Clinical statistical analysis plan for the ACCURE trial:the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial

Background: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial. Design and methods: The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life. Discussion: The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients. Trial registration: Dutch Trial Register (NTR) NTR2883. Registered May 3, 2011. ISRCTN, ISRCTN60945764. Registered August 12, 2019

Salbutamol for analgesia in renal colic : study protocol for a prospective, randomised, placebo-controlled phase II trial (SARC)

Background Renal colic is the pain experienced by a patient when a renal calculus (kidney stone) causes partial or complete obstruction of part of the renal outflow tract. The standard analgesic regimes for renal colic are often ineffective; in some studies, less than half of patients achieve complete pain relief, and a large proportion of patients require rescue analgesia within 4 h. Current analgesic regimes are also associated with significant side effects including nausea, vomiting, drowsiness and respiratory depression. It has been hypothesised that beta adrenoreceptor agonists, such as salbutamol, may reduce the pain of renal colic. They have been shown to impact a number of factors that target the physiological causes of pain in renal colic (ureteric spasm and increased peristalsis, increased pressure at the renal pelvis and prostaglandin release with inflammation). There is biological plausibility and a body of evidence sufficient to suggest that this novel treatment for the pain of renal colic should be taken to a phase II clinical trial. The aim of this trial is to test whether salbutamol is an efficacious analgesic adjunct when added to the standard analgesic regime for patients presenting to the ED with subsequently confirmed renal colic. Methods A phase II, randomised, placebo-controlled trial will be performed in an acute NHS Trust in the East Midlands. Patients presenting to the emergency department with pain requiring IV analgesia and working diagnosis of renal colic will be randomised to receive standard analgesia ± a single intravenous injection of Salbutamol. Secondary study objectives will explore the feasibility of conducting a larger, phase III trial. Discussion The trial will provide important information about the efficacy of salbutamol as an analgesic adjunct in renal colic. It will also guide the development of a definitive phase III trial to test the cost and clinical effectiveness of salbutamol as an analgesic adjunct in renal colic. Salbutamol benefits from widespread use across the health service for multiple indications, extensive staff familiarity and a good side effect profile; therefore, its potential use for pain relief may have significant benefits for patient care. Trial registration ISRCTN Registry ISRCTN14552440. Registered on 22 July 201

Appropriateness of acute admissions and last in-patient day for patients with long term neurological conditions

<p>Abstract</p> <p>Background</p> <p>To examine the appropriateness of admissions and in-patient stay for patients with long term neurological conditions (LTNCs). To identify variables predictive of appropriateness and explore management alternatives.</p> <p>Methods</p> <p>Adults admitted as acute patients to Derby Hospitals NHS Foundation Trust (England). Data were collected prospectively and examined by a multi-disciplinary expert panel to determine the appropriateness of admission and length of stay (LoS). Management alternatives were discussed.</p> <p>Results</p> <p>A total of 119 participants were recruited. 32 admissions were inappropriate and 83 were for an inappropriate duration. Whether a participant lived in their own home was predictive of an inappropriate admission. The number of LTNCs, number of presenting complaints and whether the participant lived alone in their own home were predictive of an inappropriate LoS. For admissions judged to be inappropriate, the panel suggested management alternatives.</p> <p>Conclusion</p> <p>Patients with LTNCs are being admitted to hospital when other services, e.g. ambulatory care, are available which could meet their needs. Inefficiencies in hospital procedures, such as discharge planning and patient transfers, continue to exist. Recognition of the need to plan for discharge at admission and to ensure in-patient services are provided in a timely manner may contribute towards improved efficiency.</p

Numerical investigation of the dynamics of a small body in a Maxwell Ring-type N-Body system where the central primary creates a Manev -type Post-Newtonian potential field

705 σ.Η παρούσα ερευνητική εργασία πραγματεύεται μία παραλλαγή του δακτυλιοειδούς προβλήματος των Ν+1 σωμάτων (ring problem), η οποία έγκειται στο γεγονός ότι τα ν=Ν-1 όμοια περιφερειακά σώματα κείνται στις κορυφές ενός ιδεατού κανονικού ν-γώνου και δημιουργούν Νευτώνεια δυναμικά, ενώ το το Ν-οστό πρωτεύον σώμα με διαφορετική μάζα από εκείνη των περιφερειακών δημιουργεί ένα Μετα-Νευτώνειο δυναμικό τύπου Manev , όπου Α=1 και Β=eα (όπου e καθαρός αριθμός και α η πλευρά του κανονικού πολυγωνικού σχηματισμού των περιφερειακών σωμάτων). Το δυναμικό σύστημα χαρακτηρίζεται από τρεις παραμέτρους: (i) το πλήθος ν των περιφερειακών σωμάτων, (ii) την παράμετρο β=m0/m του λόγου της μάζας του κεντρικού σώματος m0 προς τη μάζα m ενός περιφερειακού και (iii) τον συντελεστή e της "διαταραχής" του Μετα-Νευτώνειου πεδίου του κεντρικού σώματος. Σε αυτό το εξελιγμένο μοντέλο, μελετάται η δυναμική συμπεριφορά του μικρού σώματος, το οποίο κινείται στο πεδίο που δημιουργείται από όλα τα μεγάλα σώματα του σχηματισμού, χωρίς το ίδιο να επηρεάζει την κίνησή τους. Πιο συγκεκριμένα, ερευνούμε τις θέσεις ισορροπίας και την ευστάθειά τους, καθώς και την επίδραση των παραμέτρων ν, β και e σε διάφορα χαρακτηριστικά του δυναμικού προβλήματος, όπως στις καμπύλες και στις επιφάνειες μηδενικής ταχύτητας, στην ύπαρξη και εξέλιξη των εστιακών σημείων και καμπύλων, στις ελκτικές περιοχές των θέσεων ισορροπίας, στην κατανομή και παραμετρική εξέλιξη των απλών, διπλών και τριπλών περιοδικών τροχιών στο φασικό χώρο των αρχικών συνθηκών, αλλά και στην ευστάθεια και στις διακλαδώσεις τους με άλλες οικογένειες διαφορετικής πολλαπλότητας. Η διατριβή εμπλουτίζεται με 750 περίπου σχήματα και διαγράμματα, καθώς και με 76 πίνακες με ενδεικτικά αποτελέσματα.The N-body problem is one of the most important issues in Celestial Mechanics. In the relevant literature there are many particular cases for systems with N>3. One of these cases is based upon a model where the N-1 of the bodies-members of the system are considered to have equal masses m and are located at the vertices of an imaginary regular polygon, while another body with different mass m0 is located at the center of mass of the system. In the resultant force field created by the N big bodies, there is a very small body which moves without affecting the motion of the primaries. The initial statement of the problem was based on the assumption that all big bodies create Newtonian force fields. Here we consider a version of the model where the central body creates a Manev-type potential , where A=1 and B=eα with α being the side of the regular polygon of the primaries configuration. The problem is characterized by three parameters, namely the number ν of the peripheral primaries, the mass parameter β=m0/m and a coefficient e which measures the contribution of the non-Newtonian term of the potential. We investigate the equilibrium locations, their stability and the effect of the above parameters on these features as well as, the zero-velocity curves and surfaces and their parametric evolution, the existing focal points and focal curves, the basins of attraction of the equilibria, the simple, double and triple periodic orbits, their distribution in the phase space of the initial conditions, their parametric variation, as well as their stability and the bifurcations of their families. The Thesis is enriched with more than 750 figures, plots and diagrams as well as, with 76 tables containing some indicative results.Δημήτριος Γ. Φακή

Description of a novel polymorphic gene encoding for arylamine N-acetyltransferase in the rhesus macaque (Macaca mulatta), a model animal for endometriosis.

OBJECTIVES: Case-control studies have previously associated polymorphisms in the gene encoding the xenobiotic metabolizing enzyme arylamine N-acetyltransferase 2 (NAT2) with endometriosis, a common multifactorial disease in women. These studies, however, have been problematic on methodological grounds and their results are inconclusive. To better understand the possible relationship between the NAT2 gene and endometriosis, we characterized its homologue in the rhesus macaque, an animal model for the disease. METHODS: Human NAT2-specific primers were used to isolate orthologous gene sequences from four unrelated rhesus macaques of the same colony. Recombinant proteins were expressed in mammalian cells and analysed for their ability to acetylate NAT substrates and bind anti-NAT antibodies. RESULTS: A polymorphic gene, showing 94% identity to human NAT2, was identified in the rhesus macaque. Its two characterized alleles, designated (MACMU)NAT2*1 and (MACMU)NAT2*2, were differentiated by one synonymous (C(624)T) and one nonsynonymous (G(691)A) polymorphism, the latter causing a Val(231)Ile substitution. The recombinant (MACMU)NAT2 protein was not recognized by anti-(HUMAN)NAT1 antibody, but reacted with antibodies against (HUMAN)NAT2 or the active site of NAT. Rhesus NAT2 provided relatively high acetylation activity with p-anisidine, lower activity with procainamide, sulphamethazine or 5-aminosalicylate and poor activity with p-aminobenzoic acid. Differences in the activities of the two allozymes were evident with most substrates. CONCLUSIONS: A polymorphic homologue of human NAT2 was characterized in the rhesus macaque, to facilitate investigations of the postulated involvement of this isoenzyme in the toxicogenetics of endometriosis

Energy transfer in aggregated CuInS₂/ZnS core-shell quantum dots deposited as solid films

We report on the morphology and optical properties of CuInS2/ZnS core-shell quantum dots in solid films by means of AFM, SEM, HRTEM, steady state and time-resolved photoluminescence (PL) spectroscopy. The amount of aggregation of the CuInS2/ZnS QDs was controlled by changing the preparation conditions of the films. A red-shift of the PL spectrum of CuInS2/ZnS core-shell quantum dots, deposited as solid films on silicon substrates, is observed upon increasing the amount of aggregation. The presence of larger aggregates was found to lead to a larger PL red-shift. Besides, as the degree of aggregation increased, the PL decay became slower. We attribute the observed PL red-shift to energy transfer from the smaller to the larger dots within the aggregates, with the emission being realized via a long decay recombination mechanism (100-200 ns), the origin of which is discussed.</p

Chromosome mapping of the genes for murine arylamine N-acetyltransferases (NATs), enzymes involved in the metabolism of carcinogens: identification of a novel upstream noncoding exon for murine Nat2

Arylamine N-acetyltransferases (NATs) catalyse acetylation reactions which can result in either detoxification or activation of arylamine carcinogens. The human NAT loci (NAT1, NAT2, and a pseudogene, NATP) have been mapped to human chromosome 8p22, a region frequently deleted in tumours. There are three functional genes in mice (Nat1, Nat2, and Nat3) encoding for three NAT isoenzymes. Different alleles at the Nat2 locus are responsible for the acetylation polymorphism identified in different mouse strains. We show that Nat3 is close to Nat1 and Nat2, by screening of a P1 artificial chromosome (PAC) library and provide cytogenetic evidence for co-localisation of the three genes in chromosome region 8 B3.1-B3.3. The Nat region of mouse and human is homologous. We also provide sequence information and a restriction map in the vicinity of Nat1 and Nat2 and describe a noncoding exon located 6 kb upstream of the Nat2 coding region

Dynamics of Intramolecular Energy Hopping in Multi-Bodipy Self-Assembled Metallocyclic Species: A Tool for Probing Subtle Structural Distortions in Solution

The intramolecular excitation energy transfer (EET) processes in a series of fluorescent-unquenched, self-assembled metallocycles consisting of spatially fixed-separated and parallel-aligned Bodipy chromophores, are investigated here by steady-state and femtosecond-fluorescence upconversion measurements in the solution phase. These multi-Bodipy macrocycles, namely, the rhomboid (A1), the tetragon (A2) and the hexagon (A3), are formed via temperature-regulated Pt(II)-pyridyl coordination and consist, respectively, of two, four, and six Bodipy subunits, which are locked at the corners and aligned with their long molecular axes perpendicular to the rigid polygonal frame formed by the alternating B⋯Pt(II) connectivities. Extensive simulations and fits to the experimental fluorescence anisotropy decays r(t) show that EET within the cyclic scaffolds is quite uniform and much faster than the intrinsic decay rate of the Bodipy&apos;s. The equalization of the excitation survival probabilities over time of all chromophores is found to be dependent upon the size of the macrocycle. From the observed dynamics supported by geometry optimization calculations, it is concluded that, in contrast to the model compound A1, in the large macrocycles the perfect parallel orientation of the Bodipy dipoles is lifted through limited out-of-plane distortions of the metallocyclic framework from a planar conformation. Additionally, we show that, as opposed to analogous covalent macrocycles, the survival probability of excitons as well as the degree of symmetry distortion and homogeneity in dipole spacing remains nearly intact as the size of the macrocycle increases from tetragon to hexagon. (Chemical Equation Presented). © 2017 American Chemical Society

Cooperative Self-Assembly Enables Two-Dimensional H-type Aggregation of a Sterically Crowded Perylene-Bisimide Dimer

Identifying the role of multiple cooperative supramolecular interactions and the working mechanism underlying the formation of sophisticated, well-defined self-assembled architectures is definitely a challenging and formidable task in understanding the complexity in chemical systems and engineering the properties of advanced materials. The topological design of multifunctional tectons, capable of self-organizing into patterned supramolecular assemblies comprising stacked aromatic molecules, is of particular importance because it can lead to the predictable emergence of controlled functions with tailored electronic properties. Herein, we provide spectroscopic, structural, and mechanistic insights on metal-ion-mediated self-assembly of a charged, amphiphilic perylene-bisimide (PBI) dimer S into two-dimensional (2D) arrays consisting of parallel columnar PBI stacks with a precise spatial arrangement and pattern behavior, using a readily accessible design strategy. The building block (S), a centrosymmetric PBI homodimer bearing a disulfonated trans-stilbene core, was designed to concurrently feature high complexation directionality with a strong binding affinity through multiple supramolecular interactions. In solvents that efficiently solvate PBI, e.g., chloroform, the zinc ion interacts strongly through electrostatic interactions with the negatively charged core of S, and with the πcloud of the stilbene moiety (cation-πinteractions) forming simple 1:1 adducts. In methanol, the findings manifest the efficient formation of well-defined aggregates with H-type excitonic coupling. A single-crystal X-ray structure reveals, despite the sterically crowded bay area of PBIs constituting S, an unprecedented pattern of 2D arrays comprising face-to-face, slipped π-stacked PBI interdimers that pack in parallel columns. This molecular arrangement explains the quenched fluorescence in solution, as well as the appearance of weak excimer-like fluorescence both in solution and crystals. The spectroscopic and structural findings converge to the conclusion that the development of aggregates in solution proceeds by a cooperative growth process driven by a collection of different supramolecular interactions, i.e., electrostatic (core of S), π-πstacking (terminal PBIs), and multiple C-H···π(bay substituents). A corresponding aggregation model fits satisfactorily the experimental data in solution and allows extracting the association constants and spectra of the equilibrated species. © Copyright © 2019 American Chemical Society