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Background As part of the IBD-DICE (Determinants, Incidence and Consequences of CS Excess) collaborative research programme, this study examined rates of CS use and excess use in patients with IBD over time and after initial diagnosis. Methods Using IBM® MarketScan®, a representative claims database including details of >200 million individuals annually in the United States (US), we conducted a retrospective analysis of CS use from 2007 to 2018 in adult patients with IBD. Patients with conditions commonly associated with high levels of CS use (other than IBD) were excluded. CS use and excess were examined over calendar time in all patients (prevalent cohort), and in relation to the time of first IBD diagnosis in a newly diagnosed subset (incident cohort). Both a restrictive and a broader definition of CS use were examined. The restrictive definition only included claims for oral budesonide or prednisolone/prednisone with a pre-defined minimum daily equivalent dose of ≥17.5 mg, based on a typical tapering CS prescription for IBD. Under the broader definition, CS use was considered as any claim for oral prednisolone, prednisone, budesonide or methylprednisolone. Excess CS use was defined as either ≥2 CS courses in a 12-month period or ≥3 months of continuous CS use. Results The prevalent cohort (restrictive definition) included a total of 338,837 patients with 1,051,213 observation years. Rates of CS use ranged from 23.7% in 2007 to 19.3% in 2009 and plateaued in subsequent years (18.4%–21.1%). Rates of CS excess were higher from 2007 to 2009 (8.9%–11.5%) than in later years, and remained relatively stable from 2010 to 2018 (7.9%–8.6%). Similar patterns were seen with the broad definition of CS use, with CS excess rates of 15.2% in 2007 and 10.9%–11.8% from 2010 to 2018 (Figure 1). The incident cohort included 106,875 patients with 320,295 observation years. CS use was highest in the first year after diagnosis (24.2% and 29.4% with the restrictive and broad definitions, respectively) and decreased and plateaued by the second year after diagnosis (range: 10.8%–14.8% and 16.8%–21.0%, respectively). Similarly, CS excess was highest in the first year after diagnosis (11.7% and 14.6% with the restrictive and broad definitions, respectively) and decreased and levelled off by the second year after diagnosis (range: 3.6%–6.2% and 5.6%–8.6%, respectively) (Figure 2). Conclusion Despite advances in IBD treatment over the past decade and the adverse effects associated with CS, use of CS has not decreased substantially in the US in recent years. Levels of CS excess remain a concern, and may represent an opportunity for more optimised treatment and education, especially for newly diagnosed patients.

Introduction Brodie’s abscess is an uncommon variant of subacute osteomyelitis leading to a contained infectious focus within a bone. It classically occurs in young people with a history of trauma to the affected bone. We present a case of a Brodie’s abscess in a 52-year-old Crohn’s patient on dual immunosuppressive therapy. Case Description A 52 year old man with Crohn’s disease managed with adalimumab and methotrexate presented to an orthopedist with worsening left hip and thigh pain and fevers over the week prior. He reported a remote sports-related injury to the same region with mild pain intermittently over the subsequent years. MRI of the left pelvis showed an enhancing lesion of the anterior superior iliac spine with cortical erosion. He was admitted and started on broad spectrum antibiotics, and his immunosuppressive agents were held. CT-guided biopsy of the lesion returned as abscess, and culture of the lesion grew methicillin-sensitive staphylococcus aureus. The abscess was debrided in the OR and he completed a 6-week course of culture-guided antibiotic therapy. Discussion To our knowledge this is the first reported case of Brodie’s abscess associated with Crohn’s disease and dual immunosuppressive therapy. Opportunistic pathogens are most often associated with anti-TNFα therapy, though there is also evidence other bacterial infections are more frequent in these patients, particularly salmonellosis, listeriosis, and pneumococcal disease. Patients on anti-TNFα therapy appear to be at highest risk for serious infections in the first six months after initiation, but it is unclear if there is a persistent or cumulative risk with long-term therapy. The underlying mechanism of immunosuppression in anti-TNFα therapy is thought to be multifactorial, impacting both innate and adaptive immunity. Data suggests increased risk of infection in rheumatoid arthritis patients taking methotrexate. Only observational data exists regarding infection risk in Crohn’s patients on methotrexate, but it is reasonable to infer that it may have played a role in our patient’s presentation. Bone trauma seems to be associated with the development of Brodie’s abscess, and our patient reported a long history of chronic left hip and thigh pain due to a remote sports-related injury to that region. The source of his infection was most likely transient bacteremia, which seeded this nidus in his anterior superior iliac spine. While causation cannot be determined, this interesting case serves as reminder to prescribers of dual immunosuppressive therapy to be cognizant of infectious complications outside of those commonly attributed.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Facilitated by advances in analytical chemistry, soil, plant and water analysis now play a key role in the qualitative and quantitative characterisation of the environment. Ecological and health risk assessments can predict probabilities and risks of nominated environmental outcomes from the analytical data. The accuracy of these predictions, however, is dependent on data interpretability, which is constrained by our ability to determine that fraction of the contaminant that is active in biological systems. Soil analyses, for example, are used to characterise chemically contaminated sites and determine remediation thresholds. Such decisions, though, typically are based on total analyte concentrations that often are unrelated to environmental risk. While combined ecotoxicity and chemistry tests enable quantification of soil toxicity and identification of the analytes responsible, further progress may depend on development of sequential extraction and speciation tests calibrated against bioavailabi...

The impact of resort developments in three alpine streams of Kosciusko National Park was examined by the State Pollution Control Commission of NSW over 1981 and 1982. Physico-chemical measurements such as nutrient concentrations, stream flow and temperature were correlated with measures of periphyton growth using artificial substrates and the Thomas (1978) method for estimation of in-stream biomass.Stream flow was the major physical parameter controlling in-stream periphyton growth, far outweighing seasonal temperature variations. Nutrients emanating from resort developments were also a major influence on biomass and taxa. Natural accumulations occurred upstream of resort developments under low flow conditions and were associated with taxa typical of clean water conditions. The relationships between periphyton biomass and nutrient loads could be quantified.

This paper presents a design method, based on strength and stiffness criteria, which takes rational account of the effects of out-of-plane web forces and of the tendency for the stiffened panel to buckle overall. The method is validated by reference to the earlier theoretical and numerical parametric study. A method for multiple stiffeners is also proposed, but this has not yet been validated. (A)

Ecotoxicology provides a basis for making decisions on the likely impact of a chemical or effluent on the aquatic environment. It encompasses laboratory ecotoxicity tests of various types to explore relationships between exposure and effect under controlled laboratory conditions, through to studies of the effects of chemicals or effluents under a variety of ecological conditions in complex field ecosystems. This paper will focus on the value of laboratory ecotoxicity tests as a tool in assessing water quality. Laboratory tests are valuable (i) in deriving and assessing water quality criteria, (ii) for screening and ranking chemicals and predicting their hazard and risk, (iii) for establishing dilution levels of chemicals or effluents prior to discharge into water bodies, (iv) in determining cause-effect relationships in post-impact studies, and (v) for establishing and validating field bioindicators. Both the advantages and deficiencies of using ecotoxicological testing for these purposes are illustrated from research with pesticides, metals and sediments. Use of a combination of both laboratory- and field-based ecotoxicology studies is important to gain a full understanding of the effects of chemicals at the ecosystem level.

Young's equation, which was published in 1807, provides the basis for the Perry equation for the design of struts against flexural buckling. Current design for torsional flexural buckling assumes that the critical torsional flexural stress can be substituted for the Euler stress in the Perry equation. This takes no account of the actual stress distribution around the section, which differs greatly from that for flexural buckling. The paper proposes an application of Young's equation to the torsional flexural components of displacement, and a realistic stress distribution can then be found. Comparisons are given with the current design method. The calculation is readily performed with the help of a spread sheet. Alternatively, a possible simple design equation is suggested, based on the analysis in the paper. (A)

The behaviour of a simply supported plate with a single stiffener, subject to in-plane shear forces, is studied using elastic critical buckling analyses and non-linear elasto-plastic finite-element analyses. Particular attention is paid to factors relevant to design of the stiffener. Variations in stiffener rigidity, panel side ratio, panel slenderness, and imperfection shapes are considered. A primary conclusion for the panel slendernesses considered is that the stiffener behaviour depends primarily on moments caused by transverse shear forces in the panels on each side of the stiffener, and that the axial force in the stiffener has a relatively small effect. This contrasts with current design methods which are based primarily on axial forces resulting from tension field action. Stiffener requirements based on the analyses are compared with the requirements of current design codes, and rather large differences are found. Large differences between codes are also found. A subsequent paper will use the results presented in developing and validating a phenomenologically based model for stiffener design. (A)

Cladocerans (or water-fleas) are important animals in freshwater exosystems. They are widely used in toxicity tests because of their small size, ease of culture, and sensitivity to chemicals. They are particularly suited to life-cycle tests because newly-hatched young can produce offspring in less than one week. Most data are available for European and North American species, and may be not be appropriate to Australian conditions. In the present study, eight Australian cladocerans were evaluated in three-brood life-cycle tests over ten days or less. Species were evaluated by duration of life cycle, ease of handling, numbers of young produced in three broods, and stability in laboratory culture.Ceriodaphnia cfdubia was the best test species. The greatest number of young, the highest survival rate and the shortest time to produce three broods were achieved in filtered Sydney mains water, aged in the presence of fish, using blended trout pellets and alfalfa as food.

We have recently argued that manganites do not possess stripes of charge order, implying that the electron-lattice coupling is weak [Loudon et al., Phys. Rev. Lett. 94, 097202 (2005)]. Here we independently argue the same conclusion based on transmission electron microscopy measurements of a nanopatterned epitaxial film of ${\mathrm{La}}_{0.5}{\mathrm{Ca}}_{0.5}\mathrm{Mn}{\mathrm{O}}_{3}$. In strain relaxed regions, the superlattice period is modified by 2% to 3% with respect to the parent lattice, suggesting that the two are not strongly tied.

The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Neonatal estradiol injections in mice lead to follicular cystic ovaries that are similar to ovaries in patients with polycystic ovarian syndrome (PCOS). The present study examined ovarian cytokine production following neonatal estradiol injection.Female (C3H,HeJ x 129/HeJ)F1 mice were injected daily with 20 microg 17beta-estradiol from 0-3 days postpartum. At intervals, animals were sacrificed to determine ovarian architecture, circulating levels of estradiol, ovarian and peritoneal macrophage cytokine production, and ovarian P450 aromatase enzyme mRNA levels.Similar to PCOS, our results show that neonatally estradiol-injected mice have lower levels of circulating estrogen that are correlated with decreased mRNA levels of P450 aromatase enzyme. Our data also show that follicular cystic ovaries have increased tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production. This increase in TNF-alpha and IL-6 production is also observed in peritoneal macrophages of estradiol-injected mice.The present study showed that neonatal estrogen injection in mice has an overall systemic effect on cytokine production. We speculate that increased cytokine production may alter certain important steps in follicular maturation, ultimately contributing to ovarian dysfunction.

3 beta-Hydroxy-5-ene-steroid dehydrogenase/delta 5-delta 4-isomerase (3 beta HSD) is a NAD(+)-dependent membrane-bound enzyme that catalyzes the oxidation of delta 5-3 beta-hydroxysteroids to delta 4-3-keto structures during adrenal, gonadal, and placental steroidogenesis. Enzyme activity is located in both microsomes and mitochondria. In these experiments we examined the membrane topologies of 3 beta HSD in rat and calf adrenal microsomes and mitochondria by comparing access to the active sites of coenzyme and the inhibitor mersalyl, a nonpenetrant organic mercurial anion. Microsomal activity required exogenous NAD+ and was inhibited by mersalyl, indicating that the active site faced the medium in vitro and the cytoplasm in vivo. In contrast, mitochondrial 3 beta HSD used matrix space NAD+, was inhibited by reduction of intramitochondrial NAD(P)+, and was insensitive to mersalyl. Mitochondrial activity was decreased by exogenous NADH (apparent Ki, 2.8 microM) and increased by added NAD+ (apparent Ka, 2.4 microM). However, mersalyl blocked the effects of exogenous NADH and NAD+ and returned the activity to that observed before coenzyme addition. The membrane-sidedness of the NAD+ activation was examined further in submitochondrial particles prepared by sonication of pyridine nucleotide-depleted calf adrenal cortex mitochondria. Particles were prepared in the absence or presence of 10 mM NAD+ and contained none or 2.9-7.3 nmol NAD+/mg protein, respectively. Both groups of submitochondrial particles required exogenous NAD+ for 3 beta HSD activity, indicating that the active site faced the medium (the particles were everted), and the contained NAD+ was inside the particles. However, 3 beta HSD activity was increased 12-140% in particles that contained NAD+. The results suggest that mitochondrial 3 beta HSD is an integral inner membrane protein, that the active site faces the matrix space and is influenced by coenzyme availability, and that a regulatory site(s) faces the intermembrane space. Binding of NAD+ or NADH to this external site increases or decreases, respectively, the rate of catalysis at the active site. Mitochondrial 3 beta HSD activity may be enhanced by oxidation of intermembrane space NADH via an active rotenone- and antimycin-a-insensitive NADH oxidase.

3 beta-Hydroxysteroid dehydrogenase (HSD) is located in the endoplasmic reticulum and mitochondria. To determine whether the separate enzymes play different roles in steroidogenesis, the specific activity (SA) of both were measured at four different stages of the mouse estrous cycle. Microsomal HSD activity changed little throughout, averaging 8.7 +/- 0.7 nmol progesterone/min/mg protein. In contrast, mitochondrial HSD activity changed dramatically at diestrus, increasing to 14.4 nmol progesterone/min/mg protein. When measured at proestrus, estrus, and metestrus, mitochondrial HSD activity was 5.5, 7.4, and 4.5 nmol progesterone/min/mg protein, respectively. To ascertain whether the increase in mitochondrial HSD activity at diestrus could be due to a preferential induction of enzyme, its SA and the SA of a mitochondrial inner membrane enzyme, cytochrome C oxidase, were compared to the SA of a mitochondrial outer membrane enzyme, rotenone-insensitive NADH cytochrome C reductase. The SA of all three enzymes changed proportionally at diestrus, suggesting that the increase in mitochondrial HSD activity was not due to its preferential induction. Rather, we believe that the HSD activity in the mitochondrial fraction, as measured at the four stages of the estrous cycle, is a reflection of the combined contributions from an ever changing population of ovarian cells. Mitochondria from luteal cells have the highest HSD activity, and are very likely responsible for the major synthesis of progesterone during the luteal phase.

Nature 441, 315–321 (2006) We inadvertently omitted the names of the following authors: R. Banerjee, S. P. Bryant, D. C. Burford, W. D. H. Burrill, S. M. Clegg, P. Dhami, O. Dovey, L. M. Faulkner, S. M. Gribble, C. F. Langford, R. D. Pandian, K. M. Porter and E. Prigmore.

involved mathematical proofs and conceptions, and the substitution of a more descriptive, qualitative method of treatment for the earlier, quantitative method. How far this process should be carried, and at what point a proper balance obtains between descriptive and quantitative methods, is still unsettled. In the solution of this question, the first inquiry to be made is the extent to which the present teaching accomplishes its purpose in securing a thorough grasp of the underlying principles of the subject. This paper will attempt to give a solution to this problem as far as the subject of mechanics is concerned, a subject in which of necessity, if it is to be taught at all, the quantitative or simple numerical

In a paper by Prof. T. Turner * some experiments were described which show that gold leaf becomes transparent when heated in contact wild glass. The following experiments, suggested by Prof. H. A. Wilson, were undertaken to see if this effect takes place when the gold leaf is heated by itself. Hie apparatus in which the leak was heated consisted of a double walled fused quartz crucible. The outside of the crucible was 6 cm. deep and 5 cm. wide, and the inner chamber was 4·5 cm. deep and 3·5 cm. wide. Both chambers were fitted with lids. Inside the inner chamber, as near to the leaf as possible, a thermocouple, composed of platinum and nickel wires, was placed. The other ends of the couple dipped into mercury cups immersed in melting ice, from which wires led through a reversing key to a dead-beat galvanometer, with lamp and seals, a resistance of 800 ohms being included in the circuit.

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The elasto-plastic behavior of two-span composite beams is studied numerically and with reference to experimental results. It is concluded that for equal spans loaded symmetrically the second hinge will form before the first deteriorates and that the simple method of plastic design can therefore be used. When one span only is loaded, reduction in ultimate load is noted due to crushing at midspan. If the shear connectors are spaced uniformly between points of maximum and minimum moment, failure of the connectors does not occur. The results will assist the formulation of design rules for continuous composite beams.

This paper is concerned with stiffened plating to which a bending moment is applied in the plane of the stiffener webs. Owing to the initial or imposed curvature there is a radial component of force which tends to deflect the plating from its original position, and the effects of this deflexion may be considerable. There is a change in the distribution of longitudinal stress across the plate, and a transverse bending stress is induced which may exceed the longitudinal stress. The effects of initial deflexion of the plating, and of lateral load, are also considered. A numerical example illustrates the application of the analysis to the transverse bending of a ship's side. An experiment is described which confirms the theoretical conclusions for an initially flat plate.

(1989). Centre and Periphery in the Ancient World. Edited by M. Rowlands, M. Larson, and K. Kristiansen. Archaeological Journal: Vol. 146, No. 1, pp. 608-610.