Suspected sepsis: summary of NICE guidance

The UK Parliamentary and Health Service Ombudsman inquiry “Time to Act” found failures in the recognition, diagnosis, and early management of those who died from sepsis, which triggered this guidance. In sepsis the body’s immune and coagulation systems are switched on by an infection and cause one or more body organs to malfunction with variable severity. The condition is life threatening. Although most people with infection do not have and will not develop sepsis, non-specific signs and symptoms can lead to late recognition of people who might have sepsis. We would like clinicians to “think sepsis” and recognise symptoms and signs of potential organ failure when they assess someone with infection, in a similar way to thinking “Could this chest pain be cardiac in origin?”This guidance provides a pragmatic approach for patients with infection who are assessed in the community, emergency departments, and hospitals by a wide range of general and specialist healthcare professionals. It includes guidance on assessment of risk factors followed by a detailed structured assessment of potential clinical signs and symptoms of concern.Definitions of sepsis have been developed, but these offer limited explanation on how to confirm or rule out the diagnosis in general clinical settings or in the community. Current mechanisms to diagnose sepsis and guidelines for use largely apply to critical care settings such as intensive care. We recognised a need for better recognition of sepsis in non-intensive settings and for the diagnosis to be entertained sooner.While sepsis is multifactorial and rarely presents in the same way, the Guideline Development Group considered that use of an easy, structured risk assessment may help clinicians identify those most severely ill who require immediate potentially lifesaving treatment. This guideline ensures that patients defined as having sepsis by recent definitions are, as a minimum, assessed as moderate-high risk. This guidance is also about appropriate de-escalation if sepsis is unlikely and broad spectrum antibiotics or hospital admission are not appropriate.This article summarises recommendations from the National Institute for Health and Care Excellence (NICE) guideline for the recognition, diagnosis, and management of sepsis in children and adults. Recommendations and the clinical pathway are available via the NICE website, and the UK Sepsis Trust tools are being revised to align with this guidance. This article is accompanied by an infographic, which displays the NICE guideline as a decision making tool

Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment. Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions. Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance

Clonal expansion within pneumococcal serotype 6C after use of seven-valent vaccine

Streptococcus pneumoniae causes invasive infections, primarily at the extremes of life. A seven-valent conjugate vaccine (PCV7) is used to protect against invasive pneumococcal disease in children. Within three years of PCV7 introduction, we observed a fourfold increase in serotype 6C carriage, predominantly due to a single clone. We determined the whole-genome sequences of nineteen S. pneumoniae serotype 6C isolates, from both carriage (n = 15) and disease (n = 4) states, to investigate the emergence of serotype 6C in our population, focusing on a single multi-locus sequence type (MLST) clonal complex 395 (CC395). A phylogenetic network was constructed to identify different lineages, followed by analysis of variability in gene sets and sequences. Serotype 6C isolates from this single geographical site fell into four broad phylogenetically distinct lineages. Variation was seen in the 6C capsular locus and in sequences of genes encoding surface proteins. The largest clonal complex was characterised by the presence of lantibiotic synthesis locus. In our population, the 6C capsular locus has been introduced into multiple lineages by independent capsular switching events. However, rapid clonal expansion has occurred within a single MLST clonal complex. Worryingly, plasticity exists within current and potential vaccine-associated loci, a consideration for future vaccine use, target selection and design

Geospatial analysis and living urban geometry

This essay outlines how to incorporate morphological rules within the exigencies of our technological age. We propose using the current evolution of GIS (Geographical Information Systems) technologies beyond their original representational domain, towards predictive and dynamic spatial models that help in constructing the new discipline of "urban seeding". We condemn the high-rise tower block as an unsuitable typology for a living city, and propose to re-establish human-scale urban fabric that resembles the traditional city. Pedestrian presence, density, and movement all reveal that open space between modernist buildings is not urban at all, but neither is the open space found in today's sprawling suburbs. True urban space contains and encourages pedestrian interactions, and has to be designed and built according to specific rules. The opposition between traditional self-organized versus modernist planned cities challenges the very core of the urban planning discipline. Planning has to be re-framed from being a tool creating a fixed future to become a visionary adaptive tool of dynamic states in evolution

Leakage-resilient non-malleable codes

A recent trend in cryptography is to construct cryptosystems that are secure against physical attacks. Such attacks are usually divided into two classes: the \emph{leakage} attacks in which the adversary obtains some information about the internal state of the machine, and the \emph{tampering} attacks where the adversary can modify this state. One of the popular tools used to provide tamper-resistance are the \emph{non-malleable codes} introduced by Dziembowski, Pietrzak and Wichs (ICS 2010). These codes can be defined in several variants, but arguably the most natural of them are the information-theoretically secure codes in the k-split-state model (the most desired case being k=2). Such codes were constucted recently by Aggarwal et al.~(STOC 2014). Unfortunately, unlike the earlier, computationally-secure constructions (Liu and Lysyanskaya, CRYPTO 2012) these codes are not known to be resilient to leakage. This is unsatisfactory, since in practice one always aims at providing resilience against both leakage and tampering (especially considering tampering without leakage is problematic, since the leakage attacks are usually much easier to perform than the tampering attacks). In this paper we close this gap by showing a non-malleable code in the $2$-split state model that is secure against leaking almost a $1/12$-th fraction of the bits from the codeword (in the bounded-leakage model). This is achieved via a generic transformation that takes as input any non-malleable code (\Enc,\Dec) in the $2$-split state model, and constructs out of it another non-malleable code (\Enc',\Dec') in the $2$-split state model that is additionally leakage-resilient. The rate of (\Enc',\Dec') is linear in the rate of (\Enc,\Dec). Our construction requires that \Dec is \emph{symmetric}, i.e., for all $x, y$, it is the case that \Dec(x,y) = \Dec(y,x), but this property holds for all currently known information-theoretically secure codes in the $2$-split state model. In particular, we can apply our transformation to the code of Aggarwal et al., obtaining the first leakage-resilient code secure in the split-state model. Our transformation can be applied to other codes (in particular it can also be applied to a recent code of Aggarwal, Dodis, Kazana and Obremski constructed in the work subsequent to this one)

Predictable arguments of knowledge

We initiate a formal investigation on the power of predictability for argument of knowledge systems for NP. Specifically, we consider private-coin argument systems where the answer of the prover can be predicted, given the private randomness of the verifier; we call such protocols Predictable Arguments of Knowledge (PAoK). Our study encompasses a full characterization of PAoK, showing that such arguments can be made extremely laconic, with the prover sending a single bit, and assumed to have only one round (i.e., two messages) of communication without loss of generality. We additionally explore PAoK satisfying additional properties (including zero-knowledge and the possibility of re-using the same challenge across multiple executions with the prover), present several constructions of PAoK relying on different cryptographic tools, and discuss applications to cryptography

Density effect in Cu K-shell ionization by 5.1-GeV electrons

We have made an absolute measurement of the Cu K-shell impact ionization cross section by 5.1-GeV electrons, which demonstrates directly a density effect predicted by Fermi in 1940. By determining the ratio of the K x-ray yield from a thin front and back layer of the target by a novel grazing emission method, we have verified the effect of transition radiation on the x-ray production, suggested by Sorensen and reported by Bak et al