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Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.
Methods
In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.
Results
In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, PFWE = 0.002) and CA1-NAc (Z = 2.94, PFWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, PFWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, PFWE = 0.002, diazepam Z = 3.33, PFWE = 0.003; higher: placebo Z = 4.48, PFWE < 0.001, diazepam Z = 4.22, PFWE < 0.001).
Conclusions
This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.
To examine the association of posttraumatic headache (PTH) type with postconcussive symptoms (PCS), pain intensity, and fluid cognitive function across recovery after pediatric concussion.
Methods:
This prospective, longitudinal study recruited children (aged 8–16.99 years) within 24 hours of sustaining a concussion or mild orthopedic injury (OI) from two pediatric hospital emergency departments. Based on parent-proxy ratings of pre- and postinjury headache, children were classified as concussion with no PTH (n = 18), new PTH (n = 43), worse PTH (n = 58), or non-worsening chronic PTH (n = 19), and children with OI with no PTH (n = 58). Children and parents rated PCS and children rated pain intensity weekly up to 6 months. Children completed computerized testing of fluid cognition 10 days, 3 months, and 6- months postinjury. Mixed effects models compared groups across time on PCS, pain intensity, and cognition, controlling for preinjury scores and covariates.
Results:
Group differences in PCS decreased over time. Cognitive and somatic PCS were higher in new, chronic, and worse PTH relative to no PTH (up to 8 weeks postinjury; d = 0.34 to 0.87 when significant) and OI (up to 5 weeks postinjury; d = 0.30 to 1.28 when significant). Pain intensity did not differ by group but declined with time postinjury. Fluid cognition was lower across time in chronic PTH versus no PTH (d = −0.76) and OI (d = −0.61) and in new PTH versus no PTH (d = −0.51).
Conclusions:
Onset of PTH was associated with worse PCS up to 8 weeks after pediatric concussion. Chronic PTH and new PTH were associated with moderately poorer fluid cognitive functioning up to 6 months postinjury. Pain declined over time regardless of PTH type.
Mood and anxiety disorders co-occur and share symptoms, treatments and genetic risk, but it is unclear whether combining them into a single phenotype would better capture genetic variation. The contribution of common genetic variation to these disorders has been investigated using a range of measures; however, the differences in their ability to capture variation remain unclear, while the impact of rare variation is mostly unexplored.
Aims
We aimed to explore the contributions of common genetic variation and copy number variations associated with risk of psychiatric morbidity (P-CNVs) to different measures of internalising disorders.
Method
We investigated eight definitions of mood and anxiety disorder, and a combined internalising disorder, derived from self-report questionnaires, diagnostic assessments and electronic healthcare records (EHRs). Association of these definitions with polygenic risk scores (PRSs) of major depressive disorder and anxiety disorder, as well as presence of a P-CNV, was assessed.
Results
The effect sizes of both PRSs and P-CNVs were similar for mood and anxiety disorder. Compared to mood and anxiety disorder, internalising disorder resulted in higher prediction accuracy for PRSs, and increased significance of associations with P-CNVs for most definitions. Comparison across the eight definitions showed that PRSs had higher prediction accuracy and effect sizes for stricter definitions, whereas P-CNVs were more strongly associated with EHR- and self-report-based definitions.
Conclusions
Future studies may benefit from using a combined internalising disorder phenotype, and may need to consider that different phenotype definitions may be more informative depending on whether common or rare variation is studied.
Malignant plasma cell proliferations are characterised by specific clinical, immunophenotypic and genetic features. Multiparameter flow cytometry (MFC) is an essential component of the diagnosis of these diseases. Clonal proliferations can be identified through their aberrant cell-surface immunophenotype or, more precisely, by demonstrating monotypy, i.e. selective expression of the same light chain in the cytoplasm of plasma-cells. This chapter reviews these immunophenotypic features, the technical points of caution to observe for proper use of MFC at diagnosis and during therapy to assess measurable residual disease.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
Periprosthetic joint infection (PJI) may result from pathogen-to-patient transmission within the environment. High-touch surfaces (HTS) areas near the operative field from previous studies had been identified as the least likely to be thoroughly cleaned between operative cases and were utilized for this study. The purpose of this study was to assess the impact of a handheld ultraviolet-c (UV-C) light-emitting diode (LED) disinfection device on the decontamination of HTS in the operating room.
Methods:
This prospective study was conducted between 03/02/2021 and 04/20/2021. Tryptic soy agar contact plates were used to determine the bacterial load of the selected surfaces before the initiation of the case, after the case was complete, before manual cleaning, and after disinfection of the LED device. The plates were then incubated for 48 hours at 36º +/–1° C. Colony forming units (CFU) were recorded 48 hours after incubation. Mean, median, and range of CFU were recorded.
Results:
Average CFU per surface before and after the surgical case were 14.1 (range 0–200) and 13.5 (range 0–200) respectively, these were not significantly different (P = 0.9397). Manual cleaning reduced average CFU by 74% to 3.35 (range 0–200) per surface (P = 0.0162). Disinfection with the handheld LED unit further reduced the average CFU by 92% to 0.28 (range 0–4) per surface (P < 0.0001).
Conclusions:
A handheld UV-C LED disinfection device may decrease environmental contamination near the operative field in HTS areas. Further research is warranted with this technology to determine if this correlates with a decrease in PJI.
The increased severity and frequency of bushfires accompanying human-induced global warming have dire implications for biodiversity conservation. Here we investigate the response of a cryptic, cool-climate elapid, the mustard-bellied snake Drysdalia rhodogaster, to the extensive Black Summer fires of 2019/2020 in south-eastern Australia. The species is categorized as Least Concern on the IUCN Red List (last assessed in 2017), but because a large part of its range was burnt during the Black Summer and little was known about its ecology, D. rhodogaster was identified as a priority species for post-fire impact assessment. We evaluated three lines of evidence to assess the impact of the Black Summer fires on D. rhodogaster. Habitat suitability modelling indicated that c. 46% of the predicted range of the species was affected by bushfire. Field surveys conducted 9–36 months post-fire and collation of records from public databases submitted 0–24 months post-fire indicated that D. rhodogaster persisted in burnt landscapes. Fire severity and proportion of the landscape that was burnt within a 1,000-m radius of survey sites were poor predictors of site occupancy by D. rhodogaster. Although conclusions regarding the effects of fire on D. rhodogaster are limited because of the lack of baseline data, it is evident that the species has persisted across the landscape in the wake of extensive bushfires. Our work highlights the need for baseline knowledge on cryptic species even when they are categorized as Least Concern, as otherwise assessments of the impacts of catastrophic events will be constrained.
We investigated cross-sectional and longitudinal associations between neonate microbial exposure and emerging behavioral temperament measures at the ages of 1, 2, and 3 years. Infants and mothers (n = 335) were extracted from the Kuopio Birth Cohort Study. Temperament was assessed using the Infant Behavioral and Early Childhood Behavioral Questionnaires. Microbial samples were collected from oral cavity at birth and the bacterial profiles were assessed using 16S rRNA gene sequencing. Microbial diversity was characterized using alpha and beta diversity metrics. Analyses were performed for the most abundant genera. The sample was analyzed as a whole, as well as divided into subgroups representing no antibiotic use during birth (n = 198) and those with antibiotic use during birth (n = 137). No significant associations were observed between microbial profiles and behavioral measures after Bonferroni corrections. Nevertheless, our pre-correction results indicated an association between increased behavioral temperament surgency in the first year and beta diversity (high abundance of Bacteroides, Faecalibacterium and Blautia, low abundance of Lactobacillus) in the antibiotic use group. Additionally, pre-corrections, a high relative abundance of Staphylococcus was associated with increased surgency through years 1, 2, and 3 in the no antibiotics group, prompting consideration into a possible link between antibiotic use and emerging behavioral temperament.
Synthesising knowledge on the health of marine ecosystems and the human activities is crucial to informing holistic marine management. In many coastal states, however, research is conducted in an ad hoc manner and rarely compiled into accessible repositories making it challenging for marine managers to identify knowledge gaps when allocating resources. Here we conduct a structured review of existing literature to identify the current state of marine and coastal knowledge in the Isles of Scilly, an oceanic archipelago in the UK. The archipelago's marine flora and fauna are biogeographically unique in the Northeast Atlantic, with a distinct mosaic of warm and cold temperate habitats and species and are also considered a rare example of a near pristine marine environment in the otherwise highly degraded Northeast Atlantic Ocean. We found 150 sources relating to the marine biodiversity and relevant human activities in the Isles of Scilly with increasing diversification of research topics in recent years. Sources however remain dominated by specific taxa and habitats, suggesting the Isles of Scilly would particularly benefit from future research into: (1) anthropogenic impacts associated with warming waters and intense seasonal vessel activity; (2) development of repeatable survey protocols that can underpin long-term, ecosystem-based monitoring and management (notably for reef and sediment habitats and the European spiny lobster); and (3) data gaps associated with marine teleost fish and elasmobranch communities including identifying core habitat. This review can therefore act as a baseline biological synthesis for the region and importantly, can inform future research priorities.
This chapter compares two fictional texts of the imperial period that represent freed persons, Xenophon of Ephesus’ Ephesiaca and Petronius’ Cena Trimalchionis. The comparison advances our understanding of how Roman freed persons may have come to terms with the experience of slavery. Ephesiaca expresses sympathy for the enslaved elite protagonists Habrocomes and Anthia not only as enslaved elites, but as enslaved persons per se. The novel continues its sympathy for the protagonists after they have been restored to freedom. In particular, the conclusion of Ephesiaca offers a sympathetic depiction of the protagonists’ response to what they had endured in slavery: Habrocomes and Anthia dedicate memorials to their parents, who had died while the protagonists were still enslaved; they withdraw from the wider community and reconstitute a family that includes their fellow freed persons; they spend the rest of their lives in celebration that is shadowed by their recollection of the past and the anticipation of their own mortality. The same motifs, viz., memorialization, recollection of a painful past, seclusion from the wider community, family constituted on the basis of shared experience rather than biology, and melancholic celebration, mark the representation of Trimalchio and his fellow freed persons in the Cena. The parallels suggest the possibility that these motifs typified the representation of the experience of freed persons, sympathetically in Ephesiaca and derisively in the Cena.
Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.
Prenatal stress has a significant, but small, negative effect on children’s executive function (EF) in middle and high socioeconomic status (SES) households. Importantly, rates and severity of prenatal stress are higher and protective factors are reduced in lower SES households, suggesting prenatal stress may be particularly detrimental for children’s EF in this population. This study examined whether prenatal stress was linked to 5-year-old’s EF in a predominantly low SES sample and child sex moderated this association, as males may be more vulnerable to adverse prenatal experiences. Participants were 132 mother-child dyads drawn from a prospective prenatal cohort. Mothers reported on their depression symptoms, trait anxiety, perceived stress, everyday discrimination, and sleep quality at enrollment and once each trimester, to form a composite prenatal stress measure. Children’s EF was assessed at age 5 years using the parent-report Behavior Rating Inventory of Executive Function - Preschool (BRIEF-P) Global Executive Composite subscale and neuropsychological tasks completed by the children. Mixed models revealed higher prenatal stress was associated with lower BRIEF-P scores, indicating better EF, for females only. Higher prenatal stress was associated with lower performance on neuropsychological EF measures for both males and females. Results add to the limited evidence about prenatal stress effects on children’s EF in low SES households.
The crystal structure of a natural, ordered IIb-4 triclinic clinochlore has been refined in space group C1̄ from 4282 unique X-ray intensity measurements of which 3833 are greater than 3 times the statistical counting error (3σ). Unit cell parameters are a = 5.3262(6) Å; b = 9.226(1) Å; c = 14.334(3) Å; α = 90.56(2)°; β = 97.47(2)°; and γ = 89.979(9)°, which represents the greatest deviation from mono-clinic symmetry yet recorded for a triclinic chlorite. The final weighted R is 0.059 for reflections with I > 3σ and 0.064 for all reflections. The chemical formula is (Mg0.966Fe0.034)MI(Mg0.962Fe0.038)M22(Si2.96Al1.04)O10 (OH)2(Mg0.996Fe0.004)M32(Al0.841FeIII0.102Cr0.004Ti0.004)M4(OH)6, which is consistent with electron microprobe (EMP), wet chemical analyses, Mössbauer spectroscopy and X-ray structure refinement. The high degree of ordering of the divalent versus trivalent octahedral cations in the interlayer is noteworthy, with FeIII and Al in M4 and virtually no Fe in M3. In the 2:1 layer, M1 and M2 each contain similar amounts of Fe. The 2 tetrahedral sites have nearly identical mean oxygen distances and volumes, and thus show no evidence of long-range cation ordering.
Image analysis techniques provide objective and reproducible statistics for interpreting microscopy data. At higher dimensions, three-dimensional (3D) volumetric and spatiotemporal data highlight additional properties and behaviors beyond the static 2D focal plane. However, increased dimensionality carries increased complexity, and existing techniques for general segmentation of 3D data are either primitive, or highly specialized to specific biological structures. Borrowing from the principles of 2D topological data analysis (TDA), we formulate a 3D segmentation algorithm that implements persistent homology to identify variations in image intensity. From this, we derive two separate variants applicable to spatial and spatiotemporal data, respectively. We demonstrate that this analysis yields both sensitive and specific results on simulated data and can distinguish prominent biological structures in fluorescence microscopy images, regardless of their shape. Furthermore, we highlight the efficacy of temporal TDA in tracking cell lineage and the frequency of cell and organelle replication.
The Bali myna Leucopsar rothschildi has long suffered heavy trapping, leading to its near extinction in the wild and categorization as Critically Endangered on the IUCN Red List. Decades of conservation breeding, release of birds and post-release management at Bali Barat National Park have, until recently, failed to secure a viable wild population. However, over the past decade, population increases, expansion into new areas of the National Park and beyond, and successful breeding in both artificial and natural nest sites have occurred. These recent successes are associated with a change in approach by the National Park authority from concentrating efforts on the last refugium of the species (an area protected from trapping but with potentially suboptimal habitat) and towards the human-dominated landscapes around the main road through the National Park. Bali mynas tended to favour areas with extensive shorter grass cover and open canopies and to shun denser woodland. Anthropogenic landscapes such as farmland and plantations presumably mimic the original savannah habitat of the species, but nestbox provision has probably been crucial in these areas in the absence of natural cavities. A potential further factor in the increases in myna numbers and range has been a scheme involving local people in commercial breeding of the species, thereby reducing its market price, and working with communities to reduce trapping pressure. We encourage continuing operation of this management strategy inside the National Park and its further extension into adjacent tourist areas, which appear to have myna-friendly socio-ecological conditions.
We present the first systematic inventory of surge-type glaciers for the whole of Greenland compiled from published datasets and multitemporal satellite images and digital elevation models. The inventory allows us to define the spatial and climatic distribution of surge-type glaciers and to analyse the timing of surges from 1985 to 2019. We identified 274 surge-type glaciers, an increase of 37% compared to previous work. Mapping surge-type glacier distribution by temperature and precipitation variables derived from ERA5-Land reanalysis data shows that the west and east clusters occur in well-defined climatic envelopes. Analysis of the timing of surge active phases during the periods ~1985 to 2000 (T1) and ~2000 to 2019 (T2) suggests that overall surge activity is similar in T1 and T2, but there appears to be a reduction in surging in the west cluster in T2. Our climate analysis shows a coincident increase in mean annual and mean winter air temperature between T1 and T2. We suggest that as glaciers thin under current warming, some surge-type glaciers in the west cluster may be being prevented from surging due to (1) their inability to build-up sufficient mass and (2) a switch from a polythermal to a largely cold-based thermal regime.
With the aim of producing a 3D representation of tumors, imaging and molecular annotation of xenografts and tumors (IMAXT) uses a large variety of modalities in order to acquire tumor samples and produce a map of every cell in the tumor and its host environment. With the large volume and variety of data produced in the project, we developed automatic data workflows and analysis pipelines. We introduce a research methodology where scientists connect to a cloud environment to perform analysis close to where data are located, instead of bringing data to their local computers. Here, we present the data and analysis infrastructure, discuss the unique computational challenges and describe the analysis chains developed and deployed to generate molecularly annotated tumor models. Registration is achieved by use of a novel technique involving spherical fiducial marks that are visible in all imaging modalities used within IMAXT. The automatic pipelines are highly optimized and allow to obtain processed datasets several times quicker than current solutions narrowing the gap between data acquisition and scientific exploitation.
Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood.
Aims
Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research.
Method
As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant.
Results
We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation.
Conclusions
DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.