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The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Although childhood adversity is a potent determinant of psychopathology, relatively little is known about how the characteristics of adversity exposure, including its developmental timing or duration, influence subsequent mental health outcomes. This study compared three models from life course theory (recency, accumulation, sensitive period) to determine which one(s) best explained this relationship.
Prospective data came from the Avon Longitudinal Study of Parents and Children (n = 7476). Four adversities commonly linked to psychopathology (caregiver physical/emotional abuse; sexual/physical abuse; financial stress; parent legal problems) were measured repeatedly from birth to age 8. Using a statistical modeling approach grounded in least angle regression, we determined the theoretical model(s) explaining the most variability (r2) in psychopathology symptoms measured at age 8 using the Strengths and Difficulties Questionnaire and evaluated the magnitude of each association.
Recency was the best fitting theoretical model for the effect of physical/sexual abuse (girls r2 = 2.35%; boys r2 = 1.68%). Both recency (girls r2 = 1.55%) and accumulation (boys r2 = 1.71%) were the best fitting models for caregiver physical/emotional abuse. Sensitive period models were chosen alone (parent legal problems in boys r2 = 0.29%) and with accumulation (financial stress in girls r2 = 3.08%) more rarely. Substantial effect sizes were observed (standardized mean differences = 0.22–1.18).
Child psychopathology symptoms are primarily explained by recency and accumulation models. Evidence for sensitive periods did not emerge strongly in these data. These findings underscore the need to measure the characteristics of adversity, which can aid in understanding disease mechanisms and determining how best to reduce the consequences of exposure to adversity.
Perennial ryegrass varieties bred to express high water-soluble carbohydrate (WSC) concentrations have been shown to improve liveweight gain in pre-weaned lambs of grazing ewes (Lee et al., 2001) compared to conventional ryegrass. Studies have shown that the largest differential in WSC between ryegrass varieties bred for high WSC concentrations and control ryegrasses occurs 5-6 weeks after the plant is allowed to re-grow following cutting or grazing (Miller et al., 2001). Therefore, the benefits, in terms of lamb performance, of using these grasses with high WSC concentrations may be best achieved when they are rotationally rather than continuously grazed. The aim of this experiment was to compare lambs rotationally or continuously grazing either a ryegrass variety bred for high WSC concentrations or a control ryegrass.
X-ray computed tomography (CT) measurements of live sheep have been used to predict carcass composition very accurately (Macfarlane et al., 2006). The utilisation of spiral CT scans (SCTS) for quantifying muscle volumes and weights, using automatic image analysis procedures has also been shown to be very accurate in sheep (Navajas et al., 2006). Although the limiting size of the CT gantry prevents CT scanning of live beef cattle, beef primal joints are small enough to be scanned. Hence, SCTS could be used to quantify beef carcass composition, and provide valuable information for breeding programmes including composition faster than by anatomical dissection. The objective of this study was to develop a CT image analysis procedure to assess fat, muscle and bone weights of beef carcasses and to evaluate its accuracy.
Nutritional manipulation during the dry period can alter subsequent animal responses to feeding in terms of milk yield and composition. Previous research has shown interesting differences in milk production and composition due to energy or protein supply in the dry period (Moorby et al., 1996). The objective of this experiment was to test the interaction between energy and protein supplies during the dry period on subsequent milk production and composition. Effects on live weight gains and condition scores are reported in a separate summary (Jaurena et al., 2001).
Previous results have shown that during late gestation even under conditions of live weight (LW) gain, maternal body protein can be in negative balance due to the highly demanding gravid uterus and udder. It has also been claimed that current feeding standards underpredict dry cow nitrogen (N) requirement. Considering that it is not possible to measure maternal body N status independently of the requirements of the conceptus and the udder, estimation of conceptus and udder N requirements by mathematical models can help to predict maternal N requirement. The aim of this study was to assess cow N requirement during late gestation by predicting maternal N balance through a mathematical model. Previous results related with this study were presented in Jaurena et al, (2001).
The high intake characteristics of red clover silage has been recognised for many years (e.g. Thomas et al., 1985). Our previous study (Dewhurst et al., 2000) demonstrated the considerable intake and milk production potential of clover silages made using a new approach based on preparation of big-bales from wilted material with the use of biological inoculant additives. The objective of this study was to verify the positive results obtained with red and white clover silages using material taken from a further series of cuts taken in a subsequent year and to evaluate the legume silages with low levels of concentrate feeding.
Energy and protein supply during the dry period can affect subsequent milk production and composition (Moorby et al., 1996). Grass silage is a common ingredient of dry cow diets, but although it is usually adequate in crude protein concentration (CP), a high proportion is frequently in non-protein forms. Red clover silage has shown interesting characteristics that would increase true protein supply to ruminants (Broderick et al., 2000), which could avoid the use of more expensive concentrate supplements. The objective of this experiment was to compare red clover and ryegrass silage when fed as the sole source of forage to dry cows with a diet comprising ryegrass silage and a protein supplement.
Our earlier studies with dry cows have highlighted a number of factors that affect performance in the subsequent lactation, including forage intake in the peri-parturient period, body condition at calving and supply of Metabolisable Protein (MP) (Moorby et al., 1996; Dewhurst et al., 2000). There is now increased interest in making more use of grazed grass, as a cheap feed, particularly through extending grazing into the late-autumn and winter. Dry cows are suited to extended grazing because they do not need to be brought in for milking each day. The high voluntary intakes of grass may be beneficial for dry cows, though the low MP supply from autumn-grass might be a disadvantage. This experiment evaluated the effects of extended grazing, compared with housing and silage-feeding of dry cows.
Earlier work showed that red clover silage has considerable potential for milk production (e.g. Thomas et al., 1985), though low digestibility and difficulties ensiling clovers were seen as problems that needed to be addressed. Advances in legume breeding and conservation technology as well as a renewed emphasis on extensive organic production systems within Agenda 2000 meant that it was timely to reconsider the potential of legume silages for milk production.
Body fat and protein reserves at calving can affect milk production and composition (Garnsworthy, 1988; Moorby et al., 1996). Milk producers frequently feed their dry cows with a low quality diet to prevent them from becoming too fat before calving. However, the cow must nourish the foetus and develop mammary secretory tissues, which can be a problem if she is offered a low protein diet. This experiment was designed to test the interaction between energy and protein supplies during the dry period on changes in live weight (LW), condition score (CS) and muscle Longissimus dorsi depth (LD). Subsequent milk production and composition data are reported in a separate summary (Jaurena et al., 2001).
Red clover silage is an important component of many organic dairy systems. The high intake and milk production potential of red clover silage has been recognised for many years (e.g. Thomas et al., 1985). Our earlier studies confirmed this potential and showed additional benefits with increased polyunsaturated fatty acid (PUFA) content of milk (Dewhurst et al., 2002). The objective of this study was to investigate further the effect of red clover silage on milk PUFA and to examine whether supplementary vitamin E, which is needed to slow oxidative deterioration of milk with enhanced PUFA content, had an effect.
Genetic potential for milk production has increased rapidly in the Holstein-Friesian breed and there is concern that this might be causing an increased incidence of health problems. We have recently (Ingvartsen et al., 2002) reviewed the inter-relationships between lactation performance and health, demonstrating the importance of considering effects on/of body reserves as well as effects on/of milk production. Whilst we identified mechanisms whereby body reserves can have a direct effect on susceptibility to disease, disease also affects body reserves making it difficult to study their inter-relationships. The dry period is a particularly interesting period in this regard, because additional nutrients are directed towards reserves, whilst it is followed by a period (early lactation) of high disease incidence. The objective of this study was to investigate the effects of body condition score (BCS) at calving, as well as the effects of dry period diets designed to alter BCS, on disease incidences in the first 100 days of lactation.
Earlier studies (e.g. Dewhurst et al., 1996, 1999) have shown marked declines in forage voluntary intake as calving approaches. The resultant reduction in nutrient supply may compromise performance in the next lactation, because it coincides with a period of intense metabolic activity in preparation for the next lactation. Feeding concentrates to dry cows did not overcome this problem (Dewhurst et al., 1999). The objective of the current experiment was to investigate alternative dry cow strategies, using only high-quality grass silage, to minimise the severity and consequences for subsequent milk production of the reduction in nutrient supply in this period.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Methods Eighty seven people with 1-3 brain metastases were enrolled on this Phase II trial of WBRT (30Gy/10)+simultaneous FSRT, (60Gy/10). Results Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to<27) ranged from 26-38% for KPS, 32-59% for FACT-Br and 0-16%for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (<6months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. Conclusions The effects on function and quality of life of this integrated treatment of WBRT+simultaneous FSRT were similar to other published series combining WBRT+SRS.
We analyzed birth order differences in means and variances of height and body mass index (BMI) in monozygotic (MZ) and dizygotic (DZ) twins from infancy to old age. The data were derived from the international CODATwins database. The total number of height and BMI measures from 0.5 to 79.5 years of age was 397,466. As expected, first-born twins had greater birth weight than second-born twins. With respect to height, first-born twins were slightly taller than second-born twins in childhood. After adjusting the results for birth weight, the birth order differences decreased and were no longer statistically significant. First-born twins had greater BMI than the second-born twins over childhood and adolescence. After adjusting the results for birth weight, birth order was still associated with BMI until 12 years of age. No interaction effect between birth order and zygosity was found. Only limited evidence was found that birth order influenced variances of height or BMI. The results were similar among boys and girls and also in MZ and DZ twins. Overall, the differences in height and BMI between first- and second-born twins were modest even in early childhood, while adjustment for birth weight reduced the birth order differences but did not remove them for BMI.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.