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Electroconvulsive therapy (ECT) is recommended in treatment guidelines as an efficacious therapy for treatment-resistant depression. However, it has been associated with loss of autobiographical memory and short-term reduction in new learning.
To provide clinically useful guidelines to aid clinicians in informing patients regarding the cognitive side-effects of ECT and in monitoring these during a course of ECT, using complex data.
A Committee of clinical and academic experts from Australia and New Zealand met to the discuss the key issues pertaining to ECT and cognitive side-effects. Evidence regarding cognitive side-effects was reviewed, as was the limited evidence regarding how to monitor them. Both issues were supplemented by the clinical experience of the authors.
Meta-analyses suggest that new learning is impaired immediately following ECT but that group mean scores return at least to baseline by 14 days after ECT. Other cognitive functions are generally unaffected. However, the finding of a mean score that is not reduced from baseline cannot be taken to indicate that impairment, particularly of new learning, cannot occur in individuals, particularly those who are at greater risk. Therefore, monitoring is still important. Evidence suggests that ECT does cause deficits in autobiographical memory. The evidence for schedules of testing to monitor cognitive side-effects is currently limited. We therefore make practical recommendations based on clinical experience.
Despite modern ECT techniques, cognitive side-effects remain an important issue, although their nature and degree remains to be clarified fully. In these circumstances it is useful for clinicians to have guidance regarding what to tell patients and how to monitor these side-effects clinically.
Mössbauer instruments were included on the Mars Exploration Rover (MER) Mission to determine the mineralogic composition, diversity, and oxidation state of Fe-bearing igneous materials and alteration products. A total of 16 Fe-bearing phases (consistent with bulk-sample chemistry) were identified, including Fe associated with rock-forming minerals (olivine, pyroxene, magnetite, ilmenite, and chromite), Fe3+-bearing oxyhydroxides (nanophase ferric oxide, hematite, and goethite), sulfates (jarosite and an unassigned Fe3+ sulfate phase), and Fe2+ carbonate. Igneous rock types ranged from basalts to ultramafic rocks at Gusev crater. Jarosite-hematite bedrock was pervasive at Meridiani Planum, and concretions winnowed from the outcrop were mineralogically hematite. Because their structures contain hydroxyl, goethite, and jarosite provide mineralogic evidence for aqueous processes on Mars, and jarosite and Fe3+ sulfate are evidence for acid-sulfate processes at both Gusev crater and Meridiani Planum. A population of rocks on the Meridiani Planum outcrop was identified as iron and stony meteorites by the presence of Fe metal (kamacite) and the sulfide troilite. The MER mission demonstrates that Mössbauer spectrometers landed on any Fe-bearing planetary surface provide first-order information on igneous provinces, alteration state, and alteration style and provide well-constrained criteria for sample selection on planetary sample-return missions including planets, moons, and asteroids.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
Background: Observational studies have reported an association between childhood obesity and a higher risk of multiple sclerosis (MS). However, the difficulties to fully account for confounding and long recall periods make causal inference from these studies challenging. The objective of this study was to assess the contribution of childhood obesity to the development of MS through Mendelian randomization, which uses genetic associations to minimize the risk of confounding. Methods: We selected 23 independent genetic variants strongly associated with childhood body mass index (BMI) in a genome-wide association study (GWAS) which included 47,541 children. The corresponding effects of these variants on risk of MS were obtained from a GWAS of 14,802 MS cases and 26,703 controls. Standard two-sample Mendelian randomization methods were performed, with additional sensitivity analyses to assess the likelihood of bias from genetic pleiotropy. Results: The inverse-variance weighted MR analysis revealed that one standard deviation increase in childhood BMI increased odds of MS by 26% (odds ratio=1.26, 95% confidence interval 1.10-1.45, p=0.001). There was no significant heterogeneity across the individual estimates. Sensitivity analyses were consistent with the main findings and provided no evidence of pleiotropy. Conclusions: This study provides genetic support of a role for increased childhood BMI in the development of MS.
Renal disease has a high incidence in cats, and some evidence implicates dietary P as well. To investigate this further, two studies in healthy adult cats were conducted. Study 1 (36 weeks) included forty-eight cats, stratified to control or test diets providing 1·2 or 4·8 g/1000 kcal (4184 kJ) P (0 or approximately 3·6 g/1000 kcal (4184 kJ) inorganic P, Ca:P 1·2, 0·6). Study 2 (29 weeks) included fifty cats, stratified to control or test diets, providing 1·3 or 3·6 g/1000 kcal (4184 kJ) P (0 or approximately 1·5 g/1000 kcal (4184 kJ) inorganic P, Ca:P 1·2, 0·9). Health markers, glomerular filtration rate (GFR) and mineral balance were measured regularly, with abdominal ultrasound. Study 1 was halted after 4 weeks as the test group GFR reduced by 0·4 (95 % CI 0·3, 0·5) ml/min per kg, and ultrasound revealed changes in renal echogenicity. In study 2, at week 28, no change in mean GFR was observed (P >0·05); however, altered renal echogenicity was detected in 36 % of test cats. In agreement with previous studies, feeding a diet with Ca:P <1·0, a high total and inorganic P inclusion resulted in loss of renal function and changes in echogenicity suggestive of renal pathology. Feeding a diet containing lower total and inorganic P with Ca:P close to 1·0 led to more subtle structural changes in a third of test cats; however, nephrolithiasis occurred in both diet groups, complicating data interpretation. We conclude that the no observed adverse effects level for total dietary P in adult cats is lower than 3·6 g/1000 kcal (4184 kJ), however the effect of inorganic P sources and Ca:P require further investigation.
Identifying characteristics of individuals at greatest risk for prolonged grief disorder (PGD) can improve its detection and elucidate the etiology of the disorder. The Safe Passage Study, a study of women at high risk for sudden infant death syndrome (SIDS), prospectively examined the psychosocial functioning of women while monitoring their healthy pregnancies. Mothers whose infants died of SIDS were followed in bereavement.
Pre-loss data were collected from 12 000 pregnant mothers and analyzed for their associations with grief symptoms and PGD in 50 mothers whose infants died from SIDS, from 2 to 48 months after their infant's death, focusing on pre-loss risk factors of anxiety, depression, alcohol use, maternal age, the presence of other living children in the home, and previous child loss.
The presence of any four risk factors significantly predicted PGD for 24 months post-loss (p < 0.003); 2–3 risk factors predicted PGD for 12 months (p = 0.02). PGD rates increased in the second post-loss year, converging in all groups to approximately 40% by 3 years. Pre-loss depressive symptoms were significantly associated with PGD. Higher alcohol intake and older maternal age were consistently positively associated with PGD. Predicted risk scores showed good discrimination between PGD and no PGD 6–24 months after loss (C-statistic = 0.83).
A combination of personal risk factors predicted PGD in 2 years of bereavement. There is a convergence of risk groups to high rates at 2–3 years, marked by increased PGD rates in mothers at low risk. The risk factors showed different effects on PGD.
Obesity is a major challenge for people with schizophrenia.
We assessed whether STEPWISE, a theory-based, group structured lifestyle education programme could support weight reduction in people with schizophrenia.
In this randomised controlled trial (study registration: ISRCTN19447796), we recruited adults with schizophrenia, schizoaffective disorder or first-episode psychosis from ten mental health organisations in England. Participants were randomly allocated to the STEPWISE intervention or treatment as usual. The 12-month intervention comprised four 2.5 h weekly group sessions, followed by 2-weekly maintenance contact and group sessions at 4, 7 and 10 months. The primary outcome was weight change after 12 months. Key secondary outcomes included diet, physical activity, biomedical measures and patient-related outcome measures. Cost-effectiveness was assessed and a mixed-methods process evaluation was included.
Between 10 March 2015 and 31 March 2016, we recruited 414 people (intervention 208, usual care 206) with 341 (84.4%) participants completing the trial. At 12 months, weight reduction did not differ between groups (mean difference 0.0 kg, 95% CI −1.6 to 1.7, P = 0.963); physical activity, dietary intake and biochemical measures were unchanged. STEPWISE was well-received by participants and facilitators. The healthcare perspective incremental cost-effectiveness ratio was £246 921 per quality-adjusted life-year gained.
Participants were successfully recruited and retained, indicating a strong interest in weight interventions; however, the STEPWISE intervention was neither clinically nor cost-effective. Further research is needed to determine how to manage overweight and obesity in people with schizophrenia.
Declaration of interest
R.I.G.H. received fees for lecturing, consultancy work and attendance at conferences from the following: Boehringer Ingelheim, Eli Lilly, Janssen, Lundbeck, Novo Nordisk, Novartis, Otsuka, Sanofi, Sunovion, Takeda, MSD. M.J.D. reports personal fees from Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, Janssen, Servier, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceuticals International Inc.; and, grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, Janssen. K.K. has received fees for consultancy and speaker for Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Servier and Merck Sharp & Dohme. He has received grants in support of investigator and investigator-initiated trials from Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Pfizer, Boehringer Ingelheim and Merck Sharp & Dohme. K.K. has received funds for research, honoraria for speaking at meetings and has served on advisory boards for Lilly, Sanofi-Aventis, Merck Sharp & Dohme and Novo Nordisk. D.Sh. is expert advisor to the NICE Centre for guidelines; board member of the National Collaborating Centre for Mental Health (NCCMH); clinical advisor (paid consultancy basis) to National Clinical Audit of Psychosis (NCAP); views are personal and not those of NICE, NCCMH or NCAP. J.P. received personal fees for involvement in the study from a National Institute for Health Research (NIHR) grant. M.E.C. and Y.D. report grants from NIHR Health Technology Assessment, during the conduct of the study; and The Leicester Diabetes Centre, an organisation (employer) jointly hosted by an NHS Hospital Trust and the University of Leicester and who is holder (through the University of Leicester) of the copyright of the STEPWISE programme and of the DESMOND suite of programmes, training and intervention fidelity framework that were used in this study. S.R. has received honorarium from Lundbeck for lecturing. F.G. reports personal fees from Otsuka and Lundbeck, personal fees and non-financial support from Sunovion, outside the submitted work; and has a family member with professional links to Lilly and GSK, including shares. F.G. is in part funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research & Care Funding scheme, by the Maudsley Charity and by the Stanley Medical Research Institute and is supported by the by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London.
The carbon-rich AGB star V Hya is believed to be in the very brief transition phase between the AGB and a planetary nebula (PN). Using HST/STIS, we previously found a high-velocity (> 200 kms−1) jet or blob of gas ejected only a few years ago from near (< 0.3 arcsec or 150 AU) the star (Sahai et al. 2003, Sahai et al. 2016). From multi-epoch high-resolution spectroscopy we found time-variable high-velocity absorption features in the CO 4.6 μm vibration-rotation lines of V Hya (Sahai et al. 2009). Modeling shows that these are produced in compact clumps of outflowing gas with significant radial temperature gradients consistent with strong shocks. Here, we present very high resolution (∼100 milliarcsecond) imaging of the central region of V Hya using the coronagraphic mode of the Gemini Planet Imager (GPI) in the 1 μm band and spectral-spatial imaging of 4.6 μm CO 1-0 transitions using the Phoenix spectrometer. We report the detection of a compact central dust disk from GPI, and molecular emission from the Phoenix observations at relatively larger scales. We discuss models for the central structures in V Hya, in particular disks and outflows, using these and complementary images in the optical and radio.
The term ‘mood stabiliser’ is ill-defined and lacks clinical utility. We propose a framework to evaluate medications and effectively communicate their mood stabilising properties – their acute and prophylactic efficacy across the domains of mania and depression. The standardised framework provides a common definition to facilitate research and clinical practice.
Declaration of interest
The Treatment Algorithm Group (TAG) was supported logistically by Servier who provided financial assistance with travel and accommodation for those TAG members travelling interstate or overseas to attend the meeting in Sydney (held on 18 November 2017). None of the committee were paid to participate in this project and Servier have not had any input into the content, format or outputs from this project.
Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88) presented a critique of our recently published paper in Cell Reports entitled ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ (Lam et al., Cell Reports, Vol. 21, 2017, 2597–2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229–237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from ‘inflation in the FDR [false discovery rate]’, as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84–88), and are not ‘more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence’.
OBJECTIVES/SPECIFIC AIMS: The serotonin receptor 6 (5-HT6) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5-HT6 receptor availability using 11C GSK215083, a PET ligand with affinity for 5-HT6 in the striatum and 5-HT2A in the cortex. METHODS/STUDY POPULATION: In total, 28 healthy male subjects (age range: 23–52 years) were scanned with 11C-GSK215083 on the HR+PET scanner. Time-activity curves in regions-of-interest were fitted with multilinear analysis-1 method. Binding potentials (BPND) were calculated using cerebellum as the reference region and corrected for partial volume effects. RESULTS/ANTICIPATED RESULTS: In 5-HT6 rich areas, regional 11C-GSK215083 displayed a negative correlation between BPND and age in the caudate (r=−0.41, p=0.03) (14% change per decade), and putamen (r=−0.30, p=0.04) (11% change per decade), but not in the ventral striatum and pallidum. Negative correlation with age was also seen in cortical regions (r=−0.41, p=0.03) (7% change per decade), consistent with the literature on 5-HT2A availability. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first in vivo study in humans to examine the effect of age on 5-HT6 receptor availability. The study demonstrated a significant age-related decline in 5-HT6 availability (BPND) in the caudate and putamen.
The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models.
Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples.
We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected).
These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4’s developmental role.
Obesity rates are increasing worldwide. Potential reasons include excessive consumption of sugary beverages and energy-dense foods instead of more nutrient-rich options. On a per kJ basis, energy-dense grains, added sugars and fats cost less, whereas lean meats, seafood, leafy greens and whole fruit generally cost more. Given that consumer food choices are often driven by price, the observed social inequities in diet quality and health can be explained, in part, by nutrition economics. Achieving a nutrient-rich diet at an affordable cost has become progressively more difficult within the constraints of global food supply. However, given the necessary metrics and educational tools, it may be possible to eat better for less. New metrics of nutrient density help consumers identify foods, processed and unprocessed, that are nutrient-rich, affordable and appealing. Affordability metrics, created by adding food prices to food composition data, permit calculations of both kJ and nutrients per penny, allowing for new studies on the economic drivers of food choice. Merging dietary intake data with local or national food prices permits the estimation of individual-level diet costs. New metrics of nutrient balance can help identify those food patterns that provide optimal nutritional value. Behavioural factors, including cooking at home, have been associated with nutrition resilience, defined as healthier diets at lower cost. Studies of the energy and nutrient costs of the global food supply and diverse food patterns will permit a better understanding of the socioeconomic determinants of health. Dietary advice ought to be accompanied by economic feasibility studies.
First promulgated in 1959, the 3Rs of Replacement, Reduction and Refinement have evolved as fundamental principles underlying the use of animals and alternatives in science throughout the modern world. This review describes a contemporary approach to delivering the 3Rs through acknowledging the contribution of new technologies and emphasising that applying the 3Rs can be beneficial to good science as well as to animal welfare. This science-led approach moves the concept of the 3Rs out of an ethical silo where they were often considered by scientists to be an inconvenient obligation. On the contrary, relevant examples demonstrate the opportunity to practise better science using 3Rs technologies which deliver faster, more reproducible and more cost-effective results. Indeed, methods harnessing Replacement approaches may permit discoveries which are simply not feasible using animals and frequently are more flexible and agile since compliance with regulatory oversight requirements is simplified. Although the necessity for rigorous oversight is well recognised, it is important that the associated bureaucracy is not allowed to become prohibitive, causing scientists to avoid pursuing justifiable and important research involving animals. Public support for research is conditional – animals should not suffer unnecessarily and sufficient potential benefit should accrue from the research. However, society also actively seeks pioneering medical and scientific advances which can only be achieved through research. Therefore, a balance must be struck between safeguarding animal welfare whilst enabling high-quality science. It is this balance which promotes and sustains public confidence that animal based research is acceptable and being appropriately managed.
Although the implications of long-term high Ca intakes have been well documented in growing dogs, the health consequences of Ca excess in adult dogs remain to be established. To evaluate the impact of feeding a diet containing 7·1 g/4184 kJ (1000 kcal) Ca for 40 weeks on Ca balance and health parameters in adult dogs, eighteen neutered adult Labrador Retrievers, (nine males and nine females) aged 2·5–7·4 years were randomised to one of two customised diets for 40 weeks. The diets were manufactured according to similar nutritional specifications, with the exception of Ca and P levels. The diets provided 1·7 and 7·1 g/4184 kJ (1000 kcal) (200(SD26) and 881(SD145) mg/kg body weight0·75 per d, respectively) Ca, respectively, with a Ca:P ratio of 1·6. Clinical examinations, ultrasound scans, radiographs, health parameters, metabolic effects and mineral balance were recorded at baseline and at 8-week intervals throughout the study. Dogs in both groups were healthy throughout the trial without evidence of urinary, renal or orthopaedic disease. In addition, there were no clinically relevant changes in any of the measures made in either group (all P>0·05). The high-Ca diet resulted in a 3·3-fold increase in faecal Ca excretion (P<0·001), whereas apparent Ca digestibility (%) and net Ca balance (g/d) did not significantly change from baseline or differ between the groups at any time point (both P>0·05). Ca intakes of up to 7·1 g/4184 kJ (1000 kcal) are well tolerated over a period of 40 weeks, with no adverse effects that could be attributed to the diet or to a high mineral intake.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.