Risk of progression from pre-diabetes to type 2 diabetes in a large UK adult cohort.

AIMS: People with pre-diabetes are at high risk of progressing to type 2 diabetes. This progression is not well characterised by ethnicity, deprivation and age, which we describe in a large cohort of individuals with pre-diabetes. METHODS: A retrospective cohort study with The Health Improvement Network (THIN) database was conducted. Patients aged 18 years and over and diagnosed with pre-diabetes [HbA1c 42 mmol/mol (6.0%) to 48 mmol/mol (6.5%) were included]. Cox proportional hazards regression was used to calculate adjusted hazard rate ratios (aHR) for the risk of progression from pre-diabetes to type 2 diabetes for each of the exposure categories [ethnicity, deprivation (Townsend), age and body mass index (BMI)] separately. RESULTS: Of the baseline population with pre-diabetes (n = 397,853), South Asian (aHR 1.31; 95% CI 1.26-1.37) or Mixed-Race individuals (aHR 1.22; 95% CI 1.11-1.33) had an increased risk of progression to type 2 diabetes compared with those of white European ethnicity. Likewise, deprivation (aHR 1.17; 95% CI 1.14-1.20; most vs. least deprived) was associated with an increased risk of progression. Both younger (aHR 0.63; 95% CI 0.58-0.69; 18 to <30 years) and older individuals (aHR 0.85; 95% CI 0.84-0.87; ≥65 years) had a slower risk of progression from pre-diabetes to type 2 diabetes, than middle-aged (40 to <65 years) individuals. CONCLUSIONS: South Asian or Mixed-Race individuals and people with social deprivation had an increased risk of progression from pre-diabetes to type 2 diabetes. Clinicians need to recognise the differing risk across their patient populations to implement appropriate prevention strategies.

The association of vitamin D supplementation with the risk of cancer in postmenopausal women.

PURPOSE: There is inconclusive evidence on whether vitamin D therapy reduces cancer risk. We investigated the effect of vitamin D (±calcium) supplementation on the risk of breast, ovarian, uterine, colorectal, and lung cancer in women. METHODS: We conducted a case-control study using the UK Clinical Practice Research Datalink (CPRD); cases were women aged ≥55 years with a first diagnosis of either breast, colorectal, lung, ovarian, or uterine cancer between 2002 and 2009, with at least 5 years of CPRD follow-up prior to the date of diagnosis, and controls were women without cancer, frequency-matched to cases by year of birth, date of study entry, length of follow-up, and general practice. The association of vitamin D supplementation with the odds of developing each cancer was determined using multivariable logistic regression, controlling for body mass index, smoking, alcohol, and deprivation. RESULTS: Ninety-seven percent of women took vitamin D with a calcium supplement. Exposure to three or more prescriptions of vitamin D was associated with a 17 % reduced odds (95 % CI 0.71-0.97) of breast cancer versus 1-2 prescriptions, but this effect disappeared when omitting women first exposed within a year of diagnosis (OR 1.0, 95 % CI 0.82-1.23). Having more than 10 prescriptions of vitamin D was associated with a 17 % lower odds (95 % CI 0.65-1.06) of colorectal cancer, but the estimates are imprecise. There was little evidence of associations of supplements with lung or gynecological cancers. CONCLUSION: We found little evidence that vitamin D (largely with calcium) supplementation is associated with decreased breast, lung, ovarian, and uterine cancer risk. There is a possible protective association between having more than 10 prescriptions of vitamin D supplements and colorectal cancer, but it requires further investigation.

Extraordinary plasticity in aging in Strongyloides ratti implies a gene-regulatory mechanism of lifespan evolution.

Aging evolves as the result of weakened selection against late-acting deleterious alleles due, for example, to extrinsic mortality. Comparative studies of aging support this evolutionary theory, but details of the genetic mechanisms by which lifespan evolves remain unclear. We have studied aging in an unusual nematode, Strongyloides ratti, to gain insight into the nature of these mechanisms, in this first detailed examination of aging in a parasitic nematode. S. ratti has distinct parasitic and free-living adults, living in the rat small intestine and the soil, respectively. We have observed reproductive and demographic aging in parasitic adults, with a maximum lifespan of 403 days. By contrast the maximum lifespan of free-living adults is only 5 days. Thus, the two adults of S. ratti have evolved strikingly different rates of aging. Parasitic nematode species are frequently longer-lived than free-living species, presumably reflecting different extrinsic mortality rates in their respective niches. Parasitic and free-living female S. ratti are morphologically different, yet genetically identical. Thus, the 80-fold difference in their lifespans, the greatest plasticity in aging yet reported, must largely reflect evolved differences in gene expression. This suggests that interspecific differences in lifespan may evolve via similar mechanisms.

Diurnal cortisol and mental well-being in middle and older age: evidence from four cohort studies.

OBJECTIVES: We conducted an individual participant meta-analysis to test the hypothesis that cortisol patterns indicative of dysregulated hypothalamic-pituitary-adrenal axis functioning would be prospectively associated with poorer well-being at follow-up. SETTING: Four large UK-based cohort studies. PARTICIPANTS: Those providing valid salivary or serum cortisol samples (n=7515 for morning cortisol; n=1612 for cortisol awakening response) at baseline (age 44-82) and well-being data on the Warwick Edinburgh Mental Wellbeing Scale at follow-up (0-8 years) were included. RESULTS: Well-being was not associated with morning cortisol, diurnal slope or awakening response though a borderline association with evening cortisol was found. Adjusting for sex and follow-up time, each 1 SD increase in evening cortisol was associated with a -0.47 (95% CI -1.00 to 0.05) point lower well-being. This was attenuated by adjustment for body mass index, smoking and socioeconomic position. Between-study heterogeneity was low. CONCLUSIONS: This study does not support the hypothesis that diurnal cortisol is prospectively associated with well-being up to 8 years later. However, replication in prospective studies with cortisol samples over multiple days is required.

Genetic variation for total fitness in Drosophila melanogaster: complex yet replicable patterns.

The extent of genetic variation in fitness is a crucial issue in evolutionary biology and yet remains largely unresolved. In Drosophila melanogaster, we have devised a method that allows the net effects on fitness of heterozygous wild-type chromosomes to be measured, by competing them against two different "balancer" chromosomes. We have applied the method to a large sample of 40 wild-type third chromosomes and have measured fitnesses of nonlethal chromosomes as well as chromosomes bearing recessive lethals. The measurements were made in the environment to which the population was adapted and did not involve inbreeding. The results show an extraordinary similarity in the behavior of replicates of the same chromosome, indicating consistent genetic effects on total fitness. Some invading chromosomes increased rapidly and some slowly, and some rose to appreciable frequency after several months, but then declined again: in every case, the same pattern was seen in each replicate. We estimated relative fitnesses, rates of change of fitness, and relative viabilities, for each chromosome. There were significant fluctuations around the fitted model, which were also highly replicable. Wild-type chromosomes varied substantially in their effects on heterozygous fitness, and these effects vary through time, most likely as a result of genotype x environment interactions.

Determining the optimal developmental route of Strongyloides ratti: an evolutionarily stable strategy approach.

Understanding the processes that drive parasite evolution is crucial to the development of management programs that sustain long-term, effective control of infectious disease in the face of parasite adaptation. Here we present a novel evolutionarily stable strategy (ESS) model of the developmental decisions of a nematode parasite, Strongyloides ratti. The genus Strongyloides exhibits an unusual developmental plasticity such that progeny from an individual may either develop via a direct (homogonic) route, where the developing larvae are infective to new hosts, or an indirect (heterogonic) route, where the larvae develop into free-living, dioecious adults that undergo at least one bout of sexual reproduction outside the host, before producing offspring that develop into infective larvae. The model correctly predicts a number of observed features of the parasite's behavior and shows that this plasticity may be adaptive such that pure homogonic development, pure heterogonic development, or a mixed strategy may be optimal depending on the prevailing environmental conditions, both within and outside the host. Importantly, our results depend only on the benefits of an extra round of reproduction in the environment external to the host and not on benefits to sexual reproduction through the purging of deleterious mutation or the generation of novel, favorable genotypes. The ESS framework presented here provides a powerful, general approach to predict how macroparasites, the agents of many of the world's most important infectious diseases, will evolve in response to the various selection pressures imposed by different control regimes in the future.

Aging in a very short-lived nematode.

Aging has been characterised in detail in relatively few animal species. Here we describe the aging process in free-living adults of the parasitic nematode Strongyloides ratti. We find that the phenomenology of aging in S. ratti free-living females, resembles that of the short-lived free-living nematode Caenorhabditis elegans, except that it unfolds far more rapidly. The mean (3.0 +/- 0.1 days) and maximum (4.5 +/- 0.8 days) lifespans of free-living S. ratti females are approximately one quarter of equivalent values for C. elegans. Demographic senescence (a hallmark of aging) was observed in free-living S. ratti, with a mortality rate doubling time of 0.8 +/- 0.1 days (females), compared with 2.0 +/- 0.3 in C. elegans. S. ratti lifetime fertility and lifespan were affected by temperature, and there is an age-related decline in feeding rate and movement, similar to C. elegans, but occurring more quickly. Gut autofluorescence (lipofuscin) also increased with age in S. ratti free-living females, as in aging C. elegans. These findings show that the extreme brevity of life in free-living S. ratti adults, the shortest-lived nematode described to date, is the consequence of rapid aging, rather than some other, more rapid and catastrophic life-shortening pathology.

Cortisol and cognitive function in midlife: the role of childhood cognition and educational attainment.

Adult cognition and age-related cognitive decline can be influenced by dysregulation of the hypothalamic pituitary adrenal axis with concomitant changes in cortisol levels. However, very little is known about the role of childhood cognition and educational attainment in this relationship. Using data from the British 1946 birth cohort, the present study investigated: (1) associations between cortisol levels and patterns and cognitive function in midlife; (2) direct and interactive effects of childhood cognition, educational attainment and cortisol on cognitive function in midlife. Verbal memory, letter search speed and reaction time were assessed at age 60-64 years. Salivary cortisol samples (wakening, 30 min after wakening and evening) were collected at the same age. Childhood cognitive ability was measured at ages 8, 11, and 15, and educational level was reported at age 26. Associations between cortisol, childhood cognition, educational attainment and cognitive function in midlife were tested using linear regression and structural equation modelling approaches. Higher evening cortisol level was associated with slower reaction time and lower verbal memory. These associations were independent of childhood cognition and education as well as a range of other potential confounders. Childhood cognition and education were not directly associated with evening cortisol. However, there was a significant interaction effect between childhood cognition and evening cortisol on reaction time (p=.002): higher evening cortisol was associated with slower reaction time only among those with low childhood cognitive ability. There was little evidence of associations between the other cortisol measures and cognitive function.

Interventions to increase the uptake of mammography amongst low income women: a systematic review and meta-analysis.

BACKGROUND: Two previous reviews found that access-enhancing interventions were effective in increasing mammography uptake amongst low-income women. The purpose of this study was to estimate the magnitude of the effect of interventions used to increase uptake of mammography amongst low-income women. METHODS: Searches were conducted in MEDLINE and EMBASE (2002-April 2012) using relevant MeSH terms and keywords. Randomised controlled trials which aimed to increase mammography use in an asymptomatic low-income population and which had as an outcome receipt of a mammogram, were eligible for inclusion. The primary outcome was the post-intervention difference in the proportion of women who had a mammogram in the intervention and control groups. The quality of the studies was assessed using the Cochrane risk of bias tool. We calculated summary estimates using random effects meta-analyses. Possible reasons for heterogeneity were investigated using sub-group analyses and meta-regression. Publication bias was assessed using Egger's test. RESULTS: Twenty-one studies met the inclusion criteria, including 33 comparisons. Interventions increased the uptake of mammography in low income women by an additional 8.9% (95% CI 7.3 to 10.4%) compared to the control group. There was some evidence that interventions with multiple strategies were more effective than those with single strategies (p = 0.03). There was some suggestion of publication bias. The quality of the included studies was often unclear. Omitting those with high risk of bias has little effect on the results. CONCLUSIONS: Interventions can increase mammography uptake among low-income women, multiple interventions being the most effective strategy. Given the robustness of the results to sensitivity analyses, the results are likely to be reliable. The generalisability of the results beyond the US is unclear.

Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: an individual participant meta-analysis.

The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50-92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n=2146 for associations between morning Cortisol Awakening Response and balance to n=8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p<0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase -0.075, 95% CI -0.116, -0.034, p<0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance.

Telomere length and physical performance at older ages: an individual participant meta-analysis.

BACKGROUND: Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance. METHODS: Using data from four UK adult cohorts (ages 53-80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2). RESULTS: Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p =0.08) after further adjustment. CONCLUSIONS: Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.

Diurnal cortisol patterns are associated with physical performance in the Caerphilly Prospective Study.

BACKGROUND: Cross-sectional studies have suggested that elevated cortisol is associated with worse physical performance, a surrogate of ageing. We examined the relationship between repeat cortisol measures over 20 years and physical performance in later life. METHODS: Middle-aged men (45-59 years) were recruited between 1979 and 1983 (Phase 1) from the Caerphilly Prospective Study (CaPS) and re-examined 20 years later at 65-83 years of age (Phase 5). Participants included 750 and 898 subjects with either Phase 1 and/or Phase 5 data on exposure and outcomes. Outcome measures were walking speed and balance time and exposures included morning fasting serum cortisol (Phase 1) and four salivary samples on 2 consecutive days (Phase 5). RESULTS: Faster walking speed was associated with higher morning cortisol at Phase 1 [coefficient per standard deviation (SD) increase 0.68, 95% confidence interval (95% CI) 0.09-1.27; P=0.02] though this was attenuated after adjustment for covariates (coefficient per SD increase 0.45; 95% CI -0.16 to 1.07; P=0.15). Higher night-time cortisol at Phase 5 was associated with slower speed (coefficient per SD increase -1.06; 95% CI -1.60 to -0.52; P<0.001) and poorer balance (odds ratio of top tertile vs bottom 2.49; 95% CI 1.63-3.81; P<0.001). Worst performance was seen for men with a poor morning response (Phase 1) and less nocturnal decline (Phase 5). CONCLUSIONS: Dysregulation of the hypothalamic pituitary adrenal (HPA) axis is associated with worse physical performance in later life. This may reflect a causal effect of the HPA axis on ageing or that ageing itself is associated with reduced HPA reactivity.

Variation in Caenorhabditis elegans dauer larva formation.

Dauer larvae of Caenorhabditis elegans are formed when young larvae experience conditions of low food availability and high conspecific population density; non-dauer, third stage larvae are formed in conditions of plenty. This developmental response to environmental conditions is an example of phenotypic plasticity; that is, an environmentally induced change in phenotype and, as such, a manifestation of a genotype-environment interaction. Extensive variation was found in reaction norms of phenotypic plasticity of dauer formation among wild lines of C. elegans. Recombinant-inbred lines were constructed from parental lines with very different reaction norms of dauer formation. These recombinant-inbred lines had a wide range of reaction norms, of a range greater than that set by the parental lines. The natural variation in reaction norms of dauer formation in C. elegans is, presumably, an adaptation to enhance fitness under the lines' different natural prevailing conditions. The genetic basis of this variation, as well as its phenotypic consequences, are now ripe for further investigation.

Bladder augmentation in dogs using the tissue capsule formed around a perivesical tissue expander.

PURPOSE: Enterocystoplasty provides needed improvement in bladder storage parameters in many patients but it also generates significant morbidity. We evaluated the unusual potential alternative of using the capsule that forms around a standard silicone tissue expander placed perivesically to augment the bladder in dogs. MATERIALS AND METHODS: Six mongrel dogs underwent baseline videourodynamics and assessment of serum electrolytes, followed by placement of a 250 to 500 cc perivesical silicone tissue expander. Four months after implantation the tissue expander was removed and the fibrous capsule around the expander was biopsied. The capsule was opened and anastomosed to the bladder to augment storage. Serum electrolytes were determined 2 and 4 weeks after augmentation. Videourodynamics were repeated after 3 to 5 months, that is at sacrifice. The harvested bladders underwent histological evaluation. RESULTS: Five dogs underwent augmentation as described, while in an additional dog that underwent intraperitoneal placement of the tissue expander a fibrous capsule failed to form. Of the 5 augmented dogs 4 underwent repeat urodynamic and electrolyte evaluation with harvesting of the lower urinary tract, while 1 died of undetermined causes 3 weeks after augmentation. A distinct capsule formed in all dogs and augmentation was technically achievable. Anastomosis calcification in 3 dogs limited filling the augmenting capsule for cystography. Bladder capacity and compliance improved in all animals but it varied in degree. Histological examination of the capsule biopsies showed collagen rich connective tissue without epithelium or smooth muscle. After augmentation the capsular segment revealed urothelium in all cases with squamous metaplasia in 1. The subepithelial region had dense fibrosis and a thin band of osseous metaplasia occupied the lamina propria in all cases. Disorganized smooth muscle bundles were noted in all augmented bladders within the collagen of the capsule wall. CONCLUSIONS: Bladder augmentation with the collagenous capsule formed over a perivesical tissue expander is technically feasible. There was evidence of epithelial and smooth muscle ingrowth from the native bladder with improved bladder capacity and compliance in all dogs. Osseous metaplasia of the luminal surface of the collagen based capsule that developed in all animals may have been responsible for anastomotic narrowing and limited filling on cystography.

Why does HIV infection not lead to disseminated strongyloidiasis?

We investigated the hypothesis that host immunosuppression due to advancing human immunodeficiency virus (HIV) disease favors the direct development of infective larvae of Strongyloides stercoralis, which may facilitate hyperinfection and, hence, disseminated strongyloidiasis. To do this, we sought correlations between the immune status of the subjects and the development of S. stercoralis infections. Among 35 adults, there were significant negative rank correlations between CD4+ cell counts and the proportions of free-living male and female worms. Thus, in individuals with preserved immune function, direct development of S. stercoralis is favored, whereas, in individuals with lesser immune function, indirect development is relatively more common. These results may explain the notable absence of disseminated strongyloidiasis in advanced HIV disease. Because disseminated infection requires the direct development of infective larvae in the gut, the observed favoring of indirect development in individuals immunosuppressed by advancing HIV disease is not consistent with the promotion of disseminated infection.