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Nonuniform radiopharmaceutical uptake in kidney tissues leads to substructure-level absorbed dose heterogeneity, confounding the establishment of absorbed dose-effect relationships for nephrotoxicity in radiopharmaceutical therapy. We developed a model to enable nephron-level dosimetry. Methods: A multinephron computational model was developed on the basis of 3-dimensional multiphoton microscopy data, including different nephron types (superficial, midcortical, and juxtamedullary) and their main substructures (glomerulus, proximal tubule [PT], and distal tubule) in kidney tissues. Nephron-level S values were determined using Monte Carlo calculations for several β-- and α-emitting radionuclides. The multinephron dosimetry framework was applied to nonuniform kidney tissue uptake data on 225Ac, located primarily in midcortical and juxtamedullary PTs. Results: A nonuniform substructure activity distribution resulted in pronounced absorbed dose heterogeneities. S values varied substantially among nephron types, with the largest in juxtamedullary substructures. The self-dose to PTs was 7.6-15 times higher than the S value of superficial PTs for the α-emitters considered. The cross dose to juxtamedullary glomeruli was on average 20% higher than to superficial glomeruli. The case study revealed substantial absorbed dose heterogeneity, with the absorbed dose to the different PTs being 40%-73% higher than to their respective glomeruli. Additionally, the contribution of free 213Bi to the total absorbed dose differed from that of 225Ac. Conclusion: The developed multinephron framework enables nephron-level dosimetry, allowing quantification of absorbed dose heterogeneity within renal tissues. Such insights enable establishing critical nephron substructures for nephrotoxicity in radiopharmaceutical therapy, supporting nephroprotective strategies during clinical translation of novel radiopharmaceuticals.

The objective was to identify factors determining acute arthritis resolution and safety with colchicine and prednisone in acute calcium pyrophosphate (CPP) crystal arthritis. We conducted a post hoc analysis of the COLCHICORT trial, which compared colchicine and prednisone for the treatment of acute CPP crystal arthritis, using a composite outcome of secondary endpoints of the primary analysis. Factors associated with the sustained arthritis resolution with prednisone or colchicine treatment on day three, and the occurrence of gastrointestinal adverse events (AEs) with colchicine, were examined. Two different machine-learning approaches were used to identify independent factors associated with the efficacy outcome: multiple logistic regressions and a decision tree were used. In total, 43 of 89 (48.3%) of participants were considered definite responders. In univariable analysis, definitive responders were more often hospitalized for stroke (9 of 43; P = 0.04), had an age ≥80 years old (39 of 43; P = 0.045), and were dyslipidemic (25 of 43; P = 0.03), whereas poor responders were more commonly hospitalized to manage the acute arthritis episode (22 of 43; P < 0.001) In multiple logistic regression, acute arthritis of the wrists (odds ratio [OR] 4.06, 95% confidence interval [CI] 1.21-15.50.85) were associated with arthritis resolution on day three, whereas randomization in the colchicine arm (OR 0.31, 95% CI 0.11-0.83) and diuretic use (OR 0.23, 95% CI 0.097-0.95) were associated with a poor treatment response. Hospital admission for acute arthritis, C-reactive protein levels, and estimated glomerular filtration rate were decision tree nodes selected as crucial for predicting definitive flare resolution. Three candidate variables were identified in the multiple logistic regression model explaining the occurrence of gastrointestinal AEs with colchicine: male sex (OR 0.33, 95% CI 0.07-1.29) and diabetes (OR 0.24, 95% CI 0.030-1.24) seemed protective, whereas statin use (OR 3.54, 95% CI 0.83-18.82) seemed associated with their occurrence. This study identified factors associated with the definitive response to colchicine and prednisone treatment in acute CPP crystal arthritis. Colchicine was associated with poorer efficacy and was impacted by a dual effect on its safety and efficacy by medications and associated conditions.

To investigate the association between intestinal permeability alteration and erosive hand osteoarthritis (EHOA). Serum concentrations of four intestinal permeability biomarkers (lipopolysaccharide binding protein (LBP), FABP2, sCD14, Zonulin-related proteins (ZRP) along with calprotectin, and high-sensitivity C-Reactive Protein (hs-CRP) were assessed in 410 patients of the DIGICOD cohort. The study compared patients with EHOA (≥ 2 erosion in Verbruggen score N=140) to those without EHOA (N=270) using the Mann-Whitney U test. Logistic regression was performed to adjust for potential covariates. The Spearman rank test was used to investigate the correlation between intestinal permeability biomarkers and seven clinical variables associated with HOA clinical and radiographic severity. Serum levels of LBP and ZRP were found to be higher in patients with EHOA compared to those without EHOA (p=0.001, p=0.04). Additionally, LBP and ZRP remained associated with EHOA in a logistic regression model adjusted for age, body mass index, and sex (p=0.017, p=0.005). ZRP was positively correlated with Verbruggen score and Kellgren-Lawrence sum score of both hands (r=0.14 p=0.005, r=0.12 p=0.023). LBP was positively correlated with the number of erosive joints (r=0.14 p=0.0006). Hs-CRP and LBP were positively correlated with AUSCAN pain (r=0.14 p=0.008, r=0.10 p=0.042). LBP and ZRP were associated with EHOA with clinical and radiographic severity in HOA. These results overall support the role of intestinal permeability in both symptoms and structural alteration in HOA.

To investigate the temporal association between the first diagnosis of gout and cardiovascular events in the short term. We performed a self-controlled case series analysis and a cohort study using data from linked primary care, hospitalization, and mortality records from the United Kingdom's Clinical Practice Research Database-GOLD. We included individuals with a new diagnosis of gout either in the primary care or secondary care between January 1, 1997 and December 31, 2020. The first consultation at which gout was diagnosed was the exposure of interest. The main outcome consisted of cardiovascular events (ie, a composite of fatal and nonfatal myocardial infarction, ischemic or hemorrhagic stroke, and transient ischemic attack). The 4,398 patients (66.9% male, mean age 74.6 years) had a cardiovascular event within at least two years of their first recorded diagnosis of gout. The incidence of cardiovascular events was significantly higher in the 30 days after the first diagnosis of gout compared to baseline (adjusted incidence rate ratio 1.55, 95% confidence interval [CI] 1.33-1.83). Among 76,440 patients (72.9% male, mean age 63.2 years) included in the cohort study, the incidence of cardiovascular events in the 30 days after the first gout diagnosis (31.2 events per 1,000 person-years, 95% CI 27.1-35.9) was significantly higher than in days 31 to 730 after gout diagnosis (21.6 events per 1,000 person-years, 95% CI 20.8-22.4) with a rate difference of -9.6 events per 1,000 person-years (95% CI -14.0 to -5.1). Individuals had a short-term increased risk of cardiovascular events in the 30 days following the first consultation at which gout was diagnosed.

Aim: To ascertain the prevalence of calcium pyrophosphate arthritis (CPPA) at diagnosis and during follow-up of patients with gout. Methods: Inception cohort of patients with gout prospectively recruited and followed-up from 1994–2023. Gout-case was defined as crystal-proved tophus or arthritis, or the presence of tophus plus double contour with ultrasonography. CPPA was defined as the presence of intra-leukocyte calcium pyrophosphate (CPP) crystals in synovial fluid (SF) and neat chondrocalcinosis in plain radiographs. Age, gender, time from onset of symptoms, number of flares, joint distribution, previous and prescribed treatments, colchicine prophylaxis, comorbidities, alcohol intake, use of diuretics, renal function, and previous vascular disease were available for analysis. Results: A total of 1,544 patients with gout, with an average of 4-year follow-up, were available for analysis. CPPA was observed in 127/1,544 cases (8.2%). In 37/1,544 patients (2.4%) CPP and monosodium urate (MSU) crystals were observed in the same SF sample at gout diagnosis, and 90/1,544 (5.8%) showed CPP crystals apart from the diagnosis of gout. CPPA-gout cases had more flares per year, but no more frequent polyarticular distribution at baseline compared to non-CPPA-gout. CPPA-gout cases were older at baseline and showed lower renal function. Women, patients using diuretics, patients with hypertension, and those with previous vascular events showed CPPA more frequently. Multivariate analysis showed that only age and use of diuretics were independently associated with CPPA, as other variables apparently associated were dependent on aging. Interestingly, an analysis of the prevalence in the three decades available showed an increased CPPA diagnosis through time, probably associated with increased awareness of the association. Conclusions: (1) CPPA is not infrequent in patients with gout; (2) it is associated with aging and diuretic use; (3) awareness of this association may increase the rate of diagnosis.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to berequired to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 118-119 POSTER PRESENTATIONS P69 | Safety of pesticides for farm animals and pets from a regulatory point of view First published: 11 June 2023 https://doi.org/10.1111/jvp.13348Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 118-119 RelatedInformation