Will more of the same achieve malaria elimination? Results from an integrated macroeconomic epidemiological demographic model

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe data underlying the model framework are available from the authors on request and selected parameters are also tabulated in the methods paper,22 and from the Malaria Atlas Project http:// www.map.ox.ac.uk/Historic levels of funding have reduced the global burden of malaria in recent years. Questions remain, however, as to whether scaling up interventions, in parallel with economic growth, has made malaria elimination more likely today than previously. The consequences of “trying but failing” to eliminate malaria are also uncertain. Reduced malaria exposure decreases the acquisition of semi-immunity during childhood, a necessary phase of the immunological transition that occurs on the pathway to malaria elimination. During this transitional period, the risk of malaria resurgence increases as proportionately more individuals across all age-groups are less able to manage infections by immune response alone. We developed a robust model that integrates the effects of malaria transmission, demography, and macroeconomics in the context of Plasmodium falciparum malaria within a hyperendemic environment. We analyzed the potential for existing interventions, alongside economic development, to achieve malaria elimination. Simulation results indicate that a 2% increase in future economic growth will increase the US$5.1 billion cumulative economic burden of malaria in Ghana to US$7.2 billion, although increasing regional insecticide-treated net coverage rates by 25% will lower malaria reproduction numbers by just 9%, reduce population-wide morbidity by −0.1%, and reduce prevalence from 54% to 46% by 2034. As scaling up current malaria control tools, combined with economic growth, will be insufficient to interrupt malaria transmission in Ghana, high levels of malaria control should be maintained and investment in research and development should be increased to maintain the gains of the past decade and to minimize the risk of resurgence, as transmission dropsMedical Research Council (MRC

The macro-economic effects of health co-benefits associated with climate change mitigation strategies

The UK government has specific targets for greenhouse gas (GHG) emission reduction to lower the risk of dangerous climate change. Strategies to reduce GHG emissions are sometimes perceived as expensive and difficult to implement but previous work has demonstrated significant potential health co-benefits from ‘Active Travel and low carbon driving’, ‘Housing Insulation/Ventilation’, and ‘Healthy Diet’ scenarios which may be attractive to policymakers. Here a Computable General Equilibrium model is used to assess the financial effects of such health co-benefits on the wider economy including changes in labour force, social security payments and healthcare costs averted. Results suggest that for all scenarios the financial impacts of the health co-benefits will be positive and increased active travel in particular is likely to make a substantial contribution, largely due to health care costs averted. Strategies to reduce GHG emissions and improve health are likely to result in substantial and increasing positive contributions to the economy which may offset some potential economic costs and thereby be seen more favourably in times of economic austerity

Trigeminal neuralgia: New classification and diagnostic grading for practice and research

Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic. Diagnostic certainty is graded possible when pain paroxysms occur in the distribution of the trigeminal nerve branches. Triggered paroxysms permit the designation of clinically established TN and probable neuropathic pain. Imaging and neurophysiologic tests that establish the etiology of classical or secondary TN determine definite neuropathic pain

The impact of Covid-19, associated behaviours and policies on the UK economy: A computable general equilibrium model

This is the final version. Available on open access from Elsevier via the DOI in this record. We estimate the potential impact of COVID-19 on the United Kingdom economy, including direct disease effects, preventive public actions and associated policies. A sectoral, whole-economy macroeconomic model was linked to a population-wide epidemiological demographic model to assess the potential macroeconomic impact of COVID-19, together with policies to mitigate or suppress the pandemic by means of home quarantine, school closures, social distancing and accompanying business closures. Our simulations indicate that, assuming a clinical attack rate of 48% and a case fatality ratio of 1.5%, COVID-19 alone would impose a direct health-related economic burden of £39.6bn (1.73% of GDP) on the UK economy. Mitigation strategies imposed for 12 weeks reduce case fatalities by 29%, but the total cost to the economy is £308bn (13.5% of GDP); £66bn (2.9% of GDP) of which is attributable to labour lost from working parents during school closures, and £201bn (8.8% of GDP) of which is attributable to business closures. Suppressing the pandemic over a longer period of time may reduce deaths by 95%, but the total cost to the UK economy also increases to £668bn (29.2% of GDP), where £166bn (7.3% of GDP) is attributable to school closures and 502bn (21.9% of GDP) to business closures. Our analyses suggest Covid-19 has the potential to impose unprecedented economic costs on the UK economy, and whilst public actions are necessary to minimise mortality, the duration of school and business closures are key to determining the economic cost. The initial economic support package promised by the UK government may be proportionate to the costs of mitigating Covid-19, but without alternative measures to reduce the scale and duration of school and business closures, the economic support may be insufficient to compensate for longer term suppression of the pandemic which could generate an even greater health impact through major recession.EU Horizon 202

Neuropathic pain: redefinition and a grading system for clinical and research purposes.

Pain usually results from activation of nociceptive afferents by actually or potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate activation (e.g., by central sensitization), it has been difficult to distinguish neuropathic dysfunction from physiologic neuroplasticity. We present a more precise definition developed by a group of experts from the neurologic and pain community: pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory evidence from a neurologic examination. This grading system is proposed for clinical and research purposes

Agreement between questionnaires and registry data on routes to diagnosis and milestone dates of the cancer diagnostic pathway

BACKGROUND The routes to diagnosis and the time intervals along the diagnostic pathway affect cancer outcomes. Some data on routes to diagnosis and milestone dates can be extracted from registries or databases. When this data is incomplete, inaccurate or non-existing, other data sources are needed. This study investigates the agreement between multiple data sources on routes to diagnosis and milestone dates of cancer pathway. METHODS Information on routes to diagnosis and milestone dates were compared across four data sources (cancer patients, general practitioners, cancer specialists and registries) for breast, colorectal, lung and ovarian cancers across the UK, Scandinavia, Canada and Australia. Agreement on routes to diagnosis and milestone dates was assessed by Kappa and AC1 coefficients and Lin’s concordance correlation coefficient (CCC). RESULTS 4502 patients were included in the analysis of routes to diagnosis. The agreement was almost perfect (kappa = 0.15–0.88, AC1 = 0.86–0.91) for breast cancer, substantial to almost perfect (kappa = 0.07–0.86, AC1 = 0.74–0.93) for colorectal and ovarian cancers, and substantial (kappa = 0.09–0.11, AC1 = 0.65–0.74) for lung cancer. 2287 patients were included in the analysis of milestone dates. The agreement was adequate for all cancer types (CCC = 0.88–0.99); highest agreement was seen for date of diagnosis (CCC = 0.94–0.99). CONCLUSION We found a reasonable agreement between patient/physician questionnaires and registry data for routes to diagnosis and milestone dates. The agreement on routes to diagnosis was generally higher for breast cancer than for colorectal, ovarian and lung cancers. Lower agreement was seen on date of first presentation to primary care and date of treatment initiation compared to date of diagnosis

Probabilistic Graphs for Sensor Data-driven Modelling of Power Systems at Scale

The growing complexity of the power grid, driven by increasing share of distributed energy resources and by massive deployment of intelligent internet-connected devices, requires new modelling tools for planning and operation. Physics-based state estimation models currently used for data filtering, prediction and anomaly detection are hard to maintain and adapt to the ever-changing complex dynamics of the power system. A data-driven approach based on probabilistic graphs is proposed, where custom non-linear, localised models of the joint density of subset of system variables can be combined to model arbitrarily large and complex systems. The graphical model allows to naturally embed domain knowledge in the form of variables dependency structure or local quantitative relationships. A specific instance where neural-network models are used to represent the local joint densities is proposed, although the methodology generalises to other model classes. Accuracy and scalability are evaluated on a large-scale data set representative of the European transmission grid

A Viral Ubiquitin Ligase Has Substrate Preferential SUMO Targeted Ubiquitin Ligase Activity that Counteracts Intrinsic Antiviral Defence

Intrinsic antiviral resistance represents the first line of intracellular defence against virus infection. During herpes simplex virus type-1 (HSV-1) infection this response can lead to the repression of viral gene expression but is counteracted by the viral ubiquitin ligase ICP0. Here we address the mechanisms by which ICP0 overcomes this antiviral response. We report that ICP0 induces the widespread proteasome-dependent degradation of SUMO-conjugated proteins during infection and has properties related to those of cellular SUMO-targeted ubiquitin ligases (STUbLs). Mutation of putative SUMO interaction motifs within ICP0 not only affects its ability to degrade SUMO conjugates, but also its capacity to stimulate HSV-1 lytic infection and reactivation from quiescence. We demonstrate that in the absence of this viral countermeasure the SUMO conjugation pathway plays an important role in mediating intrinsic antiviral resistance and the repression of HSV-1 infection. Using PML as a model substrate, we found that whilst ICP0 preferentially targets SUMO-modified isoforms of PML for degradation, it also induces the degradation of PML isoform I in a SUMO modification-independent manner. PML was degraded by ICP0 more rapidly than the bulk of SUMO-modified proteins in general, implying that the identity of a SUMO-modified protein, as well as the presence of SUMO modification, is involved in ICP0 targeting. We conclude that ICP0 has dual targeting mechanisms involving both SUMO- and substrate-dependent targeting specificities in order to counteract intrinsic antiviral resistance to HSV-1 infection

A Shot in the Dark: Failing to Recognize the Link Between Physical and Mental Illness

A 74-year-old widowed white man with chronic rheumatoid arthritis presented with nausea and weight loss. He was diagnosed with failure to thrive and admitted for hydration. Misoprostol was determined to be the etiology of his symptoms and he was discharged home. Three days later, he killed himself with a gunshot to the head. Clinicians often fail to recognize those at high risk for suicide. Suicidal risk is increased in both psychiatric and physical illness, and particularly when both are present. Psychiatric illness, particularly depression, often underlies chronic medical illness. The purpose of this case report is to remind health care providers of the strong association between depression and chronic medical illness, and to consider this in all patients, including those who present solely with physical symptoms. Recognizing this association and screening for it, as recommended by the U.S. Preventive Services Task Force, may prevent the unnecessary tragedy of suicide

SUMO Pathway Dependent Recruitment of Cellular Repressors to Herpes Simplex Virus Type 1 Genomes

Components of promyelocytic leukaemia (PML) nuclear bodies (ND10) are recruited to sites associated with herpes simplex virus type 1 (HSV-1) genomes soon after they enter the nucleus. This cellular response is linked to intrinsic antiviral resistance and is counteracted by viral regulatory protein ICP0. We report that the SUMO interaction motifs of PML, Sp100 and hDaxx are required for recruitment of these repressive proteins to HSV-1 induced foci, which also contain SUMO conjugates and PIAS2β, a SUMO E3 ligase. SUMO modification of PML and elements of its tripartite motif (TRIM) are also required for recruitment in cells lacking endogenous PML. Mutants of PML isoform I and hDaxx that are not recruited to virus induced foci are unable to reproduce the repression of ICP0 null mutant HSV-1 infection mediated by their wild type counterparts. We conclude that recruitment of ND10 components to sites associated with HSV-1 genomes reflects a cellular defence against invading pathogen DNA that is regulated through the SUMO modification pathway