Quality of Sleep and Coexistent Psychopathology Have Significant Impact on Fatigue Burden in Patients With Inflammatory Bowel Disease.

BACKGROUND: Fatigue is common in inflammatory bowel disease (IBD) patients and is associated with factors such as psychopathology, sleep quality, and disease activity. GOAL: To investigate the combined role of all the above factors in the burden of fatigue among IBD patients. STUDY: We conducted an observational study of adult patients enrolled in an IBD clinical research registry at a tertiary care clinic. Fatigue burden was defined by Item 1 of the Short-form IBD Questionnaire (SIBDQ), which is scored on a 7-point Likert scale. Crohn's disease (CD) and ulcerative colitis (UC) disease activity were measured with the Harvey-Bradshaw Index or the UC Activity Index, respectively. Labs were obtained to assess anemia, vitamin deficiencies, and inflammatory markers. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Use of psychotropic medications and narcotics was used as proxy measure of psychopathology and pain. RESULTS: Among 685 IBD patients enrolled in the registry, 631 (238 UC, 393 CD) had a complete SIBDQ. High fatigue burden was found in 57.5% of patients (64.4% CD, 46.2% UC). Fatigue burden was significantly associated with sleep disturbance (PSQI), SIBDQ, and disease activity. CD patients had more fatigue burden than UC patients. Multivariate regression showed that poor quality of life, sleep disturbance, and being on a psychotropic medication are significantly associated with fatigue burden for both UC and CD. CONCLUSION: Because fatigue is common in IBD patients, these findings suggest that attention to quality of sleep and psychopathology is as important as medical disease management.

Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study.

Background: The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH. Methods: A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). Findings: In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24). Interpretation: AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Gene expression and generation of CD28-CD8 T cells mediated by interleukin 15.

Accumulation of CD28(-)CD8 T cells that are defective in response to antigenic stimulation is a hallmark of age-associated decline in T cell function. However, the underlying mechanism of this age-associated change is not fully understood. We recently analyzed the global gene expression profiles of CD8 T cell subsets from nai ve to memory (CD28(+) to CD28(-)) cells and the growth of CD28(+) and CD28(-)CD8 memory T cells in response to homeostatic cytokine interleukin 15 (IL-15). At the gene expression level, one of the most striking changes is the altered expression of some co-stimulatory receptors and various NK cell receptors in CD28(-)CD8 T cells. Furthermore, CD28(-)CD8 T cells appear to have a normal proliferation response to IL-15 in vitro. Interestingly, IL-15 is also capable of inducing stable loss of CD28 expression in actively dividing CD28(+)CD8 memory T cells. Together, these findings provide the gene expression features of CD28(-)CD8 T cells that differ from their CD28(+) counterparts and suggest a possible role of IL-15 in the increase of CD28(-)CD8 T cells that occurs with aging.

The Safety of Multiple Flexible Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants.

During Phase 1 pharmacokinetic/pharmacodynamics studies, participants may undergo multiple sigmoidoscopies, with a collection of 10-20 biopsies during each procedure. This article characterizes the safety of flexible sigmoidoscopies in clinical trial participants. We determined the number of flexible sigmoidoscopies and rectal biopsies that participants underwent and analyzed the frequency, duration, and severity of flexible sigmoidoscopy-related adverse events (AEs). During the study period, 278 participants underwent 1,004 flexible sigmoidoscopies with the collection of 15,930 rectal biopsies. The average number of procedures per participant was 3.6 (median 3; range 1-25), with an average time interval between procedures of 61.8 days (median 28 days; range 1-1,159). There were no serious AEs. Sixteen AEs were related to flexible sigmoidoscopy and occurred in 16 participants, leading to an overall 1.6% (16/1,004) AE rate per procedure and 0.1% (16/15,930) AE rate per biopsy. Of the 16 AEs, 8 (50%) involved abdominal pain, diarrhea, bleeding, flatulence, and bloating, with an average duration of 4.7 days (median 1 day; range 1-28). Most (14/16) AEs were categorized as Grade 1 (mild), whereas two of the AEs were Grade 2 (moderate). No participant withdrew due to procedure-related AEs. Overall, the number of AEs caused by flexible sigmoidoscopy with multiple biopsies was low and the severity was mild, suggesting that this procedure can be safely integrated into protocols requiring repeated intestinal mucosal sampling.

Genetically encoded redox sensors.

Endogenous redox sensors detect fluctuations in the intracellular redox equilibrium and are critical for the maintenance of homeostasis. Such systems have been exploited to engineer genetically encoded redox sensors to detect dynamic oxidative changes within a cellular environment. Most genetically encoded redox sensors detect reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide and hydroxyl radical. Technical hurdles including the limited temporal and spatial resolution as well as tissue heterogeneity have complicated the realization of the full potential of genetically encoded redox sensors in animals until recently. Alterations in the concentration and subcellular localization of ROS are integral to numerous disorders, including neurodegenerative diseases and cancer. Thus, genetically encoded redox sensors are useful for the study of the pathogenesis and progression of multiple diseases. Moreover, the ultimate generation of genetically encoded redox sensors provides substantial advantages over conventional methods such as ROS-sensitive fluorescent probes. Here, we review examples of genetically encoded redox sensors, present their application to various fields of biomedical investigation, including the study of oncometabolism, discuss their drawbacks and explore future developments.

Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction.

Numerous mitochondrial DNA mutations cause mitochondrial encephalomyopathy: a collection of related diseases for which there exists no effective treatment. Mitochondrial encephalomyopathies are complex multisystem diseases that exhibit a relentless progression of severity, making them both difficult to treat and study. The pathogenic and compensatory metabolic changes that are associated with chronic mitochondrial dysfunction are not well understood. The Drosophila ATP6(1) mutant models human mitochondrial encephalomyopathy and allows the study of metabolic changes and compensation that occur throughout the lifetime of an affected animal. ATP6(1)animals have a nearly complete loss of ATP synthase activity and an acute bioenergetic deficit when they are asymptomatic, but surprisingly we discovered no chronic bioenergetic deficit in these animals during their symptomatic period. Our data demonstrate dynamic metabolic compensatory mechanisms that sustain normal energy availability and activity despite chronic mitochondrial complex V dysfunction resulting from an endogenous mutation in the mitochondrial DNA. ATP6(1)animals compensate for their loss of oxidative phosphorylation through increases in glycolytic flux, ketogenesis and Kreb's cycle activity early during pathogenesis. However, succinate dehydrogenase activity is reduced and mitochondrial supercomplex formation is severely disrupted contributing to the pathogenesis seen in ATP6(1) animals. These studies demonstrate the dynamic nature of metabolic compensatory mechanisms and emphasize the need for time course studies in tractable animal systems to elucidate disease pathogenesis and novel therapeutic avenues.

A systematic review of nurse-assisted case management to improve hospital discharge transition outcomes for the elderly.

PURPOSE: This article reviews 15 clinical trials of nurse-assisted case management intended to improve posthospital transitions of elderly patients to other settings. PRIMARY PRACTICE SETTING(S): Hospitals. METHODOLOGY AND SAMPLE: The trials were selected after a systematic search of the PubMed database for the period 1996 to 2006. RESULTS: Eight of the 15 interventions showed reduced hospital readmission rates and/or fewer hospital days. These findings were observed across patients with "all cause" and heart failure, a variety of hospital types, and variations in the intervention. Reductions in the use of emergency departments were observed in 3 of the 11 studies investigating this. Lower expenditures were reported by all 6 studies reporting such comparisons. IMPLICATIONS FOR CM PRACTICE: Home visits/continuous contact with patients, early postdischarge and frequent contacts, patient education, and the use of specialized nurses who could offer appropriate training and coaching were often credited as program strengths.

Generation and growth of CD28nullCD8+ memory T cells mediated by IL-15 and its induced cytokines.

Accumulation of CD28(null)CD8+ T cells and the defects of these cells in response to antigenic stimulation are the hallmarks of age-associated decline of T cell function. However, the mechanism of these age-associated changes is not fully understood. In this study, we report an analysis of the growth of human CD28(null) and CD28+CD8+ memory T cells in response to homeostatic cytokine IL-15 in vitro. We showed that 1) there was no proliferative defect of CD28(null)CD8+ memory T cells in response to IL-15 compared with their CD28+ counterparts; 2) stable loss of CD28 expression occurred in those actively dividing CD28+CD8+ memory T cells responding to IL-15; 3) the loss of CD28 was in part mediated by TNF-alpha that was induced by IL-15; and 4) CCL4 (MIP-1beta), also induced by IL-15, had a significant inhibitory effect on the growth of CD28(null) cells, which in turn down-regulated their expression of CCL4 receptor CCR5. Together, these findings demonstrate that CD28(null)CD8+ memory T cells proliferate normally in response to IL-15 and that IL-15 and its induced cytokines regulate the generation and growth of CD28(null)CD8+ T cells, suggesting a possible role of IL-15 in the increase in CD28(null)CD8+ T cells that occurs with aging.

Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging.

Accumulation of CD28(null)CD8(+) T cells is considered as one of the hallmarks of aging in the human immune system. However, the precise changes of CD28(null)CD8(+) T cells, compared to those of the precursor CD28(+)CD8(+) memory T cells, have not been determined. In this study, we present an analysis of the global gene expression profiles of CD28(+) and CD28(null) memory phenotype CD8(+) T cells. These two CD8(+) T subsets exhibited an overall similar gene expression profile with only a few dozen genes that were differentially expressed. A wide range of functions, including co-stimulation, effector activity, signaling, and transcription, were possessed by these differentially expressed genes, reflecting significant functional changes of CD28(null) memory phenotype CD8(+) T cells from their CD28(+) counterparts. In addition, CD28(null) memory CD8(+) T cells expressed several natural killer cell receptors and high levels of granzymes, perforin, and FasL, indicating an increasing capacity for cytotoxicity during memory CD8(+) T-cell aging. Interestingly, in vitro culture of these two subsets with interleukin-15 showed that similar gene expression changes occurred in both subsets. Our analysis provides the gene expression portraits of CD28(null) memory phenotype CD8(+) T cells and alteration from their CD28(+) counterparts and suggests potential mechanisms of T-cell aging.