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This study evaluated the effects of oocyte meiosis inhibitors roscovitine (ROS) and butyrolactone I (BL-I) on in vitro production of bovine embryos. Bovine oocytes were maintained in pre in vitro maturation (pre-IVM) with 25 µM ROS or 100 µM BL-I for 24 h to delay meiosis and for 24 h in in vitro maturation (IVM). Following this treatment, the nuclear maturation index was evaluated. All embryos degenerated following this procedure. In the second set of experiments, oocytes were maintained for 6 or 12 h in pre-IVM with the following three treatments: ROS (25 µM or 12.5 µM), BL-I (100 µM or 50 µM) or a combination of both drugs (6.25 µM ROS and 12.5 µM BL-I). Oocytes were cultivated for 18 or 12 h in IVM. When a meiosis-inducing agent was used during pre-IVM for 24 h, more degenerated oocytes were observed at the end of the IVM period. This effect decreased when the meiotic blocking period was reduced to 6 or 12 h. No significant differences were observed in the blastocyst production rate of oocytes in pre-IVM for 6 h with ROS, BL-I, or ROS + BL-I compared with that of the control group (P > 0.05). However, inhibition of oocytes for 12 h resulted in decreased embryo production compared with that in the controls (P < 0.05). There was no difference in the post-vitrification embryo re-expansion rate between the study groups, showing that the meiotic inhibition for 6 or 12 h did not alter the embryo cryopreservation process.
Cognitive impairment is strongly linked with persistent disability in people with mood disorders, but the factors that explain cognitive impairment in this population are unclear.
To estimate the total effect of (a) bipolar disorder and (b) major depression on cognitive function, and the magnitude of the effect that is explained by potentially modifiable intermediate factors.
Cross-sectional study using baseline data from the UK Biobank cohort. Participants were categorised as having bipolar disorder (n = 2709), major depression (n = 50 975) or no mood disorder (n = 102 931 and n = 105 284). The outcomes were computerised tests of reasoning, reaction time and memory. The potential mediators were cardiometabolic disease and psychotropic medication. Analyses were informed by graphical methods and controlled for confounding using regression, propensity score-based methods and G-computation.
Group differences of small magnitude were found on a visuospatial memory test. Z-score differences for the bipolar disorder group were in the range −0.23 to −0.17 (95% CI −0.39 to −0.03) across different estimation methods, and for the major depression group they were approximately −0.07 (95% CI −0.10 to −0.03). One-quarter of the effect was mediated via psychotropic medication in the bipolar disorder group (−0.05; 95% CI −0.09 to −0.01). No evidence was found for mediation via cardiometabolic disease.
In a large community-based sample in middle to early old age, bipolar disorder and depression were associated with lower visuospatial memory performance, in part potentially due to psychotropic medication use. Mood disorders and their treatments will have increasing importance for population cognitive health as the proportion of older adults continues to grow.
Declaration of interest
I.J.D. is a UK Biobank participant. J.P.P. is a member of the UK Biobank Steering Committee.
We investigated human understanding of different network visualizations in a large-scale online experiment. Three types of network visualizations were examined: node-link and two different sorting variants of matrix representations on a representative social network of either 20 or 50 nodes. Understanding of the network was quantified using task time and accuracy metrics on questions that were derived from an established task taxonomy. The sample size in our experiment was more than an order of magnitude larger (N = 600) than in previous research, leading to high statistical power and thus more precise estimation of detailed effects. Specifically, high statistical power allowed us to consider modern interaction capabilities as part of the evaluated visualizations, and to evaluate overall learning rates as well as ambient (implicit) learning. Findings indicate that participant understanding was best for the node-link visualization, with higher accuracy and faster task times than the two matrix visualizations. Analysis of participant learning indicated a large initial difference in task time between the node-link and matrix visualizations, with matrix performance steadily approaching that of the node-link visualization over the course of the experiment. This research is reproducible as the web-based module and results have been made available at: https://osf.io/qct84/.
Research showing that risk for schizophrenia, bipolar disorder with psychosis, and other psychosis-spectrum diagnoses in adulthood is multidetermined has underscored the necessity of studying the additive and interactive factors in childhood that precede and predict future disorders. In this study, risk for the development of psychosis-spectrum disorders was examined in a 2-generation, 30-year prospective longitudinal study of 3,905 urban families against a sociocultural backdrop of changing economic and social conditions. Peer nominations of aggression, withdrawal, and likeability and national census information on neighborhood-level socioeconomic disadvantage in childhood, as well as changes in neighborhood socioeconomic conditions over the lifespan, were examined as predictors of diagnoses of schizophrenia, bipolar disorder, and other psychosis-spectrum disorders in adulthood relative to developing only nonpsychotic disorders or no psychiatric disorders. Individuals who were both highly aggressive and highly withdrawn were at greater risk for other psychosis-spectrum diagnoses when they experienced greater neighborhood disadvantage in childhood or worsening neighborhood conditions over maturation. Males who were highly aggressive but low on withdrawal were at greater risk for schizophrenia diagnoses. Childhood neighborhood disadvantage predicted both schizophrenia and bipolar diagnoses, regardless of childhood social behavior. Results provided strong support for multiple-domain models of psychopathology, and suggest that universal preventive interventions and social policies aimed at improving neighborhood conditions may be particularly important for decreasing the prevalence of psychosis-spectrum diagnoses in the future.
Electroconvulsive therapy (ECT) is a fast-acting intervention for major depressive disorder. Previous studies indicated neurotrophic effects following ECT that might contribute to changes in white matter brain structure. We investigated the influence of ECT in a non-randomized prospective study focusing on white matter changes over time.
Twenty-nine severely depressed patients receiving ECT in addition to inpatient treatment, 69 severely depressed patients with inpatient treatment (NON-ECT) and 52 healthy controls (HC) took part in a non-randomized prospective study. Participants were scanned twice, approximately 6 weeks apart, using diffusion tensor imaging, applying tract-based spatial statistics. Additional correlational analyses were conducted in the ECT subsample to investigate the effects of seizure duration and therapeutic response.
Mean diffusivity (MD) increased after ECT in the right hemisphere, which was an ECT-group-specific effect. Seizure duration was associated with decreased fractional anisotropy (FA) following ECT. Longitudinal changes in ECT were not associated with therapy response. However, within the ECT group only, baseline FA was positively and MD negatively associated with post-ECT symptomatology.
Our data suggest that ECT changes white matter integrity, possibly reflecting increased permeability of the blood–brain barrier, resulting in disturbed communication of fibers. Further, baseline diffusion metrics were associated with therapy response. Coherent fiber structure could be a prerequisite for a generalized seizure and inhibitory brain signaling necessary to successfully inhibit increased seizure activity.
The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets.
Using a large case–control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status.
Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD.
Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.
Crisis resolution teams (CRTs) offer brief, intensive home treatment for people experiencing mental health crisis. CRT implementation is highly variable; positive trial outcomes have not been reproduced in scaled-up CRT care.
To evaluate a 1-year programme to improve CRTs’ model fidelity in a non-masked, cluster-randomised trial (part of the Crisis team Optimisation and RElapse prevention (CORE) research programme, trial registration number: ISRCTN47185233).
Fifteen CRTs in England received an intervention, informed by the US Implementing Evidence-Based Practice project, involving support from a CRT facilitator, online implementation resources and regular team fidelity reviews. Ten control CRTs received no additional support. The primary outcome was patient satisfaction, measured by the Client Satisfaction Questionnaire (CSQ-8), completed by 15 patients per team at CRT discharge (n = 375). Secondary outcomes: CRT model fidelity, continuity of care, staff well-being, in-patient admissions and bed use and CRT readmissions were also evaluated.
All CRTs were retained in the trial. Median follow-up CSQ-8 score was 28 in each group: the adjusted average in the intervention group was higher than in the control group by 0.97 (95% CI −1.02 to 2.97) but this was not significant (P = 0.34). There were fewer in-patient admissions, lower in-patient bed use and better staff psychological health in intervention teams. Model fidelity rose in most intervention teams and was significantly higher than in control teams at follow-up. There were no significant effects for other outcomes.
The CRT service improvement programme did not achieve its primary aim of improving patient satisfaction. It showed some promise in improving CRT model fidelity and reducing acute in-patient admissions.
Mismatch negativity (MMN) is an event-related potential (ERP) component reflecting auditory predictive coding. Repeated standard tones evoke increasing positivity (‘repetition positivity’; RP), reflecting strengthening of the standard's memory trace and the prediction it will recur. Likewise, deviant tones preceded by more standard repetitions evoke greater negativity (‘deviant negativity’; DN), reflecting stronger prediction error signaling. These memory trace effects are also evident in MMN difference wave. Here, we assess group differences and test-retest reliability of these indices in schizophrenia patients (SZ) and healthy controls (HC).
Electroencephalography was recorded twice, 2 weeks apart, from 43 SZ and 30 HC, during a roving standard paradigm. We examined ERPs to the third, eighth, and 33rd standards (RP), immediately subsequent deviants (DN), and the corresponding MMN. Memory trace effects were assessed by comparing amplitudes associated with the three standard repetition trains.
Compared with controls, SZ showed reduced MMNs and DNs, but normal RPs. Both groups showed memory trace effects for RP, MMN, and DN, with a trend for attenuated DNs in SZ. Intraclass correlations obtained via this paradigm indicated good-to-moderate reliabilities for overall MMN, DN and RP, but moderate to poor reliabilities for components associated with short, intermediate, and long standard trains, and poor reliability of their memory trace effects.
MMN deficits in SZ reflected attenuated prediction error signaling (DN), with relatively intact predictive code formation (RP) and memory trace effects. This roving standard MMN paradigm requires additional development/validation to obtain suitable levels of reliability for use in clinical trials.
Many countries have a national antimicrobial resistance strategy. In Australia, primary care is especially important because this setting encompasses a high proportion of antibiotic use. While antibiotic use decreased during the 1990s, it began to increase again in the mid-2000s. In response to this, in 2009 NPS MedicineWise implemented a series of nationwide educational interventions for consumers, family physicians (general practitioners), and community pharmacies that aimed to reduce excessive antibiotic use.
For consumers a social marketing approach was used, including strategies that leveraged collectivism, nudge theory, celebrity endorsement, and co-creation. Channels included social, print, radio, and other media as well as practice waiting rooms and pharmacies. For health professionals, interventions included face-to-face education, audits, comparative prescribing feedback, case studies, and point-of-care materials. Surveys of consumers and family physicians were conducted periodically to evaluate changes in knowledge and behavior. National Pharmaceutical Benefits Scheme claims data were analyzed using a Bayesian structural time-series model to estimate the cumulative effect of interventions by comparing the observed and expected monthly dispensing volumes if the interventions had not occurred.
The consumer survey results indicated that more people were aware of antibiotic resistance (seventy-four percent in 2017 versus seventy percent in 2014), with the minority requesting or expecting antibiotics for upper respiratory tract infections (URTIs) (twenty-two percent in 2017). People underestimated the usual duration of symptoms for URTIs and were more inclined to expect antibiotics beyond that timeframe. Compared with non-participants, family physicians who participated in the program reported more frequent discussions about hand hygiene (ninety percent versus eighty-two percent) and proper use of antibiotics with patients (ninety-five percent versus eighty-eight percent). Between 2009 and 2015 there was an estimated fourteen percent reduction in prescriptions dispensed to concessional patients for antibiotics commonly prescribed for URTIs.
Family physicians and consumers have responded positively to national programs. Sustaining and building on these improvements will require continued education and further innovation.
Patients with Parkinson’s disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent’s pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2–6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.
This article argues that the modern American partisan gender gap – the tendency of men to identify more as Republicans and less as Democrats than women – emerged largely because of mass-level ideological party sorting. As the two major US political parties ideologically polarized at the elite level, the public gradually perceived this polarization and better sorted themselves into the parties that matched their policy preferences. Stable pre-existing policy differences between men and women caused this sorting to generate the modern US partisan gender gap. Because education is positively associated with awareness of elite party polarization, the partisan gender gap developed earlier and is consistently larger among those with college degrees. The study finds support for this argument from decades of American National Election Studies data and a new large dataset of decades of pooled individual-level Gallup survey responses.
In the interest of promoting open and reproducible science, the Journal of Experimental Political Science editorial team will pilot the pre-acceptance of preregistered reports. We note that the launch of this new submission option is a complement to, and does not replace, the option to submit other types of manuscripts. JEPS remains open to receiving and reviewing high quality manuscripts regardless of whether they are based on preregistered studies.
This study investigated the characteristics of subjective memory complaints (SMCs) and their association with current and future cognitive functions.
A cohort of 209 community-dwelling individuals without dementia aged 47–90 years old was recruited for this 3-year study. Participants underwent neuropsychological and clinical assessments annually. Participants were divided into SMCs and non-memory complainers (NMCs) using a single question at baseline and a memory complaints questionnaire following baseline, to evaluate differential patterns of complaints. In addition, comprehensive assessment of memory complaints was undertaken to evaluate whether severity and consistency of complaints differentially predicted cognitive function.
SMC and NMC individuals were significantly different on various features of SMCs. Greater overall severity (but not consistency) of complaints was significantly associated with current and future cognitive functioning.
SMC individuals present distinctive features of memory complaints as compared to NMCs. Further, the severity of complaints was a significant predictor of future cognition. However, SMC did not significantly predict change over time in this sample. These findings warrant further research into the specific features of SMCs that may portend subsequent neuropathological and cognitive changes when screening individuals at increased future risk of dementia.
Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.