Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study.

BACKGROUND: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. METHODS: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. DISCUSSION: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. TRIAL REGISTRATION: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

Safety and feasibility of colonoscopy in nonagenarians: A systematic review, meta-analysis and meta-regression analysis.

AIM: The aim of this work was to evaluate the safety and feasibility of performing colonoscopy in patients aged 90 years or over. METHOD: In compliance with PRISMA statement standards, a systematic review of studies reporting the outcomes of colonoscopy in patients aged ≥90 years was conducted. A proportional meta-analysis model was constructed to quantify the risk of outcomes and a direct comparison meta-analysis model was constructed to compare outcomes between nonagenarians and patients aged between 50 and 89 years via random-effects models. RESULTS: Seven studies enrolling 1304 patients (1342 colonoscopies) were included. Analyses showed that complications related to bowel preparation occurred in 0.7% (95% CI 0.1%-1.6%), procedural complications in 0.6% (0.00%-1.7%), 30-day complications in 1.5% (0.6%-2.7%), procedural mortality in 0.3% (0.0%-1.1%) and 30-day mortality in 1.1% (0.3%-2.2%). Adequate bowel preparation and colonoscopy completion were achieved in 81.3% (73.8%-87.9%) and 92.1% (86.7%-96.3%), respectively. No difference was found in bowel preparation-related complications [risk difference (RD) 0.00, p = 0.78], procedural complications (RD 0.00, p = 0.60), 30-day complications (RD 0.01, p = 0.20), procedural mortality (RD 0.00, p = 1.00) or 30-day mortality (RD 0.01, p = 0.34) between nonagenarians and patients aged between 50 and 89 years. The colorectal cancer detection rate was 14.3% (9.8%-19.5%), resulting in therapeutic intervention in 65.9% (54.5%-76.6%). CONCLUSIONS: Although the evidence is limited to a selected group of nonagenarians, it may be fair to conclude that if a colonoscopy is indicated in a nonagenarian with good performance status (based on initial less-invasive investigations), the level 2 evidence supports its safety and feasibility. Age on its own should not be a reason for failing to offer colonoscopy to a nonagenarian.

The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.

Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors1, including complex genetic elements2, patient exposures3 and the gut microbiome4. Viral infections5 and broader gut dysbioses6 have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts7,8 and a T1D mouse model9, these data support the protective effects of short-chain fatty acids in early-onset human T1D.

Temporal development of the gut microbiome in early childhood from the TEDDY study.

The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1-9 such as persistent islet autoimmunity and type 1 diabetes10-12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.

Squaric esters as peptide stapling reagents.

We report that squaric esters can serve as bifunctional reagents for selective peptide stapling reactions. Formation of the squaric amide staple occurs under mild conditions with amine-containing side chains. We show that short resin-bound peptides are readily stapled on solid phase and that stapling can occur at various relative positions along the peptide and with various amine tether lengths (e.g. Lysine, ornithine, etc). The squaric amide staples are stable to strong acid conditions used to cleave the stapled peptide from the resin and the stapled peptides show an increase in helicity as analyzed through circular dichroism.

Evidence of Hematoma Prevention After Facelift.

Hematoma is a common complication after facelift procedures. Multiple factors have been shown to increase the risk of hematoma formation, such as male gender, anticoagulant medication use, perioperative hypertension, increased intrathoracic pressure, and operative technique. The purpose of this manuscript is to provide an overview of existing literature to provide surgeons with evidence-based recommendations on how to minimize hematoma risk during facelift surgery. A literature search for hematoma and facelift surgery was performed that identified 478 unique manuscripts. Abstracts were reviewed, excluding articles not describing facelift surgery, those written before 1970, studies with a sample size of fewer than 5 patients, non-English studies, and those that did not provide postoperative hematoma rates. Forty-five articles were included in this text, with their recommendations. Measures such as the prophylactic management of pain, nausea, and hypertension, the use of fibrin glue tissue sealants, the use of local anesthesia rather than general anesthesia, and strict blood pressure control of at least <140 mmHg were found to significantly reduce hematoma formation. Quilting sutures has shown benefit in some high-risk patients. Measures such as drains, compression dressings, perioperative use of selective serotonin reuptake inhibitors, and perioperative steroids had no significant effect on hematoma formation. In addition to appropriate patient selection and careful intraoperative hemostasis, many adjunct measures have been shown to reduce postoperative hematoma formation in facelift procedures.

Tracheostomy in children is associated with neutrophilic airway inflammation.

BACKGROUND: Tracheostomies in children are associated with significant morbidity, poor quality of life, excess healthcare costs and excess mortality. The underlying mechanisms facilitating adverse respiratory outcomes in tracheostomised children are poorly understood. We aimed to characterise airway host defence in tracheostomised children using serial molecular analyses. METHODS: Tracheal aspirates, tracheal cytology brushings and nasal swabs were prospectively collected from children with a tracheostomy and controls. Transcriptomic, proteomic and metabolomic methods were applied to characterise the impact of tracheostomy on host immune response and the airway microbiome. RESULTS: Children followed up serially from the time of tracheostomy up to 3 months postprocedure (n=9) were studied. A further cohort of children with a long-term tracheostomy were also enrolled (n=24). Controls (n=13) comprised children without a tracheostomy undergoing bronchoscopy. Long-term tracheostomy was associated with airway neutrophilic inflammation, superoxide production and evidence of proteolysis when compared with controls. Reduced airway microbial diversity was established pre-tracheostomy and sustained thereafter. CONCLUSIONS: Long-term childhood tracheostomy is associated with a inflammatory tracheal phenotype characterised by neutrophilic inflammation and the ongoing presence of potential respiratory pathogens. These findings suggest neutrophil recruitment and activation as potential exploratory targets in seeking to prevent recurrent airway complications in this vulnerable group of patients.

Effects of a mediterranean diet on the gut microbiota and microbial metabolites: A systematic review of randomized controlled trials and observational studies.

Consumption of the Mediterranean dietary pattern (MedDiet) is associated with reduced risk of numerous non-communicable diseases. Modulation of the composition and metabolism of the gut microbiota represents a potential mechanism through which the MedDiet elicits these effects. We conducted a systematic literature search (Prospero registration: CRD42020168977) using PubMed, The Cochrane Library, MEDLINE, SPORTDiscuss, Scopus and CINAHL databases for randomized controlled trials (RCTs) and observational studies exploring the impact of a MedDiet on gut microbiota composition (i.e., relative abundance of bacteria or diversity metrics) and metabolites (e.g., short chain fatty acids). Seventeen RCTs and 17 observational studies were eligible for inclusion in this review. Risk of bias across the studies was mixed but mainly identified as low and unclear. Overall, RCTs and observational studies provided no clear evidence of a consistent effect of a MedDiet on composition or metabolism of the gut microbiota. These findings may be related to the diverse methods across studies (e.g., MedDiet classification and analytical techniques), cohort characteristics, and variable quality of studies. Further, well-designed studies are warranted to advance understanding of the potential effects of the MedDiet using more detailed examination of microbiota and microbial metabolites with reference to emerging characteristics of a healthy gut microbiome.

Oral antibiotics and mechanical bowel preparation for colorectal surgery: A prospective observational study of surgical site infection and microbial analysis.

PURPOSE: Surgical site infections (SSIs) are common in colorectal surgery. Mechanical bowel preparation (MBP) in conjunction with oral antibiotics (OABs) have been shown to reduce SSI rates. It however is still unclear which OABs to use, and how this can be implemented in practice. METHODS: This is a prospective observational study carried out in Swansea Bay University Health Board during 2019-2021, evaluating the introduction of OABs in a stepwise manner on the incidence of SSI in major colorectal surgery. A control group having MBP only was compared to two OAB groups: one group had MBP plus metronidazole only and the second MBP plus metronidazole and neomycin. A 30-day follow-up after surgery was ascertained via chart review and telephone contact. Logistic regression was performed to estimate the relation between OAB use and SSI, with adjustment for confounding. In a subset of patients, faecal samples were analysed through 16S rRNA amplicon sequencing before and after OAB treatment, depicting the impact of the gut microbiome. RESULTS: In total 160 patients were analysed: 46 patients had MBP only, whilst 76 patients had MBP plus metronidazole only and 38 patients had MBP with metronidazole/neomycin. The SSI rate in the entire cohort was 33.8%, whilst the adjusted ORs for the single- and dual-OAB groups were 0.76 (95% CI: 0.17-1.81) and 0.50 (95% CI: 0.17-1.52). The microbial analysis demonstrated that the relative abundance for many bacterial genera was changed before and after OAB treatment, but no link with SSI development could be shown. CONCLUSIONS: Introduction of OABs in conjunction with MBP in colorectal surgery is feasible, and may potentially lead to lower rates of SSI, as well as altering the community structure of the faecal microbiome. More research is needed, especially considering different OABs and mechanistic studies of the gut microbiome in the context of colorectal surgery.

Childhood socioeconomic status interacts with cognitive function to impact scam susceptibility among community-dwelling older adults.

OBJECTIVES: We examined whether childhood socioeconomic status (SES) is related to scam susceptibility in old age and tested the hypothesis that childhood SES interacts with cognitive function to impact scam susceptibility. METHODS: This study employed a cross-sectional design. All data were collected in participants' community-based residences. Participants were 1071 older adults (mean age = 81.05 years, SD = 7.53) without dementia (median MMSE score = 28.29, IQR = 27.86-30.00). Participants completed assessments of childhood SES, cognitive function, and scam susceptibility. We used linear regression models to examine the associations of childhood SES and cognitive function with scam susceptibility. RESULTS: In a regression model adjusted for age, gender, and education, poorer cognitive function was associated with higher scam susceptibility, but childhood SES was not. However, in an additional model that included the interaction of childhood SES and cognitive function, the interaction was significant, such that lower childhood SES was associated with higher scam susceptibility among participants with lower cognitive function. CONCLUSION: Lower childhood SES is associated with higher scam susceptibility among older adults with lower levels of cognitive function. Thus, older adults who experienced limited resources in childhood and have lower cognitive function may represent a specific group for interventions to increase scam awareness and prevent financial exploitation.

Upper Extremity Crotalid Envenomation: A Review of Incidence and Recent Trends in Management of Snakebites.

PURPOSE: The goal of this study was to evaluate the recent trends in the management of upper extremity Crotalid envenomation in the state of Georgia, United States. METHODS: A retrospective review of the Georgia Poison Center database looking at the reported snakebites to the upper extremity between 2015 and 2020 was performed. Patient demographics, timing and location of injury, severity of envenomation, treatment, including use of antivenin and surgical intervention, and reported complications related to the use of antivenin was extracted. RESULTS: A retrospective review of snakebites between 2015 and 2020 showed 2408 snakebite cases with a mean patient age of 37.4 years. Males incurred 62.8% of all bites. The highest incidence was in summer 52.5%, and between the hours of 5 PM to midnight 57.2%. Overall, 1010 (41.9%) of all bites were categorized as venomous snakebites (55.6% copperhead, 20% rattlesnake, 2.4% cottonmouth, and 22% miscellaneous [including 3 Elapid envenomations] or unidentified. The total number of venomous bites to the upper extremity was 575 (56.9%) and 567 patients received antivenin. Envenomation severity was mild in 29%, moderate in 45%, severe in 10%, and undetermined in 16% of cases. Crotalidae polyvalent immune Fab (Ovine) was the main antivenin used, with overall mean initial therapy dose of 6.2 vials and 59% of patients receiving maintenance therapy. Three patients (0.5%) had a severe anaphylactic reaction to antivenin requiring cessation of therapy. Seven patients had acute compartment syndrome of the upper extremity requiring fasciotomy (3 copperhead, 2 rattlesnake, and 2 unidentified). There was no reported mortality during this period. CONCLUSIONS: Hand surgeons should be familiar with the management of upper extremity Crotalid envenomation. Antivenin remains the main treatment for symptomatic patients. Crotalid snakebites rarely require operative intervention. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

AI-Driven Validation of Digital Agriculture Models.

Digital agriculture employs artificial intelligence (AI) to transform data collected in the field into actionable crop management. Effective digital agriculture models can detect problems early, reducing costs significantly. However, ineffective models can be counterproductive. Farmers often want to validate models by spot checking their fields before expending time and effort on recommended actions. However, in large fields, farmers can spot check too few areas, leading them to wrongly believe that ineffective models are effective. Model validation is especially difficult for models that use neural networks, an AI technology that normally assesses crops health accurately but makes inexplicable recommendations. We present a new approach that trains random forests, an AI modeling approach whose recommendations are easier to explain, to mimic neural network models. Then, using the random forest as an explainable white box, we can (1) gain knowledge about the neural network, (2) assess how well a test set represents possible inputs in a given field, (3) determine when and where a farmer should spot check their field for model validation, and (4) find input data that improve the test set. We tested our approach with data used to assess soybean defoliation. Using information from the four processes above, our approach can reduce spot checks by up to 94%.

Periacetabular osteotomy to treat hip dysplasia: a systematic review of harms and benefits.

INTRODUCTION: Periacetabular osteotomy (PAO) is often performed in patients with hip dysplasia. The aim of this systematic review and meta-analysis was to evaluate the harms and benefits of PAO in patients with hip dysplasia in studies reporting both adverse events and patient-reported hip pain and function. MATERIALS AND METHODS: A systematic search combing PAO and patient-reported outcomes was performed in the databases MEDLINE, CINAHL, EMBASE, Sports Discuss and PsychINFO. Studies including both harms and benefits defined as adverse events and patient-reported hip pain and function were included. Risk of bias was assessed using The Cochrane Risk of Bias In Non-Randomized Studies - of Interventions. RESULTS: Twenty-nine cohort studies were included, of which six studies included a comparison group. The majority of studies had serious risk of bias and the certainty of evidence was very low. The proportion of adverse events was 4.3 (95% CI 3.7; 4.9) for major adverse events and 14.0 (95% CI 13.0; 15.1) for minor adverse events. Peroneal nerve dysfunction was the most frequent adverse event among the major adverse events, followed by acetabular necrosis and delayed union or non-union. All patient-reported hip pain and function scores improved and exceeded the minimal clinically important differences after PAO. After 5 years, scores were still higher than the preoperative scores. CONCLUSION: PAO surgery has a 4% risk of major, and 14% risk of minor adverse events and a positive effect on patient-reported hip pain and function among patients with hip dysplasia.

Development of the gut microbiome in early life.

NEW FINDINGS: What is the topic of this review? The importance of the early life gut microbiome, with a focus on preterm infants and microbially related diseases. Current techniques to study the preterm gut microbiome are appraised, and the potential of recent methodological advancements is discussed. What advances does it highlight? Recent findings in the field achieved by the application of advanced technologies, the applicability of intestinally derived organoid models to study host-microbiome interactions in the preterm gut, and recent developments in enhancing the physiological relevance of such models. Preterm intestinally derived organoids may provide novel insights into the mechanisms underlying preterm disease, as well as diagnosis and treatment opportunities. These models have huge translational potential, offering a step towards precision medicine. ABSTRACT: Accumulating evidence affirms the importance of the gut microbiome in both health and disease. In early life, there exists a critical period in which the composition of gut microbes is particularly malleable and subject to a wide range of influencing factors. Disturbances to microbial communities during this time may be beneficial or detrimental to short and long-term health outcomes. For infants born prematurely, naïve immune systems, immature gastrointestinal tracts and additional clinical needs put this population at high risk of abnormal microbial colonisation, resulting in increased susceptibility to diseases including necrotising enterocolitis (NEC) and late-onset sepsis (LOS). Traditional cell culture methods, gnotobiotic animals, molecular sequencing techniques (16S rRNA gene sequencing and metagenomics) and advanced 'omics' technologies (transcriptomics, proteomics and metabolomics) have been fundamental in exploring the associations between diet, gut microbes, microbial functions and disease. Despite significant investment and ongoing research efforts, prevention and treatment strategies in NEC and LOS remain limited. Recent endeavours have focused on searching for new, more physiologically relevant models to simulate the preterm intestine. Preterm intestinally derived organoids represent a promising in vitro approach in the study of host-microbiome interactions in the preterm infant gut, offering new and exciting possibilities in this field.

Secretory immunoglobulin A in preterm infants: determination of normal values in breast milk and stool.

BACKGROUND: IgA and its secretory form sIgA impact protection from infection and necrotising enterocolitis but little is known about quantities in preterm mums own milk (MOM) or infant stool, onset of endogenous production in the preterm gut, and what affects these. METHODS: We measured by ELISA in MOM and stool from healthy preterm infants total IgA and sIgA longitudinally and additionally in MOM fresh, refrigerated, frozen, and after traversing feeding systems. RESULTS: In 42 MOM (median gestation 26 weeks), we showed total IgA levels and sIgA were highest in colostrum, fell over 3 weeks, and were not impacted by gestation. Median IgA values matched previous term studies (700 mcg/ml). In MOM recipients stool IgA was detected in the first week, at around 30% of MOM quantities. Formula fed infants did not have detectable stool IgA until the third week. Levels of IgA and sIgA were approximately halved by handling processes. CONCLUSIONS: MOM in the 3 weeks after preterm delivery contains the highest concentrations of IgA and sIgA. Endogenous production after preterm birth occurs from the 3 week meaning preterm infants are dependent on MOM for IgA which should be optimised. Routine NICU practices halve the amount available to the infant. IMPACT: (Secretory) Immunoglobulin A (IgA) is present in colostrum of maternal milk from infants as preterm as 23-24 weeks gestational age, falling over the first 3 weeks to steady levels similar to term. Gestation at birth does not impact (secretory) IgA levels in breast milk. IgA is present in very preterm infant stools from maternal milk fed infants from the first week of life, but not in formula milk fed preterm infants until week three, suggesting endogenous production from this point. Refrigeration, freezing, and feeding via plastic tubing approximately halved the amount of IgA available.

Integrating longitudinal clinical and microbiome data to predict growth faltering in preterm infants.

Preterm birth affects more than 10% of all births worldwide. Such infants are much more prone to Growth Faltering (GF), an issue that has been unsolved despite the implementation of numerous interventions aimed at optimizing preterm infant nutrition. To improve the ability for early prediction of GF risk for preterm infants we collected a comprehensive, large, and unique clinical and microbiome dataset from 3 different sites in the US and the UK. We use and extend machine learning methods for GF prediction from clinical data. We next extend graphical models to integrate time series clinical and microbiome data. A model that integrates clinical and microbiome data improves on the ability to predict GF when compared to models using clinical data only. Information on a small subset of the taxa is enough to help improve model accuracy and to predict interventions that can improve outcome. We show that a hierarchical classifier that only uses a subset of the taxa for a subset of the infants is both the most accurate and cost-effective method for GF prediction. Further analysis of the best classifiers enables the prediction of interventions that can improve outcome.

The COLO-COHORT (Colorectal Cancer Cohort) study: Protocol for a multi-centre, observational research study and development of a consent-for-contact research platform.

AIM: The COLO-COHORT study aims to produce a multi-factorial risk prediction model for colorectal neoplasia that can be used to target colonoscopy to those at greatest risk of colorectal neoplasia, ensuring that people are not investigated unnecessarily and maximizing the use of limited endoscopy resources. The study will also explore the link between neoplasia and the human gut microbiome. Additionally, the study aims to generate a cohort of colonoscopy patients who are 'research ready' through the development of a consent-for-contact (C4C) platform, to facilitate a range of colorectal cancer prevention studies to be conducted at scale and speed. METHODS AND ANALYSIS: This is a multi-centre observational study involving sites across the UK. Recruitment is over a 6-year period (2019-2025). Patients recruited to the study are those attending for colonoscopy. Patients are recruited into two groups, namely observational group A (10 000 patients) and C4C group B (10 000 patients), known as COLO-SPEED (Colorectal Cancer Screening Prevention Endoscopy and Early Diagnosis; https://colospeed.uk). Patients complete a health questionnaire, provide anthropometric measurements and submit biosamples (blood and stool-depending on the part of the study they are recruited into). Patients' colonoscopy and histology findings are also recorded. Models of factors associated with the presence of neoplasia at colonoscopy will be developed using logistic or multinomial regression. For internal validation, model discrimination and calibration will be assessed and bootstrapping and cross-validation approaches used. To enable long-term follow-up for outcomes related to colorectal cancer and polyps, patients are asked to consent to follow-up through data linkage with national databases. DISSEMINATION: In keeping with good research practice, following analysis by the study team the study investigators will make the anonymized dataset available to other researchers. The C4C platform will also be accessible to other researchers. The study findings will be submitted for publication in peer-reviewed journals and lay summaries will be disseminated to participants and the wider public.

Exploring functional metabolites in preterm infants.

AIM: Metabolomics is the study of small molecules that represent the functional end points of cellular reactions that can impact health. Necrotising enterocolitis (NEC) and late onset sepsis (LOS) are the main cause of death in preterm infants surviving the initial days of life. METHODS: This review will explore and summarise the current literature exploring metabolomics in preterm infants. RESULTS: There are a relatively limited number of studies investigating metabolomics in preterm infants with NEC and/or LOS and matched controls. Nonetheless, it is evident across longitudinally age-related metabolomic studies that there are significant changes in metabolite profiles post-partum and over the first year of life. Existing studies have reported associations between the metabolite profiles of serum, urine and stool in health and disease in preterm infants. Although some studies have found selected metabolites are associated with disease, the specific metabolites vary from study to study, and larger studies are required. Excitingly, recent work has also begun to untangle how microbially produced metabolites can impact immunoregulation of the infant. CONCLUSION: Metabolic exploration is an emerging research area with huge potential for developing novel biomarkers and better understanding disease processes in preterm infants.

Towards defining muscular regions of interest from axial magnetic resonance imaging with anatomical cross-reference: a scoping review of lateral hip musculature.

BACKGROUND: Measures of hip muscle morphology and composition (e.g., muscle size and fatty infiltration) are possible with magnetic resonance imaging (MRI). Standardised protocols or guidelines do not exist for evaluation of hip muscle characteristics, hindering reliable and valid inter-study analysis. This scoping review aimed to collate and synthesise MRI methods for measuring lateral hip muscle size and fatty infiltration to inform the future development of standardised protocols. METHODS: Five electronic databases (Medline, CINAHL, Embase, SportsDISCUS and AMED) were searched. Healthy or musculoskeletal pain populations that used MRI to assess lateral hip muscle size and fatty infiltration were included. Lateral hip muscles of interest included tensor fascia late (TFL), gluteus maximus, gluteus medius, and gluteus minimus. Data on MRI parameters, axial slice location, muscle size and fatty infiltrate measures were collected and analysed. Cross referencing for anatomical locations were made between MRI axial slice and E-12 anatomical plastinate sections. RESULTS: From 2684 identified publications, 78 studies contributed data on volume (n = 31), cross sectional area (CSA) (n = 24), and fatty infiltration (n = 40). Heterogeneity was observed for MRI parameters and anatomical boundaries scrutinizing hip muscle size and fatty infiltration. Seven single level axial slices were identified that provided consistent CSA measurement, including three for both gluteus maximus and TFL, and four for both gluteus medius and minimus. For assessment of fatty infiltration, six axial slice locations were identified including two for TFL, and four for each of the gluteal muscles. CONCLUSIONS: Several consistent anatomical levels were identified for single axial MR slice to facilitate muscle size and fatty infiltration muscle measures at the hip, providing the basis for reliable and accurate data synthesis and improvements in the validity of future between studies analyses. This work establishes the platform for standardised methods for the MRI assessment of lateral hip musculature and will aid in the examination of musculoskeletal conditions around the hip joint. Further studies into whole muscle measures are required to further optimise methodological parameters for hip muscle assessment.

Systematic Review of Syndrome of the Trephined and Reconstructive Implications.

Syndrome of the trephined (SoT) is a severe complication following decompressive craniectomy resulting in neurological decline which can progress to aphasia, catatonia, and even death. While cranioplasty can reverse neurological symptoms of SoT, awareness of SoT is poor outside of the neurosurgery community. The authors performed a systematic review of the literature on SoT with a focus on reconstructive implications. Search terms "syndrome of the trephined" and "sunken flap syndrome" were applied to PubMed to identify primary studies through October 2021. Full-text review yielded 11 articles discussing SoT and reconstructive techniques or implications with 56 patients undergoing cranial reconstruction. Average age of the patients was 41.8±9.5 years. Sixty-three percent of the patients were male. The most common indication for craniectomy was traumatic brain injury (43%), followed by tumor resection (23%), intracerebral hemorrhage (11%), and aneurysmal subarachnoid hemorrhage (2%). Patients most commonly suffered from motor deficits (52%), decreased wakefulness (30%), depression or anxiety (21%), speech deficits (16%), headache (16%), and cognitive difficulties (2%). Time until presentation of symptoms following decompression was 4.4±8.9 months. Patients typically underwent cranioplasty with polyetheretherketone (48%), titanium mesh (21%), split thickness calvarial bone (16%), full thickness calvarial bone (14%), or split thickness rib graft (4%). Eight percent of patients required free tissue transfer for soft tissue coverage. Traumatic Brain Injury (TBI) was a risk factor for development of SoT when adjusting for age and sex (odds ratio: 8.2, 95% confidence interval: 1.2-8.9). No difference significant difference was observed between length until initial improvement of neurological symptoms following autologous versus allograft reconstruction (P=0.47). SoT can be a neurologically devastating complication of decompressive craniectomy which can resolve following urgent cranioplasty. Familiarity with this syndrome and its reconstructive implications is critical for the plastic surgery provider, who may be called upon to assist with these urgent cases.