Relationship between emergency presentation, systemic inflammatory response, and cancer-specific survival in patients undergoing potentially curative surgery for colon cancer

Background Emergency presentation is recognized to be associated with poorer cancer-specific survival following curative resection for colorectal cancer. The present study examined the hypothesis that an enhanced systemic inflammatory response, prior to surgery, might explain the impact of emergency presentation on survival. Methods In all, 188 patients undergoing potentially curative resection for colorectal cancer were studied. Of these, 55 (29%) presented as emergencies. The systemic inflammatory response was assessed using the Glasgow Prognostic Score (mGPS), which is the combination of an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L). Results In the emergency group, tumor stage was greater (P < 0.01), more patients received adjuvant therapy (P < 0.01) more patients had an elevated mGPS (P < 0.01), and more patients died of their disease (P < 0.05). The minimum follow-up was 12 months; the median follow-up of the survivors was 48 months. Emergency presentation was associated with poorer 3-year cancer-specific survival in those patients aged 65 to 74 years (P < 0.01), in both males and females (P < 0.05), in the deprived (P < 0.01), in patients with tumor-node-metastasis (TNM) stage II disease (P < 0.01), in those who received no adjuvant therapy (P < 0.01), and in the mGPS 0 and 1 groups (P < 0.05) groups. On multivariate survival analysis of patients undergoing potentially curative surgery for TNM stage II colon cancer, emergency presentation (P < 0.05) and mGPS (P < 0.05) were independently associated with cancer-specific survival. Conclusions These results suggest that emergency presentation and the presence of systemic inflammatory response prior to surgery are linked and account for poorer cancer-specific survival in patients undergoing potentially curative surgery for colon cancer. Both emergency presentation and an elevated mGPS should be taken into account when assessing the likely outcome of these patients

Conformational Studies on Some Inhibitors of Thermolysin and EC 3.4.24.11

Molecular modeling is an exciting new approach in the field of drug design. A molecule's activity as a drug is dependent upon its conformation i.e. the three dimensional arrangement of its functional groups. Molecular mechanics coupled with interactive computer graphics is an excellent technique for studying the conformations of small molecules and this thesis presents a discussion of this technique and its application to some inhibitors of the enzymes Thermolysin and EC 3.4. 24.11. An introduction to the role of molecular mechanics in computer assisted drug design is given in Chapter One. Chapter Two describes the calculation of steric energies and the potential functions used to do this, while the procedures used for conformation generation and energy minimisation are discussed in Chapter Three (Appendix A lists one of the programs used for the conformation generation). The MOL software package is an interactive modeling system for small molecules which has been developed at Glasgow and Chapter Four contains a description of this system and its options. The structure and function of many enzymes is of prime importance in drug design since drugs often act by inhibition of enzymic pathways. Since very few enzyme structures are known from X-ray crystallography the primary source of information is enzyme kinetics and Chapter Five discusses some important properties of enzymes, such as their functions as catalysts, substrate and inhibitor kinetics and evolutionary pathways. EC 3.4.24.11. (a mammalian enzyme) and Thermolysin (EC 3.4.24.4, a bacterial enzyme) have very similar substrate specificities and are inhibited at comparable rates by several inhibitors. Very little is known about the active site of EC 3.4.24.11. , however, the structure of Thermolysin is well known from X-ray crystallography and in Chapter Six the known features of active sites of both enzymes are discussed and compared. It is known that two isosteric inhibitors of Thermolysin, B-Phenylpropionyl-L-Phe and Carbobenzyoxy-L-Phe, bind in completely opposite orientations. This unexpected phenomenancan be explained by conformational studies on the two inhibitors. In both cases the enzyme does not bind the lowest energy conformer, however in each case it binds the conformer which has both low energy and gives a good fit to the active site. The results of conformational studies of inhibitors of EC 3.4.24.11. are also discussed in Chapter Six and comparison of the low energy conformers with inhibitors of Thermolysin (from X-ray data) point to differences in the positions and sizes of the S1 and S2' subsites of the two enzymes. Both enzymes are highly specific for hydrophobic groups in the S1' site, with Phe being the most favoured residue. From the X-ray studies of Thermolysin it is known that the Phe side chain is bound with torsion angles of roughly 170 and 80. It is interesting to note that these torsion angle values are very common in many of the low energy conformers and it seems reasonable to assume that the high level of specificity arises from the fact that the side chain of the Phe, Leu etc. are normally in the most favourable position for binding to the S1 hydrophobic pocket without rearrangement. Several other differences between the two enzymes lead to the conclusion that their functional similarity is more likely to be a product of evolutionary convergence on function than of divergence from a common ancestor. Chapter Seven contains a brief summary of the programming which was done during the course of this project paying particular attention to both the motivation and methods involved in programming an array processor and as previously mentioned Appendix A contains a listing of the GLOMIN program - a conformation generation program which was modified to run on an array processor during the course of this project. Finally, Chapter Eight contains a discussion of work carried out in conjunction with Professor A. Y. Meyer while he was on sabbatical leave at Glasgow University. This work shows that force fields can be modified quite simply to give more transferable non-bonding parameters by the inclusion of an electrostatic term. A paper on this work has been published in the Journal of Computational Chemistry and a copy of this paper is given in Appendix B

Rapid detection of Mycobacterium tuberculosis by recombinase polymerase amplification.

Improved access to effective tests for diagnosing tuberculosis (TB) has been designated a public health priority by the World Health Organisation. In high burden TB countries nucleic acid based TB tests have been restricted to centralised laboratories and specialised research settings. Requirements such as a constant electrical supply, air conditioning and skilled, computer literate operators prevent implementation of such tests in many settings. Isothermal DNA amplification technologies permit the use of simpler, less energy intensive detection platforms more suited to low resource settings that allow the accurate diagnosis of a disease within a short timeframe. Recombinase Polymerase Amplification (RPA) is a rapid, low temperature isothermal DNA amplification reaction. We report here RPA-based detection of Mycobacterium tuberculosis complex (MTC) DNA in <20 minutes at 39 °C. Assays for two MTC specific targets were investigated, IS6110 and IS1081. When testing purified MTC genomic DNA, limits of detection of 6.25 fg (IS6110) and 20 fg (IS1081)were consistently achieved. When testing a convenience sample of pulmonary specimens from suspected TB patients, RPA demonstrated superior accuracy to indirect fluorescence microscopy. Compared to culture, sensitivities for the IS1081 RPA and microscopy were 91.4% (95%CI: 85, 97.9) and 86.1% (95%CI: 78.1, 94.1) respectively (n = 71). Specificities were 100% and 88.6% (95% CI: 80.8, 96.1) respectively. For the IS6110 RPA and microscopy sensitivities of 87.5% (95%CI: 81.7, 93.2) and 70.8% (95%CI: 62.9, 78.7) were obtained (n = 90). Specificities were 95.4 (95% CI: 92.3,98.1) and 88% (95% CI: 83.6, 92.4) respectively. The superior specificity of RPA for detecting tuberculosis was due to the reduced ability of fluorescence microscopy to distinguish Mtb complex from other acid fast bacteria. The rapid nature of the RPA assay and its low energy requirement compared to other amplification technologies suggest RPA-based TB assays could be of use for integration into a point-of-care test for use in resource constrained settings

Twenty questions about design behavior for sustainability, report of the International Expert Panel on behavioral science for design

How behavioral scientists, engineers, and architects can work together to advance how we all understand and practice design—in order to enhance sustainability in the built environment, and beyond.https://www.nature.com/documents/design_behavior_for_sustainability.pdfPublished versio

Trauma ICU Prevalence Project: the diversity of surgical critical care.

Background:Surgical critical care is crucial to the care of trauma and surgical patients. This study was designed to provide a contemporary assessment of patient types, injuries, and conditions in intensive care units (ICU) caring for trauma patients. Methods:This was a multicenter prevalence study of the American Association for the Surgery of Trauma; data were collected on all patients present in participating centers' trauma ICU (TICU) on November 2, 2017 and April 10, 2018. Results:Forty-nine centers submitted data on 1416 patients. Median age was 58 years (IQR 41-70). Patient types included trauma (n=665, 46.9%), non-trauma surgical (n=536, 37.8%), medical (n=204, 14.4% overall), or unspecified (n=11). Surgical intensivists managed 73.1% of patients. Of ICU-specific diagnoses, 57% were pulmonary related. Multiple high-intensity diagnoses were represented (septic shock, 10.2%; multiple organ failure, 5.58%; adult respiratory distress syndrome, 4.38%). Hemorrhagic shock was seen in 11.6% of trauma patients and 6.55% of all patients. The most common traumatic injuries were rib fractures (41.6%), brain (38.8%), hemothorax/pneumothorax (30.8%), and facial fractures (23.7%). Forty-four percent were on mechanical ventilation, and 17.6% had a tracheostomy. One-third (33%) had an infection, and over half (54.3%) were on antibiotics. Operations were performed in 70.2%, with 23.7% having abdominal surgery. At 30 days, 5.4% were still in the ICU. Median ICU length of stay was 9 days (IQR 4-20). 30-day mortality was 11.2%. Conclusions:Patient acuity in TICUs in the USA is very high, as is the breadth of pathology and the interventions provided. Non-trauma patients constitute a significant proportion of TICU care. Further assessment of the global predictors of outcome is needed to inform the education, research, clinical practice, and staffing of surgical critical care providers. Level of evidence:IV, prospective observational study

Pediatric Medical Subspecialist Use in Outpatient Settings

Importance A first step toward understanding whether pediatric medical subspecialists are meeting the needs of the nation’s children is describing rates of use and trends over time. Objectives To quantify rates of outpatient pediatric medical subspecialty use. Design, Setting, and Participants This repeated cross-sectional study of annual subspecialist use examined 3 complementary data sources: electronic health records from PEDSnet (8 large academic medical centers [January 1, 2010, to December 31, 2021]); administrative data from the Healthcare Integrated Research Database (HIRD) (14 commercial health plans [January 1, 2011, to December 31, 2021]); and administrative data from the Transformed Medicaid Statistical Information System (T-MSIS) (44 state Medicaid programs [January 1, 2016, to December 31, 2019]). Annual denominators included 493 628 to 858 551 patients younger than 21 years with a general pediatric visit in PEDSnet; 5 million beneficiaries younger than 21 years enrolled for at least 6 months in HIRD; and 35 million Medicaid or Children’s Health Insurance Program beneficiaries younger than 19 years enrolled for any amount of time in T-MSIS. Exposure Calendar year and type of medical subspecialty. Main Outcomes and Measures Annual number of children with at least 1 completed visit to any pediatric medical subspecialist in an outpatient setting per population. Use rates excluded visits in emergency department or inpatient settings. Results Among the study population, the proportion of girls was 51.0% for PEDSnet, 51.1% for HIRD, and 49.3% for T-MSIS; the proportion of boys was 49.0% for PEDSnet, 48.9% for HIRD, and 50.7% for T-MSIS. The proportion of visits among children younger than 5 years was 37.4% for PEDSnet, 20.9% for HIRD, and 26.2% for T-MSIS; most patients were non-Hispanic Black (29.7% for PEDSnet and 26.1% for T-MSIS) or non-Hispanic White (44.9% for PEDSnet and 43.2% for T-MSIS). Annual rates for PEDSnet ranged from 18.0% to 21.3%, which were higher than rates for HIRD (range, 7.9%-10.4%) and T-MSIS (range, 7.6%-8.6%). Subspecialist use increased in the HIRD commercial health plans (annual relative increase of 2.4% [95% CI, 1.6%-3.1%]), but rates were essentially flat in the other data sources (PEDSnet, −0.2% [95% CI, −1.1% to 0.7%]; T-MSIS, −0.7% [95% CI, −6.5% to 5.5%]). The flat PEDSnet growth reflects a balance between annual use increases among those with commercial insurance (1.2% [95% CI, 0.3%-2.1%]) and decreases in use among those with Medicaid (−0.9% [95% CI, −1.6% to −0.2%]). Conclusions and Relevance The findings of this cross-sectional study suggest that among children, 8.6% of Medicaid beneficiaries, 10.4% of those with commercial insurance, and 21.3% of those whose primary care is received in academic health systems use pediatric medical subspecialty care each year. There was a small increase in rates of subspecialty use among children with commercial but not Medicaid insurance. These data may help launch innovations in the primary-specialty care interface

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study

Introduction: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival. Methods: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that. Results: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, p 0.001). Conclusions: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias

Usage Analysis & Demonstrators - Version 2.0

This second version of the "Usage Analysis and Demonstrators " document mainly presents four case studies done during the second part of the SCOrWare project: ● (Task 3.1) Component and service-oriented architecture in the Scientific Software field (improvements of works done during the first year) ● (Task 3.2) SCA as a SOA design methodology in the domain of CDE (Collaborative Development Environment). Following the withdraw of one of the partners (eXo Platform, provider of an open-source portal solution) during the first year, some changes have been decided during the second part of the project and an alternative demonstrator has been designed. ● (Task 3.3) How SCA contributes to reusing and enriching software components. Following the first year project's review, this scenario has been reinforced, and is the major demonstrator for the SCOrWare platform in the field of enterprise business applications. ● (Task 3.5) Using the SCOrWare platform and a component-oriented architecture in the context of a network monitoring system. A new partner (Thales Communications, in collaboration with Open Wide and EBM Websourcing) has joined the SCOrWare consortium during the second part of the project, following the withdraw of Amadeus

British Association of Dermatologists and British Society for Rheumatology living guideline for managing people with Behçets 2024

The overall objective of the current iteration of this living guideline is to provide up-to-date, evidence-based recommendations for the management of Behçets disease/syndrome (henceforth termed ‘Behçets’ for simplicity, and as approved by the patient support group) in adults, children and young people. The document aims to: *offer an appraisal of all relevant literature up to 25 August 2023 focusing on any key developments // *address important, practical clinical questions relating to the primary guideline objective// *provide guideline recommendations and appropriate research recommendations.// The guideline is presented as a detailed review with highlighted recommendations for practical use in all appropriate community and hospital settings (see Section 3.0), in addition to a patient information leaflet (PIL; available on the BAD website: www.skinhealthinfo.org.uk)