Value of treatment by comprehensive stroke services for the reduction of critical gaps in acute stroke care in Europe.

Stroke is the second leading cause of death and dependency in Europe and costs the European Union more than €30bn, yet significant gaps in the patient pathway remain and the cost-effectiveness of comprehensive stroke care to meet these needs is unknown. The European Brain Council Value of Treatment Initiative combined patient representatives, stroke experts, neurological societies and literature review to identify unmet needs in the patient pathway according to Rotterdam methodology. The cost-effectiveness of comprehensive stroke services was determined by a Markov model, using UK cost data as an exemplar and efficacy data for prevention of death and dependency from published systematic reviews and trials, expressing effectiveness as quality-adjusted life-years (QALYs). Model outcomes included total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). Key unmet needs in the stroke patient pathway included inadequate treatment of atrial fibrillation (AF), access to neurorehabilitation and implementation of comprehensive stroke services. In the Markov model, full implementation of comprehensive stroke services was associated with a 9.8% absolute reduction in risk of death of dependency, at an intervention cost of £9566 versus £6640 for standard care, and long-term care costs of £35 169 per 5.1251 QALYS vs. £32 347.40 per 4.5853 QALYs, resulting in an ICER of £5227.89. Results were robust in one-way and probabilistic sensitivity analyses. Implementation of comprehensive stroke services is a cost-effective approach to meet unmet needs in the stroke patient pathway, to improve acute stroke care and support better treatment of AF and access to neurorehabilitation.

Impact of ethnicity on adverse perinatal outcome in women with chronic hypertension: a cohort study.

OBJECTIVE: To assess the impact of maternal ethnicity on the risk of adverse perinatal outcome in pregnant women with chronic hypertension. METHODS: Demographic and delivery data were collated of women with chronic hypertension and singleton pregnancy who delivered at one of three UK obstetric units between 2000 and 2014. Multivariable logistic regression models were used to calculate risk ratios (RR), according to ethnic group, for adverse perinatal outcome, adjusted for other maternal characteristics including age, parity, body mass index, smoking status, deprivation index and year of delivery. The impact of maternal ethnicity on birth-weight centile calculation was investigated by comparing the birth-weight centile chart customized for ethnicity (Gestation Related Optimal Weight; GROW) with a birth-weight centile calculator that does not adjust for that factor (INTERGROWTH-21st ). RESULTS: The study cohort included 4481 pregnancies (4045 women) with chronic hypertension. Women of white ethnicity accounted for 47% (n = 2122) of the cohort and 36% (n = 1601) were of black, 8.5% (n = 379) of Asian and 8.5% (n = 379) of other ethnicity. The overall incidence of stillbirth was 1.6%, that of preterm birth < 37 weeks was 16% and that of fetal growth restriction (birth weight < 3rd centile) was 11%. Black women, compared with white women, had the highest risk for all adverse perinatal outcomes, with stillbirth occurring in 3.1% vs 0.6% of pregnancies (adjusted RR (aRR), 5.56 (95% CI, 2.79-11.09)), preterm birth < 37 weeks in 21% vs 11% (aRR, 1.70 (95% CI, 1.43-2.01)) and birth weight < 3rd centile in 15% vs 7.4% (aRR, 2.07 (95% CI, 1.71-2.51)). Asian women, compared with white women, were also at increased risk of adverse perinatal outcome, with stillbirth occurring in 1.6% vs 0.6% (aRR, 3.03 (95% CI, 1.11-8.28)), preterm birth < 37 weeks in 20% vs 11% (aRR, 1.82 (95% CI, 1.41-2.35)) and birth weight < 3rd centile in 12% vs 7.4% (aRR, 1.69 (95% CI, 1.24-2.30)). The sensitivity and specificity for prediction of infants requiring neonatal unit admission were 40% and 93%, respectively, for those with birth weight < 3rd centile according to GROW charts, compared with 16% and 96%, respectively, for those with birth weight < 3rd centile according to INTERGROWTH-21st charts. CONCLUSIONS: Black ethnicity, compared with white, is associated with the greatest risk of adverse perinatal outcome in women with chronic hypertension, even after adjusting for other maternal characteristics. Women of Asian ethnicity are also at increased risk, but to a lesser extent. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases.

Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia-reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase-independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitrate-nitrite-NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases.

Fate of the chemical warfare agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX) on soil following accelerant-based fire and liquid decontamination.

In the event of alleged use of organophosphorus nerve agents, all kinds of environmental samples can be received for analysis. These might include decontaminated and charred matter collected from the site of a suspected chemical attack. In other scenarios, such matter might be sampled to confirm the site of a chemical weapon test or clandestine laboratory decontaminated and burned to prevent discovery. To provide an analytical capability for these contingencies, we present a preliminary investigation of the effect of accelerant-based fire and liquid decontamination on soil contaminated with the nerve agent O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate (VX). The objectives were (a) to determine if VX or its degradation products were detectable in soil after an accelerant-based fire promoted by aviation fuel, including following decontamination with Decontamination Solution 2 (DS2) or aqueous sodium hypochlorite, (b) to develop analytical methods to support forensic analysis of accelerant-soaked, decontaminated and charred soil and (c) to inform the design of future experiments of this type to improve analytical fidelity. Our results show for the first time that modern analytical techniques can be used to identify residual VX and its degradation products in contaminated soil after an accelerant-based fire and after chemical decontamination and then fire. Comparison of the gas chromatography-mass spectrometry (GC-MS) profiles of VX and its impurities/degradation products from contaminated burnt soil, and burnt soil spiked with VX, indicated that the fire resulted in the production of diethyl methylphosphonate and O,S-diethyl methylphosphonothiolate (by an unknown mechanism). Other products identified were indicative of chemical decontamination, and some of these provided evidence of the decontaminant used, for example, ethyl 2-methoxyethyl methylphosphonate and bis(2-methoxyethyl) methylphosphonate following decontamination with DS2. Sample preparation procedures and analytical methods suitable for investigating accelerant and decontaminant-soaked soil samples are presented. VX and its degradation products and/or impurities were detected under all the conditions studied, demonstrating that accelerant-based fire and liquid-based decontamination and then fire are unlikely to prevent the retrieval of evidence of chemical warfare agent (CWA) testing. This is the first published study of the effects of an accelerant-based fire on a CWA in environmental samples. The results will inform defence and security-based organisations worldwide and support the verification activities of the Organisation for the Prohibition of Chemical Weapons (OPCW), winner of the 2013 Nobel Peace Prize for its extensive efforts to eliminate chemical weapons.

Associations between air pollutants and blood pressure in an ethnically diverse cohort of adolescents in London, England.

Longitudinal evidence on the association between air pollution and blood pressure (BP) in adolescence is scarce. We explored this association in an ethnically diverse cohort of schoolchildren. Sex-stratified, linear random-effects modelling was used to examine how modelled residential exposure to annual average nitrogen dioxide (NO2), particulate matter (PM2.5, PM10) and ozone (O3), measures in µg/m3, associated with blood pressure. Estimates were based on 3,284 adolescents; 80% from ethnic minority groups, recruited from 51 schools, and followed up from 11-13 to 14-16 years old. Ethnic minorities were exposed to higher modelled annual average concentrations of pollution at residential postcode level than their White UK peers. A two-pollutant model (NO2 & PM2.5), adjusted for ethnicity, age, anthropometry, and pubertal status, highlighted associations with systolic, but not diastolic BP. A µg/m3 increase in NO2 was associated with a 0.30 mmHg (95% CI 0.18 to 0.40) decrease in systolic BP for girls and 0.19 mmHg (95% CI 0.07 to 0.31) decrease in systolic BP for boys. In contrast, a 1 µg/m3 increase in PM2.5 was associated with 1.34 mmHg (95% CI 0.85 to 1.82) increase in systolic BP for girls and 0.57 mmHg (95% CI 0.04 to 1.03) increase in systolic BP for boys. Associations did not vary by ethnicity, body size or socio-economic advantage. Associations were robust to adjustments for noise levels and lung function at 11-13 years. In summary, higher ambient levels of NO2 were associated with lower and PM2.5 with higher systolic BP across adolescence, with stronger associations for girls.

Role for endothelial nitric oxide synthase in nitrite-induced protection against renal ischemia-reperfusion injury in mice.

Nitrite is protective against renal ischemia/reperfusion injury (IRI); an effect due to its reduction to nitric oxide (NO). In addition to other reductase pathways, endothelial NO synthase (eNOS) may also facilitate nitrite reduction in ischemic environments. We investigated the role of eNOS in sodium nitrite (60 microM, 10 ml/kg applied topically 1 min before reperfusion)-induced protection against renal IRI in C57/BL6 wild-type (WT) and eNOS knockout (eNOS KO) mice subjected to bilateral renal ischemia (30 min) and reperfusion (24h). Markers of renal dysfunction (plasma [creatinine] and [urea]), damage (tubular histology) and inflammation (cell recruitment) were elevated following IRI in WT mice; effects significantly reduced following nitrite treatment. Chemiluminescence analysis of cortical and medullary sections of the kidney demonstrated rapid (within 1 min) distribution of nitrite following application. Whilst IRI caused a significant (albeit substantially reduced compared to WT mice) elevation of markers of renal dysfunction and damage in eNOS KO mice, the beneficial effects of nitrite were absent or reduced, respectively. Moreover, nitrite treatment enhanced renal dysfunction in the form of increased plasma [creatinine] in eNOS KO mice. Confirmation of nitrite reductase activity of eNOS was provided by demonstration of nitrite (100 microM)-derived NO production by kidney homogenates of WT mice, that was significantly reduced by L-NMMA. L-NMMA was without effect using kidney homogenates of eNOS KO mice. These results support a role for eNOS in the pathways activated during renal IRI and also identify eNOS as a nitrite reductase in ischemic conditions; activity which in part underlies the protective effects of nitrite.

A protease-based biosensor for the detection of schistosome cercariae.

Parasitic diseases affect millions of people worldwide, causing debilitating illnesses and death. Rapid and cost-effective approaches to detect parasites are needed, especially in resource-limited settings. A common signature of parasitic diseases is the release of specific proteases by the parasites at multiple stages during their life cycles. To this end, we engineered several modular Escherichia coli and Bacillus subtilis whole-cell-based biosensors which incorporate an interchangeable protease recognition motif into their designs. Herein, we describe how several of our engineered biosensors have been applied to detect the presence and activity of elastase, an enzyme released by the cercarial larvae stage of Schistosoma mansoni. Collectively, S. mansoni and several other schistosomes are responsible for the infection of an estimated 200 million people worldwide. Since our biosensors are maintained in lyophilised cells, they could be applied for the detection of S. mansoni and other parasites in settings without reliable cold chain access.

Determinants of clinical effectiveness and significant neurological diagnoses in an urgent brain cancer referral pathway in the United Kingdom.

BACKGROUND: Cerebral tumours can rapidly progress to life-threatening complications yet referral pathways often result in non-significant diagnoses. We aimed to identify the determinants of referrals resulting in significant neurological diagnoses after specialist review. METHODS: We reviewed all urgent brain cancer referrals to the neurology service at a British district general hospital between January 2009 and September 2013. Time to appointment, frequency of significant neurological diagnoses, appropriateness of referrals and referral heterogeneity across GP practices were measured as determinants of non-significant diagnoses. RESULTS: 31/105 patients received significant neurological diagnoses (29.5%), including ten (9.5%) tumours (7 malignant), although 2 patients were admitted prior to clinic. There was significant heterogeneity between primary care physicians in referral frequency (p = 0.008) and significant diagnoses (p = 0.005). Non-significant diagnoses were more common in inappropriate referrals and if patients were unaware of the potential diagnosis. Seizures or subacute focal symptoms were more likely to result in a significant neurological diagnosis than isolated headache syndromes (odds ratio 3.45, 1.34-18.4, p = 0.008). DISCUSSION: Despite a significant number of important neurological diagnoses and tumours, there were frequent inappropriate or low-risk referrals resulting in non-significant diagnoses, particularly if a headache syndrome was the sole reason for referral.

Segmental lymph-node infarction after fine-needle aspiration.

Wedge-shaped lymphoid depletion and sinus distention is described in the pole of an intramammary lymph node. The origin of the lesion appears to be traumatic venous thrombosis. Topographically the lesion differs from spontaneous venous infarction of lymph nodes, and resembles segmented infarction due to small arterial lesions. The usually localised trauma of fine-needle aspiration appears to account for its distinctive microanatomical distribution.

Fine needle aspiration cytology.

Fine needle aspiration cytology is an inexpensive, atraumatic technique for the diagnosis of disease sites. This paper describes the technique and illustrates how it may be applied to the management of tumours throughout the body. The limitations of the method, the dangers of false positive reports, and the inevitability of false negative diagnoses are emphasised. In a clinical context the method has much to offer by saving patients from inappropriate operations and investigations and allowing surgeons to plan quickly and more rationally. It is an economically valuable technique and deserves greater recognition.

Bacteraemia due to a rifampicin-resistant strain of Bacteroides fragilis.

A strain of Bacteroides fragilis with high-level chromosomal resistance to rifampicin was isolated by blood culture from a patient with bacteraemia after gastrointestinal surgery. He had been receiving antituberculous therapy with rifampicin for nine months. This resistance led to some difficulty in the recognition and identification of the isolate by methods that depended upon antibiotic sensitivity patterns.

The Albert Dock Hospital, London: the original site (in 1899) of Tropical Medicine as a new discipline.

The London School of Tropical Medicine, and indeed the 'new' discipline of tropical medicine, originated in 1899 at the Albert Dock Hospital - situated in London's east-end. The founder of the discipline was Patrick Manson - with a great deal of political assistance from the British Secretary of State for the Colonies (Joseph Chamberlain). The hospital (originally opened in 1890) was rebuilt in 1937-1938 and ultimately demolished in 1993.

Florid papillomatosis of the nipple: a clinico-pathological surgical problem.

Adenoma or florid papillomatosis of the nipple is a rare, benign condition which resembles the clinical appearances of Paget's disease of the nipple and the histological appearances of papillary carcinoma of the breast. We describe a case which illustrates the pitfalls in diagnosis and proposes a safe management procedure for breast and nipple lesions.

Hepatic metastases in adenoid cystic carcinoma of the submandibular gland.

We present a case of adenoid cystic carcinoma of the submandibular gland resulting in metastases to the liver, nine years following initial presentation.

Parotid Warthin's tumour Bristol Royal Infirmary (1985-1995): a study of histopathology in 33 cases.

This is a study of 33 (32 patients) confirmed Warthin's tumours (adenolymphomas) treated surgically at Bristol Royal Infirmary (1985--1995) focussing specifically upon 17 salient histopathological features together with capsular measurement by micrometry. Twenty-four out of 33 tumours had 'thin' capsules (< or = 200 microm), whereas 5/9 'thick' capsules were associated with gross tumour degeneration. The degenerative features including cystic change, squamous metaplasia, corpora amylacea like bodies, etc. were quantified. Tumours were classified into subtypes (typical, stroma poor, etc). These variations were not associated with age or sex. In 20/33 tumours a marginal sinus suggested a lymph node origin. Fine needle aspiration cytology (FNA) smears showing degeneration features are a diagnostic problem, but histopathological features are reflected in such smears and their recognition enhances diagnostic precision, enabling controlled surgical enucleation, the ideal operation, to be performed in most cases. In this study only 12 tumours were so treated; 11 others received parotidectomy. The theories of histogenesis are reviewed and discussed.

Ultrasonic Doppler studies of the breast.

The growth of a malignant tumour depends on vascularisation. The ultrasonic Doppler method can detect the blood flow associated with malignant breast tumours, the signals differing qualitatively from those due to benign lesions. Several descriptors of the Doppler signals were tested; benign and malignant lesions are best separated by the difference between the maximum systolic frequencies from suspect and contralateral sites. Corresponding main arterial sites are reliably coincident in normal breast pairs. Consideration of the powers and frequency spectra of Doppler signals leads to the rejection of models of tumour vascularisation giving Doppler signals based on capillary perfusion and on a single feed artery. The data are compatible with a multiple feed artery model, and this is supported by a contrast angiogram. Doppler ultrasound may be useful as a preliminary screening method, in the management of patients with radiologically dense breasts or diffuse dysplasia, and for monitoring unexcised tumours undergoing hormone therapy.

Relationship between Ca(2+) release, sarcoplasmic Ca(2+), glycolysis and meat quality in halothane-sensitive and halothane-insensitive pigs.

Post-mortem assessment of porcine stress susceptibility and meat quality by measurements of mitochondrial calcium (content and rate of release), water-holding capacity, pH at 1h post mortem and colour on M. longissimus dorsi confirm the usefulness of the halothane test for detecting stress susceptibility. Good correlations were observed between halothane sensitivity and meat quality. Post-mortem samples of M. longissimus dorsi of halothane-sensitive pigs showed significantly higher levels of sarcoplasmic calcium than similar muscle from halothane-insensitive pigs. This strongly suggests that elevated sarcoplasmic calcium levels are linked to the formation of PSE meat.

A cytological study of mammary disease.

An analysis is presented of 887 cytological biopsies performed on 610 patients with mammary disease, including 510 fine needle aspirations. Technical details of fine needle biopsy, imprints, and scrape-smears are provided, together with both histological and cytological descriptions. The case material has been classified into 6 series, the most important being a clinicocytological study in which fine needle biopsy achieved a 96.2% accuracy rate in respect of breast cancer. The status of cytology in the clinical management of mammary disease is evaluated.

Will screening for breast cancer reduce mortality? Evidence from the first year of screening in Avon.

In the first year of screening in Avon, 93 malignant lesions were detected of which one-half were impalpable. Of the impalpable lesions, one-half were in situ or showed areas of microinvasion only. One-fifth of the malignant lesions were invasive tumours of special histological type which are known to carry a good prognosis even when not detected by screening. One-quarter of the lesions had clinical or pathological features which would be expected to confer a poor prognosis. Only 16 invasive ductal carcinomas measuring 1 cm or less in diameter were detected--a small proportion of the total number of malignant lesions. Although these early figures suggest that the effect of screening on mortality from breast cancer may be small, continued high-quality screening and careful detailed analysis are essential to determine the effect of screening on the mortality from breast cancer and the effect on the population as a whole.

Rate and classification of interval cancers in the breast screening programme.

There has been concern about the number of interval cancers which have been detected within the National Breast Screening Programme. A series of 134 women presenting with interval cancers was studied by prospective audit and the rate and radiological classification of the tumours determined. The cancers were classified as true (67), false-negative (22), unclassifiable (28), occult (12), and minimal sign (5). The interval cancer rate did not achieve the new National Guidelines in either the first 2 years or the 3rd interval year. The false-negative cancers presented mainly in the 1st interval year, whereas the true cancers were predominantly confined to the 2nd and 3rd years. These data suggest that alterations to the screening programme may be beneficial. It may be, however, that the programme is still on the learning curve and this should be taken into account when interpreting these data.