https://hdl.handle.net/20.500.14178/901 2026-09-27T03:34:50Z https://hdl.handle.net/20.500.14178/3959 Catheter-Directed Thrombolysis in Intermediate-High-Risk Pulmonary Embolism Kroupa, Josef; Radvan, Martin; Mrózek, Jan; Sluka, Martin; Jirouš, Štěpán; Hlinomaz, Ota; Plíva, Milan; Pudil, Jan; Voběrková, Hana; Bartošková, Karolína; Poloczek, Martin; Kameník, Martin; Brabec, Michal; Lichnerová, Eva; Hutyra, Martin; Bernat, Ivo; Novák, Martin; Horáková, Johana; Jelínková, Lucie; Kníže, Tomáš; Toušek, Petr; Štěchovský, Cyril; Varhaník, Filip; Coufal, Zdeněk; Jarkovský, Jiří; Kočka, Viktor BACKGROUND: Whether catheter-directed thrombolysis improves clinical outcomes in patients with intermediate-high-risk pulmonary embolism, as compared with anticoagulation alone, is uncertain. METHODS: In this multicenter, open-label, randomized trial, we randomly assigned patients with intermediate-high-risk acute pulmonary embolism (defined by hemodynamic stability, a simplified Pulmonary Embolism Severity Index score of >=1, and right ventricular dysfunction plus an elevated level of cardiac troponin or natriuretic peptide) in a 1:1 ratio to receive catheter-directed thrombolysis with alteplase plus anticoagulation therapy (thrombolysis group) or anticoagulation therapy alone (standard-care group). The primary outcome was a composite of death from any cause, recurrence of pulmonary embolism, or cardiorespiratory decompensation or collapse within 7 days after randomization. Secondary outcomes included clinically relevant bleeding as defined by the Bleeding Academic Research Consortium, major bleeding as defined in the Global Use of Strategies to Open Occluded Coronary Arteries guidelines, and intracranial hemorrhage. RESULTS: A total of 558 patients underwent randomization; 280 were assigned to the thrombolysis group, and 278 to the standard-care group. The median age was 64 years, and 40.9% were female. A primary-outcome event occurred in 2 patients (0.7%) in the thrombolysis group and in 19 patients (6.8%) in the standard-care group (relative risk, 0.10; 95% confidence interval, 0.02 to 0.44; P<0.001); this difference was driven mainly by the lower incidence of cardiorespiratory decompensation or collapse in the thrombolysis group. By day 7, clinically relevant bleeding had occurred in 13 patients (4.6%) in the thrombolysis group and in 14 patients (5.0%) in the standard-care group (P = 0.85); major bleeding in 4 (1.4%) and 6 (2.2%), respectively (P = 0.54); and intracranial hemorrhage in 2 (0.7%) and none. One patient in the thrombolysis group died within 30 days, and 4 patients in the standard-care group died within 7 days. CONCLUSIONS: Among patients with intermediate-high-risk acute pulmonary embolism, catheter-directed thrombolysis with alteplase plus anticoagulation therapy led to a lower risk of death from any cause, recurrent pulmonary embolism, or cardiorespiratory decompensation or collapse within 7 days after randomization than anticoagulation therapy alone. (Funded by the Ministry of Health of the Czech Republic and others; PRAGUE-26 ClinicalTrials.gov number, NCT05493163; EudraCT number, 2022-002218-18; European Union Clinical Trials number, 2024-516144-25-00.). 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3895 Comparable outcomes of BTK inhibitors and fixed-duration venetoclax plus rituximab in second-line treatment of chronic lymphocytic leukaemia: a real-world analysis by the Czech CLL study group Mihályová, Jana; Panovská, Anna; Šimkovič, Martin; Smolej, Lukáš; Špaček, Martin; Shokralla, Tereza; Kubová, Zuzana; Zuchnická, Jana; Arpáš, Tomáš; Vodárek, Pavel; Turcsányi, Peter; Polcerová, Lenka; Chrápavá, Marika; Lysák, Daniel; Brejcha, Martin; Móciková, Heidi; Doubek, Michael In relapsed/refractory (RR) chronic lymphocytic leukaemia (CLL), Bruton tyrosine kinase inhibitors (BTKi) are administered as monotherapy until disease progression. In contrast, venetoclax, a B-cell lymphoma 2 (BCL-2) protein inhibitor, is typically combined with rituximab (VenR) as a time-limited regimen. To date, neither randomized nor retrospective trials have directly compared these approaches in RR CLL, and only limited data are available comparing venetoclax plus obinutuzumab (VenObi) to BTKi in the first-line setting. We retrospectively analysed 352 patients receiving second-line therapy: 93 VenR and 259 BTKi (ibrutinib: n = 222; acalabrutinib: n = 37). Baseline characteristics were well balanced, except for a higher incidence of TP53 mutation and trisomy 12 in BTKi-treated patients. At a median follow-up of 13.8 months (VenR) and 22.1 months (BTKi), 12-month progression-free survival (PFS) and overall survival (OS) were comparable (PFS: 85.1% vs. 82.2%, p = 0.265; OS: 87.6% vs. 88.4%, p = 0.291). Estimated median PFS (45.4 vs. 37.9 months, p = 0.265) and OS (83.6 vs. 74.2 months, p = 0.291) also showed no significant differences between the VenR and BTKi cohorts. Treatment discontinuation due to adverse events before month 24 was more frequent with BTKi (22.5% with VenR vs. 34.3% with BTKi), primarily due to infections (10.6% vs. 28.6%) and disease progression (14.3% vs. 22.5%). These preliminary data suggest comparable outcomes and manageable toxicity profiles for both regimens. 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3878 Mechanistic modeling of recessive disease through allelic integration of variant effects Cubuk, Hasan; Plech, Marcin; Aslanzadeh, Vahid; Zikánová, Marie; Škopová, Václava; Kmoch, Stanislav; Shen, Yuxin; Marsh, Joseph A.; Kudla, Grzegorz Interpreting variants in recessive diseases is difficult because clinical severity depends on the combined function of both alleles. Deep mutational scanning (DMS) experiments can provide functional measurements at scale, but their scores often relate nonlinearly to true biochemical activity. Here, we describe a method for inferring enzymatic activities for thousands of variants by running two fitness assays at different expression levels and modeling the nonlinear activity-fitness relationship. These inferred activities allow the computation of a bi-allelic pathogenicity score that captures the joint effect of two alleles. We applied this approach to adenylosuccinate lyase (ADSL), quantifying the effects of >8,000 coding variants in a yeast-based DMS assay. The inferred activities separated pathogenic from benign alleles, and the bi-allelic scores correlated strongly with biochemical measurements and clinical outcomes, outperforming existing predictors. This framework provides a broadly applicable strategy for the mechanistic interpretation of variants in recessive enzymes. 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3877 A missense mutation in the SAA1 protein causing hereditary amyloid A amyloidosis Leung, Nelson; Hnízda, Aleš; McPhail, Ellen D.; Dasari, Surendra; Nosková, Lenka; Vyleťal, Petr; Mikšátko, Jiří; Piherová, Lenka; Kmochová, Tereza; Mušálková, Dita; Vaníčková, Zdislava; Radina, Martin; Zima, Tomáš; Hodaňová, Kateřina; Hartmannová, Hana; Stránecký, Viktor; Nasr, Samih H.; Ryšavá, Romana; Živná, Martina; Sikora, Jakub; Theis, Jason D.; Vrana, Julie A.; Buadi, Francis K.; Crooke, Stanley T.; Bleyer, Anthony; Kmoch, Stanislav In summary, guided by the patient's clinical course and diagnostic challenges, we report, for the first time, a family with autosomal dominant hereditary AA amyloidosis caused by a heterozygous SAA1 missense mutation, p.D34V. This mutation alters the primary structure of SAA1, dominantly enhances its aggregation, and produces a highly amyloidogenic protein capable of forming amyloid even at normal plasma SAA levels, affecting patients in their 20s and 30s. Importantly, the mutant protein escapes detection by routine clinical MS/MS amyloid typing because of its location between 2 trypsin cleavage sites. These findings highlight the need for genetic testing in AA amyloidosis without an inflammatory cause and caution that segmental duplications within SAA genes may complicate variant calling from short-read sequencing, further challenging diagnosis. Because of the unique pathogenesis of this family, the traditional immunosuppressive therapy used in AA amyloidosis would have no effect because the SAA levels were already low or normal. A novel approach to AA amyloidosis therapy would be required to treat members of this family and others like them. 2026-01-01T00:00:00Z