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We report the results from the first 12 months of a 2-year maintenance phase of a study evaluating long-term efficacy and safety of venlafaxine extended-release (XR) in preventing recurrence of depression.
Patients with recurrent unipolar depression (N=1096) were randomly assigned in a 3:1 ratio to 10-week treatment with venlafaxine XR (75 mg/d to 300 mg/d) or fluoxetine (20 mg/d to 60 mg/d). Responders (HAM-D17 total score ≤12 and ≥50% decrease from baseline) entered a 6-month, double-blind, continuation phase on the same medication. Continuation phase responders enrolled into the maintenance treatment period consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine XR responders were randomly assigned to double-blind treatment with venlafaxine XR or placebo; fluoxetine responders continued for each period. Time to recurrence (HAM-D17 total score >12 and <50% reduction from acute phase baseline at 2 consecutive visits or the last visit prior to discontinuation) was evaluated using Kaplan-Meier methods and compared between groups using log-rank tests.
At the end of the continuation phase, venlafaxine XR responders were randomly assigned to venlafaxine XR (n=164) or placebo (n=172); 129 patients in each group were evaluated for efficacy. The cumulative probability of recurrence through 12 months was 23.1% (95% CI: 15.3, 30.9) for venlafaxine XR and 42.0% (95% CI: 31.8, 52.2) for placebo (P=0.005).
Twelve months of venlafaxine XR maintenance treatment was effective in preventing recurrence in depressed patients who had been successfully treated with venlafaxine XR during acute and continuation therapy.
This study evaluated the efficacy and safety of venlafaxine extended-release (XR) in preventing recurrence of depression.
Outpatients with recurrent unipolar depression (N=1096) were randomly assigned in a 3:1 ratio to 10-week treatment with venlafaxine XR (75 mg/d to 300 mg/d) or fluoxetine (20 mg/d to 60 mg/d). Responders (HAM-D17 ≤12 and ≥50% decrease from baseline) entered a 6-month, double-blind, continuation phase on the same medication. Continuation phase responders enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine XR responders were randomized to double-blind treatment with venlafaxine XR or placebo; fluoxetine responders continued on fluoxetine. Time to recurrence (HAM-D17 >12 and <50% reduction from acute phase baseline at 2 consecutive visits or the last valid visit prior to discontinuation) was evaluated using Kaplan-Meier methods and compared between groups using log-rank tests.
In the second maintenance phase, the cumulative probabilities of recurrence through 12 months in the venlafaxine XR (n=43) and placebo (n=40) groups were 8.0% (95% CI: 0.0, 16.8) and 44.8% (95% CI: 27.6, 62.0), respectively (P<0.001). The probabilities of recurrence over 24 months for patients assigned to venlafaxine XR (n=129) or placebo (n=129) for the first maintenance phase were 28.5% (95% CI 18.3, 37.8) and 47.3% (95% CI 36.4, 58.2), respectively (P=0.005).
An additional 12 months of venlafaxine XR maintenance therapy was effective in preventing recurrence in depressed patients who had responded to venlafaxine XR after acute, continuation, and 12 months' initial maintenance therapy.
A growing number of studies are revealing that many Milky Way globular clusters possess extended stellar structures beyond their traditional boundaries. Just how ubiquitous these structures are, and how they originate, are key questions to explore. In this contribution, we present a Bayesian technique that we have developed to separate probable members of globular clusters from the dominant Milky Way fore/background at large clustercentric radii and hence facilitate quantitative analyses of these intriguing structures. We demonstrate the promise of our method by showing how it recovers the known extended features around Palomar 5 and NGC 7089.
Red Supergiant Stars (RSGs) are important probes of stellar and chemical evolution in star-forming environments. They represent the brightest near-IR stellar components of external galaxies and probe the most recent stellar population to provide robust, independent abundance estimates. The Local Group dwarf irregular galaxy, NGC6822, is a reasonably isolated galaxy with an interesting structure and turbulent history. Using RSGs as chemical abundance probes, we estimate metallicities in the central region of NGC6822, finding a suggestion of a metallicity gradient (in broad agreement with nebular tracers), however, this requires further study for confirmation. With intermediate resolution Multi-object spectroscopy (from e.g. KMOS, EMIR, MOSFIRE) combined with state-of-the-art stellar model atmospheres, we demonstrate how RSGs can be used to estimate stellar abundances in external galaxies. In this context, we compare stellar and nebular abundance tracers in NGC 6822 and by combining stellar and nebular tracers we estimate an abundance gradient of −0.18 ± 0.05 dex/kpc.
In ewe lambs, acceleration of growth and accumulation of both muscle and fat leads to earlier sexual maturity and better reproductive performance. The next stage in the development of this theme is to test whether these aspects of growth in young ewes affect milk production in their first lactation and the growth of their first progeny. We studied 75 young Merino ewes that had known phenotypic values for depth of eye muscle (EMD) and fat (FAT), and known Australian Sheep Breeding Values for post-weaning weight (PWT) and depths of eye muscle (PEMD) and fat (PFAT). They lambed for the first time at 1 year of age. Their lambs were weighed weekly from birth to weaning at 10 weeks to determine live weight gain and weaning weight. Progeny birth weight was positively associated with live weight gain and weaning weight (P<0.001). The PWT of the mothers was positively associated with birth weight (P<0.01), live weight gain and weaning weight of the progeny (P<0.05); however, these progeny traits were not influenced by EMD, FAT, PEMD, PFAT of the mothers (P>0.05). The PWT of the sire was positively associated with live weight gain (P<0.05) and weaning weight of the progeny (P<0.01). At around day 20 postpartum, we measured milk production and milk composition (fat, protein, lactose, total solids). Milk production was influenced positively by birth type (single or twin; P<0.05) and negatively by birth weight (P<0.05), but not by mother phenotype or genotype, sire genotype of the mother or the sex of the progeny (P>0.05). The concentrations of fat, protein, lactose and total solids in the milk were not affected by the phenotype or genotype of the mothers or of the sires of the mothers, or by the sex of the progeny (P>0.05). We conclude that selection of young Merino ewes for better growth, and more rapid accumulation of muscle and fat, will lead to progeny that are heavier at birth, grow faster and are heavier at weaning. Moreover, milk production and composition do not seem to be affected by the genetic merit of the mother for post-weaning live weight or PEMD or PFAT. Therefore, Merino ewes can lamb at 1 year of age without affecting the production objectives of the Merino sheep industry.
Plasmodium knowlesi is increasingly recognized as a major cause of malaria in Southeast Asia. Anopheles leucosphyrous group mosquitoes transmit the parasite and natural hosts include long-tailed and pig-tailed macaques. Despite early laboratory experiments demonstrating successful passage of infection between humans, the true role that humans play in P. knowlesi epidemiology remains unclear. The threat posed by its introduction into immunologically naïve populations is unknown despite being a public health priority for this region. A two-host species mathematical model was constructed to analyse this threat. Global sensitivity analysis using Monte Carlo methods highlighted the biological processes of greatest influence to transmission. These included parameters known to be influential in classic mosquito-borne disease models (e.g. vector longevity); however, interesting ecological components that are specific to this system were also highlighted: while local vectors likely have intrinsic preferences for certain host species, how plastic these preferences are, and how this is shaped by local conditions, are key determinants of parasite transmission potential. Invasion analysis demonstrates that this behavioural plasticity can qualitatively impact the probability of an epidemic sparked by imported infection. Identifying key vector sub/species and studying their biting behaviours constitute important next steps before models can better assist in strategizing disease control.
In most countries, male pigs are physically castrated soon after birth to reduce the risk of boar taint and to avoid behaviours such as fighting and mounting. However, entire male pigs are more feed efficient and deposit less fat than barrows. In addition, many animal welfare organizations are lobbying for a cessation of castration, with a likelihood that this could lead to inferior pork unless an alternative method is used to control boar taint. An alternative to physical castration is immunization against gonadotrophin releasing factor (GnRF) which allows producers to capitalize on the superior feed efficiency and carcass characteristics of boars without the risk of boar taint. From a physiological perspective, immunized pigs are entire males until shortly after the second dose, typically given 4 to 6 weeks before slaughter. Following full immunization, there is a temporary suppression of testicular function and a hormonal status that resembles that of a barrow. Nutrient requirements will be different in these two phases, before and after full immunization. Given that there have been few published studies comparing the lysine requirements of entire males and barrows in contemporary genotypes, it is useful to use gilt requirements as a benchmark. A series of meta-analyses comparing anti-GnRF immunized boars and physical castrates and use of nutritional models suggest that the lysine requirement of entire males before the second immunization is 5% higher than for gilts, from 25 to 50 kg BW, and by 8% from 50 to 95 kg. Given that the penalty in growth performance for having inadequate dietary lysine is greater in males than in gilts or barrows, it is important to ensure that lysine requirements are met to obtain the maximum benefits of entire male production during this phase. After the second immunization, the lysine requirement of immunized males decreases and may become more like that of barrows. In addition, a consistent effect of full immunization is a marked increase in voluntary feed intake from about 10 days after the second dose. Putting these together, the estimated lysine requirement, expressed in terms of diet composition, falls to 94% of the gilt level. Although general principles can be described now, further research is needed to fully define the lysine requirements of immunized boars. It is important that the temporal pattern of tissue deposition rates and feed intake be explored to be incorporated into models to predict nutrient requirements over the period of rapidly changing metabolism.
Studies to quantify genetic variation in cassava germplasm, available within the national breeding programmes in Africa, have been limited. Here, we report on the nature and extent of genetic variation that exists within 1401 cassava varieties from seven countries: Tanzania (270 genotypes); Uganda (268); Kenya (234); Rwanda (184); Democratic Republic of Congo (DRC; 177); Madagascar (186); Mozambique (82). The vast majority of these genotypes do not exist within a formal germplasm conservation initiative and were derived from farmers' fields and National Agricultural Research Systems breeding programmes. Genotypes were assayed using 26 simple sequence repeat markers. Moderate genetic variation was observed with evidence of a genetic bottleneck in the region. Some differentiation was observed among countries in both cultivars and landraces. Euclidean distance revealed the pivotal position of Tanzanian landraces in the region, and STRUCTURE analysis revealed subtle and fairly complex relationships among cultivars and among landraces and cultivars analysed together. This is likely to reflect original germplasm introductions, gene flow including farmer exchanges, disease pandemics, past breeding programmes and the introduction of cultivars from the International Institute of Tropical Agriculture – Nigeria. Information generated from this study will be useful to justify and guide a regional cassava genetic resource conservation strategy, to identify gaps in cassava diversity in the region and to guide breeding strategies.
The reproductive efficiency of the entire sheep flock could be improved if ewe lambs go through puberty early and produce their first lamb at 1 year of age. The onset of puberty is linked to the attainment of critical body mass, and therefore we tested whether it would be influenced by genetic selection for growth rate or for rate of accumulation of muscle or fat. We studied 136 Merino ewe lambs with phenotypic values for depth of eye muscle (EMD) and fat (FAT) and Australian Sheep Breeding Values at post-weaning age (200 days) for live weight (PWT), eye muscle depth (PEMD) and fat depth (PFAT). First oestrus was detected with testosterone-treated wethers and then entire rams as the ewes progressed from 6 to 10 months of age. Blood concentrations of leptin and IGF-I were measured to test whether they were related to production traits and reproductive performance (puberty, fertility and reproductive rate). In total, 97% of the lambs reached first oestrus at average weight 39.4 ± 0.4 kg (mean ± s.e.m.) and age 219 days (range 163 to 301). Age at first oestrus decreased with increases in values for PWT (P < 0.001), and concentrations of IGF-I (P < 0.05) and leptin (P < 0.01). The proportion of ewe lambs that achieved puberty was positively related with increases in values for EMD (P < 0.01), FAT (P < 0.05) or PWT (P < 0.01), and 75% of the ewe lambs were pregnant at average weight 44.7 ± 0.5 kg and age 263 days (range 219 to 307). Ewe lambs that were heavier at the start of mating were more fertile (P < 0.001) and had a higher reproductive rate (P < 0.001). Fertility and reproductive rate were positively correlated with increases in values for EMD (P < 0.01), FAT (P < 0.05), PWT (P < 0.01) and leptin concentration (P < 0.01). Fertility, but not reproductive rate, increased as values for PFAT increased (P < 0.05). Leptin concentration increased with increases in values for EMD (P < 0.001), FAT (P < 0.001), PWT (P < 0.001), PEMD (P < 0.05) and PFAT (P < 0.05). Many of these relationships became non-significant when PWT or live weight was added to the statistical model. We conclude that selection for genetic potential for growth can accelerate the onset of puberty and increase fertility and reproductive rate of Merino ewe lambs. The metabolic hormones, IGF-I and leptin, might act as a physiological link between the growing tissues and the reproductive axis.
The objective of this research was to assess current patterns of hospital antibiotic prescribing in Northern Ireland and to determine targets for improving the quality of antibiotic prescribing. A point prevalence survey was conducted in four acute teaching hospitals. The most commonly used antibiotics were combinations of penicillins including β-lactamase inhibitors (33·6%), metronidazole (9·1%), and macrolides (8·1%). The indication for treatment was recorded in 84·3% of the prescribing episodes. A small fraction (3·9%) of the surgical prophylactic antibiotic prescriptions was for >24 h. The results showed that overall 52·4% of the prescribed antibiotics were in compliance with the hospital antibiotic guidelines. The findings identified the following indicators as targets for quality improvement: indication recorded in patient notes, the duration of surgical prophylaxis and compliance with hospital antibiotic guidelines. The results strongly suggest that antibiotic use could be improved by taking steps to address the identified targets for quality improvement.
Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65–1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.
Bioimpedance spectroscopy (BIS) has been used to track changes in total body water (TBW). Accurate TBW estimations can be influenced by both methodological and biological factors. One methodological variation that contributes to BIS TBW errors is the electrode placement. The purpose of the present study was to compare the reproducibility and validity of fixed-distance electrode placements (5 cm) with the standard single-site electrode placements. Twenty-nine subjects (fifteen men and fourteen women) participated in the reproducibility study, while sixty-nine subjects (thirty-three men and thirty-six women) participated in the validity study. The reproducibility study included two measurements that were taken 24 h apart, while the validity study consisted of a 12-week exercise intervention with measurements taken at weeks 1 and 12. TBW was estimated using BIS and 2H techniques. Reproducibility results indicated that fixed-distance electrodes reduced the day-to-day standard error of the measurement in men (from 1·13 to 0·81 litres) but not in women (0·47 litres). sem values were lower for women than for men, suggesting that BIS TBW estimates are sex dependent. Validity results produced similar accurate findings (mean difference < 0·21 litres). However, fixed-distance electrodes improved delta TBW errors (mean difference improvements>0·04 litres in men, women, and men and women combined). When tracking changes in TBW, fixed-distance electrodes may reduce reproducibility errors and allow for smaller changes to be detected. However, the reduction of reproducibility errors may be greater for men than for women. Therefore, reproducibility calculations should be based on the sex of the sample population.
Carrying a functional single nucleotide polymorphism (L503F, c. 1672 C>T) in the gene for the Na-dependent organic cation transporter (OCTN1), increases the risk of Crohn's disease (CD) in some, but not all, populations. Case–control data on New Zealand Caucasians show no differences for CD risk between individuals carrying the L503F OCTN1 C-allele when compared with those carrying the variant T-allele. However, more of the New Zealand CD cases report intolerance to maize and mushrooms than those who report beneficial effects or no differences. The OCTN1 gene encodes a transporter for ergothionine, a fungal metabolite at high levels in mushrooms but not widely common in other dietary items. An inability to tolerate mushrooms showed statistically significant associations with the variant OCTN1 genotype. That is, among those individuals reporting adverse effects from mushrooms, there was a higher frequency of the variant T-allele when compared with the general population, or with CD patients overall. We believe that this is a novel gene–diet association, suggesting that individuals carrying the OCTN1 variant single nucleotide polymorphism may have an enhanced risk of adverse symptoms associated with consuming mushrooms. Nutrigenomic approaches to dietary recommendations may be appropriate in this group.