Ten-year follow-up of two cohorts with an increased risk of variant CJD: donors to individuals who later developed variant CJD and other recipients of these at-risk donors.

BACKGROUND: Transmission of variant Creutzfeldt-Jakob disease (vCJD) through blood transfusion is implicated in three deaths and one asymptomatic infection. Based on this evidence, individuals assessed to be at increased risk of vCJD through donating blood transfused to individuals who later developed vCJD, or through being other recipients of such donors, are followed up to further understand the risks of vCJD transmission through blood. OBJECTIVES: To provide a ten-year follow-up of these at-risk cohorts. METHODS: Blood donors to patients who later died from vCJD were identified by the Transfusion Medicine Epidemiological Review (TMER) study. A reverse risk probability assessment quantified the risk of blood transfusion or exposure through diet as the source of vCJD in the recipients. Donors to these recipients, and these donors' other recipients, with a probability risk above 1%, are classified as at increased risk of vCJD for public health purposes. These cohorts are monitored for any vCJD occurrences. RESULTS: A total of 112 donors and 33 other recipients of their donated blood have been classified as at increased risk. After 2397 and 492 vCJD-free years of follow-up, respectively, no deaths in either at-risk cohort were of vCJD-related causes. CONCLUSIONS: The at-risk cohorts have survived disease-free far longer than the estimated incubation time for dietary-acquired vCJD (donors) and transfusion-acquired disease (other recipients). However, due to our still limited understanding of, and a lack of a reliable test for, asymptomatic vCJD infection, public health follow-up is necessary for continued monitoring of at-risk cohorts.

Non-clinical health services--what do they contribute to patient care and how can we measure their contribution?

BACKGROUND AND AIMS: Assessing the contribution of 'support services' to improving healthcare is challenging. Despite involving a significant part of the NHS budget, there is very little published literature on methods and approaches. This article describes the development of an integrated approach to assessing and measuring the health impact of these services. METHODS AND RESULTS: An empirical approach was developed by the main provider of national support services to NHS Scotland. This involved identifying meaningful ways to describe health impact of services several steps removed from patient care, applying this to the full range of national support services provided by NHS National Services Scotland and developing relevant measurement methodologies. Through this approach it was possible to assess the relative health impact of all 63 NSS services and to use this for planning and prioritisation. CONCLUSION: Assessing the contribution of support services to improving patient outcomes is a neglected area, despite the significant dependency of direct patient care services upon these services and the resource involved. The methods described in this article have potential to be used across the range of support services within the NHS to improve quality and efficiency of healthcare services.

Risk factors for variant Creutzfeldt-Jakob disease in dental practice: a case-control study.

OBJECTIVE: To assess the risk of variant Creutzfeldt-Jakob Disease (vCJD) associated with dental treatment. DESIGN: Case-control study, investigation of links between cases. SETTING: National CJD surveillance, general dental practice and practice boards in Great Britain, 2008-2009. METHODS: Variant CJD cases were recruited from all those referred between May 1995 and August 2009 (n = 160); controls were recruited from the general population in 2003 using randomly selected geographic clusters and age-weighted sampling of individuals (n = 584). Risk factors were ascertained from dental records, with consent, using a structured questionnaire. RESULTS: Dental records were available for fewer cases (49%, 78 out of 160) than control subjects (78%, 457 out of 584). Variant CJD cases were no more or less likely than control subjects to have undergone dental treatment (p ≥0.05). Two cases had attended the same dental practice, but the type and timing of treatments did not provide strong evidence that this was linked to the route of transmission. CONCLUSION: There is no evidence of a vCJD risk associated with dental treatment, but because dental information is limited we cannot exclude this possibility. Improved methods for dental record keeping are recommended to aid future investigations of associations between infectious diseases and dental treatment.

Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia.

SUMMARY: All UK patients with bleeding disorders treated with any UK-sourced pooled factor concentrates between 1980 and 2001 have been informed that they may be at an increased risk of infection with variant Creutzfeldt-Jakob disease (vCJD). We describe a study to detect disease-associated, protease-resistant prion protein (PrP(res)) in 17 neurologically aymptomatic patients with haemophilia considered to be at increased risk of vCJD. Materials from 11 autopsy and seven biopsy cases were analysed for PrP(res). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrP(res) by Western blot analysis. This tissue came from a 73-year-old male patient with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure through diet, surgery, endoscopy, blood transfusion and receipt of UK-sourced plasma products suggest that by far the most likely route of infection in this patient was receipt of UK plasma products.

A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions.

BACKGROUND: To date, four instances of probable transfusion-transmission of variant Creutzfeldt-Jakob disease (vCJD) infection have been described, and surviving recipients of vCJD-implicated blood components have been informed that they may be 'at risk' of vCJD. Nearly two-thirds of all recipients of vCJD-implicated blood components are deceased, and many died before the vCJD risk was known. The primary aim of this study was to determine retrospectively whether there was evidence that any of the other deceased recipients of vCJD-implicated blood components had any clinical signs or symptoms suggestive of vCJD in life. In addition, pathological material from recipients, stored at the time of surgery or autopsy, was sought to allow testing for evidence of vCJD infection. A secondary aim of the study was to obtain information on invasive healthcare procedures undertaken on recipients following the transfusion to identify the potential for onward transmission of infection. METHODS: A retrospective review of medical case notes of deceased recipients of vCJD-implicated blood components was carried out, and relevant information was extracted. In cases undergoing post-mortem, details of the findings were obtained. RESULTS: The medical case notes of 33 (83%) deceased recipients of vCJD-implicated blood components, not already known to be infected with vCJD, were reviewed. The median age of recipients was 68 years (interquartile range 57-79 years). Almost half (16) were male. The median time from transfusion to death was 175 days (interquartile range 43-701 days). Most (66%) recipients died in hospital. None of the recipients had documented evidence of clinical signs or symptoms suggestive of vCJD. Only two recipients, both of whom died within a year of transfusion, underwent autopsy examination. Neither brain nor peripheral lymphoreticular tissue was available from either recipient, and pathological material was unavailable from any of the other deceased recipients. Almost half of all recipients underwent at least one invasive healthcare procedure post-transfusion. CONCLUSIONS: A retrospective review of the medical case notes of the deceased recipients of vCJD-implicated blood components found no evidence that any further cases expressed clinical signs or symptoms suggestive of vCJD during life, but only four of the recipients survived for more than 5 years post-transfusion.

Variant Creutzfeldt-Jakob disease and exposure to fractionated plasma products.

BACKGROUND: The risk to public health of onward transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion and plasma product administration is of on-going concern, particularly with the recent reported detection of abnormal prion protein in a person with haemophilia. OBJECTIVES: To describe the history of fractionated plasma product exposure in clinical cases of vCJD in the UK. METHODS: Through examination of records held at the National CJD Surveillance Unit (from relatives, general practices and hospitals). RESULTS: Nine out of 168 UK vCJD cases had a history of receipt of fractionated plasma products on 12 different occasions (1 pre-vCJD risk in 1970, the remaining between 1989-1998). According to the UK CJD Incident Panel risk assessment criteria, 11 were low-risk products and one was low or medium risk. CONCLUSION: It is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. However, the possibility that such transmission may result in vCJD cases in the future cannot be excluded.

Dental treatment and risk of variant CJD--a case control study.

OBJECTIVE: Knowledge of risk factors for variant CJD (vCJD) remains limited, but transmission of prion proteins via re-useable medical devices, including dental instruments, or enhanced susceptibility following trauma to the oral cavity is a concern. This study aimed to identify whether previous dental treatment is a risk factor for development of vCJD. DESIGN: Case control study. METHODS: Risk factor questionnaires completed by interview with relatives of 130 vCJD patients and with relatives of 66 community and 53 hospital controls were examined by a dental surgeon. Responses regarding dental treatments were analysed. RESULTS: We did not find a statistically significant excess of risk of vCJD associated with dental treatments with the exception of extractions in an unmatched analysis of vCJD cases with community controls (p = 0.02). However, this result may be explained by multiple testing. CONCLUSIONS: This is the first published study to date to examine potential links between vCJD and dental treatment. There was no convincing evidence found of an increased risk of variant CJD associated with reported dental treatment. However, the power of the study is restricted by the number of vCJD cases to date and does not preclude the possibility that some cases have resulted from secondary transmission via dental procedures. Due to the limitations of the data available, more detailed analyses of dental records are required to fully exclude the possibility of transmission via dental treatment.

A case-control study of sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of clustering.

BACKGROUND: The authors investigated whether cases of sporadic Creutzfeldt-Jakob disease (CJD) had lived closer to one another at some time in life than individuals without sporadic CJD. Such a phenomenon would be compatible with some cases resulting from transmission. METHODS: UK sporadic CJD cases occurring from 1990 to 1998 were identified. Age-, sex- and hospital-matched controls were recruited. Lifetime residential histories were obtained by interview, usually with a proxy respondent. With use of Monte Carlo simulation, the residential proximity of cases during various time periods was compared with that expected in the absence of any clustering, using the information collected on the controls. RESULTS: Two hundred twenty sporadic CJD disease cases and 220 controls were included. Cases lived closer together than might be expected in the absence of any disease-clustering mechanism. This evidence became stronger as the critical period during which residential proximity was required to have occurred extended further into the past. CONCLUSIONS: These findings are consistent with some sporadic Creutzfeldt-Jakob disease (CJD) cases resulting from exposure to a common external factor. The rarity of sporadic CJD suggests that repeated point-source outbreaks of infection are more likely to explain our observations than direct case-to-case transmission. Identifying sources of such outbreaks many years after the event will be extremely difficult.

Clinical features of variant Creutzfeldt-Jakob disease.

The possibility that a new form of human prion disease, variant Creutzfeldt-Jakob disease (vCJD) had occurred in the UK was first raised by the identification of a small number of cases with unusual clinical characteristics. Atypical features included a young age at death, a predominantly psychiatric presentation, a relatively extended duration of illness and the absence of the 'typical' periodic electroencephalogram seen in sporadic CJD. Diagnostic criteria for vCJD have now been formulated and partially validated. Magnetic resonance imaging of the brain shows high signal in the posterior thalamus in the great majority of cases and all tested cases to date have been methionine homozygous at codon 129 of the prion protein gene (PRNP). There is a need to try and improve early diagnosis, particularly if effective treatments are developed.

The epidemiology of variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) was identified as a new disease in 1996. It was linked to infection with the bovine spongiform encephalopathy (BSE) agent although the epidemiological evidence for this was not strong, but later strain typing studies confirmed the association. The disease has affected predominantly young adults whose dietary and other characteristics are unexceptional compared to control groups, other than that all patients to date have been methoinine homozygous at codon 129 of the prion protein gene and the incidence has been about two times higher in the North of the UK. The number of cases in the 7 years after first identification of the disease has been considerably lower than initially feared, given the likely widespread exposure of the UK population to the BSE agent through contaminated beef products. Predictions of the possible future course of the epidemic have many associated uncertainties, but current mathematical models suggest that more than a few thousand cases is unlikely. Such modelling is limited by the absence of a test for infection with the vCJD agent. The development of a test that could be used on easily accessible tissue to detect infection early in the incubation period would not only advance understanding of the epidemiology of infection with the agent but would also aid the implementation of control measures to prevent potential iatrogenic spread.

Variant Creutzfeldt-Jakob disease.

Variant CJD is a novel human prion disease that represents the first known occasion in which animal prion diseases have been transmitted to humans. There are many uncertainties concerning vCJD, including the mechanism of transmission between species, the extent of human exposure to the BSE agent, the infectious dose for humans, and the future burden of human disease. It is hoped that continuing scientific research may lead to answers to some of these questions and that further understanding of the mechanism of prion replication may lead to the development of effective treatment. Indeed a recent publication has suggested that the drugs quinacrine or chloropromazine may be candidates for the treatment of human prion diseases [42].

Deaths from variant Creutzfeldt-Jakob disease in the UK.

In 2002, 17 people died from variant CJD (vCJD) in the UK, compared with 20 in 2001 and 28 in 2000. We analysed data for deaths from vCJD since 1995 and estimated the underlying trend in mortality. The trend had a quadratic component (p=0.005), suggesting that the increase was not exponential, and that the previously increasing trend is slowing down. The death rate peaked in 2000. These findings are encouraging, but mortality might increase again in the future.

Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls.

BACKGROUND: The cause of sporadic Creutzfeldt-Jakob disease (CJD) is unknown. Previous studies found a link with a history of surgery but had methodologic problems. OBJECTIVE: To help elucidate medical and associated risk factors for sporadic CJD as part of the 1993 to 1995 European Union collaborative studies of CJD. METHODS: Medical and associated risk factors from 326 patients with sporadic CJD, taken from population-based studies performed between 1993 and 1995 in France, Germany, the Netherlands, and the UK, were compared with 326 community controls recruited by telephone in 2000. RESULTS: A history of surgery was significantly associated with the risk of sporadic CJD (odds ratio [OR]: 1.8; 95% CI: 1.2 to 2.6), which was not dependent on the number of surgical procedures, and was stronger in females (OR: 2.5; 95% CI: 1.5 to 4.0). Gynecologic (OR: 1.5; 95% CI: 1.0 to 2.3) and "other" operations (any operation other than neurologic, eye, ear, gallbladder, gastrointestinal, and gynecologic operations, tonsillectomy, and appendectomy) (OR: 1.5; 95% CI: 1.1 to 2.1) were associated with risk of CJD. Tonsillectomy (OR: 0.3; 95% CI: 0.2 to 0.5) and appendectomy (OR: 0.6; 95% CI: 0.4 to 0.8) were observed less frequently in cases. An increased risk was also found with a history of ear piercing in females (OR: 1.6; 95% CI: 1.1 to 2.5) and psychiatric visit(s) (OR: 2.6; 95% CI: 1.5 to 4.3). CONCLUSIONS: These results support the hypothesis that cases of sporadic CJD may result from hitherto unrecognized surgical contamination events. However, because of the limits of the study design, the rarity of the disease, and the potential for bias, the results should be interpreted with caution.

Cocaine use, hypertension, and end-stage renal disease.

Cocaine use has been associated with both acute renal failure and hypertension (HTN), but only recently have data suggested it may lead to a chronic insidious form of renal failure. We designed a cross-sectional study to compare the association of cocaine use in hemodialysis patients with and without a diagnosis of HTN-related end-stage renal disease (HTN-ESRD). Two hundred one black patients from two outpatient hemodialysis units in an urban community were evaluated. There were 193 eligible patients, 106 men and 87 women, aged 49.28 +/- 14.4 years. A history of significant cocaine use before dialysis was reported by 55 of 193 subjects (28.5%). A diagnosis of HTN-ESRD was reported in 49 of 55 cocaine users (89.1%) compared with 64 of 138 nonusers (46.38%; odds ratio, 9.44; 95% confidence interval, 3.79 to 23.49; P < 0.0005). Of the 113 subjects with HTN-ESRD, 49 subjects (43.4%) had a history of cocaine abuse, either alone or in combination with other drugs. Subjects with HTN-ESRD with cocaine use were younger than those without cocaine use (40.7 +/- 9.0 versus 53.8 +/-15.3 years; P < 0.0005) and had a shorter reported duration of HTN (5.3 +/- 5.4 versus 12.7 +/- 9.8 years; P < 0.0005, adjusted for age and sex). In our urban dialysis population, a clinical diagnosis of HTN-ESRD was strongly associated with a history of cocaine use and earlier onset of ESRD. Cocaine should be considered as a cause of ESRD in patients without a clear cause of renal failure.

A clinic and community-based approach to hypertension control for an underserved minority population: design and methods.

This paper describes the design and methodology of the Community Hypertension Intervention Project (CHIP). CHIP is investigating the environmental and psychosocial factors related to treatment adherence and examining the effects of combining usual hypertension care with the effects of three interventions designed to improve patient compliance with treatment for high blood pressure in a high-risk, underserved minority population. Thirteen hundred and sixty-seven inner-city hypertension patients (75% black and 25% Hispanic) have agreed to participate in the 4-year longitudinal study. These participants were randomized to usual care or one of three intervention groups: individualized counseling sessions; home visits/discussion groups; or computerized appointment-tracking system. Participants are representative of the surrounding, predominantly low-income minority community and are treated in a hospital-based clinic and in a private clinic in the community. About 65% have blood pressure levels considered to be out of control. It was concluded that structural changes at the clinic site, along with the targeted interventions, would improve patient satisfaction, increase treatment adherence, and improve blood pressure control.

Technology evaluation: gene therapy (FGF-5), Vical.

Vical, in collaboration with Merck, is developing gene-based therapies, including its 'naked DNA', for the potential treatment of ischemic heart disease. Vical has obtained preclinical data in animal models showing that a gene for a potent growth factor, FGF-5, can be delivered and expressed in coronary arteries stimulating the formation of new blood vessels. This new blood vessel formation may provide supplemental blood flow and necessary cardiac tissue oxygenation in areas of the heart where atherosclerotic blockages are present. Vical anticipates that its FGF-5 gene-based product would be used in conjunction with balloon angioplasty to stimulate new blood vessel formation at the site of the blockage. A series of experiments have been conducted in rats, whereby genes encoding FGF-5 were injected directly into rat heart muscle. The DNA was absorbed and the FGF-5 protein was expressed by cardiac myocytes. Active FGF-5 was released into the extracellular spaces of the heart muscle cells and new blood vessels formed throughout the local area. Quantitative measurements of blood vessel formation indicated that capillary density increased significantly in the hearts of treated rats compared to untreated controls. Further studies are underway to evaluate the persistence of new blood vessels following FGF-5 gene injection, and measurements will be made to assess the extent of improved blood flow in the affected region [177118]. In December 1996, the US patent office issued patent number US-05580859, covering Vical's naked DNA technology [227199].