Large-scale sequencing of SARS-CoV-2 genomes from one region allows detailed epidemiology and enables local outbreak management.

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.

Long term monitoring in refractory epilepsy: the Gowers Unit experience.

INTRODUCTION: Guidelines from the National Institute for Health and Clinical Excellence (NICE) and the International League Against Epilepsy recommend long term EEG monitoring (LTM) in patients for whom seizure or syndrome type is unclear, and in patients for whom it is proving difficult to differentiate between epilepsy and non-epileptic attack disorder (NEAD). The purpose of this study was to evaluate this recommended use of LTM in the setting of an epilepsy tertiary referral unit. METHODS: This study reviewed the case notes of all admissions to the Sir William Gowers Unit at the National Society for Epilepsy in the years 2004 and 2005. A record was made of the type, duration and result of all LTM performed both prior to and during the admission. Pre- and post-admission diagnoses were compared, and patients were divided according to whether LTM had resulted in a change in diagnosis, refinement in diagnosis or no change in diagnosis. The distinction between change and a refinement in the diagnosis was made on the basis of whether or not this alteration resulted in a change in management. RESULTS: 612 patients were admitted during 2004 and 2005, 230 of whom were referred for diagnostic clarification. Of these, LTM was primarily responsible for a change in diagnosis in 133 (58%) and a refinement of diagnosis in 29 (13%). In 65 (29%) patients the diagnosis remained the same after LTM. In those patients in whom there was a change in diagnosis, the most common change was in distinguishing epilepsy from NEAD in 73 (55%) and in distinguishing between focal and generalised epilepsy in 47 (35%). LTM was particularly helpful in differentiating frontal lobe seizures from generalised seizures and non-epileptic attacks. Inpatient ambulatory EEG proved as effective as video telemetry in helping to distinguish between NEAD, focal and generalised epilepsy. DISCUSSION: The study revealed that LTM led to an alteration in the diagnosis of 71% of patients referred to a tertiary centre for diagnostic clarification of possible epilepsy. Although LTM is relatively expensive, time consuming and of limited availability, this needs to be balanced against the considerable financial and social cost of misdiagnosed and uncontrolled seizures. This service evaluation supports the use of performing LTM (either video or ambulatory) in a specialist setting in patients who present diagnostic difficulty.

Risks, costs, and compliance limit colorectal adenoma surveillance: lessons from a randomised trial.

BACKGROUND AND AIMS: In the USA and many other countries, endoscopic surveillance of colorectal adenoma patients is now widely practised. However, the optimal frequency and mode of such surveillance are not yet established. The aim of this trial was to compare surveillance at one, two, or five year intervals using either flexible sigmoidoscopy or colonoscopy. METHODS: Analysis of a randomised trial of flexible sigmoidoscopy and colonoscopy over one, two, or five years after stratification for "high" or "low" risk of recurrent adenomas. The trial started in 1984. RESULTS: A total of 776 patients were stratified into "high" (n=307) and "low" (n=469) recurrence risk groups and randomised to flexible sigmoidoscopy or colonoscopy at varying intervals. Only 81 recurrent adenomas (30/81 were >1 cm in diameter) were detected in the 2307 person years of follow up within the surveillance study. Adenoma recurrence was significantly higher in the high risk group (relative rate 1.82; 95% confidence interval 1.2-2.9) but recurrence rates per 1000 person years were low and not significantly different in those surveyed by colonoscopy or flexible sigmoidoscopy. Loss to follow up was greatest in those having an annual examination compared with two or five yearly surveillance examinations. Despite surveillance, invasive cancer developed in four patients compared with an expected value of 9.12 for the general population in England (p=0.10); of these four patients who developed cancers, only one was detected by surveillance examination. CONCLUSIONS: Adenoma recurrence rates were much lower than expected in both high and low risk groups. This suggests that endoscopic surveillance should be targeted at high risk groups. A surveillance interval of five years was as effective as shorter intervals in terms of cancer prevention, and was associated with similar compliance to two yearly examinations.

ARCTIC: assessment of haemodynamic response in patients with congestive heart failure to telmisartan: a multicentre dose-ranging study in Canada.

BACKGROUND: The aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects. METHODS AND RESULTS: After baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses. CONCLUSIONS: The acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit.

Exposure assessment: serum levels of TCDD in Seveso, Italy.

Accurate exposure assessment is an important step in both risk assessment and epidemiologic studies involving potential human exposure to environmental toxicants. Various methods have been used to assess human exposure. These methods include models based on one's temporal and spatial nearness to the source, environmental levels of toxicant, and biological measures. We believe that the latter measure is the "gold standard." In this article we present the serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in residents of the contaminated zones in Seveso, Italy, in 1976, and delineate these data by age and gender. Some of these serum levels are among the highest ever reported and thus this population serves as a benchmark for comparison of human exposure and potential adverse health effects. One such potential population is that population consuming potentially contaminated fish.

Assessment of current National Cholesterol Education Program guidelines for total cholesterol triglyceride, HDL-cholesterol, and LDL-cholesterol measurements.

We examine the effect of systematic bias and random error, quality control, and intraperson biological variation on the National Cholesterol Education Program (NCEP) clinical classifications for reported lipid measurements. We consider misclassification to occur if a true lipid homeostatic set point is within a desirable range but the reported lipid value is in a high-risk range, or if a true lipid homeostatic set point is in a high-risk range but the reported lipid value is in a desirable range. To evaluate the overall adequacy of the NCEP guidelines to ensure correct patient classification, we construct operating characteristic curves for total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. We demonstrate that if laboratories are meeting the NCEP guidelines for inherent bias and analytic precision and are using standard quality-control (QC) procedures incorporating at least two QC samples per analytical run from each of two QC pools (for a total of 4 QC samples), the current NCEP guidelines are adequate to ensure (probability >0.90) correct patient classifications regardless of the size of the systematic bias of the laboratory or increased random analytic error. Thus we suggest that at least two concentrations of QC material be included in the QC scheme to ensure that the measurement system is operating within desired specifications across the entire range of desirable and high-risk lipid concentrations and to ensure with high probability that patients are correctly classified.

The costs of treating breast cancer in the United Kingdom: implications for screening.

Total treatment costs by stage at diagnosis are estimated for a sample of breast cancer patients. At 4 years, stage 4 cancers emerge as being more expensive to treat than those at earlier stages, although this difference fails to achieve significance when expected lifetime costs are considered. The inclusion of treatment cost estimates in a screening model indicates that screening may increase expected treatment costs by a marginal amount, although the model also suggests that the cost-effectiveness ratio of breast cancer screening might be better than had originally been thought.

Firearm ownership in households with children.

BACKGROUND/PURPOSE: Increased morbidity and mortality rates in children injured by firearms has been well documented during this past decade. The aim of this study was to determine the socioeconomic factors affecting firearm ownership in families with children living in suburban/rural versus inner-city environments, and to identify predictors of firearm ownership in these families. METHODS: Parents of children less than 19 years old seen in a suburban (n = 751) or inner-city hospital (n = 406) anonymously completed a questionnaire regarding firearm ownership. RESULTS: Firearm ownership was 54% in rural locations, versus 18% among inner-city residents (P< .05). Firearm ownership in white households was 45% versus 20% in African-American households (P< .05). Mean number of all types of firearms in white households was 3.38 versus 1.78 in black households (P< .001). Firearm ownership was 19% in the less than $20,000 income bracket, significantly lower than households with greater incomes, and was significantly lower in households in which parents had the least education (19.7%) versus those with college degrees (38.5%; P< .05). Firearm owners of rifles and shotguns significantly more often cited hunting, collection, and target shooting as reasons for owning firearms, in contrast to revolver owners who cited protection and collection as reasons for firearm ownership (P < .05). CONCLUSIONS: Firearm ownership is higher in rural, caucasian versus inner-city African-American residents and is significantly less in households with lower income and educational levels. Significant predictors for firearm ownership were number of parents in households, educational level of parents, and population of residence.

The geographical assignment of cancer units: patient accessibility as an optimal allocation problem.

The seminal report A Policy Framework for Commissioning Cancer Services provides the foundation for a major reorganisation of cancer service provision in England and Wales. One central recommendation of the report, the establishment of a tier of specialised cancer units in each Health Authority Region has raised the fundamental question of where those units are to be located. In particular, a declared objective of the report is for services to be planned to maximise their accessibility to patients. This paper demonstrates a classical method (location-allocation modelling) by which the accessibility criterion can be used to determine the optimal number, location and capacity of units for a given cancer site. The method is illustrated with reference to cervical cancer in Trent Health Authority Region. The implications of the method for the guidance of access-related decisions on the placement of cancer services are considered, and the wider relevance of the method to the organisation of service provision in other branches of medicine is suggested.

Fit for the future? A role for health professionals in housing management.

The institutions of the welfare state have traditionally catered to some health needs through housing interventions. A key strategy has been to award people with health problems and mobility difficulties priority access to council rented homes. Medical rehousing has required input from both housing managers and health professionals, especially public health physicians. This paper draws on a postal survey of health advisers to English housing departments to analyse the form, and consider the future, of this approach to housing for health.

Role of spiral volumetric computed tomographic scanning in the assessment of patients with clinical suspicion of pulmonary embolism and an abnormal ventilation/perfusion lung scan.

BACKGROUND: A study was carried out to evaluate the potential place of spiral volumetric computed tomography (SVCT) in the diagnostic strategy for pulmonary embolism. METHODS: In a prospective study 249 patients with clinical suspicion of pulmonary embolism were evaluated with various imaging techniques. In all patients a ventilation/perfusion (V/Q) scan was performed. Seventy seven patients with an abnormal V/Q scan underwent SVCT. Pulmonary angiography was then performed in all 42 patients with a non-diagnostic V/Q scan and in three patients with a high probability V/Q scan without emboli on the SVCT scan. Patients with an abnormal perfusion scan also underwent ultrasonography of the legs for the detection of deep vein thrombosis. RESULTS: One hundred and seventy two patients (69%) had a normal V/Q scan. Forty two patients (17%) had a non-diagnostic V/Q scan, and in five of these patients pulmonary emboli were found both by SVCT and pulmonary angiography. In one patient, although SVCT showed no emboli, the angiogram was positive for pulmonary embolism. In one of the 42 patients the SVCT scan showed an embolus which was not confirmed by pulmonary angiography. The other 35 patients showed no sign of emboli. Thirty five patients (14%) had a high probability V/Q scan, and in 32 patients emboli were seen on SVCT images. Two patients had both a negative SVCT scan and a negative pulmonary angiogram. In one who had an inconclusive SVCT scan pulmonary angiography was positive. The sensitivity for pulmonary embolism was 95% and the specificity 97%; the positive and negative predicted values of SVCT were 97% and 97%, respectively. CONCLUSIONS: SVCT is a relatively noninvasive test for pulmonary embolism which is both sensitive and specific and which may serve as an alternative to ventilation scintigraphy and possibly to pulmonary angiography in the diagnostic strategy for pulmonary embolism.

Healthy alliance? The relevance of health professionals to housing management.

British public policy now relies on the development of 'healthy alliances' to meet the care, support and servicing needs of people with health problems and mobility difficulties. Such alliances are not, however, new; notably, housing policy is frequently used as a health intervention. This paper examines the character and effectiveness of the resulting alliance between health professionals and housing managers, and considers its future prospects.

Effect of human leucocyte antigen matching on the incidence of acute rejection in renal transplantation.

The influence of human leucocyte antigen (HLA) matching on the incidence of acute rejection and graft survival was examined in 181 consecutive patients receiving cadaveric renal transplants. Allografts with better HLA-DR and HLA-B matching showed significantly lower rejection rates than less well matched grafts on both univariate (rejection rates 25, 62 and 82 per cent for zero, one and two DR mismatches; P < 0.001) and multivariate analysis. Rejection episodes occurred earlier in mismatched grafts (P < 0.001). Superior matching was associated with improved graft function at 1 year after transplantation (mean serum creatinine level 137, 180 and 225 mumol l-1 for zero, one and two DR mismatches; P < 0.05). No association was, however, demonstrated between the degree of matching and overall graft survival. Good HLA matching reduces the number of acute rejection episodes, producing significant savings in drug costs and hospital stay. Long-term graft function is improved and minimizing early graft damage helps to avoid later development of chronic rejection.

Health status and the housing system.

Most research on housing and health seeks causal links between dwelling conditions and the incidence of physical and mental disease. Less attention has been paid to the more sociological question of how health status affects housing opportunities. This paper shows how, and considers why, medical factors influence access to housing, whether in the public sector (where accommodation is traditionally allocated according to 'need') or in the housing market (where dwelling availability depends on ability to pay). In Britain, whose experience is taken as an example, a shrinking council housing stock can no longer accommodate general medical needs. Consequently, notwithstanding the importance of 'special' housing initiatives, many sick people are forced to seek accommodation in the private sector. Whether they succeed or fail (and so become homeless), this raises questions concerning the health selective role of the housing system which analysts have scarcely begun to address.

Cholesterol-based personal risk assessment in coronary heart disease.

Using data from the National Health and Nutrition Examination Survey (NHANES II) 1976-1980, we demonstrate how cross-sectional total serum cholesterol surveillance data can be used by an individual to assess current and future personal cholesterol risk status. We propose statistical models, based on a person's current measured cholesterol level and the relationship between cross-sectional age and cholesterol percentile estimates, that will allow prediction of future cholesterol levels or the age at which specified cholesterol risk levels will be reached if no cholesterol-altering intervention is taken. These models incorporate the observed variation in the NHANES II data and expected intraperson biological variation and intralaboratory analytical variation. We illustrate the adequacy of the models using data from the longitudinal Framingham Study.

Comparison of five assays for immune complexes in the rheumatic diseases. An assessment of their validity for rheumatoid arthritis.

Clinical assessment (disease activity, severity, and extraarticular manifestations) of 101 rheumatoid arthritis patients was correlated with several laboratory tests, including 5 immune complex assays: the bovine conglutinin, 125I-Clq binding, monoclonal rheumatoid factor inhibition, Raji cell, and staphylococci binding assays. Elevated disease activity indices were most closely associated with the presence of immune complexes detected by the 125I-Clq and staphylococci binding assays. There were significant but weak correlations between the level of disease activity and the level of immune complexes as measured by the bovine conglutinin, 125I-Clq binding, Raji cell, and staphylococci binding assays. Articular disease severity, as measured by anatomic stage, was discriminated by the bovine conglutinin, monoclonal rheumatoid factor inhibition, and staphylococci binding assays. Extraarticular manifestations were best discriminated by the Raji cell and staphylococci binding assays. We concluded that the sensitivity, specificity, predictive value, and overlap of the associations were not sufficient to warrant their wide use for the diagnosis and management of rheumatoid arthritis in individual patients. Conversely, the 125I-Clq and staphylococci binding assays were as good as the erythrocyte sedimentation rate and the IgG rheumatoid factor test (the 2 best of many examined) in assessing disease activity. Further prospective studies with these assays will determine their usefulness in following rheumatoid arthritis for a prolonged period.