A national study of 23 major trauma centres to investigate the effect of frailty on clinical outcomes in older people admitted with serious injury in England (FiTR 1): a multicentre observational study.

BACKGROUND: Older people are the largest group admitted to hospital with serious injuries. Many older people are living with frailty, a risk factor for poor recovery. We aimed to examine the effect of preinjury frailty on outcomes. METHODS: In this multicentre observational study (FiTR 1), we extracted prospectively collected data from all 23 adult major trauma centres in England on older people (aged ≥65 years) admitted with serious injuries over a 2·5 year period from the Trauma Audit and Research Network (TARN) database. Geriatricians assessed the preinjury Clinical Frailty Scale (CFS), a 9-point scale of fitness and frailty, with a score of 1 indicating a patient is very fit and a score of 9 indicating they are terminally ill. The primary outcome was inpatient mortality, with patients censored at hospital discharge. We used a multi-level Cox regression model fitted with adjusted hazards ratios (aHRs) to assess the association between CFS and mortality, with CFS scores being grouped as follows: a score of 1-2 indicated patients were fit; a score of 3 indicated patients were managing well; and a score of 4-8 indicated patients were living with frailty (4 being very mild, 5 being mild, 6 being moderate, and 7-8 being severe). FINDINGS: Between March 31, 2019, and Oct 31, 2021, 193 156 patients had records were held by TARN, of whom 16 504 had eligible records. Median age was 81·9 years (IQR 74·7-88·0), 9200 (55·7%) were women, and 7304 (44·3%) were men. Of 16 438 patients with a CFS score of 1-8, 11 114 (67·6%) were living with frailty (CFS of 4-8). 1660 (10·1%) patients died during their hospital stay, with a median time from admission to death of 9 days (IQR 4-18). Compared in patients with a CFS score of 1-2, risk of inpatient death was increased in those managing well (CFS score of 3; aHR 1·82 [95% CI 1·39-2·40]), living with very mild frailty (CFS score of 4: 1·99 [1·51-2·62]), living with mild frailty (CFS score of 5: 2·61 [1·99-3·43]), living with moderate frailty (CFS score of 6: 2·97 [2·26-3·90]), and living with severe frailty (CFS score of 7-8: 4·03 [3·04-5·34]). INTERPRETATION: Our findings support inclusion of the CFS in trauma pathways to aid patient management. Additionally, people who exercise regularly (CFS of 1-2) have better outcomes than those with lower activity levels (CFS of ≥3), supporting exercise as an intervention to improve trauma outcomes. FUNDING: None.

Predicting 1 year mortality after traumatic injury using the Clinical Frailty Scale.

BACKGROUND: Frailty is known to affect how people admitted with traumatic injuries recover during their inpatient stay and shortly after discharge. However, few studies have examined the effect of frailty on long-term mortality when adjusted for significant factors including age. We aimed to determine the effect of frailty on 1-year morality in older adults admitted with traumatic injuries. METHODS: We undertook an observational study at the Severn Major Trauma Network's major trauma centre based in South West England. Patients ≥65 years old admitted between November 2018 and September 2019 with traumatic injuries were included. Isolated hip fractures and inpatient injuries were excluded. A geriatrician assessed all patients for frailty using the Clinical Frailty Scale. Follow-up occurred at 1 year. A multivariable Cox proportional baseline hazards model assessed the effect of frailty on time-to-mortality. The adjusted model included age, sex, multimorbidity, surgery, most injured site, injury severity, postinjury complications, and geriatrician review. RESULTS: Five hundred and eighty-five patients were included. Median age was 81 years old (IQR 74-88), and median injury severity score was 13 (IQR 9-25). At 1 year 147 (25.1%) patients had died. Living with frailty was associated with mortality. The risk of dying increased with frailty severity. Compared to CFS 1-3: CFS 4 aHR = 1.73 (95% CI 0.89-3.36, p = 0.11); CFS 5 aHR = 3.82 (95% CI 2.11-6.93, p < 0.001); CFS 6 aHR = 4·05 (95% CI 2.21-7.45, p < 0.001); CFS 7-8 aHR = 6.57 (95% CI 3.43-12.59, p < 0.001). CONCLUSION: This study is the first to demonstrate a consistent effect of frailty, at all levels of severity and independent of age, on older peoples' survival 1 year after traumatic injury. These data support performing an admission frailty assessment to aid long-term management decisions and provide opportunity to modify frailty to improve outcomes.

Mechanical thrombectomy in stroke - planning for service expansion using discrete event simulation.

Mechanical thrombectomy (MT) is a very effective, but highly time dependent, reperfusion technique in the management of acute ischaemic stroke caused by large artery occlusion. MT is provided by 24 neuroscience centres (NSCs) in the UK which receive patients directly ('mothership') and via transfer from district general hospitals (DGHs), the 'drip and ship' pathway. NSCs currently provide a within hours service but are working on service expansion to enable 24/7 availability. DGHs, too, will need to prepare for this service expansion to ensure good outcomes for their patients. We discuss options for service expansion in a DGH and regional stroke network in south-west England and use Sentinel Stroke National Audit Programme data and discrete event simulation to model and compare alternative workflow options to aid the planning process. We suggest that our modelled options could be considered by all NHS DGHs in their preparation for MT service expansion.

Single-molecule imaging of Bacteroides fragilis AddAB reveals the highly processive translocation of a single motor helicase.

The AddAB helicase and nuclease complex is used for repairing double-strand DNA breaks in the many bacteria that do not possess RecBCD. Here, we show that AddAB, from the Gram-negative opportunistic pathogen Bacteroides fragilis, can rescue the ultraviolet sensitivity of an Escherichia coli recBCD mutant and that addAB is required for survival of B. fragilis following DNA damage. Using single-molecule observations we demonstrate that AddAB can translocate along DNA at up to 250 bp per second and can unwind an average of 14,000 bp, with some complexes capable of unwinding 40,000 bp. These results demonstrate the importance of processivity for facilitating encounters with recognition sequences that modify enzyme function during homologous recombination.

A morphology- and kinetics-based cascade for human neural cell high content screening.

The prospect of manipulating endogenous neural stem cells to replace damaged tissue and correct functional deficits represents a novel mechanism for treating a variety of central nervous system disorders. Using human neural precursor cultures and a variety of assays for studying stem cell behavior we have screened two libraries of commercially available compounds using an endpoint high content screening assay. We then performed detailed follow-up mechanistic studies on confirmed hits using endpoint and kinetics assays to characterize and differentiate the mechanisms of action of these compounds. The screening cascade employed successfully identified a number of active compounds with differing mechanisms of action. This approach shows how hits from a phenotypic screen can be prioritized and characterized by high content screening to identify potentially novel mechanisms and druggable targets to take forward into more conventional high-throughput screening approaches.