Comorbidities in patients with gout prior to and following diagnosis: case-control study

OBJECTIVES: To determine the burden of comorbidities in patients with gout at diagnosis and the risk of developing new comorbidities post diagnosis. METHODS: There were 39 111 patients with incident gout and 39 111 matched controls identified from the UK Clinical Practice Research Data-link. The risk of comorbidity before (ORs) and after the diagnosis of gout (HRs) were estimated, adjusted for age, sex, diagnosis year, body mass index, smoking and alcohol consumption. RESULTS: Gout was associated with adjusted ORs (95% CIs) of 1.39 (1.34 to 1.45), 1.89 (1.76 to 2.03) and 2.51 (2.19 to 2.86) for the Charlson index of 1-2, 3-4 and >/=5, respectively. Cardiovascular and genitourinary diseases, in addition to hyperlipidaemia, hypothyroidism, anaemia, psoriasis, chronic pulmonary diseases, osteoarthritis and depression, were associated with a higher risk for gout. Gout was also associated with an adjusted HR (95% CI) of 1.41 (1.34 to 1.48) for having a Charlson index >/=1. Median time to first comorbidity was 43 months in cases and 111 months in controls. Risks for incident comorbidity were higher in cardiovascular, genitourinary, metabolic/endocrine and musculoskeletal diseases, in addition to liver diseases, hemiplegia, depression, anaemia and psoriasis in patients with gout. After additionally adjusting for all comorbidities at diagnosis, gout was associated with a HR (95% CI) for all-cause mortality of 1.13 (1.08 to 1.18; p<0.001). CONCLUSIONS: The majority of patients with gout have worse pre-existing health status at diagnosis and the risk of incident comorbidity continues to rise following diagnosis. The range of associated comorbidities is broader than previously recognised and merits further evaluation

Factors influencing the crystallization of monosodium urate: a systematic literature review

BACKGROUND: Gout is a chronic disease of monosodium urate (MSU) crystal deposition. Although hyperuricaemia is the central risk factor for development of gout, not all people with hyperuricaemia have subclinical MSU crystal deposition or indeed, symptomatic disease. The aim of this systematic literature review was to identify factors that contribute to MSU crystallization. METHODS: A search was conducted of the electronic databases PubMed, Science Direct and Scopus. Articles were included if they contained original data related to MSU crystallization. The methods and results were summarized and categorized into articles describing at least one of the three key steps in MSU crystallization (reduced urate solubility, nucleation and growth). RESULTS: A total of 2175 articles were initially identified in our systematic search with 35 of these articles included in the final analysis. Elevated urate concentration was identified as a central factor driving all three stages of MSU crystallization. Factors that were found to consistently reduce urate solubility were reduced temperatures, pH 7–9 and various ions including sodium ions. Connective tissue factors including bovine cartilage homogenates and healthy human synovial fluid and serum all enhanced urate solubility. MSU nucleation was found to be increased by a number of factors, including sodium ions, uric acid binding antibodies, and synovial fluid or serum from patients with gout. Other than elevated urate concentrations, no other specific factors were identified as promoters of MSU crystal growth. CONCLUSIONS: Increased urate concentration is the key factor required at each stage of MSU crystallization. Different proteins and factors within connective tissues may promote MSU crystallization and may be important for determining the sites at which MSU crystallization occurs in the presence of elevated urate concentrations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12891-015-0762-4) contains supplementary material, which is available to authorized users

Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

In November 2016, the American College of Physicians (ACP) published a clinical practice guideline on the management of acute and recurrent gout. This guideline differs substantially from the latest guidelines generated by the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) and 3e (Evidence, Expertise, Exchange) Initiative, despite reviewing largely the same body of evidence. The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) convened an expert panel to review the methodology and conclusions of these four sets of guidelines and examine possible reasons for discordance between them. The G-CAN position, presented here, is that the fundamental pathophysiological knowledge underlying gout care, and evidence from clinical experience and clinical trials, supports a treat-to-target approach for gout aimed at lowering serum urate levels to below the saturation threshold at which monosodium urate crystals form. This practice, which is truly evidence-based and promotes the steady reduction in tissue urate crystal deposits, is promoted by the ACR, EULAR and 3e Initiative recommendations. By contrast, the ACP does not provide a clear recommendation for urate-lowering therapy (ULT) for patients with frequent, recurrent flares or those with tophi, nor does it recommend monitoring serum urate levels of patients prescribed ULT. Results from emerging clinical trials that have gout symptoms as the primary end point are expected to resolve this debate for all clinicians in the near term future

Collegiate wrestler with a bicuspid aortic valve and aortic dilation

Bicuspid aortic valve and aortopathy are generally considered contraindications to isometric exercise. For athletes with mild disease at low risk of adverse events, a shared decision-making approach for continued sports participation is reasonable. We present a case of a collegiate wrestler with bicuspid aortic valve and aortopathy to illustrate shared decision making.

Flavanone-3-Hydroxylase Plays an Important Role in the Biosynthesis of Spruce Phenolic Defenses Against Bark Beetles and Their Fungal Associates

Conifer forests worldwide are becoming increasingly vulnerable to attacks by bark beetles and their fungal associates due to the effects of global warming. Attack by the bark beetle Ips typographus and the blue-stain fungus it vectors (Endoconidiophora polonica) on Norway spruce (Picea abies) is well known to induce increased production of terpene oleoresin and polyphenolic compounds. However, it is not clear whether specific compounds are important in resisting attack. In this study, we observed a significant increase in dihydroflavonol and flavan-3-ol content after inoculating Norway spruce with the bark beetle vectored fungus. A bioassay revealed that the dihydroflavonol taxifolin and the flavan-3-ol catechin negatively affected both I. typographus and E. polonica. The biosynthesis of flavan-3-ols is well studied in Norway spruce, but little is known about dihydroflavonol formation in this species. A flavanone-3-hydroxylase (F3H) was identified that catalyzed the conversion of eriodictyol to taxifolin and was highly expressed after E. polonica infection. Down-regulating F3H gene expression by RNA interference in transgenic Norway spruce resulted in significantly lower levels of both dihydroflavonols and flavan-3-ols. Therefore F3H plays a key role in the biosynthesis of defense compounds in Norway spruce that act against the bark beetle-fungus complex. This enzyme forms a defensive product, taxifolin, which is also a metabolic precursor of another defensive product, catechin, which in turn synergizes the toxicity of taxifolin to the bark beetle associated fungus

Flavanone-3-hydroxylase plays an important role in the biosynthesis of spruce phenolic defenses against bark beetles and their fungal associates

Conifer forests worldwide are becoming increasingly vulnerable to attacks by bark beetles and their fungal associates due to the effects of global warming. Attack by the bark beetle Ips typographus and the blue-stain fungus it vectors (Endoconidiophora polonica) on Norway spruce (Picea abies) is well known to induce increased production of terpene oleoresin and polyphenolic compounds. However, it is not clear whether specific compounds are important in resisting attack. In this study, we observed a significant increase in dihydroflavonol and flavan-3-ol content after inoculating Norway spruce with the bark beetle vectored fungus. A bioassay revealed that the dihydroflavonol taxifolin and the flavan-3-ol catechin negatively affected both I. typographus and E. polonica. The biosynthesis of flavan-3-ols is well studied in Norway spruce, but little is known about dihydroflavonol formation in this species. A flavanone-3-hydroxylase (F3H) was identified that catalyzed the conversion of eriodictyol to taxifolin and was highly expressed after E. polonica infection. Down-regulating F3H gene expression by RNA interference in transgenic Norway spruce resulted in significantly lower levels of both dihydroflavonols and flavan-3-ols. Therefore F3H plays a key role in the biosynthesis of defense compounds in Norway spruce that act against the bark beetle-fungus complex. This enzyme forms a defensive product, taxifolin, which is also a metabolic precursor of another defensive product, catechin, which in turn synergizes the toxicity of taxifolin to the bark beetle associated fungus.The Max Planck Institute for Chemical Ecology and the University of Pretoria RDP program.http://www.frontiersin.org/Plant_Scienceam2019Forestry and Agricultural Biotechnology Institute (FABI)Zoology and Entomolog

Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia

Objective In gout, hyperuricemia promotes urate crystal deposition that stimulates the NLRP3 inflammasome and IL-1β-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis meeting ACR/EULAR gout classification criteria in a normouricemic young adult female. Methods Whole genome sequencing, quantitative proteomics, whole blood RNA-seq, and IL-1β-induced murine knee synovitis characterized proband candidate genes, biomarkers, and pathogenic mechanisms. Results Lubricin was attenuated in proband serum, associated with elevated acute phase reactants and inflammatory whole blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of Inter-Alpha-Trypsin Inhibitor Heavy Chain 3, an inhibitor of lubricin-degrading Cathepsin G. Proband serum protein interactome network changes supported enhanced lubricin degradation, with Cathepsin G activity increased relative to its inhibitors SERPINB6 and Thrombospondin1. TLR2 activation suppressed cultured human synovial fibroblast lubricin mRNA and release (p\u3c0.01). Lubricin blunted urate crystal precipitation, and IL-1β induction of xanthine oxidase and urate in cultured macrophages (p\u3c0.001). In lubricin-deficient mice, IL-1β knee injection increased xanthine oxidase positive synovial resident M1 macrophages (p\u3c0.05). Conclusion We linked normouricemic erosive gout to attenuated lubricin, with impaired control of Cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization, and blunted IL-1β-induced increases in macrophage xanthine oxidase and urate. Collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated Cathepsin G, and synovial fibroblast TLR2 signaling

The South African Statistical Association and its role in science in South Africa

The South African Statistical Association (SASA) turned 70 years old in 2023, having made huge impacts in South Africa and beyond. Through SASA, the statistics community in South Africa has made significant strides in the field, both locally and internationally, ensuring the importance of the discipline is concreted into the academic and industry playing fields. The statistics community continues to grow and remains passionate about growth and development of school learners, undergraduate and postgraduate students, academics and statisticians in industry. The opportunities for statisticians in South Africa are endless, and important to the economic sustainability of South Africa. This paper provides an historical overview of the impacts of the South African Statistical Association and statistics in South Africa.http://www.sajs.co.zahj2024GeologyStatisticsNon

The Politics of Empire: a Study of the Res Gestae of Ammianus Marcellinus in the Context of the Roman Historiographical Tradition

The aim of this thesis is to ascertain what intellectual stance (if any) underlies the Res Gestae of Ammianus Marcellinus. That is to say, are we able to isolate a single idea or set of ideas underlying the historian's interpretation of the events depicted in his work? Clearly this will require an understanding of the nature of his work and his proud career. At the conclusion of his work, Ammianus Marcellinus declares, it seems with pride, that he has composed to the best of his ability a complete narrative of the years encompassed by the respective deaths of the emperors Nerva and Valens - a period of some 280 years. 31.16.7: haec ut miles quondam et Graecus, a principatu Caesaris Nervae exorsus, ad usque Valentis interitum, pro virium explicavi mensura: opus veritatem professum numquam (ut arbitror) sciens silentio ausus corrumpere, vel mendacio. ("This is the history of events from the reign of the emperor Nerva to the death of Valens, which I, a former soldier and a Greek, have composed to the best of my ability. It claims to be the truth, which I have never ventured to pervert either by silence or lie"). For all of my quotations from the Res Gestae, I have used the text of Rolf (1925). For translations I have generally followed Hamilton (1986), although I have made some changes where I have considered them necessary. Unfortunately the iniquities of time have ensured that the first 13 of the original 31 books have been lost. It might be argued, however, that it is the better and more informative portion of the work that has survived. Although the part of the work that is extant amounts to little more than half of the original, it covers a period of only 24 years from 354-378 - a small fraction of the overall period originally covered by the work. Yet this section, which chronicles the reigns of five emperors contemporary to the historian's own life and public career, examines in extraordinary detail the social and political developments of a critical period of Roman history that was representative of the first signs of the decline of Rome as a world power. Among the more important issues are the increasing number of military crises, both civil and foreign in origin, among which is recorded the crushing defeat of the Roman legions by Gothic armies outside Adrianople; this massacre would also see the death in battle of Valens, emperor of the Eastern Empire. Also of note is the emphasis in the history on religion, in particular the growing influence within the imperial administration of the Christian church, which was rapidly gaining an acceptance in society at large. It was this interesting choice of topics, along with the history's position as the only surviving text of any real substance for this period, that ensured a place for the Res Gestae in the hearts and minds of later scholars. This is illustrated most clearly by none other than Edward Gibbon, who, in the conclusion of his own account of Adrianople in The Decline and Fall of the Roman Empire, gives the following final farewell to Ammianus