GlcNAc-1,6-anhydro-MurNAc Moiety Affords Unusual Glycosyl Acceptor that Terminates Peptidoglycan Elongation.

Peptidoglycan (PG), an essential exoskeletal polymer in bacteria, is a well-known antibiotic target. PG polymerization requires the action of bacterial transglycosylases (TGases), which couple the incoming glycosyl acceptor to the donor. Interfering with the TGase activity can interrupt the PG assembly. Existing TGase inhibitors like moenomycin and Lipid II analogues always occupy the TGase active sites; other strategies to interfere with proper PG elongation have not been widely exploited. Inspired by the natural 1,6-anhydro-MurNAc termini that mark the ends of PG strands in bacteria, we hypothesized that the incorporation of an anhydromuramyl-containing glycosyl acceptor by TGase into the growing PG may effectively inhibit PG elongation. To explore this possibility, we synthesized 4-O-(N-acetyl-ß-d-glucosaminyl)-1,6-anhydro-N-acetyl-ß-d-muramyl-l-Ala-γ-d-Glu-l-Lys-d-Ala-d-Ala, 1, within 15 steps, and demonstrated that this anhydromuropeptide and its analogue lacking the peptide, 1-deAA, were both utilized by bacterial TGase as noncanonical anhydro glycosyl acceptors in vitro. The incorporation of an anhydromuramyl moiety into PG strands by TGases afforded efficient termination of glycan chain extension. Moreover, the preliminary in vitro studies of 1-deAA against Staphylococcus aureus showed that 1-deAA served as a reasonable antimicrobial adjunct of vancomycin. These insights imply the potential application of such anhydromuropeptides as novel classes of PG-terminating inhibitors, pointing toward novel strategies in antibacterial agent development.

Ligand Sulfur Oxidation State Progressively Alters Galectin-3-Ligand Complex Conformations To Induce Affinity-Influencing Hydrogen Bonds.

Galectins play biological roles in immune regulation and tumor progression. Ligands with high affinity for the shallow, hydrophilic galectin-3 ligand binding site rely primarily on a galactose core with appended aryltriazole moieties, making hydrophobic interactions and π-stacking. We designed and synthesized phenyl sulfone, sulfoxide, and sulfide-triazolyl thiogalactoside derivatives to create affinity-enhancing hydrogen bonds, hydrophobic and π-interactions. Crystal structures and thermodynamic analyses revealed that the sulfoxide and sulfone ligands form hydrogen bonds while retaining π-interactions, resulting in improved affinities and unique binding poses. The sulfoxide, bearing one hydrogen bond acceptor, leads to an affinity decrease compared to the sulfide, whereas the corresponding sulfone forms three hydrogen bonds, two directly with Asn and Arg side chains and one water-mediated to an Asp side chain, respectively, which alters the complex structure and increases affinity. These findings highlight that the sulfur oxidation state influences both the interaction thermodynamics and structure.

An initial genomic blueprint of the healthy human oesophageal microbiome.

Background: The oesophageal microbiome is thought to contribute to the pathogenesis of oesophageal cancer. However, investigations using culture and molecular barcodes have provided only a low-resolution view of this important microbial community. We therefore explored the potential of culturomics and metagenomic binning to generate a catalogue of reference genomes from the healthy human oesophageal microbiome, alongside a comparison set from saliva. Results: Twenty-two distinct colonial morphotypes from healthy oesophageal samples were genome-sequenced. These fell into twelve species clusters, eleven of which represented previously defined species. Two isolates belonged to a novel species, which we have named Rothia gullae. We performed metagenomic binning of reads generated from UK samples from this study alongside reads generated from Australian samples in a recent study. Metagenomic binning generated 136 medium or high-quality metagenome-assembled genomes (MAGs). MAGs were assigned to 56 species clusters, eight representing novel Candidatus species, which we have named Ca. Granulicatella gullae, Ca. Streptococcus gullae, Ca. Nanosynbacter quadramensis, Ca. Nanosynbacter gullae, Ca. Nanosynbacter colneyensis, Ca. Nanosynbacter norwichensis, Ca. Nanosynococcus oralis and Ca. Haemophilus gullae. Five of these novel species belong to the recently described phylum Patescibacteria . Although members of the Patescibacteria are known to inhabit the oral cavity, this is the first report of their presence in the oesophagus. Eighteen of the metagenomic species were, until recently, identified only by hard-to-remember alphanumeric placeholder designations. Here we illustrate the utility of a set of recently published arbitrary Latinate species names in providing user-friendly taxonomic labels for microbiome analyses.Our non-redundant species catalogue contained 63 species derived from cultured isolates or MAGs. Mapping revealed that these species account for around half of the sequences in the oesophageal and saliva metagenomes. Although no species was present in all oesophageal samples, 60 species occurred in at least one oesophageal metagenome from either study, with 50 identified in both cohorts. Conclusions: Recovery of genomes and discovery of new species represents an important step forward in our understanding of the oesophageal microbiome. The genes and genomes that we have released into the public domain will provide a base line for future comparative, mechanistic and intervention studies.

Clinical and genetic determinants of severe acute pancreatitis: A genetic association study in the UK Biobank.

BACKGROUND AND AIM: The clinical severity of acute pancreatitis is unpredictable, ranging from self-limiting disease to life-threatening inflammation. The determinants of severe acute pancreatitis (SAP) are unclear. We aim to identify clinical variables and single nucleotide polymorphisms (SNP) associated with SAP. METHODS: We used UK Biobank data to conduct a case-control clinical and genetic association study. Pancreatitis patients were identified through national hospital and mortality records across the United Kingdom. Clinical covariates and SAP were analyzed for associations. Genotyped data that included 35 SNPs were assessed for independent associations with SAP and SNP to SNP interaction. RESULTS: A total of 665 patients with SAP and 3304 non-SAP patients were identified. Male sex and older age increased odds of developing SAP (odds ratio [OR] 1.48; 95% confiden interval [CI] 1.24-1.78, P < 0.0001) and (OR 1.23; 95% CI 1.17-1.29), P < 0.0001), respectively. SAP was associated with diabetes (OR 1.46; 95% CI 1.15-1.86, P = 0.002), chronic kidney disease (OR 1.74; 95% CI 1.26-2.42, P = 0.001), and cardiovascular disease (OR 2.00; 95% CI 1.54-2.61, P = 0.0001). A significant association was established between IL-10 rs3024498 and SAP (OR 1.24; 95% CI 1.09-1.41, P = 0.0014). Epistasis analysis revealed that the odds of SAP was greater by an interaction between TLR 5 rs5744174 and Factor V rs6025 (ORinteraction 7.53; P = 6.64 × 10-5 ). CONCLUSION: This study reports clinical risk factors for SAP. We also show evidence for an interaction between rs5744174 and rs6025 as determinants for SAP in addition to rs3024498 independently altering the severity of acute pancreatitis.

Complications of diagnostic upper Gastrointestinal endoscopy: common and rare - recognition, assessment and management.

A clear understanding of the potential complications or adverse events (AEs) of diagnostic endoscopy is an essential component of being an endoscopist. Creating a culture of safety and prevention of AEs should be part of routine endoscopy practice. Appropriate patient selection for procedures, informed consent, periprocedure risk assessments and a team approach, all contribute to reducing AEs. Early recognition, prompt management and transparent communication with patients are essential for the holistic and optimal management of AEs. In this review, we discuss the complications of diagnostic upper gastrointestinal endoscopy, including their recognition, treatment and prevention.

Oesophageal adenocarcinoma metastasis into a microcystic meningioma: a rare occurrence of tumour to tumour metastasis.

A 78-year-old male was admitted with a history of a fall following seizures. This occurred 2 years post-curative treatment (minimally invasive oesophagectomy with neo-adjuvant chemotherapy) for an oesophageal adenocarcinoma staged T3N0M0. On examination, patient had left-sided hemiparesis. A CT and magnetic resonance image (MRI) of the head confirmed a right frontotemporal meningioma with features suggestive of internal haemorrhage or calcification and mild local mass effect. A joint decision was made between the local neuro-surgical and neurology departments to manage this conservatively. However, due to progressive neurological deterioration and a concomitant increase in the size of the haemorrhagic lesion, emergent surgical intervention was indicated. The patient underwent a Simpson one complete resection (complete tumour resection including associated dura matter and abnormal underlying bone). Postoperative histology confirmed a rare case of metastatic oesophageal adenocarcinoma to a microcystic meningioma (World Health Organization Grade I). The meningioma was the only known site of distant metastasis for the oesophageal adenocarcinoma. Our case highlights the only documented case of the adenocarcinoma subtype of oesophageal tumour metastasizing to a meningioma. This case demonstrates the rare but well-documented occurrence of tumour to tumour metastasis. It highlights the importance played by imaging and clinical correlation when assessing progressively growing meningiomas in patients with a history of or underlying malignancy.

Completely minimally invasive versus hybrid Ivor-Lewis oesophagectomy for oesophageal and gastro-oesophageal junctional cancer: a UK multi-centre comparative study.

BACKGROUND: Limited robust evidence exists comparing outcomes following completely minimally invasive oesophagectomy (CMIO) to hybrid oesophagectomy (HO) in the treatment of resectable oesophageal and gastro-oesophageal junctional (GOJ) cancer. This multi-centre study aims to assess postoperative morbidity between HO and CMIO according to the full Esophagectomy Complications Consensus Group (ECCG) complication platform. METHODS: All consecutive patients undergoing an Ivor-Lewis HO or Ivor-Lewis CMIO for cancer between 2016 and 2018 in three UK tertiary centres were included. The primary study outcome was 30-day overall complications, evaluated by the ECCG complication subgroups. Secondary outcomes included survival outcomes and perioperative parameters between the two approaches. RESULTS: Of the 382 patients included, 228 (59.7%) patients had HOs and 154 (40.3%) patients had CMIOs with no inter-group baseline differences. Patients undergoing CMIO experienced less 30-day postoperative complications compared to those under undergoing HO (43.5% vs 57.0%, p = 0.010). ECCG defined pulmonary and infective complications were less frequent in the CMIO group. Anastomotic leak rates and oncological outcomes were similar between the two groups. Independent predictors of 30-day postoperative complications include surgical approach with HO and high ASA grade on multivariable analysis. CONCLUSIONS: Ivor-Lewis CMIO demonstrates superior short-term surgical outcomes when compared to Ivor-Lewis HO with no compromise in oncological feasibility. Anastomotic leak rates were equivalent between both groups. A robust randomised controlled trial is required to validate the findings of this study.

The oesophageal microbiome and cancer: hope or hype?

The human oesophagus is home to a complex microbial community, the oesophageal microbiome. Despite decades of work, we still have only a poor, low-resolution view of this community, which makes it hard to distinguish hope from hype when it comes to assessing links between the oesophageal microbiome and cancer. Here we review the potential importance of this microbiome and discuss new approaches, including culturomics, metagenomics, and recovery of whole-genome sequences, that bring renewed hope for an in-depth characterisation of this community that could deliver translational impact.

Easy access to secondary and tertiary alcohols via metal-free and light mediated radical carbonyl allylation.

Here we report a strategy for carbonyl addition with unactivated alkenes using an organic photocatalyst on both aldehyde and ketone substrates. This protocol grants us a good alternative to the traditional Barbier-Grignard allylation that exhibits poor functional group tolerance. With this method the stoichiometric use of metals can be avoided, high atom economy can be achieved and fewer by-products are generated.

Gastric lymphoma at high risk of perforation successfully managed with chemotherapy alone.

We report the case of a previously healthy 49-year-old woman who presented with upper gastrointestinal bleeding, which was found at laparotomy to be due to high-grade B cell gastric lymphoma. CT scans showed that this was partially adherent to the spleen, with erosion of the gastric wall and suggested impending perforation. Given the risk of perforation, further surgical intervention (gastrectomy and splenectomy) was considered; however, after multidisciplinary team discussion, we chose to offer chemotherapy and careful inpatient observation instead.Our patient made a full recovery with no perforation.The message from our experience and literature review is that medical management may lead to a more favourable outcome in gastric lymphoma than surgery, despite radiological appearances suggesting impending perforation. This approach avoids the risk of the lymphoma progressing at other anatomical sites secondary to delays in giving chemotherapy. If this approach is followed, the patient must be carefully monitored.

Minimizing the hidden dangers of cholecystectomy in vascular Ehlers-Danlos syndrome through a multidisciplinary approach.

Ehlers-Danlos syndrome, specifically EDS4, can be a dangerous condition. Clinicians should be aware of this when referring such patients for any interventional procedure. An MDT approach should be adopted to help plan perioperative treatment and care.

Lumbar hernia diagnosed after laparoscopic hiatal hernia surgery.

The presence of a new lumbar swelling or pain in the postoperative period following laparoscopic surgery should raise the suspicion of a lumbar hernia. Cross-sectional imaging can be used to establish an early diagnosis to enable successful management.

Effect Monitoring and Insights from Vaccination program of Healthcare Workforce from a tertiary level hospital in India against SARS-CoV-2.

Immunization is expected to confer protection against infection and severe disease for vaccinees, while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies, we show that during a severe SARS-CoV2 Delta-variant outbreak in Delhi, 25.3% (95% CI 16.9 - 35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare-workers (HCW) were infected within a period of less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, IQR 374) or not (342 U/ml, IQR 497), as was induction of neutralization activity to wildtype. Most infections were unrecognized. The Delta-variant thus causes frequent unrecognized breakthrough infections in adequately immunized subjects, reducing any herd-effect of immunity, and requiring reinstatement of preventive measures such as masking.