A normative microbiome is not restored following kidney transplantation.

Dialysis and kidney transplantation (Ktx) mitigate some of the physiological deficits in chronic kidney disease (CKD), but it remains to be determined if these mitigate microbial dysbiosis and the production of inflammatory microbial metabolites, which contribute significantly to the uraemic phenotype. We have investigated bacterial DNA signatures present in the circulation of CKD patients and those receiving a KTx. Our data are consistent with increasing dysbiosis as CKD progresses, with an accompanying increase in trimethylamine (TMA) producing pathobionts Pseudomonas and Bacillus. Notably, KTx patients displayed a significantly different microbiota compared with CKD5 patients, which surprisingly included further increase in TMA producing Bacillus and loss of salutogenic Lactobacilli. Only two genera (Viellonella and Saccharimonidales) showed significant differences in abundance following KTx that may reflect a reciprocal relationship between TMA producers and utilisers, which supersedes restoration of a normative microbiome. Our metadata analysis confirmed that TMA N-oxide (TMAO) along with one carbon metabolism had significant impact upon both inflammatory burden and the composition of the microbiome. This indicates that these metabolites are key to shaping the uraemic microbiome and might be exploited in the development of dietary intervention strategies to both mitigate the physiological deficits in CKD and enable the restoration of a more salutogenic microbiome.

Association of Extubation Failure Rates With High-Flow Nasal Cannula, Continuous Positive Airway Pressure, and Bilevel Positive Airway Pressure vs Conventional Oxygen Therapy in Infants and Young Children: A Systematic Review and Network Meta-Analysis.

Importance: Extubation failure (EF) has been associated with worse outcomes in critically ill children. The relative efficacy of different modes of noninvasive respiratory support (NRS) to prevent EF is unknown. Objective: To study the reported relative efficacy of different modes of NRS (high-flow nasal cannula [HFNC], continuous positive airway pressure [CPAP], and bilevel positive airway pressure [BiPAP]) compared to conventional oxygen therapy (COT). Data Sources: MEDLINE, Embase, and CINAHL Complete through May 2022. Study Selection: Randomized clinical trials that enrolled critically ill children receiving invasive mechanical ventilation for more than 24 hours and compared the efficacy of different modes of postextubation NRS. Data Extraction and Synthesis: Random-effects models were fit using a bayesian network meta-analysis framework. Between-group comparisons were estimated using odds ratios (ORs) or mean differences with 95% credible intervals (CrIs). Treatment rankings were assessed by rank probabilities and the surface under the cumulative rank curve (SUCRA). Main Outcomes and Measures: The primary outcome was EF (reintubation within 48 to 72 hours). Secondary outcomes were treatment failure (TF, reintubation plus NRS escalation or crossover to another NRS mode), pediatric intensive care unit (PICU) mortality, PICU and hospital length of stay, abdominal distension, and nasal injury. Results: A total of 11 615 citations were screened, and 9 randomized clinical trials with a total of 1421 participants were included. Both CPAP and HFNC were found to be more effective than COT in reducing EF and TF (CPAP: OR for EF, 0.43; 95% CrI, 0.17-1.0 and OR for TF 0.27, 95% CrI 0.11-0.57 and HFNC: OR for EF, 0.64; 95% CrI, 0.24-1.0 and OR for TF, 0.34; 95% CrI, 0.16- 0.65). CPAP had the highest likelihood of being the best intervention for both EF (SUCRA, 0.83) and TF (SUCRA, 0.91). Although not statistically significant, BiPAP was likely to be better than COT for preventing both EF and TF. Compared to COT, CPAP and BiPAP were reported as showing a modest increase (approximately 3%) in nasal injury and abdominal distension. Conclusions and Relevance: The studies included in this systematic review and network meta-analysis found that compared with COT, EF and TF rates were lower with modest increases in abdominal distension and nasal injury. Of the modes evaluated, CPAP was associated with the lowest rates of EF and TF.

A Network Meta-analysis of Dexamethasone for Preventing Postextubation Upper Airway Obstruction in Children.

Rationale: Periextubation corticosteroids are commonly used in children to prevent upper airway obstruction (UAO). However, the best timing and dose combination of corticosteroids is unknown. Objectives: To compare effectiveness of different corticosteroid regimens in preventing UAO and reintubation. Methods: MEDLINE, CINAHL, and Embase search identified randomized trials in children using corticosteroids to prevent UAO. All studies used dexamethasone. The studies were categorized based on timing of initiation of dexamethasone (early use: >12 h before extubation) and the dose (high dose: ⩾0.5 mg/kg/dose). We performed Bayesian network meta-analysis with studies grouped into four regimens: high dose, early use (HE); low dose, early use (LE); high dose, late use (HL); and low dose, late use. Results: Eight trials (n = 903) were included in the analysis. For preventing UAO (odds ratio; 95% credible interval), HE (0.13; 0.04-0.36), HL (0.39; 0.19-0.74), and LE (0.15; 0.04-0.58) regimens appear to be more effective than no dexamethasone (low certainty). HE and LE had the highest probability of being the top-ranked regimens for preventing UAO (surface under the cumulative ranking curve 0.901 and 0.808, respectively). For preventing reintubation, the effect estimate was imprecise for all four dexamethasone regimens compared with no dexamethasone (very low certainty). HE and LE were the top-ranked regimens (surface under the cumulative ranking curve 0.803 and 0.720, respectively) for preventing reintubation. Sensitivity analysis showed that regimens that started >12 hours before extubation were likely more effective than regimens started >6 hours before extubation. Conclusions: Periextubation dexamethasone can prevent postextubation UAO in children, but effectiveness is highly dependent on timing and dosing regimen. Early initiation (ideally >12 h before extubation) appears to be more important than the dose of dexamethasone. Ultimately, the specific steroid strategy should be personalized, considering the potential for adverse events associated with dexamethasone and the individual risk of UAO and reintubation.

Executive Summary: International Clinical Practice Guidelines for Pediatric Ventilator Liberation, A Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Document.

Rationale: Pediatric-specific ventilator liberation guidelines are lacking despite the many studies exploring elements of extubation readiness testing. The lack of clinical practice guidelines has led to significant and unnecessary variation in methods used to assess pediatric patients' readiness for extubation. Methods: Twenty-six international experts comprised a multiprofessional panel to establish pediatrics-specific ventilator liberation clinical practice guidelines, focusing on acutely hospitalized children receiving invasive mechanical ventilation for more than 24 hours. Eleven key questions were identified and first prioritized using the Modified Convergence of Opinion on Recommendations and Evidence. A systematic review was conducted for questions that did not meet an a priori threshold of ⩾80% agreement, with Grading of Recommendations, Assessment, Development, and Evaluation methodologies applied to develop the guidelines. The panel evaluated the evidence and drafted and voted on the recommendations. Measurements and Main Results: Three questions related to systematic screening using an extubation readiness testing bundle and a spontaneous breathing trial as part of the bundle met Modified Convergence of Opinion on Recommendations criteria of ⩾80% agreement. For the remaining eight questions, five systematic reviews yielded 12 recommendations related to the methods and duration of spontaneous breathing trials, measures of respiratory muscle strength, assessment of risk of postextubation upper airway obstruction and its prevention, use of postextubation noninvasive respiratory support, and sedation. Most recommendations were conditional and based on low to very low certainty of evidence. Conclusions: This clinical practice guideline provides a conceptual framework with evidence-based recommendations for best practices related to pediatric ventilator liberation.

Operational Definitions Related to Pediatric Ventilator Liberation.

BACKGROUND: Common, operational definitions are crucial to assess interventions and outcomes related to pediatric mechanical ventilation. These definitions can reduce unnecessary variability among research and quality improvement efforts, to ensure findings are generalizable, and can be pooled to establish best practices. RESEARCH QUESTION: Can we establish operational definitions for key elements related to pediatric ventilator liberation using a combination of detailed literature review and consensus-based approaches? STUDY DESIGN AND METHODS: A panel of 26 international experts in pediatric ventilator liberation, two methodologists, and two librarians conducted systematic reviews on eight topic areas related to pediatric ventilator liberation. Through a series of virtual meetings, we established draft definitions that were voted upon using an anonymous web-based process. Definitions were revised by incorporating extracted data gathered during the systematic review and discussed in another consensus meeting. A second round of voting was conducted to confirm the final definitions. RESULTS: In eight topic areas identified by the experts, 16 preliminary definitions were established. Based on initial discussion and the first round of voting, modifications were suggested for 11 of the 16 definitions. There was significant variability in how these items were defined in the literature reviewed. The final round of voting achieved ≥ 80% agreement for all 16 definitions in the following areas: what constitutes respiratory support (invasive mechanical ventilation and noninvasive respiratory support), liberation and failed attempts to liberate from invasive mechanical ventilation, liberation from respiratory support, duration of noninvasive respiratory support, total duration of invasive mechanical ventilation, spontaneous breathing trials, extubation readiness testing, 28 ventilator-free days, and planned vs rescue use of post-extubation noninvasive respiratory support. INTERPRETATION: We propose that these consensus-based definitions for elements of pediatric ventilator liberation, informed by evidence, be used for future quality improvement initiatives and research studies to improve generalizability and facilitate comparison.

The Impact of Enriched Resistant Starch Type-2 Cookies on the Gut Microbiome in Hemodialysis Patients: A Randomized Controlled Trial.

INTRODUCTION: Resistant starch type-2 (RS2) can mitigate inflammation and oxidative stress in hemodialysis (HD) patients. However, there is still a lack of knowledge on the impact of the RS2 on the gut microbiota community in these patients. Thus, this study aims to evaluate the effects of enriched RS2 cookies on the gut microbiome in HD patients. METHODS AND RESULTS: This comprises a randomized, double-blind, placebo-controlled trial of age-, sex-, and BMI-matched patients and controls. The RS2 group receives enriched RS2 cookies (16 g d-1 of Hi-Maize 260, Ingredion) for 4 weeks, while the placebo group received cookies made with manioc flour. Fecal microbiota composition is evaluated by the 16S ribosomal RNA gene. Analysis of the microbiota reveals that Pielou's evenness is significantly decreased after RS2 supplementation. Notably, it is observed that RS2 intervention upregulates significantly 8 Amplicon Sequencing Variants (ASV's), including Roseburia and Ruminococcus gauvreauii, which are short-chain fatty acids (SCFA) producers. Furthermore, it is associated with the downregulation of 11 ASVs, such as the pro-inflammatory Dialister. CONCLUSIONS: RS2 intervention for 4 weeks in HD patients effectively alters SCFA producers in the gut microbiota, suggesting that it could be a good nutritional strategy for patients with chronic kidney disease (CKD) on HD.

Socioeconomic position links circulatory microbiota differences with biological age.

Imbalanced nutrition is associated with accelerated ageing, possibly mediated by microbiota. An analysis of the circulatory microbiota obtained from the leukocytes of participants in the MRC Twenty-07 general population cohort was performed. We now report that in this cohort, the most biologically aged exhibit a significantly higher abundance of circulatory pathogenic bacteria, including Neisseria, Rothia and Porphyromonas, while those less biologically aged possess more circulatory salutogenic (defined as being supportive of human health and wellbeing) bacteria, including Lactobacillus, Lachnospiraceae UCG-004 and Kocuria. The presence of these salutogenic bactreria is consistent with a capacity to metabolise and produce Nrf2 agonists. We also demonstrate that associated one carbon metabolism, notably betaine levels, did not vary with chronological age, but displayed a difference with socioeconomic position (SEP). Those at lower SEP possessed significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group. Our data suggest a clear route to improving age related health and resilience based on dietary modulation of the microbiota.

Potential Benefit With Complementary and Alternative Medicine in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) may pursue complementary and alternative medicine (CAM). We conducted a comprehensive systematic review and meta-analysis examining efficacy of CAM vs. placebo or sham in adults with IBS. METHODS: Publication databases were searched for randomized controlled trials of CAM therapies (herbal therapy, dietary supplements, mind-body based, body-based, and energy-healing) in adults with IBS. Data were extracted to obtain pooled estimates of mean improvement in abdominal pain (standardized mean difference [SMD]) and relative risk (RR) of overall response using random effects models. Sensitivity and subgroup analyses along with quality assessments were completed. RESULTS: Among 2825 articles identified, 66 were included. Herbal therapy (SMD=0.47, 95% CI: 0.20 to 0.75, I2=82%) demonstrated significant benefit over placebo for abdominal pain (low confidence in estimates). Benefit with mind-body based therapy for abdominal pain was of borderline significance (SMD=0.29, 95% CI: -0.01 to 0.59, I2=78%). Herbal therapy (RR=1.57, 95% CI: 1.31 to 1.88, I2=77%), dietary supplements (RR=1.95, 95% CI: 1.02 to 3.73, I2=75%), and mind-body based therapy (RR=1.67, 95% CI: 1.13 to 2.49, I2=63%) showed benefit for overall response compared to placebo (low confidence in estimates). Body-based and energy healing therapies demonstrated no significant benefit over placebo or sham for abdominal pain or overall response. CONCLUSIONS: CAM therapies such as herbal or dietary supplements and mind-body based approaches may be beneficial for abdominal pain and overall response in IBS. However, overall quality of evidence is low. Rigorous, high quality clinical trials are warranted to investigate CAM in IBS.

Perspectives on Colon Cancer Screening-A Physician Panel Discussion for Preclinical Medical Students.

Introduction: Colon cancer is the third most common cancer in the US, and the survival rate improves drastically with early detection. It is important for medical students to understand screening options, and to be able to effectively discuss these options with their patients. While basic information about colon cancer screening is ubiquitous in US medical school curricula, no published curricula describe teaching students the nuances of negotiating this discussion with patients and tailoring screening to individual patients' needs. Methods: We developed a 90-minute session for second-year medical students as part of a gastroenterology and nutrition course. We provided a short lecture on colon cancer screening. We then had a panel of practicing gastroenterologists and a primary care physician discuss their approaches to six hypothetical cases. The students reflected in writing on what they learned from the session and on their opinions of the session format. Results: Of second-year medical students, 139 attended the session and 110 submitted written reflections on the session (79% response rate). The students perceived significant gains in knowledge, communication skills, and attitudes around the discussions. Discussion: This expert panel session taught medical students knowledge and communication skills related to colon cancer screening. The session could be easily implemented at any medical school, either at the preclinical or clinical level.

Genetic Testing and Counseling in Metabolic Liver Disease: An Interactive Lecture for Medical Students.

Introduction: Medical students have limited opportunities to learn about current genetic testing. This session provided exposure to different types of testing and the complex issues that physicians may encounter when counseling patients on proper testing and interpreting results. Methods: We designed a 1-hour interactive lecture for second-year medical students. We presented an overview of the topic, then applied the concepts to specific disorders and cases. Students were asked to answer questions regarding cases using an audience response system, and we used their responses as the basis for our in-class discussion. This session has been held twice, with 25 students attending in 2018 and 31 students in 2019. The session was also recorded so that additional students not in attendance could watch, and was available to 151 students in 2018 and 333 students in 2019. Results: Students answered questions via audience response system. There was a range of 47%-100% of students giving the correct answers in 2018, and 55%-93% in 2019. Exam questions covering genetic counseling issues were answered correctly by 66% and 77% of students in 2018, and 70% and 68% of students in 2019. Discussion: This session provided an opportunity for medical students to be exposed to some of the complex ethical and psychosocial issues that may arise with genetic testing for liver disease and to consider how to navigate them. Using an audience response system during the lecture made the session more interactive and allowed the teacher to correct errors and teach based on the responses.

Drug-Induced Liver Injury Module for Medical Students.

Introduction: No published curricula exist to introduce medical students to drug-induced liver injury (DILI). However, DILI is the most common cause of acute liver failure in the US, and drug-drug interactions are tested on the USMLE Step 1. Methods: We developed an independent study module to introduce students to DILI. This module consisted of a narrated PowerPoint introduction, a journal article, and four example cases. Students completed the module independently. To evaluate the effectiveness of the activity, exam data and responses to the cases were reviewed, and end-of-course survey data were used. These responses were used to modify questions for clarity and to develop a feedback rubric. Results: Mean scores on case-related questions in the module ranged from 44% to 73%. However, mean scores on test questions related to DILI ranged from 61% to 98%. It is possible that students learned from receiving feedback in the form of correct answers to the cases. On course evaluations, 52.4% of students agreed or strongly agreed that the online modules as a group (which included the DILI module) were an effective teaching method. Discussion: This module introduces students to DILI and enables them to interact with valuable resources. We hope that modifications will improve the learning experience and effectiveness of the module. Going forward, we plan to collect validity evidence for the feedback rubric and develop an advanced version of the module for gastroenterology fellows.

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape.

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.