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Biomedical subjects

R Booy

Publications and source records attributed to R Booy.

At least 19 recordsLinked to original sources
PubMed2000

The new system of review by multicentre research ethics committees: prospective study.

OBJECTIVE: To assess the function of the new system of review by multicentre research ethics committees and to highlight areas where improvement is still needed. DESIGN: Prospectively collected data from a multicentre study was examined with respect to the ethics review process. Administrative, financial, and time elements of the review process were audited. SETTING: A single multicentre research ethics committee and 125 local ethics committees from six regions of England. MAIN OUTCOME MEASURES: Time to reply, time to approval, and number of non-local changes to the application requested. RESULTS: Only 40% of local ethics committees considered our study in the manner specified in the 1998 directive. Less than a third of committees replied within the 21 day period stipulated, although committees acting by executive subcommittee replied more quickly than those not acting by executive subcommittee. There was a tendency for executive subcommittees to approve studies in a shorter time. Local ethics committees asked for a large number of non-local changes to the application. The financial cost of applying to multiple ethics committees remains high, mainly because multiple copies of research applications are being requested. CONCLUSIONS: The new system of approval by multicentre research ethics committee for multicentre studies was introduced to reduce administrative costs, speed up the process of reviews by multiple research ethics committees, and standardise the conclusions of the local research ethics committees. Since its introduction an improvement has been seen, but the system is not yet universally functioning as intended. Ethics review still remains a hindrance to the financial resources and commencement of national studies. We strongly support the structure of review by multicentre research ethics committees but suggest that the system has yet to achieve its aims.

Costs and Cost Analysis↗
PubMed1999

4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group.

BACKGROUND: Intravascular coagulation with infarction of skin, digits, and limbs is a characteristic feature of meningococcal sepsis. Children with meningococcal sepsis have higher than normal concentrations of plasminogen activator inhibitor 1 (PAI-1) in plasma. Combined with the widespread venous thrombosis, this finding suggests an impairment of fibrinolysis. A common functional insertion/deletion (4G/5G) polymorphism exists in the promoter region of the PAI-1 gene. We tested the hypothesis that children with the 4G/4G genotype produce higher concentrations of PAI-1, develop more severe coagulopathy, and are at greater risk of death during meningococcal sepsis. METHODS: The relation between meningococcal disease outcome, PAI-1 concentration, and PAI-1 genotype was investigated in 175 children with meningococcal disease (37 from Rotterdam, the Netherlands, and 138 from London, UK) and 226 controls (137 from Rotterdam, 89 from London). PAI-1 concentrations in plasma were measured by ELISA, and the 4G/5G PAI-1 polymorphism was detected by PCR and hybridisation. FINDINGS: Concentrations of PAI-1 on admission correlated with presentation (sepsis or meningitis) and outcome. The median PAI-1 concentration in children who died was substantially higher than that in survivors (2448 [IQR 1115-3191] vs 370 [146-914] ng/mL; p<0.0001). Patients with the 4G/4G genotype had significantly higher PAI-1 concentrations than those with the 4G/5G or 5G/5G genotype (1051 [550-2440] vs 436 [198-1225] ng/mL; p=0.03), and had an increased risk of death (relative risk 2.0 [1.0-3.8] for the two cohorts combined, and 4.8 [1.8-13] for the London cohort). INTERPRETATION: A genetic predisposition to produce high concentrations of PAI-1 is associated with poor outcome of meningococcal sepsis. This finding suggests that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis.

Adolescent↗
PubMed1999

Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease. Meningococcal Research Group.

BACKGROUND: The reasons why meningococcal disease develops in only a small proportion of individuals carrying the causative bacteria are unknown. Differences in host responses to bacterial colonisation are thought to be involved, since people with deficiencies in the terminal components of the complement pathway, or of properdin, are susceptible to meningococcal disease. We postulate that genetic variants of mannose-binding lectin (MBL), a plasma opsonin that initiates another pathway of complement activation, might similarly cause susceptibility to meningococcal disease. METHODS: The frequency of variants of the MBL gene was ascertained in children with meningococcal disease and controls from two independent studies; one hospital-based (194 patients and 272 controls [patients with non-infectious disorders]), and one community-based (72 patients and 110 controls [healthy individuals]), by means of PCR and restriction-enzyme digestion, with confirmation by DNA sequencing. FINDINGS: The proportion of people homozygous for MBL-variant alleles was higher in patients with meningococcal disease than in controls in the hospital study (15 [7.7%] vs four [1.5%]; odds ratio 6.5 [95% CI 2.0-27.2]) and in the community study (six [8.3%] vs three [2.7%]; 4.5 [0.9-29.1]). The population attributable fraction of cases attributable to MBL variants (homozygous and heterozygous) was 32%. INTERPRETATION: The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.

Adolescent↗
PubMed1999

Pasteurella multocida meningitis in infancy - (a lick may be as bad as a bite).

UNLABELLED: Pasteurella multocida is the commonest cause of local infection after an animal bite, but is an unusual cause of meningitis. We report a case of P. multocida meningitis occurring in a 7-week-old infant which was contracted after non-traumatic contact with a household pet, that is, without any animal bite or scratch. The organism may be easily confused with more common Gram-negative pathogens. In this case, it was initially incorrectly diagnosed as Haemophilus influenzae type b (Hib); a possibility which has important implications in the era of routine use of Hib vaccine in infant immunisation programs. CONCLUSION: Pasteurella multocida is an unusual, but serious cause of meningitis in infancy. It is potentially preventable by the avoidance of contact between young infants and the saliva of household pets, in particular by assiduous hand hygiene.

Animals↗
PubMed1999

Carbamazepine hypersensitivity and the use of lymphocyte proliferation responses.

This report describes a case of multisystem failure in a 5-year-old boy who was being treated with carbamazepine for a seizure disorder. Carbamazepine hypersensitivity was diagnosed from the combination of the clinical constellation and the results of the patient's peripheral blood monocyte proliferation responses to both carbamazepine and a panel of other medications.

Anticonvulsants↗
PubMed1999

Effect of the Factor V Leiden mutation on the severity of meningococcal disease.

BACKGROUND: One of the most serious complications of meningococcal disease is the syndrome of purpura fulminans, which is characterized by intravascular thrombosis and hemorrhagic infarction of skin, limbs and digits. The reasons why some patients with meningococcal disease develop purpura fulminans while others have minimal thrombotic and skin involvement despite having profound septic shock are not yet understood. The Factor V Leiden mutation (FV(L)) is associated with thrombotic events, and we hypothesized that children carrying FV(L) who develop meningococcal disease may be at increased risk of purpura fulminans. METHODS: We determined the FV(L) genotype by PCR and restriction enzyme digestion (Mnl1) in 259 children with meningococcal disease and 80 healthy controls. In addition 79 parents of children with fatal meningococcal disease were studied. RESULTS: There was no significant increase in the frequency of FV(L) in patients with meningococcal disease (10%) as compared with healthy controls (9%) or with the parents of children who died of meningococcal disease (12%). Although the mortality was not increased in patients heterozygous for FV(L), they had increased complications of purpura fulminans, as assessed by requirement for skin grafting, referral to plastic surgeon and/or amputation. Among survivors 5 of 24 (21%) of those heterozygous for FV(L) had complications, compared with 14 of 233 (7%) who were wild type [P < 0.03; relative risk, 3.1 (95% confidence intervals, 1.2 to 7.9)]. CONCLUSIONS: FV(L) exacerbates purpura fulminans in meningococcal disease but does not have a significant effect on mortality.

Child↗
PubMed1999

Humoral immune responses to Neisseria meningitidis in children.

An understanding of the nature of immunity to serogroup B meningococci in childhood is necessary in order to establish the reasons for poor responses to candidate vaccines in infancy. We sought to examine the nature of humoral immune responses following infection in relation to age. Serum bactericidal activity was poor in children under 12 months of age despite recent infection with Neisseria meningitidis. The highest levels of bactericidal activity were seen in children over 10 years of age. However, infants produced levels of total immunoglobulin G (IgG) and IgG subclass antibodies similar to those in older children in a meningococcal enzyme-linked immunosorbent assay. Most antibody was of the IgG1 and IgG3 subclasses. This striking age dependency of bactericidal antibody response following infection is not apparently due to failure of class switching in infants but might be due to qualitative differences in antibody specificity or affinity.

Adult↗
PubMed1999

Cellular immune responses to Neisseria meningitidis in children.

There is an urgent need for effective vaccines against serogroup B Neisseria meningitidis. Current experimental vaccines based on the outer membrane proteins (OMPs) of this organism provide a measure of protection in older children but have been ineffective in infants. We postulated that the inability of OMP vaccines to protect infants might be due to age-dependent defects in cellular immunity. We measured proliferation and in vitro production of gamma interferon (IFN-gamma), tumor necrosis factor alpha, and interleukin-10 (IL-10) in response to meningococcal antigens by peripheral blood mononuclear cells (PBMCs) from children convalescing from meningococcal disease and from controls. After meningococcal infection, the balance of cytokine production by PBMCs from the youngest children was skewed towards a TH1 response (low IL-10/IFN-gamma ratio), while older children produced more TH2 cytokine (higher IL-10/IFN-gamma ratio). There was a trend to higher proliferative responses by PBMCs from older children. These responses were not influenced by the presence or subtype of class 1 (PorA) OMP or by the presence of class 2/3 (PorB) or class 4 OMP. Even young infants might be expected to develop adequate cellular immune responses to serogroup B N. meningitidis vaccines if a vaccine preparation can be formulated to mimic the immune stimulus of invasive disease, which may include stimulation of TH2 cytokine production.

Adult↗
PubMed1999

Pertussis is increasing in unimmunized infants: is a change in policy needed?

The proportion and trend in absolute number of pertussis notifications in young infants has increased each year in England and Wales since the accelerated immunization schedule was introduced. We report five infants all less than 3 months of age admitted with life threatening pertussis infection to two paediatric intensive care units. Despite aggressive cardiorespiratory support measures, three of the infants died. Pertussis remains a significant cause of morbidity and mortality in unimmunized infants. In this age group presentation is likely to be atypical and infection more severe. Public health measures to prevent the disease could be strengthened. Chemoprophylaxis should be offered to susceptible contacts and booster vaccinations against pertussis considered.

Age of Onset↗
PubMed1998

Bacterial meningitis and meningococcal infection.

Now that invasive disease caused by Haemophilus influenzae type b has been largely controlled in the developed world, the principal bacterial pathogen causing meningitis in most countries is the meningococcus. Serogroup B and C strains predominate in most industrialised countries in contrast to the situation in sub-Saharan Africa, where serogroup A meningococcal disease is periodically a problem of massive epidemic proportions. This review focuses on developments in our understanding of the diagnosis and treatment of meningococcal disease, of host factors important in susceptibility to, and severity of, this infection, and on advances which may eventually lead to its prevention.

Child↗
PubMed1998

Avoidable deficiencies in the delivery of health care to children with meningococcal disease.

OBJECTIVES: It is apparent that delays and inadequate or inappropriate management occur frequently and may contribute to the continued high mortality seen in meningococcal disease. An attempt has been made to define the major sources of delay or inappropriate treatment. METHODS: A prospective, descriptive study of children with meningococcal disease referred to a tertiary centre paediatric intensive care and infectious disease unit. Definitions of optimal care were established at three stages: parental; general practitioner (GP)/accident and emergency (A&E) department; and hospital. Duration of symptoms and management were recorded from direct questioning of parents and carers, and from hospital records. RESULTS: 54 consecutive children with meningococcal disease were recruited to the study. Delayed parental recognition occurred in 16 children. GPs correctly diagnosed 19 of 35 children. Delay of 2.5-21 hours occurred in those who were incorrectly diagnosed. Two of 15 children who presented to the A&E department with specific features were incorrectly diagnosed. Hospital treatment was suboptimal in 71%. Shock was not recognised or treated in 50%, 20% of children had unnecessary lumbar punctures. Time from illness onset to treatment was longer in fatal disease (median 18.3, range 8-24 hours), compared with survivors (median 12, range 2-48 hours; p < 0.01, Mann-Whitney U test). CONCLUSION: Suboptimal treatment in meningococcal disease is due to failure of parents, GPs, and hospital doctors to recognise specific features of the illness. Improvement by public education and better training of clinicians in recognition, resuscitation, and stabilisation of seriously ill children.

Adolescent↗
PubMed1997

Vaccine failures after primary immunisation with Haemophilus influenzae type-b conjugate vaccine without booster.

BACKGROUND: Diseases of early childhood associated with Haemophilus influenzae type b (Hib) can now be prevented by vaccination. The rapid implementation of routine infant vaccination with Hib polysaccharide-tetanus protein conjugate (PRP-T) vaccine has allowed us to assess whether an accelerated 2, 3, and 4 month schedule can protect in the longer term without a booster dose and whether carrier priming influences protective efficacy. The degree of protection afforded by a catch-up programme with Hib oligosaccharide conjugate (HbOC) for older children was also assessed. METHODS: Paediatricians and microbiologists in the UK were asked to report all cases of invasive H influenzae infection in children who had received at least one dose of Hib-conjugate vaccine. Serum samples from convalescent children were obtained and the isolate was verified. Efficacy was estimated by comparing observed rates of Hib disease in those who had been vaccinated with rates predicted by age adjustment of disease rates from the prevaccine era. FINDINGS: Of 164 reports of invasive infection between Oct 1, 1992, and Oct 1, 1995, 43 were considered true vaccine failures. The estimated overall efficacy for three doses of PRP-T was 98.1% (95% CI 97.3-98.7%). Efficacy in infants aged 5-11 months was 99.1%, 12-23 months 97.3%, and 24-35 months 94.7%. In infants aged 3-11 months, who received their first dose of PRP-T after tetanus toxoid vaccination, disease was unlikely from 1 week after one dose of PRP-T vaccine (88.6% protection in the second to fourth weeks [66.8-97.7%]). The disease rate in vaccinated infants aged 2 months has declined year on year. In children aged 13 months to 2 years given HbOC, as a catch-up vaccine, the estimated efficacy was 94.0% (84.7-98.4%). INTERPRETATION: A high degree of efficacy has been observed with PRP-T vaccine given as a three-dose schedule in infancy and with HbOC as a single dose in older children. Efficacy of PRP-T appears to be enhanced by carrier priming. Although with increasing age there was a small decline in efficacy of PRP-T, Hib disease is now close to being eliminated in the UK, and we suggest that a booster is not necessary in the second year of life.

Age Factors↗