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Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia.
Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage.
Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p < 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p < 0.005), who scored significantly lower on all cognitive domains (p < 0.005).
Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population.
Psychiatric morbidity was measured in a prospective follow-up study of 51 patients admitted to hospital after minor head injury. By means of self report questionnaires (eg General Health Questionnaire (SHQ) and Impact of Event Scale), semistructured interviews and symptom-checklists, it was found that nearly half of the patients suffered considerable discomfort after 1 week. Improvement during the 3 months follow-up was generally poor. Both concussional symptoms and stress response contributed to the compromised well-being as measured by the GHQ, but outcome did not correlate to severity of injury. The GHQ-60 score of 1 week showed a strong positive correlation with outcome after 3 months. The incidence of post-traumatic stress disorder was low.
Impaired cognition is a prominent feature of schizophrenia. To what extent the heterogeneous cognitive impairments can be accounted for by considering only a single underlying impairment or a small number of core impairments remains elusive. This study examined whether cognitive impairments in antipsychotic-naïve, first-episode schizophrenia patients may be determined by a relative slower speed of information processing.
Forty-eight antipsychotic-naïve patients with first-episode schizophrenia and 48 matched healthy controls were administered a comprehensive battery of neuropsychological tests to assess domains of cognitive impairments in schizophrenia. Composite scores were calculated, grouping tests into cognitive domains.
There were significant differences between patients and healthy controls on global cognition and all cognitive domains, including verbal intelligence, processing speed, sustained attention, working memory, reasoning and problem solving, verbal learning and memory, visual learning and memory, and reaction time. All these significant differences, except for verbal intelligence and global cognition, disappeared when processing speed was included as a covariate.
At the first stage of illness, antipsychotic-naïve patients with schizophrenia display moderate/severe impairments in all the cognitive domains assessed. The results support the contention of a global cognitive dysfunction in schizophrenia that to some extent may be determined by impaired processing speed.
This study directly compares the effectiveness of aripiprazole once-monthly 400 mg (AOM) and paliperidone palmitate once-monthly (PP) on the validated and symptom-focused Heinrichs-Carpenter Quality-of-Life Scale (QLS) in schizophrenia.
A 28-week, randomized, open-label rater-blinded, head-to-head study (NCT01795547) of AOM and PP in adult patients (18-60 years) needing a change from current oral antipsychotic treatment for any reason. The study comprised oral conversion, initiation of AOM or PP treatment according to labels, and treatment continuation with injections every 4 weeks. The primary endpoint assessed non-inferiority and subsequently superiority on change from baseline to week 28 in QLS total score analyzed using a mixed model for repeated measurements.
Of 295 randomized patients, 100/148 (67.6%) of AOM and 83/147 (56.5%) of PP patients completed 28 weeks of treatment. In treated patients, adverse events (AEs) were the most frequent reason for discontinuation; AOM: 16/144 (11.1%), PP: 27/137 (19.7%). The difference in change from baseline to week 28 on QLS total score was statistically significant (4.67 [95%CI: 0.32;9.02], p=0.036), confirming non-inferiority and establishing superiority of AOM compared to PP. The respective changes were 7.47±1.53 for AOM and 2.80±1.62 for PP. AEs occurring at rates ≥5% in either group in the treatment continuation phase were weight increased (AOM: 12/119 [10.1%]; PP: 17/109 [15.6%]), psychotic disorder (AOM: 3/119 [2.5%]; PP: 6/109 [5.5%]) and insomnia (AOM: 3/119 [2.5%]; PP: 6/109 [5.5%]).
Superior improvements on the clinician-rated QLS and lower rates of all-cause discontinuation suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate.
Arrhythmia is a potentially fatal side effect of antipsychotics. A biologic predictive tool to prevent it is missing.
Identification of a genetic profile at risk for antipsychotic induced arrhythmia.
Identifying a molecular pathway enriched for antipsychotic induced QT-modifications.
Seven hundred and sixty-five SKZ individuals, M = 556, age = 40.93 ± 11.03 were included. QT-variation was a phase-specific created variable. A nested mixed regression served in R for clinical and molecular pathway analyses. Plink served for genetic analyses. Quality checking was standard, inflation factor was controlled by lambda values.
Quetiapine and Perphenazine were associated with QT variation (P = 0.002; Estimate = 5.79 and P = 5.67e-06; Estimate = 8.96 respectively). No other significant association was detected. No inflation was detected. Axon guidance and Collagen biosynthesis (Table 1) were associated with QT variation at a conservative (adjusted) P value < 0.01.
Two molecular pathways were identified as possibly involved in QT modifications during antispsychotic treatment in SKZ patients. Previous evidence supports a role of the same pathways in cardiac disorders [1,2]. Interaction of specific SNPs with the drugs will be focus of further research.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
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.
Sub-Saharan Africa has the highest natural twinning rate in the world. Unfortunately, due to lack of adequate care during pregnancy, labor and postnatally, twin mortality in Sub-Saharan Africa also remains very high. Thus, it has been estimated that one in five twins dies during the childhood years. In spite of this, surprisingly few twin studies have been conducted in the region, making additional epidemiological data much needed. In 2009, we established one of the first twin registries in Sub-Saharan Africa at the Bandim Health Project in Guinea-Bissau. The registry had two main objectives. First, we wanted to describe the twinning rate and mortality patterns among newborn twins, including mortality risk factors and hospitalization patterns. Such studies can help the local clinicians improve twin health by identifying the most vulnerable children. Second, and in light of the rapidly increasing diabetes rates in Africa, we wanted to use the registry to particularly focus on metabolic disorders. Twins are often born with low birth weight, which according to the ‘thrifty phenotype hypothesis’ could predispose them to metabolic disorders later in life. Yet, no such ‘fetal programming’ data have previously been available from African twins despite the fact that nutritional patterns and influences from other factors (e.g., infections) could be markedly different here compared to high-income settings. In this article, we summarize the findings and current status of the Guinea-Bissau twin registry.
It has been reported that foetal death follows a seasonal pattern. Influenza virus infection has been postulated as one possible contributor to this seasonal variation. This ecological study explored the temporal association between the influenza activity and the frequency of foetal death. Time series analysis was conducted using weekly influenza-like illness consultation proportions from the Danish sentinel surveillance system and weekly proportions of spontaneous abortions and stillbirths from hospital registers from 1994 to 2009. The association was examined in an autoregressive (AR) integrated (I) moving average (MA) model and subsequently analysed with cross-correlation functions. Our findings confirmed the well-known seasonality in influenza, but also seasonality in spontaneous abortion. No clear pattern of seasonality was found for stillbirths, although the analysis exposed dependency between observations. One final AR integrated MA model was identified for the influenza-like illness (ILI) series. We found no statistically significant relationship between weekly influenza-like illness consultation proportions and weekly spontaneous abortion proportions (five lags: P = 0.52; 11 lags: P = 0.91) or weekly stillbirths (five lags: P = 0.93; 11 lags: P = 0.40). Exposure to circulating influenza during pregnancy was not associated with rates of spontaneous abortions or stillbirths. Seasonal variations in spontaneous abortion were confirmed and this phenomenon needs further investigation.
Tail damage within the production of finisher pigs is an animal welfare problem. Recent research suggests that removal of known risk factors may not be enough to eliminate tail biting, especially in undocked pigs, thus a different strategy is worth investigating. This could be early detection of tail biting, using behavioural changes observed before tail damage. If these early stages of tail biting can be detected before tail damage occurs, then tail damage could be prevented by early interventions. The first step in developing such a strategy is to identify the types of behaviour changes that emerge during early stages of tail biting. Thus, the aim of the current study was to investigate whether pen level activity and object manipulation evolved differently during the last 7 days before the scoring of tail damage (day 0) for pens scored with tail damage (tail damage pens) and pens not scored with tail damage (matched control pens). The study included video recordings for twenty-four tail damage pens and thirty-two matched control pens. Activity level and object manipulation were observed the last 7 days before day 0 during the morning (0600 to 0800 h), afternoon (1600 to 1800 h) and evening (2200 to 2400 h, only activity level). Both activity level and object manipulation were analysed using generalised linear mixed effects models with a binomial distribution for activity level and a negative binomial distribution for object manipulation. The probability of being active was higher in tail damage pens compared to control pens during the afternoon the last 5 days before day 0 (P<0.001). This was seen due to a decrease in activity level in the control pens, which makes it difficult to identify future tail damage pens from this difference. Object manipulation was lower in tail damage pens compared to the control pens on all 7 days before day 0, but only in pens with undocked pigs (P<0.01). Thus, it is still unknown when this difference in object manipulation initiated. It was concluded that both activity level and object manipulation seemed related to ongoing tail biting and should be investigated through more detailed observations and for a longer time to establish the normal behaviour pattern for a particular pen. Thus, it is suggested that future research focusses on developing automatic monitoring methods for pen level activity and object manipulation and applies algorithms that establish and detect deviations from the normal behaviour pattern of the pen before tail damage.
Piglet mortality in outdoor production systems varies across the year, and a reason for this variation could be fluctuations in hut climate, as ambient temperature might influence piglet survival, both directly and indirectly. Therefore, the aim of the current study was to investigate the impact of farrowing hut climate and year variation on stillbirth and liveborn mortality. A large-scale observational study was conducted at five commercial organic pig-producing herds in Denmark from June 2015 to August 2016. Both year variation (F3,635=4.40, P=0.004) and farrowing hut temperature (F2,511=6.46, P=0.002) affected the rate of stillbirths. The risk of stillborn piglets was lowest in winter and during this season larger changes in hut temperature between day 1 prepartum and the day of farrowing increased the risk of stillbirths (F1,99=6.39, P=0.013). In addition, during the warm part of the year stillbirth rate increased at temperatures ⩾27°C. Year variation also affected liveborn mortality (F3,561=3.86, P=0.009) with a lower rate of liveborn deaths in spring. However, the hut climate did not influence liveborn deaths. Consequently, other factors than hut climate may explain the influence of year variation on liveborn mortality. These could be light differences causing seasonality in reproduction and lactation.
Assessing the relationship between antimicrobial usage (AMU) and antimicrobial resistance (AMR) requires the accurate and precise utilisation of register data. Therefore, validation of register-based data is essential for evaluating the quality and, subsequently, the internal validity of studies based on the data.
In this study, different smoothing methods for Veterinary Medicine Statistic Program database (VetStat)-records were validated by comparing these with farm-records. Comparison between measurements included accuracy as; completeness and correctness, and precision as; a relative difference of the error, correlation with Fisher's z transformation and reliability coefficient. The most valid methods of those examined were then used in re-analyses of the abundance of AMR genes in 10 finisher batches from a previous study.
Improved accuracy was found when detailed smoothing methods were applied. Although the precision also increased, the effect was not as pronounced, as the usage estimate of all smoothing methods deviated moderately compared with the farm-registrations. Applying the most valid methods to the 10 finisher batches increased estimates of statistical model fit for aminoglycosides, lincosamides, tetracyclines and decreased estimates of statistical model fit for macrolides. The estimates of statistical model fit for sulfonamides and broad-spectrum penicillins remained the same.
Through refined data transformation, VetStat-records can be used to calculate a daily amount of AMU per pig reflecting the true usage accurately and moderately precisely, which is the foundation for calculating lifetime AMU.
Deficit irrigation (DI) improves water use efficiency (WUE), but the reduced water input often limits plant growth and nutrient uptake. The current study examined whether arbuscular mycorrhizal fungi (AMF) could alleviate abiotic stress caused by low phosphorus (P) fertilization and DI.
A greenhouse experiment was conducted with potato grown with (P1) or without (P0) P fertilization, with AMF (M1+: Rhizophagus irregularis or M2+: Glomus proliferum) or AMF-free control (M−) and subjected to full irrigation (FI), DI or partial root-zone drying (PRD).
Inoculation of M1+ and M2+ maintained or improved plant growth and P/nitrogen (N) uptake when subjected to DI/PRD and P0. However, the positive responses to AMF varied with P level and irrigation regime. Functional differences were found in ability of AMF species alleviating plant stress. The largest positive plant biomass response to M1+ and M2+ was found under FI, both at P1 and P0 (25% increase), while plant biomass response to M1+ and M2+ under DI/PRD (14% increase) was significantly smaller. The large growth response to AMF inoculation, particularly under FI, may relate to greater photosynthetic capacity and leaf area, probably caused by stimulation of plant P/N uptake and carbon partitioning toward roots and tubers. However, plant growth response to AMF was not related to the percentage of AMF root colonization. Arbuscular mycorrhizal fungi can maintain and improve P/N uptake, WUE and growth of plants both at high/low P levels and under FI/DI. If this is also the case under field conditions, it should be implemented for sustainable potato production.
The aim of this study was to validate the estimated habitual dietary intake from a newly developed web-based FFQ (WebFFQ), for use in an adult population in Norway. In total, ninety-two individuals were recruited. Total energy expenditure (TEE) measured by doubly labelled water was used as the reference method for energy intake (EI) in a subsample of twenty-nine women, and multiple 24-h recalls (24HR) were used as the reference method for the relative validation of macronutrients and food groups in the entire sample. Absolute differences, ratios, crude and deattenuated correlations, cross-classifications, Bland–Altman plot and plots between misreporting of EI (EI–TEE) and the relative misreporting of food groups (WebFFQ–24HR) were used to assess the validity. Results showed that EI on group level was not significantly different from TEE measured by doubly labelled water (0·7 MJ/d), but ranking abilities were poor (r −0·18). The relative validation showed an overestimation for the majority of the variables using absolute intakes, especially for the food groups ‘vegetables’ and ‘fish and shellfish’, but an improved agreement between the test and reference tool was observed for energy adjusted intakes. Deattenuated correlation coefficients were between 0·22 and 0·89, and low levels of grossly misclassified individuals (0–3 %) were observed for the majority of the energy adjusted variables for macronutrients and food groups. In conclusion, energy estimates from the WebFFQ should be used with caution, but the estimated absolute intakes on group level and ranking abilities seem acceptable for macronutrients and most food groups.
One challenge of intensive pig production is tail damage caused by tail biting, and farmers often decrease the prevalence of tail damage through tail docking. However, tail docking is not an optimal preventive measure against tail damage and thus, it would be preferable to replace it. The aim of the current study was to investigate the relative effect of three possible preventive measures against tail damage. The study included 112 pens with 1624 finisher pigs divided between four batches. Pens were randomly assigned to one level of each of three treatments: (1) tail-docked (n=60 pens) v. undocked (n=52 pens), (2) 150 g of straw provided per pig per day on the solid floor (n=56 pens) v. no straw provided (n=56 pens), (3) stocking density of 1.21 m2/pig (11 pig/pen; n=56 pens) v. 0.73 m2/pig (18 pigs/pen; n=56 pens). Tail damage was recorded three times per week throughout the finisher period by scoring the tail of each individual pig. A pen was recorded as a tail damage pen and no longer included in the study if at least one pig in a pen had a bleeding tail wound; thus, only the first incidence of tail damage on pen level was recorded. Data were analysed by a Cox regression for survival analysis assuming proportional hazards. Results are presented as hazards, and a higher hazard means that a pen has a higher risk of tail damage and of it happening earlier in the finisher period. Pens with undocked pigs had a 4.32-fold higher hazard of tail damage compared with pens with docked pigs (P<0.001). Pens with no straw provided had a 2.22-fold higher hazard of tail damage compared with pens with straw provided (P<0.01). No interactions was seen between the treatments, but the effect of tail docking was higher than the effect of straw provision (P<0.001). Stocking density did not have a significant effect on the hazard of tail damage (hazard rate ratios (HRR)=1.67; P=0.064). However, a combination of straw provision and lowered stocking density showed a similar hazard of tail damage as seen with only tail docking (HRR=1.58; P=0.39). In conclusion, tail docking and straw provision were preventive measures against tail damage, and tail docking reduced the risk more than straw provision. A combination of other preventive measures is necessary to reduce the risk of tail damage in undocked pigs to the same level as in docked pigs.
The objectives were to present three approaches for calculating antimicrobial (AM) use in pigs that take into account the rearing period and rearing site, and to study the association between these measurements and phenotypical resistance and abundance of resistance genes in faeces samples from 10 finisher batches. The AM use was calculated relative to the rearing period of the batches as (i) ‘Finisher Unit Exposure’ at unit level, (ii) ‘Lifetime Exposure’ at batch level and (iii) ‘Herd Exposure’ at herd level. A significant effect on the occurrence of tetracycline resistance measured by cultivation was identified for Lifetime Exposure for the AM class: tetracycline. Furthermore, for Lifetime Exposure for the AM classes: macrolide, broad-spectrum penicillin, sulfonamide and tetracycline use as well as Herd Unit Exposure for the AM classes: aminoglycoside, lincosamide and tetracycline use, a significant effect was observed on the occurrence of genes coding for the AM resistance classes: aminoglycoside, lincosamide, macrolide, β-lactam, sulfonamide and tetracycline. No effect was observed for Finisher Unit Exposure. Overall, the study shows that Lifetime Exposure is an efficient measurement of AM use in finisher batches, and has a significant effect on the occurrence of resistance, measured either by cultivation or metagenomics.
Background: Cerebral palsy (CP) is a debilitating disorder (1). Based on neuromotor impairments it is divided to spastic, dyskinetic and ataxic types (2). Inborn Errors of Metabolism (IEMs), monogenic and chromosomal disorders mimic CP (3). We aimed to identify causal genetic variants in patients with atypical dyskinetic CP in whom known IEMs were ruled out. Timely diagnosis is essential for proper management, especially in conditions that mimic CP and are treatable. Methods: We enrolled 23 patients with unexplained atypical dyskinetic CP, for whole exome sequencing. Variants were filtered against public and in-house databases to identify variants predicted as damaging (in silico tools and ACMG criteria). We applied a virtual gene panel of known and suspected CP and movement disorder genes and investigated each sample. Results: The participants presented with symptoms including: spasticity, dystonia, choera-athetosis, ataxia and cognitive delays. We identified 23 diagnoses: 13 dominant,6 recessive and 4 X-linked. 12 patients had movement disorders. In 4, the diagnoses enabled targeted treatment (neurotransmitter supplements in Unverricht Lundborg diseases (CSTB) and PAK3 deficiency, deep brain stimulation in GNAO1 deficiency, medical diet in Glutaric Aciduria (GCDH). Conclusions: Whole Exome Sequencing contributes to establishing diagnosis in patients with atypical dyskinetic CP resulting in precision medicine and improved health outcomes.
In a longitudinal study including 642 healthy 8–11-year-old Danish children, we investigated associations between vitamin D dependent SNP and serum 25-hydroxyvitamin D (25(OH)D) concentrations across a school year (August–June). Serum 25(OH)D was measured three times for every child, which approximated measurements in three seasons (autumn, winter, spring). Dietary and supplement intake, physical activity, BMI and parathyroid hormone were likewise measured at each time point. In all, eleven SNP in four vitamin D-related genes: Cytochrome P450 subfamily IIR1 (CYP2R1); 7-dehydrocholesterol reductase/nicotinamide adenine dinucleotide synthetase-1(DHCR7/NADSYN1); group-specific complement (GC); and vitamin D receptor were genotyped. We found minor alleles of CYP2R1 rs10500804, and of GC rs4588 and rs7041 to be associated with lower serum 25(OH)D concentrations across the three seasons (all P<0·01), with estimated 25(OH)D differences of −5·8 to −10·6 nmol/l from major to minor alleles homozygosity. In contrast, minor alleles homozygosity of rs10741657 and rs1562902 in CYP2R1 was associated with higher serum 25(OH)D concentrations compared with major alleles homozygosity (all P<0·001). Interestingly, the association between season and serum 25(OH)D concentrations was modified by GC rs7041 (Pinteraction=0·044), observed as absence of increase in serum 25(OH)D from winter to spring among children with minor alleles homozygous genotypes compared with the two other genotypes of rs7041 (P<0·001). Our results suggest that common genetic variants are associated with lower serum 25(OH)D concentrations across a school year. Potentially due to modified serum 25(OH)D response to UVB sunlight exposure. Further confirmation and paediatric studies investigating vitamin D-related health outcomes of these genotypic differences are needed.
We present a combined numerical (particle vortex method) and experimental (soap film tunnel) study of a symmetric foil undergoing prescribed oscillations in a two-dimensional free stream. We explore pure pitching and pure heaving, and contrast these two generic types of kinematics. We compare measurements and simulations when the foil is forced with pitching oscillations, and we find a close correspondence between flow visualisations using thickness variations in the soap film and the numerically determined vortex structures. Numerically, we determine wake maps spanned by oscillation frequency and amplitude, and we find qualitatively similar maps for pitching and heaving. We determine the drag–thrust transition for both pitching and heaving numerically, and we discuss it in relation to changes in wake structure. For heaving with low oscillation frequency and high amplitude, we find that the drag–thrust transition occurs in a parameter region with wakes in which two vortex pairs are formed per oscillation period, in contrast to the common transition scenario in regions with inverted von Kármán wakes.