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Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.
Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.
Aims
To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.
Method
This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists.
Results
The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI −0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = −0.53, 95% CI −0.86 to −0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms.
Conclusions
This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.
Cancer has been associated with lower risk of dementia, although methodological issues raise concerns about the validity of this association. We recruited 31,080 men aged 65–85 years who were free of cancer and dementia, and followed them for up to 22 years. We used health record linkage to identify incident cases of cancer and dementia, and split time span to investigate this association. 18,693 (60.1%) and 6897 (22.2%) participants developed cancer and dementia during follow-up. The hazard ratio (HR) of dementia associated with cancer was 1.13 (95% CI = 1.07, 1.20) and dropped to 0.85 (95% CI = 0.80, 0.91) when 449 participants who developed dementia within 2 years were excluded. The diagnosis of cancer seems to facilitate the early detection of dementia cases. Older participants who survive cancer for 2 or more years have lower risk of receiving the diagnosis of dementia over time. The factors that mediate this association remain unclear.
Glyphosate’s efficacy is influenced by the amount absorbed and translocated throughout the plant to inhibit 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS). Glyphosate resistance can be due to target-site (TS) or non–target site (NTS) resistance mechanisms. TS resistance includes an altered target site and gene overexpression, while NTS resistance includes reduced absorption, reduced translocation, enhanced metabolism, and exclusion/sequestration. The goal of this research was to elucidate the mechanism(s) of glyphosate resistance in common ragweed (Ambrosia artemisiifolia L.) from Ontario, Canada. The resistance factor for this glyphosate-resistant (GR) A. artemisiifolia biotype is 5.1. No amino acid substitutions were found at positions 102 or 106 of the EPSPS enzyme in this A. artemisiifolia biotype. Based on [14C]glyphosate studies, there was no difference in glyphosate absorption or translocation between glyphosate-susceptible (GS) and GR A. artemisiifolia biotypes. Radio-labeled glyphosate metabolites were similar for GS and GR A. artemisiifolia 96 h after application. Glyphosate resistance in this A. artemisiifolia biotype is not due to an altered target site due to amino acid substitutions at positions 102 and 106 in the EPSPS and is not due to the NTS mechanisms of reduced absorption, reduced translocation, or enhanced metabolism.
In April 2019, the U.S. Fish and Wildlife Service (USFWS) released its recovery plan for the jaguar Panthera onca after several decades of discussion, litigation and controversy about the status of the species in the USA. The USFWS estimated that potential habitat, south of the Interstate-10 highway in Arizona and New Mexico, had a carrying capacity of c. six jaguars, and so focused its recovery programme on areas south of the USA–Mexico border. Here we present a systematic review of the modelling and assessment efforts over the last 25 years, with a focus on areas north of Interstate-10 in Arizona and New Mexico, outside the recovery unit considered by the USFWS. Despite differences in data inputs, methods, and analytical extent, the nine previous studies found support for potential suitable jaguar habitat in the central mountain ranges of Arizona and New Mexico. Applying slightly modified versions of the USFWS model and recalculating an Arizona-focused model over both states provided additional confirmation. Extending the area of consideration also substantially raised the carrying capacity of habitats in Arizona and New Mexico, from six to 90 or 151 adult jaguars, using the modified USFWS models. This review demonstrates the crucial ways in which choosing the extent of analysis influences the conclusions of a conservation plan. More importantly, it opens a new opportunity for jaguar conservation in North America that could help address threats from habitat losses, climate change and border infrastructure.
Understanding the clinical risk factors for COVID-19 disease severity and outcomes requires a combination of data from electronic health records and patient reports. To facilitate the collection of patient-reported data, as well as accelerate and standardize the collection of data about host factors, we have constructed a COVID-19 survey. This survey is freely available to the scientific community to send electronically for patients to complete online. This patient survey is designed to be comprehensive, yet not overly burdensome, to gather data useful for a range of clinical investigations, and to accommodate a wide variety of implementation settings including at a COVID-19 testing site, at home during infection or after recovery, and/or for individuals while they are hospitalized. A widely adopted standardized survey that can be implemented online with minimal resources can serve as a critical tool for combining and comparing data across studies to improve our understanding of COVID-19 disease.
Poultry production is an important way of enhancing the livelihoods of rural populations, especially in low- and middle-income countries (LMICs). As poultry production in LMICs remains dominated by backyard systems with low inputs and low outputs, considerable yield gaps exist. Intensification can increase poultry productivity, production and income. This process is relatively recent in LMICs compared to high-income countries. The management practices and the constraints faced by smallholders trying to scale-up their production, in the early stages of intensification, are poorly understood and described. We thus investigated the features of the small-scale commercial chicken sector in a rural area distant from major production centres. We surveyed 111 commercial chicken farms in Kenya in 2016. We targeted farms that sell the majority of their production, owning at least 50 chickens, partly or wholly confined and provided with feeds. We developed a typology of semi-intensive farms. Farms were found mainly to raise dual-purpose chickens of local and improved breeds, in association with crops and were not specialized in any single product or market. We identified four types of semi-intensive farms that were characterized based on two groups of variables related to intensification and accessibility: (i) remote, small-scale old farms, with small flocks, growing a lot of their own feed; (ii) medium-scale, old farms with a larger flock and well located in relation to markets and (iii) large-scale recently established farms, with large flocks, (iii-a) well located and buying chicks from third-party providers and (iii-b) remotely located and hatching their own chicks. The semi-intensive farms we surveyed were highly heterogeneous in terms of size, age, accessibility, management, opportunities and challenges. Farm location affects market access and influences the opportunities available to farmers, resulting in further diversity in farm profiles. The future of these semi-intensive farms could be compromised by several factors, including the competition with large-scale intensive farmers and with importations. Our study suggests that intensification trajectories in rural areas of LMICs are potentially complex, diverse and non-linear. A better understanding of intensification trajectories should, however, be based on longitudinal data. This could, in turn, help designing interventions to support small-scale farmers.
We examined demographic, clinical, and psychological characteristics of a large cohort (n = 368) of adults with dissociative seizures (DS) recruited to the CODES randomised controlled trial (RCT) and explored differences associated with age at onset of DS, gender, and DS semiology.
Methods
Prior to randomisation within the CODES RCT, we collected demographic and clinical data on 368 participants. We assessed psychiatric comorbidity using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and a screening measure of personality disorder and measured anxiety, depression, psychological distress, somatic symptom burden, emotional expression, functional impact of DS, avoidance behaviour, and quality of life. We undertook comparisons based on reported age at DS onset (<40 v. ⩾40), gender (male v. female), and DS semiology (predominantly hyperkinetic v. hypokinetic).
Results
Our cohort was predominantly female (72%) and characterised by high levels of socio-economic deprivation. Two-thirds had predominantly hyperkinetic DS. Of the total, 69% had ⩾1 comorbid M.I.N.I. diagnosis (median number = 2), with agoraphobia being the most common concurrent diagnosis. Clinical levels of distress were reported by 86% and characteristics associated with maladaptive personality traits by 60%. Moderate-to-severe functional impairment, high levels of somatic symptoms, and impaired quality of life were also reported. Women had a younger age at DS onset than men.
Conclusions
Our study highlights the burden of psychopathology and socio-economic deprivation in a large, heterogeneous cohort of patients with DS. The lack of clear differences based on gender, DS semiology and age at onset suggests these factors do not add substantially to the heterogeneity of the cohort.
Examine impact of audit and feedback on antipsychotic prescribing in schizophrenia over 4.5-years.
Methods:
Clinical files in three outpatient psychiatric services in Auckland, New Zealand were reviewed at two time-points (March-2000;October-2004). After the first audit, feedback was provided to all three services. Baseline prescribing variations between services were found for antipsychotic combinations and atypical prescribing, in particular clozapine. In two services audit and feedback continued with two interim reviews (October-2001;March-2003). Specific feedback and interventions targeting clozapine use were introduced in both services. No further audit or feedback occurred in the third service until the final audit. Data were collected (patient characteristics, diagnosis, antipsychotic treatment) and analysed at each audit.
Results:
Three prescribing variables (antipsychotic monotherapy, atypical and clozapine use) were consistent with practice recommendations at the final audit (85.7%, 82.7% and 34.5% respectively) and had changed in the desired direction for all three services over 4.5-years. At baseline there were differences between the three services. One service had baseline prescribing variables closest to recommendations, was actively involved in audit, and improved further. The second service, also actively involved in audit had baseline prescribing variables further from recommendations but improved the most. The service not involved in continuing audit and feedback made smaller changes, and atypical and clozapine use at endpoint were significantly lower despite at baseline being comparable to the service which improved the most.
Conclusions:
We found high intensity audit and feedback was an effective intervention in closing the gap between recommended and clinical practice for antipsychotic prescribing.
The aim of this study was to test the hypotheses that differences in residual feed intake (RFI) of beef steers are related to diet sorting, diet nutrient composition, energy intake and apparent digestibility. To phenotype steers for RFI, 69 weaned Angus × Hereford steers were fed individually for 56 days. A finishing diet was fed twice daily on an ad libitum basis to maintain approximately 0.5 to 1.0 kg refusals. Diet offered and refused was measured daily, and DM intakes (DMI) were calculated by difference. Body weights were recorded at 14-day intervals following an 18-h solid feed withdrawal. The residual feed intake was determined as the residual of the regression of DMI versus mid-test metabolic BW (BW0.75) and average daily gain (ADG). Particle size distributions of diet and refusals were determined using the Penn State Particle Separator to quantify diet sorting. Sampling of diet, refusals and feces were repeated in four sampling periods which occurred during weeks 2, 4, 6 and 8 of the study. Particle size distributions of refusals and diet were analyzed in weeks 2, 4 and 6, and sampling for chemical analysis of refusals and feces occurred in all four periods. Indigestible neutral detergent fiber (288 h in situ) was used as an internal marker of apparent digestibility. We conclude that preference for the intakes of particles > 19 mm and 4 to 8 mm were negatively correlated to RFI and ADG, respectively. Although steers did sort to consume a different diet composition than offered, diet sorting did not impact intake energy, digestible energy or DM digestibility.
To describe snacking characteristics and patterns in children and examine associations with diet quality and BMI.
Design:
Children’s weight and height were measured. Participants/adult proxies completed multiple 24 h dietary recalls. Snack occasions were self-identified. Snack patterns were derived for each sample using exploratory factor analysis. Associations of snacking characteristics and patterns with Healthy Eating Index-2010 (HEI-2010) score and BMI were examined using multivariable linear regression models.
Setting:
Childhood Obesity Prevention and Treatment Research (COPTR) Consortium, USA: NET-Works, GROW, GOALS and IMPACT studies.
Two snack patterns were derived for three studies: a meal-like pattern and a beverage pattern. The IMPACT study had a similar meal-like pattern and a dairy/grains pattern. A positive association was observed between meal-like pattern adherence and HEI-2010 score (P for trend < 0⋅01) and snack occasion frequency and HEI-2010 score (β coefficient (95 % CI): NET-Works, 0⋅14 (0⋅04, 0⋅23); GROW, 0⋅12 (0⋅02, 0⋅21)) among younger children. A preference for snacking while using a screen was inversely associated with HEI-2010 score in all studies except IMPACT (β coefficient (95 % CI): NET-Works, −3⋅15 (−5⋅37, −0⋅92); GROW, −2⋅44 (−4⋅27, −0⋅61); GOALS, −5⋅80 (−8⋅74, −2⋅86)). Associations with BMI were almost all null.
Conclusions:
Meal-like and beverage patterns described most children’s snack intake, although patterns for non-Hispanic Blacks or adolescents may differ. Diets of 2–5-year-olds may benefit from frequent meal-like pattern snack consumption and diets of all children may benefit from decreasing screen use during eating occasions.
Introduction: Emergency department (ED) staff carry a high risk for the burnout syndrome of increased emotional exhaustion, depersonalization and decreased personal accomplishment. Previous research has shown that task-oriented coping skills were associated with reduced levels of burnout compared to emotion-oriented coping. ED staff at one hospital participated in an intervention to teach task-oriented coping skills. We hypothesized that the intervention would alter staff coping behaviors and ultimately reduce burnout. Methods: ED physicians, nurses and support staff at two regional hospitals were surveyed using the Maslach Burnout Inventory (MBI) and the Coping Inventory for Stressful Situations (CISS). Surveys were performed before and after the implementation of communication and conflict resolution skills training at the intervention facility (I) consisting of a one-day course and a small group refresher 6 to 15 months later. Descriptive statistics and multivariate analysis assessed differences in staff burnout and coping styles compared to the control facility (C) and over time. Results: 85/143 (I) and 42/110 (C) ED staff responded to the initial survey. Post intervention 46 (I) and 23(C) responded. During the two year study period there was no statistically significant difference in CISS or MBI scores between hospitals (CISS: (Pillai's trace = .02, F(3,63) = .47, p = .71, partial η2 = .02); MBI: (Pillai's trace = .01, F(3,63) = .11, p = .95, partial η2 = .01)) or between pre- and post-intervention groups (CISS: (Pillai's trace = .01, F(3,63) = .22, p = .88, partial η2 = .01); MBI: (Pillai's trace = .09, F(3,63) = 2.15, p = .10, partial η2 = .01)). Conclusion: We were not able to measure improvement in staff coping or burnout in ED staff receiving communication skills intervention over a two year period. Burnout is a multifactorial problem and environmental rather than individual factors may be more important to address. Alternatively, to demonstrate a measurable effect on burnout may require more robust or inclusive interventions.
Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such ‘non-standard’ interventions. This analysis proposes a framework to aid this decision.
Declaration of interest
In the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.
In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.
Objectives: This study investigated the relationship between close proximity to detonated blast munitions and cognitive functioning in OEF/OIF/OND Veterans. Methods: A total of 333 participants completed a comprehensive evaluation that included assessment of neuropsychological functions, psychiatric diagnoses and history of military and non-military brain injury. Participants were assigned to a Close-Range Blast Exposure (CBE) or Non-Close-Range Blast Exposure (nonCBE) group based on whether they had reported being exposed to at least one blast within 10 meters. Results: Groups were compared on principal component scores representing the domains of memory, verbal fluency, and complex attention (empirically derived from a battery of standardized cognitive tests), after adjusting for age, education, PTSD diagnosis, sleep quality, substance abuse disorder, and pain. The CBE group showed poorer performance on the memory component. Rates of clinical impairment were significantly higher in the CBE group on select CVLT-II indices. Exploratory analyses examined the effects of concussion and multiple blasts on test performance and revealed that number of lifetime concussions did not contribute to memory performance. However, accumulating blast exposures at distances greater than 10 meters did contribute to poorer performance. Conclusions: Close proximity to detonated blast munitions may impact memory, and Veterans exposed to close-range blast are more likely to demonstrate clinically meaningful deficits. These findings were observed after statistically adjusting for comorbid factors. Results suggest that proximity to blast should be considered when assessing for memory deficits in returning Veterans. Comorbid psychiatric factors may not entirely account for cognitive difficulties. (JINS, 2018, 24, 466–475)
The ice-sheet margin at Russell Glacier, West Greenland, advanced ∼7 m a−1 between 1968 and 1999. As the ice advanced over moraine ridges, small changes in position caused major changes in the routing of proglacial water and sediment. These included changes in the distribution of ice-marginal lakes, in the periodic drainage of ice-dammed lakes, in the routing and sediment content of meltwater draining into the proglacial zone, and in the release of sediment from the moraines by erosion and mass movements. Proglacial hydrology and sediment flux appear to be controlled not simply by glacier mass balance, but by evolving ice-marginal geomorphology, which must be accounted for in palaeoenvironmental interpretation of proglacial sediments.
Sediment production at a terrestrial section of the ice-sheet margin in West Greenland is dominated by debris released through the basal ice layer. The debris flux through the basal ice at the margin is estimated to be 12–45 m3 m−1 a−1. This is three orders of magnitude higher than that previously reported for East Antarctica, an order of magnitude higher than sites reported from in Norway, Iceland and Switzerland, but an order of magnitude lower than values previously reported from tidewater glaciers in Alaska and other high-rate environments such as surging glaciers. At our site, only negligible amounts of debris are released through englacial, supraglacial or subglacial sediment transfer. Glaciofluvial sediment production is highly localized, and long sections of the ice-sheet margin receive no sediment from glaciofluvial sources. These findings differ from those of studies at more temperate glacial settings where glaciofluvial routes are dominant and basal ice contributes only a minor percentage of the debris released at the margin. These data on debris flux through the terrestrial margin of an outlet glacier contribute to our limited knowledge of debris production from the Greenland ice sheet.
The livestock sector is one of the fastest growing subsectors of the agricultural economy and, while it makes a major contribution to global food supply and economic development, it also consumes significant amounts of natural resources and alters the environment. In order to improve our understanding of the global environmental impact of livestock supply chains, the Food and Agriculture Organization of the United Nations has developed the Global Livestock Environmental Assessment Model (GLEAM). The purpose of this paper is to provide a review of GLEAM. Specifically, it explains the model architecture, methods and functionality, that is the types of analysis that the model can perform. The model focuses primarily on the quantification of greenhouse gases emissions arising from the production of the 11 main livestock commodities. The model inputs and outputs are managed and produced as raster data sets, with spatial resolution of 0.05 decimal degrees. The Global Livestock Environmental Assessment Model v1.0 consists of five distinct modules: (a) the Herd Module; (b) the Manure Module; (c) the Feed Module; (d) the System Module; (e) the Allocation Module. In terms of the modelling approach, GLEAM has several advantages. For example spatial information on livestock distributions and crops yields enables rations to be derived that reflect the local availability of feed resources in developing countries. The Global Livestock Environmental Assessment Model also contains a herd model that enables livestock statistics to be disaggregated and variation in livestock performance and management to be captured. Priorities for future development of GLEAM include: improving data quality and the methods used to perform emissions calculations; extending the scope of the model to include selected additional environmental impacts and to enable predictive modelling; and improving the utility of GLEAM output.