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Background and Aims: Fully covered self-expandable metal stents are commonly used for managing GI adverse events like perforations, leaks, fistulas, and strictures. Although effective, stent length and migration can be a limitation when dealing with larger defects. Over-the-scope clips and over-the-scope suturing can be used to mitigate migration risk; however, their role is limited for stent-to-stent suturing to create longer stents. We present a novel application of through-the-scope suturing (TTSS) system for creating longer stents to manage larger GI defects. Methods: We demonstrate using a video case series the applicability of TTSS for fixing multiple coaxially placed stents to create a longer stent and simultaneously anchor them to underlying GI wall to mitigate stent migration. Results: We illustrate our success in managing 3 cases of large esophageal and/or gastric pathologies (stenosis and leak) using the TTSS system to create longer stents through stent-in-stent fixation. Conclusions: TTSS is a novel endoscopic suturing platform that is compatible with most endoscopes and can be navigated to challenging narrow and angulated location, giving it an advantage over over-the-scope suturing/over-the-scope clips. Our case series demonstrates that stent-in-stent fixation of multiple fully covered self-expandable metal stents to create longer stents using the TTSS system is an effective technique when managing larger GI defects.

β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. One such target is the main protease (M pro ) that plays an indispensable role in viral replication. The availability of over 270 M pro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all nonredundant ligand-binding sites available for SARS-CoV2, SARS-CoV, and MERS-CoV M pro . Extensive adaptive sampling has been used to investigate structural conservation of ligand-binding sites using Markov state models (MSMs) and compare conformational dynamics employing convolutional variational auto-encoder-based deep learning. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-CoV homologs. This highlights the complexity in targeting all three M pro enzymes with a single pan inhibitor.

Background and Objectives: Reports comparing the characteristics of patients and their clinical outcomes between community-acquired (CA) and hospital-acquired (HA) COVID-19 have not yet been reported in the literature. We aimed to characterise and compare clinical, biochemical and haematological features, in addition to clinical outcomes, between these patients., Methods: This multi-centre, retrospective, observational study enrolled 488 SARS-CoV-2 positive patients - 339 with CA infection and 149 with HA infection. All patients were admitted to a hospital within the University Hospitals of Morecambe Bay NHS Foundation Trust between March 7th and May 18th , 2020., Results: The CA cohort comprised of a significantly younger population, median age 75 years, versus 80 years in the HA cohort (P = 0·0002). Significantly less patients in the HA group experienced fever (P = 0·03) and breathlessness (P < 0·0001). Furthermore, significantly more patients had anaemia and hypoalbuminaemia in the HA group, compared to the CA group (P < 0·0001 for both). Hypertension and a lower median BMI were also significantly more pronounced in the HA cohort (P = 0·03 and P = 0·0001, respectively). The mortality rate was not significantly different between the two cohorts (34% in the CA group and 32% in the HA group, P = 0·64). However, the CA group required significantly greater ICU care (10% versus 3% in the HA group, P = 0·009)., Conclusion: Hospital-acquired and community-acquired COVID-19 display similar rates of mortality despite significant differences in baseline characteristics of the respective patient populations. Delineation of community- and hospital-acquired COVID-19 in future studies on COVID-19 may allow for more accurate interpretation of results., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In prior studies, we delineated the landscape of neoantigens arising from nonsynonymous point mutations in a murine pancreatic cancer model, Panc02. We developed a peptide vaccine by targeting neoantigens predicted using a pipeline that incorporates the MHC binding algorithm NetMHC. The vaccine, when combined with immune checkpoint modulators, elicited a robust neoepitope-specific antitumor immune response and led to tumor clearance. However, only a small fraction of the predicted neoepitopes induced T cell immunity, similarly to that reported for neoantigen vaccines tested in clinical studies. While these studies have used binding affinities to MHC I as surrogates for T cell immunity, this approach does not include spatial information on the mutated residue that is crucial for TCR activation. Here, we investigate conformational alterations in and around the MHC binding groove induced by selected minimal neoepitopes, and we examine the influence of a given mutated residue as a function of its spatial position. We found that structural parameters, including the solvent-accessible surface area (SASA) of the neoepitope and the position and spatial configuration of the mutated residue within the sequence, can be used to improve the prediction of immunogenic neoepitopes for inclusion in cancer vaccines.

Background: As the pediatric population requiring health services rises globally, developing countries are struggling to cater to the growing burden of non-communicable diseases - particularly those requiring specialized surgical care., Main Body: Despite the literature supporting specialized pediatric surgical care, the developing world is far from meeting the American Pediatric Surgical Association (APSA) Manpower taskforce recommendation of at least 1 qualified pediatric surgeon per 100,000 patients (0-15 years-old). In Pakistan, there is an unmet surgical need in the pediatric population due to a multitude of short shortcomings, notably in quality and quantity of the training programs on offer, and urgent short- and long-term steps are needed to improve this dire situation., Conclusion: It is crucial for the global surgical community to take steps, especially with regards to pediatric surgical training, to ensure delivery of accessible and quality surgical care to the world's children.

Introduction: Common sites of occurrence of extraosseous Ewing's sarcoma include the soft tissues and bones of the lower extremity, 12 paravertebral, and retroperitoneal regions. Primary intracranial Ewing's sarcoma/pPNET is usually intraparenchymal located 13 when supratentorially, and an extraaxial epidural tumor radiographically mimicking a meningioma is extremely rare., Case Presentation: A 20-year14 old male presented to the emergency department with a 1-day history of drowsiness, headache, and fever. Neurological exam15 ination revealed decreased muscle strength (4/5) in the left lower limb. Head computed tomography scan showed an epidural 16 space-occupying lesion in the right temporoparietal region, which was assumed to be a meningioma by radiographic criteria. However, the surgical specimen was diagnosed as Ewing's sarcoma., Conclusion: Primary intracranial extraosseous Ewing's sarcoma is a rare condition that may mimic a meningioma on imaging. Physicians must be cognizant of this possibility, particularly in any young individual with a solitary contrast-enhancing dural-based lesion.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment., (Copyright © 2018 Elsevier Inc. All rights reserved.)