We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
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.
This paper provides a generalization of the Procrustes problem in which the errors are weighted from the right, or the left, or both. The solution is achieved by having the orthogonality constraint on the transformation be in agreement with the norm of the least squares criterion. This general principle is discussed and illustrated by the mathematics of the weighted orthogonal Procrustes problem.
This editorial considers the value and nature of academic psychiatry by asking what defines the specialty and psychiatrists as academics. We frame academic psychiatry as a way of thinking that benefits clinical services and discuss how to inspire the next generation of academics.
We use large-eddy simulations to study the penetration of a buoyant plume carrying a passive tracer into a stably stratified layer with constant buoyancy frequency. Using a buoyancy-tracer volume distribution, we develop a method for objectively partitioning plume fluid in buoyancy-tracer space into three regions, each of which corresponds to a coherent region in physical space. Specifically, we identify a source region where undiluted plume fluid enters the stratified layer, a transport region where much of the transition from undiluted to mixed fluid occurs in the plume cap and an accumulation region corresponding to a radially spreading intrusion. This method enables quantification of different measures of turbulence and mixing within each of the three regions, including potential energy and turbulent kinetic energy dissipation rates, an activity parameter and the instantaneous mixing efficiency. We find that the most intense buoyancy gradients lie in a thin layer at the cap of the penetrating plume. This provides the primary stage of mixing between plume and environment and exhibits a mixing efficiency around 50 %. Newly generated mixtures of environmental and plume fluid join the intrusion and experience relatively weak turbulence and buoyancy gradients. As the intrusion spreads radially, environmental fluid surrounding the intrusion is mixed into the intrusion with moderate mixing efficiency. This dominates the volume of environmental fluid entrained into the region containing plume fluid. However, the ‘strongest’ entrainment, as measured by the specific entrainment rate, is largest in the plume cap, where the most buoyant environmental fluid is entrained.
We present radio observations of the galaxy cluster Abell S1136 at 888 MHz, using the Australian Square Kilometre Array Pathfinder radio telescope, as part of the Evolutionary Map of the Universe Early Science program. We compare these findings with data from the Murchison Widefield Array, XMM-Newton, the Wide-field Infrared Survey Explorer, the Digitised Sky Survey, and the Australia Telescope Compact Array. Our analysis shows the X-ray and radio emission in Abell S1136 are closely aligned and centered on the Brightest Cluster Galaxy, while the X-ray temperature profile shows a relaxed cluster with no evidence of a cool core. We find that the diffuse radio emission in the centre of the cluster shows more structure than seen in previous low-resolution observations of this source, which appeared formerly as an amorphous radio blob, similar in appearance to a radio halo; our observations show the diffuse emission in the Abell S1136 galaxy cluster contains three narrow filamentary structures visible at 888 MHz, between $\sim$80 and 140 kpc in length; however, the properties of the diffuse emission do not fully match that of a radio (mini-)halo or (fossil) tailed radio source.
Edited by
William J. Brady, University of Virginia,Mark R. Sochor, University of Virginia,Paul E. Pepe, Metropolitan EMS Medical Directors Global Alliance, Florida,John C. Maino II, Michigan International Speedway, Brooklyn,K. Sophia Dyer, Boston University Chobanian and Avedisian School of Medicine, Massachusetts
For large entertainment tours composed of 100 to 200 personnel moving from one city (or country) to another every few days over several months’ time, the odds of numerous untoward health events occurring, some very serious, become reasonably high. Beyond rigorous schedules and living/dining in close quarters, understandable reticence to abandon one’s post can occasionally delay timely care. Accordingly, having veteran medical specialists as part of the touring team has been found to be invaluable, not only for pre-emptive minor interventions and continuity of care, but also for immediate, expert handling of serious emergencies. Experienced, well-connected touring medical specialists also provide prospective contingency plans for each destination city and venue. These medical advance plans detail the most-knowledgeable local physicians or facilities for best managing any respective medical condition. They also identify the local “point-persons” to contact for coordination of true emergencies and especially if there is a need for multi-casualty incident management at the venue. They anticipate health risks such as air quality, altitude sickness, endemic disease vectors and other concerning threats at each destination. They also train touring staff in basic life support, bleeding control and emergency equipment readiness. Touring specialists should also be well-integrated into security team functions.
OBJECTIVES/GOALS: Patients frequently need or desire fat grafting to improve common issues such as implant visibility and contour deformity, often done as a second, staged procedure following immediate reconstruction. This study aimed to identify which patient factors and reconstructive techniques predict the need for revision with AFG after IBBR METHODS/STUDY POPULATION: Patients who underwent IBBR with either tissue expanders or implants following mastectomy from 2017 to 2021 were identified. Demographics, comorbidities, and the postoperative course were reviewed. The primary outcome variable was AFG after the initial reconstruction. Univariate and regression analyses were performed to identify factors predictive of AFG. RESULTS/ANTICIPATED RESULTS: Five-hundred twenty-nine patients were included in our analysis, with 43% having AFG. Univariate regression displayed single-stage reconstruction (OR=0.53, 95% 0.37-0.75) and previous radiation (OR 0.59, 95% 0.35-0.99) negatively predicted the need for AFG, while bilateral breast reconstruction (BBR) was a predictor (OR 2.32, 95% 1.58-3.4). On multivariate analysis, decreasing age and BBR remained predictive of AFG. The odds of AFG decreased by 3% for every one-unit increase in age (95% CI [0.96, 0.99]). Interestingly, neither pre-pectoral breast reconstruction nor specimen weight:implant ratio was associated with increased need for AFG on univariate/multivariate analysis. DISCUSSION/SIGNIFICANCE: Patients requiring AFG were likely younger and had undergone BBR with tissue expanders. Plane of implant did not appear to affect need for AFG. Knowledge of these predictive factors may help plastic surgeons in preoperative counseling before implant-based breast reconstruction.
Presented is a novel way to combine snapshot compressive imaging and lateral shearing interferometry in order to capture the spatio-spectral phase of an ultrashort laser pulse in a single shot. A deep unrolling algorithm is utilized for snapshot compressive imaging reconstruction due to its parameter efficiency and superior speed relative to other methods, potentially allowing for online reconstruction. The algorithm’s regularization term is represented using a neural network with 3D convolutional layers to exploit the spatio-spectral correlations that exist in laser wavefronts. Compressed sensing is not typically applied to modulated signals, but we demonstrate its success here. Furthermore, we train a neural network to predict the wavefronts from a lateral shearing interferogram in terms of Zernike polynomials, which again increases the speed of our technique without sacrificing fidelity. This method is supported with simulation-based results. While applied to the example of lateral shearing interferometry, the methods presented here are generally applicable to a wide range of signals, including Shack–Hartmann-type sensors. The results may be of interest beyond the context of laser wavefront characterization, including within quantitative phase imaging.
Ips typographus (L.) and Pityogenes chalcographus (L.) (Coleoptera: Curculionidae) are two common bark beetle species on Norway spruce in Eurasia. Multiple biotic and abiotic factors affect the life cycles of these two beetles, shaping their ecology and evolution. In this article, we provide a comprehensive and comparative summary of selected life-history traits. We highlight similarities and differences in biotic factors, like host range, interspecific competition, host colonization, reproductive behaviour and fungal symbioses. Moreover, we focus on the species' responses to abiotic factors and compare their temperature-dependent development and flight behaviour, cold adaptations and diapause strategies. Differences in biotic and abiotic traits might be the result of recent, species-specific evolutionary histories, particularly during the Pleistocene, with differences in glacial survival and postglacial recolonization. Finally, we discuss future research directions to understand ecological and evolutionary pathways of the two bark beetle species, for both basic research and applied forest management.
Double-cropping winter rye cover crops (CC) with soybean in the North Central US could help with the global effort to sustainably intensify agriculture. Studies addressing the management of these systems are limited. Therefore, a field study was conducted from 2017 to 2019 in Central Iowa, US to evaluate winter rye CC biomass production, aboveground N accumulation, estimated economics, estimated within-field energy balance and estimated greenhouse gas (GHG) emissions under three N application rates (0, 60, 120 kg N ha−1) and three planting methods (pre- and post-harvest broadcast and post-harvest drilling). Averaged over N rates, all planting methods resulted in >5.0 Mg ha−1 year−1 rye aboveground biomass dry matter. Averaged over the 2-year study and compared with unfertilized treatments, applying 60 kg N ha−1 produced 1.1 Mg ha−1 more aboveground biomass (6.1 vs 5.0 Mg ha−1), accumulated 30 kg ha−1 more N in aboveground biomass (88 vs 58 kg N ha−1), and led to 20 GJ ha−1 more net energy. Biomass production was not significantly higher with 120 kg N ha−1 compared with the 60 kg N ha−1 rate. Even when accounting for an estimated 0.75 Mg ha−1 of above ground rye biomass left in the field after harvesting, more N was removed than applied at the 60 kg N ha−1 rate. The minimum rye prices over the 2-year study needed for double-cropping winter rye CC to be profitable (breakeven prices) averaged $117 and $104 Mg−1 for the 0 and 60 kg N ha−1 rates, which factors in estimated soybean yield reductions in 2019 compared with local averages but not off-site transportation. GHG emissions were estimated to increase approximately threefold between the unfertilized and 60 kg N ha−1 rates without considering bioenergy offsets. While environmental tradeoffs need further study, results suggest harvesting fertilized rye CC biomass before planting soybean is a promising practice for the North Central US to maximize total crop and net energy production.
This article is a clinical guide which discusses the “state-of-the-art” usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion—this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy—while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward “bridging” methods that may be used to transition simply and safely from other antidepressants to MAOIs.
Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants’ biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants’ serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants’ fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
The years between 1258 and 67 comprise one of the most influential periods in the Middle Ages in England. This turbulent decade witnessed a bitter power struggle between King Henry III and his baronsover who should control the government of the realm. Before England eventually descended into civil war, a significant proportion of the baronage had attempted to transform its governance by imposingon the crown a programme of legislative and administrative reform far more radical and wide-ranging than Magna Carta in 1215. Constituting a critical stage in the development of parliament, the reformist movement would remain unsurpassed in its radicalism until the upheavals of the seventeenth century. Simon de Montfort, the baronial champion, became the first leader of a political movement to seize power and govern in the king's name. The essays collected here offer the most recent research into and ideas on this pivotal period. Several contributions focus upon the roles played in the political struggle by particular sections of thirteenth-century society, including the Midland knights and their political allegiances, aristocratic women, and the merchant elite in London. The events themselves constitute the second major theme of this volume, with subjects such as the secret revolution of 1258, Henry III's recovery of power in 1261, and the little studied maritime theatre during the civil wars of 1263-7 being considered.
Adrian Jobson is an Associate Lecturer at Canterbury Christ Church University.
Contributors: Sophie Ambler, Nick Barratt, David Carpenter, Peter Coss, Mario Fernandes, Andrew H. Hershey, Adrian Jobson, Lars Kjaer, John A. McEwan, Tony Moore, Fergus Oakes, H.W. Ridgeway, Christopher David Tilley, Benjamin L. Wild, Louise J. Wilkinson.
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.
Diets varying in SFA and MUFA content can impact glycaemic control; however, whether underlying differences in genetic make-up can influence blood glucose responses to these dietary fatty acids is unknown. We examined the impact of dietary oils varying in SFA/MUFA content on changes in blood glucose levels (primary outcome) and whether these changes were modified by variants in the stearoyl-CoA desaturase (SCD) gene (secondary outcome). Obese men and women participating in the randomised, crossover, isoenergetic, controlled-feeding Canola Oil Multicenter Intervention Trial II consumed three dietary oils for 6 weeks, with washout periods of ˜6 weeks between each treatment. Diets studied included a high SFA/low MUFA Control oil (36·6 % SFA/28·2 % MUFA), a conventional canola oil (6·2 % SFA/63·1 % MUFA) and a high-oleic acid canola oil (5·8 % SFA/74·7 % MUFA). No differences in fasting blood glucose were observed following the consumption of the dietary oils. However, when stratified by SCD genotypes, significant SNP-by-treatment interactions on blood glucose response were found with additive models for rs1502593 (P = 0·01), rs3071 (P = 0·02) and rs522951 (P = 0·03). The interaction for rs3071 remained significant (P = 0·005) when analysed with a recessive model, where individuals carrying the CC genotype showed an increase (0·14 (sem 0·09) mmol/l) in blood glucose levels with the Control oil diet, but reductions in blood glucose with both MUFA oil diets. Individuals carrying the AA and AC genotypes experienced reductions in blood glucose in response to all three oils. These findings identify a potential new target for personalised nutrition approaches aimed at improving glycaemic control.