Tuberculosis: the implications for anaesthesia

Tuberculosis is a common problem in South Africa, and provides a number of challenges for the anaesthetist. Patients may present in a variety of ways. Constitutional and pulmonary symptoms are the most common. These may impact on fitness for surgery and choice of anaesthesia. Tuberculosis treatment has the potential for a number of significant drug interactions. These are primarily mediated through induction of the cytochrome P450 enzyme system by rifampicin. Guidelines for the prevention of tuberculosis in the theatre environment need to be followed to avoid placing staff and other patients in danger.Keywords: tuberculosis, antitubercular agents, drug interactions, transmission, bacterial filte

Modeling of arylamide helix mimetics in the p53 peptide binding site of hDM2 suggests parallel and anti-parallel conformations are both stable.

The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix

Delirium, frailty and mortality: interactions in a prospective study of hospitalized older people

BACKGROUND: It is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty. METHODS: We undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged ≥70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality. RESULTS: The sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8–3.3, p<0.01; frailty (per SD): HR 3.5, 95%CI 1.2–9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1–5.6); tertile 2 HR 2.7 (95%CI 1.5–4.6); tertile 3 HR 1.9 (95% CI 1.2–3.0). CONCLUSION: While delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals

Mapping the X-Ray Emission Region in a Laser-Plasma Accelerator

The x-ray emission in laser-plasma accelerators can be a powerful tool to understand the physics of relativistic laser-plasma interaction. It is shown here that the mapping of betatron x-ray radiation can be obtained from the x-ray beam profile when an aperture mask is positioned just beyond the end of the emission region. The influence of the plasma density on the position and the longitudinal profile of the x-ray emission is investigated and compared to particle-in-cell simulations. The measurement of the x-ray emission position and length provides insight on the dynamics of the interaction, including the electron self-injection region, possible multiple injection, and the role of the electron beam driven wakefield.Comment: 5 pages, 4 figure

Serratia spp. bacteria evolved in Aotearoa-New Zealand for infection of endemic scarab beetles

The Melolonthinae branch of the beetle family Scarabaeidae has evolved in isolation in Aotearoa, radiating into >100 endemic species, since Aotearoa separated from Gondwanaland 82 million years ago. The group includes important pasture pests, such as the New Zealand grass grub Costelytra giveni and the manuka beetle Pyronota festiva. These beetles, like other organisms, host their own distinctive microflora including beneficial microbial symbionts and pathogens. A wide range of microbial pathogens infect the Scarabaeidae, but in Aotearoa the bacteria Serratia entomophila, S. proteamaculans and S. quinivorans (Enterobacteriaceae) are frequently found causing natural disease epizootics in C. giveni. S. entomophila is widespread in Aotearoa pasture soils, with only rare isolations of S. entomophila documented in other countries. In contrast S. proteamaculans and S. quinivorans are globally ubiquitous, and are widely distributed within Aotearoa, with some isolates active against either C. giveni or Pyronota spp. larvae, or both. Virulence determinants that impart differential host specificity and potency are located on variants of the amber disease associated plasmid (pADAP). The host specificity of the Serratia-scarab system and the absence of similar systems in other geographies, suggests that the relationship between Serratia spp. and endemic scarabs has evolved in Aotearoa

Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations. $\textbf{SIGNIFICANCE}$: Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AACRJ.S. Brown, B. O'Carrigan, and T.A. Yap acknowledge support from the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Research in The Jackson laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A18796. Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P. Jackson receives his salary from the University of Cambridge, UK, supplemented by CRUK

The STELLAR trial protocol: a prospective multicentre trial for Richter’s syndrome consisting of a randomised trial investigation CHOP-R with or without acalabrutinib for newly diagnosed RS and a single-arm platform study for evaluation of novel agents in relapsed disease

Background Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter’s syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton’s tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. Methods The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. Discussion The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. Trial registration EudraCT: 2017–004401-40, registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057, registered on the 04-Mar-2019. ClinicalTrials.gov: NCT03899337, registered on 02-April-2019

Non-invasive MRI biomarkers for the early assessment of iron overload in a humanized mouse model of β-thalassemia

β-thalassemia (βT) is a genetic blood disorder causing profound and life threatening anemia. Current clinical management of βT is a lifelong dependence on regular blood transfusions, a consequence of which is systemic iron overload leading to acute heart failure. Recent developments in gene and chelation therapy give hope of better prognosis for patients, but successful translation to clinical practice is hindered by the lack of thorough preclinical testing using representative animal models and clinically relevant quantitative biomarkers. Here we demonstrate a quantitative and non-invasive preclinical Magnetic Resonance Imaging (MRI) platform for the assessment of βT in the γβ(0)/γβ(A) humanized mouse model of βT. Changes in the quantitative MRI relaxation times as well as severe splenomegaly were observed in the heart, liver and spleen in βT. These data showed high sensitivity to iron overload and a strong relationship between quantitative MRI relaxation times and hepatic iron content. Importantly these changes preceded the onset of iron overload cardiomyopathy, providing an early biomarker of disease progression. This work demonstrates that multiparametric MRI is a powerful tool for the assessment of preclinical βT, providing sensitive and quantitative monitoring of tissue iron sequestration and cardiac dysfunction- parameters essential for the preclinical development of new therapeutics

Escaping the oligotrophic gyre? The year-round movements, foraging behaviour and habitat preferences of Murphy’s petrels

The South Pacific Gyre is the world’s largest expanse of oligotrophic ocean and supports communities of endemic gadfly petrels Pterodroma spp, yet little is known about their foraging ecology in this nutrient-poor environment. We tracked Murphy’s petrels Pterodroma ultima with geolocators from Henderson Island, Pitcairn Islands, for two consecutive years (2011 - 2013). During pre-laying exodus, petrels travelled south and southwest of the colony, with males travelling further than females to more productive waters. During incubation, birds foraged at the southern and eastern edges of the Gyre, with some travelling over 4,800 km from the colony, the greatest recorded foraging range of any breeding seabird. During non-breeding, the petrels migrated to the Subarctic Gyre in the North Pacific to forage in cool, mesotrophic waters. Habitat models revealed that birds do not have clear preferences for oceanographic (such as fronts or eddies) or topographic features (seamounts), generally favouring deep and unproductive waters. Analyses of activity patterns indicated Murphy’s petrels are amongst the most active of all seabirds, particularly during incubation when they spent c.95% of their time at sea in flight. The birds did not appear to forage during darkness, but flight activity peaked at dawn, particularly during non-breeding, suggesting they feed on mesopelagic prey that are diel vertical migrants. At-sea protection for such a wide-ranging species would require management at huge spatial scales, and hence in the short term, the principal focus for conservation should be on eliminating the immediate threat from invasive mammals at breeding sites.T.A.C. was supported by a studentship funded as part of the Natural Environment Research Council (NERC) Standard Grant NE/J021083/1. This study represents a contribution to the Ecosystems component of the British Antarctic Survey Polar Science for Planet Earth Programme, funded by NERC

Myocardial Viability Imaging using Manganese-Enhanced MRI in the First Hours after Myocardial Infarction

Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping-manganese-enhanced MRI (MEMRI) reveals elevated and increasing Mn uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold-standard technique, late-gadolinium-enhanced MRI. These data, coupled with the re-emergence of clinical Mn -based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients