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[FeFe]-hydrogenases function as both H 2 catalysts and sensors. While catalysis is well investigated, details regarding the H 2 sensing mechanism are limited. Here, we relate protein structure changes to H 2 sensing, similar to light-driven bio-sensors. Our results highlight how identical cofactors incorporated in alternative protein scaffolds serve different functions in nature.

Objectives: In order to evaluate the impact of the surfactant of choice selection, primary end points were to compare the average number of doses per patient, need for mechanical ventilation on day 3, hospital length of stay, and in-hospital mortality between calfactant and poractant alfa in preterm infants with respiratory distress syndrome (RDS). Secondary outcomes included administration complications, development of bronchopulmonary dysplasia (BPD), and estimated average per patient cost among the study population., Methods: A retrospective chart review was performed at a level IV neonatal intensive care unit between January 2020 and December 2021 to compare the efficacy, safety, and pharmacoeconomic outcomes -following a surfactant of choice switch from calfactant to poractant alfa in preterm infants with RDS., Results: Final analysis included 253 premature infants with gestational age (GA) between 22 and 36 weeks who met inclusion criteria. A total of 118 patients who received calfactant required higher average number of doses, 1.5 vs 1.3 doses (p = 0.031), and had more administration complications than 135 patients who received poractant alfa (10.2 vs 2.2%, p = 0.008). The need for redosing, mechanical ventilation on day 3, hospital length of stay, in-hospital mortality, and development of BPD were comparable between both groups. However, the estimated average per patient cost for poractant alfa was 32% higher than calfactant ($1,901 vs $1,439, p <0.001)., Conclusions: Despite the pharmacoeconomic disadvantage, preterm infants who received poractant alfa needed fewer doses and were less likely to have administration complications compared with those who received calfactant., Competing Interests: Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors have full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.)

Background: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials., Methods: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels., Results: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival., Conclusion: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JAS reports personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Roche, personal fees from BMS, personal fees from Amgen, personal fees from LEO pharma, personal fees from Novartis, personal fees from Takeda, outside of the submitted work. FCA has received a research grant from Novartis, support for attending meetings and/or travel from Amgen, and consultant fees from IQVIA.PD has nothing to disclose. JR has nothing to disclose. AT has nothing to disclose. ANH has nothing to disclose. NF reports personal fees from AbbVie, Amgen, AstraZeneca, BeiGene, Berlinchemie, Boehringer Ingelheim, Bristol Myers&Squibb, Lilly, Merck Sharp&Dohme, Merck, Novartis, Pfizer, Roche, Sanofi, Takeda, outside of the submitted work. HY has nothing to disclose. PC has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. OB has nothing to disclose. CMB has nothing to disclose. ABVD has nothing to disclose. JA has nothing to disclose. SPA as nothing to disclose. MW has nothing to disclose. SK has nothing to disclose. MU has nothing to disclose. GT has nothing to disclose. CFW has nothing to disclose. AR reports grants from AbbVie, grants from AstraZeneca, grants from BMS, grants from Boehringer Ingelheim, grants from Daichi Sankyo, grants from Eli Lilly, grants from GSK, grants from MSD, grants from Novartis, grants from Pfizer, grants from Roche, outside the submitted work. PH has nothing to disclose. JB has nothing to disclose. HGK has nothing to disclose. CG has nothing to disclose. MSch has nothing to disclose. CSch has nothing to disclose. FG reports personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, Ariad, Abbvie, Tesaro / GSK, Sanofi, Daiichi-Sankyo, Beigene, outside of the submitted work. MSch has nothing to disclose. MS reports personal fees from Lilly, Astra-Zeneca, Bristol-Myers & Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Roche, AbbVie, Boehringer-Ingelheim, Celgene, Novartis, grants from Astra Zeneca outside the submitted work. NR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from GSK, personal fees from Hoffmann-La Roche, personal fees from Janssen, personal fees from MSD, personal fees from Merck, personal fees from Lilly, personal fees from Pfizer, personal fees from Takeda, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accurate and fast understanding of the patient's anatomy is crucial in surgical decision making and particularly important in visceral surgery. Sophisticated visualization techniques such as 3D Volume Rendering can aid the surgeon and potentially lead to a benefit for the patient. Recently, we proposed a novel volume rendering technique called Adaptive Volumetric Illumination Sampling (AVIS) that can generate realistic lighting in real-time, even for high resolution images and volumes but without introducing additional image noise. In order to evaluate this new technique, we conducted a randomized, three-period crossover study comparing AVIS to conventional Direct Volume Rendering (DVR) and Path Tracing (PT). CT datasets from 12 patients were evaluated by 10 visceral surgeons who were either senior physicians or experienced specialists. The time needed for answering clinically relevant questions as well as the correctness of the answers were analyzed for each visualization technique. In addition to that, the perceived workload during these tasks was assessed for each technique, respectively. The results of the study indicate that AVIS has an advantage in terms of both time efficiency and most aspects of the perceived workload, while the average correctness of the given answers was very similar for all three methods. In contrast to that, Path Tracing seems to show particularly high values for mental demand and frustration. We plan to repeat a similar study with a larger participant group to consolidate the results.

The enzyme FeFe-hydrogenase catalyzes H 2 evolution and oxidation at an active site that consists of a [4Fe-4S] cluster bridged to a [Fe 2 (CO) 3 (CN) 2 (azadithiolate)] subsite. Previous investigations of its mechanism were mostly conducted on a few "prototypical" FeFe-hydrogenases, such as that from Chlamydomonas reinhardtii (Cr HydA1), but atypical hydrogenases have recently been characterized in an effort to explore the diversity of this class of enzymes. We aim at understanding why prototypical hydrogenases are active in either direction of the reaction in response to a small deviation from equilibrium, whereas the homologous enzyme from Thermoanaerobacter mathranii (Tam HydS) shows activity only under conditions of very high driving force, a behavior that was referred to as "irreversible catalysis". We follow up on previous spectroscopic studies and recent developments in the kinetic modeling of bidirectional reactions to investigate and compare the catalytic cycles of Cr HydA1 and Tam HydS under conditions of direct electron transfer with an electrode. We compare the hypothetical catalytic cycles described in the literature, and we show that the observed changes in catalytic activity as a function of potential, pH, and H 2 concentration can be explained with the assumption that the same catalytic mechanism applies. This helps us identify which variations in properties of the catalytic intermediates give rise to the distinct "reversible" or "irreversible" catalytic behaviors.