English lessons: can publishing an atlas of variation stimulate the discussion on appropriateness of care?

NHS England has published series of atlases to highlight variation in costs, outcomes and intervention rates as part of a large scale transformational program to increase value and close the quality gap in health care. The NHS Atlas of Variation series has stimulated the search for unwarranted variation, an important step in the quest to improve quality and reduce harm. This article describes how the series was conceived, shares some of the lessons of preparing and publishing an atlas of variation, and considers how it can stimulate the discussion on appropriate care.

The 1960s cervical screening incident at National Women's Hospital, Auckland, New Zealand: insights for screening research, policy making, and practice.

BACKGROUND AND OBJECTIVES: This article examines a cervical screening incident from the 1960s and draws lessons for screening policy. STUDY DESIGN AND SETTING: Concern about harmful overtreatment of symptomless lesions prompted university gynecologist Herbert Green to study, between 1965 and 1970, a 'special series' of 33 women with carcinoma in situ (CIS) who were managed with only limited punch or wedge biopsy. These women were carefully followed up but not treated unless they showed evidence of progression to invasive cancer. This paper examines source documents and subsequent publications in order to ascertain lessons from this incident. RESULTS: In keeping with the 1964 Helsinki Declaration, written consent was not sought. Green published the outcomes for his patients with CIS including the 'special series.' A Judicial inquiry (the Cartwright Inquiry) in 1987 concluded that some women had suffered harm and some had died, but numbers and evidence were not clearly stated. Medical case review for the Inquiry identified 25 women with only punch or wedge biopsy; in 21 of these, there were reasons why no further treatment was given; two had developed cervical cancer, and none were recorded as having died. The case review found eight patients, not necessarily in the 'special series,' who 'in retrospect and by 1987 standards' might have benefited from earlier conisation or hysterectomy. CONCLUSION: Subsequent claims relating to Green's practice have wrongly stated that as many as one hundred women or more had treatment withheld and over 30 died as a result. These claims are inaccurate.

Frequency-specific relation between hippocampal theta rhythm, behavior, and amobarbital action.

The frequency of the hippocampal theta rhythm in freely moving rats varies predictably in relation to behavior in a simple learning situation. The theta rhythm may be driven by electrical stimulation of the medial septal area at frequencies within the theta range. The threshold for septal driving is lowest at that frequency which the rat displays in response to frustrative nonreward; the driving threshold is selectively raised at this frequency by sodium amobarbital. It is suggested that the behavioral effects of amobarbital are due to a disruption of the theta frequency normally displayed in response to nonreward.

A simple genetic basis for a complex psychological trait in laboratory mice.

Psychological traits are commonly inferred from covariation in sets of behavioral measures that otherwise appear to have little in common. Emotionality in mice is such a trait, defined here by covariation in activity and defecation in a novel environment and emergence into the open arms of an elevated plus maze. Behavioral and quantitative trait analyses were conducted on four measures obtained from 879 mice from an F2 intercross. Three loci, on murine chromosomes 1, 12, and 15, were mapped that influence emotionality. This trait, inferred from studies of strain, sex, and individual differences in rodents, may be related to human susceptibility to anxiety or neuroticism.

Functional magnetic resonance imaging of synesthesia: activation of V4/V8 by spoken words.

In 'colored-hearing' synesthesia, individuals report color experiences when they hear spoken words. If the synesthetic color experience resembles that of normal color perception, one would predict activation of parts of the visual system specialized for such perception, namely the human 'color center', referred to as either V4 or V8. Using functional magnetic resonance imaging (fMRI), we here locate the region activated by speech in synesthetes to area V4/V8 in the left hemisphere, and demonstrate overlap with V4/V8 activation in normal controls in response to color. No activity was detected in areas V1 or V2, suggesting that activity in primary visual cortex is not necessary for such experience. Control subjects showed no activity in V4/V8 when imagining colors in response to spoken words, despite overtraining on word-color associations similar to those spontaneously reported by synesthetes.

Knowledge-based commissioning.

People who pay for health care aim to maximize value in allocating resources between and within patient groups. With limited health care budgets, new high value innovations will replace, not supplement, lower value interventions. Every society and its health care system must consider the issue of value and be aware that the values of payer, provider, clinician, and patient will always be different. Knowledge, while necessary, is never sufficient when commissioning health care. At times, decision maker's subjective values may outweigh objective evidence.

Better value healthcare--the 21st century agenda.

Health services are faced with increasing cost pressure, and cost-effectiveness is playing a growing role in decision-making in health care. The three elements of decision-making are the evidence available, the values of the population served, and the other needs of the population. There are different types of values: those of patients, clinicians, health service managers, payers of healthcare, and industry. The sharp distinction between traditional functions in healthcare, such as "allocative efficiency" and "technical efficiency", is increasingly being broken down. The effect of this new approach is the rise of programme budgeting, with healthcare resources being allocated to different programmes of care (for example, mental health programmes), making the consequences of moving resources much clearer. Best current evidence about effectiveness and cost-effectiveness is of vital importance in clarifying the opportunities that face people who pay for or manage healthcare.

Muscarinic agonists for senile dementia: past experience and future trends.

Clinical experience with muscarinic agonists in the symptomatic treatment of Alzheimer's disease includes studies of the effects of pilocarpine, arecoline, bethanechol, oxotremorine and RS 86. Although the results are somewhat conflicting, there is evidence that a subgroup of patients may respond with an improvement of cognitive and/or behavioural function. The existing agents tend to induce adverse effects due to the stimulation of peripheral muscarinic receptors. Furthermore they reduce (at least in vitro) acetylcholine release by an action on presynaptic receptors. Strategies to overcome these problems include the development of potent agonists with high blood-brain barrier penetration, the search for agents selective for muscarinic receptor subtypes (using cloned receptors as tools) and the identification of agents acting as presynaptic receptor antagonists, to increase acetylcholine release.

Effects of chromosomal inversion on cell fitness in Escherichia coli K-12.

In an effort to learn what factors might mitigate the establishment of Escherichia coli variants bearing major chromosomal rearrangements, we have examined the effects on cell growth of two inversions between rRNA operons. One of these inversions, IN(rrnD-rrnE), had been propagated in a commonly used subline of E. coli K-12 for approximately 30 yr before its discovery, a fact that illustrates the absence of obvious detrimental effects associated with the inversion. We found that culturing under conditions requiring repeated transition from stationary phase to rapid growth led to the replacement of IN(rrnD-rrnE) cells by cells that had undergone either of two types of additional chromosomal inversion: one type fully restored the wild-type order, while the other partially restored it. The partial reinversion was also between rrn operons, but it left a small transposition. The tendency for overgrowth by these revertants persisted through several rounds of periodic selection. In contrast, the other inversion, IN(rrnG-rrnE), was associated with severe, detrimental effects. The effects of IN(rrnG-rrnE) were also alleviated by full or partial reinversion. The probable relationship between the severity of the effects caused by the inversions and the degree of displacement of the replication origin is discussed. Spontaneous inversion events between rrn operons separated by 18% of the chromosome were estimated to occur at a frequency of roughly 10(-5). If extended to natural situations, the growth disadvantage together with the relatively high frequency of reinversion suggest that clones of cells with an inversion between these rrn operons would be readily overgrown by revertants.

A pre-clinical study showing how dopaminergic drugs administered during pre-exposure can impair or facilitate latent inhibition.

RATIONALE: It has been suggested that, in classical conditioning, dopamine (DA) codes for (a) attention to the conditioned stimulus (CS) or (b) the intensity of the unconditioned stimulus. OBJECTIVES: To clarify the role of DA in pre-clinical classical conditioning studies. METHODS: An existing model of classical conditioning presented by Schmajuk, Lam, and Gray (J Exp Psychol Anim Behav Process 22:321-349, 1996) suggests that DA cells in the ventral midbrain area code for the attentionally modulated internal representation of the CS. It is assumed that this representation is increased by dopaminergic agonists and decreased by dopaminergic antagonists. Computer simulations with the model describe the effect of nicotine and haloperidol on latent inhibition. RESULTS: Simulations replicate experimental results demonstrating that both nicotine and haloperidol affect latent inhibition when administered during the pre-exposure phase. In addition, the model reproduces data showing that administration of nicotine or haloperidol results in the impairment or facilitation of latent inhibition depending on the duration of CS or the number of CSs. CONCLUSIONS: The model demonstrates that pre-clinical experimental results, including cell activity and pharmacological data, are consistent with an attentional role for DA in classical conditioning.

Fulminant hepatitis associated with disulfiram. Report of a case.

Disulfiram is used commonly as reinforcement in the treatment of chronic alcoholism. Although the drug is generally considered safe, there are reports of side effects including psychosis and hepatitis. We report a case of fatal fulminant hepatitis caused by the use of disulfiram in a man with previously normal hepatocellular function.

HIV-1 infection among female commercial sex workers in rural Thailand.

OBJECTIVE: To reconstruct past HIV-1 incidence and identify risk factors for HIV-1 seroconversion among female commercial sex workers in a semi-rural setting in northern Thailand. DESIGN: Retrospective cohort of sex workers attending a sexually transmitted disease (STD) clinic at Mae Chan District Hospital, Chiang Rai Province, Thailand. METHODS: Information included demographic data, HIV-1 antibody testing and STD diagnosis was collected in 821 sex workers attending the STD clinic from 1989 through 1993. HIV-1 incidence among initially HIV-1-seronegative sex workers who underwent repeat HIV-1 antibody testing during follow-up was determined and possible predictive factors for seroconversion including diagnosis of other STD were examined. RESULTS: HIV-1 seroprevalence among 556 sex workers who underwent antibody testing was 52%, rising from 29% at initial test in 1989 to 53-63% for 1990-1993. Among 96 initially HIV-1-negative sex workers who underwent repeat testing, 64 HIV-1 seroconversions occurred, giving an incidence rate of 12.6/100 person months (PM). Incidence increased from 12.0/100 PM for 1989 and 1990 to 17.0/100 PM for 1991, with a subsequent decline to 9.3/100 PM for 1992-1993. The cumulative risk of seroconversion 6 months following initial negative HIV-1 antibody test was 57%. There were higher rates among younger sex workers (14-19 years old) and those from Hilltribes, but only a diagnosis of chancroid was significantly associated with HIV-1 seroconversion (P = 0.014). CONCLUSION: An explosive epidemic of HIV-1 occurred among sex workers in a semi-rural area of northern Thailand from 1989. These HIV-1 incidence estimates, which are among the highest rates of sexual transmission ever reported, highlight the extreme vulnerability of female sex workers to HIV infection, even in a non-urban setting.

PIP: A retrospective study of 821 commercial sex workers attending a sexually transmitted disease (STD) clinic in northern Thailand's Chiang Rai Province from 1989 to 1993 revealed an explosive epidemic of human immunodeficiency virus (HIV). The overall seroprevalence among the 556 women for whom antibody tests were available was 52.3%. However, a dramatic increase in HIV-1 seroprevalence occurred from 1989 (29.3%) to 1990 (54.1%), followed by a leveling off through 1993. Among the 96 (36.2%) initial seronegatives who underwent subsequent testing, 64 seroconverted over a mean follow-up period of 5.9 months, yielding an incidence rate of 12.6/100 person-months. Incidence increased from 12.0/100 person-months in 1989 and 1990 to 17.0/100 person-months for 1991, and then declined to 9.3/100 person-months in 1992-93. The cumulative risk of seroconversion was 57% at 6 months after initial testing and 77% after 12 months. Diagnosis of chancroid during follow up was the only factor significantly associated with seroconversion. Although the retrospective nature of this study limits analysis of predictors of HIV infection in this population, the findings suggest a need for improved STD management.

Comparison between the behavioural effects of septal and hippocampal lesions: a review.

The literature on the behavioural effects of septal and hippocampal lesions is classified according to behavioural paradigm. The effects of the two kinds of lesion are summarized and compared to each other. A 'septo-hippocampal syndrome,' consisting of the effects common to both lesions, is delineated, and divergences between the effects of the two lesions are noted.

Loss of the Kamin blocking effect in acute but not chronic schizophrenics.

Differences between research diagnostic criteria (RDC)-diagnosed acute and chronic schizophrenics and normal controls were studied using a Kamin blocking procedure. Blocking is an established animal learning procedure, thought by some researchers to reflect selective attention; decreased blocking indicates increased processing of irrelevant stimuli. It was predicted that this pattern would be obtained in acute schizophrenics, tested soon after admission, for two reasons: (1) evidence from previous clinical studies indicates that acute schizophrenics are more aware of nonsalient aspects of their environment than controls; and (2) blocking is disrupted in animals in a hyperdopaminergic state and restored by neuroleptic medication. This was the case: acute, but not chronic, schizophrenics showed disrupted blocking. This disruption was especially clear in those acute schizophrenics tested within 2 weeks of hospital admission. By the second test session (in a cross-over design), there was some evidence of normalization in performance in the acute schizophrenics. These findings are considered with regard to the dopamine hypothesis of schizophrenia.

Antipyrine kinetics in liver disease and liver transplantation.

Antipyrine kinetics were studied in seven normal subjects, 10 patients with liver disease, and 13 clinically stable patients who received a liver transplant. Five patients were studied both before and after liver transplantation. Antipyrine concentrations in saliva after oral dosing were measured by HPLC. The antipyrine t1/2 was significantly longer (P less than 0.05) in patients with liver disease than in patients undergoing liver transplantation and normal subjects. Antipyrine clearance was not significantly different between patients undergoing liver transplantation and normal subjects, but it was significantly reduced (P less than 0.05) in patients with liver disease. In five patients who were studied before and after liver transplantation, there was a significant (P less than 0.05) increase in the antipyrine clearance and a marked reduction in its t1/2 after liver transplantation. These results indicate that liver transplantation improves the drug metabolizing ability of patients with liver disease and that the oxidative metabolizing capacity of the liver in clinically stable patients after liver transplantation is similar to that of normal subjects.

Enhanced startle reactions to acoustic stimuli in patients with obsessive-compulsive disorder.

OBJECTIVE: Anxiety states induced experimentally or occurring naturally potentiate the startle reflex elicited by sudden sensory stimuli in both animals and human beings. The authors investigated whether patients with obsessive-compulsive disorder (OCD) show exaggerated startle reactions to acoustic probes, especially during negative-affect-toned stimuli, compared with healthy subjects. METHOD: Ten patients with OCD and 10 age- and sex-matched comparison subjects were shown a series of film clips. Two of the film clips had positive valence, two had negative valence, and two had relatively neutral valence. The subjects' eyeblink startle response was measured in reaction to startle-eliciting stimuli presented three times binaurally during each film clip. RESULTS: Patients with OCD produced larger startle reflexes and shorter latencies to onset of startle response than the comparison subjects over the entire session. CONCLUSIONS: Patients with OCD were excessively responsive to startle-eliciting stimuli. This effect may be associated with the development or maintenance of OCD.

Dopamine release in the nucleus accumbens: the perspective from aberrations of consciousness in schizophrenia.

Studies of the cognitive abnormalities that underlie positive symptoms in acute schizophrenia, and animal experiments that attempt to model similar cognitive abnormalities and to elucidate the brain mechanisms underlying them, suggest that the release of dopamine from A 10 terminals in the nucleus (n.) accumbens, in interaction with the projection to n. accumbens from the retrohippocampal region, is closely related to stimulus salience and perhaps to the heightened states of awareness reported by schizophrenics.