To characterise symptoms, key findings and clinical outcomes in older adults with COVID-19. 12% of older individuals did not present with classical COVID-19 symptoms, though fever, dyspnoea, delirium and raised inflammation were associated with higher mortality. Compared with fitter older individuals, some measures of immune activity were lower in frailer patients. COVID-19 may present without cardinal symptoms as well as implicate a possible role for age-related changes in immunity in mediating the relationship between frailty and mortality. To describe the clinical features of COVID-19 in older adults, and relate these to outcomes. A cohort study of 217 individuals (median age 80, IQR 74–85 years; 62% men) hospitalised with COVID-19, followed up for all-cause mortality, was conducted. Secondary outcomes included cognitive and physical function at discharge. C-reactive protein and neutrophil:lymphocyte ratio were used as measures of immune activity. Cardinal COVID-19 symptoms (fever, dyspnoea, cough) were common but not universal. Inflammation on hospitalisation was lower in frail older adults. Fever, dyspnoea, delirium and inflammation were associated with mortality. Delirium at presentation was an independent risk factor for cognitive decline at discharge. COVID-19 may present without cardinal symptoms as well as implicate a possible role for age-related changes in immunity in mediating the relationship between frailty and mortality.

To investigate functional and cognitive outcomes among patients with delirium in COVID-19. Delirium in COVID-19 was prevalent (42%), but only a minority had been recognised by the clinical team. At 4-week follow-up, delirium was significantly associated with worse functional outcomes, independent of pre-morbid frailty. Cognitive outcomes were not appreciably worse. The presence of delirium is a significant factor in predicting worse functional outcomes in patients with COVID-19. To ascertain delirium prevalence and outcomes in COVID-19. We conducted a point-prevalence study in a cohort of COVID-19 inpatients at University College Hospital. Delirium was defined by DSM-IV criteria. The primary outcome was all-cause mortality at 4 weeks; secondary outcomes were physical and cognitive function. In 71 patients (mean age 61, 75% men), 31 (42%) had delirium, of which only 12 (39%) had been recognised by the clinical team. At 4 weeks, 20 (28%) had died, 26 (36%) were interviewed by telephone and 21 (30%) remained as inpatients. Physical function was substantially worse in people after delirium − 50 out of 166 points (95% CI − 83 to − 17, p = 0.01). Mean cognitive scores at follow-up were similar and delirium was not associated with mortality in this sample. Our findings indicate that delirium is common, yet under-recognised. Delirium is associated with functional impairments in the medium term.

• There is amino acid sequence homology between the ADP-ribose binding sites of human PARP14 and SARS-CoV-2 ADRP. • This homology is even more pronounced in bat species. • The model proposed highlights the potential of the PARP axis to yield druggable targets for the treatment of COVID-19.

AbstractPurposeTo describe the clinical features of COVID-19 in older adults, and relate these to outcomes.MethodsCohort study of 217 individuals (≥70 years) hospitalised with COVID-19, followed up for allcause mortality. Secondary outcomes included cognitive and physical function at discharge. C-reactive protein and neutrophil: lymphocyte ratio were used as measures of immune activity.ResultsCardinal COVID-19 symptoms (fever, dyspnoea, cough) were common but not universal. Inflammation on hospitalisation was lower in frail older adults. Fever, dyspnoea, delirium and inflammation were associated with mortality. Delirium at presentation was an independent risk factor for cognitive decline at discharge.ConclusionsCOVID-19 may present without cardinal symptoms as well as implicate a possible role for age-related changes in immunity in mediating the relationship between frailty and mortality.Key summary pointsAimTo characterise symptoms, key findings and clinical outcomes in older adults with COVID-19Findings12% of older individuals did not present with classical COVID-19 symptoms, though fever, dyspnoea, delirium and raised inflammation were associated with higher mortality. Compared with fitter older individuals, immune activity was lower in frailer patients.MessageCOVID-19 may present without cardinal symptoms as well as implicate a possible role for age-related changes in immunity in mediating the relationship between frailty and mortality.

To describe associations between frailty, ethnicity, socioeconomic position and mortality in a cohort of older patients presenting to hospital with COVID-19. Frailty did not appear to be associated with mortality rates after COVID-19, though an interaction was evident indicating much larger excess mortality in fitter, compared with frailer patients. Frailty may not be a good measure of prognosis in COVID-19 and different mechanisms may underlie pathways to death depending on pre-morbid frailty. Our aim was to quantify the mortality from COVID-19 and identify any interactions with frailty and other demographic factors. Hospitalised patients aged ≥ 70 were included, comparing COVID-19 cases with non-COVID-19 controls admitted over the same period. Frailty was prospectively measured and mortality ascertained through linkage with national and local statutory reports. In 217 COVID-19 cases and 160 controls, older age and South Asian ethnicity, though not socioeconomic position, were associated with higher mortality. For frailty, differences in effect size were evident between cases (HR 1.02, 95% CI 0.93–1.12) and controls (HR 1.99, 95% CI 1.46–2.72), with an interaction term (HR 0.51, 95% CI 0.37–0.71) in multivariable models. Our findings suggest that (1) frailty is not a good discriminator of prognosis in COVID-19 and (2) pathways to mortality may differ in fitter compared with frailer older patients.

Purpose: eIF4A is an RNA helicase that forms part of the machinery of translation initiation. Proteomic analysis demonstrated eIF4A expression to be at least two-fold greater in a radioresistant derivative of T-47D breast cancer cells compared to parental cells. Inhibition of eIF4A has previously been shown to re-sensitize lymphomas to chemotherapeutic agents that cause DNA damage. The objective of this work is to investigate whether inhibition of eIF4A using silvestrol sensitizes breast cancer cells to radiotherapy in tissue culture, using T-47D as a model system. Methods and materials: T-47D cells were incubated in medium containing 0 nM to 1 nM silvestrol either for 24 h prior to irradiation at 0 Gy to 10 Gy, delivered by linear accelerator (LINAC) or continually for six days post irradiation. MTT viability and clonogenic assays were used to quantify response. Results: Pre-treatment of T-47D cells with 1 nM silvestrol caused a 34% reduction (p = 0.014) in viability on irradiation at 2 Gy compared to treatment with a DMSO control, as assessed by MTT assay. Maintenance of cells in 1 nM silvestrol for six days following irradiation at 2 Gy caused a 58% reduction (p = <0.001) in tumor cell viability. Clonogenic assays performed on cells maintained in 1 nM silvestrol following irradiation showed a dose modifying factor (DMF) of 1.4 (p = <0.001, one-way ANOVA). Conclusions: Low concentrations of silvestrol sensitize T-47D breast cancer cells to radiation with minimal effects on unirradiated cells. This highlights the possible usefulness of eIF4A inhibition in potentiating radiation-induced damage at the tumor site without causing systemic toxicity. (c) 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

Background: Until 1990, there was an upward trend in mortality from breast, lung, prostate, and colon cancers in the United Kingdom. With improvements in cancer treatment there has, in general, been a fall in mortality over the last 20 years. We evaluate regional cancer mortality trends in the United Kingdom between 1991 and 2007. Methods: We analysed mortality trends for breast, lung, prostate, and colon cancers using data obtained from the EUREG cancer database. We have described changes in age-standardised rates (using European standard population) per 100 000 for cancer mortality and generated trends in mortality for the 11 regions using Joinpoint regression. Results: Across all regions in the United Kingdom there was a downward trend in mortality for the four most common cancers in males and females. Overall, deaths from colon cancer decreased most rapidly and deaths from prostate cancer decreased at the slowest rate. Similar downward trends in mortality were observed across all regions of the United Kingdom with the data for lung cancer exhibiting the greatest variation. Conclusions: Mortality from the four most common cancers decreased across all regions of the United Kingdom; however, the rate of decline varied between cancer type and in some instances by region.

The expression of epidermal growth factor receptor (EGFR/ERBB1/HER1) is implicated in the progress of numerous cancers, a feature that has been exploited in the development of EGFR antibodies and EGFR tyrosine kinase inhibitors as anti-cancer drugs. However, EGFR also has important normal cellular functions, leading to serious side effects when EGFR is inhibited. One damaging characteristic of many oncogenes is the ability to be expressed in the hypoxic conditions associated with the tumour interior. It has previously been demonstrated that expression of EGFR is maintained in hypoxic conditions via an unknown mechanism of translational control, despite global translation rates generally being attenuated under hypoxic conditions. In this report, we demonstrate that the human EGFR 5′ untranslated region (UTR) sequence can initiate the expression of a downstream open reading frame via an internal ribosome entry site (IRES). We show that this effect is not due to either cryptic promoter activity or splicing events. We have investigated the requirement of the EGFR IRES for eukaryotic initiation factor 4A (eIF4A), which is an RNA helicase responsible for processing RNA secondary structure as part of translation initiation. Treatment with hippuristanol (a potent inhibitor of eIF4A) caused a decrease in EGFR 5′ UTR-driven reporter activity and also a reduction in EGFR protein level. Importantly, we show that expression of a reporter gene under the control of the EGFR IRES is maintained under hypoxic conditions despite a fall in global translation rates.

Alzheimer's disease (AD) is the main cause of dementia in our increasingly aging population. The debilitating cognitive and behavioral symptoms characteristic of AD make it an extremely distressing illness for patients and carers. Although drugs have been developed to treat AD symptoms and to slow disease progression, there is currently no cure. The incidence of AD is predicted to increase to over one hundred million by 2050, placing a heavy burden on communities and economies, and making the development of effective therapies an urgent priority. Two proteins are thought to have major contributory roles in AD: the microtubule associated protein tau, also known as MAPT; and the amyloid-beta peptide (A-beta), a cleavage product of amyloid precursor protein (APP). Oxidative stress is also implicated in AD pathology from an early stage. By targeting eIF4A, an RNA helicase involved in translation initiation, the synthesis of APP and tau, but not neuroprotective proteins, can be simultaneously and specifically reduced, representing a novel avenue for AD intervention. We also show that protection from oxidative stress is increased upon eIF4A inhibition. We demonstrate that the reduction of these proteins is not due to changes in mRNA levels or increased protein degradation, but is a consequence of translational repression conferred by inhibition of the helicase activity of eIF4A. Inhibition of eIF4A selectively and simultaneously modulates the synthesis of proteins involved in Alzheimer's disease: reducing A-beta and tau synthesis, while increasing proteins predicted to be neuroprotective.