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Opaque ontology: neuroimaging classification of ICD-10 diagnostic groups in the UK Biobank.
BACKGROUND: The use of machine learning to classify diagnostic cases versus controls defined based on diagnostic ontologies such as the International Classification of Diseases, Tenth Revision (ICD-10) from neuroimaging features is now commonplace across a wide range of diagnostic fields. However, transdiagnostic comparisons of such classifications are lacking. Such transdiagnostic comparisons are important to establish the specificity of classification models, set benchmarks, and assess the value of diagnostic ontologies. RESULTS: We investigated case-control classification accuracy in 17 different ICD-10 diagnostic groups from Chapter V (mental and behavioral disorders) and Chapter VI (diseases of the nervous system) using data from the UK Biobank. Classification models were trained using either neuroimaging (structural or functional brain magnetic resonance imaging feature sets) or sociodemographic features. Random forest classification models were adopted using rigorous shuffle-splits to estimate stability as well as accuracy of case-control classifications. Diagnostic classification accuracies were benchmarked against age classification (oldest vs. youngest) from the same feature sets and against additional classifier types (k-nearest neighbors and linear support vector machine). In contrast to age classification accuracy, which was high for all feature sets, few ICD-10 diagnostic groups were classified significantly above chance (namely, demyelinating diseases based on structural neuroimaging features and depression based on sociodemographic and functional neuroimaging features). CONCLUSION: These findings highlight challenges with the current disease classification system, leading us to recommend caution with the use of ICD-10 diagnostic groups as target labels in brain-based disease prediction studies.
Going ‘meta’: a systematic review of metacognition and functional neurological disorder
In functional neurological disorder (FND), there is a fundamental disconnect between an apparently intact nervous system and the individuals’ ability to consistently perform motor actions, perceive sensory signals and/or access effective cognition. Metacognition, the capacity to self-evaluate cognitive performance, appears highly relevant to FND pathophysiology. Poor metacognition is a potential mechanism via which abnormal models of self and the state of the world could arise and persist unchecked. There is therefore a justified enthusiasm that studies of metacognition may give substance to FND’s intangible nature. However, many assume an impairment in metacognition even though experimental studies are still in their infancy. This systematic review provides an analytical checkpoint of the evidence after the first five years of experimental work. We firstly summarize current methods for testing metacognition, prerequisite knowledge that allows readers to independently evaluate the evidence. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we then screened the 21 articles on this topic and review the experimental data of the eight studies that specifically tested metacognition in subjects with FND. Questionnaire metrics used to estimate global metacognition and general confidence in FND revealed a mixed picture of low or normal confidence. Of the five studies that used performance-controlled metrics, the gold-standard to estimate local metacognition in FND, four found metacognition to be equivalent to healthy controls and one paper supported impaired metacognition. We consequently try and broaden the debate and discuss alternative headline scenarios. We review how positive studies may offer insight and debate whether null studies could represent false negatives. However, since most studies find equivalent metacognition to controls, we also discuss whether metacognition could be intact and how this could inform mechanistic models of FND and have potential clinical utility. In summary, this review highlights signal of interest within the data, exposes current limitations and flags the many open questions.
A feline model of spontaneously occurring autoimmune limbic encephalitis.
Autoimmune encephalitis (AE) is an important cause of encephalitis in humans and occurs at a similar rate to infectious encephalitis. It is frequently associated with antibodies against the extracellular domain of neuronal proteins. Among human AE, that with antibodies against leucine-rich glioma-inactivated 1 (LGI1) is one of the most prevalent forms, and was recently described in cats with limbic encephalitis (LE). In this study, we describe a large cohort (n = 32) of cats with AE, tested positive for voltage gated potassium channel (VGKC)-antibodies, of which 26 (81%) harboured LGI1-antibodies. We delineate their clinical and paraclinical features as well as long-term outcomes up to 5 years. Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%). Among feline AE patients, there was no seizure type or other clinical characteristic that could distinguish LGI1-antibody positive from negative cats, unlike the pathognomic faciobrachial dystonic seizures seen in humans. Although six cats were euthanased in the first year for epilepsy-associated reasons, those attaining at least 1-year survival had good seizure control and quality of life with appropriate veterinary care and medication. Acute-phase immunotherapy (prednisolone) was given to the most severely unwell cases and its effect is retrospectively evaluated in 10 cats. Our data show LGI1-antibodies are an important cause of feline encephalitis, sharing many features with human AE. Further research should examine optimal therapeutic management strategies and the cause of LE in seronegative cats, building on paradigms established in the counterpart human disease.
European Stroke Organisation (ESO) standard operating procedure for white papers (expert consensus based clinical guidance).
Promoting the highest quality, evidence-based research across Europe is a priority of the European Stroke Organisation (ESO). The ESO Guideline Board communicate and promote evidence-based recommendations for clinical practice through their Guidelines. However, there are many aspects of stroke care where robust scientific evidence may be unavailable or difficult to obtain. Thus, there is a need for practical, consensus guidance, produced following robust, consistent, and transparent methods, that is suitable for high-priority clinical scenarios where evidence is currently lacking. The ESO Guideline Board developed methods for producing practical clinical guidance based on expert consensus in response to this need. These ESO' White Papers' are intended to complement standard ESO Guidelines. Here, we outline the ESO White Papers' standard operating procedure (SOP). We will describe the motivation for creating White Papers, the preferred composition of writing groups and expert consensus panellists, the methods for achieving consensus, and how results will be communicated. To ensure that all voting members have an equal voice, our methods are based upon the Delphi process of repeated rounds of anonymous voting, feedback and review. We hope that the White Papers will add further value to the clinical practice guidance that is offered by ESO. We look forward to receiving suggestions for White Paper topics from the stroke community.
The LRR receptor-like kinase ALR1 is a plant aluminum ion sensor.
Plant survival requires an ability to adapt to differing concentrations of nutrient and toxic soil ions, yet ion sensors and associated signaling pathways are mostly unknown. Aluminum (Al) ions are highly phytotoxic, and cause severe crop yield loss and forest decline on acidic soils which represent ∼30% of land areas worldwide. Here we found an Arabidopsis mutant hypersensitive to Al. The gene encoding a leucine-rich-repeat receptor-like kinase, was named Al Resistance1 (ALR1). Al ions binding to ALR1 cytoplasmic domain recruits BAK1 co-receptor kinase and promotes ALR1-dependent phosphorylation of the NADPH oxidase RbohD, thereby enhancing reactive oxygen species (ROS) generation. ROS in turn oxidatively modify the RAE1 F-box protein to inhibit RAE1-dependent proteolysis of the central regulator STOP1, thus activating organic acid anion secretion to detoxify Al. These findings establish ALR1 as an Al ion receptor that confers resistance through an integrated Al-triggered signaling pathway, providing novel insights into ion-sensing mechanisms in living organisms, and enabling future molecular breeding of acid-soil-tolerant crops and trees, with huge potential for enhancing both global food security and forest restoration.
An LRH-RSL4 feedback regulatory loop controls the determinate growth of root hairs in Arabidopsis.
Root hairs are tubular-shaped outgrowths of epidermal cells essential for plants acquiring water and nutrients from the soil. Despite their importance, the growth of root hairs is finite. How this determinate growth is precisely regulated remains largely unknown. Here we identify LONG ROOT HAIR (LRH), a GYF domain-containing protein, as a unique repressor of root hair growth. We show that LRH inhibits the association of eukaryotic translation initiation factor 4Es (eIF4Es) with the mRNA of ROOT HAIR DEFECTIVE6-LIKE4 (RSL4) that encodes the master regulator of root hair growth, repressing RSL4 translation and thus root hair elongation. RSL4 in turn directly transactivates LRH expression to maintain a proper LRH gradient in the trichoblasts. Our findings reveal a previously uncharacterized LRH-RSL4 feedback regulatory loop that limits root hair growth, shedding new light on the mechanism underlying the determinate growth of root hairs.
Improving rice nitrogen-use efficiency by modulating a novel monouniquitination machinery for optimal root plasticity response to nitrogen.
Plant nitrogen (N)-use efficiency (NUE) is largely determined by the ability of root to take up external N sources, whose availability and distribution in turn trigger the modification of root system architecture (RSA) for N foraging. Therefore, improving N-responsive reshaping of RSA for optimal N absorption is a major target for developing crops with high NUE. In this study, we identified RNR10 (REGULATOR OF N-RESPONSIVE RSA ON CHROMOSOME 10) as the causal gene that underlies the significantly different root developmental plasticity in response to changes in N level exhibited by the indica (Xian) and japonica (Geng) subspecies of rice. RNR10 encodes an F-box protein that interacts with a negative regulator of auxin biosynthesis, DNR1 (DULL NITROGEN RESPONSE1). Interestingly, RNR10 monoubiquitinates DNR1 and inhibits its degradation, thus antagonizing auxin accumulation, which results in reduced root responsivity to N and nitrate (NO3-) uptake. Therefore, modulating the RNR10-DNR1-auxin module provides a novel strategy for coordinating a desirable RSA and enhanced N acquisition for future sustainable agriculture.
ART1 and putrescine contribute to rice aluminum resistance via OsMYB30 in cell wall modification.
Cell wall is the first physical barrier to aluminum (Al) toxicity. Modification of cell wall properties to change its binding capacity to Al is one of the major strategies for plant Al resistance; nevertheless, how it is regulated in rice remains largely unknown. In this study, we show that exogenous application of putrescines (Put) could significantly restore the Al resistance of art1, a rice mutant lacking the central regulator Al RESISTANCE TRANSCRIPTION FACTOR 1 (ART1), and reduce its Al accumulation particularly in the cell wall of root tips. Based on RNA-sequencing, yeast-one-hybrid and electrophoresis mobility shift assays, we identified an R2R3 MYB transcription factor OsMYB30 as the novel target in both ART1-dependent and Put-promoted Al resistance. Furthermore, transient dual-luciferase assay showed that ART1 directly inhibited the expression of OsMYB30, and in turn repressed Os4CL5-dependent 4-coumaric acid accumulation, hence reducing the Al-binding capacity of cell wall and enhancing Al resistance. Additionally, Put repressed OsMYB30 expression by eliminating Al-induced H2 O2 accumulation, while exogenous H2 O2 promoted OsMYB30 expression. We concluded that ART1 confers Put-promoted Al resistance via repression of OsMYB30-regulated modification of cell wall properties in rice.
The potential of stable carbon and nitrogen isotope analysis of foxtail and broomcorn millets for investigating ancient farming systems.
Foxtail and broomcorn millets are the most important crops in northern China since the early Neolithic. However, little evidence is available on how people managed these two crops in the past, especially in prehistory. Previous research on major C3 crops in western Eurasia demonstrated the potential of stable carbon and nitrogen isotope analysis of charred archaeobotanical remains to reveal the management of water and manure, respectively. Here, we evaluate the feasibility of a similar approach to C4 millets. Foxtail and broomcorn millet plants grown in pots in a greenhouse under different manuring and watering regimes were analysed to test the effects of management on stable carbon and nitrogen isotope values of grains. Stable nitrogen isotope values of both millets increased as manuring level increased, ranging from 1.7 ‰ to 5.8 ‰ in different conditions; hence, it appears a feasible tool to identify manuring practices, in agreement with results from recent field studies. However, the two millets exhibit opposing trends in stable carbon isotope values as watering level increased. The shift in stable carbon isotope values of millets is also smaller than that observed in wheat grown in the same experimental environment, making it difficult to identify millet water status archaeologically. In addition, we charred millet grains at different temperatures and for varying durations to replicate macro-botanical remains recovered archaeologically, and to evaluate the offsets in carbon and nitrogen isotope values induced by charring. We found that the stable nitrogen isotope values of foxtail millet and broomcorn millet can shift up to 1-2 ‰ when charred, while the stable carbon isotope values change less than 0.3 ‰. Overall, we demonstrate that stable nitrogen isotope values of charred foxtail and broomcorn millet seeds could provide insight into past field management practices, and both carbon and nitrogen isotope values can together inform palaeodietary reconstruction.
Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors.
The worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of MAP3K13, which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified MAP3K13. Inhibition of LZK suppressed tumor growth in MAP3K13-amplified xenografts derived from HNSCC patients. LZK stabilized the transcription factor c-MYC through its kinase activity and gain-of-function mutants of p53 in a kinase-independent manner. We designed a proteolysis-targeting chimera (PROTAC) that induced LZK degradation, leading to decreased abundance of both c-MYC and gain-of-function p53, and reduced the viability of HNSCC cells. Our findings demonstrate that LZK-targeted therapeutics, particularly PROTACs, may be effective in treating HNSCCs with MAP3K13 amplification.
Assessment of frailty in patients with heart failure: A new Heart Failure Frailty Score developed by Delphi consensus.
AIMS: The Heart Failure Frailty Score (HFFS) is a novel, multidimensional tool to assess frailty in patients with heart failure (HF). It has been developed to overcome limitations of existing frailty assessment tools while being practical for clinical use. The HFFS reflects the concept of frailty as a multidimensional, dynamic and potentially reversible state, which increases vulnerability to stressors and risk of poor outcomes in patients with HF. METHODS AND RESULTS: The HFFS was developed through a Delphi consensus process involving 54 international experts. This approach involved iterative rounds of questionnaires and interviews, where a panel of experts provided their opinions on specific questions prepared by the Steering Committee. The experts were invited to vote and share their views anonymously, using a 5-point Likert scale over iterative rounds. An 80% threshold was set for agreement or disagreement for each statement. Twenty-two variables from four domains (clinical, functional, psycho-cognitive and social) have been selected for inclusion in the HFFS after the third round of the Delphi process. A shorter version (S-HFFS), including 10 variables, has also been developed for daily clinical use. CONCLUSIONS: The HFFS is a new multidimensional tool for the identification of frailty in patients with HF. It should also enables healthcare providers to identify potential 'red flags' for frailty in order to develop personalized care plans. The next step will be to validate the new score in patients with HF.
A service evaluation of the implementation of a novel digital intervention for hypertension self-monitoring and management system in primary care (SHIP): protocol for a mixed methods study.
BACKGROUND: Hypertension is a key risk factor for death and disability, and blood pressure reduction is associated with significant reductions in cardiovascular risk. Large trials have shown that interventions including self-monitoring of blood pressure can reduce blood pressure but real-world data from wider implementation are lacking. AIM: The self-monitoring and management service evaluation in primary care (SHIP) study will evaluate a novel digital intervention for hypertension management and medication titration platform ("Hypertension-Plus") that is currently undergoing initial implementation into primary care in several parts of the UK. METHODS AND ANALYSES: The study will use a mixed methods approach including both quantitative analysis of anonymised electronic health record data and qualitative analyses of interview and customer support log data. Pseudonymised data will be extracted from electronic health records and outcomes compared between those using the digital intervention and their own historical data, as well as to those not registered to the system. The primary outcome will be difference in systolic blood pressure in the 12 months before and after implementation. A further analysis will utilise self-monitored blood pressure data from the Hypertension-Plus system itself. Semi-structured qualitative interviews will be completed with implementation and clinical leads, staff and patients in six general practices located in two different geographical areas in England. Informed by the non-adoption, abandonment, scale-up, spread, and sustainability (NASSS) framework, our analysis will identify the challenges to successful implementation and sustainability of the digital intervention in routine clinical practice and in patients' homes. ETHICS AND DISSEMINATION: The analyses of pseudonymised data were assessed by the sponsor (The University of Oxford) as service evaluation not requiring individual consent and hence did not require ethical approval. Ethics approval for the qualitative analyses was provided by Wales REC 4 (21/WA/0280) and individual written informed consent will be gained for all participants. Results will be published in peer-reviewed journals, presented at national and international conferences and disseminated via patient and health service organisations. DISCUSSION: This study will provide an in-depth analysis of the impact and acceptance of initial implementation of a novel digital intervention, enhancing our understanding and supporting more effective implementation of telemonitoring based hypertension management systems for blood pressure control in England.
European expert consensus recommendations on the primary care use of direct oral anticoagulants in patients with venous thromboembolism.
BACKGROUND: Direct oral anticoagulants for the treatment of venous thromboembolism are supported by robust clinical trial evidence. Despite published guidance, general practitioners are faced with increasingly complex decisions and implementation remains sub-optimal in certain real-world scenarios. METHODS: A two stage formal consensus exercise was performed to formulate consensus statements and a summary guide, facilitating optimal management of direct oral anticoagulants in venous thromboembolism patients by generalist physicians across Europe. An online questionnaire distributed to a broad panel (Phase 1), followed by a virtual panel discussion by an expert group (Phase 2) were conducted. Phase 1 statements covered nine management domains, and were developed via a literature review and expert steering committee. Participants rated statements by their level of agreement. Phase 1 responses were collated and analysed prior to discussion and iterative refinement in Phase 2. RESULTS: In total 56 participants from across Europe responded to Phase 1. The majority had experience working as general practitioners. Consensus indicated that direct oral anticoagulants are the treatment of choice for managing patients with venous thromboembolism, at initiation and for extended treatment, with a review at three to six months to re-assess treatment effect and risk profile. Direct oral anticoagulant choice should be based on individual patient factors and include shared treatment choice between clinicians and patients; the only sub-group of patients requiring specific guidance are those with cancer. CONCLUSION: Results demonstrate an appreciation of best practices, but highlight challenges in clinical practice. The patient pathway and consensus recommendations provided, aim to highlight key considerations for general practice decision making, and aid optimal venous thromboembolism treatment.