interesting telemedicine tool to start and maintain KDTs.

Impact of the COVID-19 pandemic on the work of clinical psychologists in Austria: results of a mixed-methods study.

Introduction: Clinical psychologists in Austria shouldered a large part of the massive increase in demand for mental health services caused by the COVID-19 pandemic. This study aimed to find out how the pandemic affected their work and to gather information on how best to support the profession in the event of a crisis. Methods: N = 172 Austrian clinical psychologists participated in a cross-sectional online survey between 11 April 2022 and 31 May 2022, including both closed and open-ended questions about their work. Open-ended questions were analyzed using qualitative content analysis. A mixed-methods analysis was conducted to test correlations between the categories derived from the qualitative analysis and professional variables. Results: The analyses revealed that clinical psychologists, especially those with more years of experience, perceived an increased need for clinical psychological treatment, especially for children and adolescents, a lack of coverage for clinical psychological treatment by health insurance, a change to remote treatment formats, and a number of burdens associated with complying with COVID-19 measures. Discussion: Clinical psychologists reported an urgent need to increase resources in both outpatient and inpatient settings and to promote health insurance coverage. To support the clinical psychology profession in providing high-quality work in times of crisis, there is a need to facilitate more opportunities for team and peer exchange, as well as financial support in the event of loss of income.

Ten years of a geriatric oncology service at a public university cancer centre in Brazil.

The implementation of a geriatric oncology service is challenging in both high-income and low-and-middle-income countries. The Octavio Frias de Oliveira Institute of Cancer of Sao Paulo (ICESP) is a tertiary healthcare complex of the Clinics Hospital of the University of Sao Paulo Medical School and is considered a model of excellence in oncology in Latin America. The objective of this manuscript is to describe 10 years of the geriatric oncology service at ICESP and the challenges for its implementation. We performed a narrative description of the ICESP's geriatric oncology service and a general retrospective descriptive analysis of data collected from routine structured medical records of patients referred to the service from 2011 to 2021. This article highlights the different settings in which the service operates (outpatient, pre-operative and hospital follow-up). In this period, 1,700 patients were assessed for preoperative evaluation (median age 83.9, SD 4.95), 468 patients were evaluated for therapeutic decision (median age 79.4, SD 7.38), 968 in general geriatric oncology care outpatient clinics from 2012 to 2021 (median age 78.7, SD 7.91) and 1,391 inpatient evaluations. In the past 10 years, our geriatric oncology team has grown exponentially and changed its characteristics in order to adjust them to the hospital demands, raising awareness among the oncology teams about the benefit of using geriatric assessment and promoting multidisciplinary discussions.

The Biological Variability of Plasma Ceramides in Healthy Subjects.

BACKGROUND: Ceramides are bioactive lipid species that mediate numerous cell-signaling events. Elevated plasma ceramides concentration constitutes a risk factor for several pathologies. Multiple studies have affirmed the plasma concentrations of 4 specific ceramides (Cer16:0, Cer18:0, Cer24:0, and Cer24:1) can predict cardiovascular disease risk. Furthermore, these ceramides can be altered by many lipid-lowering therapies. Understanding the biological variability within an individual, and within a population, will further inform the clinical use of plasma ceramides as a biomarker. In this study, we aimed to define the intra- and interbiological variability of ceramides in a healthy reference population in a weekly and monthly manner. METHODS: Fasting plasma from 24 healthy adults was collected daily (5 days), weekly (4 weeks), and monthly (7 months). Ceramide concentrations were measured with liquid chromatography-mass spectrometry (LC-MS). For analysis, we used random-effects regression models to estimate variance components. RESULTS: The analytical variability was smaller compared to the biological variability overall. The greatest variation reported was between-subject variation for all ceramide species. The critical difference-reference change value (RCV) for within-subject variations monthly were 0.07 mcmol/L (Cer16:0), 0.04 mcmol/L (Cer18:0), 1.09 mcmol/L (Cer24:0), and 0.27 mcmol/L (Cer24:1). The index of individuality (IOI) of ceramides were 0.82 (Cer16:0), 0.96 (Cer18:0), 1.06 (Cer24:0), and 0.89 (Cer24:1). The most consistent ceramide species was Cer18:0 with the lowest within- and between-subject critical differences in weekly and monthly measurements. CONCLUSIONS: Overall, this study demonstrates that the variability of ceramide concentrations at different time points is minimal within individuals, allowing a single draw to be sufficient at least in a yearly time frame.

Adipose Tissue Inflammation Is Not Related to Adipose Insulin Resistance in Humans.

The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

Insulin-Stimulated Muscle Glucose Uptake and Insulin Signaling in Lean and Obese Humans.

PURPOSE: Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial. METHODS: We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2). RESULTS: Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects. CONCLUSIONS: We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.

Senescent cells in human adipose tissue: A cross-sectional study.

OBJECTIVE: Adipose tissue (AT) senescence is associated with AT dysfunction in rodents, but little is known about human AT senescence. The study goal was to define the distribution of senescent cells in two subcutaneous depots and understand relationships with adiposity and inflammation. METHODS: Sixty-three volunteers (48 females) underwent abdominal and femoral subcutaneous fat biopsies. Fat cell size, senescent cells using senescence-associated ß-galactosidase staining per 100 nucleated cells (percentage), and mRNA expression of four cytokines were measured. RESULTS: There was a larger proportion of senescent cells in femoral than abdominal subcutaneous AT (mean difference 1.6% [95% CI: 0.98%-2.3%], p < 0.001), and the percentage of femoral AT senescent cells was greater in women than men (median 3.9% vs. 2.1%, p < 0.01). There was a positive correlation between senescence and fat cell size in abdominal (rs  = 0.44, p < 0.001) and femoral (rs  = 0.35, p = 0.007) AT depots. Abdominal AT tumor necrosis factor alpha (rs  = 0.49, p < 0.01) and interleukin-1ß (rs  = 0.44, p = 0.01) expression was positively correlated with abdominal, but not femoral, AT senescence. CONCLUSIONS: In human subcutaneous AT, there are more senescent cells in femoral than abdominal depots; abdominal AT senescent cells are more associated with inflammatory signals than femoral AT senescent cells.

Evaluation of sporadic bovine alkaline phosphatase interference in the Beckman Access unconjugated estriol (uE3) assay affecting maternal serum screening results.

OBJECTIVES: Bovine alkaline phosphatase (BALP) mediated interference is a potential issue in the Beckman Access unconjugated estriol (uE3) assay. As the uE3 assay is a component of second trimester maternal serum screening characterizing this interference is essential for delivering accurate trisomy 18 and trisomy 21 risks. DESIGN AND METHODS: Residual serum samples (n = 517) were measured by two different lots of uE3 assay. Scavenger BALP (sBALP) was added to all samples to remove potential BALP dependent interference and assessed using both lots of uE3 reagent. RESULTS: BALP mediated interference was observed in similar frequency in both lots of reagent (~3%), although the patterns of positive and negative interference differed between the lots. Pretreatment with sBALP improved lot-to-lot comparison. The presence of BALP related interference was not related to the concentration of endogenous human alkaline phosphatase. The use of polyethylene glycol and sBALP treatment appeared to mitigate BALP mediated interference equally well, and resulted in concordance in measured uE3 concentrations between reagent lots. Additionally, heterophile antibody interference was observed in two samples affected with BALP interference, and the heterophile antibody interference was resolved by both PEG and heterophile antibody blocking reagent treatment, but not sBALP treatment. While the maternal screen numeric risk for affected samples changed, the risk classification changed from a negative to positive screen in two samples. CONCLUSIONS: Interference in the uE3 assay has the potential to affect maternal serum risk calculations in different reagent lots, and pretreatment of samples with scavenger BALP or PEG should be considered in cases of unexplained uE3 concentrations.

Electro-bioremediation of nitrate and arsenite polluted groundwater.

The coexistence of different pollutants in groundwater is a common threat. Sustainable and resilient technologies are required for their treatment. The present study aims to evaluate microbial electrochemical technologies (METs) for treating groundwater contaminated with nitrate (NO3-) while containing arsenic (in form of arsenite (As(III)) as a co-contaminant. The treatment was based on the combination of nitrate reduction to dinitrogen gas and arsenite oxidation to arsenate (exhibiting less toxicity, solubility, and mobility), which can be removed more easily in further post-treatment. We operated a bioelectrochemical reactor at continuous-flow mode with synthetic contaminated groundwater (33 mg N-NO3- L-1 and 5 mg As(III) L-1) identifying the key operational conditions. Different hydraulic retention times (HRT) were evaluated, reaching a maximum nitrate reduction rate of 519 g N-NO3- m3Net Cathodic Compartment d-1 at HRT of 2.3 h with a cathodic coulombic efficiency of around 100 %. Simultaneously, arsenic oxidation was complete at all HRT tested down to 1.6 h reaching an oxidation rate of up to 90 g As(III) m-3Net Reactor Volume d -1. Electrochemical and microbiological characterization of single granules suggested that arsenite at 5 mg L-1 did not have an inhibitory effect on a denitrifying biocathode mainly represented by Sideroxydans sp. Although the coexistence of abiotic and biotic arsenic oxidation pathways was shown to be likely, microbial arsenite oxidation linked to denitrification by Achromobacter sp. was the most probable pathway. This research paves the ground towards a real application for treating groundwater with widespread pollutants.

Sex and Depot Differences in Palmitoleic Acid Content of Human Blood and Fat.

Palmitoleic acid has been classified as an insulin-sensitizing lipokine, but evidence for this from human studies has been inconsistent. We hypothesized that this is related to either the types of samples or conditions under which samples are collected. We measured plasma palmitoleic acid and total free fatty acids (FFA) using ultra-performance liquid chromatography in blood samples collected from 34 adults under a variety of conditions. We collected duplicate samples of adipose (n = 10), FFA (n = 9), and very low density lipoprotein triacylglycerol (VLDL-TAG) (n = 7) to measure the palmitoleic acid as a percentage of total fatty acids. We tested whether the percentage of palmitoleic acid was correlated with insulin resistance, as measured by homeostatic model of insulin resistance (HOMA-IR). Adipose stearoyl-coenzyme A desaturase 1 (SCD-1) protein was measured by capillary Western blotting. FFA-palmitoleic acid percentage increased as a function of total FFA and was greater (p < 0.005) in females than males. Adipose palmitoleic acid percentage was greater in females than males (p < 0.001), as was adipose SCD-1. Palmitoleic acid was greater in femoral fat than in abdominal fat in both females and males (p < 0.001), and correlated positively with HOMA-IR only in females. The test-retest reliability values for percentage palmitoleic acid were 7 ± 10% for adipose, 24 ± 26% for VLDL, and 53 ± 31% for FFA. Because FFA-palmitoleic acid percentage varies as a function of total FFA, investigators should re-evaluate how palmitoleic acid data is presented. The positive relationship between adipose palmitoleic acid and HOMA-IR in females suggests that it is not a potent insulin-sensitizing lipokine in humans.

Caracterización del uso de tofacitinib como tratamiento para COVID-19 / si

Objetivo: El propósito principal de este estudio es caracterizar y comparar la población que recibió tofacitinib con aquella que no fue tratada con este fármaco para la COVID-19 en la Clínica Unión Médica del Norte, durante el año 2020. Métodos: Se realizó un estudio de tipo observacional, retrospectivo transversal de tipo exploratorio y de fuente secundaria. Se analizaron las características de los participantes y su tratamiento en relación con los parámetros de laboratorio y las características clínicas. Resultados: Se incluyeron 507 pacientes ingresados en la unidad de COVID-19 de la Clínica Unión Médica del Norte. Se determinó que las defunciones fueron menores en el grupo que se medicó con tofacitinib (6,45%) en comparación con el grupo que no utilizó dicho fármaco. Asimismo, los medicados con esta terapia ameritaron en menos proporción soporte ventilatorio, sin embargo, hubo más proporción de ingresos a la Unidad de Cuidados Intensivos. Además, se identificó una reducción mayor en la glucemia en aquellos pacientes medicados con tofacitinib, aunque mayores niveles de ferritina y dímero D. Conclusiones: El fármaco tofacitinib puede actuar de manera beneficiosa en relación con la mortalidad y la reducción del uso de ventilación mecánica. En adición, podría colaborar con la evolución de los pacientes. No obstante, nuestra investigación no es concluyente. Es necesario realizar futuras investigaciones confirmatorias de la eficacia de la terapia con tofacitinib para los pacientes con COVID-19.

Objective: The main purpose of this study is to characterize and compare the population that received tofacitinib with those that were not treated with the drug for COVID-19 at the Clínica Unión Médica del Norte, in 2020. Methods: An observational, retrospective, cross-sectional, exploratory, and secondary source study was conducted. A comparison was made between clinical and sociodemographic characteristics, laboratory results and their treatment option. Results: Five hundred and seven patients admitted to the COVID-19 unit of the Clínica Unión Médica del Norte were included. It was determined that lower death rates were registered in the group that received tofacitinib (6.45%) compared to the group that did not use the drug. Likewise, those receiving this therapy required less mechanical ventilation, however, a higher proportion of these patients were admitted to the Intensive Care Unit. In addition, a greater reduction in glycaemia was identified in the patients receiving tofacitinib, but they had higher levels of ferritin and D-dimer. Conclusions: Tofacitinib may be beneficial in terms of mortality rates and reduction in the use of mechanical ventilation. Furthermore, it is promising with respect to positive patient progression. However, our research is not conclusive. Future confirmatory research is needed on the efficacy of tofacitinib therapy for COVID-19 patients.

Efficacy of lactulose in the prophylaxis of hepatic encephalopathy in cirrhotic patients presenting gastrointestinal bleeding.

INTRODUCTION: Hepatic encephalopathy (HE) is a bad prognostic factor in patients with liver cirrhosis and its incidence is associated with several triggering factors being the most prevalent gastrointestinal bleeding. Lactulose, despite its questionable efficacy in the literature, is considered a first line treatment in patients with HE. OBJECTIVE: To evaluate the effectiveness of lactulose in preventing HE in cirrhotic patients with gastrointestinal bleeding. METHOD: A systematic review of the literature using the Medline scientific database. Only randomized controlled clinical trials evaluating the efficacy of lactulose for HE prophylaxis in cirrhotic patients with gastrointestinal bleeding were included. RESULTS: The incidence of HE in the intervention group was 7%, while the control group was 26% (p=0.01). There was no significant difference in the incidence of mortality in the group treated with lactulose compared to the group that was not treated (p=0.48). CONCLUSION: Administering lactulose to cirrhotic patients with upper gastrointestinal bleeding reduces the incidence of hepatic encephalopathy.