A Case of Epididymo-orchitis after intravesical bacille Calmette-Guérin therapy for superficial bladder carcinoma in a patient with latent tuberculosis infection

Background: Intravesical instillation of bacille Calmette-Guérin (BCG) has been established as efficient therapy for superficial bladder carcinoma. Overall, intravesical BCG is well tolerated and results in complications of less than 5 %. However, adverse effects such as granulomatous prostatitis, pneumonitis, hepatitis, sepsis, and hypersensitivity reactions may occur. The reported rate for tuberculous orchitis after BCG intravesical therapy is 0.4 %. Findings: We report a case of monolateral tuberculous orchitis occurring one month after the second course of intravescical instillation of bacille Calmette-Guérin in a patient with proven superficial bladder carcinoma and latent tuberculosis infection. Conclusions: In our opinion intravesical instillation of BCG should be considered on an individual patient basis, with full patient disclosure of the potentially significant risks. A screening with an intradermal Mantoux before starting the first cycle of BCG instillation should be recommended and isoniazid would be indicated as the treatment for latent tuberculosis infection

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P < .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Diagnosis of liver fibrosis in ageing patients with HIV at risk for non-alcoholic fatty liver disease in Italy and Canada: assessment of a two-tier pathway

Background: Since the introduction of effective antiretroviral therapy, liver-related mortality has increased ten-fold in ageing people with HIV. This trend is driven by ageing-related metabolic conditions that cause non-alcoholic fatty liver disease (NAFLD), which affects 35-65% of people with HIV. Clinically significant (stage 2-4) liver fibrosis develops in over 15% of people with HIV who have NAFLD. Strategies are needed to identify people with HIV at risk for significant liver fibrosis and reduce cirrhosis-related complications. Non-invasive tests to diagnose liver fibrosis include ultrasound-based transient elastography and serum biomarkers. Transient elastography is a feasible tool to assess liver fibrosis, but it is not largely accessible in HIV clinics. We aimed to determine whether a two-tier care pathway with assessment of simple serum biomarkers for fibrosis as first tier could reduce the need for the specialist transient elastography test (second tier). Methods: Patients were consecutively identified through a clinical programme for liver disease in people with HIV in Canada and Italy. We applied a two-tier care pathway to three prospective cohorts of people with HIV at risk for NAFLD, defined as those with elevated liver transaminases, body mass index (BMI) of 25 or greater, or diabetes. Patients with alcohol abuse or coinfection with hepatitis B or C viruses were excluded. Five simple serum biomarkers of fibrosis, based on liver transaminases, platelets, and BMI (fibrosis-4 index [FIB-4], BARD [BMI, AST to ALT ratio, diabetes] score, NAFLD fibrosis score, AST to ALT ratio, and AST-to-platelet ratio index [APRI]) were applied as a first-tier assessment to exclude significant liver fibrosis. All patients then received transient elastography. We assessed the decrease in referral for transient elastography that would have occurred based on biomarker assessment and discordance between high transient elastography (≥7·1 kPa), indicating significant liver fibrosis, and low serum fibrosis biomarkers (FIB-4 <1·3, BARD score 0-1, NAFLD fibrosis score less than -1·455, AST to ALT ratio <0·8, and APRI <0·5). We also assessed independent factors associated with that discordance by multivariable logistic regression analysis. Findings: We included 1202 people with HIV at risk for NAFLD (mean age 51·2 years [SD 10·1], 914 [76%] male and 288 [24%] female, mean HIV duration 16·3 years [SE 9·7], mean BMI 26·5 Kg/m2 [SD 4·5]; prevalence of diabetes 49·5%). 222 (18·5%) of these participants had significant liver fibrosis according to transient elastography. Assessment of simple fibrosis biomarkers would have decreased transient elastography referrals between 22·5% (BARD score) and 82·4% (APRI). Discordance rate ranged from 3·9% (NAFLD fibrosis score) to 11·1% (APRI). After adjustment for age, sex, presence of diabetes, level of HDL cholesterol, and CD4 cell count, BMI (odds ratio 1·12, 95% CI 1·07-1·17) and triglyceride level (1·25, 1·08-1·46) were independent predictors of discordance for low APRI and high transient elastography. Interpretation: Use of a two-tier pathway to identify liver fibrosis in ageing people with HIV at risk for NAFLD could reduce transient elastography examinations by a substantial proportion, reducing costs and helping to optimise use of resources in HIV care

Circulating levels of soluble adhesion molecules in patients with ANCA-associated vasculitis

BACKGROUND: During inflammation, activated vascular endothelial cells and other cell types express various adhesion molecules, which facilitate the binding of circulating leukocytes and their extravasation in surrounding tissue (i.e. renal tissue). The serum concentration of circulating soluble adhesion molecules is supposed to reflect the degree of this activation. OBJECTIVE: In the first part of the study, we determined if the serum levels of the soluble intercellular adhesion molecule (sICAM)-1 and the soluble endothelial cell-leukocyte adhesion molecule (sELAM)-1, in patients affected by microscopic polyangiitis (MPA), associated with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibodies (ANCA), were related to the active and the inactive vasculitis phase. In the second part of the study, we examined the changes in circulating sICAM-1 and sELAM-1 levels and the clinical outcome of renal function in these patients. METHODS: We examined 20 MPO-ANCA-positive MPA patients in an acute phase and in a remission phase, after 6 months of treatment, and 50 subjects as controls, 30 with autosomal dominant polycystic kidney disease (ADPKD) in stable chronic renal failure (CRF) and 20 healthy volunteers (HS) with normal renal function. RESULTS: Regarding serum creatinine (Cr) concentration, no significant differences were found comparing active and inactive phases in the MPA group and the CRF group. Mean serum adhesion molecule levels in the MPA group were higher in the active phase compared to the inactive phase and to the CRF and HS groups. In addition, considering the outcome of serum Cr concentrations in the MPA group, the serum adhesion molecule levels were higher and decreased more slowly in patients with final high serum Cr concentrations than in patients with final normal serum Cr concentrations. CONCLUSION: Our data suggest that in MPO-ANCA-positive MPA patients, higher sICAM-1 and sELAM-1 levels during the active phase and their slower decline during the treatment period, could be a prognostic risk factor for CRF development

Fibroscan-aspartate aminotransferase (FAST) score predicts liver-related outcomes, but not extra-hepatic events, in a multicenter cohort of people with HIV

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is frequent in people with HIV (PWH). The Fibroscan-aspartate aminotransferase (FAST) score was developed to identify patients with nonalcoholic steatohepatitis (NASH) and significant fibrosis. We investigated prevalence of NASH with fibrosis and the value of FAST score in predicting clinical outcomes in PWH. METHODS: Transient elastography (Fibroscan) was performed in PWH without viral hepatitis coinfection from four prospective cohorts. We used FAST>0.35 to diagnose NASH with fibrosis. Incidence and predictors of liver-related outcomes (hepatic decompensation, hepatocellular carcinoma) and extra-hepatic events (cancer, cardiovascular disease) were evaluated through survival analysis. RESULTS: Of the 1472 PWH included, 8% had FAST>0.35. On multivariable logistic regression, higher BMI (adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 1.14-1.29), hypertension (aOR 2.24, 95% CI 1.16-4.34), longer time since HIV diagnosis (aOR 1.82, 95% CI 1.20-2.76) and detectable HIV viral load (aOR 2.22, 95% CI 1.02-4.85) were associated with FAST>0.35. 882 patients were followed for a median of 3.8 years (interquartile range 2.5-4.2). Overall, 2.9% and 11.1% developed liver-related and extra-hepatic outcomes, respectively. Incidence of liver-related outcomes was higher in patients with FAST>0.35 vs. FAST0.35 remained an independent predictor of liver-related outcomes (adjusted hazard ratio 4.97, 95% CI 1.97-12.51). Conversely, FAST did not predict extra-hepatic events. CONCLUSION: A significant proportion of PWH without viral hepatitis coinfection may have NASH with significant liver fibrosis. FAST score predicts liver-related outcomes and can help risk stratification and management in this high-risk population

Fibroscan-aspartate aminotransferase (FAST) score predicts liver-related outcomes, but not extra-hepatic events, in a multicenter cohort of people with HIV

Background: Nonalcoholic fatty liver disease (NAFLD) is frequent in people with HIV (PWH). The Fibroscan-aspartate aminotransferase (FAST) score was developed to identify patients with nonalcoholic steatohepatitis (NASH) and significant fibrosis. We investigated prevalence of NASH with fibrosis and the value of FAST score in predicting clinical outcomes in PWH. Methods: Transient elastography (Fibroscan) was performed in PWH without viral hepatitis coinfection from four prospective cohorts. We used FAST>0.35 to diagnose NASH with fibrosis. Incidence and predictors of liver-related outcomes (hepatic decompensation, hepatocellular carcinoma) and extra-hepatic events (cancer, cardiovascular disease) were evaluated through survival analysis. Results: Of the 1472 PWH included, 8% had FAST>0.35. On multivariable logistic regression, higher BMI (adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 1.14-1.29), hypertension (aOR 2.24, 95% CI 1.16-4.34), longer time since HIV diagnosis (aOR 1.82, 95% CI 1.20-2.76) and detectable HIV viral load (aOR 2.22, 95% CI 1.02-4.85) were associated with FAST>0.35. 882 patients were followed for a median of 3.8 years (interquartile range 2.5-4.2). Overall, 2.9% and 11.1% developed liver-related and extra-hepatic outcomes, respectively. Incidence of liver-related outcomes was higher in patients with FAST>0.35 vs. FAST<0.35 (45.1, 95% CI 26.2-77.7 vs. 5.0, 95% 2.9-8.6 per 1000 person-years). On multivariable Cox regression analysis, FAST>0.35 remained an independent predictor of liver-related outcomes (adjusted hazard ratio 4.97, 95% CI 1.97-12.51). Conversely, FAST did not predict extra-hepatic events. Conclusion: A significant proportion of PWH without viral hepatitis coinfection may have NASH with significant liver fibrosis. FAST score predicts liver-related outcomes and can help risk stratification and management in this high-risk population

Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists

: A library of potent and highly A3AR selective pyrimidinebased compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A(1) Antagonists

We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A(1)AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarily evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R-4 and R-6 of the pyrimidine core but most importantly the prominent role to the unprecedented A(1)AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A(1) and A(2A)ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series