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Prior to the arrival of HLB in a region large-scale surveillance programs are usually instigated in order to detect the disease as early as possible.  Early detection is necessary to minimise the impact of the disease and facilitate any containment or eradication interventions.  Large-scale surveillance surveys are however expensive, covering large geographic regions and stretching fiscal and manpower resources.  Available resources must thus be deployed in the most optimal way.  The choice of which locations within a region to survey is a complex problem since there may be hundreds of thousands of possibilities to choose from. Predicting how the epidemic will spread through a heterogonous landscape of citrus plantings and how this relates to where sampling resources should be deployed to find the ‘needle in the haystack’ is challenging and most surveys are consequently sub-optimal.  We bring together state of the art epidemiological modelling and stochastic optimisation techniques to determine the optimal pattern of sampling deployment across a landscape.  We find that the optimal pattern of sampling resources in a region is often counter-intuitive; for example simply targeting the highest risk locations is rarely the optimal course of action.  We show how the optimal pattern depends subtly on epidemiological factors such as the spatial pattern of citrus plantings and vector densities in a region.  We also show how geo-referenced information on likely entry points into a region, e.g. trade and travel hubs, can be incorporated to improve the probability of achieving early detection.

The detection of a new HLB epidemic in a planting often occurs when the disease has already reached high incidence.  This is problematic and once the epidemic has become established it is difficult to recover the economic productivity of the grove.  However, if new epidemics can be detected early enough then more can be done to control the disease.  Early detection requires that surveillance surveys be in place before the disease arrives; that is, a number of trees within a healthy grove should be inspected at regular intervals for symptoms of HLB.  Exactly how many trees should be surveyed and how frequently this should be done is a non-trivial problem and one that has not previously been addressed in plant pathology.  We present a theoretical method that relates the dynamics of an invading epidemic to the dynamics of a monitoring program.  The method determines exactly how an early detection survey should be designed in order to achieve a high probability of detecting an epidemic whilst it is at an early stage.  We compare the theoretical method to a complex simulation model which replicates the spatial and temporal dynamics of HLB in the field.  By running the model thousands of times we can make probabilistic predictions on early detection survey design that can be directly compared with the theoretical method.  We find striking similarities between the simple theoretical and more complicated simulation approach that enables us to make valuable new insights as well as deliver methods for transfer into practice.

To the Editor, It has recently been suggested that saliva tests might provide a useful diagnostic tool for patients infected by the novel coronavirus that has caused over 92,000 cases worldwide (as of 3 March 2020). Diagnosing coronavirus disease (COVID-19) from saliva samples has advantages compared to more invasive procedures based on nasopharyngeal or oropharyngeal samples. Sampling and testing saliva samples could provide an easy-to-use diagnostic method for COVID-19, and other diagnostic methods do not have perfect sensitivity either. [Extracted from the article]

The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as 'High-risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by plants of hybrids of Prunus cerasus x Prunus canescens imported from Ukraine, taking into account the available scientific information, including the technical information provided by Ukraine. All pests that may be associated with the hybrids of P. cerasus x P. canescens were evaluated against specific criteria for their relevance for this opinion. None of the pests fulfilled all relevant criteria due to the production method and risk mitigation measures carried out by the nursery; therefore, none were selected for further evaluation., (© 2024 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

The European Commission requested the EFSA Panel on Plant Health to evaluate the probability of entry of pests (likelihood of pest freedom at entry), including both regulated and non-regulated pests, associated with unrooted cuttings of the genera Petunia and Calibrachoa produced under physical isolation in Costa Rica. The relevance of any pest for this opinion was based on evidence collected according to specific criteria, following the methodology used for high-risk plants adapted for the specificity of this assessment. Twenty-two EU regulated pests (beet curly top virus, Bemisia tabaci , Chloridea virescens , Eotetranychus lewisi , Epitrix cucumeris , Epitrix tuberis , euphorbia mosaic virus, Helicoverpa zea , Liriomyza huidobrensis , Liriomyza sativae , Liriomyza trifolii , pepper golden mosaic virus, potato spindle tuber viroid, Ralstonia pseudosolanacearum , Ralstonia solanacearum , Spodoptera ornithogalli , squash leaf curl virus, Thrips palmi , tomato golden mosaic virus, tomato leaf curl Sinaloa virus, tomato spotted wilt virus, tomato yellow leaf curl virus) and one pest that is not regulated in the EU ( Aleurodicus dispersus ) fulfilled all relevant criteria and were selected for further evaluation. For these pests, the risk mitigation measures proposed in the technical dossier from Costa Rica were evaluated taking into account possible factors limiting their efficacies. Additionally, an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. The estimated degree of pest freedom varies among the pests evaluated, with tomato spotted wilt virus being the pest most frequently expected on the imported cuttings. The expert knowledge elicitation indicated, with 95% certainty that between 9927 and 10,000 bags containing unrooted cuttings of Petunia spp. and Calibrachoa spp. per 10,000 would be free of tomato spotted wilt virus., (© 2024 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as 'High risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by plants of Betula pendula and B. pubescens imported from the United Kingdom (UK) taking into account the available scientific information, including the technical information provided by the UK. The commodities were grouped in the risk assessment as (a) bundles of 10-20 graftwood/budwood (up to 1-year-old), (b) bare root plants which include bundles of 25 or 50 seedlings or transplants (1-2 years-old), bundles of 5, 10 or 15 whips (1-2 years-old) and single bare root plants (1-7 years-old), (c) plants in pots which include bundles of 5 and 10 cell-grown plants (1-2 years-old) and rooted plants in pots (1-7 years-old), and (d) large specimen trees up to 15-years-old. All pests associated with the commodities were evaluated against specific criteria for their relevance for this opinion. Two EU quarantine pests i.e. Meloidogyne fallax and Phytophthora ramorum (non-EU isolates) and two protected zone quarantine pests i.e. Entoleuca mammata and Thaumetopoea processionea fulfilled all relevant criteria and were selected for further evaluation. For the selected pests, the risk mitigation measures described in the technical dossier from the UK were evaluated considering the possible limiting factors. For these pests an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. In the assessment of risk, the age of the plants was considered, as larger trees are more likely to be infested mainly due to longer time grown in the field. In addition, larger canopies and root systems are more difficult to inspect, thereby making the detection of pests more challenging on large trees. The likelihood of pest freedom varies among the pests evaluated, with M. fallax being the pest most frequently expected on the imported plants. The Expert Knowledge Elicitation (EKE) indicated with 95% certainty that between 9735 and 10,000 per 10,000 large specimen trees will be free from M. fallax ., Competing Interests: If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact interestmanagement@efsa.europa.eu., (© 2024 European Food Safety Authority. EFSA Journal published by Wiley‐VCH GmbH on behalf of European Food Safety Authority.)

Plant diseases caused by viruses share many common features with those caused by other pathogen taxa in terms of the host-pathogen interaction, but there are also distinctive features in epidemiology, most apparent where transmission is by vectors. Consequently, the host-virus-vector-environment interaction presents a continuing challenge in attempts to understand and predict the course of plant virus epidemics. Theoretical concepts, based on the underlying biology, can be expressed in mathematical models and tested through quantitative assessments of epidemics in the field; this remains a goal in understanding why plant virus epidemics occur and how they can be controlled. To this end, this review identifies recent emerging themes and approaches to fill in knowledge gaps in plant virus epidemiology. We review quantitative work on the impact of climatic fluctuations and change on plants, viruses, and vectors under different scenarios where impacts on the individual components of the plant-virus-vector interaction may vary disproportionately; there is a continuing, sometimes discordant, debate on host resistance and tolerance as plant defense mechanisms, including aspects of farmer behavior and attitudes toward disease management that may affect deployment in crops; disentangling host-virus-vector-environment interactions, as these contribute to temporal and spatial disease progress in field populations; computational techniques for estimating epidemiological parameters from field observations; and the use of optimal control analysis to assess disease control options. We end by proposing new challenges and questions in plant virus epidemiology., Competing Interests: The author(s) declare no conflict of interest.

Remyelination is the regenerative process by which lost myelin sheaths are restored to demyelinated axons. It is a key target in the treatment of chronic demyelinating disorders such as multiple sclerosis (MS), in which inflammation results in destruction of myelin. In the central nervous system (CNS), remyelination typically requires the differentiation of oligodendrocyte progenitor cells (OPCs) into the myelinating oligodendrocytes (OL). Following successes in preclinical studies, several putative pro-regenerative therapies aimed at enhancing remyelination are under clinical investigation. However, there is a translational barrier in identifying successful outcomes: preclinical measures of remyelination do not translate well to clinical studies, and the paraclinical measures currently deployed in trials are challenging to apply to small rodent models of remyelination. Here, we describe the current approaches to identifying remyelination both in preclinical and clinical settings and highlight exciting translational candidates, which may help to bridge the current impasse., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A key aim in biology is to identify which genetic changes contributed to the evolution of form through time. Apical dominance, the inhibitory effect exerted by shoot apices on the initiation or outgrowth of distant lateral buds, is a major regulatory mechanism of plant form. 1 Nearly a century of studies in the sporophyte of flowering plants have established the phytohormone auxin as a front-runner in the search for key factors controlling apical dominance, 2 , 3 identifying critical roles for long-range polar auxin transport and local auxin biosynthesis in modulating shoot branching. 4-10 A capacity for lateral branching evolved by convergence in the gametophytic shoot of mosses and primed its diversification; 11 however, polar auxin transport is relatively unimportant in this developmental process, 12 the contribution of auxin biosynthesis genes has not been assessed, and more generally, the extent of conservation in apical dominance regulation within the land plants remains largely unknown. To fill this knowledge gap, we sought to identify genetic determinants of apical dominance in the moss Physcomitrium patens. Here, we show that leafy shoot apex decapitation releases apical dominance through massive and rapid transcriptional reprogramming of auxin-responsive genes and altering auxin biosynthesis gene activity. We pinpoint a subset of P. patens TRYPTOPHAN AMINO-TRANSFERASE (TAR) and YUCCA FLAVIN MONOOXYGENASE-LIKE (YUC) auxin biosynthesis genes expressed in the main and lateral shoot apices and show that they are essential for coordinating branch initiation and outgrowth. Our results demonstrate that local auxin biosynthesis acts as a pivotal regulator of apical dominance in moss and constitutes a shared mechanism underpinning shoot architecture control in land plants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The retinoid X receptor agonist bexarotene promotes remyelination in patients with multiple sclerosis. Murine studies have also demonstrated that RXR agonists have anti-inflammatory effects by enhancing the ability of all-trans-retinoic acid ( at RA) to promote T-regulatory cell (Treg) induction and reduce Th17 differentiation in vitro. By stimulating human naïve CD4 T-cells in the presence of Treg or Th17 skewing cytokines, we show that bexarotene also tips the human Treg/Th17 axis in favor of Treg induction, but unlike murine cells this occurs independently of at RA and retinoic acid receptor signaling. Tregs induced in the presence of bexarotene express canonical markers of T-regulation and are functionally suppressive in vitro. Circulating Treg numbers did not increase in the blood of trial patients receiving bexarotene; we believe this is because Treg induction is likely to occur within tissues. These findings lend support to developing RXR agonists as treatments of autoimmune diseases, in particular multiple sclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaunt, Rainbow, Mackenzie, Jarvis, Mousa, Cunniffe, Georgieva, Brown, Coles and Jones.)

Objective: To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS)., Methods: We long-listed licensed drugs with evidence of human safety, blood-brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review., Results: From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine., Conclusions: We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS., Competing Interests: Competing interests: DB received compensation for consultancy activity from Canbex Therapeutics, Japan Tobacco, Lundbeck, InMune Bio, Merck, Novartis, and Roche in the past 3 years. AC received honoraria and travel support from Genzyme (a Sanofi company) prior to 2017. MC has received honoraria for educational events and/or consultancy from Biogen, Merck, Roche, AbbVie and Novartis. GG has received compensation for serving as a consultant in relation to multiple sclerosis drug development from AbbVie, Actelion, Atara Bio, Biogen, Celgene, EMD Serono, Japanese Tobacco, Sanofi-Genzyme, Genentech, GlaxoSmithKline, GW Pharma, Merck KGa, Novartis, Roche and Teva. LH holds a small number of GSK shares as part of her renumeration when she was an employee, which she left 4 years ago. DM received consultancy fees from Biogen, MedDay and SanofiGenzyme and Novartis. BN holds a patent regarding the treatment of demyelinating diseases including metformin: WO2019/206419 A1, Treatment for demyelinating disease. SP is cofounder, CSO and shareholder (>5%) of CITC Ltd and iSTEM Therapeutics, and cofounder and non-executive director at Asitia Therapeutics. LP-J is Head of Research at iSTEM Therapeutics. AW receives research support from Roche not associated with drug development or use., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we report that COVID-19 hospitalization rates follow an exponential relationship with age, doubling for every 16 years of age or equivalently increasing by 4.5% per year of life ( R 2 = 0.98). This mirrors the well-studied exponential decline of both thymus volume and T-cell production, which halve every 16 years. COVID-19 can therefore be added to the list of other diseases with this property, including those caused by methicillin-resistant Staphylococcus aureus , MERS-CoV, West Nile virus, Streptococcus pneumoniae and certain cancers, such as chronic myeloid leukaemia and brain cancers. In addition, the incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. Since these properties are shared with some non-contagious diseases, we hypothesized that the age dependence does not come from social-mixing patterns, i.e. that the probability of hospitalization given infection rises exponentially, doubling every 16 years. A Bayesian analysis of daily hospitalizations, incorporating contact matrices, found that this relationship holds for every age group except for the under 20s. While older adults have fewer contacts than young adults, our analysis suggests that there is an approximate cancellation between the effects of fewer contacts for the elderly and higher infectiousness due to a higher probability of developing severe disease. Our model fitting suggests under 20s have 49-75% additional immune protection beyond that predicted by strong thymus function alone, consistent with increased juvenile cross-immunity from other viruses. We found no evidence for differences between age groups in susceptibility to infection or infectiousness to others (given disease state), i.e. the only important factor in the age dependence of hospitalization rates is the probability of hospitalization given infection. These findings suggest the existence of a T-cell exhaustion threshold, proportional to thymic output and that clonal expansion of peripheral T-cells does not affect disease risk. The strikingly simple inverse relationship between risk and thymic T-cell output adds to the evidence that thymic involution is an important factor in the decline of the immune system with age and may also be an important clue in understanding disease progression, not just for COVID-19 but other diseases as well.

The greatest unmet need in multiple sclerosis (MS) are treatments that delay, prevent or reverse progression. One of the most tractable strategies to achieve this is to therapeutically enhance endogenous remyelination; doing so restores nerve conduction and prevents neurodegeneration. The biology of remyelination-centred on the activation, migration, proliferation and differentiation of oligodendrocyte progenitors-has been increasingly clearly defined and druggable targets have now been identified in preclinical work leading to early phase clinical trials. With some phase 2 studies reporting efficacy, the prospect of licensed remyelinating treatments in MS looks increasingly likely. However, there remain many unanswered questions and recent research has revealed a further dimension of complexity to this process that has refined our view of the barriers to remyelination in humans. In this review, we describe the process of remyelination, why this fails in MS, and the latest research that has given new insights into this process. We also discuss the translation of this research into clinical trials, highlighting the treatments that have been tested to date, and the different methods of detecting remyelination in people.

Epidemiological models are routinely used to predict the effects of interventions aimed at reducing the impacts of Ebola epidemics. Most models of interventions targeting symptomatic hosts, such as isolation or treatment, assume that all symptomatic hosts are equally likely to be detected. In other words, following an incubation period, the level of symptoms displayed by an individual host is assumed to remain constant throughout an infection. In reality, however, symptoms vary between different stages of infection. During an Ebola infection, individuals progress from initial non-specific symptoms through to more severe phases of infection. Here we compare predictions of a model in which a constant symptoms level is assumed to those generated by a more epidemiologically realistic model that accounts for varying symptoms during infection. Both models can reproduce observed epidemic data, as we show by fitting the models to data from the ongoing epidemic in the Democratic Republic of the Congo and the 2014-16 epidemic in Liberia. However, for both of these epidemics, when interventions are altered identically in the models with and without levels of symptoms that depend on the time since first infection, predictions from the models differ. Our work highlights the need to consider whether or not varying symptoms should be accounted for in models used by decision makers to assess the likely efficacy of Ebola interventions., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Mathematical models provide a rational basis to inform how, where and when to control disease. Assuming an accurate spatially explicit simulation model can be fitted to spread data, it is straightforward to use it to test the performance of a range of management strategies. However, the typical complexity of simulation models and the vast set of possible controls mean that only a small subset of all possible strategies can ever be tested. An alternative approach-optimal control theory-allows the best control to be identified unambiguously. However, the complexity of the underpinning mathematics means that disease models used to identify this optimum must be very simple. We highlight two frameworks for bridging the gap between detailed epidemic simulations and optimal control theory: open-loop and model predictive control. Both these frameworks approximate a simulation model with a simpler model more amenable to mathematical analysis. Using an illustrative example model, we show the benefits of using feedback control, in which the approximation and control are updated as the epidemic progresses. Our work illustrates a new methodology to allow the insights of optimal control theory to inform practical disease management strategies, with the potential for application to diseases of humans, animals and plants. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.

The deployment of crop varieties that are partially resistant to plant pathogens is an important method of disease control. However, a trade-off may occur between the benefits of planting the resistant variety and a yield penalty, whereby the standard susceptible variety outyields the resistant one in the absence of disease. This presents a dilemma: deploying the resistant variety is advisable only if the disease occurs and is sufficient for the resistant variety to outyield the infected standard variety. Additionally, planting the resistant variety carries with it a further advantage in that the resistant variety reduces the probability of disease invading. Therefore, viewed from the perspective of a grower community, there is likely to be an optimal trade-off and thus an optimal cropping density for the resistant variety. We introduce a simple stochastic, epidemiological model to investigate the trade-off and the consequences for crop yield. Focusing on susceptible-infected-removed epidemic dynamics, we use the final size equation to calculate the surviving host population in order to analyse the yield, an approach suitable for rapid epidemics in agricultural crops. We identify a single compound parameter, which we call the efficacy of resistance and which incorporates the changes in susceptibility, infectivity and durability of the resistant variety. We use the compound parameter to inform policy plots that can be used to identify the optimal strategy for given parameter values when an outbreak is certain. When the outbreak is uncertain, we show that for some parameter values planting the resistant variety is optimal even when it would not be during the outbreak. This is because the resistant variety reduces the probability of an outbreak occurring., (© 2016 The Author(s).)

Covert Hepatic Encephalopathy (CHE), previously known as Minimal Hepatic Encephalopathy, is a subtle cognitive defect found in 30-70 % of cirrhosis patients. It has been linked to poor quality of life, impaired fitness to drive, and increased mortality: treatment is possible. Despite its clinical significance, diagnosis relies on psychometric tests that have proved unsuitable for use in a clinical setting. We investigated whether measurement of saccadic latency distributions might be a viable alternative. We collected data on 35 cirrhosis patients at Addenbrooke's Hospital, Cambridge, with no evidence of clinically overt encephalopathy, and 36 age-matched healthy controls. Performance on standard psychometric tests was evaluated to determine those patients with CHE as defined by the World Congress of Gastroenterology. We then compared visually-evoked saccades between those with CHE and those without, as well as reviewing blood test results and correlating saccadic latencies with biochemical parameters and prognostic scores. Cirrhosis patients have significantly longer median saccadic latencies than healthy controls. Those with CHE had significantly prolonged saccadic latencies when compared with those without CHE. Analysis of a cirrhosis patient's saccades can diagnose CHE with a sensitivity of 75 % and a specificity of 75 %. We concluded that analysis of a cirrhosis patient's saccadic latency distributions is a fast and objective measure that can be used as a diagnostic tool for CHE. This improved early diagnosis could direct avoidance of high-risk activities such as driving, and better inform treatment strategies.

Aims: Patients on follow-up after orchidectomy or chemotherapy for testicular germ cell tumours follow a protocol of outpatient appointments and investigations designed to detect relapse. We wanted to investigate the contribution of clinical examination to patient management., Materials and Methods: The notes of 70 consecutive patients who suffered a first systemic relapse of their germ cell tumour within the last 10 years were studied to determine how the relapse was detected. Second testicular tumours were excluded., Results: Of the 69 patients whose notes were available, only one had a significant finding on physical examination, concurrent with abnormal markers., Conclusions: We suggest that, for patients following a planned programme of appointments and investigations, physical examination rarely contributes to the detection of systemic relapse in the follow-up of testicular germ cell tumours. It may therefore be possible to reconfigure follow-up to focus on investigations and telephone contact. We estimate that this change might be appropriate for 40% of attendances and might be welcomed by patients, many of whom find follow-up burdensome. If such a change were considered, patient education would be essential to ensure continuing compliance with the follow-up protocol., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)