Mapping domains of early life determinants of future multimorbidity across three UK longitudinal cohort studies.

Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.

Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and ß-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and ß-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not ß-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and ß-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies.

This combined analysis investigated the effect of marimastat, a specific inhibitor of matrix metalloproteinases, on markers of tumor progression measured in patients with advanced cancer. By defining the tolerability and biological activity of the drug, it aimed to establish an appropriate dose range for use in Phase III trials. Patients with advanced, serologically progressive ovarian, prostatic, pancreatic, and colorectal cancer were recruited into six nonrandomized, dose ranging, multicenter clinical trials in North America and Europe. The biological activity of marimastat was assessed by serial measurements of the serum tumor markers carcinoembryonic antigen, CA125, CA19-9, and prostate-specific antigen. Patients were recruited with tumor markers rising by more than 25% averaged over a 4-week screening period. A biological effect was defined as a level of tumor marker at the end of treatment no greater than at study entry; a partial biological effect was defined as a rise in the level of tumor marker over the treatment period of 0-25% per 4 weeks. Pharmacokinetic and safety data were collected and assessed as the studies progressed. All patients were followed up for survival.

Phase variation in meningococcal lipooligosaccharide biosynthesis genes.

Neisseria meningitidis expresses a range of lipooligosaccharide (LOS) structures, comprising of at least 13 immunotypes (ITs). Meningococcal LOS is subject to phase variation of its terminal structures allowing switching between ITs, which is proposed to have functional significance in disease. The objectives of this study were to investigate the repertoire of structures that can be expressed in clinical isolates, and to examine the role of phase-variable expression of LOS genes during invasive disease. Southern blotting was used to detect the presence of LOS biosynthetic genes in two collections of meningococci, a global set of strains previously assigned to lineages of greater or lesser virulence, and a collection of local clinical isolates which included paired throat and blood isolates from individual patients. Where the phase-variable genes lgtA, lgtC or lgtG were identified, they were amplified by PCR and the homopolymeric tracts, responsible for their phase-variable expression, were sequenced. The results revealed great potential for variation between alternate LOS structures in the isolates studied, with most strains capable of expressing several alternative terminal structures. The structures predicted to be currently expressed by the genotype of the strains agreed well with conventional immunotyping. No correlation was observed between the structural repertoire and virulence of the isolate. Based on the potential for LOS phase variation in the clinical collection and observations with the paired patient isolates, our data suggest that phase variation of LOS structures is not required for translocation between distinct compartments in the host.

Investigation of gaseous ozone for MRSA decontamination of hospital side-rooms.

A domestic, gaseous ozone generator was investigated for use in the decontamination of hospital side-rooms that have housed patients colonized with methicillin-resistant Staphylococcus aureus (MRSA). Three models of bacterial contamination were used. These were exposed to ozone generation in a standard hospital side-room for 4 and 7 h. A methicillin-sensitive and a methicillin-resistant strain of S. aureus were compared. Ozone concentrations of 0.14 ppm were reached, levels which are sufficient to cause mild pulmonary toxicity. Bacterial counts were reduced in the vicinity of the gas generator in most instances, but the effect elsewhere in the room was, at best, limited. MRSA appeared more resistant to the effects of ozone than methicillin-sensitive S. aureus. We conclude that the device tested would be inadequate for the decontamination of such hospital side-rooms.

Molecular analysis of the meningococcal LPS expression.

Lipopolysaccharide (LPS) is one of the major virulence factors of Neisseria meningitidis (1), with proposed roles in bacterial attachment to the host, invasion of host tissues, serum resistance, evasion of the host immune response, and the pathogenesis of sepsis syndrome. Accordingly it has become an important target for research.

100 years of observation on British radiologists: mortality from cancer and other causes 1897-1997.

Radiologists and radiotherapists were one of the earliest occupational groups to be exposed to ionizing radiation. Their patterns of mortality provide information on the long-term effects of fractionated external radiation exposure. British radiologists who registered with a radiological society between 1897 and 1979 have now been followed-up until 1 January 1997, and the mortality experience examined among those who registered with a society after 1920, when the first radiological protection recommendations were published. The observed number of cancer deaths in those who registered after 1920 was similar to that expected from death rates for all medical practitioners combined (SMR=1.04; 95% CI 0.89-1.21). However, there was evidence of an increasing trend in risk of cancer mortality with time since first registration with a radiological society (p=0.002), such that in those registered for more than 40 years there was a 41% excess risk of cancer mortality (SMR=1.41; 95% CI 1.03-1.90). This is probably a long-term effect of radiation exposure in those who first registered during 1921-1935 and 1936-1954. There was no evidence of an increase in cancer mortality among radiologists who first registered after 1954, in whom radiation exposures are likely to have been lower. Non-cancer causes of death were also examined in more detail than has been reported previously. There was no evidence of an effect of radiation on diseases other than cancer even in the earliest radiologists, despite the fact that doses of the size received by them have been associated with more than a doubling in the death rate among the survivors of the Japanese atomic bombings.

Two-stage algorithm for Clostridium difficile: glutamate-dehydrogenase-positive toxin-negative enzyme immunoassay results may require further testing.

This study investigated 102 episodes in which a glutamate dehydrogenase-positive enzyme immunoassay (EIA)-toxin-negative result was obtained with a C. difficile testing protocol. Of these 102 stool samples, 46% were culture positive with a toxigenic strain and nine were followed by an EIA-toxin-positive result within 2-32 days. The data accord with our policy of keeping these patients in side-rooms until asymptomatic and of encouraging treatment of those with otherwise unexplained persistent diarrhoea. Adding a third testing modality [toxigenic culture or polymerase chain reaction (PCR)] appears desirable but there may be significant differences in sensitivity between different toxigenic culture or PCR methods.

Effect of ribotype on all-cause mortality following Clostridium difficile infection.

BACKGROUND: Clostridium difficile infection (CDI) is significantly associated with subsequent all-cause mortality. Although a number of studies have investigated mortality associated with CDI, few have compared all-cause mortality between ribotypes. AIM: We aimed to estimate all-cause mortality following CDI and to investigate the relationship between mortality, ribotype and other available variables. METHODS: We undertook a retrospective cohort study. All patients with toxin-positive CDI in North East England between July 2009 and June 2011 were matched to death registration data. Differences in all-cause 30-day case fatality were explored using Poisson regression with robust error variances. For survival analysis, an accelerated failure time model with generalized gamma distribution was chosen. FINDINGS: In total, 1426 patients were included. All-cause case fatality was 10.2%, 16.4%, 25.7% and 38.1% at 7, 14, 30 and 90 days respectively. In multivariate analysis, ribotype 027 (risk ratio: 1.34; 95% confidence interval: 1.02-1.75) and ribotype 015 (0.46; 0.26-0.82) were significantly associated with higher and lower all-cause 30-day case fatality rates, respectively. In survival analysis, only ribotype 015 had significantly lower predicted mortality (P = 0.008). Patients whose infection was hospital-acquired had significantly higher predicted mortality (P < 0.001). CONCLUSION: This is the first population-based study of comparative mortality between multiple ribotypes. Our study identified a high rate of all-cause mortality following CDI. We found evidence of variability in mortality between ribotypes in this cohort with mortality significantly higher for ribotype 027 at 30 days following diagnosis and significantly lower for ribotype 015.

Epidemiological survey of Clostridium difficile ribotypes in the North East of England during an 18-month period.

During an 18-month period, 1606 stool specimens from laboratory-confirmed cases of Clostridium difficile infection in the North East of England were ribotyped using unrestricted polymerase chain reaction. Of these, 87.6% grew C. difficile on culture; 70% had one of 10 recognizable ribotypes of which 001, 106 and 027 were the most prevalent. The proportions of ribotypes 002 and 015 declined during the study period, whereas ribotypes 016 and 023 increased. Ribotype 005 was significantly more numerous in males and ribotype 027 was associated with significantly higher mean age. Our findings differ from national data derived from more selective testing.

Constructing period parity progression ratios from household survey data.

"An own-child analysis is applied to the household composition data of two rounds of the U.K. Labour Force Survey, each of which has a sample size of about 200 thousand people. Period parity progression ratios and the corresponding total fertility measure (TFPPR) are derived for up to twenty years before the survey date. The biases that arise when using such a source are discussed and assessed by replication using surveys in different years. Methods for correcting bias are developed. Analysis of the standard errors of the measures suggests that such sources provide the most precise, routine and timely indicators of period fertility in many situations...."

Generalized least squares for the synthesis of correlated information.

This paper deals with the synthesis of information from different studies when there is lack of independence in some of the contrasts to be combined. This problem can arise in several different situations in both case-control studies and clinical trials. For efficient estimation we appeal to the method of generalized least squares to estimate the summary effect and its standard error. This method requires estimates of the covariances between those contrasts that are not independent. Although it is not possible to estimate the covariance between effects that have been adjusted for confounding factors we present a method for finding upper and lower bounds for this covariance. In the simplest discussion homogeneity of the relative risks is assumed but the method is then extended to allow for heterogeneity in an overall estimate. We then illustrate the method with several examples from an analysis in which case-control studies of cervical cancer and oral contraceptive use are synthesized.

Clostridium difficile: a questionnaire survey of laboratory practice in England, Wales, and Northern Ireland.

Since January 2004, the incidence of Clostridium difficile associated disease (CDAD) has been monitored by a systematic, national, laboratory surveillance system. This system incorporates the recommendations of a body of experts, the National Clostridium difficile Standards Group, which was convened in 2002 to advise the Department of Health (DoH). The recommendations of the group were informed by a questionnaire survey of current practice, and the results of that survey have been used to assess the implications of the recommendations on laboratory practice. Large variability was found as to the specimens selected, tested, and reported on for C. difficile. Standardisation of the diagnosis and reporting of CDAD is desirable and necessary to increase understanding of its epidemiology.

Overview of the relationship between use of progestogen-only contraceptives and bone mineral density.

OBJECTIVES: To summarise the available epidemiological evidence regarding the relationship between the use of progestogen-only contraceptives and bone mineral density. DESIGN AND METHODS: Overview of the published epidemiological literature. RESULTS: Overall, 17 studies of the use of progestogen-only contraceptives and bone mineral density were identified, involving 1529 women exposed to progestogen-only contraceptives and 2086 controls. Sixty-eight percent of the data relate to the effects of use of depot medroxyprogesterone acetate. Average bone mineral density was reduced in current users of depot medroxyprogesterone acetate compared with non-users, although density in users was within one standard deviation of the mean in non-users. There was significant heterogeneity between the results of different studies (P < 0.0001). The reduction in bone mineral density appeared to be greater at the lumbar spine, femoral neck and ultradistal forearm than at the midshaft of the ulna. Studies involving women with a longer average duration of use of depot medroxyprogesterone acetate displayed greater reductions in bone mineral density compared with studies of women with shorter durations of use. Based on limited data, no difference in bone mineral density was observed between former and never users of depot medroxyprogesterone acetate. Results regarding the effect of levonorgestrel implants were conflicting. Studies of progestogen-only oral contraceptives and the progesterone vaginal ring were small and restricted to lactating women. CONCLUSIONS: Women currently using depot medroxyprogesterone acetate have a lower average bone mineral density than non-users. The magnitude of this effect is uncertain but appears to be greater with longer durations of use.