Effects of bowel preparation on intestinal bacterial associated urine and faecal metabolites and the associated faecal microbiome.

BACKGROUND: Urinary and faecal metabolic profiling have been extensively studied in gastrointestinal diseases as potential diagnostic markers, and to enhance our understanding of the intestinal microbiome in the pathogenesis these conditions. The impact of bowel cleansing on the microbiome has been investigated in several studies, but limited to just one study on the faecal metabolome. AIM: To compare the effects of bowel cleansing on the composition of the faecal microbiome, and the urine and faecal metabolome. METHODS: Urine and faecal samples were obtained from eleven patients undergoing colonoscopy at baseline, and then at day 3 and week 6 after colonoscopy. 16S rRNA gene sequencing was used to analyse changes in the microbiome, and metabonomic analysis was performed using proton nuclear magnetic resonance (1H NMR) spectroscopy. RESULTS: Microbiomic analysis demonstrated a reduction in alpha diversity (Shannon index) between samples taken at baseline and three days following bowel cleansing (p = 0.002), and there was no significant difference between samples at baseline and six weeks post colonoscopy. Targeted and non-targeted analysis of urinary and faecal bacterial associated metabolites showed no significant impact following bowel cleansing. CONCLUSIONS: Bowel cleansing causes a temporary disturbance in bacterial alpha diversity measured in faeces, but no significant changes in the faecal and urine metabolic profiles, suggesting that overall the faecal microbiome and its associated metabolome is resistant to the effects of an induced osmotic diarrhoea.

Safety and clinical outcomes of outpatient parenteral antibiotic therapy for infective endocarditis in Christchurch, New Zealand: A retrospective cohort study.

OBJECTIVES: We examined the safety and clinical outcomes of outpatient parenteral antibiotic therapy (OPAT) for patients with infective endocarditis (IE) in Christchurch, New Zealand. METHODS: Demographic and clinical data were collected from all adult patients treated for IE over 5 years. Outcomes were stratified by receipt of at least partial OPAT vs entirely hospital-based parenteral therapy. RESULTS: There were 172 episodes of IE between 2014 and 2018. OPAT was administered in 115 cases (67%) for a median of 27 days after a median of 12 days of inpatient treatment. In the OPAT cohort, viridans group streptococci were the commonest causative pathogens (35%) followed by Staphylococcus aureus (25%) and Enterococcus faecalis (11%). There were six (5%) antibiotic-related adverse events and 26 (23%) readmissions in the OPAT treatment group. Mortality in OPAT patients was 6% (7/115) at 6 months and 10% (11/114) at 1 year and for patients receiving wholly inpatient parenteral therapy was 56% (31/56) and 58% (33/56), respectively. Three patients (3%) in the OPAT group had a relapse of IE during the 1-year follow-up period. CONCLUSION: OPAT can be used safely in patients with IE, even in selected cases with complicated or difficult-to-treat infections.

Repetitive, but Not Single, Mild Blast TBI Causes Persistent Neurological Impairments and Selective Cortical Neuronal Loss in Rats.

Exposure to repeated mild blast traumatic brain injury (mbTBI) is common in combat soldiers and the training of Special Forces. Evidence suggests that repeated exposure to a mild or subthreshold blast can cause serious and long-lasting impairments, but the mechanisms causing these symptoms are unclear. In this study, we characterise the effects of single and tightly coupled repeated mbTBI in Sprague-Dawley rats exposed to shockwaves generated using a shock tube. The primary outcomes are functional neurologic function (unconsciousness, neuroscore, weight loss, and RotaRod performance) and neuronal density in brain regions associated with sensorimotor function. Exposure to a single shockwave does not result in functional impairments or histologic injury, which is consistent with a mild or subthreshold injury. In contrast, exposure to three tightly coupled shockwaves results in unconsciousness, along with persistent neurologic impairments. Significant neuronal loss following repeated blast was observed in the motor cortex, somatosensory cortex, auditory cortex, and amygdala. Neuronal loss was not accompanied by changes in astrocyte reactivity. Our study identifies specific brain regions particularly sensitive to repeated mbTBI. The reasons for this sensitivity may include exposure to less attenuated shockwaves or proximity to tissue density transitions, and this merits further investigation. Our novel model will be useful in elucidating the mechanisms of sensitisation to injury, the temporal window of sensitivity and the evaluation of new treatments.

Rectal swabs as a viable alternative to faecal sampling for the analysis of gut microbiota functionality and composition.

Faecal or biopsy samples are frequently used to analyse the gut microbiota, but issues remain with the provision and collection of such samples. Rectal swabs are widely-utilised in clinical practice and previous data demonstrate their potential role in microbiota analyses; however, studies to date have been heterogenous, and there are a particular lack of data concerning the utility of swabs for the analysis of the microbiota's functionality and metabolome. We compared paired stool and rectal swab samples from healthy individuals to investigate whether rectal swabs are a reliable proxy for faecal sampling. There were no significant differences in key alpha and beta diversity measures between swab and faecal samples, and inter-subject variability was preserved. Additionally, no significant differences were demonstrated in abundance of major annotated phyla. Inferred gut functionality using Tax4Fun2 showed excellent correlation between the two sampling techniques (Pearson's coefficient r = 0.9217, P < 0.0001). Proton nuclear magnetic resonance (1H NMR) spectroscopy enabled the detection of 20 metabolites, with overall excellent correlation identified between rectal swab and faecal samples for levels all metabolites collectively, although more variable degrees of association between swab and stool for levels of individual metabolites. These data support the utility of rectal swabs in both compositional and functional analyses of the gut microbiota.

Impact of COVID-19 mitigations on anxiety and depression amongst university students: A systematic review and meta-analysis.

Background: While much research has addressed mental health concerns related to the coronavirus disease 2019 (COVID-19) pandemic, there remains a scarcity of studies specifically exploring the changes in anxiety and depression among university students before and after the implementation of COVID-19 mitigation measures. Methods: In this systematic review and meta-analysis, we searched databases including MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), CINAHL (EBSCO), ERIC (EBSCO), the WHO COVID-19 database, Scopus, and Science Citation Index (Web of Science) as of 15 February 2023. We included studies that used a validated tool to measure changes in anxiety or depression at two distinct time points - before (T1) and during (T2); during (T2) and after (T3); or before (T1) and after (T3) COVID-19 mitigation. The quality of studies was assessed using an adapted Joanna Briggs Institute Checklist for longitudinal studies. Utilising random-effects models, we synthesised changes in continuous outcomes as standardised mean difference (SMD) with 95% confidence interval (CI) and binary outcomes as risk difference (RD) with 95% CI. Results: In total, 15 studies were included in this review, with eight of moderate and seven of high quality. In most of the included studies (n = 13), the majority of participants were women. Eleven studies analysed mental health outcomes between T1 and T2 of COVID-19 mitigations. Continuous symptom changes were a minimal or small improvement for anxiety (SMD = -0.03, 95% CI = -0.24 to 0.19, I2 = 90%); but worsened for depression (SMD = 0.26, 95% CI = -0.01 to 0.62). However, the proportions of students reporting moderate-to-severe symptoms, defined by specific cut-offs, increased during COVID-19 mitigation measures for both anxiety (RD = 0.17, 95% CI = -0.04 to 0.38, I2 = 95%) and depression (RD = 0.12, 95% CI = 0.03 to 0.22, I2 = 72%). Sensitivity analyses, which distinguished between baseline periods based on awareness of COVID-19, demonstrated an exacerbation of both symptoms when comparing the period before the global awareness of the COVID-19 outbreak (before December 2019) with the period during the implementation of mitigation measures. Conclusions: Mental health outcomes, especially depressive symptoms, were observed to worsen in university students during COVID-19 mitigations. Despite considerable heterogeneity requiring careful interpretation of results, the impact of COVID-19 mitigations on mental health in university students is evident. Registration: PROSPERO (CRD42021266889).

Systematic review: the association between the gut microbiota and medical therapies in inflammatory bowel disease.

BACKGROUND: The gut microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD), with Faecalibacterium prausnitizii associated with protection, and certain genera (including Shigella and Escherichia) associated with adverse features. The variability of patient response to medical therapies in IBD is incompletely understood. Given the recognised contribution of the microbiota to treatment efficacy in other conditions, there may be interplay between the gut microbiota, IBD medical therapy and IBD phenotype. AIMS: To evaluate the bidirectional relationship between IBD medical therapies and the gut microbiota. METHODS: We conducted a systematic search of MEDLINE and EMBASE. All original studies analysing interactions between the gut microbiota and established IBD medical therapies were included. RESULTS: We screened 1296 records; 19 studies were eligible. There was heterogeneity in terms of sample analysis, treatment protocols, and outcome reporting. Increased baseline α-diversity was observed in responders versus non-responders treated with exclusive enteral nutrition (EEN), infliximab, ustekinumab or vedolizumab. Higher baseline Faecalibacterium predicted response to infliximab and ustekinumab. A post-treatment increase in Faecalibacterium prausnitzii was noted in responders to aminosalicylates, anti-TNF medications and ustekinumab; conversely, this species decreased in responders to EEN. Escherichia was a consistent marker of unfavourable drug response, and its presence in the gut mucosa correlated with inflammation in aminosalicylate-treated patients. CONCLUSIONS: Both gut microbiota diversity and specific taxonomic features (including high abundance of Faecalibacterium) are associated with the efficacy of a range of IBD therapies. These findings hold promise for a potential role for the gut microbiota in explaining the heterogeneity of patient response to IBD treatments.

Metabolomic Analysis in Inflammatory Bowel Disease: A Systematic Review.

BACKGROUND AND AIMS: The inflammatory bowel diseases [IBD], Crohn's disease and ulcerative colitis, are chronic, idiopathic gastrointestinal diseases. Although their precise aetiology is unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, probably microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics [the study of small molecular intermediates and end products of metabolism in biological samples] provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in IBD populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings. METHODS: A comprehensive, systematic search was carried out using Medline and Embase. All studies were reviewed by two authors independently using predefined exclusion criteria. Sixty-four relevant papers were assessed for quality and included in the review. RESULTS: Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine [such as hippurate] and stool [such as secondary bile acids] samples. CONCLUSIONS: This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian-microbial co-metabolism associated with disease status.

Inflammatory Bowel Disease Outcomes Following Fecal Microbiota Transplantation for Recurrent C. difficile Infection.

BACKGROUND: Recurrent Clostridioides difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is a clinical challenge. Fecal microbiota transplantation (FMT) has emerged as a recurrent CDI therapy. Anecdotal concerns exist regarding worsening of IBD activity; however, prospective data among IBD patients are limited. METHODS: Secondary analysis from an open-label, prospective, multicenter cohort study among IBD patients with 2 or more CDI episodes was performed. Participants underwent a single FMT by colonoscopy (250 mL, healthy universal donor). Secondary IBD-related outcomes included rate of de novo IBD flares, worsening IBD, and IBD improvement-all based on Mayo or Harvey-Bradshaw index (HBI) scores. Stool samples were collected for microbiome and targeted metabolomic profiling. RESULTS: Fifty patients enrolled in the study, among which 15 had Crohn's disease (mean HBI, 5.8 ± 3.4) and 35 had ulcerative colitis (mean partial Mayo score, 4.2 ± 2.1). Overall, 49 patients received treatment. Among the Crohn's disease cohort, 73.3% (11 of 15) had IBD improvement, and 4 (26.6%) had no disease activity change. Among the ulcerative colitis cohort, 62% (22 of 34) had IBD improvement, 29.4% (11 of 34) had no change, and 4% (1 of 34) experienced a de novo flare. Alpha diversity significantly increased post-FMT, and ulcerative colitis patients became more similar to the donor than Crohn's disease patients (P = 0.04). CONCLUSION: This prospective trial assessing FMT in IBD-CDI patients suggests IBD outcomes are better than reported in retrospective studies.

Outpatient parenteral antimicrobial therapy (OPAT) in Christchurch: 18 years on.

AIM: Outpatient parenteral antimicrobial therapy (OPAT) has become an established option for management infections requiring intravenous therapy. As the uptake of OPAT has increased, the clinical governance has changed and is now managed via virtual clinics and increased use of district nurses in addition to specialist outpatient review. The aim of this study was to report the characteristics, diagnoses, treatment and outcomes of patients managed by the service over 12 months in 2015/6 and compared these features with those of patients treated with OPAT in 1999. METHODS: Cases for 2015/6 were identified from the OPAT service database which records prospectively all information on diagnosis, antibiotic choice and duration of treatment, complications and requirement for review by the ID physicians and OPAT nurses prospectively. The outcomes, complications and readmissions were found by reviewing computerised records of Christchurch Hospital. All results were entered into a Microsoft® Excel database for analysis. Statistical analyses were performed using OpenEpi software. Data for 1999 was taken from an earlier publication. RESULTS: OPAT treatment in 12 months from 1 July 2015 was administered 407 times to 385 patients, which represented a 2.7 times increase in treatment courses than in 1999. The median age was 55 years in 1999 and 61 in 2015/6. There was a substantial increase in the proportion of bone and joint, abdominal and urinary tract infections but a fall in cellulitis and soft tissue infection. The number and proportion of patients treated with broad spectrum agents including piperacillin + tazobactam, ceftriaxone and carbapenems increased from 1% in 1999 to 20% in 2015/6. Unplanned readmission to hospital increased from 15 (10%) in 1999 to 62 patients (15%) in 2015/6. The most common reason for readmission in 2015/6 was for ongoing symptoms or progression of the infection requiring OPAT. Eight patients (2%) required readmission from adverse reactions to antimicrobial therapy. Two patients on palliative care died while on OPAT and 35 (9%) within 12 months of the index admission. CONCLUSION: OPAT use has increased and is used to treat patients with comorbidities, who are older, and with a different case-mix than 1999. Safety has not been compromised but the risk of treatment failure has increased. A better understanding of the reasons for treatment failure would improve patient selection and management with OPAT.

Native Joint Septic Arthritis: Epidemiology, Clinical Features, and Microbiological Causes in a New Zealand Population.

OBJECTIVE: To determine the epidemiology, clinical features, and microbiology of adult native joint septic arthritis in Canterbury, New Zealand, over a 5-year period in individuals with and without an underlying rheumatic disorder. METHODS: Patients with native joint septic arthritis were identified retrospectively and classified by Newman's criteria. The clinical characteristics were described and comparisons made between those with and without underlying rheumatic disease. RESULTS: Two hundred forty-eight cases of native joint septic arthritis (mean age 60, range 16-97 yrs) were identified with an overall incidence rate of 12.0/100,000/year (95% CI 10.6-13.6). Yearly incidence increased with age to a maximum of 73.4/100,000 in those > 90 years of age. Septic arthritis was iatrogenic in 16.9% of cases while 27% had an underlying inflammatory arthritis including gout (14.9%), calcium pyrophosphate disease (8.5%), and rheumatoid arthritis (4%). Few patients were taking immunosuppressant therapy, with just 1 taking a biological agent. Staphylococcus aureus was the most commonly identified organism. Those with underlying inflammatory arthritis were significantly older (73.6 yrs vs 55.6 yrs; p < 0.001), more likely to be female (55.2% vs 26.0%; p < 0.001), and to have septic polyarthritis (16.4% vs 4.4%; p = 0.002). The 30-day mortality was 2%, increasing to 6% at 90 days. CONCLUSION: The incidence of septic arthritis in Canterbury, New Zealand, is higher than in previous studies. Crystal arthropathy commonly coexisted with infection although autoimmune arthritis and immunosuppression was less of a factor than anticipated.

Home intravenous antimicrobial service--twelve months experience in Christchurch.

AIM: To review the clinical practice and complications of the home intravenous antimicrobial service at Christchurch Hospital after twelve months of full operation. METHODS: Clinical and microbiological diagnoses, antimicrobial therapy, and complications of home intravenous antimicrobial therapy were entered prospectively on an Excel data base. RESULTS: Of the 153 patients, 113 (74%) suffered from skin, soft tissue or bone and joint disease. A bacteriological diagnosis was made in 108 patients (71%). 119 patients were treated with the narrow spectrum agents--penicillin 20 (13%), flucloxacillin 55 (36%) and cephazolin 44 (29%). Ceftriaxone was used for treatment in fifteen (10%) patients. Peripherally inserted central catheters (PICC's) were used in 129 patients, midlines fifteen, peripheral angiocaths in eight, and a Portacath in one. An elastomeric infusion device was used in 80 patients and an infusion pump in 34. Complications developed in 31 (20%) patients including three infections and one jugular vein thrombosis. Fifteen patients (10%) were readmitted within one month of discharge. CONCLUSIONS: The home intravenous therapy programme successfully used first line narrow spectrum agents initiated in hospital with avoidance of unnecessary broad spectrum agents. Complication rates were acceptable and likely to improve with experience in patient selection and provision of support services.

Outpatient intravenous treatment for infective endocarditis: safety, effectiveness and one-year outcomes.

OBJECTIVES: To describe the use and outcomes of outpatient antimicrobial therapy (OPAT) for infective endocarditis (IE) within the Canterbury region of New Zealand over an 8 year period. METHODS: All cases of IE admitted to Christchurch Hospital were reviewed. Prospectively collected data from our OPAT service's database and retrospective data from case notes were analysed. RESULTS: There were 213 episodes of IE meeting modified Duke Criteria over this time. Patients received OPAT in 100 episodes. Viridans streptococci were the infecting organism in 34, Staphylococcus aureus in 27, and enterococci in 10. Adverse events were encountered in 27 episodes. Of these, 24 were related to intravenous lines, infusion devices or adverse drug reactions which resolved with change of treatment. There were 3 serious adverse events which were likely to have occurred in hospital. During 12-month follow-up there were 5 further episodes of IE and 2 deaths unlikely to be directly related to the episode of IE. CONCLUSIONS: Despite significant co-morbidities and complications, nearly half of all patients with IE, including those with disease due to S. aureus and enterococci, successfully completed their treatment as outpatients. Continuous infusion devices were successfully used in 32 patients, including 22 with disease due to S. aureus.

Protein binding of cefazolin is saturable in vivo both between and within patients.

AIMS: The aims of the study were a) to determine if there is evidence of saturable protein binding of cefazolin in plasma across the range of concentrations achieved clinically (between patient variability) and b) to investigate whether saturable protein binding is also evident from trough and peak concentrations in the same patient (within patient variability). METHODS: Unbound and total plasma concentrations were measured in patients who were treated with cefazolin intravenously by continuous infusion or intermittent injection. In study (i) single random samples were taken from one series of patients. In study (ii) paired samples (troughs and peaks) were taken from a second series of patients. RESULTS: Thirty-one patients were included in study (i). Linear regression analysis of the percentage unbound vs. unbound plasma concentrations revealed a slope significantly different from zero, suggesting saturable protein binding. Mean values for percentage unbound ranged from 9% at low concentrations (8.5 mg l(-1)) to 51% at high concentrations (140 mg l(-1)). Twelve patients were investigated in study (ii). Values for protein binding ranged from 85% at low concentrations (2.7 mg l(-1)) to 52% at high concentrations (200.3 mg l(-1)). The percentage unbound was significantly higher (P < 0.0001) at high (peak) concentrations than at lower (trough) concentrations, confirming saturable protein binding. CONCLUSIONS: The protein binding of cefazolin is saturable in vivo in humans, both between and within patients.

Stability of benzylpenicillin during continuous home intravenous therapy.

OBJECTIVES: The aim of this study was to investigate the temperature profile of home intravenous (iv) antibiotic reservoirs and the stability of 16 megaunits of benzylpenicillin sodium in 120 mL of sodium chloride 0.9% at constant and variable temperatures. METHODS: A Tinytag computerized thermometer recorded temperatures every minute in the home iv antibiotic reservoir pouches of nine patients over a 24 h period. Similar bags containing benzylpenicillin sodium (16 megaunits) were maintained either at a constant 36 degrees C, 26 degrees C or 21-22 degrees C or were worn in a pouch by five healthy volunteers for a 24 h period. Other bags were stored at 3-5 degrees C for 10 days. The bags were sampled at timed intervals and benzylpenicillin concentrations assayed by HPLC. RESULTS: Median temperatures recorded in the infusion bags worn by the nine patients were in the range 16.7-34.1 degrees C. For infusion bags maintained at 36 degrees C, 26 degrees C and 21-22 degrees C, the concentrations of benzylpenicillin dropped below 90% of the initial concentration at a mean time of 5 h 18 min, 12 h 54 min and 13 h 20 min, respectively, whereas for bags worn by the healthy volunteers the mean time for 10% loss of benzylpenicillin was 9 h 20 min. In contrast, at 3-5 degrees C, concentrations of benzylpenicillin only dropped below 90% of the initial concentration at 8 days. CONCLUSIONS: Significant temperature-dependent degradation of benzylpenicillin occurs during continuous home iv antibiotic programme infusions, which could result in loss of efficacy.