From the banal to the bizarre: Unravelling immune recognition and response to microbial lipids

Microbes produce a rich array of lipidic species that through their location in the cell wall and ability to mingle with host lipids represent a privileged class of immune-active molecules....

Now you see it, now you don’t: dynamism amplifies the typicality effect

Some safety events do not stabilise in a coherent state, presenting with transient or intermittent features. Such dynamism may pose problems for human performance, especially if combined with non-typical stimuli that are rarely encountered in everyday work. This may explain undesirable pilot behaviour and could be an important cognitive factor in recent aircraft accidents. Sixty-five airline pilots tested a real-world typicality gradient, composed of two cockpit events, a typical event, and a non-typical event, across two different forms of dynamism, a stable, single system transition, and an unstable, intermittent system transition. We found that non-typical event stimuli elicited a greater number of response errors and incurred an increased response latency when compared to typical event stimuli, replicating the typicality effect. These performance deteriorations were amplified when a form of unstable system dynamism was introduced. Typical stimuli were unaffected by dynamism. This indicates that dynamic, non-typical events are problematic for pilots and may lead to poor event recognition and response. Typical is advantageous, even if dynamic. Manufacturers and airlines should evolve pilot training and crew procedures to take account of variety in event dynamics.

Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC–ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite.

Systems for recognition and response to deteriorating emergency department patients: a scoping review

Background Assessing and managing the risk of clinical deterioration is a cornerstone of emergency care, commencing at triage and continuing throughout the emergency department (ED) care. The aim of this scoping review was to assess the extent, range and nature of published research related to formal systems for recognising and responding to clinical deterioration in emergency department (ED) patients. Materials and methods We conducted a scoping review according to PRISMA-ScR guidelines. MEDLINE complete, CINAHL and Embase were searched on 07 April 2021 from their dates of inception. Human studies evaluating formal systems for recognising and responding to clinical deterioration occurring after triage that were published in English were included. Formal systems for recognising and responding to clinical deterioration were defined as: i) predefined patient assessment criteria for clinical deterioration (single trigger or aggregate score), and, or ii) a predefined, expected response should a patient fulfil the criteria for clinical deterioration. Studies of short stay units and observation wards; deterioration during the triage process; system or score development or validation; and systems requiring pathology test results were excluded. The following characteristics of each study were extracted: author(s), year, design, country, aims, population, system tested, outcomes examined, and major findings. Results After removal of duplicates, there were 2696 publications. Of these 33 studies representing 109,066 patients were included: all were observational studies. Twenty-two aggregate scoring systems were evaluated in 29 studies and three single trigger systems were evaluated in four studies. There were three major findings: i) few studies reported the use of systems for recognising and responding to clinical deterioration to improve care of patients whilst in the ED; ii) the systems for recognising clinical deterioration in ED patients were highly variable and iii) few studies reported on the ED response to patients identified as deteriorating. Conclusion There is a need to re-focus the research related to use of systems for recognition and response to deteriorating patients from predicting various post-ED events to their real-time use to improve patient safety during ED care.

Romidepsin (HDACi) plus cisplatin and nivolumab triplet combination in patients with metastatic triple negative breast cancer (mTNBC).

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]