Structural engineering from an inverse problems perspective.

The field of structural engineering is vast, spanning areas from the design of new infrastructure to the assessment of existing infrastructure. From the onset, traditional entry-level university courses teach students to analyse structural responses given data including external forces, geometry, member sizes, restraint, etc.-characterizing a forward problem (structural causalities → structural response). Shortly thereafter, junior engineers are introduced to structural design where they aim to, for example, select an appropriate structural form for members based on design criteria, which is the inverse of what they previously learned. Similar inverse realizations also hold true in structural health monitoring and a number of structural engineering sub-fields (response → structural causalities). In this light, we aim to demonstrate that many structural engineering sub-fields may be fundamentally or partially viewed as inverse problems and thus benefit via the rich and established methodologies from the inverse problems community. To this end, we conclude that the future of inverse problems in structural engineering is inexorably linked to engineering education and machine learning developments.

Statistics of highly heterogeneous flow fields confined to three-dimensional random porous media.

We present a strong relationship between the microstructural characteristics of, and the fluid velocity fields confined to, three-dimensional random porous materials. The relationship is revealed through simultaneously extracting correlation functions R_{uu}(r) of the spatial (Eulerian) velocity fields and microstructural two-point correlation functions S_{2}(r) of the random porous heterogeneous materials. This demonstrates that the effective physical transport properties depend on the characteristics of complex pore structure owing to the relationship between R_{uu}(r) and S_{2}(r) revealed in this study. Further, the mean excess plot was used to investigate the right tail of the streamwise velocity component that was found to obey light-tail distributions. Based on the mean excess plot, a generalized Pareto distribution can be used to approximate the positive streamwise velocity distribution.

Flow cytometry is a promising and rapid method for differentiating between freely suspended Escherichia coli and E. coli attached to clay particles.

AIM: A standard procedure does not exist to distinguish between attached and unattached micro-organisms. In this study, we compared two methods to quantify between Escherichia coli attached to clay particles and E. coli freely suspended in solution: flow cytometry (attachment assay and viability assay) and settling (or centrifugation followed by settling). METHODS AND RESULTS: Methods were tested using three environmental strains collected from swine facilities (A, B and C) and one purchased modified pathogenic strain (ATCC 43888); four clay particles: Hectorite, Kaolinite, Ca-Montmorillonite, Montmorillonite K-10; and a range of surface area ratios (particle surface area to E. coli surface area). When comparing the two methods, the per cent attached obtained from the flow cytometry was lower, but not significantly different from the per cent attached obtained from the settling method for all conditions except when the particle was Hectorite or Montmorillonite K-10; when the strain was C; and when the surface area ratio was below 100. Differences between the methods are likely because traditional culture-based methods cannot detect the viable but nonculturable (VBNC) population, whereas flow cytometry can detect the fraction of VBNC with intact membranes. CONCLUSION: Our results indicate that flow cytometry is a rapid and culture-independent method for differentiating between attached and unattached micro-organisms. SIGNIFICANCE AND IMPACT OF THE STUDY: Flow cytometry is useful for laboratory-based studies of micro-organism-particle interactions.

Structure of the 2,4'-dihydroxyacetophenone dioxygenase from Alcaligenes sp. 4HAP.

The enzyme 2,4'-dihydroxyacetophenone dioxygenase (DAD) catalyses the conversion of 2,4'-dihydroxyacetophenone to 4-hydroxybenzoic acid and formic acid with the incorporation of molecular oxygen. Whilst the vast majority of dioxygenases cleave within the aromatic ring of the substrate, DAD is very unusual in that it is involved in C-C bond cleavage in a substituent of the aromatic ring. There is evidence that the enzyme is a homotetramer of 20.3 kDa subunits, each containing nonhaem iron, and its sequence suggests that it belongs to the cupin family of dioxygenases. In this paper, the first X-ray structure of a DAD enzyme from the Gram-negative bacterium Alcaligenes sp. 4HAP is reported, at a resolution of 2.2 Å. The structure establishes that the enzyme adopts a cupin fold, forming dimers with a pronounced hydrophobic interface between the monomers. The catalytic iron is coordinated by three histidine residues (76, 78 and 114) within a buried active-site cavity. The iron also appears to be tightly coordinated by an additional ligand which was putatively assigned as a carbonate dianion since this fits the electron density optimally, although it might also be the product formate. The modelled carbonate is located in a position which is highly likely to be occupied by the α-hydroxyketone group of the bound substrate during catalysis. Modelling of a substrate molecule in this position indicates that it will interact with many conserved amino acids in the predominantly hydrophobic active-site pocket where it undergoes peroxide radical-mediated heterolysis.

The changing face of internal medicine: patient centred care.

Patient centred care is now considered the gold standard and there should be 'no decision about me, without me'. Internists who treat patients with complex multi-morbidities should consider patients' preferred outcomes, following a 'goal-oriented' principle. Perhaps the most important barrier to goal-oriented care is that medicine is deeply rooted in a disease-outcome-based paradigm. Rather than asking what patients want, the culture of modern medicine has prioritised optimal disease management according to guidelines and population goals. Doing what is right for the patient should be based on trust. Patients and internists must therefore meet as equals: 'I' and 'you' should be replaced by 'we'.

The glucose and lipid effects of colesevelam as monotherapy in drug-naïve type 2 diabetes.

Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥7.5% and ≤9.5%) with diet and exercise alone were randomized to receive colesevelam 3.75 g/day (n=176) or placebo (n=181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (-2.92 mmol/mol [0.3%]; p=0.01) and fasting plasma glucose (-10.3 mg/dl; p=0.04) at week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (-11.2%; p<0.0001), total cholesterol (-5.1%; p=0.0005), non-high-density lipoprotein cholesterol (-7.4%; p=0.0001), and apolipoprotein B (-6.5%; p=0.0001) and increased apolipoprotein A-I (+ 2.4%; p=0.04), and triglycerides (+ 9.7%; p=0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved.ClinicalTrials.gov identifier: NCT00789737.

Studies of pear-shaped nuclei using accelerated radioactive beams.

There is strong circumstantial evidence that certain heavy, unstable atomic nuclei are 'octupole deformed', that is, distorted into a pear shape. This contrasts with the more prevalent rugby-ball shape of nuclei with reflection-symmetric, quadrupole deformations. The elusive octupole deformed nuclei are of importance for nuclear structure theory, and also in searches for physics beyond the standard model; any measurable electric-dipole moment (a signature of the latter) is expected to be amplified in such nuclei. Here we determine electric octupole transition strengths (a direct measure of octupole correlations) for short-lived isotopes of radon and radium. Coulomb excitation experiments were performed using accelerated beams of heavy, radioactive ions. Our data on (220)Rn and (224)Ra show clear evidence for stronger octupole deformation in the latter. The results enable discrimination between differing theoretical approaches to octupole correlations, and help to constrain suitable candidates for experimental studies of atomic electric-dipole moments that might reveal extensions to the standard model.

Direct observation of long-lived isomers in 212Bi.

Long-lived isomers in (212)Bi have been studied following (238)U projectile fragmentation at 670 MeV per nucleon. The fragmentation products were injected as highly charged ions into a storage ring, giving access to masses and half-lives. While the excitation energy of the first isomer of (212)Bi was confirmed, the second isomer was observed at 1478(30) keV, in contrast to the previously accepted value of >1910 keV. It was also found to have an extended Lorentz-corrected in-ring half-life >30 min, compared to 7.0(3) min for the neutral atom. Both the energy and half-life differences can be understood as being due a substantial, though previously unrecognized, internal decay branch for neutral atoms. Earlier shell-model calculations are now found to give good agreement with the isomer excitation energy. Furthermore, these and new calculations predict the existence of states at slightly higher energy that could facilitate isomer deexcitation studies.

Chemical engineering of molecular qubits.

We show that the electron spin phase memory time, the most important property of a molecular nanomagnet from the perspective of quantum information processing, can be improved dramatically by chemically engineering the molecular structure to optimize the environment of the spin. We vary systematically each structural component of the class of antiferromagnetic Cr(7)Ni rings to identify the sources of decoherence. The optimal structure exhibits a phase memory time exceeding 15 µs.

Evidence for a smooth onset of deformation in the neutron-rich Kr isotopes.

The neutron-rich nuclei 94,96Kr were studied via projectile Coulomb excitation at the REX-ISOLDE facility at CERN. Level energies of the first excited 2(+) states and their absolute E2 transition strengths to the ground state are determined and discussed in the context of the E(2(1)(+)) and B(E2;2(1)(+)→0(1)(+)) systematics of the krypton chain. Contrary to previously published results no sudden onset of deformation is observed. This experimental result is supported by a new proton-neutron interacting boson model calculation based on the constrained Hartree-Fock-Bogoliubov approach using the microscopic Gogny-D1M energy density functional.

Schottky mass measurement of the 208Hg isotope: implication for the proton-neutron interaction strength around doubly magic 208Pb.

Time-resolved Schottky mass spectrometry has been applied to uranium projectile fragments which yielded the mass value for the 208Hg (Z=80, N=128) isotope. The mass excess value of ME=-13 265(31) keV has been obtained, which has been used to determine the proton-neutron interaction strength in 210Pb, as a double difference of atomic masses. The results show a dramatic variation of the strength for lead isotopes when crossing the N=126 neutron shell closure, thus confirming the empirical predictions that this interaction strength is sensitive to the overlap of the wave functions of the last valence neutrons and protons.

Engineering silica particles as oral drug delivery vehicles.

Porous silica particles are emerging as complementary systems to polyester microspheres for the encapsulation and controlled delivery of small-organic drugs. Their recent application in pharmaceutics is strengthened by well-established characterization and synthetic routes from the chemical engineering sciences. Silica is an interesting scaffold material for the encapsulation of organic molecules. It can be formed into hierarchical structures over a wide range of length scales and interconnectivities. Encapsulation can therefore be tailored not only to the drug but the desired release properties. In addition to surfactant-templating of hierarchical silica structures, polypeptides from marine organisms may offer biological routes to novel silica materials. Silica sol-gels have also been evaluated as delivery vehicles, particularly with regard to generating hybrid systems with mesoporous silica or composite xerogels. This review will first focus on the detailed characterisation of pore size and structure of mesoporous silica with regards water penetration and drug diffusion. We then describe the pharmaceutical applications of silica materials with regard to improving oral bioavailability, multiparticulate systems for gastroretention or sustained release, composite xerogels and in vivo biocompatibility.

The Sjögren's Syndrome Damage Index--a damage index for use in clinical trials and observational studies in primary Sjögren's syndrome.

OBJECTIVE: To validate a tool for assessment of accumulated damage in patients with Primary SS (PSS). METHODS: Of the total 114 patients fulfilling American-European Consensus Group (AECG) criteria for PSS 104 were included in the study and assessed by rheumatologists at T (time) = 0 months and T = 12 months. On each occasion, damage and activity data, and autoantibody status were collected. SF-36 and Profile of Fatigue and Discomfort-Sicca Symptoms Inventory (PROFAD-SSI) questionnaires were completed. Cross-sectional analysis of this data was subject to a process of expert validation by 11 ophthalmologists, 14 oral medicine specialists and 8 rheumatologists. Items were removed from the index if >or= 50% of respondents recommended exclusion. Statistical validation was performed on remaining items. Spearman's rank analysis was used to investigate associations between damage scores and other disease status measures and Wilcoxon matched-pair analysis to assess sensitivity to change in the damage score. RESULTS: Based on the expert validation, a 29-item damage score was agreed incorporating ocular, oral and systemic domains. Total damage score correlated with disease duration at study entry (r = 0.436; P < 0.001), physical function as measured by SF-36 (r = 0.250, T = 0 months; r = 0.261 T = 12 months) and activity as measured by the Sjögren's Systemic Clinical Activity Index (r = 0.213, T = 0 months; r = 0.215, T =12 months). Ocular damage score correlated with the 'eye dry' domain of PROFAD-SSI (r = 0.228, T = 0 months; r = 0.365, T = 12 months). Other associations not present on both assessments were considered clinically insignificant. On Wilcoxon analysis, the index was sensitive to change over 12 months (z = -3.262; P < 0.01). CONCLUSION: This study begins validation of a tool for collection of longitudinal damage data in PSS. We recommend further trial in both the experimental and clinical environment.

Interferon and ribavirin therapy does not select for resistance mutations in hepatitis C virus polymerase.

Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon α. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase.

A randomized group intervention trial to enhance mood and self-efficacy in people with multiple sclerosis.

OBJECTIVES: To document mood, self-efficacy, and resiliency in people with multiple sclerosis (MS) following a brief group psychological intervention, and to examine whether benefits were greater than those derived from provision of education or group social interaction. DESIGN: A randomized controlled intervention trial assessing outcomes at five time points over a 1-year follow-up. METHODS: Participants with MS were assigned to one of three groups: one receiving brief group psychological intervention (PG) comprising three 90 minute cognitive behavioural sessions supported by an Information Booklet dealing with mental and emotional issues relating to MS; a group provided only with educational material - the information booklet group (IBG); and a group who not only received the booklet but also participated in non-structured social discussion (SDG) sessions similar in length and number to PG participants. Outcomes were documented using questionnaires. RESULTS: Outcomes were assessed using area under the curve (AUC) analysis: a summary measure that considers individual changes serially over time to provide a more meaningful picture than the one based on single time points. Ninety participants were followed up over the 12-month post-intervention, and their data are included in the analysis. Analyses indicated benefits in all outcome dimensions for the psychotherapeutic (PG) and social discussion groups (SDG) relative to the IBG group, but no differences between PG and SDG. CONCLUSION: The study indicates benefits from psychosocial intervention compared with bibliotherapy, with some additional benefit from psychological intervention compared with a social discussion group. Results suggest that much of the benefit may derive from non-specific therapeutic components. Without psychosocial intervention, the psychological status of people with MS worsened over time.

Sjögren's Systemic Clinical Activity Index (SCAI)--a systemic disease activity measure for use in clinical trials in primary Sjögren's syndrome.

OBJECTIVE: This article describes the development of the Sjögren's Systemic Clinical Activity Index (SCAI) for the measurement of systemic disease activity in patients with primary Sjögren's syndrome (PSS). METHODS: A pilot tool was developed based on expert consensus and previous published data. One hundred and four patients with PSS were evaluated in a cross-sectional analysis, of whom 65 were reviewed at 3-monthly intervals, using this index, over a 12-month period. Factor analysis was used to evaluate the proposed domain structure. External validation was assessed by comparison with relevant domains of the Profile of Fatigue and Discomfort (PROFAD), Medical Outcomes Study Short Form-36 (SF-36) and The World Health Organization Quality of Life-Bref (WHOQOL-BREF). Sensitivity to change was assessed by comparing SCAI-derived flares with physician-designated disease flare and intention-to-treat analysis. A reliability and repeatability workshop was also held. RESULTS: Factor analysis supported the proposed domain structure. There were strong correlations between the SCAI fatigue, musculoskeletal and Raynaud's components and the PROFAD fatigue, arthralgia and vascular domains. There was a significant correlation between change in therapy and SCAI-defined flares (P = 0.01). The mean kappa-test results both for reliability of the SCAI and for physician repeatability were 0.71. CONCLUSION: This initial evaluation supports the potential for the SCAI as a tool for systemic activity assessment in patients with PSS but additional work is required to assess sensitivity to change in clinical therapeutic trials.

Worries and concerns of patients with multiple sclerosis: development of an assessment scale.

This study examined the nature of worry in adult patients with multiple sclerosis (MS) in the UK. A measure of worry in MS was developed and the relationship between worry and standard scale measures of anxiety and depression was examined. Thirty-nine patients with MS and 40 controls completed the new worry scale (WQMS) that was psychometrically evaluated, together with the Penn State Worry Questionnaire (PSWQ), the Hospital Anxiety and Depression Scale (HAD) and a previously developed scale to assess self-efficacy in MS (SESMS). The scores for both anxiety (t = 2.34; P < 0.05) and depression (t = 5.52; P <0.01) were higher in MS patients than controls, as was the new scale for worry--the WQMS. A factor analysis (explaining 65.73% of the variance) suggests that the worries of patients may be dichotomized into those concerned with the physical effects of the disease and those relating to the impact on social interaction, family relationships and daily activity in the home and/or work. Worry in patients with MS was associated with a decreased sense of being able to produce positive activities or effect positive outcomes (low self-efficacy). The questionnaire provides a framework for investigation in clinic of specific concerns and level of worry they engender.