Eastbourne District General Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

The neuropsychological performance of 85 women with early stage breast cancer scheduled for chemotherapy, 43 women scheduled for endocrine therapy and/or radiotherapy and 49 healthy control subjects was assessed at baseline (T1), postchemotherapy (or 6 months) (T2) and at 18 months (T3). Repeated measures analysis found no significant interactions or main effect of group after controlling for age and intelligence. Using a calculation to examine performance at an individual level, reliable decline on multiple tasks was seen in 20% of chemotherapy patients, 26% of nonchemotherapy patients and 18% of controls at T2 (18%, 14 and 11%, respectively, at T3). Patients who had experienced a treatment-induced menopause were more likely to show reliable decline on multiple measures at T2 (OR=2.6, 95% confidence interval (CI) 0.823-8.266 P=0.086). Psychological distress, quality of life measures and self-reported cognitive failures did not impact on objective tests of cognitive function, but were significantly associated with each other. The results show that a few women experienced objective measurable change in their concentration and memory following standard adjuvant therapy, but the majority were either unaffected or even improve over time.

BACKGROUND: Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. Assessment of the full range of evidence generated to date to understand the characteristics of the antibody response, its dynamics over time, its determinants and the immunity it confers will have a range of clinical and policy implications for this novel pathogen. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020. METHODS: Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the Public Health Ontario Meta-tool for Quality Appraisal of Public Health Evidence (MetaQAT) tool, with resolution of disagreements by consensus. Findings were narratively synthesised. RESULTS: 150 papers were included. Most studies (113 or 75%) were observational in design, were based wholly or primarily on data from hospitalised patients (108, 72%) and had important methodological limitations. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, up to around three months from disease onset, but the picture regarding correlates of the antibody response was inconsistent. IgM was consistently detected before IgG in included studies, peaking at weeks two to five and declining over a further three to five weeks post-symptom onset depending on the patient group; IgG peaked around weeks three to seven post-symptom onset then plateaued, generally persisting for at least eight weeks. Neutralising antibodies were detectable within seven to 15 days following disease onset, with levels increasing until days 14-22 before levelling and then decreasing, but titres were lower in those with asymptomatic or clinically mild disease. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross-reactivity but limited cross-neutralisation with other human coronaviridae was reported. Evidence for protective immunity in vivo was limited to small, short-term animal studies, showing promising initial results in the immediate recovery phase. CONCLUSIONS: Literature on antibody responses to SARS-CoV-2 is of variable quality with considerable heterogeneity of methods, study participants, outcomes measured and assays used. Although acute phase antibody dynamics are well described, longer-term patterns are much less well evidenced. Comprehensive assessment of the role of demographic characteristics and disease severity on antibody responses is needed. Initial findings of low neutralising antibody titres and possible waning of titres over time may have implications for sero-surveillance and disease control policy, although further evidence is needed. The detection of potent neutralising antibodies in convalescent plasma is important in the context of development of therapeutics and vaccines. Due to limitations with the existing evidence base, large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.

BACKGROUND: Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. METHODS: For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. RESULTS: 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. CONCLUSION: A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

ECG loop recorders have a retrospective (loop) memory which continuously records and deletes the patient's ECG. They include a patient-activation function that allows the patient to activate ECG storage as a result of symptoms and an auto-activation feature that allows the capture of arrhythmic events without relying on patient compliance or perception of symptoms. Loop recorder devices can be both implantable (ILR) and external (ELR). Table 1 summarizes the characteristics of the most common diagnostic loop recorders. The retrospective memory differentiates loop recorders from prospective-only event recorders. While event recorders have some usefulness in patients with intermittent palpitations, they have no indication to detect syncope. View this table: Table 1 Most common implantable and external loop recorders Knowledge of what occurs during a spontaneous event is the ideal gold standard for evaluation. Patients with infrequent short-duration transient symptoms, recurring over weeks or months, are unlikely to be diagnosed by conventional Holter monitoring, since the likelihood of symptom-ECG correlation is very low. Consideration should be given to patient-activated event recording in such patients, but this technique has important limitations that might prevent a successful ECG recording of the event, especially for those with syncope, as it implies the activation of recording by the patients once the patient has already recovered consciousness. In such circumstances, consideration should be given to implantable and external ECG loop recorders. It is likely that loop recorders will become increasingly important, and their use will increasingly be appropriate instead of, or before, many current conventional investigations. This early loop recorder approach implies, on the one hand, the need for careful initial risk stratification in order to exclude from such a strategy patients with potential life-threatening conditions that require immediate hospitalization or intensive evaluation and treatment. On the other hand, as a general rule ECG loop recorders are indicated only when there is …

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Abstract Adoptive cell transfer using chimeric antigen receptors (CAR) has emerged as one of the most promising new therapeutic modalities for patients with relapsed or refractory B-cell malignancies. Thus far, results in patients with advanced solid tumors have proven disappointing. Constitutive tonic signaling in the absence of ligand is an increasingly recognized complication when deploying these synthetic fusion receptors and can be a cause of poor antitumor efficacy, impaired survival, and reduced persistence in vivo. In parallel, ligand-dependent tonic signaling can mediate toxicity and promote T-cell anergy, exhaustion, and activation-induced cell death. Here, we review the mechanisms underpinning CAR tonic signaling and highlight the wide variety of effects that can emerge after making subtle structural changes or altering the methodology of CAR transduction. We highlight strategies to prevent unconstrained tonic signaling and address its deleterious consequences. We also frame this phenomenon in the context of endogenous TCR tonic signaling, which has been shown to regulate peripheral tolerance, facilitate the targeting of foreign antigens, and suggest opportunities to coopt ligand-dependent CAR tonic signaling to facilitate in vivo persistence and efficacy. Mol Cancer Ther; 17(9); 1795–815. ©2018 AACR.

AIMS: Increasing evidence exists suggesting that biventricular pacing improves outcome and symptoms in severe heart failure if various selection criteria are fulfilled. It is unsure how many people might benefit from this therapy. Our aim was to provide such data. METHODS AND RESULTS: Over one calendar year all patients admitted to a large U.K. District General Hospital, that were classified with a diagnosis of heart failure, were audited. The selection criteria were; (1) severe heart failure (NYHA class III or IV), (2) heart failure due to a dilated cardiomyopathy, (3) QRS duration greater than 120 ms or (4) the presence of a bundle branch block pattern. Subjects were divided into those in sinus rhythm to determine those who would be suitable for atrially synchronized biventricular pacing and those with an abnormally long PR interval (>210 ms) who might additionally benefit from improved atrioventricular synchrony. 1042 patients were coded with heart failure. 721 fulfilled diagnostic criteria and were studied. 202 (28%) had severe heart failure, 178 (25%) had a QRS of at least 120 ms, 437 (61%) had an ischaemic cardiomyopathy, 176 (24%) an idiopathic cardiomyopathy and 433 (60%) were in sinus rhythm. Overall mortality at the time of census was 29%. 43 patients were suitable for biventricular pacing with a further 29 atrial patients fibrillation who might benefit from biventricular pacing alone. CONCLUSION: Using our criteria, approximately 10% of an unselected group of heart failure admitted to a typical U.K. district general hospital over a calendar year would be appropriate for biventricular pacing. This represents a large number of patients who might derive benefit from this new therapy.

AIMS: Implantable loop recorders (ILR) provide an opportunity to record ECG data from a spontaneous syncopal event. We conducted a randomized study to investigate the impact of the Reveal Plus ILR on an unselected population of patients with recurrent syncope. Initial follow-up (at least 6 months) did not demonstrate a reduction in syncopal events or an improvement in quality of life. We report the planned extension of follow-up to 18 months. METHODS AND RESULTS: All patients presenting acutely with recurrent unexplained syncope over a 16-month period, following a basic clinical work-up, were randomized to receive the ILR or conventional investigation and management. A total of 421 patients presented, 201 were eligible, median age 74, (IQ range 61-81) 54% female, with median syncopes 3 (IQ range 2-6). Median follow-up 17 months (IQ range 9-23). 42 (43%) of ILR patients and 8 (6%) of conventional patients received an ECG diagnosis (hazard ratio 6.53, 95% CI 3.73-11.4, P<0.001). Time to second syncope was significantly longer for ILR patients, although of borderline significance (P=0.04). A greater variety of diagnoses and treatments were seen in ILR patients. ILR patients had fewer post-randomization investigations and fewer days in hospital; however, cost savings were not statistically significant. There was improved quality of life in the ILR group (visual analogue scales, P=0.03) for general wellbeing. Overall mortality was 12% with no difference between the two groups. CONCLUSION: Investigation by the ILR significantly increases the diagnostic rate and ECG directed treatments in a typical unselected syncopal population. Long-term follow-up has demonstrated a significant subsequent reduction in syncopal events with improved quality of life.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

There have been significant advances in the field of echocardiography with the introduction of a number of new techniques into standard clinical practice. Consequently, a 'standard' echocardiographic examination has evolved to become a more detailed and time-consuming examination that requires a high level of expertise. This Guideline produced by the British Society of Echocardiography (BSE) Education Committee aims to provide a minimum dataset that should be obtained in a comprehensive standard echocardiogram. In addition, the layout proposes a recommended sequence in which to acquire the images. If abnormal pathology is detected, additional views and measurements should be obtained with reference to other BSE protocols when appropriate. Adherence to these recommendations will promote an increased quality of echocardiography and facilitate accurate comparison of studies performed either by different operators or at different departments.

Oomycetes are a diverse group of eukaryotes in terrestrial, limnic and marine habitats worldwide and include several devastating plant pathogens, for example Phytophthora infestans (potato late blight). The cytochrome c oxidase subunit 2 gene (cox2) has been widely used for identification, taxonomy and phylogeny of various oomycete groups. However, recently the cox1 gene was proposed as a DNA barcode marker instead, together with ITS rDNA. The cox1 locus has been used in some studies of Pythium and Phytophthora, but has rarely been used for other oomycetes, as amplification success of cox1 varies with different lineages and sample ages. To determine which out of cox1 or cox2 is best suited as a universal oomycete barcode, we compared these two genes in terms of (i) PCR efficiency for 31 representative genera, as well as for historic herbarium specimens, and (ii) sequence polymorphism, intra- and interspecific divergence. The primer sets for cox2 successfully amplified all oomycete genera tested, while cox1 failed to amplify three genera. In addition, cox2 exhibited higher PCR efficiency for historic herbarium specimens, providing easier access to barcoding-type material. Sequence data for several historic type specimens exist for cox2, but there are none for cox1. In addition, cox2 yielded higher species identification success, with higher interspecific and lower intraspecific divergences than cox1. Therefore, cox2 is suggested as a partner DNA barcode along with ITS rDNA instead of cox1. The cox2-1 spacer could be a useful marker below species level. Improved protocols and universal primers are presented for all genes to facilitate future barcoding efforts.

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

The scale of the COVID-19 pandemic means that a significant number of patients who have previously been infected with SARS-CoV-2 will require surgery. Given the potential for multisystem involvement, timing of surgery needs to be carefully considered to plan for safe surgery. This consensus statement uses evidence from a systematic review and expert opinion to highlight key principles in the timing of surgery. Shared decision-making regarding timing of surgery after SARS-CoV-2 infection must account for severity of the initial infection; ongoing symptoms of COVID-19; comorbid and functional status; clinical priority and risk of disease progression; and complexity of surgery. For the protection of staff, other patients and the public, planned surgery should not be considered during the period that a patient may be infectious. Precautions should be undertaken to prevent pre- and peri-operative infection, especially in higher risk patients. Elective surgery should not be scheduled within 7 weeks of a diagnosis of SARS-CoV-2 infection unless the risks of deferring surgery outweigh the risk of postoperative morbidity or mortality associated with COVID-19. SARS-CoV-2 causes either transient or asymptomatic disease for most patients, who require no additional precautions beyond a 7-week delay, but those who have persistent symptoms or have been hospitalised require special attention. Patients with persistent symptoms of COVID-19 are at increased risk of postoperative morbidity and mortality even after 7 weeks. The time before surgery should be used for functional assessment, prehabilitation and multidisciplinary optimisation. Vaccination several weeks before surgery will reduce risk to patients and might lessen the risk of nosocomial SARS-CoV-2 infection of other patients and staff. National vaccine committees should consider whether such patients can be prioritised for vaccination. As further data emerge, these recommendations may need to be revised, but the principles presented should be considered to ensure safety of patients, the public and staff.

Utilizing T cells expressing chimeric antigen receptors (CARs) to identify and attack solid tumors has proven challenging, in large part because of the lack of tumor-specific targets to direct CAR binding. Tumor selectivity is crucial because on-target, off-tumor activation of CAR T cells can result in potentially lethal toxicities. This study presents a stringent hypoxia-sensing CAR T cell system that achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by inadequate oxygen supply. Using murine xenograft models, we demonstrate that, despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate unlimited expansion of the CAR T cell target repertoire for treating solid malignancies.

We reviewed 231 patients who had undergone total knee replacement with an AGC (Biomet) implant over a period of 2.5 years. After applying exclusion criteria and with some loss to follow-up, there were 144 patients available for study. These were divided into two groups; those who had received intra-articular steroid in the 11 months before surgery and those who had not. There were three deep infections, all of which occurred in patients who had received a steroid injection. The incidence of superficial infection was not significantly different in the two groups. Five patients had undergone investigation for suspected deep infection because of persistent swelling or pain and all of these had received an intra-articular injection pre-operatively. We conclude that the decision to administer intra-articular steroids to a patient who may be a candidate for total knee replacement should not be taken lightly because of a risk of post-operative deep infection.

BACKGROUND: In patients presenting with new-onset heart failure of uncertain etiology, the role of coronary angiography (CA) is unclear. Although conventionally performed to differentiate underlying coronary artery disease from dilated cardiomyopathy, CA is associated with a risk of complications and may not detect an ischemic cause resulting from arterial recanalization or an embolic episode. In this study, we assessed the diagnostic accuracy of a cardiovascular magnetic resonance (CMR) protocol incorporating late gadolinium enhancement (LGE) and magnetic resonance CA as a noninvasive gatekeeper to CA in determining the etiology of heart failure in this subset of patients. METHODS AND RESULTS: One hundred twenty consecutive patients underwent CMR and CA. The etiology was ascribed by a consensus panel that used the results of the CMR scans. Similarly, a separate consensus group ascribed an underlying cause by using the results of CA. The diagnostic accuracy of both strategies was compared against a gold-standard panel that made a definitive judgment by reviewing all clinical data. The study was powered to show noninferiority between the 2 techniques. The sensitivity of 100%, specificity of 96%, and diagnostic accuracy of 97% for LGE-CMR were equivalent to CA (sensitivity, 93%; specificity, 96%; and diagnostic accuracy, 95%). As a gatekeeper to CA, LGE-CMR was also found to be a cheaper diagnostic strategy in a decision tree model when United Kingdom-based costs were assumed. The economic merits of this model would change, depending on the relative costs of LGE-CMR and CA in any specific healthcare system. CONCLUSION: This study showed that LGE-CMR is a safe, clinically effective, and potentially economical gatekeeper to CA in patients presenting with heart failure of uncertain etiology.

BACKGROUND: Syncope is a common, disabling symptom. The most useful data for diagnosing and managing syncope is the recording of physical parameters such as the ECG and blood pressure during a spontaneous event. Implantable loop recorders (ILR) provide an opportunity to record ECG data from a spontaneous event. The purpose of the Eastbourne Syncope Assessment Study (EaSyAS) was to investigate the impact of ILRs on an unselected population of syncopal patients presenting acutely to our institution. METHODS: All patients presenting acutely with recurrent, unexplained syncope over a 16-month period, were randomised after a basic clinical workup to receive the Reveal Plus ILR or conventional investigation. All patients were followed up for at least 6 months (mean 276+/-134 days) following randomisation. The primary outcome measure was time to ECG diagnosis. RESULTS: Four hundred twenty-one patients presented, 201 were eligible, median age 74 years (interquartile range 61-81 years), 54% female, with a median of three previous syncopes (IQ range 2-6). Thirty-three percent of ILR patients and 4% of conventional patients had an ECG diagnosis (hazard ratio 8.93, 95% CI 3.17-25.2, p < or = 0.0001). Introduction of ECG-directed therapy was quicker for ILR patients (hazard ratio 7.9, 95% CI 2.8-22.3, p < 0.0001). ILR patients had fewer post-randomisation investigations and fewer hospital days, resulting in a saving of costs, 406 UK pounds versus 1210 UK pounds (mean difference 809 UK pounds, 95% CI 123-2730 UK pounds). There was no difference in the number of subsequent syncopal episodes, mortality, or quality of life. CONCLUSIONS: LR significantly increased the rate of diagnosis in an unselected Western population with recurrent syncope. There was a significant decrease in the rates of hospitalisation and investigation in patients receiving an ILR.

ABSTRACT Window‐based Euler deconvolution is commonly applied to magnetic and sometimes to gravity interpretation problems. For the deconvolution to be geologically meaningful, care must be taken to choose parameters properly. The following proposed process design rules are based partly on mathematical analysis and partly on experience. The interpretation problem must be expressible in terms of simple structures with integer Structural Index (SI) and appropriate to the expected geology and geophysical source. The field must be sampled adequately, with no significant aliasing. The grid interval must fit the data and the problem, neither meaninglessly over‐gridded nor so sparsely gridded as to misrepresent relevant detail. The required gradient data (measured or calculated) must be valid, with sufficiently low noise, adequate representation of necessary wavelengths and no edge‐related ringing. The deconvolution window size must be at least twice the original data spacing (line spacing or observed grid spacing) and more than half the desired depth of investigation. The ubiquitous sprays of spurious solutions must be reduced or eliminated by judicious use of clustering and reliability criteria, or else recognized and ignored during interpretation. The process should be carried out using Cartesian coordinates if the software is a Cartesian implementation of the Euler deconvolution algorithm (most accessible implementations are Cartesian). If these rules are not adhered to, the process is likely to yield grossly misleading results. An example from southern Africa demonstrates the effects of poor parameter choices.

Interleukin-6 (IL-6) is a pleiotropic cytokine that activates a classic signalling pathway upon binding to its membrane-bound receptor (IL-6R). Alternatively, IL-6 may 'trans-signal' in a manner that is facilitated by its binding to a soluble derivative of the IL-6 receptor (sIL-6R). Resultant signal transduction is, respectively, driven by the association of IL-6/IL-6R or IL-6/sIL-6R complex with the membrane-associated signal transducer, gp130 (Glycoprotein 130). Distinct JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) and other signalling pathways are activated as a consequence. Of translational relevance, overexpression of IL-6 has been documented in several neoplastic disorders, including but not limited to colorectal, ovarian and breast cancer and several haematological malignancies. This review attempts to summarise our current understanding of the role of IL-6 in cancer development. In short, these studies have shown important roles for IL-6 signalling in tumour cell growth and survival, angiogenesis, immunomodulation of the tumour microenvironment, stromal cell activation, and ultimate disease progression. Given this background, we also consider the potential for therapeutic targeting of this system in cancer.