Royston Hospital

Abstract Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security 1 . Here we examined the genetic and phenotypic diversity of the A. E. Watkins landrace collection 2 of bread wheat ( Triticum aestivum ), a major global cereal, by whole-genome re-sequencing of 827 Watkins landraces and 208 modern cultivars and in-depth field evaluation spanning a decade. We found that modern cultivars are derived from two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium-based haplotypes and association genetics analyses link Watkins genomes to the thousands of identified high-resolution quantitative trait loci and significant marker–trait associations. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritized quantitative trait loci in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilizing genetic diversity in crop improvement to achieve sustainable food security.

We introduce a Bayesian method for guiding future directions for detection of life on exoplanets. We describe empirical and theoretical work necessary to place constraints on the relevant likelihoods, including those emerging from better understanding stellar environment, planetary climate and geophysics, geochemical cycling, the universalities of physics and chemistry, the contingencies of evolutionary history, the properties of life as an emergent complex system, and the mechanisms driving the emergence of life. We provide examples for how the Bayesian formalism could guide future search strategies, including determining observations to prioritize or deciding between targeted searches or larger lower resolution surveys to generate ensemble statistics and address how a Bayesian methodology could constrain the prior probability of life with or without a positive detection. Key Words: Exoplanets-Biosignatures-Life detection-Bayesian analysis. Astrobiology 18, 779-824.

The active site for a Au/C catalysts for acetylene hydrochlorination involves a Au⁺–Au³⁺couple.

Shipping is a heavily regulated industry and responsible for around 3% of global carbon emissions. Global trade is highly dependent on shipping which covers around 90% of commercial demand. Now the industry is expected to navigate through many twists and turns of different situations like upcoming regulations, climate change, energy shortages and technological revolutions. Technological development is apparent across all marine sectors due to the rapid development of sensor technology, IT, automation and robotics. The industry must continue to develop at a rapid pace over the next decade in order to be able to adapt to upcoming regulations and market pressure. Ship intelligence will be the driving force shaping the future of the industry. Ships generate a large volume of data from different sources and in different formats. So big data has become the talk of the industry nowadays. Big data analysis discovers correlations between different measurable or unmeasurable parameters to determine hidden patterns and trends. This analysis will have a significant impact on vessel performance monitoring and provide performance prediction, real-time transparency, and decision-making support to the ship operator. Big data will also bring new opportunities and challenges for the maritime industry. It will increase the capability of performance monitoring, remove human error and increase interdependencies of components. However, the industry will have to face many challenges such as data processing, reliability, and data security. Many regulations rely on ship data including the new EU MRV (Monitoring, Reporting and Verification) regulation to quantify the CO2 emissions for ships above 5000 gross tonnage. As a result, ship operators will have to monitor and report the verified amount of CO2 emitted by their vessels on voyages to, from and between EU ports and will also be required to provide information on energy efficiency parameters. The MRV is a data-oriented regulation requiring ship operators to capture and monitor the ship emissions and other related data and although it is a regional regulation at the moment there is scope for the International Maritime Organisation (IMO) to implement it globally in the near future.

Department of Anesthesia The Scarborough Hospital, Toronto, Ontario, Canada oyston@oyston.com Temporarily jpoyston@hotmail.comNew York School of Regional Anesthesia URL: http://www.nysora.com Authors: Admir Hadzic and Jerry Vloka John Oyston, M.B., B.S., F.R.C.P.(C.) Department of Anesthesia The Scarborough Hospital, Toronto, Ontario, Canada oyston@oyston.com Temporarily jpoyston@hotmail.comDrs. Hadzic and Vloka have produced one of the best regional anesthesia Web sites, without sponsorship from any equipment or pharmaceutical company. They have assembled an impressive team of assistants to produce a site that has quality content and an elegant, professional appearance.The site was established in 1996 and has had three different addresses and several major revisions, the last of which (December 2000) occurred during the drafting of this review. It describes their practice of regional anesthesia at St. Luke’s–Roosevelt Hospital Center in New York City. It has all the usual features, such as links to other sites, details of meetings, information about anesthesia training at St. Luke’s, backgrounds of the authors, and a bulletin board. One nice touch is a collection of tributes from some of the surgeons at St. Luke’s–Roosevelt, who obviously appreciate the advantages of regional anesthesia.The main feature of the site is detailed information about how to perform a variety of peripheral nerve blocks. The descriptions are based on the authors’ practice and research. In many cases, useful, practical tips are offered. Some blocks are not referenced; others have many references. There are sections about setting up equipment, with details of their cart and block trays, which are well-illustrated. There is also a guide to choosing local anesthetics.The nerve blocks described include infraclavicular and interscalene blocks, thoracic paravertebral blocks, combined epidural–spinal blocks, and a wide variety of lower extremity blocks. The descriptions are clear and concise and are accompanied by excellent detailed photographs, including, in many cases, dissections of cadavers to display the relevant anatomy.The authors have prepared a number of short video clips, which are used to display information that could not be represented in any other way, such as a needle being inserted or a muscle twitching. The clips are not narrated but are documented clearly in the adjacent text. They are available in Real Video and QuickTime formats, in versions for different connection speeds. The authors are commended for attempting to use streaming video as a teaching aid, for producing excellent quality video images, and for resisting the temptation to use “talking heads.” However, I felt the clips could have been a little longer.The descriptions of the blocks are all written by the authors, except for two guest contributions.The authors have considerable practical experience related to regional anesthesia at a major academic center and have published many articles in established journals. The site expresses the authors’ experience and, like a conventional textbook, it is not peer reviewed. One assumes that no one would go to the effort of publishing a textbook unless he or she had useful and accurate information to propagate. There are a few typographical errors that have escaped spell checking but that might have been caught by an editor. Although the site offers excellent educational material, there is no method of testing one’s knowledge or of gaining continuing medical education credits.Navigation can be confusing. For example, a list of meetings is given in the What’s New section, although information about past meetings is included. Information about a specific nerve block could be available under Concepts, Techniques, or Guest Contributors. There is a site map, which reduces the confusion somewhat, and an efficient search engine.This is an excellent Web site, with a wealth of practical and research information about regional anesthesia.It shows how useful the Web can be as a teaching medium. It is especially good regarding peripheral blocks of the lower extremities, a rather neglected aspect of regional anesthesia.

PURPOSE: The purpose of this study was to explore rehabilitation professionals' perspectives about goal setting, and more particularly, the use of two specific forms of goal setting used within the same setting; 'usual participation' and 'increased participation'. METHODS: A qualitative research approach was identified as being particularly pertinent for the aims of this study. Fifteen rehabilitation professionals representing five different professions and having experience of usual and increased participation goal setting approaches used in one Neurological Rehabilitation Unit participated in two focus groups. The focus group questions were designed to elicit staff views about goal setting generally, and to invite comparison regarding their experiences of using two goal setting approaches. The focus group transcripts were analysed according to thematic analysis principles. FINDINGS: Five themes were identified: the goal setting tools (including views about the folder developed for one form of goal setting); barriers to goal setting (including lack of time, professional group work patterns and lack of experience), the keyworker role (including prerequisites for effective keyworking); patient characteristics (disease, personality and expectations); and the nature of goals. CONCLUSIONS: Whilst the 'increased participation' mode of goal setting was seen as having the potential to allow patients a stronger voice within the goal setting process, both time and resources are required to ensure that this potential is fully realised.

A long-term goal of exoplanet studies is the identification and detection of biosignature gases. Beyond the most discussed biosignature gas O2, only a handful of gases have been considered in detail. In this study, we evaluate phosphine (PH3). On Earth, PH3 is associated with anaerobic ecosystems, and as such, it is a potential biosignature gas in anoxic exoplanets. We simulate the atmospheres of habitable terrestrial planets with CO2- and H2-dominated atmospheres and find that PH3 can accumulate to detectable concentrations on planets with surface production fluxes of 1010 to 1014 cm-2 s-1 (corresponding to surface concentrations of 10s of ppb to 100s of ppm), depending on atmospheric composition and ultraviolet (UV) irradiation. While high, the surface flux values are comparable to the global terrestrial production rate of methane or CH4 (1011 cm-2 s-1) and below the maximum local terrestrial PH3 production rate (1014 cm-2 s-1). As with other gases, PH3 can more readily accumulate on low-UV planets, for example, planets orbiting quiet M dwarfs or with a photochemically generated UV shield. PH3 has three strong spectral features such that in any atmosphere scenario one of the three will be unique compared with other dominant spectroscopic molecules. Phosphine's weakness as a biosignature gas is its high reactivity, requiring high outgassing rates for detectability. We calculate that tens of hours of JWST (James Webb Space Telescope) time are required for a potential detection of PH3. Yet, because PH3 is spectrally active in the same wavelength regions as other atmospherically important molecules (such as H2O and CH4), searches for PH3 can be carried out at no additional observational cost to searches for other molecular species relevant to characterizing exoplanet habitability. Phosphine is a promising biosignature gas, as it has no known abiotic false positives on terrestrial planets from any source that could generate the high fluxes required for detection.

The search for possible biosignature gases in habitable exoplanet atmospheres is accelerating, although actual observations are likely years away. This work adds isoprene, C 5 H 8 , to the roster of biosignature gases. We found that isoprene geochemical formation is highly thermodynamically disfavored and has no known abiotic false positives. The isoprene production rate on Earth rivals that of methane (CH 4 ; ∼500 Tg/year). Unlike methane, on Earth isoprene is rapidly destroyed by oxygen-containing radicals. Although isoprene is predominantly produced by deciduous trees, isoprene production is ubiquitous to a diverse array of evolutionary distant organisms, from bacteria to plants and animals—few, if any, volatile secondary metabolites have a larger evolutionary reach. Although non-photochemical sinks of isoprene may exist, such as degradation of isoprene by life or other high deposition rates, destruction of isoprene in an anoxic atmosphere is mainly driven by photochemistry. Motivated by the concept that isoprene might accumulate in anoxic environments, we model the photochemistry and spectroscopic detection of isoprene in habitable temperature, rocky exoplanet anoxic atmospheres with a variety of atmosphere compositions under different host star ultraviolet fluxes. Limited by an assumed 10 ppm instrument noise floor, habitable atmosphere characterization when using James Webb Space Telescope (JWST) is only achievable with a transit signal similar or larger than that for a super-Earth-sized exoplanet transiting an M dwarf star with an H 2 -dominated atmosphere. Unfortunately, isoprene cannot accumulate to detectable abundance without entering a run-away phase, which occurs at a very high production rate, ∼100 times the Earth's production rate. In this run-away scenario, isoprene will accumulate to >100 ppm, and its spectral features are detectable with ∼20 JWST transits. One caveat is that some isoprene spectral features are hard to distinguish from those of methane and also from other hydrocarbons containing the isoprene substructure. Despite these challenges, isoprene is worth adding to the menu of potential biosignature gases.

In Brief PURPOSE: Following cardiac surgery via median sternotomy, patients are routinely advised to adhere to upper limb restrictions to prevent the development of sternal complications. However, there is no definitive evidence to support the clinical application of such restrictions. The purpose of this study was to investigate current physiotherapy practice regarding upper limb exercise guidelines for this population, within outpatient cardiac rehabilitation in Australia. METHODS: Physiotherapists working within outpatient cardiac rehabilitation programs in Australia were invited to complete a Web survey. RESULTS: The response rate was 77%. The majority of respondents (96%) prescribed upper limb exercises to patients following median sternotomy, with 95% placing restrictions on these exercises. At 6 weeks postoperatively, 58% and 73% of respondents still placed restrictions on unloaded and loaded unilateral upper limb elevation exercises respectively; similarly, 55% and 74% placed restrictions on unloaded and loaded bilateral upper limb elevation exercises, respectively. However, there was a lack of consensus on the type and timing of these restrictions, with patient-reported pain being the main parameter used to guide upper limb exercise prescription and progression. Only 43% reported screening for sternal instability, and if detected, the majority based their management on clinical experience. CONCLUSIONS: There is significant variation in practice with respect to the prescription and progression of upper limb exercises, within outpatient cardiac rehabilitation in Australia. Further research is warranted to establish evidence-based guidelines for the upper limb rehabilitation of patients following cardiac surgery via median sternotomy. Physiotherapists working in outpatient cardiac rehabilitation programs in Australia were surveyed to investigate current upper limb exercise guidelines prescribed to patients following cardiac surgery via a median sternotomy. The results revealed significant variation in practice regarding upper limb exercise prescription and highlighted the need for further research in this area.

Abstract Wounds can commonly become infected with polymicrobial biofilms containing bacterial and fungal microorganisms. Microbial colonization of the wound can interfere with sufficient healing and repair, leading to high rates of chronicity in certain individuals, which can have a huge socioeconomic burden worldwide. One route for alleviating biofilm formation in chronic wounds is sufficient treatment of the infected area with topical wound washes and ointments. Thus, the primary aim here was to create a complex in vitro biofilm model containing a range of microorganisms commonly isolated from the infected wound milieu. These polymicrobial biofilms were treated with three conventional anti-biofilm wound washes, chlorhexidine (CHX), povidone-iodine (PVP-I), and hydrogen peroxide (H 2 O 2 ), and efficacy against the microorganisms assessed using live/dead qPCR. All treatments reduced the viability of the biofilms, although H 2 O 2 was found to be the most effective treatment modality. These biofilms were then co-cultured with 3D skin epidermis to assess the inflammatory profile within the tissue. A detailed transcriptional and proteomic profile of the epidermis was gathered following biofilm stimulation. At the transcriptional level, all treatments reduced the expression of inflammatory markers back to baseline (untreated tissue controls). Olink technology revealed a unique proteomic response in the tissue following stimulation with untreated and CHX-treated biofilms. This highlights treatment choice for clinicians could be dictated by how the tissue responds to such biofilm treatment, and not merely how effective the treatment is in killing the biofilm.

Single nuclei RNA-sequencing (sNuc-Seq) is a methodology which uses isolated nuclei instead of whole cells to profile gene expression. By using droplet microfluidic technologies, users are able to profile thousands of single transcriptomes at high throughput from their chosen tissue. This article aims to introduce sNuc-Seq as a method and its utility in multiple tissue types. Furthermore, we discuss the risks associated with the use of nuclei, which must be considered before committing to a methodology.

A number of histological parameters in clinically normal skin from the vulva throughout the female life span were studied. These are compared and evaluated to establish a base line to assist with the interpretation of diseased vulval skin.

Periodontitis is a long-term condition affecting up to half of the population globally and causing significant impacts on life quality. Successful management depends on taking life-long ownership of the condition by those affected. There is a wealth of research to inform on management options. However, most of the research has been designed by professional experts with outcomes to gauge benefits and harms based on parameters that inform on the disease process but which might not be informative to support decision-making in people with lived experience (PWLE) of periodontal ill-health (including both patients and carers). The importance of relevant outcomes is highlighted in the concept of the "expert patient" which aims to strengthen the capacity of PWLE to make health-care choices that are important for them, elements of which are likely to be already familiar to many clinicians delivering periodontal health care. Therefore, the voice and collaboration of PWLE in research are recognised as crucial to developing high quality, relevant evidence especially for long-term conditions. In this paper, we review what is known about the relevance of treatment outcomes to PWLE. We also examine the degree to which PWLE have been involved in identifying outcomes that are important to them as well as the diversity and therefore representativeness of PWLE recruited for studies. We consider why having more relevant outcomes could enhance the expertise of PWLE in managing their periodontitis. We then conclude with key learnings from our review which we hope will encourage more rapid development of these initiatives in periodontology for the benefit of global health and wellbeing.

SUMMARY The numbers of patients with urinary tuberculosis are greatly reduced, but new cases are still to be expected. A history of previous tuberculosis is not so likely now. The age incidence has changed and there are now relatively more patients over the age of 50 years. Because of the change in age, streptomycin should be used with caution since toxic manifestations are more likely in the older patients. The best drug in our results is still isoniazid, used in a combination of drugs, but good results are being obtained with ethambutol and Rifampicin. The duration of chemotherapy should be 18 to 24 months. Operation is still advisable in patients with advanced renal disease and a persistent positive urine after 3 months' therapy. Bladder reconstruction operations are indicated in some. The death rate due to tuberculosis is very small.

Scientists have long speculated about the potential habitability of Venus, not at the 700K surface, but in the cloud layers located at 48–60 km altitudes, where temperatures match those found on Earth's surface. However, the prevailing belief has been that Venus' clouds cannot support life due to the cloud chemical composition of concentrated sulfuric acid—a highly aggressive solvent. In this work, we study 20 biogenic amino acids at the range of Venus' cloud sulfuric acid concentrations (81% and 98% w/w, the rest water) and temperatures. We find 19 of the biogenic amino acids we tested are either unreactive (13 in 98% w/w and 12 in 81% w/w) or chemically modified in the side chain only, after 4 weeks. Our major finding, therefore, is that the amino acid backbone remains intact in concentrated sulfuric acid. These findings significantly broaden the range of biologically relevant molecules that could be components of a biochemistry based on a concentrated sulfuric acid solvent.

We report the use of silver hydroxylamine nanoparticles functionalised with single stranded monothiolated DNA for the detection of fungal infections. The four different species of fungi that were targeted were Candida albicans, Candida glabrata, Candida krusei and Aspergillus fumigatus. Rational design of synthetic targets and probes was carried out by carefully analysing the 2-D folding of the DNA and then by global alignment of the sequences to ensure specificity. The effects of varying the concentrations of the DNA and dye surrounding the nanoparticles on the resultant surface enhanced Raman scattering (SERS) signal were also investigated to ensure compatibility of the probes in a multiplexed environment. Using principal components analysis (PCA) it was possible to detect the individual presence of each target and group them accordingly. The move to detect the C. krusei single stranded PCR product (ssPCR) was significant to demonstrate that the methodology could be employed for the detection and diagnosis of invasive fungal infections (IFDs) within a clinical setting. Initially the PCR product was subjected to an alkali shock method in order to separate the strands ready for detection using the nanoparticle probes system. This time 18 base probes were employed to enhance hybridisation efficiency and dextran sulfate was found to have a vital role in ensuring that detection of the C. krusei target was achieved. This demonstrated the use of DNA functionalised silver nanoparticle for the detection of clinically relevant DNA relating to a specific fungal infection and offers significant promise for future diagnostic applications.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Despite the recent introduction of new treatments and improvements in clinical outcomes, multiple myeloma (MM) remains a medical problem. The majority of patients relapse and die from their disease, underscoring the need for new treatments (Kumar et al, 2017). The nuclear factor (NF)-κB pathway is aberrantly activated in virtually all cases of MM, where it enables tumour cell survival, and is therefore considered an effective therapeutic route in MM. Yet, following an aggressive 30-year effort by the pharmaceutical industry, no specific NF-κB inhibitor has been clinically approved, due to the dose-limiting toxicities associated with the general NF-κB suppression. Agents indicated in MM, e.g., proteasome inhibitors and immunomodulatory drugs, inhibit NF-κB, but also many other pathways, and neither specifically target cancer cells nor afford their clinical benefit through NF-κB inhibition (Greten et al, 2007; Di Donato et al, 2012; Begalli et al, 2017; Bennett et al, 2018). Therefore, there is a need for a fresh approach to safely block NF-κB signalling in MM. To overcome the barrier to safe NF-κB inhibition, we developed a novel class of NF-κB-targeting therapeutics. We identified the interaction between the JNK-activating kinase, MKK7, and the NF-κB-regulated antiapoptotic factor, GADD45β (De Smaele et al, 2001; Papa et al, 2004; Tornatore et al, 2014; Capece et al, 2018), as an essential, cancer-restricted survival module downstream of NF-κB in MM. Accordingly, GADD45β is selectively highly expressed in MM cells, where it denotes shorter patient overall survival (Tornatore et al, 2014). We developed the first-in-class GADD45β/MKK7 inhibitor, DTP3, which selectively kills MM cells by inducing MKK7/JNK-dependent apoptosis, ex vivo and in vivo, without toxicity to normal tissues (Tornatore et al, 2014). Further preclinical investigations demonstrated that DTP3 combines on-target-selective pharmacology and favourable drug-like properties with tolerability and none of the preclusive toxicities of conventional IKKβ/NF-κB-targeting agents (Tornatore et al unpublished observations). Due to this unique mode of action, DTP3 represents a significant opportunity for managing MM patients. The success rate for novel drug candidates in oncology from first-in-human trial to market registration is only ~5%, due to the heterogeneity of tumours and absence of drug-specific biomarkers, clearly demonstrating therapeutic target engagement (Kola & Landis, 2004). Considering that any GADD45β/MKK7-targeting drug would potentially benefit only a discrete subset of patients, we conducted a preclinical proof-of-concept study (REC 11/LO/1628) to develop a companion biomarker platform capable of assessing pharmacodynamic response in the earliest stages of the DTP3 clinical development. The current Letter reports the clinical proof-of-concept for an NF-κB-targeting strategy as a safe and mechanistically effective novel therapy in MM patients. We sought to first verify the cancer-selective mechanistic specificity of DTP3 in primary MM cells (Supplementary Methods). DTP3 was effective in inducing JNK phosphorylation, denoting therapeutic target engagement and caspase-3 cleavage, an apoptosis hallmark, in malignant CD138+ cells, ex vivo (Fig 1A). By contrast, DTP3 produced no such effects in healthy CD20+ cells nor in peripheral blood mononuclear cells (PBMCs) from the same patients, even at 30-fold higher concentrations (Fig 1B, C). Given the wide distribution and overall high levels of GADD45B expression in MM cells (Fig 1D, Supplementary Figure S1), we evaluated whether the cancer-selective pharmacodynamic response to DTP3 depended on GADD45B expression. As shown in Fig 1E, in 13 samples of malignant CD138+ cells which responded to DTP3, GADD45B expression was significantly higher than in any of the unresponsive CD138+-cell samples or any sample of normal CD20+ cells or PBMCs. Hence, the capacity of DTP3 to trigger JNK-driven apoptosis in primary MM cells correlates with a high significance with the GADD45B expression levels (Fig 1E). These results demonstrate that the on-target-specific therapeutic response to DTP3 can be monitored and potentially predicted by an objective measurement of GADD45B expression and JNK-dependent apoptosis in tumour cells. Interestingly, upon clinical validation, this approach could inform a patient stratification platform predictive of objective clinical response to support the clinical development of DTP3. Accordingly, we initiated the first-in-human phase-I/IIa trial of DTP3 to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of this novel NF-κB-targeting therapeutic in patients with relapsed or refractory MM (EudraCT: 2015-003459-23; Supplementary Methods). Three single-patient, dose-escalation cohorts have been investigated to date, evaluating DTP3 at the dose levels of 0·5, 1 and 2 mg/kg, administered by rapid intravenous infusion three times a week (Fig 2A, Supplementary Figure S2). All patients had progressive disease at the point of entry into the study, despite having received multiple prior lines of therapy. All three patients completed their first 28-day treatment cycle with no complications. No reportable adverse effects, nor any grade 2 or greater toxicity were recorded at any point, in any patient, indicating that DTP3 was tolerated at all dose levels investigated (Fig 2A). Notably, Patient 002 demonstrated a reduction in serum free light-chain and paraprotein levels in response to DTP3, consistent with stable disease, according to the International Myeloma Working Group criteria. This patient was maintained on DTP3 therapy for a total of three 4-week treatment cycles before developing progressive disease, in the absence of any adverse effect (Fig 2A). To evaluate the pharmacodynamic response to DTP3, we analysed blood and bone marrow samples collected 18–36 h following administration of dose 4, on day 8 of treatment. Strikingly, Patient 001, who had been treated at the starting dose of 0·5 mg/kg, demonstrated a distinct shift in the signals corresponding to JNK phosphorylation and caspase-3 cleavage in MM (CD138+) cells, but, crucially, neither in normal CD20+ cells, nor in PBMCs concurrently isolated from blood (Fig 2B–D). As expected, no such signals denoting JNK activation or apoptosis were detected in MM cells, B lymphocytes or PBMCs isolated at screening, prior to treatment with DTP3 (Fig 2B–D). Hence, consistent with its ex-vivo mode of action and on-target-selective pharmacology (Fig 1A–C; Tornatore et al unpublished observations), DTP3 demonstrated the clinical capacity to trigger a cancer-specific pharmacodynamic response, inducing JNK-driven apoptosis in MM, but not normal cells (Fig 2B), thereby establishing clinical proof-of-mechanism. Notably, DTP3 produced these clinical effects in refractory MM patients, as a single agent, with a potential 40-fold margin for dose escalation in the trial. Collectively, the preclinical data and encouraging initial clinical results introduce DTP3 as a first-in-class NF-κB-targeting therapeutic with a novel mode of action in oncology. This work was supported in part by Cancer Research UK programme grant A15115, Medical Research Council (MRC) Biomedical Catalyst grant MR/L005069/1 and Bloodwise project grant 15003 to G.F., and Cancer Research UK Clinician Scientist Fellowship C41494/A15448 to H.W.A. JFA is a UK NIHR Senior Investigator. The infrastructure support for this study was generously provided by the NIHR CRF at Imperial College Healthcare NHS Trust. [Correction added on 25 October 2018, after first online publication: The preceding acknowledgement has been inserted in this current version.] J.F.A. and H.W.A. acknowledge the support of the Imperial College London NIHR Biomedical Research Centre (BRC). H.W.A. also acknowledges the Cancer Research UK Imperial Centre, and the Imperial Experimental Cancer Medicine Centre. G.F., L.T. and M.R. are named inventors on patents relating to this research. L.T. G.A., R.B., H.E.O., M.F.K., A.W. J.F.A. H.W.A. and G.F. designed experiments. L.T., D.C., F.B., D.V. and J.B. performed experiments. L.T., D.D., G.A., L.E.C., J.K., M.T., N.A., J.F.A.; H.W.A. and G.F. analysed data. L.T. G.A., L.E.C., J.K., M.T., N.A., S.B., J.F.A. H.W.A. and G.F. contributed to the preparation of the regulatory documentation for MHRI approval. A.L., A.S., D.R., M.R., A.C., M.O., M.J.A., R.S. K., I.G., R.B. and H.W.A. contributed clinical samples or key reagents. G.F. and L.T. wrote the paper. D.C., D.D. and H.W.A. contributed to writing the paper. Fig S1. Selective therapeutic target engagement by DTP3 in primary multiple myeloma cells expressing GADD45B. Fig S2. List of inclusion and exclusion criteria of the phase I trial (MHRA reference number: 19174/0369/001-0001). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

OBJECTIVE: The main objective of this study is to obtain data assessing normative scores, test-retest reliability, critical differences, and the effect of age for two closed-set consonant-discrimination tests. DESIGN: The two tests are intended for use with children aged 2 to 8 years. The tests were evaluated using normal-hearing children within the appropriate age range. The tests were (1) the closed-set consonant confusion test (CCT) and (2) the consonant-discrimination subtest of the closed-set Chear Auditory Perception Test (CAPT). Both were word-identification tests using stimuli presented at a low fixed level, chosen to avoid ceiling effects while avoiding the use of background noise. Each test was administered twice. RESULTS: All children in the age range 3 years 2 months to 8 years 11 months gave meaningful scores and were able to respond reliably using a computer mouse or a touch screen to select one of four response options displayed on a screen for each trial. Assessment of test-retest reliability showed strong agreement between the two test runs (interclass correlation ≥ 0.8 for both tests). The critical differences were similar to those for other monosyllabic speech tests. Tables of these differences for the CCT and CAPT are provided for clinical use of the measures. Performance tended to improve with increasing age, especially for the CCT. Regression equations relating mean performance to age are given. CONCLUSIONS: The CCT is appropriate for children with developmental age in the range 2 to 4.5 years and the CAPT is appropriate as a follow-on test from the CCT. If a child scores 80% or more on the CCT, they can be further tested using the CAPT, which contains more advanced vocabulary and more difficult contrasts. This allows the assessment of consonant perception ability and of changes over time or after an intervention.

#### Case scenario A 19 year old female student consulted her general practitioner about two recent episodes of syncope, both of which occurred while playing hockey. Her team mates reported that she collapsed suddenly with little warning, recovering rapidly within 30 seconds without confusion. She was otherwise well, although she was taking erythromycin for an infected leg abrasion at the time of the events. As part of the routine evaluation for syncope, her general practitioner performed a 12 lead electrocardiogram, which showed a prolonged corrected QT interval of 510 ms. Congenital long QT syndrome is a potential cause of avoidable sudden cardiac death. Affected individuals may have ventricular arrhythmias, leading to palpitations, syncope, and, if sustained, cardiac arrest.1 The syndrome is inherited in an autosomal dominant fashion, with variable disease expression: those severely affected may die in fetal or neonatal life, but others remain asymptomatic throughout their life. At a cellular level, genetically encoded abnormalities in sodium and potassium ion channels within the cell membrane lengthen cardiac repolarisation, which manifests as a prolongation of the QT interval in the electrocardiogram. QT prolongation may be acquired secondary to certain medications, metabolic disturbance, cerebral injury, myocardial disease, and hypothermia—factors that may also unmask the congenital syndrome in a previously asymptomatic individual. #### How common is long QT syndrome? Syncope is highly prevalent in young adults. Among 394 students, 154 reported at least one episode of syncope.4 In a young, fit adult (such as outlined in the scenario box), important differential diagnoses include the most common and benign cause of …