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.

Can metabolic profiling provide a new description of osteoarthritis and enable a personalised medicine approach?

Osteoarthritis (OA) is a multifactorial disease contributing to significant disability and economic burden in Western populations. The aetiology of OA remains poorly understood, but is thought to involve genetic, mechanical and environmental factors. Currently, the diagnosis of OA relies predominantly on clinical assessment and plain radiographic changes long after the disease has been initiated. Recent advances suggest that there are changes in joint fluid metabolites that are associated with OA development. If this is the case, biochemical and metabolic biomarkers of OA could help determine prognosis, monitor disease progression and identify potential therapeutic targets. Moreover, for focussed management and personalised medicine, novel biomarkers could sub-stratify patients into OA phenotypes, differentiating metabolic OA from post-traumatic, age-related and genetic OA. To date, OA biomarkers have concentrated on cytokine action and protein signalling with some progress. However, these remain to be adopted into routine clinical practice. In this review, we outline the emerging metabolic links to OA pathogenesis and how an elucidation of the metabolic changes in this condition may provide future, more descriptive biomarkers to differentiate OA subtypes.

Differences in the composition of hip and knee synovial fluid in osteoarthritis: a nuclear magnetic resonance (NMR) spectroscopy study of metabolic profiles.

OBJECTIVE: The hip and knee joints differ biomechanically in terms of contact stresses, fluid lubrication and wear patterns. These differences may be reflected in the synovial fluid (SF) composition of the two joints, but the nature of these differences remains unknown. The objective was to identify differences in osteoarthritic hip and knee SF metabolites using metabolic profiling with Nuclear Magnetic Resonance (NMR) spectroscopy. DESIGN: Twenty-four SF samples (12 hip, 12 knee) were collected from patients with end-stage osteoarthritis (ESOA) undergoing hip/knee arthroplasty. Samples were matched for age, gender, ethnicity and had similar medical comorbidities. NMR spectroscopy was used to analyse the metabolites present in each sample. Principal Component Analysis and Orthogonal Partial Least Squares Discriminant Analysis were undertaken to investigate metabolic differences between the groups. Metabolites were identified using 2D NMR spectra, statistical spectroscopy and by comparison to entries in published databases. RESULTS: There were significant differences in the metabolic profile between the groups. Four metabolites were found in significantly greater quantities in the knee group compared to the hip group (N-acetylated molecules, glycosaminoglycans, citrate and glutamine). CONCLUSIONS: This is the first study to indicate differences in the metabolic profile of hip and knee SF in ESOA. The identified metabolites can broadly be grouped into those involved in collagen degradation, the tricarboxylic acid cycle and oxidative metabolism in diseased joints. These findings may represent a combination of intra and extra-articular factors.

A systematic review of the small molecule studies of osteoarthritis using nuclear magnetic resonance and mass spectroscopy.

OBJECTIVE: To perform a systematic review of the small molecule metabolism studies of osteoarthritis utilising nuclear magnetic resonance (NMR) or mass spectroscopy (MS) analysis (viz., metabolomics or metabonomics), thereby providing coherent conclusions and reference material for future study. METHOD: We applied PRISMA guidelines (PROSPERO 95068) with the following MESH terms: 1. "osteoarthritis" AND ("metabolic" OR "metabonomic" OR "metabolomic" OR "metabolism") 2. ("synovial fluid" OR "cartilage" OR "synovium" OR "serum" OR "plasma" OR "urine") AND ("NMR" or "Mass Spectroscopy"). Databases searched were "Medline" and "Embase". Studies were searched in English and excluded review articles not containing original research. Study outcomes were significant or notable metabolites, species (human or animal) and the Newcastle-Ottawa Score. RESULTS: In the 27 studies meeting the inclusion criteria, there was a shift towards anaerobic and fatty acid metabolism in OA disease, although whether this represents the inflammatory state remains unclear. Lipid structure and composition was altered within disease subclasses including phosphatidyl choline (PC) and the sphingomyelins. Macromolecular proteoglycan destruction was described, but the correlation to disease factors was not demonstrated. Collated results suggested arachidonate signalling pathways and androgen sex hormones as future metabolic pathways for investigation. CONCLUSION: Our meta-analysis demonstrates significant small molecule differences between sample types, between species (such as human and bovine), with potential OA biomarkers and targets for local or systemic therapies. Studies were limited by numbers and a lack of disease correlation. Future studies should use NMR and MS analysis to further investigate large population subgroups including inflammatory arthropathy, OA subclasses, age and joint differences.

Microbiome manipulation with faecal microbiome transplantation as a therapeutic strategy in Clostridium difficile infection.

Faecal microbiome transplantation (FMT) has generated huge recent interest as it presents a potential solution to a significant clinical problem--the increasing incidence of Clostridium difficile infection (CDI). In the short term, however, there remain many practical questions regarding its use, including the optimal selection of donors, material preparation and the mechanics of delivery. In the longer term, enhanced understanding of the mechanisms of action of FMT may potentiate novel therapies, such as targeted manipulation of the microbiome in CDI and beyond.

Performance in the FRCR (UK) Part 2B examination: analysis of factors associated with success.

AIM: To assess factors that influence pass rates and examination scores in the Fellowship of the Royal College of Radiologists (FRCR) 2B examination. MATERIALS AND METHODS: 2238 attempts at the FRCR 2B examination were evaluated between Spring 2006 and Spring 2010. Pass rates and examination scores were analysed by gender and ethnicity, and the influence of factors such as radiology training (UK versus non-UK), sitting (Spring versus Autumn), and the presence of an undergraduate or postgraduate degree were examined. RESULTS: 1571 candidates made 2238 examination attempts, with an overall pass rate of 59.4% (63.1% at first attempt). 66.2% entrants were male; 48.8% attempts were by candidates from a UK radiology training scheme. UK candidates were significantly more likely to pass than non-UK candidates (p < 0.0001). White candidates were more likely to pass at first or second attempt than non-white candidates (p < 0.0001), but when restricted to UK entrants ethnicity did not influence success at first attempt. Overall, females were more successful than males (p < 0.001). Presence of an undergraduate (p = 0.19) or postgraduate (p = 0.80) degree did not affect pass rate at first attempt for UK candidates. However, logistic regression demonstrated that the only significant factor influencing pass rates at first attempt was whether radiology training was undertaken in the UK (p < 0.0001). A trend towards increased pass rates in autumn sittings was seen (p = 0.06), but ethnicity (p = 0.99) and gender (p = 0.41) were not significant factors. CONCLUSION: The FRCR 2B examination is non-discriminatory for UK candidates with respect to gender and ethnicity. Poorer performance of non-UK trained candidates is a consistent outcome in the literature.

CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.

Sarcoidosis and Crohn's disease are heterogeneous systemic diseases characterised by granulomatous inflammation. Caspase recruitment domain (CARD)15 is a major susceptibility gene for Crohn's disease, and specifically for ileal and fibrostenotic subtypes. The C-C chemokine receptor (CCR)5 gene has been associated with both parenchymal pulmonary sarcoidosis and perianal Crohn's disease. This study explored associations between CARD15 polymorphisms, CCR5 haplotype and distinct pulmonary sarcoidosis subtypes. 185 Caucasian sarcoidosis patients were genotyped for CARD15 and CCR5 polymorphisms. The genetic data were compared with 347 healthy controls and were examined for associations with serial pulmonary function tests and chest radiographs. CARD15 genotypes did not differ between the unselected sarcoidosis cohort and controls. However, patients carrying the functional 2104T (702W) polymorphism were more likely to have radiographic stage IV disease at 4-yr follow-up. All patients possessing both CARD15 2104T and CCR5 HHC haplotype had stage IV disease at presentation. Carriage of 2104T was associated with worse forced expiratory volume in 1 s, whereas carriage of the CARD15 1761G (587R) polymorphism was associated with better lung function. For the first time, an association between two CARD15 polymorphisms and specific sarcoidosis phenotypes has been demonstrated, as well as an additive effect of possessing CARD15 2104T and CCR5 HHC haplotype.

Biomimetic reliability strategies for self-healing vascular networks in engineering materials.

Self-healing via a vascular network is an active research topic, with several recent publications reporting the application and optimization of these systems. This work represents the first consideration of the probable failure modes of a self-healing system as a driver for network design. The critical failure modes of a proposed self-healing system based on a vascular network were identified via a failure modes, effects and criticality analysis and compared to those of the human circulatory system. A range of engineering and biomimetic design concepts to address these critical failure modes is suggested with minimum system mass the overall design driver for high-performance systems. Plant vasculature has been mimicked to propose a segregated network to address the risk of fluid leakage. This approach could allow a network to be segregated into six separate paths with a system mass penalty of only approximately 25%. Fluid flow interconnections that mimic the anastomoses of animal vasculatures can be used within a segregated network to balance the risk of failure by leakage and blockage. These biomimetic approaches define a design space that considers the existing published literature in the context of system reliability.

Minimum mass vascular networks in multifunctional materials.

A biomimetic analysis is presented in which an expression for the optimum vessel diameter for the design of minimum mass branching or vascular networks in engineering applications is derived. Agreement with constructal theory is shown. A simple design case is illustrated and application to more complex cases with branching networks of several generations discussed. The analysis is also extended into the turbulent flow regime, giving an optimization tool with considerable utility in the design of fluid distribution systems. The distribution of vessel lengths in different generations was also found to be a useful design variable. Integrating a network into a structure is also discussed. Where it is necessary to adopt a non-optimum vessel diameter for structural integration, it has been shown that small deviations from the minimum mass optimum can be tolerated, but large variations could be expected to produce a punitive and rapidly increasing mass penalty.

Self-healing polymer composites: mimicking nature to enhance performance.

Autonomic self-healing materials, where initiation of repair is integral to the material, are being developed for engineering applications. This bio-inspired concept offers the designer an ability to incorporate secondary functional materials capable of counteracting service degradation whilst still achieving the primary, usually structural, requirement. Most materials in nature are themselves self-healing composite materials. This paper reviews the various self-healing technologies currently being developed for fibre reinforced polymeric composite materials, most of which are bioinspired, inspired by observation of nature. The most recent self-healing work has attempted to mimic natural healing through the study of mammalian blood clotting and the design of vascular networks found in biological systems. A perspective on current and future self-healing approaches using this biomimetic technique is offered. The intention is to stimulate debate outside the engineering community and reinforce the importance of a multidisciplinary approach in this exciting field.

The significance of rectal bleeding after pelvic radiotherapy.

BACKGROUND: Rectal bleeding after pelvic radiotherapy is often attributed to radiation proctitis and patients do not routinely undergo flexible endoscopy. AIMS: To assess the significance of bleeding after radiotherapy. METHODS: We maintained a prospective register of all such patients referred to our endoscopy unit. RESULTS: One hundred and thirty-nine men (median age 70 years; range 31-82), and 32 women (median age 61 years; range 30-81) were referred with rectal bleeding (median 2 years; range 0-21) after pelvic radiotherapy. Primary tumour sites were urological (n = 139), gastrointestinal (n = 7) and gynaecological (n = 25). Ninety patients had bleeding alone; 81 had other symptoms. One hundred and forty-one had typical radiation proctitis; in 65 this was the sole diagnosis; eight had cancer, nine had high-risk adenomas, and six had three or more small adenomas. Ninety-five other diagnoses were made. Eleven (73%) patients with advanced polyps or cancer required only flexible sigmoidoscopy to make the diagnosis, while four (27%) diagnoses were made only after colonoscopy; 47% of these patients had no other symptoms apart from rectal bleeding. CONCLUSIONS: After pelvic radiotherapy, clinical symptoms are not reliable in differentiating between radiation proctitis alone or more significant pathology. It is mandatory that all patients with new onset rectal bleeding are investigated with, at least, flexible sigmoidoscopy.

The role of the biochemistry department in the diagnosis of pituitary apoplexy.

A 47-year-old man presented with severe clinical hypoglycaemia. He had long-standing insulin-dependent diabetes with previously good glycaemic control. Intense headaches and vomiting initiated hospitalization. A brain computed tomography (CT) scan was normal, and a lumbar puncture showed elevated cerebrospinal fluid (CSF) protein [0.67 g/L; normal range (NR) 0.15-0.45 g/L], suggesting resolving viral meningitis. Routine thyroid function tests were abnormal (free thyroxine 10.6 pmol/L, NR 9-22.5 pmol/L; thyroid-stimulating hormone 0.16 mU/L, NR 0.35-5 mU/L). In the absence of evident thyroid therapy, the laboratory policy required an urgent cortisol assay to be added; this was very abnormal (42 nmol/L), suggesting hypopituitarism. Later analysis showed that concentrations of gonadotrophins and adrenocorticotrophin were low. An urgent pituitary magnetic resonance imaging scan revealed an unsuspected pituitary tumour with recent haemorrhage (pituitary apoplexy). The patient was given intravenous hydrocortisone and then stabilized on oral hydrocortisone, thyroxine and mesterolone. He made a full recovery and the hypoglycaemia resolved. The normal brain CT scan was falsely reassuring and the CSF protein was not due to viral meningitis but to haemorrhage into the pituitary tumour. If laboratory policy had not required the urgent cortisol assay be added, the diagnosis of hypopituitarism would have been delayed or even missed altogether. This could have led to the death of the patient.

CCR5, CXCR4, and CD4 are clustered and closely apposed on microvilli of human macrophages and T cells.

The chemokine receptors CCR5 and CXCR4 act synergistically with CD4 in an ordered multistep mechanism to allow the binding and entry of human immunodeficiency virus type 1 (HIV-1). The efficiency of such a coordinated mechanism depends on the spatial distribution of the participating molecules on the cell surface. Immunoelectron microscopy was performed to address the subcellular localization of the chemokine receptors and CD4 at high resolution. Cells were fixed, cryoprocessed, and frozen; 80-nm cryosections were double labeled with combinations of CCR5, CXCR4, and CD4 antibodies and then stained with immunogold. Surprisingly, CCR5, CXCR4, and CD4 were found predominantly on microvilli and appeared to form homogeneous microclusters in all cell types examined, including macrophages and T cells. Further, while mixed microclusters were not observed, homogeneous microclusters of CD4 and the chemokine receptors were frequently separated by distances less than the diameter of an HIV-1 virion. Such distributions are likely to facilitate cooperative interactions with HIV-1 during virus adsorption to and penetration of human leukocytes and have significant implications for development of therapeutically useful inhibitors of the entry process. Although the mechanism underlying clustering is not understood, clusters were observed in small trans-Golgi vesicles, implying that they were organized shortly after synthesis and well before insertion into the cellular membrane. Chemokine receptors normally act as sensors, detecting concentration gradients of their ligands and thus providing directional information for cellular migration during both normal homeostasis and inflammatory responses. Localization of these sensors on the microvilli should enable more precise monitoring of their environment, improving efficiency of the chemotactic process. Moreover, since selectins, some integrins, and actin are also located on or in the microvillus, this organelle has many of the major elements required for chemotaxis.

Substituted 2-aminopyridines as inhibitors of nitric oxide synthases.

A series of substituted 2-aminopyridines was prepared and evaluated as inhibitors of human nitric oxide synthases (NOS). 4,6-Disubstitution enhanced both potency and specificity for the inducible NOS with the most potent compound having an IC50 of 28 nM.

Complications of tibial shaft soccer fractures.

A retrospective study of AO type 42 tibial diaphyseal fractures that presented to a teaching hospital over a 54 month period was made to identify the proportion sustained whilst playing soccer, determine their characteristics and report treatment and outcome. Sport accounts for 73/329 (22.1%) of these fractures and soccer 58/73 (79. 5%) of these. All patients were male with mean age of 24.3 years (range 8-48). Fifty-four fractures were closed and 93.1% (54/58) were situated in the middle third or at the junction of the middle and distal thirds of the diaphysis. Fifty-six (96.6%) had simple or wedge patterns and 45 (77.6%) were right sided. Forty-four (76.2%) were treated non-operatively in plaster, 12 (20.3%) by intramedullary nails and two (3.4%) with external fixators. Two patients were lost to follow-up and the remaining 56 fractures united at a mean of 6.5 months. There were 21 complications in 19/56 (33.9%) patients which included 8/56 (14.3%) delayed/non-unions requiring surgery. There was a significantly higher complication rate for operated fractures (p<0.005) but no significant link to AO fracture type. Thus we cannot assume that treatment of these common fractures is without risk, especially if they are treated operatively.

Castleman's disease of the erector spinae muscle.

Castleman's disease, angio-follicular lymph node hyperplasia, is a relatively rare benign tumour. It typically arises in the mediastinum. We report a unique case arising in the erector spinae muscle. The case demonstrates the importance of radiological investigation and embolisation prior to obtaining a tissue diagnosis and subsequent surgical excision.