Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF

Circulation, Ahead of Print. BACKGROUND:A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction).METHODS:In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSEs score of ≥3 points), cognitive impairment (MMSE score

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Mendelian randomisation analysis reveals the possible causal relationship between infections, microbiota and clinical disease

We read with interest the recent report by Nashed et al that described changes in the microbiota caused by viral infections, which in turn affected the severity of the clinical disease.1–4 Interactions between viral infections and microbiota complicate their relationship with host immunity and clinical diseases. However, it is unclear whether those associations are causal. Furthermore, the interactions between the microbiota and infections, as well as the outcomes of those interactions, have only been studied to a limited extent.5–8 We conducted an in-depth statistical analysis based on two-sample bidirectional Mendelian randomisation (MR) to broaden our understanding and provide a comprehensive assessment of the causal relationship between 9 common infections, 140 microbes and 38 clinical diseases. As instrumental variables for MR analysis, independent genetic variants with genome-wide suggestive significance (p

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Proton pump inhibitors alter gut microbiota by promoting oral microbiota translocation: a prospective interventional study

Background
The mechanism by which proton pump inhibitors (PPIs) alter gut microbiota remains to be elucidated. We aimed to learn whether PPI induced gut microbiota alterations by promoting oral microbial translocation.

Methods
Healthy adult volunteers were randomly assigned: PP group (n=8, 40 mg esomeprazole daily for seven days) and PM group (n=8, 40 mg esomeprazole along with chlorhexidine mouthwash after each meal for seven days). Fecal and saliva samples were analysed using 16S ribosomal RNA sequencing. Mouse models were introduced to confirm the findings in vivo, while the effect of pH on oral bacteria proliferation activity was investigated in vitro.

Results
Taxon-based analysis indicated that PPI administration increased Streptococcus abundance in gut microbiota (P

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Clarithromycin-containing triple therapy for Helicobacter pylori eradication is inducing increased long-term resistant bacteria communities in the gut

The current European guidelines (Maastricht VI/Florence consensus report) on the management of Helicobacter pylori infection1 recommend population-based H. pylori screening programmes for asymptomatic individuals in the general population to eradicate the microorganism for gastric cancer prevention. However, this is expected to result in a considerable increase in antibiotic use2 as half of the global population are estimated to be infected.3 Therefore, the guidelines suggest that caution is required in choosing the appropriate antibiotics to minimise antimicrobial resistance.1 The importance of gut resistome induction following H. pylori eradication therapies has been debated for years, and the available information is controversial; the general thought is that normal gut microbiota is restored 3–6 months after antibiotic treatment.4 Therefore, we conducted a randomised controlled clinical trial as part of the GISTAR study5 in Latvia by evaluating alterations in gut microbiota before…

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Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target

Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.

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The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines

The first British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS)-endorsed faecal microbiota transplant (FMT) guidelines were published in 2018. Over the past 5 years, there has been considerable growth in the evidence base (including publication of outcomes from large national FMT registries), necessitating an updated critical review of the literature and a second edition of the BSG/HIS FMT guidelines. These have been produced in accordance with National Institute for Health and Care Excellence-accredited methodology, thus have particular relevance for UK-based clinicians, but are intended to be of pertinence internationally. This second edition of the guidelines have been divided into recommendations, good practice points and recommendations against certain practices. With respect to FMT for Clostridioides difficile infection (CDI), key focus areas centred around timing of administration, increasing clinical experience of encapsulated FMT preparations and optimising donor screening. The latter topic is of particular relevance given the COVID-19 pandemic, and cases of patient morbidity and mortality resulting from FMT-related pathogen transmission. The guidelines also considered emergent literature on the use of FMT in non-CDI settings (including both gastrointestinal and non-gastrointestinal indications), reviewing relevant randomised controlled trials. Recommendations are provided regarding special areas (including compassionate FMT use), and considerations regarding the evolving landscape of FMT and microbiome therapeutics.

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Compared to histamine-2 receptor antagonist, proton pump inhibitor induces stronger oral-to-gut microbial transmission and gut microbiome alterations: a randomised controlled trial

Objective
We aim to compare the effects of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) on the gut microbiota through longitudinal analysis.

Design
Healthy volunteers were randomly assigned to receive either PPI (n=23) or H2RA (n=26) daily for seven consecutive days. We collected oral (saliva) and faecal samples before and after the intervention for metagenomic next-generation sequencing. We analysed intervention-induced alterations in the oral and gut microbiome including microbial abundance and growth rates, oral-to-gut transmissions, and compared differences between the PPI and H2RA groups.

Results
Both interventions disrupted the gut microbiota, with PPIs demonstrating more pronounced effects. PPI usage led to a significantly higher extent of oral-to-gut transmission and promoted the growth of specific oral microbes in the gut. This led to a significant increase in both the number and total abundance of oral species present in the gut, including the identification of known disease-associated species like Fusobacterium nucleatum and Streptococcus anginosus. Overall, gut microbiome-based machine learning classifiers could accurately distinguish PPI from non-PPI users, achieving an area under the receiver operating characteristic curve (AUROC) of 0.924, in contrast to an AUROC of 0.509 for H2RA versus non-H2RA users.

Conclusion
Our study provides evidence that PPIs have a greater impact on the gut microbiome and oral-to-gut transmission than H2RAs, shedding light on the mechanism underlying the higher risk of certain diseases associated with prolonged PPI use.

Trial registration number
ChiCTR2300072310.

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B and T cell responses to the BNT162b2 COVID-19 mRNA vaccine are not impaired in germ-free or antibiotic-treated mice

As reviewed by us recently,1 an increasing number of studies suggest that the gut microbiota is an important regulator of immune responses to vaccination. Consistent with these data, several recent clinical studies,2–4 including three published in Gut,5–7 uncover correlations between the composition of the faecal/gut microbiota and antibody responses to different COVID-19 vaccines. Additionally, recent antibiotic usage has also been associated with a lower seroconversion rate following BNT162b2 vaccination.8 These studies suggest that the gut microbiota plays a significant role in regulating optimal immune responses to COVID-19 vaccines. Despite these important studies, the causal and mechanistic links between the gut microbiota and responses to COVID-19 vaccines remain to be elucidated. To investigate these links, we turned to two well-established models used previously to assess the relationship between the gut microbiota and responses to…

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An observational study protocol to capture, validate and characterise lucid episodes in people living with advanced dementia receiving hospice care

Introduction
Lucid episodes (LEs) in advanced neurodegenerative disease, characterised by a transient recovery of abilities, have been reported across neurological conditions, including Alzheimer’s disease and related dementias. Evidence on LEs in dementia is extremely limited and draws predominantly from retrospective case reports. Lucidity in dementia has received growing attention given the clinical, caregiving and potential epidemiological implications of even a temporary return of abilities in advanced disease. Following a funding initiative by the National Institute on Aging, several new investigations are focused on establishing foundational evidence on lucidity in dementia. The objectives of this study are to capture, characterise and validate potential LEs via audiovisual observation, computational linguistic and timed-event coding of audiovisual data, and informant case review for face validation of LEs.

Methods and analysis
This prospective multifaceted observational study will investigate LEs in advanced dementia through longitudinal audiovisual observation within an inpatient hospice unit. Audiovisual data will be coded to generate variables of participant verbal output, verbal expressions, non-verbal communicative actions and functional behaviours to enable measurement of features that can be used to characterise LEs. Multiple methods will be used to identify potential LEs including field interviews with caregivers/clinicians who witness significant events during data collection, reports from research staff who witness significant events during data collection and detection by researchers during video data processing procedures. Potential LEs will undergo a structured case review with informants familiar with the participant to facilitate validation and enable triangulation across measures generated through coding.

Ethics and dissemination
This study will be conducted in accordance with all Federal Policies for the Protection of Human Subjects and the protocol (ID 2021-1243) has been approved by the University of Wisconsin-Madison Institutional Review Board. Findings will be disseminated via scientific conferences, journal publications and newsletters shared with participants and through dementia-focused and caregiver-focused networks.

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The Progression of Microbiome Therapeutics for the Management of Gastrointestinal Diseases and Beyond

There has been an increased ability to investigate human microbiota through next generation sequencing and functional assessment. This advancement has rapidly expanded our ability to study and manipulate the gastrointestinal microbiome to mitigate disease. Fecal microbiota transplantation (FMT), a therapy which broadly transfers the entire intestinal ecosystem, has been explored as a potential therapeutic in a variety of gastrointestinal, hepatic and extraintestinal conditions. The field however continues to evolve with a movement towards precision microbiome therapeutics individualizing care for various disorders.

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