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Objectives: Rituximab is being increasingly prescribed for the treatment of autoimmune glomerular diseases. While it is highly effective for some diseases, the response is less predictable for others, which may be due to differing requirements in terms of the dosing according to the disease type and variations concerning exposure to the drug. Methods: We compiled novel rituximab dosing schedules according to pharmacokinetic analysis of data gathered from rituximab treated patients in a tertiary referral nephrology centre between May 2020 and June 2023. The population-pharmacokinetic analysis was based on the rituximab dosing, the patients’ characteristics, rituximab levels and anti-rituximab antibodies. Results: The analysis, which was based on data from 185 patients, clearly highlighted differing rituximab dosing requirements for patients with ANCA associated vasculitis and minimal change disease compared to those with membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This corresponded to the good treatment response of the first two diseases and the unreliable efficacy for the others. The model predicts the rituximab pharmacokinetics with high degree of accuracy when body weight, proteinuria, type of glomerulonephritis, treatment length and anti-rituximab antibodies formation are used as covariates. We proposed a dosing schedule with shortened dosing intervals for difficult-to-treat diagnoses with high proteinuria. Conclusion: In order to ensure reliable and comparable exposure of rituximab with respect to the full range of glomerular diseases, the dosing schedule should be adjusted for membranous nephropathy, focal-segmental glomerulosclerosis and lupus nephritis. This is largely, but not solely, due to the enhanced level of unselective proteinuria in these diseases.

Objectives: Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib. Methods: A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications. Results: Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P-value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P

Summary: Background: Mitochondria present an emerging target for cancer treatment. We have investigated the effect of mitochondrially targeted tamoxifen (MitoTam), a first-in-class anti-cancer agent, in patients with solid metastatic tumours. Methods: MitoTam was tested in an open-label, single-centre (Department of Oncology, General Faculty Hospital, Charles University, Czech Republic), phase I/Ib trial in metastatic patients with various malignancies and terminated oncological therapies. In total, 75 patients were enrolled between May 23, 2018 and July 22, 2020. Phase I evaluated escalating doses of MitoTam in two therapeutic regimens using the 3 + 3 design to establish drug safety and maximum tolerated dose (MTD). In phase Ib, three dosing regimens were applied over 8 and 6 weeks to evaluate long-term toxicity of MitoTam as the primary objective and its anti-cancer effect as a secondary objective. This trial was registered with the European Medicines Agency under EudraCT 2017-004441-25. Findings: In total, 37 patients were enrolled into phase I and 38 into phase Ib. In phase I, the initial application of MitoTam via peripheral vein indicated high risk of thrombophlebitis, which was avoided by central vein administration. The highest dose with acceptable side effects was 5.0 mg/kg. The prevailing adverse effects (AEs) in phase I were neutropenia (30%), anaemia (30%) and fever/hyperthermia (30%), and in phase Ib fever/hyperthermia (58%) together with anaemia (26%) and neutropenia (16%). Serious AEs were mostly related to thromboembolic (TE) complications that affected 5% and 13% of patients in phase I and Ib, respectively. The only statistically significant AE related to MitoTam treatment was anaemia in phase Ib (p = 0.004). Of the tested regimens weekly dosing with 3.0 mg/kg for 6 weeks afforded the best safety profile with almost all being grade 1 (G1) AEs. Altogether, five fatalities occurred during the study, two of them meeting criteria for Suspected Unexpected Serious Adverse Events Reporting (SUSAR) (G4 thrombocytopenia and G5 stroke). MitoTam showed benefit evaluated as clinical benefit rate (CBR) in 37% patients with the largest effect in renal cell carcinoma (RCC) where four out of six patients reached disease stabilisation (SD), one reached partial response (PR) so that in total, five out of six (83%) patients showed CBR. Interpretation: In this study, the MTD was established as 5.0 mg/kg and the recommended dose of MitoTam as 3.0 mg/kg given once per week via central vein with recommended preventive anti-coagulation therapy. The prevailing toxicity included haematological AEs, hyperthermia/fever and TE complications. One fatal stroke and non-fatal G4 thrombocytopenia were recorded. MitoTam showed high efficacy against RCC. Funding: Smart Brain Ltd. Translation: For the Czech translation of the abstract see Supplementary Materials section.

Objectives: To explore the feasibility and effectiveness of a yoga program in improving health-related quality of life (HQOL), physical and psychological functioning in rheumatoid arthritis (RA) patients. Design: Single-centre parallel-arms randomized controlled trial comparing yoga (n = 30) and education control group (n = 27). Setting: Tertiary care University hospital. Intervention: A 12-week yoga program, based on the Yoga in Daily Life system, included 2x weekly/90-minute sessions. The control group had 1xweekly/60-minute educational lectures on arthritis-related topics. Main outcome measures: Assessments were performed at baseline, 12 (post-intervention) and 24 weeks (follow-up). The primary outcome was change in The Short Form-36 (SF-36) HQOL at 12 weeks. Linear regression analysis was adjusted for baseline scores. Results: No significant between-group differences were found for SF-36 (all p > 0.05). At 12 weeks the adjusted mean difference between groups favoured yoga for Functional Assessment of Chronic Illness Therapy-fatigue (5.08 CI 1.29 to 8.86; p = 0.009) and Hospital Anxiety and Depression Scale (HADS)-depression (−1.37 CI −2.38 to −0.36); p = 0.008) and at 24 weeks for HADS-anxiety (−1.79 CI −3.34 to − 0.23; p = 0.025), while the impact on fatigue was sustained (5.43 CI 1.33 to 9.54, p = 0.01). The program had no impact on RA disease activity. Feasibility outcomes included recruitment rate 16 %, retention 80.7 %, and adherence to yoga 87.5 vs 82.7 % for control. No serious adverse events were recorded. Conclusions: Yoga in Daily Life program was not associated with change in health-related quality of life of RA patients. Significant improvements in fatigue and mood were observed at postintervention and follow-up. This yoga program was found feasible and safe for patients and may complement standard RA treat-to-target strategy.

Empyema is a severe complication of different diseases and traumas. Management of this complication is difficult and should comprise general and local procedures. The general procedure is mainly based on administering wide-spectrum antibiotics. Local management depends on patient general condition, but in all cases the essential procedure is to insert a drain into the pleural cavity and to evacuate the pus. Sometimes pus is very thick and its evacuation and following re-expansion of the lung is rather impossible. In these patients surgical intervention is needed. The use of intrapleural enzymes to support the drainage was first described in 1949 by Tillett and Sherry using a mixture of streptokinase and streptococcal deoxyribonuclease. Nowadays, purified streptokinase has come into widespread use, but recent studies reported no streptokinase effect on pus viscosity. On the other side, deoxyribonuclease reduces pus viscosity and may be more useful in treatment. We report two cases of intrapleural administration of Pulmozyme (alfa dornase - deoxyribonuclease (HOFFMANN-LA ROCHE AG) in dosage 2 × 2.5 mg with a significant improvement caused by changes in pus viscosity.

Empyema is a severe complication of different diseases and traumas. Management of this complication is difficult and should comprise general and local procedures. The general procedure is mainly based on administering wide-spectrum antibiotics. Local management depends on patient general condition, but in all cases the essential procedure is to insert a drain into the pleural cavity and to evacuate the pus. Sometimes pus is very thick and its evacuation and following re-expansion of the lung is rather impossible. In these patients surgical intervention is needed. The use of intrapleural enzymes to support the drainage was first described in 1949 by Tillett and Sherry using a mixture of streptokinase and streptococcal deoxyribonuclease. Nowadays, purified streptokinase has come into widespread use, but recent studies reported no streptokinase effect on pus viscosity. On the other side, deoxyribonuclease reduces pus viscosity and may be more useful in treatment. We report two cases of intrapleural administration of Pulmozyme (alfa dornase - deoxyribonuclease (HOFFMANN-LA ROCHE AG) in dosage 2 × 2.5 mg with a significant improvement caused by changes in pus viscosity.

Glutathione S-transferase genotypes GSTT1, GSTM1, GSTP1 were characterised in 155 middle-aged men and compared with parameters of oxidative stress at the level of DNA and lipids, with antioxidant enzymes, and with plasma antioxidants in smokers and non-smokers. Smokers had on average significantly lower levels of Vitamin C, beta-carotene and beta-cryptoxanthin and higher amounts of oxidised purines and pyrimidines in lymphocyte DNA. The GSTM1 null genotype was associated with elevated glutathione as well as with higher Vitamin C concentration in plasma. Vitamin C was higher in GSTT1+ compared with GSTT1 null--as was glucose-6-phosphate dehydrogenase activity. The homozygous GSTP1 a/a genotype was associated with significantly higher levels of GST activity measured in lymphocytes, in comparison with the b/b genotype. Using multifactorial statistical analysis we found significant associations between smoking, GSTP1 genotype, plasma Vitamin C, and purine base damage in lymphocyte DNA. The difference in Vitamin C plasma levels between smokers and non-smokers was seen only with the GSTP1 b/b genotype. This group accounted also for most of the increase in purine oxidation in smokers. In contrast, the link between smoking and oxidised pyrimidines in DNA was seen only in the GSTT1 null group. It seems that polymorphisms in the phase II metabolising enzyme glutathione S-transferase may be important determinants of commonly measured biomarkers.