Northwick Park Hospital

Journal Article Cellular and Molecular Immunology Get access A M Denman A M Denman Division of Immunology, Clinical Research Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ Search for other works by this author on: Oxford Academic Google Scholar Postgraduate Medical Journal, Volume 68, Issue 798, April 1992, Page 305, https://doi.org/10.1136/pgmj.68.798.305 Published: 01 April 1992

Difficult intubation has been classified into four grades, according to the view obtainable at laryngoscopy. Frequency analysis suggests that, in obstetrics, the main cause of trouble is grade 3, in which the epiglottis can be seen, but not the cords. This group is fairly rare so that a proportion of anaesthetists will not meet the problem in their first few years and may thus be unprepared for it in obstetrics. However the problem can be simulated in routine anaesthesia, so that a drill for managing it can be practised. Laryngoscopy is carried out as usual, then the blade is lowered so that the epiglottis descends and hides the cords. Intubation has to be done blind, using the Macintosh method. This can be helpful as part of the training before starting in the maternity department, supplementing the Aberdeen drill.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

A mental test score consisting of 26 questions testing memory and orientation was used in a large inpatient study of mental impairment of the elderly. Analysis shows that the questions varied considerably in their discriminatory value. Deletion of the less effective questions results in an abbreviated test of ten questions with similar discriminatory powers to the full test. Shorter tests of this kind are recommended for further practical evaluation in geriatric departments.

Over the ensuing seven months she had three more clinical relapses, each accompanied by reappearance in the stools of either the organism or its cytotoxin, or both. Each improvement after vancomycin (eight to 14-day- courses) was accompanied by disappearance of the organism. At one point she was given cholestyramine, but she was unable to tolerate it. Her illness was punctuated by malnutrition and episodes of heart failure. She was given no other antibiotics. After the sixth relapse maintenance treatment with oral vancomycin 125 mg eight-hourly was begun. With this regimen diarrhoea was controlled and stools over the next 10 weeks remained negative for C difficile and its cytotoxin. There was no adverse reaction to vancomycin throughout.

Statistical parametric maps (SPMs) are potentially powerful ways of localizing differences in regional cerebral activity. This potential is limited by uncertainties in assessing the significance of these maps. In this report, we describe an approach that may partially resolve this issue. A distinction is made between using SPMs as images of change significance and using them to identify foci of significant change. In the first case, the SPM can be reported nonselectively as a single mathematical object with its omnibus significance. Alternatively, the SPM constitutes a large number of repeated measures over the brain. To reject the null hypothesis, that no change has occurred at a specific location, a threshold adjustment must be made that accounts for the large number of comparisons made. This adjustment is shown to depend on the SPM's smoothness. Smoothness can be determined empirically and be used to calculate a threshold required to identify significant foci. The approach models the SPM as a stationary stochastic process. The theory and applications are illustrated using uniform phantom images and data from a verbal fluency activation study of four normal subjects.

BACKGROUND: Arterial distensibility measures, generally from pulse-wave velocity (PWV), are widely used with little knowledge of relationships to patient outcome. We tested whether aortic PWV predicts cardiovascular and all-cause mortality in type 2 diabetes and glucose-tolerance-tested (GTT) multiethnic population samples. METHODS AND RESULTS: Participants were randomly sampled from (1) a type 2 diabetes outpatient clinic and (2) primary care population registers, from which nondiabetic control subjects were given a GTT. Brachial blood pressures and Doppler-derived aortic PWV were measured. Mortality data over 10 years' follow-up were obtained. At any level of systolic blood pressure (SBP), aortic PWV was greater in subjects with diabetes than in controls. Mortality risk doubled in subjects with diabetes (hazard ratio 2.34, 95% CI 1.5 to 3.74) and in those with glucose intolerance (2.12, 95% CI 1.11 to 4.0) compared with controls. For all groups combined, age, sex, and SBP predicted mortality; the addition of PWV independently predicted all-cause and cardiovascular mortality (hazard ratio 1.08, 95% CI 1.03 to 1.14 for each 1 m/s increase) but displaced SBP. Glucose tolerance status and smoking were other independent contributors, with African-Caribbeans experiencing reduced mortality risk (hazard ratio 0.41, 95% CI 0.25 to 0.69). CONCLUSIONS: Aortic PWV is a powerful independent predictor of mortality in both diabetes and GTT population samples. In displacing SBP as a prognostic factor, aortic PWV is probably further along the causal pathway for arterial disease and may represent a useful integrated index of vascular status and hence cardiovascular risk.

The main aim of the trial was to determine whether drug treatment of mild hypertension (phase V diastolic pressure 90-109 mm Hg) reduced the rates of stroke, of death due to hypertension, and of coronary events in men and women aged 35-64 years. Subsidiary aims were: to compare the course of blood pressure in two groups, one taking bendrofluazide and one taking propranolol, and to compare the incidence of suspected adverse reactions to these two drugs. The study was single blind and based almost entirely in general practices; 17 354 patients were recruited, and 85 572 patient years of observation have accrued. Patients were randomly allocated at entry to take bendrofluazide or propranolol or placebo tablets. The primary results were as follows. The stroke rate was reduced on active treatment: 60 strokes occurred in the treated group and 109 in the placebo group, giving rates of 1.4 and 2.6 per 1000 patient years of observation respectively (p less than 0.01 on sequential analysis). Treatment made no difference, however, to the overall rates of coronary events: 222 events occurred on active treatment and 234 in the placebo group (5.2 and 5.5 per 1000 patient years respectively). The incidence of all cardiovascular events was reduced on active treatment: 286 events occurred in the treated group and 352 in the placebo group, giving rates of 6.7 and 8.2 per 1000 patient years respectively (p less than 0.05 on sequential analysis). For mortality from all causes treatment made no difference to the rates. There were 248 deaths in the treated group and 253 in the placebo group (rates 5.8 and 5.9 per 1000 patient years respectively). Several post hoc analyses of subgroup results were also performed but they require very cautious interpretation. The all cause mortality was reduced in men on active treatment (157 deaths versus 181 in the placebo group; 7.1 and 8.2 per 1000 patient years respectively) but increased in women on active treatment (91 deaths versus 72; 4.4 and 3.5 per 1000 patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05). Comparison of the two active drugs showed that the reduction in stroke rate on bendrofluazide was greater than that on propranolol (p = 0.002). The stroke rate was reduced in both smokers and non-smokers taking bendrofluazide but only in non-smokers taking propranolol. This difference between the responses to the two drugs was significant (p = 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND: Existing scales for assessing faecal incontinence have not been validated against clinical assessment, or with regard to reproducibility. They also fail to take into account faecal urgency, and the use of antidiarrhoeal medications. AIMS: To establish the validity, and sensitivity to change, of existing scales and a newly designed incontinence scale. METHODS: (1) Twenty three patients (21 females, median age 57 years) were prospectively evaluated by two independent clinical observers, using three established scales (Pescatori, Wexner, American Medical Systems), a newly devised scale which also includes details about urgency and antidiarrhoeal drugs, and by a 28 day diary. (2) A further 10 female patients were assessed by the same scales before and after surgery for faecal incontinence. RESULTS: (1) Assessments by two independent clinicians correlated well. All four scales and a diary card correlated highly and significantly with the clinical impression, with the new scale reaching the highest correlation (r=0.79, p<0.001). (2) All except one score changed significantly in response to surgical treatment; the new scale showed the greatest change, at the highest level of significance (p=0.004), and correlated best with the clinicians' assessment of change (r=0.94, p<0.001). CONCLUSIONS: Existing scales for the assessment of faecal incontinence correlate well with careful clinical impression of severity, and serve as useful and reproducible measures for comparison of patients and treatments. A newly devised scale has shown high clinical validity and utility.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. Low read depth sequencing of whole genomes and high read depth exomes of nearly 10,000 extensively phenotyped individuals are combined to help characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits; in addition to describing population structure and providing functional annotation of rare and low-frequency variants the authors use the data to estimate the benefits of sequencing for association studies. This paper, combining data and initial findings from the different arms of the UK10K project, describes insights from low-read-depth sequencing of whole genomes or high-read-depth exome sequencing of nearly 10,000 individuals sampled from a range of disease collections, as well as participants from healthy population based cohorts. The authors characterize novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with lipid-related traits. In addition to describing population structure and providing functional annotation of rare and low frequency variants, they use the data to estimate the benefits of sequencing for association studies.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

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 prevalence of urinary incontinence was investigated by determining the number of incontinent patients under the care of various health and social service agencies in two London boroughs and by a postal survey of the 22 430 people aged 5 years and over on the practice lists of 12 general practitioners in different parts of the country. The prevalence of incontinence known to the health and social service agencies was 0.2% in women and 0.1% in men aged 15-64 and 2.5% in women and 1.3% in men aged 65 and over. The postal survey, to which 89% of the people whose correct address was known replied, showed a prevalence of urinary incontinence of 8.5% in women and 1.6% in men aged 15-64 and 11.6% in women and 6.9% in men aged 65 and over. Nulliparous women had a lower prevalence than those who had had one, two, or three babies, but within the parity range of one to three there were no differences in prevalence. The prevalence was appreciably increased in women who had had four or more babies. Incontinence was moderate or severe in a fifth of those who reported it in the postal survey, of whom less than a third were receiving health or social services for the condition. Incontinence is a common symptom, and many unrecognised cases appear to exist. There may be considerable scope for improving its management.

In order to localize cerebral cognitive or sensorimotor function, activation paradigms are being used in conjunction with PET measures of cerebral activity (e.g., rCBF). The changes in local cerebral activity have two components: a global, region independent change and a local or regional change. As the first step in localizing the regional effects of an activation, global variance must be removed by a normalization procedure. A simple normalization procedure is division of regional values by the whole brain mean. This requires the dependence of local activity on global activity to be one of simple proportionality. This is shown not to be the case. Furthermore, a systematic deviation from a proportional relationship across brain regions is demonstrated. Consequently, any normalization must be approached on a pixel-by-pixel basis by measuring the change in local activity and change in global activity. The changes associated with an activation can be partitioned into global and local effects according to two models: one assumes that the increase in local activity depends on global values and the other assumes independence. It is shown that the increase in activity due to a cognitive activation is independent of global activity. This independence of the (activation) condition effect and the confounding linear effect of global activity on observed local activity meet the requirements for an analysis of covariance, with the “nuisance” variable as global activity and the activation condition as the categorical independent variable. These conclusions are based on analysis of data from 24 scans: six conditions over four normal subjects using a verbal fluency paradigm. A technique is described based on ANCOVA and using statistical parametric mapping to localize foci in the brain that have been significantly perturbed by the cognitive tasks. This technique represents a fundamental and necessary departure from ROI-based approaches allowing the separation of global and local effects pixel by pixel, and provides an image of affected regions whose significance can be quantified. The specificity and sensitivity of the described method of change detection is assessed.

Goal attainment scaling is a mathematical technique for quantifying the achievement (or otherwise) of goals set, and it can be used in rehabilitation. Because several different approaches are described in the literature, this article presents a simple practical approach to encourage uniformity in its application. It outlines the process of setting goals appropriately, so that the achievement of each goal can be measured on a 5-point scale ranging from -2 to +2, and then explains a method for quantifying the outcome in a single aggregated goal attainment score. This method gives a numerical T-score which is normally distributed about a mean of 50 (if the goals are achieved precisely) with a standard deviation of around this mean of 10 (if the goals are overachieved or underachieved). If desired, the approach encompasses weighting of goals to reflect the opinion of the patient on the personal importance of the goal and the opinion of the therapist or team on the difficulty of achieving the goal. Some practical tips are offered, as well as a simple spreadsheet (in Microsoft Excel) allowing easy calculation of the T-scores.

The two-syndrome concept postulates two "dimensions of pathology" underlying schizophrenia--a reversible (and potentially neuroleptic-responsive) component and a sometimes progressive and relatively irreversible component associated with the deficit state and poor long-term outcome. Negative symptoms (narrowly defined) appear to be more closely associated with the latter component (the type II syndrome), as also are cognitive impairments, abnormal involuntary movements, and behavioral deterioration. This syndrome is assumed to be more closely related than the type I syndrome of positive symptoms to the structural brain changes inferred from pneumoencephalograms, computed tomography scans, and recent post-mortem studies. However, since both syndromes often occur in the same patient--sometimes at the same point in time--they presumably have the same etiology.

The COVID-19 pandemic is an unprecedented challenge for society. Supporting the mental health of medical staff and affiliated healthcare workers (staff) is a critical part of the public health response. This paper details the effects on staff and addresses some of the organisational, team and individual considerations for supporting staff (pragmatically) during this pandemic. Leaders at all levels of health care organisations will find this a valuable resource.

OBJECTIVE: To determine effectiveness of advice from general practitioners to heavy drinkers to reduce their excessive alcohol consumption (35 U or more a week for men, 21 U or more for women). DESIGN: Randomised, controlled double blind trial over 12 months with interim assessment at six months. SETTING: Group practices (n = 47; list size averaging 10,000) recruited from Medical Research Council's general practice research framework, mostly in rural or small urban settings. PATIENTS: Patients recruited after questionnaire survey. Of total of 2571 (61.2%) of 4203 patients invited for interview who attended, 909 (35.4%) stated that in past seven days they had drunk above the limits set for study and had not received advice; they were randomised to control and treatment groups. INTERVENTIONS: Patients in treatment group were interviewed by general practitioner (who had had a training session) and received advice and information about how to reduce consumption and also given a drinking diary. END POINT: Study aimed at detecting a reduction in proportion of men with excessive alcohol consumption of 30% in treatment group and 20% in control group (for women 40% and 20%, respectively) with a power of 90% at 5% level of significance. In addition, corroborative measures such as estimation of gamma-glutamyltransferase activity were included. MEASUREMENTS AND MAIN RESULTS: At one year a mean reduction in consumption of alcohol of 18.2 (SE 1.5) U/week had occurred in treated men compared with a reduction of 8.1 (1.6) U/week in controls (p less than 0.001). The proportion of men with excessive consumption at interview had dropped by 43.7% in the treatment group compared with 25.5% in controls (p less than 0.001). A mean reduction in weekly consumption of 11.5 (1.6) U occurred in treated women compared with 6.3 (2.0) U in controls (p less than 0.05), with proportionate reductions of excessive drinkers in treatment and control groups of 47.7% and 29.2% respectively. Reduction in consumption increased significantly with number of general practitioner interventions. At one year the mean value for gamma-glutamyltransferase activity had dropped significantly more in treated men (-2.4 (0.9)IU/l) than in controls (+1.1(1.0)IU/l; t = 2.7, p less than 0.01). Reduction in gamma-glutamyltransferase activity tended to increase with number of intervention sessions in men. Changes in gamma-glutamyltransferase activity in women and changes in other indicators in both sexes did not differ significantly between treatment and control groups. CONCLUSIONS: If the results of this study were applied to the United Kingdom intervention by general practitioners could each year reduce to moderate levels the alcohol consumption of some 250000 men and 67500 women who currently drink to excess. General practitioners and other members of the primary health care team should therefore be encouraged to include counselling about alcohol consumption in their preventive activities.

The CNS maintains a fundamental distinction between actions elicited by external stimuli and actions elicited by internal goals (acts of will). As a result the intact organism can monitor centrally three aspects of its own actions: (1) the action appropriate to current external stimulation (stimulus intention or meaning); (2) the action appropriate to current goals (willed intention); and (3) the action which was actually selected (corollary discharge). In Type I (acute) schizophrenic patients, intentions of will lead to actions, but these willed intentions are not monitored correctly. This apparent discrepancy between will and action gives rise to experiential (1st rank) positive symptoms (e.g. delusions of control and passivity). In Type II (chronic) patients, intentions of will are no longer properly formed and so actions are rarely elicited via this route. This gives rise to behavioural negative signs (e.g. poverty of speech). The behaviour of Type II schizophrenics has surface similarities to that shown by patients with Parkinson's disease and patients with frontal lobe lesions in that all three types of patient show a relative deficit of actions elicited by willed intentions. Dopamine blocking drugs reduce positive symptoms in Type I patients precisely because they induce Parkinsonism, i.e. reduce the likelihood of actions being initiated by willed intentions. This in turn reduces the likelihood that actions will occur for which the patient had no awareness of his intention to act.