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Biomedical subjects

T E Peto

Publications and source records attributed to T E Peto.

At least 19 recordsLinked to original sources
PubMed2003

Invasive pneumococcal disease in Oxford, 1985-2001: a retrospective case series.

AIMS: To describe a series of children with invasive pneumococcal disease (IPD). METHODS: A review of patient records for children aged 0-18 years admitted to the John Radcliffe Hospital with IPD from 1985 to 2001. Social deprivation was measured by the Jarman index. The proportion of children with congenital abnormalities was compared with national data. RESULTS: We identified 140 children with IPD; complete data were available for 136 children. The median age at diagnosis was 1.5 years. The social deprivation score of households of children with IPD was higher than that of the average Oxfordshire household (-2.5 v -7.3, p < 0.001). Forty four per cent of cases had at least one preceding health problem. The children with preceding health problems were significantly older than those with no preceding problems (median age 2.67 years, interquartile range 1.21 to 6.20 versus 1.11 years, interquartile range 0.51 to 2.21; p < 0.001). There was an increased risk of IPD for children with central nervous system malformations (OR = 99, 95% CI 31 to 236), congenital heart disease (OR = 62, 95% CI 24 to 131), and chromosomal abnormalities (OR = 32, 95% CI 6.6 to 96). CONCLUSIONS: There is an increased risk of IPD associated with increased social deprivation; and also with central nervous system malformations, congenital heart disease, and chromosomal abnormalities.

Adolescent↗
PubMed2001

Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia.

Chronic hyperbilirubinaemia, gallstone formation, and gall bladder disease are unusually common in people with haemoglobin E beta thalassaemia in Sri Lanka. To determine whether this has a genetic basis we compared the bilirubin levels and frequency of gallstones in patients with different alleles of the UGT*1 gene. There was a significantly higher bilirubin level in those with the 7/7 genotypes compared with 6/6 and 6/7 genotype (p=0.032 and 0.0015 respectively), who also appeared more prone to gallstone formation. These results suggest that the UGT*1 genotpe is of importance in the genesis of gallstones in this population of patients.

Alleles↗
PubMed2000

Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group.

BACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in the future, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.

Adult↗
PubMed2000

Epidemiological studies of large resistance plasmids in Haemophilus.

The distribution of large conjugative Haemophilus influenzae plasmids in the nasopharyngeal haemophili of a group of people and in a large collection of 541 H. influenzae type b (Hib) isolates was studied. A newly developed PCR-based assay was used to detect the plasmids. The target sequences were chosen from sequence analysis of part of p1056, a large multiresistance plasmid isolated from a clinical Hib isolate, 1056. Fifty-nine per cent of people were found to carry beta-lactamase-positive (beta-lac(+)), ampicillin-resistant (ampR) haemophili with detectable plasmid sequences. Of these, 83% were in Haemophilus parainfluenzae and 17% were in H. influenzae. In the collection of 541 Hib, antibiotic resistance [beta-lac(+)ampR, beta-lac(+)ampR plus tetracycline resistance (tetR) or tetR] was highly correlated with large plasmids. It was found that 2.3% of the isolates contained large cryptic plasmids (i.e. these isolates were susceptible to antibiotics). The distribution of plasmids between invasive and carried Hib did not differ significantly (25 of 245 and 23 of 276, respectively). Isolates with large plasmids occur at high frequency in the nasopharynx of the normal human population and consist of two populations in Hib, one associated with specific antibiotic resistance traits and the other cryptic. These plasmids do not appear to influence the invasiveness of Hib.

Adult↗
PubMed1999

Prevention of cerebral malaria in children in Papua New Guinea by southeast Asian ovalocytosis band 3.

Southeast Asian ovalocytosis (SAO) occurs at high frequency in malarious regions of the western Pacific and may afford a survival advantage against malaria. It is caused by a deletion of the erythrocyte membrane band 3 gene and the band 3 protein mediates the cytoadherence of parasitized erythrocytes in vitro. The SAO band 3 variant may prevent cerebral malaria but it exacerbates malaria anemia and may also increase acidosis, a major determinant of mortality in malaria. We undertook a case-control study of children admitted to hospital in a malarious region of Papua New Guinea. The SAO band 3, detected by the polymerase chain reaction, was present in 0 of 68 children with cerebral malaria compared with six (8.8%) of 68 matched community controls (odds ratio = 0, 95% confidence interval = 0-0.85). Median hemoglobin levels were 1.2 g/dl lower in malaria cases with SAO than in controls (P = 0.035) but acidosis was not affected. The remarkable protection that SAO band 3 affords against cerebral malaria may offer a valuable approach to a better understanding of the mechanisms of adherence of parasitized erythrocytes to vascular endothelium, and thus of the pathogenesis of cerebral malaria.

Animals↗
PubMed1999

Reduced soluble transferrin receptor concentrations in acute malaria in Vanuatu.

Soluble transferrin receptor (sTfR) concentration is a sensitive index of iron deficiency when used in conjunction with ferritin measurements in adults. One advantage of this assay is that unlike ferritin it does not appear to be affected by a range of infectious and inflammatory conditions or by pregnancy, rendering it a promising adjunct to the diagnosis of iron deficiency in tropical populations. We have measured plasma sTfR concentrations in a group of malaria patients (n = 21) and asymptomatic (18) and aparasitemic (76) controls in Vanuatu. Plasma sTfR concentration was significantly reduced in individuals with acute malaria (P = 0.003). While this observation provides evidence that erythropoeitic suppression may be an important etiologic component in malarial anemia, it also suggests that malaria may be a confounding factor when interpreting sTfR concentrations in such populations. The role of sTfR in the diagnosis of iron deficiency in tropical populations remains to be established.

Adolescent↗
PubMed1998

Markers of HIV infection in the Concorde trial. Concorde Co-ordinating Committee.

The Concorde trial compared immediate (Imm) with deferred (Def) AZT monotherapy in asymptomatic HIV-positive participants. Haematological and immunological markers and weight were measured throughout, and correlated with clinical endpoints. Markers associated with disease progression (CD4 lymphocyte count and percentage, platelets, p24 antigen and beta 2 microglobulin favoured Imm: those associated with toxicity (haemoglobin, neutrophils and white cell count) favoured Def. CD8 and total lymphocyte count did not differ significantly between groups. In multivariate analysis, the combination of baseline CD4, p24 antigen and beta 2m was the best baseline predictor of disease. Including change in CD4 and beta 2m at 12 weeks, or changes over follow-up in these markers significantly improved the fit. Markers were also incorporated into the definition of 'clinical' endpoints. Hazard ratio estimates from end-points that included CD4 < 50 and CD4 < 25 were closest to those for AIDS or death alone, but added very few extra events. Use of other landmark CD4 counts (100 or greater) or relative decreases in counts (25% or more) increased the number of events, but overestimated the effect of immediate AZT. Although AZT had a beneficial effect on the surrogate markers of efficacy evaluated, these changes did not predict clinical outcome, nor could the markers be usefully incorporated into an endpoint definition.

Anti-HIV Agents↗
PubMed1998

Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group.

A prospective study was performed to establish criteria for the microbiological diagnosis of prosthetic joint infection at elective revision arthroplasty. Patients were treated in a multidisciplinary unit dedicated to the management and study of musculoskeletal infection. Standard multiple samples of periprosthetic tissue were obtained at surgery, Gram stained, and cultured by direct and enrichment methods. With reference to histology as the criterion standard, sensitivities, specificities, and likelihood ratios (LRs) were calculated by using different cutoffs for the diagnosis of infection. We performed revisions on 334 patients over a 17-month period, of whom 297 were evaluable. The remaining 37 were excluded because histology results were unavailable or could not be interpreted due to underlying inflammatory joint disease. There were 41 infections, with only 65% of all samples sent from infected patients being culture positive, suggesting low numbers of bacteria in the samples taken. The isolation of an indistinguishable microorganism from three or more independent specimens was highly predictive of infection (sensitivity, 65%; specificity, 99.6%; LR, 168.6), while Gram staining was less useful (sensitivity, 12%; specificity, 98%; LR, 10). A simple mathematical model was developed to predict the performance of the diagnostic test. We recommend that five or six specimens be sent, that the cutoff for a definite diagnosis of infection be three or more operative specimens that yield an indistinguishable organism, and that because of its low level of sensitivity, Gram staining should be abandoned as a diagnostic tool at elective revision arthroplasty.

Arthroplasty, Replacement, Hip↗
PubMed1997

alpha+-Thalassemia protects children against disease caused by other infections as well as malaria.

In the South West Pacific region, the striking geographical correlation between the frequency of alpha+-thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy provides a selective advantage against malaria. In Vanuatu, paradoxically, alpha+-thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and alpha+-thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in alpha+-thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0. 36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0. 38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of alpha+-thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.

Child↗
PubMed1997

Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results.

BACKGROUND: Standard laboratory techniques, such as viral culture and serology, provide only circumstantial or retrospective evidence of viral infections of the central nervous system (CNS). We assessed the diagnostic accuracy of PCR of cerebrospinal fluid (CSF) in the diagnosis of viral infections of the CNS. METHODS: We examined all the CSF samples that were received at our diagnostic virology laboratory between May, 1994, and May, 1996, by nested PCR for viruses associated with CNS infections in the UK. We collected clinical and laboratory data for 410 patients from Oxford city hospitals (the Oxford cohort) whose CSF was examined between May, 1994, and May, 1995. These patients were classified according to the likelihood of a viral infection of the CNS. We used stratified logistic regression analysis to identify the clinical factors independently associated with a positive PCR result. We calculated likelihood ratios to estimate the clinical usefulness of PCR amplification of CSF. FINDINGS: We tested 2233 consecutive CSF samples from 2162 patients. A positive PCR result was obtained in 143 patients, including 22 from the Oxford cohort. Logistic regression analysis of the Oxford cohort showed that fever, a virus-specific rash, and a CSF white-cell count of 5/microL or more were independent predictors of a positive PCR result. The likelihood ratio for a definite diagnosis of viral infection of the CNS in a patient with a positive PCR result, relative to a negative PCR result, was 88.2 (95% CI 20.6-378). The likelihood ratio for a possible diagnosis of viral infection of the CNS in a patient with a negative PCR result, relative to a positive PCR result, was 0.10 (0.03-0.39). INTERPRETATION: A patient with a positive PCR result was 88 times as likely to have a definite diagnosis of viral infection of the CNS as a patient with a negative PCR result. A negative PCR result can be used with moderate confidence to rule out a diagnosis of viral infection of the CNS. We believe that PCR will become the first-line diagnostic test for viral meningitis and encephalitis.

Adolescent↗
PubMed1997

Plasmodium vivax: a cause of malnutrition in young children.

We studied the aetiology of malnutrition in a cohort of 1511 children < 10 years old in Espiritu Santo, Vanuatu. Malnutrition was categorized using standard anthropometric criteria as: underweight [weight-for-age (WA) Z score < -2], wasting [weight-for-height (WH) Z < -2], or stunting [height-for-age (HA) Z < -2]. On multiple logistic regression analysis, the only factors significantly associated with wasting were age < 5 years [OR (95% CI) 1.8 (1.2-2.9), p = 0.01] and having suffered one or more episodes of clinical P. vivax malaria in the 6 months preceding nutritional assessment [OR 2.4 (1.3-4.4), p = 0.006]. The incidence of P. vivax infection was significantly higher during the 6 months preceding assessment in underweight vs. non-underweight children [incidence rate ratio (IRR) 2.6 (1.5-4.4), p < or = 0.0001). These groups had similar incidences of clinical P. falciparum infection during the same period [IRR 1.1 (0.57-2.1) p = 0.8] and of either species during the 6 months following assessment [IRR P. vivax 1.3 (0.9-2.0) p = 0.2; IRR P. falciparum 1.3 (0.9-1.9) p = 0.2]. In these children, P. vivax malaria was a major predictor of acute malnutrition; P. falciparum was not. Wasting neither predisposed to nor protected against malaria of either species. Although P. vivax malaria is generally regarded as benign, it may produce considerable global mortality through malnutrition.

Age Factors↗
PubMed1996

High incidence of malaria in alpha-thalassaemic children.

The alpha+-thalassaemias are the commonest known human genetic disorders, affecting up to 80 per cent of some populations. Although there is good evidence from both epidemiological and clinical studies that these gene frequencies reflect selection by, and protection from, malaria, the mechanism is unknown. We have studied the epidemiology of malaria in childhood on the southwestern Pacific island of Espiritu Santo in Vanuatu and here we report that, paradoxically, both the incidence of uncomplicated malaria and the prevalence of splenomegaly, an index of malaria infection, are significantly higher in young children with alpha+-thalassaemia than in normal children. Furthermore, this effect is most marked in the youngest children and for the non-lethal parasite Plasmodium vivax. The alpha+-thalassaemias may have been selected for their ability beneficially to increase susceptibility to P. vivax, which, by acting as a natural vaccine in this community, induces limited cross-species protection against subsequent severe P. falciparum malaria.

Animals↗
PubMed1996

A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria.

BACKGROUND: Artemisinin (qinghaosu) and its derivatives are rapidly effective antimalarial drugs derived from a Chinese plant. Preliminary studies suggest that these drugs may be more effective than quinine in the treatment of severe malaria. We studied artemether in Vietnam, where Plasmodium falciparum has reduced sensitivity to quinine. METHODS: We conducted a randomized, double-blind trial in 560 adults with severe falciparum malaria. Two hundred seventy-six received intramuscular quinine dihydrochloride (20 mg per kilogram of body weight followed by 10 mg per kilogram every eight hours), and 284 received intramuscular artemether (4 mg per kilogram followed by 2 mg per kilogram every eight hours). Both drugs were given for a minimum of 72 hours. RESULTS: There were 36 deaths in the artemether group (13 percent) and 47 in the quinine group (17 percent; P = 0.16; relative risk of death in the patients given artemether, 0.74; 95 percent confidence interval, 0.5 to 1.11). The parasites were cleared more quickly from the blood in the artemether group (mean, 72 vs. 90 hours; P < 0.001); however, in this group fever resolved more slowly (127 vs. 90 hours, P < 0.001), the time to recovery from coma was longer (66 vs. 48 hours, P = 0.003), and the hospitalization was longer (288 vs. 240 hours, P = 0.005). Quinine treatment was associated with a higher risk of hypoglycemia (relative risk, 2.7; 95 percent confidence interval, 1.7 to 4.4; P < 0.001), but there were no other serious side effects in either group. CONCLUSIONS: Artemether is a satisfactory alternative to quinine for the treatment of severe malaria in adults.

Adolescent↗
PubMed1996

Red blood cell phenotypes in the alpha + thalassaemias from early childhood to maturity.

The alpha+ thalassaemias are the most common single gene disorders of humans, yet little is known about their haematological characteristics in childhood. Blood samples have been collected randomly from more than 2000 individuals in village communities in Vanuatu in the South West Pacific and analysed for alpha thalassaemia and associated haematological changes. Here we describe the haematological effects of the alpha+ thalassaemias from early childhood through to maturity in this population. Mean cell volume (MCV) and mean cell haemoglobin (MCH) levels in individuals of normal, heterozygous and homozygous genotype differed significantly from one another throughout the entire age range (2P < 0.05). In contrast, haemoglobin levels in heterozygous and homozygous individuals were well maintained throughout development. Adults of normal genotype attain Hb levels which are indistinguishable from Caucasian reference values, a finding made all the more remarkable given the high frequency of clinical malaria in this population. It is clear from these findings that haematological data are valuable in screening for carriers of alpha+ thalassaemia in this population. MCH is clearly the most sensitive discriminator. None of the homozygous adults tested had an MCH of > 27 pg, whereas < 10% of normals had a value of < 27 pg. These data provide reference values for areas in which the alpha+ thalassaemias are common and often confused with iron-deficiency anaemia.

Adolescent↗
PubMed1996

Safe intravenous antibiotic therapy at home: experience of a UK based programme.

Outpatient i.v. antibiotic therapy is well developed in the United States, largely because of pressures from third-party payers to reduce costs of medical care. We have developed an outpatient i.v. antibiotic programme in Oxford, that has evolved from a desire to provide high quality i.v. therapy to AIDS patients with cytomegalovirus retinitis. We describe the rationale of the service and report on our first two years' experience. We treated 67 consecutive patients (eight with HIV infection) at home with i.v. antibiotics. This resulted in a saving of 2275 hospital days for those patients without HIV infection. HIV positive patients received 69 months of home i.v. therapy. Minor intravascular catheter complications occurred in only five patients (7.5%). The only serious complications were three episodes of catheter-related sepsis (4.5%), all occurring in AIDS patients who had lines in for more than six months. We have shown that home i.v. antibiotic therapy can be delivered safely to patients with a wide variety of infectious problems using the existing network of community nurses in the National Health Service. Essential components to the programme include a multidisciplinary team working between the hospital and community and a written shared care protocol. Such a programme can result in reduced lengths of hospital stay and patient, community nurse and physician satisfaction.

Anti-Bacterial Agents↗