Lambeth Hospital

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Although humans have cospeciated with their gut-resident microbes, it is difficult to infer features of our ancestral microbiome. Here, we examine the microbiome profile of 350 stool samples collected longitudinally for more than a year from the Hadza hunter-gatherers of Tanzania. The data reveal annual cyclic reconfiguration of the microbiome, in which some taxa become undetectable only to reappear in a subsequent season. Comparison of the Hadza data set with data collected from 18 populations in 16 countries with varying lifestyles reveals that gut community membership corresponds to modernization: Notably, the taxa within the Hadza that are the most seasonally volatile similarly differentiate industrialized and traditional populations. These data indicate that some dynamic lineages of microbes have decreased in prevalence and abundance in modernized populations.

BACKGROUND: Tumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical images METHODS: Image texture analysis is an approach of quantifying heterogeneity that may not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform-based methods. RESULTS: Early evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice. CONCLUSION: This review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging. TEACHING POINTS : • Tumor spatial heterogeneity is an important prognostic factor. • Image texture analysis is an approach of quantifying heterogeneity. • Different methods can be applied, including statistical-, model-, and transform-based methods. • Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment.

STUDY OBJECTIVES: To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. DESIGN: Subjects were genotyped using polymerase chain reaction. PATIENTS OR PARTICIPANTS: Subjects with defined diurnal preference as determined by the Horne-Ostberg questionnaire and patients with delayed sleep phase syndrome. MEASUREMENTS AND RESULTS: The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. CONCLUSION: The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.

OBJECTIVE: To evaluate the effectiveness of a service for early psychosis. DESIGN: Randomised controlled clinical trial. SETTING: Community mental health teams in one London borough. PARTICIPANTS: 144 people aged 16-40 years presenting to mental health services for the first or second time with non-organic, non-affective psychosis. INTERVENTIONS: Assertive outreach with evidence based biopsychosocial interventions (specialised care group) and standard care (control group) delivered by community mental health teams. PRIMARY OUTCOME MEASURES: Rates of relapse and readmission to hospital. RESULTS: Compared with patients in the standard care group, those in the specialised care group were less likely to relapse (odds ratio 0.46, 95% confidence interval 0.22 to 0.97), were readmitted fewer times (beta 0.39, 0.10 to 0.68), and were less likely to drop out of the study (odds ratio 0.35, 0.15 to 0.81). When rates were adjusted for sex, previous psychotic episode, and ethnicity, the difference in relapse was no longer significant (odds ratio 0.55, 0.24 to 1.26); only total number of readmissions (beta 0.36, 0.04 to 0.66) and dropout rates (beta 0.28, 0.12 to 0.73) remained significant. CONCLUSIONS: Limited evidence shows that a team delivering specialised care for patients with early psychosis is superior to standard care for maintaining contact with professionals and for reducing readmissions to hospital. No firm conclusions can, however, be drawn owing to the modest sample size.

We have investigated the use of a novel technique, in situ end-labelling, as a means of the specific identification of apoptotic cells in formalin-fixed, paraffin-processed tissue sections. The technique relies on the presence of DNA strand breaks in apoptotic cells, caused by activation of endogenous nuclease activity during the process of cell death. These strands are labelled with a non-isotopic reporter molecule in the presence of a DNA polymerase, and labelled DNA is identified immunohistochemically. We show that in situ end-labelling stains cells with the morphological characteristics of apoptosis, and greatly simplifies their identification. Furthermore, in two model systems, the number of labelled cells parallels the number of cells undergoing apoptosis as measured by alternative techniques. The ability of the Klenow fragment of DNA polymerase to label apoptotic nuclei suggests that the characteristic DNA fragmentation seen during this process involves the formation of DNA breaks with a 5' overhang. In situ end-labelling will be valuable for the identification and quantitation of apoptosis in a range of normal tissues and in a variety of pathological states. However, the technique is not specific for programmed cell death, and results must be interpreted with caution and correlated with morphological criteria of apoptosis.

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

Psoriasis is a chronic, genetically influenced, remitting and relapsing scaly and inflammatory skin disorder that affects 1 to 3 percent of the world's population. The diagnosis is made on clinical grounds, although histologic examination of a skin-biopsy specimen may be helpful. Psoriasis is a disabling, though rarely life-threatening, disease with a social and economic impact that is underestimated by physicians and other health care providers. Recently, progress has been made in understanding the pathogenesis of psoriasis, and therapeutic advances are improving the care of even severely affected patients.There are several types of psoriasis, including pustular, guttate, and arthritic variants. . . .

peer reviewed

BACKGROUND: In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg), an antibody-targeted chemotherapy for CD33-positive acute myeloid leukemia (AML). METHODS: Patients with CD33-positive AML in first recurrence were entered in 3 open-label, single-arm, Phase II studies. Patients received monotherapy with GO 9 mg/m(2) as a 2-hour intravenous infusion in 2 doses separated by 2 weeks. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Two hundred seventy-seven patients (median age, 61 yrs) were treated with GO, and 71 patients (26%) achieved remission, which was defined as < or = 5% blasts in the bone marrow without leukemic blasts in the peripheral blood, neutrophil recovery to > or = 1500/microL, hemoglobin > or = 9 g/dL, and independence from red blood cell and platelet transfusions. Complete remission (CR) with platelet recovery (> or = 100,000/microL) or without full platelet recovery (< 100,000/microL) (CRp) was observed in 35 patients (13%) and 36 patients (13%), respectively. The median recurrence-free survival was 6.4 months for patients who achieved CR and 4.5 months for patients who achieved CRp. Although expected incidences of Grade 3 or 4 neutropenia (98%) and thrombocytopenia (99%) were observed, the incidence of Grade 3 or 4 sepsis (17%) and pneumonia (8%) was relatively low. Grade 3 or 4 hyperbilirubinemia and hepatic aspartate aminotransferase and alanine aminotransferase elevations were reported in 29%, 18%, and 9% of patients, respectively; 0.9% of patients who did not undergo prior or subsequent hematopoietic stem cell transplantation developed hepatic venoocclusive disease after GO treatment. CONCLUSIONS: When it was administered to patients with CD33-positive AML in first recurrence, single-agent GO induced a 26% remission rate with a generally acceptable safety profile.

PURPOSE: To correlate computed tomographic (CT) texture in non-small cell lung cancer (NSCLC) with histopathologic markers for angiogenesis and hypoxia. MATERIALS AND METHODS: The study was institutional review board approved, and informed consent was obtained. Fourteen patients with NSCLC underwent CT prior to intravenous administration of pimonidazole (0.5 g/m(2)), a marker of hypoxia, 24 hours before surgery. Texture was assessed for unenhanced and contrast material-enhanced CT images by using a software algorithm that selectively filters and extracts texture at different anatomic scales (1.0 [fine detail] to 2.5 [coarse features]), with quantification of the standard deviation (SD) of all pixel values and the mean value of positive pixels (MPP) and uniformity of distribution of positive gray-level pixel values (UPP). After surgery, matched tumor sections were stained for angiogenesis (CD34 expression) and for markers of hypoxia (glucose transporter protein 1 [Glut-1] and pimonidazole). The percentage and average intensity of the tumor stained were assessed. A linear mixed-effects model was used to assess the correlations between CT texture and staining intensity. RESULTS: SD and MPP quantified from medium to coarse texture on contrast-enhanced CT images showed significant associations with the average intensity of tumor staining with pimonidazole (for SD: filter value, 2.5; slope = 0.003; P = .0003). UPP (medium to coarse texture) on unenhanced CT images showed a significant inverse association with tumor Glut-1 expression (filter value, 2.5; slope = -115.13; P = .0008). MPP quantified from medium to coarse texture on both unenhanced and contrast-enhanced CT images showed significant inverse associations with tumor CD34 expression (unenhanced CT: filter value, 1.8; slope = -0.0008; P = .003; contrast-enhanced CT: filter value, 1.8; slope = -0.0006; P = .004). CONCLUSION: Texture parameters derived from CT images of NSCLC have the potential to act as imaging correlates for tumor hypoxia and angiogenesis. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112428/-/DC1.

PURPOSE: To determine if computed tomographic (CT) texture features of primary colorectal cancer are related to 5-year overall survival rate. MATERIALS AND METHODS: Institutional review board waiver was obtained for this retrospective analysis. Texture features of the entire primary tumor were assessed with contrast material-enhanced staging CT studies obtained in 57 patients as part of an ethically approved study and by using proprietary software. Entropy, uniformity, kurtosis, skewness, and standard deviation of the pixel distribution histogram were derived from CT images without filtration and with filter values corresponding to fine (1.0), medium (1.5, 2.0), and coarse (2.5) textures. Patients were followed up until death and were censored at 5 years if they were still alive. Kaplan-Meier analysis was performed to determine the relationship, if any, between CT texture and 5-year overall survival rate. The Cox proportional hazards model was used to assess independence of texture parameters from stage. RESULTS: Follow-up data were available for 55 of 57 patients. There were eight stage I, 19 stage II, 17 stage III, and 11 stage IV cancers. Fine-texture feature Kaplan-Meier survival plots for entropy, uniformity, kurtosis, skewness, and standard deviation of the pixel distribution histogram were significantly different for tumors above and below each respective threshold receiver operating characteristic (ROC) curve optimal cutoff value (P = .001, P = .018, P = .032, P = .008, and P = .001, respectively), with poorer prognosis for ROC optimal values (a) less than 7.89 for entropy, (b) at least 0.01 for uniformity, (c) less than 2.48 for kurtosis, (d) at least -0.38 for skewness, and (e) less than 61.83 for standard deviation. Multivariate Cox proportional hazards regression analysis showed that each parameter was independent from the stage predictor of overall survival rate (P = .001, P = .009, P = .006, P = .02, and P = .001, respectively). CONCLUSION: Fine-texture features are associated with poorer 5-year overall survival rate in patients with primary colorectal cancer. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120254/-/DC1.

Erectile dysfunction (ED) is a common condition and studies predict that it will become even more common in the future. There is increasing evidence to suggest that it is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. The common pathological process is at the level of the endothelium, and cardiovascular risk factor control may be the key to preventing ED. Many men with established cardiovascular disease have ED. Specific guidelines for the management of ED in these patients have been produced by an expert panel. Cardiovascular risk stratification is an important initial step in managing such patients. In cardiac patients considered to have low cardiovascular risk, the management of ED can be safe and effective.

The rapid pace of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges to the robust collection of population-scale data to address this global health crisis. We established the COronavirus Pandemic Epidemiology (COPE) Consortium to unite scientists with expertise in big data research and epidemiology to develop the COVID Symptom Study, previously known as the COVID Symptom Tracker, mobile application. This application-which offers data on risk factors, predictive symptoms, clinical outcomes, and geographical hotspots-was launched in the United Kingdom on 24 March 2020 and the United States on 29 March 2020 and has garnered more than 2.8 million users as of 2 May 2020. Our initiative offers a proof of concept for the repurposing of existing approaches to enable rapidly scalable epidemiologic data collection and analysis, which is critical for a data-driven response to this public health challenge.

BACKGROUND: older people undergoing elective surgery have significant post-operative problems prolonging hospitalisation. OBJECTIVE: to design, embed, and evaluate an evidence-based comprehensive geriatric assessment (CGA) service for at-risk older patients undergoing elective surgery. SETTING: urban teaching hospital. SUBJECTS: elective surgical patients aged 65+. INTERVENTION: multidisciplinary preoperative CGA service with post-operative follow-through (proactive care of older people undergoing surgery ['POPS']). METHODS: observational cohort study and multilevel surveys (development and modelling phase). Prospective 'before and after' comparison (exploratory evaluation). RESULTS: findings from the development phase showed high levels of preoperative co-morbidity, no multidisciplinary preoperative input, and multiple potentially preventable post-operative problems delaying discharge in older elective surgery patients. Comparison of 2 cohorts of elective orthopaedic patients (pre-POPS vs POPS, N = 54) showed the POPS group had fewer post-operative medical complications including pneumonia (20% vs 4% [p = 0.008]) and delirium (19% vs 6% [p = 0.036]), and significant improvements in areas reflecting multidisciplinary practice including pressure sores (19% vs 4% [p = 0.028]), poor pain control (30% vs 2% [p<0.001]), delayed mobilisation (28% vs 9% [p = 0.012]) and inappropriate catheter use (20% vs 7% [p = 0.046]). Length of stay was reduced by 4.5 days. There were fewer delayed discharges relating to medical complications (37% vs 13%) or waits for OT assessment or equipment (20% vs 4%). CONCLUSION: a proactive evidence-based CGA service for at-risk older elective surgical patients was developed according to MRC framework for complex interventions. Pre/post comparison in elective orthopaedic patients showed improved (within methodological limitations) post-operative outcomes indicative of better clinical effectiveness and efficiency, and contributed to the service obtaining mainstream funding. Informed by the present study, a randomised controlled trial is ongoing.

Studies in both humans and experimental animals addressing the 'Fetal Origins of Adult Disease' hypothesis have established a relationship between an adverse intrauterine environment and offspring disease in adult life. This phenomenon, termed 'fetal programming' describes a process whereby a stimulus in utero establishes a permanent response in the fetus leading to enhanced susceptibility to later disease. However, the environment, during periods of developmental plasticity in postnatal life, can also 'programme' function. Thus, the terms 'developmental programming' and the 'Developmental Origins of Adult Health and Disease' are preferentially utilized. The 'Thrifty Phenotype' hypothesis explained the association between insufficient in utero nutrition and the later development of Type 2 diabetes. Most recently the 'Predictive Adaptive Response' hypothesis proposes that the degree of mismatch between the pre- and postnatal environments is an important determinant of subsequent disease. Epidemiological studies have indicated that fetal growth restriction correlates with later disease, implying that fetal nutritional deprivation is a strong programming stimulus. This prompted the development of experimental animal models using controlled maternal calorie, protein or macronutrient deficiency during key periods of gestation. However, in many societies, maternal and postnatal nutrition are either sufficient or excessive. Here, we examine findings from a range of nutritional studies examining maternal and/or postnatal nutritional excess. There is supportive evidence from a limited number of studies to test the 'Predictive Adaptive Response' hypothesis. These suggest that maternal over-nutrition is deleterious to the health of offspring and can result in a phenotype of the offspring that is characteristic of metabolic syndrome.

Though rarely life-threatening, widespread urticaria and its associated angioedema can be both debilitating and frightening. In some cases, lingual swelling requires treatment with epinephrine. Although accurate data on the prevalence of urticaria are unavailable, 15 to 23 percent of the U.S. population may have had this condition,1,2 which in many cases is prolonged and relapsing. On the basis of published data,3 a similar prevalence in the United Kingdom seems probable. Chronic urticaria is likely to be present at some time in about 25 percent of patients with urticaria. By chronic urticaria, I mean the occurrence of widespread wheals daily . . .

OBJECTIVE: To perform a health maintenance organization-based case-control study to evaluate the association of total and high density lipoprotein (HDL) cholesterol with the risk of stroke subtypes and in patient subgroups. METHODS: Cases had a confirmed incident ischemic stroke (n = 1,242) or hemorrhagic stroke (n = 313). Controls (n = 6,455) were identified in a companion myocardial infarction study. Risk of stroke was modeled using logistic regression. RESULTS: The highest total cholesterol quintile was associated with an increased risk of ischemic stroke compared to the lowest quintile (OR = 1.6, 95% CI 1.3 to 2.0) with the strongest subtype associations for atherosclerotic stroke (OR = 3.2) and lacunar stroke (OR = 2.4). The highest HDL cholesterol quintile was associated with a decreased risk of ischemic stroke compared to the lowest quintile (OR = 0.8, CI 0.6 to 1.0). Subgroup analyses suggested that the total cholesterol association was more important for patients < 66 years of age and those with HDL < 50 mg/dL; the HDL association was more important for patients without diabetes or atrial fibrillation. The second through fourth total cholesterol quintiles were associated with a decreased risk of hemorrhagic stroke compared to the lowest quintile (OR = 0.7, CI 0.5 to 1.0). CONCLUSIONS: Higher total and lower HDL cholesterol levels were associated with increased risk of ischemic stroke, especially certain stroke subtypes and patient subgroups. The lowest levels of total cholesterol were associated with an increased risk of all hemorrhagic strokes.

The chapter reviews some of recent evidence which suggests that one neurotrophin, nerve growth factor (NGF), is a peripherally produced mediator of some persistent pain states, notably those associated with inflammation. The evidence for this proposal is as follows. 1. The endogenous production of NGF regulates the sensitivity of nociceptive systems. Behavioural and electrophysiological studies have shown that sequestration of constitutively produced NGF leads to decrease nociceptor sensitivity. 2. In a wide variety of experimental inflammatory conditions NGF levels are rapidly increased in the inflamed tissue. 3. The high-affinity NGF receptor, trkA, is selectively expressed by nociceptive sensory neurons particularly those containing sensory neuropeptides such as substance P and CGRP. 4. The systematic or local application of exogenous NGF produces a rapid and prolonged behavioural hyperalgesia in both animals and humans. Exogenous NGF has also been found to activate and sensitize fine calibre sensory neurons. 5. In a number of animal models, much of the hyperalgesia associated with experimental inflammation is blocked by pharmacological "antagonism' of NGF. The mechanisms by which NGF up-regulation in inflamed tissues might lead to sensory abnormalities is also discussed. In particular, evidence is reviewed which suggests that increased NGF levels leads to both peripheral sensitization of nociceptors and central sensitization of dorsal horn neurons responding to noxious stimuli.

The primary sensory neurons that respond to noxious stimulation and project to the spinal cord are known to fall into two distinct groups: one sensitive to nerve growth factor and the other sensitive to glial cell-line-derived neurotrophic factor. There is currently considerable interest in the ways in which these factors may regulate nociceptor properties. Recently, however, it has emerged that another trophic factor-brain-derived neurotrophic factor (BDNF)-may play an important neuromodulatory role in the dorsal horn of the spinal cord. BDNF meets many of the criteria necessary to establish it as a neurotransmitter/neuromodulator in small-diameter nociceptive neurons. It is synthesized by these neurons and packaged in dense core vesicles in nociceptor terminals in the superficial dorsal horn. It is markedly up-regulated in inflammatory conditions in a nerve growth factor-dependent fashion. Postsynaptic cells in this region express receptors for BDNF. Spinal neurons show increased excitability to nociceptive inputs after treatment with exogenous BDNF. There are both electrophysiological and behavioral data showing that antagonism of BDNF at least partially prevents some aspects of central sensitization. Together, these findings suggest that BDNF may be released from primary sensory nociceptors with activity, particularly in some persistent pain states, and may then increase the excitability of rostrally projecting second-order systems. BDNF released from nociceptive terminals may thus contribute to the sensory abnormalities associated with some pathophysiological states, notably inflammatory conditions.