Metabolism of L-arabinose converges with virulence regulation to promote enteric pathogen fitness.

Virulence and metabolism are often interlinked to control the expression of essential colonisation factors in response to host-associated signals. Here, we identified an uncharacterised transporter of the dietary monosaccharide ʟ-arabinose that is widely encoded by the zoonotic pathogen enterohaemorrhagic Escherichia coli (EHEC), required for full competitive fitness in the mouse gut and highly expressed during human infection. Discovery of this transporter suggested that EHEC strains have an enhanced ability to scavenge ʟ-arabinose and therefore prompted us to investigate the impact of this nutrient on pathogenesis. Accordingly, we discovered that ʟ-arabinose enhances expression of the EHEC type 3 secretion system, increasing its ability to colonise host cells, and that the underlying mechanism is dependent on products of its catabolism rather than the sensing of ʟ-arabinose as a signal. Furthermore, using the murine pathogen Citrobacter rodentium, we show that ʟ-arabinose metabolism provides a fitness benefit during infection via virulence factor regulation, as opposed to supporting pathogen growth. Finally, we show that this mechanism is not restricted to ʟ-arabinose and extends to other pentose sugars with a similar metabolic fate. This work highlights the importance integrating central metabolism with virulence regulation in order to maximise competitive fitness of enteric pathogens within the host-niche.

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.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

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.

Gut microbiome derived short chain fatty acids: Promising strategies in necrotising enterocolitis.

Necrotising enterocolitis (NEC) is a devastating condition that poses a significant risk of morbidity and mortality, particularly among preterm babies. Extensive research efforts have been directed at identifying optimal treatment and diagnostic strategies but results from such studies remain unclear and controversial. Among the most promising candidates are prebiotics, probiotics and their metabolites, including short chain fatty acids (SCFAs). Such metabolites have been widely explored as possible biomarkers of gut health for different clinical conditions, with overall positive effects on the host observed. This review aims to describe the role of gut microbiome derived SCFAs in necrotising enterocolitis. Until now, information has been conflicting, with the primary focus on the main three SCFAs (acetic acid, propionic acid, and butyric acid). While numerous studies have indicated the relationship between SCFAs and NEC, the current evidence is insufficient to draw definitive conclusions about the use of these metabolites as NEC biomarkers or their potential in treatment strategies. Ongoing research in this area will help enhance both our understanding of SCFAs as valuable indicators of NEC and their practical application in clinical settings.

Low versus standard central venous pressure during laparoscopic liver resection: A systematic review, meta-analysis and trial sequential analysis.

To compare the outcomes of low central venous pressure (CVP) to standard CVP during laparoscopic liver resection. The study design was a systematic review following the PRISMA statement standards. The available literature was searched to identify all studies comparing low CVP with standard CVP in patients undergoing laparoscopic liver resection. The outcomes included intraoperative blood loss (primary outcome), need for blood transfusion, mean arterial pressure, operative time, Pringle time, and total complications. Random- effects modelling was applied for analyses. Type I and type II errors were assessed by trial sequential analysis (TSA). A total of 8 studies including 682 patients were included (low CVP group, 342; standard CVP group, 340). Low CVP reduced intraoperative blood loss during laparoscopic liver resection (mean difference [MD], -193.49 mL; 95% confidence interval [CI], -339.86 to -47.12; p = 0.01). However, low CVP did not have any effect on blood transfusion requirement (odds ratio [OR], 0.54; 95% CI, 0.28-1.03; p = 0.06), mean arterial pressure (MD, -1.55 mm Hg; 95% CI, -3.85-0.75; p = 0.19), Pringle time (MD, -0.99 minutes; 95% CI, -5.82-3.84; p = 0.69), operative time (MD, -16.38 minutes; 95% CI, -36.68-3.39; p = 0.11), or total complications (OR, 1.92; 95% CI, 0.97-3.80; p = 0.06). TSA suggested that the meta-analysis for the primary outcome was not subject to type I or II errors. Low CVP may reduce intraoperative blood loss during laparoscopic liver resection (moderate certainty); however, this may not translate into shorter operative time, shorter Pringle time, or less need for blood transfusion. Randomized controlled trials with larger sample sizes will provide more robust evidence.

Patterns of Craniomaxillofacial Trauma at an Urban Level I Trauma Center.

Background: There is a paucity in the literature concerning craniomaxillofacial trauma (CMF) in the USA. Better recognition of these fracture patterns and their management clarifies how to best evaluate and treat them. Methods: A retrospective chart review was conducted of CMF trauma patients who required surgical intervention at a level I trauma center between 2015 and 2018. Descriptive statistics and univariate and bivariate analyses were conducted (α = 0.05). Results: A total of 1001 patients were included. Most patients were Black (n = 665; 66%) and/or male individuals (n = 813; 57%) with an average age of 37 years (range 15 -110). The most common etiologies were assault (n = 471; 44%), motor vehicle collision (n = 238; 22%), and fall (n = 117; 11%). The mechanism of injury was a determinant of fracture type (P = 0.045). The most common CMF injuries were mandibular fracture (n = 953; 95%), maxillary fracture (n = 815; 81%), and orbital fracture (n = 206; 21%). Male sex predicted panfacial fractures (P = 0.045). Black patients experienced more severe CMF trauma compared with other races (P < 0.001). ORIF was the most common treatment for mandibular (n = 481; 73%) and maxillary (n = 62; 66%) fractures. Conclusions: Etiology and patterns of CMF trauma differ globally, with assault and motor vehicle collisions being the leading causative factors in our patient population. Patient demographics are relatively consistent worldwide, with most injuries occurring in 30- to 40-year-old men. This study offers insight into at-risk populations and guidance on their management.

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.

SCAN for Abuse: Electronic Health Record-Based Universal Child Abuse Screening.

BACKGROUND: Identification of physical abuse at the point of care without a systematic approach remains inherently subjective and prone to judgement error. This study examines the implementation of an electronic health record (EHR)-based universal child injury screen (CIS) to improve detection rates of child abuse. METHODS: CIS was implemented in the EHR admission documentation for all patients age 5 or younger at a single medical center, with the following questions. 1) "Is this patient an injured/trauma patient?" 2) "If this is a trauma/injured patient, where did the injury occur?" A "Yes" response to Question 1 would alert a team of child abuse pediatricians and social workers to determine if a patient required formal child abuse clinical evaluation. Patients who received positive CIS responses, formal child abuse work-up, and/or reports to Child Protective Services (CPS) were reviewed for analysis. CPS rates from historical controls (2017-2018) were compared to post-implementation rates (2019-2021). RESULTS: Between 2019 and 2021, 14,150 patients were screened with CIS. 286 (2.0 %) patients screened received positive CIS responses. 166 (58.0 %) of these patients with positive CIS responses would not have otherwise been identified for child abuse evaluation by their treating teams. 18 (10.8 %) of the patients identified by the CIS and not by the treating team were later reported to CPS. Facility CPS reporting rates for physical abuse were 1.2 per 1000 admitted children age 5 or younger (pre-intervention) versus 4.2 per 1000 (post-intervention). CONCLUSIONS: Introduction of CIS led to increased detection suspected child abuse among children age 5 or younger. LEVEL OF EVIDENCE: Level II. TYPE OF STUDY: Study of Diagnostic Test.

The association between lateral hip muscle size/intramuscular fat infiltration and hip strength in active young adults with long standing hip/groin pain.

OBJECTIVES: To investigate associations between lateral hip muscle size/intramuscular fat infiltration (MFI) and hip strength in active young adults with longstanding hip/groin pain. DESIGN: Cross-sectional study. SETTING: University/Clinical. PARTICIPANTS: Sub-elite soccer and Australian Football players (n = 180; 37 female) with long standing hip/groin pain. MAIN OUTCOME MEASURES: Muscle size (volume) and MFI of gluteus maximus, medius, and minimis, and tensor fascia latae (TFL) were assessed using magnetic resonance imaging. Isometric hip strength was measured with handheld dynamometry. Associations between muscle size/MFI were assessed using linear regression models, adjusted for body mass index and age, with sex-specific interactions. RESULTS: Positive associations were identified between lateral hip muscle volume and hip muscle strength, particularly for gluteus maximus and gluteus minimus volume. For all muscles, hip abduction was associated with an increase in strength by up to 0.69 N (R2 ranging from 0.29 to 0.39). These relationships were consistent across sexes with no sex interactions observed. No associations were found between MFI and strength measures. CONCLUSION: Greater lateral hip muscle volumes are associated with greater hip strength in active young adults with long standing hip/groin pain, irrespective of sex. Gluteus maximus and minimus volume showed the most consistent relationships with hip strength across multiple directions.

A Consultation for Pediatric Neck Mass Resulting in a Rare Diagnosis of Klippel-Feil Syndrome: A Case Report.

Klippel-Feil syndrome (KFS) is a rare congenital cervical vertebrae fusion syndrome characterized by the clinical triad of low posterior hairline, limited head and neck range of motion, and short neck. The gene defects described with this syndrome are involved in the maturation and differentiation of bone during embryological development. As such, related defects seen in patients with KFS include genitourinary anomalies, cardiac defects, neurological abnormalities, and other musculoskeletal anomalies. Patients with this syndrome should be worked up for these related malformations, evaluated for risk of comorbidities, and educated on avoiding contact sports or activities that may put the cervical spine at risk for trauma. The case report here describes a pediatric patient who presents to the outpatient otolaryngologist complaining of a pediatric neck mass. Workup of the mass, including imaging, revealed a diagnosis of Klippel-Feil syndrome. The presentation of this case highlights the importance of maintaining KFS on the list of possible diagnoses along with scoliosis, synostosis syndrome, and Wildervanck syndrome for the otolaryngologist working up a neck mass and the role making an early diagnosis can have in preventing patient morbidity and mortality.

Natural language processing with machine learning methods to analyze unstructured patient-reported outcomes derived from electronic health records: A systematic review.

OBJECTIVE: Natural language processing (NLP) combined with machine learning (ML) techniques are increasingly used to process unstructured/free-text patient-reported outcome (PRO) data available in electronic health records (EHRs). This systematic review summarizes the literature reporting NLP/ML systems/toolkits for analyzing PROs in clinical narratives of EHRs and discusses the future directions for the application of this modality in clinical care. METHODS: We searched PubMed, Scopus, and Web of Science for studies written in English between 1/1/2000 and 12/31/2020. Seventy-nine studies meeting the eligibility criteria were included. We abstracted and summarized information related to the study purpose, patient population, type/source/amount of unstructured PRO data, linguistic features, and NLP systems/toolkits for processing unstructured PROs in EHRs. RESULTS: Most of the studies used NLP/ML techniques to extract PROs from clinical narratives (n = 74) and mapped the extracted PROs into specific PRO domains for phenotyping or clustering purposes (n = 26). Some studies used NLP/ML to process PROs for predicting disease progression or onset of adverse events (n = 22) or developing/validating NLP/ML pipelines for analyzing unstructured PROs (n = 19). Studies used different linguistic features, including lexical, syntactic, semantic, and contextual features, to process unstructured PROs. Among the 25 NLP systems/toolkits we identified, 15 used rule-based NLP, 6 used hybrid NLP, and 4 used non-neural ML algorithms embedded in NLP. CONCLUSIONS: This study supports the potential utility of different NLP/ML techniques in processing unstructured PROs available in EHRs for clinical care. Though using annotation rules for NLP/ML to analyze unstructured PROs is dominant, deploying novel neural ML-based methods is warranted.

The core phageome and its interrelationship with preterm human milk lipids.

Phages and lipids in human milk (HM) may benefit preterm infant health by preventing gastrointestinal pathobiont overgrowth and microbiome modulation. Lipid association may promote vertical transmission of phages to the infant. Despite this, interrelationships between lipids and phages are poorly characterized in preterm HM. Shotgun metagenomics and untargeted lipidomics of phage and lipid profiles from 99 preterm HM samples reveals that phages are abundant and prevalent from the first week and throughout the first 100 days of lactation. Phage-host richness of preterm HM increases longitudinally. Core phage communities characterized by Staphylococcus- and Propionibacterium-infecting phages are significantly correlated with long-chain fatty acid abundances over lactational age. We report here a phage-lipid interaction in preterm HM, highlighting the potential importance of phage carriage in preterm HM. These results reveal possible strategies for phage carriage in HM and their importance in early-life microbiota development.

Intracranial Hemorrhage and Facial Fractures After Nose Blowing and Sternutation: A Case Report.

INTRODUCTION: Blowing the nose and sneezing are ubiquitous physiologic processes. While exceedingly rare, traumatic injuries have been described. We detail a case of spontaneous intracranial hemorrhage and orbital fractures sustained as a result of these two phenomena in an otherwise healthy adult without known risk factors for bleeding or intracranial hemorrhage. CASE REPORT: A 79-year-old female presented to the emergency department after blowing her nose with an episode of sneezing following mild epistaxis. She denied any history of trauma, anticoagulation use, bleeding disorders, or pain associated with her symptoms. On examination, she had notable right periorbital swelling. Computed tomography revealed multiple areas of intracranial hemorrhage along with right-sided orbital and zygomatic fractures. After consulting trauma surgery and neurosurgery, we elected to pursue conservative management with repeat imaging. The patient had an uneventful course and was discharged with outpatient follow-up two days later. CONCLUSION: To our knowledge, this is the first case described of this constellation of injuries after a relatively benign process. Despite not having increased risk factors for intracranial hemorrhage (anticoagulation use, history of trauma, history of coagulopathy), this patient had severe injuries that presented with few external symptoms. This case serves as a reminder that while physiologic processes are almost always benign, serious traumatic injuries can result. Clinicians should have a low threshold for advanced imaging when there is a high clinical suspicion of facial fractures or more ominous processes.

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.

Bacteriophage communities are a reservoir of unexplored microbial diversity in neonatal health and disease.

Acquisition and development of the gut microbiome are vital for immune education in neonates, especially those born preterm. As such, microbial communities have been extensively studied in the context of postnatal health and disease. Bacterial communities have been the focus of research in this area due to the relative ease of targeted bacterial sequencing and the availability of databases to align and validate sequencing data. Recent increases in high-throughput metagenomic sequencing accessibility have facilitated research to investigate bacteriophages within the context of neonatal gut microbial communities. Focusing on unexplored viral diversity, has identified novel bacteriophage species and previously uncharacterised viral diversity. In doing so, studies have highlighted links between bacteriophages and bacterial community structure in the context of health and disease. However, much remains unknown about the complex relationships between bacteriophages, the bacteria they infect and their human host. With a particular focus on preterm infants, this review highlights opportunities to explore the influence of bacteriophages on developing microbial communities and the tripartite relationships between bacteriophages, bacteria and the neonatal human host. We suggest a focus on expanding collections of isolated bacteriophages that will further our understanding of the growing numbers of bacteriophages identified in metagenomes.

Prepectoral Two Stage Implant-Based Breast Reconstruction with Poly-4-Hydroxybutyrate (P4HB) for Pocket Control without the use of Acellular Dermal Matrix (ADM): A 4-Year Review.

BACKGROUND: As an alternative to biologic materials, absorbable meshes have been utilized to mitigate the potential drawbacks of ADM based breast reconstruction. Poly-4-hydroxybutyrate has been demonstrated to be a lower cost, safe, and effective alternative to ADM in subpectoral breast reconstruction. The aim of this study is to present the largest long-term observational study to date using P4HB for pocket control and implant support in immediate two stage pre-pectoral breast reconstruction looking at non-integration, capsular contracture, and implant malposition, along with patient comorbidities and risk factors. METHODS: A retrospective review of a single surgeon's (KM) experience was performed over a 4year span for patients who had undergone immediate two-stage prepectoral implant-based breast reconstruction with P4HB mesh. The review examined complications including implant loss, rippling, capsular contracture, malposition, and patient satisfaction throughout follow up. RESULTS: From 2018 to 2022, 105 patients underwent breast reconstruction using P4HBmesh for a total of 194 breasts. P4HBmesh integration was 97%. Overall, 16 breasts (8.2%) experienced minor complications while 10.3% of devices required explantation which was significantly higher in the radiated group at 28.6% (P<0.01). Older patients, higher BMI, active smokers, or increased mastectomy specimen size were more likely to undergo explantation. The rate of capsular contracture was 1.0 %. The overall rate of lateral malposition was also 1.0%. Visible rippling was present in 15.6% of breasts. There was no significant difference between smile mastopexy and inferolateral incision with regards to capsular contracture, lateral malposition, or rippling. Overall, patients demonstrated a high level of satisfaction and there were no significant predictors of capsular contracture, lateral malposition, or visible rippling. CONCLUSIONS: We have shown the safety and efficacy of P4HB in 2-stage pre-pectoral breast reconstruction. There appears to be equal, if not reduced, capsular contracture rates when compared to the published data on the use of ADM. Lastly, this represents a large cost reduction to both the patient and health care system.

Diet-microbe-host interaction in early life.

Breast milk bioactives are important for infant microbiome and immunity.