Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. the level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.AbbVieAustralian National Health and Medical Research Council (NHMRC)Hosp Gen Univ Elda, Dept Reumatol, Elda 03600, SpainHosp Gen Univ Alicante, Dept Reumatol, Alicante, SpainUniv Camilo Jose Cela, Fac Ciencias Salud, Madrid, SpainUniv British Columbia, Div Rheumatol, Vancouver, BC V5Z 1M9, CanadaRoyal Melbourne Hosp, Parkville, Vic 3050, AustraliaUniv Hosp Southampton NHS Fdn Trust, Southampton, Hants, EnglandNIHR Wellcome Trust Clin Res Facil, Southampton, Hants, EnglandCtr Hosp Univ Liege, Liege, BelgiumMaastricht Univ, Med Ctr, Dept Internal Med Rheumatol, Maastricht, NetherlandsAtrium Med Ctr, Heerlen, NetherlandsUniv Toronto, Div Rheumatol, Toronto, ON, CanadaRepatriat Gen Hosp, Rheumatol Res Unit, Adelaide, SA, AustraliaFlinders Univ S Australia, Adelaide, SA 5001, AustraliaMed Univ Vienna, Dept Internal Med 3, Div Rheumatol, Vienna, AustriaUniv Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, CanadaMt Sinai Hosp, Univ Hlth Network, Toronto Gen Res Inst, Div Clin Decis Making & Hlth Care, Toronto, ON M5G 1X5, CanadaCabrini Hosp, Monash Dept Clin Epidemiol, Malvern, Vic, AustraliaMonash Univ, Dept Epidemiol & Prevent Med, Malvern, Vic, AustraliaUniv Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, NetherlandsUniv Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, NetherlandsUniv Nova Lisboa, Fac Ciencias Med, CEDOC, P-1200 Lisbon, PortugalEPE Hosp Egas Moniz, CHLO, Dept Rheumatol, Lisbon, PortugalHosp Gen Mexico City, Rheumatol Unit, Mexico City, DF, MexicoKarolinska Univ Hosp, Dept Rheumatol, Stockholm, SwedenKarolinska Inst, Stockholm, SwedenGhent Univ Hosp, Dept Rheumatol, Ghent, BelgiumUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilSt Georges Healthcare NHS Trust, Dept Rheumatol, London, EnglandState Hosp Stockerau, Ctr Rheumatol, Lower Austria, Stockerau, AustriaUniv Pavia, IRCCS Policlin S Matteo, Cattedra Reumatol, I-27100 Pavia, ItalyUniv Giessen, Kerckhoff Klin, Dept Rheumatol & Clin Immunol, Bad Nauheim, GermanyCopenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res, Glostrup, DenmarkMenzies Res Inst Tasmania, Hobart, Tas, AustraliaColumbia Univ, Med Ctr, New York, NY USALeiden Univ, Med Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilWeb of Scienc

Antibacterial efficacy of core-shell nanostructures encapsulating gentamicin against an in vivo intracellular Salmonella model

Pluronic based core-shell nanostructures encapsulating gentamicin were designed in this study. Block copolymers of (PAA −+ Na- b -(PEO- b -PPO- b -PEO)-b-PAA −+ Na) were blended with PAA − Na + and complexed with the polycationic antibiotic gentamicin to form nanostructures. Synthesized nanostructures had a hydrodynamic diameter of 210 nm, zeta potentials of −0.7 (±0.2), and incorporated ∼20% by weight of gentamicin. Nanostructures upon co-incubation with J774A.1 macrophage cells showed no adverse toxicity in vitro . Nanostructures administered in vivo either at multiple dosage of 5 μg g −1 or single dosage of 15 μg g −1 in AJ-646 mice infected with Salmonella resulted in significant reduction of viable bacteria in the liver and spleen. Histopathological evaluation for concentration-dependent toxicity at a dosage of 15 μg g −1 revealed mineralized deposits in 50% kidney tissues of free gentamicin-treated mice which in contrast was absent in nanostructure-treated mice. Thus, encapsulation of gentamicin in nanostructures may reduce toxicity and improve in vivo bacterial clearance

Protection of BALB/c mice against homologous and heterologous species of Brucella by rough strain vaccines derived from Brucella melitensis and Brucella suis biovar 4

Objective - To evaluate stable rough mutants derived from Brucella melitensis 16M and B suis 2579 (biovar 4) as vaccines against homologous and heterologous Brucella spp in the BALB/c mouse model. Design, animals, and procedure - Rough mutants VTRM1 and VTRS1 were obtained from B melitensis 16M and B suis 2579, respectively, by allelic exchange of the rfbU gene encoding mannosyltransferase with a Tn5-disrupted rfbU gene. Mice were vaccinated with VTRM1 or VTRS1 and challenge exposed 8 weeks later. Results - VTRM1 and VTRS1 replicated extensively in the spleen during the first 3 weeks of infection, then decreased rapidly. Antibodies specific for the O polysaccharide were not detected in sera of mice inoculated with either rough strain. Vaccination with VTRM1 or VTRS1 induced protection against virulent strains of B abortus (2308), B melitensis (16M), B suis biovar 1 (750), and B suis biovar 4 (2579). VTRM1 also protected against B ovis (PA) and against 4 field isolates of B abortus from bison or elk. VTRS1 conferred protection against 4 field isolates of B suis biovar 4 from reindeer. Vaccines prepared from live VRTM1 or VTRS1 provided significantly greater protection than that afforded by vaccines of killed cells in QS-21 adjuvant. Vaccination with VTRM1 containing VTRS1 gave minimal protection against the antigenically unrelated Listeria monocytogenes, thus demonstrating the immunologic specificity of protection against Brucella spp. Conclusions and clinical relevance - Results encourage evaluation, in primary host species, of VTRM1 and VTRS1, along with RB51, as alternative vaccines to strain 19, Rev. 1, or other smooth phase vaccines

Prevalence of NUDT15 genetic variants and incidence of thiopurine-induced leukopenia in Inflammatory Bowel Disease: A systematic review and meta-analysis

BACKGROUND AND AIMS: Nudix hydrolase 15 (NUDT15) genetic variants confer an increased risk of thiopurine-induced leukopenia (TIL), however their global prevalence in Inflammatory Bowel Disease (IBD) patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants, were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early (≤8 weeks) and late (>8 weeks) leukopenia, and relative risk of developing leukopenia. RESULTS: 20 studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C>T C/T diplotype was 13% (95% CI: 10-18%), *3/*3 c.415C>T T/T diplotype was 2% (95% CI: 1-2%), *1/*5 c.52G>A G/A diplotype was 2% (95% CI: 1-3%) and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% (95% CI: 4-12%). The pooled prevalence of *1/*3 was high in Japanese (20%, 95% CI: 16-24%) and Chinese patients (18%, 95% CI: 12-27%). The incidence of early leukopenia was 20% (95% CI: 16-26%) in *1/*3 patients, 99% (95% CI: 7-100%) in *3/*3 patients and 49% (95% CI: 29-69%) in *1/*6 patients. The incidence of late leukopenia was 36% (95% CI: 26-49%) in *1/*3 patients. CONCLUSIONS: NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations to guide thiopurine dosing and prevent myelotoxicity.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text