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The psychedelic research renaissance is gaining traction. Preliminary clinical studies of the hallucinogenic fungi, psilocybin, with psychological support, have indicated improvements in mood, anxiety and quality of life. A seminal, open-label study demonstrated marked reductions in depression symptoms in participants with treatment-resistant depression (TRD). The associated neurobiological processes involve alterations in brain connectivity, together with altered amygdala and default mode network activity. At the cellular level, psychedelics promote synaptogenesis and neural plasticity. Prompted by the promising preliminary studies, a randomized, double-blind trial has recently been launched across Europe and North America to investigate the efficacy of psilocybin in TRD. One of these centres is based in Ireland – CHO Area 7 and Tallaght University Hospital. The outcome of this trial will determine whether psilocybin with psychological support will successfully translate into the psychiatric clinic for the benefit of patients.
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.
This paper presents a review of the current status of photodiode array systems adapted for Energy Dispersive EXAFS (EDE) using a synchrotron radiation source. The performance of a conventional Reticon PDA is compared with that of a hybrid CCD. The specification of a new detector system for EDE is discussed in the light of experience gained with current linear detectors.
X-ray diffraction angles are measured precisely, conveniently, and automatically by a specially designed instrument, the automatic precision X-ray goniometer connected on line to an Elliott 903B data processor. A monitor program controls two such instruments and two diffractometers simultaneously and allows a comprehensive set of experiments to be performed. The sensitivity is such that, when translated into terms of changes in the crystal-lattice parameter, a precision of 1 part in 10,000,000 is being attained, and indications are that absolute measurements are almost as good. The procedures, instrument, and automatic control are described, and the results of performance tests and some applications are given.
Effective treatments for patients with high levels of negative symptoms of schizophrenia are lacking. Brexpiprazole is a serotonin–dopamine activity modulator that is a partial agonist at 5-HT1A and dopamine D2 receptors, and an antagonist at 5-HT2A and noradrenaline alpha1B/2C receptors, all with subnanomolar potency. Long-term treatment with brexpiprazole demonstrated broad efficacy across all five Marder factor groupings, including positive, negative, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. This post-hoc analysis of long-term effects of brexpiprazole in patients with clinically relevant levels of negative symptoms of schizophrenia is based on data from two similarly designed short-term, placebo-controlled studies (Vector; NCT01396421 or Beacon; NCT01393613) for the brexpiprazole-treated patients who continued into an open-label extension study (Zenith; NCT01397786).
In the short-term studies, patients with acute schizophrenia were randomly assigned to fixed once-daily doses of brexpiprazole 0.25mg (Vector), 1mg (Beacon), 2mg , 4mg or placebo for 6weeks. The long-term study was an open-label, 52-week (amended to 26weeks), safety extension study with flexible-dose (1–4mg/day) brexpiprazole. The post-hoc analyses were performed on brexpiprazole-treated patients from the short-term studies who continued into the long-term study, and who had clinically relevant negative symptoms, defined as PANSS Factor Score for Negative Symptoms (PANSS-FSNS; N1, N2, N3, N4, G7, G16) of ≥24, and score of ≥4 on at least two of three core negative symptom PANSS items at randomization in the parent study. The outcome of the analysis included change from baseline to up to 58weeks in PANSS-FSNS, PANSS Total, and PSP. Safety was also assessed.
A total of 187 patients with clinically relevant levels of negative symptoms in the parent study rolled-over into the open-label extension study and were available for analysis. Eighty-three of these patients remained in the studies for 58weeks. Due to the study amendment, not all patients had the opportunity of complete 52weeks of open-label treatment. Baseline PANSS Total score was 104.4, while baseline PANSS-FSNS was 27.6 and baseline PSP Total score was 41.3. Mean change (SD) from baseline in PANSS-FSNS was –10.9 (5.0), and –44.2 (17.5) for PANSS Total score at Week 58. Change from baseline (SD) to Week 58 for PSP Total score was 24.8 (12.9) with improvement in all domains (socially useful activities, personal and social relationship, self-care, and disturbing and aggressive behaviors). The TEAEs reported ≥5% were schizophrenia (18.9%), insomnia (8.6%), weight increased (5.9%) and akathisia (5.9%).
This post-hoc analysis suggests that brexpiprazole has long-term effectiveness on negative symptoms and functioning in patients with schizophrenia and clinically relevant levels of negative symptoms.
Funding Acknowledgements: The study was funded by Otsuka Pharmaceutical Development & Commercialization Inc. and H. Lundbeck A/S
Here we present the synthesis of porous platinum–palladium macrobeams templated from high aspect ratio Magnus’ salt needle derivatives. The combination of [PtCl4]2− and/or [PdCl4]2− with [Pt(NH3)4]2+ ions results in salt needles ranging from 15 to 300 µm in length. Electrochemical reduction of the salt templates results in porous macrobeams with a square cross-section. Porous side wall texture and elemental composition was controlled with initial platinum to palladium salt ratio. Macrobeam free-standing films exhibited a specific capacitance up to 11.73 F/g and a solvent accessible surface area of 26.6 m2/g. These salt-templated porous platinum–palladium macrobeams offer a promising material for fuel cell catalysis.
To assess, using standardised tools, the quality and readability of online tinnitus information that patients are likely to access.
A standardised review was conducted of websites relating to tinnitus and its management. Each website was scored using the DISCERN instrument and the Flesch Reading Ease scale.
Twenty-seven unique websites were evaluated. The mean DISCERN score of the websites was 34.5 out of 80 (standard deviation = 11.2). This would be considered ‘fair’ in quality. Variability in DISCERN score between websites was high (range, 15–57: ‘poor’ to ‘very good’). Website readability was poor, with a mean Flesch Reading Ease score of 52.6 (standard deviation = 7.7); this would be considered ‘difficult’ to read.
In general, the quality of tinnitus websites is fair and the readability is poor, with substantial variability in quality between websites. The Action on Hearing Loss and the British Tinnitus Association websites were identified as providing the highest quality information.
To evaluate whole-genome sequencing (WGS) as a molecular typing tool for MRSA outbreak investigation.
Investigation of MRSA colonization/infection in a neonatal intensive care unit (NICU) over 3 years (2014–2017).
Single-center level IV NICU.
NICU infants and healthcare workers (HCWs).
Infants were screened for MRSA using a swab of the anterior nares, axilla, and groin, initially by targeted (ring) screening, and later by universal weekly screening. Clinical cultures were collected as indicated. HCWs were screened once using swabs of the anterior nares. MRSA isolates were typed using WGS with core-genome multilocus sequence typing (cgMLST) analysis and by pulsed-field gel electrophoresis (PFGE). Colonized and infected infants and HCWs were decolonized. Control strategies included reinforcement of hand hygiene, use of contact precautions, cohorting, enhanced environmental cleaning, and remodeling of the NICU.
We identified 64 MRSA-positive infants: 53 (83%) by screening and 11 (17%) by clinical cultures. Of 85 screened HCWs, 5 (6%) were MRSA positive. WGS of MRSA isolates identified 2 large clusters (WGS groups 1 and 2), 1 small cluster (WGS group 3), and 8 unrelated isolates. PFGE failed to distinguish WGS group 2 and 3 isolates. WGS groups 1 and 2 were codistributed over time. HCW MRSA isolates were primarily in WGS group 1. New infant MRSA cases declined after implementation of the control interventions.
We identified 2 contemporaneous MRSA outbreaks alongside sporadic cases in a NICU. WGS was used to determine strain relatedness at a higher resolution than PFGE and was useful in guiding efforts to control MRSA transmission.
Conservation resources are limited, yet an increasing number of species are under threat. Assessing species for their conservation needs is, therefore, a vital first step in identifying and prioritizing species for both ex situ and in situ conservation actions. Using a transparent, logical and objective method, the Conservation Needs Assessment process developed by Amphibian Ark uses current knowledge of species in the wild to determine those with the most pressing conservation needs, and provides a foundation for the development of holistic conservation action plans that combine in situ and ex situ actions as appropriate. These assessments allow us to maximize the impact of limited conservation resources by identifying which measures could best serve those species requiring help. The Conservation Needs Assessment complements the IUCN Red List assessment, and together they provide a more holistic guide to conservation priorities and actions. Conservation Needs Assessments generate national prioritized lists of species recommended for conservation action. These can subsequently be used to assist in the development of species recovery plans and national action plans, or to inform national conservation priorities better. Additional tools that will evaluate the recommendations for ex situ rescues, to determine the best candidates for conservation breeding programmes, are currently under development.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a disease continuum with common genetic causes and molecular pathology. We recently identified mutations in the T-cell restricted intracellular antigen-1 (TIA1) protein as a cause of ALS +/− FTD. TIA1 is an RNA-binding protein containing a low complexity domain (LCD) that promotes the assembly of membrane-less organelles, such as stress granules (SG). Whole exome sequencing of two family members with fALS/FTD revealed a novel missense mutation in the TIA1 LCD (P362L). Subsequent screening identified five more TIA1 mutations in six additional ALS patients, but none in controls. All mutation carriers presented with weakness, behavioral abnormalities or language impairments and had a final diagnosis of ALS +/− FTD. Autopsy on five TIA1 mutation carriers showed widespread neurodegeneration with TDP-43 pathology. Round eosinophilic inclusions in lower motor neurons were a consistent feature. Cellular assays revealed abnormal SG dynamics in the presence of TIA1 mutations. In summary, missense mutations in the LCD of TIA1 are a newly recognized cause of ALS/FTD with TDP-43 pathology and strengthen the role of RNA metabolism in the pathogenesis in this disease.
Azaperone can reduce stress caused by weaning and relocation of breeding sows, but its effects on reproductive processes are still poorly understood. The primary aim of this study was to describe and compare the endocrine and ovarian activity in ultrasonographically monitored second parity sows, with or without azaperone treatment at weaning (2 mg/kg BW i.m.). The intervals from weaning to the onset of estrus and ovulation were both greater (P<0.05) in azaperone-treated (n=12) than in control sows (n=12) by ~12 h. Mean daily growth rates of identified antral follicles were less (P<0.05) in azaperone-treated than in control sows (1.08±0.17 v.1.23±0.18 mm/day; mean±SD) and treated animals exceeded (P<0.05) controls in the mean ovulation rate (13.7±1.3 v. 12.6±1.2). A transient suppression of cortisol release was observed in the treatment group (at 10 and 30 min after azaperone injections) but circulating cortisol concentrations were variable in both groups of sows for the remainder of the study. The preovulatory rise in LH and estradiol secretion was delayed (P<0.05), and the duration of the LH surge was greater (P<0.001) in azaperone-treated sows compared with their control counterparts. The amplitude of episodic fluctuations in serum cortisol concentrations was correlated with the number of stillborn piglets in control sows (r=0.63, P=0.04). The amplitude and concentration of the preovulatory rise in estradiol secretion were negatively correlated with ovulatory response and litter size (r=−0.63 to −0.82, P<0.05), whereas the time at which the LH surge ended was directly related to the number of live-born piglets (r=0.82, P=0.002) in azaperone-treated animals. The present results indicate that administration of azaperone at weaning had a profound effect on preovulatory LH secretion as well as growth kinetics and estrogenicity of ovarian antral follicles. However, the causative associations among various characteristics of the preovulatory LH discharge, ovarian and adrenal steroid secretion post-weaning, and reproductive variables in sows remain equivocal.
The study aimed to examine the effects of diurnal Ramadan fasting (RF) on substrate oxidation, energy production, blood lipids and glucose as well as body composition. Nine healthy Muslim men (fasting (FAST) group) and eight healthy non-practicing men (control (CNT) group) were assessed pre- and post-RF. FAST were additionally assessed at days 10, 20 and 30 of RF in the morning and evening. Body composition was determined by hydrodensitometry, substrate oxidation and energy production by indirect calorimetry, blood metabolic profile by biochemical analyses and energy balance by activity tracker recordings and food log analyses. A significant group×time interaction revealed that chronic RF reduced body mass and adiposity in FAST, without changing lean mass, whereas CNT subjects remained unchanged. In parallel to these findings, a significant main diurnal effect (morning v. evening) of RF on substrate oxidation (a shift towards lipid oxidation) and blood metabolic profile (a decrease in glucose and an increase in total cholesterol and TAG levels, respectively) was observed, which did not vary over the course of the Ramadan. In conclusion, although RF induces diurnal metabolic adjustments (morning v. evening), no carryover effect was observed throughout RF despite the extended daily fasting period (18·0 (sd 0·3) h) and changes in body composition.
Globally, some species and habitats receive protection through local belief systems (e.g. indigenous religions) and informal institutions (e.g. social norms and taboos). Where such systems represent the only form of protection for threatened species or environments, they may be critical to the survival of those taxa and sites. We evaluated the effectiveness of long-standing social taboos protecting the Endangered Sclater's monkey Cercopithecus sclateri and forest groves in a community complex in Nigeria. Across its range (southern Nigeria), Sclater's monkey is effectively protected only through informal institutions. At our study site, we conducted a census of the monkey population; measured the area of sacred groves; and compared our findings with estimates from 2010 and 2005, respectively. We observed a 36% increase in the monkey population (from 249 to 339 individuals) in a core survey area. No groves that we assessed in 2005 had been fully cleared. Although we observed a decline in tree cover for several sacred forests, most groves used regularly by monkeys had changed little. The social taboos related to monkeys and sacred groves remain largely intact; however, other factors threaten the monkey population and remaining forests in this community complex, including the removal of tree patches to accommodate the construction of large residential buildings and the demand for cropland, as well as increased dumping of waste in forested sites. This study highlights the conservation importance and limitations of local cultural protection, as well as the challenges presented when such protection conflicts with community-perceived development needs.
The molecular, neurobiological, and physical health impacts of child maltreatment are well established, yet mechanistic pathways remain inadequately defined. Telomere length (TL) decline is an emerging molecular indicator of stress exposure with definitive links to negative health outcomes in maltreated individuals. The multiple confounders endemic to human maltreatment research impede the identification of causal pathways. This study leverages a unique randomized, cross-foster, study design in a naturalistic translational nonhuman primate model of infant maltreatment. At birth, newborn macaques were randomly assigned to either a maltreating or a competent control mother, balancing for sex, biological mother parenting history, and social rank. Offspring TL was measured longitudinally across the first 6 months of life (infancy) from peripheral blood. Hair cortisol accumulation was also determined at 6, 12, and 18 months of age. TL decline was greater in animals randomized to maltreatment, but also interacted with biological mother group. Shorter TL at 6 months was associated with higher mean cortisol levels through 18 months (juvenile period) when controlling for relevant covariates. These results suggest that even under the equivalent social, nutritional, and environmental conditions feasible in naturalistic translational nonhuman primate models, early adverse caregiving results in lasting molecular scars that foreshadow elevated health risk and physiologic dysregulation.
Poor animal performance associated with low digestibility silages results partly from the reduced nutrient yield per unit intake, but also from the associated lower intakes which were presumed to be a consequence of rumen fill effects. Legume silages have a lower average digestibility than grass silages, and yet often have higher intake characteristics. The objective of this work was to compare rumen fill and rumen particle size distribution for animals fed grass silage or legume silage-based diets.
The efficiency of grass nitrogen utilisation for milk production tends to be low, due partly to the slow rate of release of energy in the rumen which reduces the efficiency of capture of rapidly degradable plant proteins by the rumen microbial population. When additional sugars are infused into the rumen, microbial protein production is increased (Rooke et al., 1987). The objective of this study was to assess milk production using a grass variety that has been bred to express elevated water soluble carbohydrate (WSC) concentrations.
Eight multiparous Holstein-Friesian dairy cows in mid lactation (176 days ± s.e. 3.6) were used in a continuous design, zero-grazing experiment. Following covariate measurements taken from all animals on a standard grazing diet, four animals were each offered one of two varieties of perennial ryegrass at ad libitum rate: AberDove, bred to express high WSC concentrations; and AberElan, a commercially available variety, used as a control.