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The pathogenic spirochete Leptospira interrogans disseminates throughout its hosts via the bloodstream, then invades and colonizes a variety of host tissues. Infectious leptospires are resistant to killing by their hosts' alternative pathway of complement-mediated killing, and interact with various host extracellular matrix (ECM) components. The LenA outer surface protein (formerly called LfhA and Lsa24) was previously shown to bind the host ECM component laminin and the complement regulators factor H and factor H-related protein-1. We now demonstrate that infectious L. interrogans contain five additional paralogs of lenA, which we designated lenB, lenC, lenD, lenE and lenF. All six genes encode domains predicted to bear structural and functional similarities with mammalian endostatins. Sequence analyses of genes from seven infectious L. interrogans serovars indicated development of sequence diversity through recombination and intragenic duplication. LenB was found to bind human factor H, and all of the newly-described Len proteins bound laminin. In addition, LenB, LenC, LenD, LenE and LenF all exhibited affinities for fibronectin, a distinct host extracellular matrix protein. These characteristics suggest that Len proteins together facilitate invasion and colonization of host tissues, and protect against host immune responses during mammalian infection.
The decay behavior of low-lying dipole states in 140Ce was investigated exploiting the γ3-setup at the HIγS facility using quasi-monochromatic photon beams. Branching ratios of individual excited states as well as average branching ratios to low-lying states have been extracted using γ – γ coincidence measurements. The comparison of the average branching ratios to QPM calculations shows a remarkable agreement between experiment and theory in the energy range from 5.0 to 8.5 MeV.
The decay properties of the Pygmy Dipole Resonance (PDR) have been investigated in the semi-magic N=82 nucleus 140Ce using a novel combination of nuclear resonance fluorescence and γ–γ coincidence techniques. Branching ratios for transitions to low-lying excited states are determined in a direct and model-independent way both for individual excited states and for excitation energy intervals. Comparison of the experimental results to microscopic calculations in the quasi-particle phonon model exhibits an excellent agreement, supporting the observation that the Pygmy Dipole Resonance couples to the ground state as well as to low-lying excited states. A 10% mixing of the PDR and the [21+ x PDR] is extracted.
Background: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1‐INH‐HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS‐2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo.
Methods: OPuS‐2 was a Phase 3, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator‐confirmed attacks.
Results: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack‐free during the 84‐day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE‐QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated.
Conclusions: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1‐INH‐HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.
Background: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA®, CSL Behring) was established in the 16-week COMPACT trial.
Objective: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC).
Methods: Open-label, randomised, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naïve or who had completed the COMPACT trial, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional up-titration to optimise prophylaxis. ClinicalTrials.gov registration: NCT02316353.
Results: 126 patients with a monthly attack rate of 4.3 in 3 months prior to entry in the COMPACT program were enrolled and treated for a mean of 1·5 years; 44 patients (34·9%) had >2 years exposure. Median steady-state C1-INH functional activity increased to a maximum of 73.0% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11·3 and 8·5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualised attack rates were 1·3 and 1·0, respectively and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for >2 years, 19 (83%) were attack-free during months 25–30 of treatment.
Conclusion: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
