Clinical and oncological outcomes of pelvic exenteration surgery for anal squamous cell carcinoma.

AIM: Anal cancer incidence and mortality rates are rising in the United Kingdom (UK). Surgery is an important treatment modality for persistent or recurrent disease. There is a paucity of data on outcomes for patients undergoing pelvic exenteration for anal squamous cell carcinoma (SCC) for persistent or recurrent disease. The aim of this study was to investigate the outcomes for patients who were treated with pelvic exenteration for anal SCC from two high-volume, high-complexity pelvic exenteration units in the UK. METHOD: A retrospective review of prospectively maintained databases from 2011 to 2020 was undertaken. Primary endpoints included R0 resection rates, overall and disease-free survival at 2 and 5 years. RESULTS: From 2011 to 2020, 35 patients with anal SCC were selected for exenteration. An R0 resection was achieved in 26 patients (77%). Of the remaining patients, seven patients had an R1 resection and one had a R2 resection. One further patient was excluded from additional analysis as the disease was inoperable at the time of laparotomy. With a median follow-up of 19.5 months (interquartile range 7.9-53.5 months), overall survival was 50% (17/34). Patients with an R1/2 resection had a significantly poorer overall survival [0.27 (0.09-0.76), p = 0.021] than those patients in whom R0 resection was achieved. Disease-free survival was 38.2% (13/34) and an R1/R2 resection was associated with a significantly reduced disease-free survival [0.12 (0.04-0.36), p < 0.001]. CONCLUSION: Complete R0 resection for recurrent or persistent anal SCC is possible in the majority of patients and improves overall and disease-free survival compared with R1/R2 resection.

Exosomes; a Potential Source of Biomarkers, Therapy, and Cure for Type-1 Diabetes.

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their "origin", and (b) their "content", which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or ß-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome "specificity" makes them suitable as biomarkers or predictors, and their "mobility" and "content" lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic ß-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications.

Synthesis of 1-Deoxymannojirimycin from d-Fructose using the Mitsunobu Reaction.

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).

Computational discoveries of reaction mechanisms: recent highlights and emerging challenges.

This review examines some of the notable advances and trends that have shaped the field of computational elucidation of organic reaction mechanisms over the last 10-15 years. It highlights the types of mechanistic problems that have recently become possible to study and summarizes the methodological developments that have permitted these new advances. Case studies are taken from three representative areas of organic chemistry-asymmetric catalysis, glycosylation reactions, and single electron transfer reactions-which illustrate themes common to the broader field. These include the trend towards modelling systems that are increasingly complex (both structurally and mechanistically), the growing appreciation of the mechanistic roles of non-covalent interactions, and the increasing ability to explore dynamical features of reaction mechanisms. Some interesting new challenges that have emerged in the field are identified.

Synthesis of New Triazolopyrazine Antimalarial Compounds.

A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.

Genome-Inspired Chemical Exploration of Marine Fungus Aspergillus fumigatus MF071.

The marine-derived fungus Aspergillus fumigatus MF071, isolated from sediment collected from the Bohai Sea, China, yielded two new compounds 19S,20-epoxy-18-oxotryprostatin A (1) and 20-hydroxy-18-oxotryprostatin A (2), in addition to 28 known compounds (3-30). The chemical structures were established on the basis of 1D, 2D NMR and HRESIMS spectroscopic data. This is the first report on NMR data of monomethylsulochrin-4-sulphate (4) and pseurotin H (10) as naturally occurring compounds. Compounds 15, 16, 20, 23, and 30 displayed weak antibacterial activity (minimum inhibitory concentration: 100 µg/mL). Compounds 18 and 19 exhibited strong activity against S. aureus (minimum inhibitory concentration: 6.25 and 3.13 µg/mL, respectively) and E. coli (minimum inhibitory concentration: 6.25 and 3.13 µg/mL, respectively). A genomic data analysis revealed the putative biosynthetic gene clusters ftm for fumitremorgins, pso for pseurotins, fga for fumigaclavines, and hel for helvolinic acid. These putative biosynthetic gene clusters fundamentally underpinned the enzymatic and mechanistic function study for the biosynthesis of these compounds. The current study reported two new compounds and biosynthetic gene clusters of fumitremorgins, pseurotins, fumigaclavines and helvolinic acid from Aspergillus fumigatus MF071.

Reaction of Papaverine with Baran DiversinatesTM.

The reaction of papaverine with a series of Baran DiversinatesTM is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C-H functionalization. Ten papaverine analogues (2-11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the DiversinateTM reactions with this particular scaffold are discussed.

Platelet response to direct thrombin inhibitor or fondaparinux treatment in patients with suspected heparin-induced thrombocytopenia.

Making a definitive diagnosis of heparin-induced thrombocytopenia (HIT) can be problematic. A prompt platelet rise following treatment has been proposed as a "post-test" criterion for diagnosis. However, the platelet response following discontinuation of heparin and initiation of a recommended alternative anticoagulant remains largely undefined and unstudied. This study aimed to characterize platelet response to initial treatment in patients with a low, intermediate, or high likelihood of having HIT. This was a multicenter retrospective cohort study. Patients were over 18 years in age, underwent serologic testing for HIT, and received alternative anticoagulation treatment for HIT. Classification of each patient's likelihood of having HIT was based on an empiric, pre-hoc combination of the 4T score and serology results. The primary outcome for this study was a platelet count response after initiation of direct thrombin inhibitor (DTI) or fondaparinux therapy within 48 h. 124 patients were analyzed. The sensitivity and specificity of having an immediate platelet rise of at least 10,000/µL by day 2 after starting treatment among high-likelihood for HIT patients were 0.71 (95% CI 0.55-0.84) and 0.64 (95% CI 0.5-0.76), respectively. The negative predictive value of no platelet rise was 75.5% (95% CI 0.61-0.86). A prompt platelet count rise may be appropriate to consider along with other known criteria for the clinical diagnosis of HIT. The rise should be immediate following discontinuation of heparin and initiation of recommended treatment, with an upward rise within 48 h.

Parameter dependence of high-frequency nonlinear oscillations and intrinsic chaos in short GaAs/(Al, Ga)As superlattices.

We explore the design parameter space of short (5-25 period), n-doped, Ga/(Al,Ga)As semiconductor superlattices (SSLs) in the sequential resonant tunneling regime. We consider SSLs at cool (77 K) and warm (295 K) temperatures, simulating the electronic response to variations in (a) the number of SSL periods, (b) the contact conductivity, and (c) the strength of disorder (aperiodicities). Our analysis shows that the chaotic dynamical phases exist on a number of sub-manifolds of codimension zero within the design parameter space. This result provides an encouraging guide towards the experimental observation of high-frequency intrinsic dynamical chaos in shorter SSLs.

Ionic and Neutral Mechanisms for C-H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide.

Exploiting C-H bond activation is difficult, although some success has been achieved using precious metal catalysts. Recently, it was reported that C-H bonds in aromatic heterocycles were converted to C-Si bonds by reaction with hydrosilanes under the catalytic action of potassium tert-butoxide alone. The use of Earth-abundant potassium cation as a catalyst for C-H bond functionalization seems to be without precedent, and no mechanism for the process was established. Using ambient ionization mass spectrometry, we are able to identify crucial ionic intermediates present during the C-H silylation reaction. We propose a plausible catalytic cycle, which involves a pentacoordinate silicon intermediate consisting of silane reagent, substrate, and the tert-butoxide catalyst. Heterolysis of the Si-H bond, deprotonation of the heteroarene, addition of the heteroarene carbanion to the silyl ether, and dissociation of tert-butoxide from silicon lead to the silylated heteroarene product. The steps of the silylation mechanism may follow either an ionic route involving K+ and tBuO- ions or a neutral heterolytic route involving the [KOtBu]4 tetramer. Both mechanisms are consistent with the ionic intermediates detected experimentally. We also present reasons why KOtBu is an active catalyst whereas sodium tert-butoxide and lithium tert-butoxide are not, and we explain the relative reactivities of different (hetero)arenes in the silylation reaction. The unique role of KOtBu is traced, in part, to the stabilization of crucial intermediates through cation-π interactions.

Interaction Heterogeneity can Favorably Impact Colloidal Crystal Nucleation.

Colloidal particles with short-ranged attractions, e.g., micron-scale spheres functionalized with single-stranded DNA oligomers, are susceptible to becoming trapped in disordered configurations even when a crystalline arrangement is the ground state. Moreover, for reasons that are not well understood, seemingly minor variations in the particle formulation can lead to dramatic changes in the crystallization outcome. We demonstrate, using a combination of equilibrium and nonequilibrium computer simulations, that interaction heterogeneity-variations in the energetic interactions among different particle pairs in the population-may favorably impact crystal nucleation. Specifically, interaction heterogeneity is found to lower the free energy barrier to nucleation via the formation of clusters comprised preferentially of strong-binding particle pairs. Moreover, gelation is inhibited by "spreading out over time" the nucleation process, resulting in a reduced density of stable nuclei, allowing each to grow unhindered and larger. Our results suggest a simple and robust approach for enhancing colloidal crystallization near the "sticky sphere" limit, and support the notion that differing extents of interaction heterogeneity arising from various particle functionalization protocols may contribute to the otherwise unexplained variations in crystallization outcomes reported in the literature.

Hydrodynamics selects the pathway for displacive transformations in DNA-linked colloidal crystallites.

The degree to which DNA-linked particle crystals, particularly those composed of micrometer-scale colloids, are able to dynamically evolve or whether they are kinetically arrested after formation remains poorly understood. Here, we study a recently observed displacive transformation in colloidal binary superlattice crystals, whereby a body-centered cubic to face-centered cubic transformation is found to proceed spontaneously under some annealing conditions. Using a comprehensive suite of computer simulation tools, we develop a framework for analyzing the many displacive transformation pathways corresponding to distinct, but energetically degenerate, random hexagonal close-packed end states. Due to the short-ranged, spherically symmetric nature of the particle interactions the pathways are all barrierless, suggesting that all end states should be equally likely. Instead, we find that hydrodynamic correlations between particles result in anisotropic mobility along the various possible displacive pathways, strongly selecting for pathways that lead to the fcc-CuAu-I configuration, explaining recent experimental observations. This finding may provide clues for discovering new approaches for controlling structure in this emerging class of materials.

Transfusing Wisely: Clinical Decision Support Improves Blood Transfusion Practices.

BACKGROUND: The cost and risks of red blood cell (RBC) transfusions, along with evidence of overuse, suggest that improving transfusion practices is a key opportunity for health systems to improve both the quality and value of patient care. Previous work, which included a BestPractice Advisory (BPA), was adapted in a quality improvement project designed to reduce both exposure to unnecessary blood products and costs. METHODS: A prospective, pre-post study was conducted at an academic medical center with a diverse patient population. All noninfant inpatients without gastrointestinal bleeding who were not within 12 hours of surgical procedures were included. The interventions were education, a BPA, and other enhancements to the computerized provider order entry system. RESULTS: The percentage of multiunit (≥ 2 units) RBC transfusions decreased from 59.9% to 41.7% during the intervention period and to 19.7% postintervention (p < 0.0001). The percentage of inpatient RBC transfusion units administered for hemoglobin (Hb) ≥ 7 g/dL declined from 72.3% to 57.8% during the intervention period and to 38.0% for the postintervention period (p < 0.0001). The overall rate of inpatient RBC transfusion (units administered per 1,000 patient-days without exclusions) decreased from 89.8 to 78.1 during the intervention period and to 72.7 during the postintervention period (p <0.0001). The estimated annual cost savings was $1,050,750. CONCLUSION: The interventions reduced multiunit transfusions (by 67.1%) and transfusions for Hb ≥ 7 g/dL (by 47.4%). The improvement in the overall transfusion rate (19.0%) was less marked, limited by better baseline performance relative to other centers.

Predictive value of the present-on-admission indicator for hospital-acquired venous thromboembolism.

BACKGROUND: Hospital-acquired venous thromboembolic (HA-VTE) events are an important, preventable cause of morbidity and death, but accurately identifying HA-VTE events requires labor-intensive chart review. Administrative diagnosis codes and their associated "present-on-admission" (POA) indicator might allow automated identification of HA-VTE events, but only if VTE codes are accurately flagged "not present-on-admission" (POA=N). New codes were introduced in 2009 to improve accuracy. METHODS: We identified all medical patients with at least 1 VTE "other" discharge diagnosis code from 5 academic medical centers over a 24-month period. We then sampled, within each center, patients with VTE codes flagged POA=N or POA=U (insufficient documentation) and POA=Y or POA=W (timing clinically uncertain) and abstracted each chart to clarify VTE timing. All events that were not clearly POA were classified as HA-VTE. We then calculated predictive values of the POA=N/U flags for HA-VTE and the POA=Y/W flags for non-HA-VTE. RESULTS: Among 2070 cases with at least 1 "other" VTE code, we found 339 codes flagged POA=N/U and 1941 flagged POA=Y/W. Among 275 POA=N/U abstracted codes, 75.6% (95% CI, 70.1%-80.6%) were HA-VTE; among 291 POA=Y/W abstracted events, 73.5% (95% CI, 68.0%-78.5%) were non-HA-VTE. Extrapolating from this sample, we estimated that 59% of actual HA-VTE codes were incorrectly flagged POA=Y/W. POA indicator predictive values did not improve after new codes were introduced in 2009. CONCLUSIONS: The predictive value of VTE events flagged POA=N/U for HA-VTE was 75%. However, sole reliance on this flag may substantially underestimate the incidence of HA-VTE.

Interactions and stress relaxation in monolayers of soft nanoparticles at fluid-fluid interfaces.

Nanoparticles with grafted layers of ligand molecules behave as soft colloids when they adsorb at fluid-fluid interfaces. The ligand brush can deform and reconfigure, adopting a lens-shaped configuration at the interface. This behavior strongly affects the interactions between soft nanoparticles at fluid-fluid interfaces, which have proven challenging to probe experimentally. We measure the surface pressure for a stable 2D interfacial suspension of nanoparticles grafted with ligands, and extract the interaction potential from these data by comparison to Brownian dynamics simulations. A soft repulsive potential with an exponential form accurately reproduces the measured surface pressure data. A more realistic interaction potential model is also fitted to the data to provide insights into the ligand configuration at the interface. The stress of the 2D interfacial suspension upon step compression exhibits a single relaxation time scale, which is also attributable to ligand reconfiguration.

Interaction potentials from arbitrary multi-particle trajectory data.

Understanding the complex physics of particle-based systems at the nanoscale and mesoscale increasingly relies on simulation methods, empowered by exponential advances in computing speed. A major impediment to progress lies in reliably obtaining the interaction potential functions that control system behavior - which are key inputs for any simulation approach - and which are often difficult or impossible to obtain directly using traditional experimental methods. Here, we present a straightforward methodology for generating pair potential functions from large multi-particle trajectory datasets, with no operational constraints regarding their state of equilibration, degree of damping or presence of hydrodynamic interactions. Using simulated datasets, we demonstrate that the method is highly robust against trajectory perturbations from Brownian motion and common errors introduced by particle tracking algorithms. Given the recent rapid pace of advancement in high-speed and three-dimensional microscopy and associated particle tracking algorithms, we anticipate a near future experimental regime where easily collected high-dimensional trajectory sets can be rapidly converted to the detailed interaction and hydrodynamic force fields required to replicate the system's physics in simulation.

Where should we operate on the preterm neonate?

The ideal venue for neonatal surgical procedures has been the subject of a contentious debate between the leading pediatric hospitals throughout the world. Bias toward the location of neonatal surgery tends to be based on institutional practices. The following opposing viewpoints from two leading pediatric institutions in the United Kingdom and the United States highlight the relevant issues.

Letter to the editor on "Antimicrobial compounds isolated from Tropaeolum tuberosum".

A bisphosphonate recently isolated from Tropaeolum tuberosum is almost certainly a contaminant and not a genuine natural product.

Machine Learning and Augmented Intelligence Enables Prognosis of Type 2 Diabetes Prior to Clinical Manifestation.

BACKGROUND: The global incidence of type 2 diabetes (T2D) persists at epidemic proportions. Early diagnosis and/or preventive efforts are critical to attenuate the multi-systemic clinical manifestation and consequent healthcare burden. Despite enormous strides in the understanding of pathophysiology and on-going therapeutic development, effectiveness and access are persistent limitations. Among the greatest challenges, the extensive research efforts have not promulgated reliable predictive biomarkers for early detection and risk assessment. The emerging fields of multi-omics combined with machine learning (ML) and augmented intelligence (AI) have profoundly impacted the capacity for predictive, preventive, and personalized medicine. OBJECTIVE: This paper explores the current challenges associated with the identification of predictive biomarkers for T2D and discusses potential actionable solutions for biomarker identification and validation. METHODS: The articles included were collected from PubMed queries. The selected topics of inquiry represented a wide range of themes in diabetes biomarker prediction and prognosis. RESULTS: The current criteria and cutoffs for T2D diagnosis are not optimal nor consider a myriad of contributing factors in terms of early detection. There is an opportunity to leverage AI and ML to significantly enhance the understanding of the underlying mechanisms of the disease and identify prognostic biomarkers. The innovative technologies being developed by GATC are expected to play a crucial role in this pursuit via algorithm training and validation, enabling comprehensive and in-depth analysis of complex biological systems. CONCLUSION: GATC is an emerging leader guiding the establishment of a systems approach towards research and predictive, personalized medicine. The integration of these technologies with clinical data can contribute to a more comprehensive understanding of T2D, paving the way for precision medicine approaches and improved patient outcomes.