Opposing diet, microbiome, and metabolite mechanisms regulate inflammatory bowel disease in a genetically susceptible host.

Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, interleukin-10, we show that a fiber-deprived gut microbiota promotes the deterioration of colonic mucus, leading to lethal colitis. Inflammation starts with the expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Lethal colitis is then driven by Th1 immune responses to increased activities of mucin-degrading bacteria that cause inflammation first in regions with thinner mucus. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Our findings underscore the importance of focusing on microbial functions-not taxa-contributing to IBDs and that some diet-mediated functions can oppose those that promote disease.

Dexmedetomidine Sublingual Film: A New Treatment to Reduce Agitation in Schizophrenia and Bipolar Disorders.

OBJECTIVE: The objective of this study was to review the available literature for dexmedetomidine sublingual film use in the treatment of acute agitation associated with schizophrenia and bipolar disorders. DATA SOURCES: A literature search of PubMed (January 2017-March 2023) and EMBASE (January 2017-March 2023) was performed using the terms: Igalmi, dexmedetomidine, schizophrenia, bipolar disorder, and agitation. Additional information sources include ClinicalTrials.gov, scientific posters, and articles identified through review of references from clinical trials publications. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language articles conducted in humans were considered, with a preference for phase 3 clinical trials. Trial analyses and articles discussing pharmacology, pharmacokinetics, efficacy, and safety were also evaluated. DATA SYNTHESIS: Dexmedetomidine sublingual film was evaluated for use in schizophrenia in the SERENITY 1 pivotal trial and for bipolar disorders in the SERENITY 2 pivotal trial. Both studies found treatment of mild to moderate agitation with dexmedetomidine sublingual film 180 and 120 µg to be superior to placebo in reducing the severity of agitation. Treatment effect was seen as early as 20 minutes. Somnolence was the most common adverse effect in both studies. Cardiovascular adverse effects were mild and transient in most cases. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Dexmedetomidine sublingual film is a new and novel treatment for agitation and gives clinicians an alternative to antipsychotic and benzodiazepine use. It has advantageous properties including its noninvasive route of administration, fast absorption, and rapid onset of effect. Cost may limit its use. CONCLUSION: Dexmedetomidine sublingual film provides an alternative approach to treatment of acute agitation in adults with schizophrenia and bipolar disorders based on both mechanism of action and route of administration.

Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont.

Exclusive enteral nutrition (EEN) with fiber-free diets is an effective steroid-sparing treatment to induce clinical remission in children with Crohn's disease (CD). However, the mechanism underlying the beneficial effects of EEN remains obscure. Using a model of microbiota-dependent colitis with the hallmarks of CD, we find that the administration of a fiber-free diet prevents the development of colitis and inhibits intestinal inflammation in colitic animals. Remarkably, fiber-free diet alters the intestinal localization of Mucispirillum schaedleri, a mucus-dwelling pathobiont, which is required for triggering disease. Mechanistically, the absence of dietary fiber reduces nutrient availability and impairs the dissimilatory nitrate reduction to ammonia (DNRA) metabolic pathway of Mucispirillum, leading to its exclusion from the mucus layer and disease remission. Thus, appropriate localization of the specific pathobiont in the mucus layer is critical for disease development, which is disrupted by fiber exclusion. These results suggest strategies to treat CD by targeting the intestinal niche and metabolism of disease-causing microbes.

H2 generated by fermentation in the human gut microbiome influences metabolism and competitive fitness of gut butyrate producers.

BACKGROUND: Hydrogen gas (H2) is a common product of carbohydrate fermentation in the human gut microbiome and its accumulation can modulate fermentation. Concentrations of colonic H2 vary between individuals, raising the possibility that H2 concentration may be an important factor differentiating individual microbiomes and their metabolites. Butyrate-producing bacteria (butyrogens) in the human gut usually produce some combination of butyrate, lactate, formate, acetate, and H2 in branched fermentation pathways to manage reducing power generated during the oxidation of glucose to acetate and carbon dioxide. We predicted that a high concentration of intestinal H2 would favor the production of butyrate, lactate, and formate by the butyrogens at the expense of acetate, H2, and CO2. Regulation of butyrate production in the human gut is of particular interest due to its role as a mediator of colonic health through anti-inflammatory and anti-carcinogenic properties. RESULTS: For butyrogens that contained a hydrogenase, growth under a high H2 atmosphere or in the presence of the hydrogenase inhibitor CO stimulated production of organic fermentation products that accommodate reducing power generated during glycolysis, specifically butyrate, lactate, and formate. Also as expected, production of fermentation products in cultures of Faecalibacterium prausnitzii strain A2-165, which does not contain a hydrogenase, was unaffected by H2 or CO. In a synthetic gut microbial community, addition of the H2-consuming human gut methanogen Methanobrevibacter smithii decreased butyrate production alongside H2 concentration. Consistent with this observation, M. smithii metabolic activity in a large human cohort was associated with decreased fecal butyrate, but only during consumption of a resistant starch dietary supplement, suggesting the effect may be most prominent when H2 production in the gut is especially high. Addition of M. smithii to the synthetic communities also facilitated the growth of E. rectale, resulting in decreased relative competitive fitness of F. prausnitzii. CONCLUSIONS: H2 is a regulator of fermentation in the human gut microbiome. In particular, high H2 concentration stimulates production of the anti-inflammatory metabolite butyrate. By consuming H2, gut methanogenesis can decrease butyrate production. These shifts in butyrate production may also impact the competitive fitness of butyrate producers in the gut microbiome. Video Abstract.

Unravelling specific diet and gut microbial contributions to inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, diet and gut bacteria are thought to be prominent features contributing to IBD, but little is known about the precise mechanisms involved. Here, we show that low dietary fiber promotes bacterial erosion of protective colonic mucus, leading to lethal colitis in mice lacking the IBD-associated cytokine, interleukin-10. Diet-induced inflammation is driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of some bacteria. Surprisingly, an exclusive enteral nutrition diet, also lacking dietary fiber, reduced disease by increasing bacterial production of isobutyrate, which is dependent on the presence of a specific bacterial species, Eubacterium rectale. Our results illuminate a mechanistic framework using gnotobiotic mice to unravel the complex web of diet, host and microbial factors that influence IBD.

Ketamine Infusions Administered Solely by Psychiatric Staff.

Even though intravenous ketamine is not an FDA-approved depression treatment, multiple studies have shown a robust antidepressant effect which has led to an increase in clinical practices implementing its use to manage treatment-resistant depression. Traditionally, this therapy has been provided in both outpatient and inpatient settings, with anesthesia specialists and psychiatrists working collaboratively on most cases. Several studies have been conducted in various psychiatric settings to study the effects of ketamine in depression, mostly in a collaborative manner. Thorough search of the literature found no published reports on the use of ketamine infusions merely for clinical purposes in a psychiatric hospital setting, implemented solely by a psychiatric-based team without collaboration from anesthesia specialists. In an effort to explore the utilization of ketamine infusions, the Missouri University Psychiatric Center (MUPC), an acute mental inpatient facility, formed a ketamine infusion team composed solely of mental health clinicians and staff to investigate the use of ketamine infusions by a psychiatric team. To our knowledge, this is the first-time ketamine infusions have been administered by a clinically based psychiatric team in a psychiatric hospital. The MUPC ketamine team has proved that ketamine infusions may provide a unique intervention safely and efficaciously without the need for collaboration with other medical specialties since initiating this pilot program.

Diverse events have transferred genes for edible seaweed digestion from marine to human gut bacteria.

Humans harbor numerous species of colonic bacteria that digest fiber polysaccharides in commonly consumed terrestrial plants. More recently in history, regional populations have consumed edible macroalgae seaweeds containing unique polysaccharides. It remains unclear how extensively gut bacteria have adapted to digest these nutrients. Here, we show that the ability of gut bacteria to digest seaweed polysaccharides is more pervasive than previously appreciated. Enrichment-cultured Bacteroides harbor previously discovered genes for seaweed degradation, which have mobilized into several members of this genus. Additionally, other examples of marine bacteria-derived genes, and their mobile DNA elements, are involved in gut microbial degradation of seaweed polysaccharides, including genes in gut-resident Firmicutes. Collectively, these results uncover multiple separate events that have mobilized the genes encoding seaweed-degrading-enzymes into gut bacteria. This work further underscores the metabolic plasticity of the human gut microbiome and global exchange of genes in the context of dietary selective pressures.

Adenomatous polyposis coli in cancer and therapeutic implications.

Inactivating mutations of the adenomatous polyposis coli (APC) gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests APCmutations are also found in gastric, breast and other cancers. The APC gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an APC mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to APC mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with APC mutations.

Uncovering the Value of a Historical Paper-Based Collaborative Artifact: The Nursing Unit's Kardex System.

We identify useful functions and usability characteristics of a historical cognitive artifact used by nurses working in a hospital unit, the Kardex. By identifying aspects of a widely used artifact, we uncover opportunities to improve the usefulness of current systems for hospital nurses. We conducted semi-structured interviews with registered nurses about their prior experience with the Kardex. Questions included what elements of the Kardex are missing from their current electronic support. Memos were generated iteratively from interview transcript data and grouped into themes. Eighteen nurses from multiple clinical areas participated and had a median of 25-29 years of nursing experience. The themes were: (1) a status at a glance summary for each patient, (2) a prospective memory aid, (3) efficiency and ease of use, (4) updating information required to maintain value, (5) activity management, (6) verbal handover during shift-to-shift report, (7) narrative charting and personalized care, and (8) non-clinical care communication. Implications for digital support are to provide immediate, portable access to a standardized patient summary, support for nurses to manage their planned activities during a series of shifts, provide unstructured text fields for narrative charting, and to support adding informal notes for personalized care.

Value and Usage of a Workaround Artifact: A Cognitive Work Analysis of "Brains" Use by Hospital Nurses.

We identify the value and usage of a cognitive artifact used by hospital nurses. By analyzing the value and usage of workaround artifacts, unmet needs using intended systems can be uncovered. A descriptive study employed direct observations of registered nurses at two hospitals using a paper workaround ("brains") and the Electronic Health Record. Field notes and photographs were taken; the format, size, layout, permanence, and content of the artifact were analyzed. Thirty-nine observations, spanning 156 hr, were conducted with 20 nurses across four clinical units. A total of 322 photographs of paper-based artifacts for 161 patients were collected. All participants used and updated "brains" during report, and throughout the shift, most were self-generated. These artifacts contained patient identifiers in a header with room number, last name, age, code status, and physician; clinical data were recorded in the body with historical chronic issues, detailed assessment information, and planned activities for the shift. Updates continuously made during the shift highlighted important information, updated values, and tracked the completion of activities. The primary functional uses of "brains" are to support nurses' needs for clinical immediacy through personally generated snapshot overviews for clinical summaries and updates to the status of planned activities.

HOW NURSES IDENTIFY HOSPITALIZED PATIENTS ON THEIR PERSONAL NOTES: FINDINGS FROM ANALYZING 'BRAINS' HEADERS WITH MULTIPLE RATERS.

The overarching objective of this research is to reduce the burden of documentation in electronic health records by registered nurses in hospitals. Registered nurses have consistently reported that e-documentation is a concern with the introduction of electronic health records. As a result, many nurses use handwritten notes in order to avoid using electronic health records to access information about patients. At the top of these notes are patient identifiers. By identifying aspects of good and suboptimal headers, we can begin to form a model of how to effectively support identifying patients during assessments and care activities. The primary finding is that nurses use room number as the primary patient identifier in the hospital setting, not the patient's last name. In addition, the last name, gender, and age are sufficiently important identifiers that they are frequently recorded at the top of handwritten notes. Clearly distinguishable field labels and values are helpful in quickly scanning the identifier for identifying information. A web based annotator was designed as a first step towards machine learning approaches to recognize handwritten or printed data on paper sheets in future research.

APPLYING HUMAN FACTORS ENGINEERING TO IMPROVE USABILITY AND WORKFLOW IN PATHOLOGY INFORMATICS.

Human factors engineering is an underutilized approach in the design, evaluation, and implementation of health information technology. Heuristic evaluation of the usability of an interface is a 'low-hanging fruit' for identifying a set of relatively simple modifications to a software program that can make software easier to use. In this paper, we describe recommendations to improve the usability of a software package used to view digitized images of tissues by pathologists. Several recommendations were immediately implemented, and others are planned for future releases. The changes are anticipated to be more compatible with user expectations from interacting with similar elements in other packages, and thus easier to learn and use.

Patient-Centered Handovers: Ethnographic Observations of Attending and Resident Physicians: Ethnographic Observations of Attending and Resident Physicians.

Handover communication improvement initiatives typically employ a "one size fits all" approach. A human factors perspective has the potential to guide how to tailor interventions to roles, levels of experience, settings, and types of patients. We conducted ethnographic observations of sign-outs by attending and resident physicians in 2 medical intensive care units at one institution. Digitally audiotaped data were manually analyzed for content using codes and time spent using box plots for emergent categories. A total of 34 attending and 58 resident physician handovers were observed. Resident physicians spent more time for "soon to be discharged" and "higher concern" patients than attending physicians. Resident physicians spent less time discussing patients which they had provided care for within the last 3 days ("handbacks"). The study suggested differences for how handovers were conducted for attending and resident physicians for 3 categories of patients; handovers differ on the basis of role or level of expertise, patient type, and amount of prior knowledge of the patient. The findings have implications for new directions for subsequent research and for how to tailor quality improvement interventions based upon the role, level of experience, level of prior knowledge, and patient categories.

Two Case Reports on Use of Prazosin for Drug Dreams.

Substance abuse and dependence is estimated to cost roughly $700 billion annually including direct and indirect care in the United States. Drug dreams (DD), or using dreams, are a reportedly common phenomenon among patients with substance abuse, and have been postulated as triggers for relapse. Prazosin is an alpha-1 receptor antagonist originally approved by the United States Food and Drug Administration for the treatment of hypertension. Prazosin passes the blood brain barrier easily, contributing to central and cognitive effects. Prazosin's efficacy has been demonstrated in the management of posttraumatic stress disorder (PTSD), and associated nightmares. We present the cases of two patients with substance use disorder experiencing DD which resolved after the addition of prazosin during an acute psychiatric hospitalization. To our knowledge, this is the first time treatment of DD with prazosin has been reported in the literature. Both patients reported an alleviation of their DD after the medication was initiated. The effect was immediate and results were seen on the same night of the initial dose. The precise mechanism of this effect is unclear, but we hypothesize it is related to the decrease in noradrenaline effects at α-1 adrenoreceptors in the brain, similar to the effect on nightmares in PTSD. The key limitation is the low number of patients and lack of follow up presented in this report. No causal relationship can be established between the use of prazosin and resolution of DD in our patients.

Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers.

In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure-activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones' effects to rescue neurons subjected to ROS-induced stress created by the addition of ß-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.

Antipsychotic treatment in breast cancer patients.

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.

Interactive questioning in critical care during handovers: a transcript analysis of communication behaviours by physicians, nurses and nurse practitioners.

OBJECTIVE: Although there is a growing recognition of the importance of active communication behaviours from the incoming clinician receiving a patient handover, there are currently no agreed-upon measures to objectively describe those behaviours. This study sought to identify differences in incoming clinician communication behaviours across levels of clinical training for physicians and nurses. METHODS: Handover observations were conducted during shift changes for attending physicians, resident physicians, registered nurses and nurse practitioners in three medical intensive care units from July 2011 to August 2012. Measures were the number of interjections from the incoming clinician and the communication mode of those interjections. Each collaborative cross-check, a specific type of interactive question, was subsequently classified by level of assertiveness. RESULTS: 133 patient handovers were analysed. Statistical differences were found in both measures. Higher levels of training were associated with fewer interjections, and a higher proportion of interactive questioning to detect erroneous assessments and actions by the incoming provider. All groups were observed to use the least assertive level of a collaborative cross-check, which contributed to misunderstandings. Nurses used less assertive collaborative cross-checks than physicians. CONCLUSIONS: Differences across clinician type and levels of clinical training were found in both measures during patient handovers. The findings suggest that training could enable physicians and nurses to learn communication competencies during patient handovers which were used more frequently by more experienced practitioners, including interjecting less frequently and using interactive questioning strategies to clarify understanding, and assertively question the appropriateness of diagnoses, treatment plans and prognoses. Accompanying cultural change initiatives might be required to routinely employ these strategies in the clinical setting, particularly for nursing personnel.

Carbamazepine in bipolar disorder with pain: reviewing treatment guidelines.

OBJECTIVE: To determine if any monotherapy drug treatment has robust efficacy to treat comorbid bipolar disorder and chronic pain. DATA SOURCES: The American Psychiatric Association (APA) treatment guidelines for bipolar mood disorder and the 2012 Cochrane database for pain disorders. STUDY SELECTION: We relied on the treatment guides to determine if the drugs that are APA guideline-supported to treat bipolar disorder have supporting data from the Cochrane database for chronic pain. DATA SYNTHESIS: No single drug was mentioned by either guideline to treat this comorbidity. However, carbamazepine was the only drug that has guideline-supported robust efficacy in the management of each condition separately. CONCLUSIONS: Carbamazepine was found to have strong preclinical data for the treatment of comorbid bipolar mood disorder and chronic pain disorders. While requiring more studies in this population, we propose that this treatment modality may benefit patients.

Analysis of cost avoidance from pharmacy students' clinical interventions at a psychiatric hospital.

OBJECTIVE: To analyze the cost avoidance resulting from clinical interventions made by pharmacy students completing an advanced pharmacy practice experience (APPE) at a psychiatric hospital. METHODS: A retrospective database review of documented clinical interventions by pharmacy students was conducted to classify interventions by type and significance. Interventions were assigned a cost avoidance value determined by an evaluation of the literature. RESULTS: Three hundred-twenty interventions were documented by 15 pharmacy students during the 1-year study period. The majority of interventions were related to psychiatric medication classes and most (n = 197; 61.6%) were classified as being of moderate significance. The most common interventions included patient education (13.1%), order clarification (11.6%), therapeutic dosing adjustments (10.9%), and laboratory order monitoring (8.8%). The estimated cost avoidance from all interventions made by pharmacy students was approximately $23,000. CONCLUSIONS: Pharmacy students completing APPEs at a psychiatric hospital contributed to a variety of significant clinical interventions and provided considerable cost avoidance value to the institution.

Mental health stability in veterans with posttraumatic stress disorder receiving varenicline.

PURPOSE: The effects of varenicline treatment for smoking cessation on mental health (MH) stability in veterans with posttraumatic stress disorder (PTSD) was studied. METHODS: Data were collected by retrospective chart review at a Veterans Affairs medical center. Patients with PTSD who were prescribed varenicline for smoking cessation between May 2006 and July 2008 were included; all patients had failed previous attempts to quit using nicotine replacement therapy, bupropion, or both. The average numbers of encounters per month with MH professionals in a six-month baseline period before varenicline, during treatment, and after treatment were compared. The numbers of MH encounters were compared for patients with multiple MH disorders including major depressive disorder, schizophrenia, or bipolar disorder and those with PTSD alone. Patients who had completed a full course of varenicline therapy (4-12 weeks) without MH decompensation were surveyed to determine the rate of smoking cessation. RESULTS: Data were analyzed for 78 patients. MH encounters during varenicline therapy increased 29% over baseline. There was no significant difference in the numbers of encounters in the baseline and postvarenicline periods. MH decompensations were documented for 4 patients during varenicline therapy and 2 after completion of therapy. Before, during, and after varenicline, patients with multiple MH disorders had significantly more MH encounters than those with PTSD alone. Of the 42 patients in the follow-up survey, 19 (45%) said they refrained from smoking for 30 days and 13 (31%) for 90 days. CONCLUSION: Varenicline appeared to have destabilizing effects on MH in veterans with PTSD.