Despite the increasing volume of available data, the proportion of experimentally measured data remains small compared to the virtual chemical space of possible chemical structures. Therefore, there is a strong interest in simultaneously predicting different ADMET and biological properties of molecules, which are frequently strongly correlated with one another. Such joint data analyses can increase the accuracy of models by exploiting their common representation and identifying common features between individual properties. In this work we review the recent developments in multi‐learning approaches as well as cover the freely available tools and packages that can be used to perform such studies. For example, humans, who can draw on vast amounts of previously‐learned information, can be trained on a new task with a relatively tiny number of examples. In contrast, traditional machine learning algorithms, which usually learn from scratch, and require large example sets to do so. Therefore, there is active development and interest in machine learning to design new methods having the same speed and accuracy as humans. Early examples of such types of learning have been successfully reported since the mid‐1990s, e. g. the use of neural network weights trained with one task as a starting point for new ones to increase the development speed and the accuracy of models.In our review we will cover new developments in the field, which have appeared during the recent years. Also, we will mainly focus on the methods where the analysed properties are simultaneously modelled within a single model, which corresponds to Figure Multi‐task Learning (MTL) is a technique which aims improve ML efficacy by simultaneously co‐modelling multiple properties within a single model. A lot of developments in this field were done in in 1990s by Rich Caruana,MTL trains tasks in parallel, sharing their representation internally. As a result, the training data from the extra tasks serve as an inductive bias, acting in effect as constraints for the others, improving general accuracy and the speed of learning. Caruana noted mechanisms by which MTL may show improvement over Single Task Learning (STL) to be a) amplification of statistical data; b) attention focusing ; c) eavesdropping (learning “hints” from simpler tasks); d) representation bias and feature selection and e) regularisation (less overfitting).As MTL implies sharing information between all tasks, it is possible to define three main types of MTL based on the type of data sharing: feature, instance and parameter‐based.2Neural networks are the primary platform for multi‐learning. Rich Caruana was one of the first to develop multi‐task learning using backpropagated neural networks. He found out that four separate neural networks performing only one task can be reduced to one network with multiple outputs that performs the tasks simultaneously. As a result, he created a multi‐task neural network able to perform parallel learning. One should also mention the earlier work of Suddarth and Kergosien,The network forms a set of features on the hidden layer(s), which can fit several tasks simultaneously. Moreover, the activation patterns of neurons in neural networks with several hidden layers contribute to the formation of features, which are known to be important for the analysed type of properties, e. g. toxicophores for the prediction of toxicological end‐points.One of the first successful applications of MTL in chemoinformatics was done by Varnek et al.,Regarding multi‐learning one can distinguish two primary architectures with respect to the sharing of parameters: hard and soft. “Hard” parameter sharing is similar to that of shallow neural networks and implies the sharing of hidden layers between all tasks, except some task‐specific output layers. “Soft” parameter sharing gives each task its own model with its own parameters, where these model parameters have a regularized distance to facilitate the sharing of learning.J. Ma et al.Multi‐task learning provided the best model according to the ROC AUC (Receiver Operator Characteristic Area Under Curve) metric for the Tox21 challenge.in vivo endpoints.In another comprehensive study the authors compared the performance of MTL and STL approaches in predicting the toxicity of chemical compounds from the Registry of Toxic Effects of Chemical Substances (RTECT) database totalling 29 toxicity end‐points and more than 120 k measurements.Xu et al.Similar molecules modelling correlated properties will boost the predictive performance of the DNN, and likewise uncorrelated properties will degrade performance.Structurally dissimilar molecules have no influence on the predictive performance of the MTL DNN, regardless of whether or not tasks are correlated.Their conclusions are important for the identification of strategies for designing datasets for MTL learning.MTL can be used to simultaneously learn both regression and classification in one model, as was demonstrated by Xu et al.Human cytochrome P450 inhibition for 5 kinases were predicted using a pre‐trained autoencoder‐based DNN.Multi‐task feature learning for sparse data using other methods. The problem of feature‐selection has an exact mathematical formulation and an analytical solution for linear methods. For example, Varnek et al.One such method is Macau.3Task learning explores task relationships to better learn common parameters of models as overviewed below.Metric‐learning algorithms. k‐Nearest Neighbour approaches provide predictions for new samples based on their nearest neighbours. Usually, it uses a Mahalanobis distance, which is defined as:i and xj are two samples and Mis a matrix, which acts as a global linear transformation of the input space. The Mmatrix is thus an optimizable parameter of the method. The most straightforward way is to use the same metric to model all tasks simultaneously. However, better performance can be expected by using different matrices, which are optimised to each individual class. If tasks are correlated, the matrix Mcan be decomposed into a common M0and individual task‐specific Mtparts, aswhere and xM0and M1,⋯,MTare the global matrix and task‐specific additional matrices respectively. The larger the similarity is between the tasks, the larger the determinant of matrix M0relative to those of individual tasks Mt. This idea was first applied to multi kNN by Parameswaran et al.where Similarity learning. Metric learning, in contrast to feature selection, directly optimises the parameters of the method itself. The main idea is that similar tasks can provide better generalization by using similar parameters. For example, when classifying several related properties one can identify a common separation hyperplane given by a vector 0w, which will be only slightly different for separation hyperplanes iw for individual propertiesviaccounts for features specific for property i. This separation is thus similar to that used for global and task‐specific matrices in eq. (2) where w0and vicorrespond to matrices 0M and tM respectively. Figure where s in eq.  where w0One of the promising current approaches in the field is based on MTL networks with “soft” parameter sharing ,In machine learning there are a number of other approaches that can explore task similarity, including task clustering or multi‐level approaches as reviewed elsewhere.4As it was aforementioned, networks with soft parameter sharing can provide a richer variety of network architectures  ports several neural network architectures, which were recently introduced to work with graphs, to chemical structures. DeepChem supports the majority of ChemChainer methods as well as providing several other approaches, some of which were originally developed by the authors of the toolbox. DeepChem also provides a port of machine learning methods from the Scikit‐learn python package. Since the latter methods support only single‐task learning, DeepChem uses an embedded wrapper to calculate models for each task, and provides a combined result of STL models in way similar to that of MTL, thus allowing an easy comparison of STL and MTL models. Thus, the user can apply both types of methods to datasets containing several properties using a similar interface. ChemChainer and DeepChem are based on Python and are built around Chainer and TensorFlow frameworks, respectively. Both packages use the RDkit library,OCHEM providesBelow we overview several methods implemented in these packages. The majority of these methods are neural networks that operate on chemical graphs. Thus, these approaches are different from traditional ones that analyse molecules by converting them to a set of descriptors. The first publication about the direct application of neural networks to graphs was proposed as an extension of recurrent neural networks in 2005.Neural Network Fingerprints (NNF). The method shows that the representation of chemical structures as circular fingerprints (e. g. Morgan fingerprints or Extended Connectivity Circular Fingerprints (ECFP)) can be extended with a more advanced method based on neural networks.Weave network.Renormalized Spectral Graph Convolutional Network (RSGCN).A continuous‐filter convolutional neural network for modeling quantum interactions (SchNet)Gated Graph Neural Network (GGNN). This network was specifically developed to predict sequences of outputs, allowing better predictions of their relationships.Message Passing Neural Networks (MPNN)Directed Acyclic Graphs (DAG)Influence Relevance Voters (IRV)Text Convolutional Neural Networks (TEXTCNN)The variety of powerful and freely accessible methods will enable their wide use to address various multi‐learning tasks.6Despite the promising performance of MTL there are several issues, which either have not been properly addressed or remain open. Surprisingly, there is no good understanding as to which tasks are considered similar and could thus profit from multi‐learning.7The multi‐task learning approaches are gaining popularity in various fields of science, including chemoinformatics. Successful use of these methods can result in models with higher prediction accuracies compared to the development of models for each individual property. The conditions when MTL can provide better results over STL are clearly formulated by Xu et al.8Both industrial and academic partners share high expectations from “Big Data” in chemistry, which is a new emerging area of research on the borders of several disciplines.IVT is CEO of BIGCHEM GmbH, which licenses the OCHEM.Sergey Sosnin is a Ph.D. student in the Center for Computational and Data‐Intensive Science and Engineering in Skolkovo Institute of Science and Technology. He gained his Master′s degree in Bioorganic chemistry from Moscow State University. His main research interests are chemoinformatics, computational methods of drug discovery, QSAR/QSPR.Pavel Karpov obtained his PhD in organic and medicinal chemistry from Moscow State University, Russia. His main research interests lie in the development of new machine‐learning approaches for drug discovery. Now he is working as a postdoctoral fellowship in the Institute of Structural Biology in Helmholtz‐Zentrum Munchen.Michael Withnall is a doctoral student at the Technical University of Munich, studying machine learning in chemoinformatics, and is industrially partnered with AstraZeneca. He has a Master′s degree in Chemistry from the University of Nottingham where he worked on OF‐DFT. His main research interests are chemoinformatics, quantum chemistry, and deep learning.Mariia Vashurina is a junior researcher at the Research Institute of Agricultural Microbiology of Russian Academy of Sciences. She was working under supervision of Dr. Tetko in Helmholtz Zentrum München and obtained her Master′s degree in Chemoinformatics from both Strasbourg University (France) and ITMO University (Russia). Currently she is working on the transmembrane molecular modeling and has a strong interest in machine learning methods.Professor Maxim Fedorov is Director of the Centre for Computational and Data‐Intensive Science and Engineering (CDISE) at Skolkovo Institute of Science and Technology. He holds a PhD degree in Biophysics and DSc in Physical Chemistry (both degrees from the Russian Academy of Sciences). His current research is mainly focused on applications of artificial intelligence, data analysis and high‐performance computing in molecular sciences and biomedicine.Igor Tetko is Coordinator of Marie Skłodowska‐Curie Innovative Training Network European Industrial Doctorate Horizon2020 project “Big Data in Chemistry” and CEO of BIGCHEM GmbH (http://bigchem.de), which offers innovative solutions for Big Data analysis. His research interests include (Q)SAR/QSPR, development and application of machine learning approaches to predict physico‐chemical properties and biological activities of molecules.


MRI) is increasingly used for target volume delineation in radiotherapy due to its superior soft tissue visualisation compared to computed tomography (CT). The aim of this study was to assess the impact of a radiologist‐led workshop on inter‐observer variability in volume delineation on MRI.Magnetic resonance imaging  and volume similarity (VOLSIM) index comparing reference and observer volumes.Data from three separate studies evaluating the impact of GTV) were smaller than pre‐workshop volumes for lung with a mean percentage reduction of 10.4%. Breast clinical target volumes (CTV) were similar but seroma volumes were smaller post‐workshop on both supine (65% reduction) and prone MRI (73% reduction). Based on DSC scores, improvement in inter‐observer variability was seen for the seroma cavity volume on prone MRI with a reduction in DSC score range from 0.4–0.8 to 0.7–0.9. Breast CTV demonstrated good inter‐observer variability scores (mean DSC 0.9) for both pre‐ and post‐workshop. Post‐workshop observer delineated cervix GTV was smaller than pre‐workshop by 26.9%.Post‐workshop primary gross tumour volumes (CTV, seroma volumes and cervix GTV.A radiologist‐led workshop did not significantly reduce inter‐observer variability in volume delineation for the three clinical sites. However, some improvement was noted in delineation of breast  Accurate and reproducible delineation of target volumes and organs at risk (OARs) is a prerequisite for effective high‐dose conformal radiation therapy. Variability in volume delineation is the largest source of error in radiotherapy.Magnetic resonance imaging (MRI) is increasingly being utilised in radiotherapy for gross target volume (GTV) and OAR delineation.For treatment sites such as brainThere have been a limited number of studies which have demonstrated reduction in inter‐observer variability in volume delineation with the introduction of an educational programme or workshop.Data from three separate studies assessing the impact of MRI in radiotherapy planning for lung, breast and cervix cancers were selected. Each study had a component that assessed target volume delineation before and after a radiologist‐led education workshop. These studies were being performed to educate observers before larger planned studies evaluating the impact of MRI on target volume delineation for the same sites. These studies were approved by the institutional Human Research Ethics Committee. For the lung study, three patients  were selected, with four radiation oncology observers and one thoracic radiologist observer from three different tertiary hospitals. There was one post‐operative breast cancer case (T1bN0M0) with six observers (four radiation oncologists and two radiologists) from a single centre. The cervix cancer study included one patient case (T2bN0M0) with eight observers (six radiation oncologist and two radiologists) from six tertiary hospitals. All observers participating in the study had more than 5 years of clinical experience working in their sub‐specialities.Lung images were acquired on a 1.5T MRI scanner with the surface coil placed directly on the patient's thorax to maximise signal. Patients were positioned in a supine position with their arms above their head. The field of view encompassed the entire thorax, with a 20‐sec breath‐hold instruction at inspiration given to patients during imaging. Breast images were acquired on a 3T scanner, patients underwent scans in two positions: (1) supine with a vacbag on a flat wing board  with arms raised above the head; and (2) prone position, on a dedicated breast coil . The supine MRI was acquired with a surface coil held close to but not touching the breast tissue (to avoid deformation of the anterior breast contour) using a foam bridge. Cervix images were acquired on a 1.5T scanner in a supine position, with surface coil placed directly on patient pelvis. Detailed imaging parameters are presented in Table All observers were asked to delineate baseline target volumes prior to the workshop. Observers were given clinical and imaging information pertinent to the clinical site. Observers delineating on the lung datasets were provided with each patient's clinical history, diagnostic CT and planning PET report. Observers were instructed to delineate the primary and nodal GTV. The planning CT along with the T1‐ and T2‐weighted MRI image dataset was provided for delineation. For the breast case, no additional patient‐specific imaging report or patient history was provided, all observers were instructed to delineate the whole breast tissue as clinical target volume (CTV) and the seroma cavity on the supine and prone T2‐weighted MRI provided. Observers for the cervix case study were instructed to contour the GTV and specific structures  individually and then combine these structures to create the CTV. To assist in volume delineation for cervix cases, observers were given the diagnostic MRI and PET report as well as examination under anaesthesia report. Observers were given the planning CT and the T2‐weighted MRI dataset for delineation.Site‐specific training in target volume delineation was given by expert radiologists sub‐specialised in each clinical site. Each clinical site workshop was conducted separately as a group session lasting for 2 h. The workshops were interactive with the expert radiologist discussing interpretation of MRI images and definition of tumour volumes with the observers.After a minimum of a 2 weeks gap, the observers were asked to delineate their post‐workshop target volumes on the datasets. The initial instructions were again provided to the clinicians to assist with delineation and an additional MRI‐based contouring guide specific to each site was also provided.Each clinical site selected a different strategy to define the reference volume to reflect the true volume. For lung cases, the radiologist volume was selected as the reference volume, as it was felt that a thoracic radiologist volume would most closely represent the true volume given their experience in thoracic MRI compared to radiation oncologists. Simultaneous truth and performance level estimation (STAPLE)Deviations of the observer volumes from the reference volume were assessed using open‐source image manipulation software MilxView.Lung patients 1 and 3 demonstrated observer variation in defining the boundary between primary GTV (GTVp) and atelectasis (Appendix I). Post‐workshop GTVps for most observers were marginally smaller compared to pre‐workshop volumes Fig. . For GTVPost‐workshop supine and prone seroma cavity volumes were smaller compared to pre‐workshop volumes for almost all observers; breast CTV did not demonstrate a trend between pre‐ and post‐workshop volumes. Fig. . Mean CTOn average GTV volume reduced by 26.9%, cervix by 57.2% and vagina volume increased by 73% between pre‐ and post‐workshop. The CTV was similar pre‐ and post‐workshop . Outlier observers were noted for uterus, parametrium and CTV (Fig. Variation in DSC scores was seen between the three lung cases Fig. . The aveBreast CTV showed good initial inter‐observer agreement in volume delineation for both supine and prone positions, range 0.95–0.68 for supine and 0.96–0.88 for prone DSC score improvement was noted for both positions post‐workshop (Fig. GTV, uterus and cervix volumes for the cervix data showed improved agreement post‐workshop based on the spread of the DSC scores Fig. . Uterus Volume delineation in radiotherapy planning is a complex task and requires guidelines to improve accuracy and consistency.The routine imaging modality used to train radiation oncologists is CT imaging. Training in interpretation and use of MRI is variable depending on access. We therefore assessed whether a radiologist‐led workshop would improve target volume delineation for the three chosen clinical sites. Our findings were not consistent with only some volumes showing reduction in inter‐observer variability after the workshop. The largest improvement was seen in seroma cavity delineation, in the prone setup position for breast.These results slightly differ from other studies which have demonstrated the impact of a contouring workshop or teaching session in improving inter‐observer variability.This study compared the impact of an educational MRI workshop for different clinical sites, where MRI is and is not routinely used for target volume delineation. For lung volumes, patient‐specific factors had a larger effect on inter‐observer variability based on DSC score. Patients 1 and 3 who had tumours with surrounding atelectasis demonstrated the largest variation in tumour boundary definition. Tumour and atelectasis interface variability between observers was also demonstrated by Karki et al.The results from this study highlight the challenge of introducing MRI into the radiotherapy planning process. The inclusion of the radiologist‐led workshop did not show a significant impact on improving inter‐observer variability for all sites and structures; however, a pattern in reduction in DSC scores for seroma cavity, breast CTV, cervix, cervix GTV and uterus was seen. With the rapid uptake of MRI into radiotherapy planning process this needs to be taken into account.There are limitations to this study. The data was obtained from pilot studies in three clinical sites, with limited sample size and slightly differing methodology. Selection of the reference volume between each clinical site was different. While the radiologist volume would have been ideal reference contour across all three sites, differences in GTV delineation between radiation oncologists and radiologist have been reportedThe teaching method was performed in an informal setting and the study did not assess whether the teaching intervention had a lasting effect on the observers to influence their volume delineation outside of the study. Changes in clinician confidence for volume delineation before and after the workshop was not measured. Variation in clinician experience with utilising MRI data was also not assessed, which may have an effect on improving delineation agreement at an individual clinician level. Technical factors such as MRI slice thickness and resolution may have had an impact on delineation variability. While MRI has excellent soft tissue resolution, motion artefacts can impact image resolution and thus contouring variability. It should also be noted that all imaging was performed without contrast injection to highlight nodal disease, tumour volumes or seroma cavity.A radiologist‐led workshop did not significantly reduce inter‐observer variability in volume delineation for the three clinical sites studied, except for seroma cavity volumes and selected cervix contours. As MRI is increasingly being adopted into radiotherapy planning and treatment, appropriate training and education needs should be considered to allow for this change in practice, particularly for sites currently not routinely using MRI. Further research is needed to design the most appropriate education or training intervention to support the use of MRI in radiotherapy.The authors have no conflict of interest to declare.


There is an urgent and unmet need to develop effective vaccines to reduce the global burden of infectious disease in both animals and humans, and in particular for the majority of pathogens that infect via mucosal sites. Here we summarise the impediments to developing mucosal vaccines and review the new and emerging technologies aimed at overcoming the lack of effective vaccine delivery systems that is the major obstacle to developing new mucosal vaccines. Vaccination is an efficient and cost‐effective form of infectious disease prevention that can lead to global eradication, as seen for smallpox 1980) and rinderpest 2011). However, there is an urgent and growing need for the development of new and improved vaccines to further reduce the global burden of infectious disease morbidity and mortality, particularly against those targeting the respiratory and gastrointestinal (GI) tract. The paucity of effective vaccines is also acute in veterinary medicine, which is compounded by increasing multi‐drug and antibiotic resistance 980 and r011. HoweThe majority of mucosal vaccines are administered by the oral and nasal routes with the vaginal, rectal, ocular and sublingual routes being less frequently used. However, not all routes of administration induce an equivalent immune response in terms of potency and longevity, reflecting differences in the organization and cellular make‐up of lymphoid structures in different mucosal tissues Size is another important consideration in the design of mucosal vaccines and targeting uptake to inductive immune sites to generate T cell and/or B cell responses. Goblet cell‐associated passageways allow the entry of soluble protein antigens, but not inert particles (0·02–2 µm) into the underlying lamina propria The majority of currently licensed human mucosal vaccines comprise attenuated strains of pathogenic bacteria or viruses that retain their immunogenicity during transit through the upper GI tract and can target inductive immune sites in the small and large intestine or upper respiratory tract Table . The ora®, Shanchol™ and Euvichol®), which have been shown to provide high levels (60–95%) of long‐lived (>2 years) protection in support of the concept that non‐living vaccines can be effective for mucosal delivery and vaccination Apart from live attenuated vaccines, three World Health Organization (WHO) prequalified inactivated oral vaccines are in use for cholera  in Europe Cynomys spp.) in the United States Mycobacterium bovis is a causative agent of tuberculosis (TB), and remains one the most difficult diseases of livestock to control, due largely to the prevalence of a wildlife reservoir. Bacillus Calmette–Guérin (BCG) vaccines were developed to protect cattle against bovine tuberculosis with subsequent experimental and field studies, showing that they may be efficacious in the control of M. bovis in wild animals after mucosal administration. White‐tailed deer (Odocoileus virginianus) vaccinated with BCG Danish strain 1331 by oral bait or oral liquid had fewer tuberculosis lesions 5 months post‐M. bovis challenge than control deer Meles meles) against TB; however, capturing animals for injection is labour‐intensive and stressful. Oral administration of BCG has been shown to reduce M. bovis lesions in badgers Mucosal vaccines have been more successful in the veterinary field, with spray and drinking water vaccines routinely used for mass vaccination in poultry farming. Recent introduction of edible gel‐bead‐based vaccine systems offer a more stable mucosal delivery, protecting live vaccines against environmental inactivation to improve bioavailability. Use of gel‐beads to deliver Despite many trials, there are no licensed vaccines for many human mucosal‐transmitted pathogens Table , or the Escherichia coli O157:H7 vaccine formulations during oral delivery New technologies are being developed with the aim of protecting and preserving antigen structural integrity, as well as increasing bioavailability and induction of local and systemic neutralizing immune responses Table . All theVibrio cholerae toxin (CT) and heat‐labile enterotoxin from E. coli to non‐specifically boost cellular and humoral immune responses ® vaccine). rCTB stimulates the production of both anti‐bacterial and anti‐toxin antibodies without any side effects The inclusion of alginate, polyvinyl alcohol, hyaluronan and cellulose to micro‐ and nanoparticle‐based vaccines increases their viscosity and augments the retention time at mucosal surfaces promoting antigen uptake. Molecules that target the carrier or vaccine antigen directly to surface receptors on M cells or antigen‐presenting cells [e.g. Toll‐like receptors (TLRs)] have also been used Chlamydomonas reinhardtii has been used in experimental Staphylococcus aureus vaccine formulations Schizochytrium sp. have been used to develop novel zika virus vaccines Plants can be used as bioreactors to produce large quantities of vaccine that are then purified from plant extracts or can be consumed directly as an edible plant vaccine. The plants of choice are rice, lettuce or maize, with an edible rice‐based cholera vaccine containing rCTB (MucoRice‐CTB) currently in Phase I clinical trials ® vaccine against equine influenza for parenteral delivery, although Ghazi et al. have demonstrated protection in mice immunized orally with influenza virus subunit vaccines that incorporate ISCOM Immunostimulatory complex (ISCOM) technology has been incorporated into commercial veterinary vaccines such as Equip FVirus‐like particles (VLP) are an attractive option as a vaccine delivery vehicle due to their useful properties, such as the ability to induce adaptive immune response and to induce long‐term expression of non‐self‐proteins Gene gun bombardment is a biolistic system for mucosal DNA vaccination. This needle‐free technology is based on propelling DNA‐coated colloidal gold microprojectiles at exposed tissue surfaces  and penetrating the cytosol and cell nucleus of cells within deeper layers of the tissue. Lactoccus lacti engineered to express the HPV‐16 E6 oncoprotein generated humoral and cellular immune response in mice after oral administration, as well being shown to have an inhibitory effect on tumour growth The use of genetically modified probiotic strains of bacteria to deliver vaccine antigens has been explored for human papilloma virus (HPV) vaccines. Although a commercial HPV vaccine is available, it does not confer protection to all HPV‐related cancers Neisseria meningitidis OMVs  have been successfully used to vaccinate both adults and children and to control outbreaks of meningococcal B infection in several countries SalmonellaShigella flexneriV. choleraeBacteroides engineered to express in their OMVs bacterial or viral vaccine antigens or human therapeutic proteins for delivery to the respiratory and GI tracts.A safer alternative to using viable bacteria as vaccine delivery vehicles are non‐viable nanometer‐sized lipid‐containing microvesicles  that are naturally produced and secreted by most Gram‐negative bacteria In summary, while mucosal vaccines represent the ideal means of protecting against the majority of infections, there are very few licensed vaccines for either humans or animals. A raft of new technologies and innovations in vaccine antigen encapsulation and delivery are being developed to overcome the obstacles of protecting and preserving antigen structural integrity as well as increasing bioavailability and induction of local and systemic neutralizing immune responses during transit to mucosal inductive immune sites, particularly in the GI tract.The authors report no conflicts of interest.


To provide a systematic review of economic evaluations that has been conducted for onchocerciasis interventions, to summarise current key knowledge and to identify research gaps.MEDLINE) and ISI Web of Science electronic databases. No date or language stipulations were applied to the searches.A systematic review of the literature was conducted on the 8th of August 2018 using the PubMed (MDA). The estimated cost per disability‐adjusted life year (DALY) averted of annual MDA varies between US$3 and US$30 (cost year variable).We identified 14 primary studies reporting the results of economic evaluations of onchocerciasis interventions, seven of which were cost‐effectiveness analyses. The studies identified used a variety of different approaches to estimate the costs of the investigated interventions/programmes. Originally, the studies only quantified the benefits associated with preventing blindness. Gradually, methods improved and also captured onchocerciasis‐associated skin disease. Studies found that eliminating onchocerciasis would generate billions in economic benefits. The majority of the cost‐effectiveness analyses evaluated annual mass drug administration (The cost benefit and cost effectiveness of onchocerciasis interventions have consistently been found to be very favourable. This finding provides strong evidential support for the ongoing efforts to eliminate onchocerciasis from endemic areas. Although these results are very promising, there are several important research gaps that need to be addressed as we move towards the 2020 milestones and beyond. Onchocerca volvulus. It is transmitted by the bites of Simulium blackflies. Of the 120 million people at risk, 99% live in sub‐Saharan Africa, although the disease has also been endemic in six countries of Latin America and is present in Yemen Human onchocerciasis, also known as ‘river blindness’, is a parasitic infection caused by the filarial nematode ®), a drug suitable for mass treatment, was registered for human use against onchocerciasis, and large‐scale chemotherapeutic control programmes became feasible During the last 40 years, there has been a remarkable expansion of onchocerciasis control programmes worldwide Box 1The Onchocerciasis Control Programme in West Africa : The OCP was launched in 1974–1975, and originally covered a core area in seven countries of West Africa African Programme for Onchocerciasis Control : The APOC was initiated in 1995 including 19 African countries The Onchocerciasis Elimination Program for the Americas : The OEPA started in 1992 in six countries of the Americas (across 13 discrete foci) In 1987, Merck & Co. committed to supply ivermectin to onchocerciasis endemic countries ‘as much as necessary for as long as necessary’ Motivated by the successful elimination of the infection in some foci of Mali and Senegal The coverage of NTD mass drug administration (MDA) programmes has notably expanded over the last 10 years. In 2017, 1.762 billion treatments were delivered worldwide The aim of this paper was to provide a systematic review of economic evaluations that have been conducted for onchocerciasis interventions, to summarise current key knowledge and to identify research gaps in this area.A systematic review of the literature was conducted on the 8th of August 2018 using the PubMed (MEDLINE) and ISI Web of Science electronic databases. Variants of the following search terms were used to find relevant papers: river blindness, onchocerciasis, cost(s), cost‐benefit, cost‐effectiveness, economic(s), economic evaluation. No date or language stipulations were applied to the searches. A more detailed summary of the search terms and the PRISMA checklist are supplied in Appendix We identified 14 primary studies reporting the results of economic evaluations of onchocerciasis interventions, which are described in Tables A key component of any cost‐benefit or cost‐effectiveness analysis Box  of an inBox 2Cost‐benefit analysis: A type of economic evaluation which compares the cost of an intervention to its monetary benefits. The results are typically expressed as an internal rate of return or net present value.Cost‐effectiveness analysis: A type of economic evaluation in which the cost of an intervention is compared to the quantity of a single non‐monetary effectiveness measure (such as the number of deaths or cases averted). This avoids the issues associated with monetising the benefits of healthcare interventions. The results are expressed as a cost per unit of outcome (see cost‐effectiveness ratio).Cost‐effectiveness ratio: A statistic used to summarise the cost‐effectiveness of an intervention. It is calculated by dividing the cost of an intervention by its effectiveness measure, such as a cost per disability‐adjusted life year (DALY) averted or healthy life year gained. An incremental cost‐effectiveness ratio is calculated by dividing the difference in costs by the difference in effectiveness outcomes of two alternative options .Community‐directed distributors (CDDs): Also referred to as community drug distributors, these are volunteers selected by their communities to distribute treatment.Disability‐adjusted life years (DALYs): A measure of disease burden that is calculated as the sum of the years of life lost due to premature mortality and the years of healthy life lost due to disability. The number of years of healthy life lost due to disability is calculated using a disability weight factor (between 0 and 1) that reflects the severity of the disease/disability. One DALY can be thought of as one year of ‘healthy’ life lost.Economic costs (opportunity costs): These define the cost of a resource as its value in its next best alternative use . This is a broader conceptualisation of a resource's value than its financial cost, as it recognises that using a resource makes it unavailable for productive use elsewhere. The rationale behind economic costs is that they are intended to represent the full value of all the resources used for an intervention, and they account for the fact that resources can have a value that is not (fully) captured by their financial costs . This is particularly important when considering issues related to the sustainability and replicability of interventions.Economies of scale: The reduction in the average cost per unit resulting from increased production/output; in this case, the reduction in the cost per treatment as a result of increasing the number of people treated.Economies of scope: The reduction in the average cost per unit resulting when providing multiple goods/services jointly; in this case, the reduction in the cost per treatment when delivering more than one intervention at once (e.g. integrated control programmes or using the CDD platform to deliver more than a single intervention). Examples include administering treatment for both schistosomiasis and soil‐transmitted helminthiases within the same programme .Financial costs: The actual expenditure (i.e. the amount paid) for the goods, resources and services that are purchased.Friction cost approach: The approach that takes the employer's perspective for valuing lost productivity, and therefore only counts as lost, the hours not worked by a sick employee before another employee takes over the work Human capital approach: The approach that takes the patient's perspective for valuing lost productivity and therefore counts all the work they miss, as a productivity loss. With this approach, all potential production not performed by an individual because of morbidity or premature mortality is counted as a production loss Indirect costs (productivity costs): Indirect cost represents the value of productivity losses that result from illness, treatment, or premature death.Internal rate of return (IRR): The discount rate applied to the monetised benefits and costs of an intervention, that makes its net present value equal to zero. Also known as the economic rate of return (ERR).Mass drug administration (MDA): The large‐scale distribution of drugs to eligible people within populations at risk of infection, irrespective of current individual infection status, i.e. without the need for screening for or diagnosing infection prior to each treatment round.Net present value (NPV): The difference between an intervention's monetised benefits and its cost. A positive NPV is an indicator of a successful investment.Perspective: The viewpoint from which the intervention's costs and consequences are evaluated. When adopting the healthcare providers perspective, the costs falling outside the healthcare sector are ignored. In contrast, when adopting the societal perspective, all relevant cost categories should be included, including those incurred by the patients.Time horizon: The time horizon for the analysis; the duration over which outcomes and costs are calculated.The estimated intervention costs tended to be higher for the studies evaluating OCP activities. This is likely because the control measures used by the OCP (vector control and mass treatment delivered via mobile teams) were more expensive than the community‐directed treatment approach subsequently used by other programmes Often it was difficult to compare the reported costs from the different studies, as it was not always clear how costs were estimated, what activities were costed, and whether reported values were discounted or not. Some studies appeared only to adjust the costs for inflation and not discount them Box .Box 3Healthcare interventions typically incur costs and generate health outcomes over a number of years. However, society does not place an equal value on costs or health outcomes that occur now compared to those that occur in the future. This is because there is an opportunity cost to spending money (as it could be invested to yield returns) and a desire to have benefits now rather than in the future. Economic evaluations therefore need to weight differently costs and health outcomes that occur in the future.Discounting is the process used to convert costs or health outcomes occurring in the future into a present value When different analyses have used different discount rates, it makes the results harder to compare them directly. The WHO's guide to cost‐effectiveness analysis recommends using a 3% discount rate for both costs and health outcomes  et al. The studies evaluating programmes using community‐based mass treatment generally assumed delivery costs of around US$0.50 per treatment. This is consistent with the findings of a systematic review by Keating et al. There are very few studies that have investigated the costs of alternative onchocerciasis interventions to annual community‐directed MDA (with ivermectin) Several studies also considered the potential for cost‐recovery/cost‐sharing, where the communities contribute financially to the cost of the programme The majority of the studies considered only the financial costs of the intervention. However, when performing economic evaluations of healthcare interventions, it is typically recommended to use ‘economic costs’ et al. vs. US$0.45 (2011 prices)) in a study in Ghana Ndyomugyenyi et al. A key economic cost for many MDA programmes is the value of the unpaid contribution of the volunteer CDDs. Turner et al. Some of the identified studies considered the economic value of the donated ivermectin within their cost‐effectiveness analysis. Most used the quoted commercial value from the Mectizan Donation Program, i.e. US$1.50 (and US$0.0018 in shipping costs) per tablet. Assuming that, on average, a treatment requires 2.8 tablets, this results in an estimated average economic value of donated ivermectin of US$4.21 per treatment et al. In the context of these economic evaluations, it should be noted that it is difficult to estimate the true economic value of a donated drug These arguments need to be interpreted with caution. Firstly, there is the issue of drug quality, which is a major challenge in low‐income countries, and especially with anthelmintics and similar popular drugs which commonly attract counterfeit manufacturers. Secondly, the donations themselves have a chilling effect on the markets, driving generic prices downwards. There is in fact, no established way to estimate the ‘real’ market price of these drugs, and it is notable that even the lowest estimates of the value of the donations are very substantial, measured in hundreds of millions of dollars per year. What is clear is that the ivermectin donation was the first substantial donation of its type, and its success led to the concept of the NTDs as solvable diseases of poverty, and to the massive donation of some 1.5 billion treatments for a range of NTDs by some 14 other pharmaceutical companies during the London Declaration The foundation of onchocerciasis control programmes is based on the commitment of ivermectin donation from Merck & Co. for as long as needed et al. We identified several cost‐benefit analyses of onchocerciasis interventions Table . The estet al. et al. More recently, Redekop et al. The identified studies quantified three different types of economic benefits of onchocerciasis interventions , but there was variation across the studies regarding how and which economic benefits were quantified Table . Many ofet al. Onchocerciasis‐associated morbidity can affect an individual's economic productivity. Lenk A key component of estimating the economic benefits of onchocerciasis interventions is the productivity gains that result from preventing onchocerciasis morbidity. The cost‐benefit analyses identified appeared to estimate only the productivity gains associated with preventing onchocerciasis‐associated blindness. However, the productivity losses associated with onchocerciasis‐associated skin disease and visual impairment are also significant Tables  and 5. Cet al. et al. et al. et al.'s In contrast, both Kim For these types of estimates, it is important to consider which method is used to value the productivity gains. Estimating the income of individuals affected by NTDs is challenging, as many of them are in informal employment (such as subsistence farmers). The analyses identified used a variety of different methods and sources to approximate the typical income of someone with onchocerciasis‐associated morbidity (such as the per capita gross domestic product (GDP), subsistence wage, the GDP per capita of the lowest income quintile). In some cases, the income source was not clearly stated. It is important to note that different income sources can give very different estimates of an individual's typical income, even when they relate to the same type of profession/socioeconomic status et al. et al. Kim et al. In all studies productivity gains were estimated using the human capital approach, which takes the patient's perspective for valuing lost productivity. It should be noted that if the friction cost approach was used  on health‐related expenditures over a six‐month period compared with those from the same community without these manifestations We identified seven studies performing cost‐effectiveness analyses of onchocerciasis interventions. The majority of the studies evaluated annual MDA Table . As withet al. Many older studies have used ‘healthy life years averted’ as their effectiveness metric (which was based on reductions in the number of onchocerciasis‐related blindness cases). These studies generally assumed that blindness results in complete disability, and that each year lived with blindness is equal to one full healthy life year lost, i.e. they assumed a disability weight of 1, which is equivalent to death Table . One excet al. More recent studies have used disability‐adjusted life years (DALYs) averted, a standardised and more comprehensive effectiveness metric. When excluding the economic value of the donated ivermectin, the estimated cost per DALY averted of annual MDA varies between US$3 and US$30 (cost year variable). In comparison the cost per DALY averted for the MDA delivered within the Global Programme to Eliminate Lymphatic Filariasis was estimated to be US$24 when using financial costs and US$64 when using economic costs including the value of the donated drugs (2014 prices) The most favourable cost‐effectiveness estimates relate to interventions in savannah settings The estimated cost‐effectiveness ratio was also dependent on the assumed pre‐control endemicity level, with the cost per DALY averted being lower in higher endemicity settings. In the long term, this range is narrower than might be expected as, although fewer DALYs are averted in lower endemicity settings, the total cost of the intervention is also lower (as fewer treatment rounds will be needed to achieve a similar degree of control or to reach elimination) Table .et al. The majority of studies have taken the healthcare providers perspective, which does not consider the costs falling on those outside of the healthcare sector. All the cost‐effectiveness analyses appeared to consider only the cost of the intervention, i.e. none of them included potential savings to outpatient services, prevented out‐of‐pocket costs, or productivity gains that result from prevented morbidity. Only a few identified studies considered the economic value of the donated ivermectin. Including this significantly increases interventions estimated cost and, therefore, decreases the estimated cost‐effectiveness. For example, Turner et al. Numerous approaches have been used to quantify the effectiveness of onchocerciasis interventions. Many older studies based the effectiveness on reductions in the incidence of blindness on limited empirical data and projected similar putative reductions with continuing intervention. More recent studies have used mathematical transmission models to project the ongoing future effectiveness of interventions more accurately, explicitly modelling disease dynamics through time DALYs are calculated as the sum of two components; the years of healthy life lost due to disability, and the years of life lost due to premature mortality et al. For the 2010 GBD study, the disability weights for vision loss were notably decreased compared to previous studies, whereas the weights for skin disease were increased Table . Consequet al. Several studies have accounted for the excess mortality associated with onchocerciasis visual morbidity In cost‐effectiveness analyses, the cost per DALY averted is compared to a willingness to pay threshold to determine whether an intervention is cost effective. However, the most appropriate cost‐effectiveness thresholds are debated and remain somewhat arbitrary et al. et al., the absolute cost of the intervention and the time it takes to achieve the desired elimination goal can be more informative. The same framework was applied to an economic evaluation of moxidectin https://www.medicinesdevelopment.com/news-180613.htm). Kastner et al. Traditional cost‐effectiveness analyses of new interventions evaluate their incremental effectiveness and incremental cost compared to the current practice . Efforts were made to minimise this bias by searching the bibliographies of selected studies. There could also be a degree of publication bias, with economic evaluations with negative or unfavourable results less likely to be published. It should be noted that the selection of studies was not performed independently by two researchers.The results of the systematic review highlight that the standard onchocerciasis control strategies are consistently found to be very cost effective. However, there are some important research gaps that need further research.The costs of MDA delivery have been shown to vary across different settings In addition, further studies are needed to investigate how integrating NTD control programmes The cost of onchocerciasis control programmes will likely increase significantly as they approach the ‘last mile’ towards elimination Further studies are needed on quantifying the medical costs incurred by those with onchocerciasis seeking treatment. Such studies could yield more robust estimates of the economic benefits of onchocerciasis control Our analysis also revealed that studies used cost data collected in different years, but it was not always clear if and how costs were adjusted for inflation. Future studies should report this more explicitly Wolbachia therapies and new macrofilaricidal drugs In certain epidemiological and programmatic circumstances, alternative strategies to annual MDA will be required to achieve the current goals for onchocerciasis control/elimination Loa loa co‐endemic areas. It has been recently predicted that, at the 2025 horizon, two‐thirds of onchocerciasis remaining cases will be living in hypoendemic areas for onchocerciasis where the risk of Loa‐related post‐ivermectin severe adverse events (SAEs) has so far been considered to outweigh the benefits for the communities. The paradigm shift from control to elimination implies that hypoendemic areas start receiving community treatment with ivermectin. A test‐and‐not‐treat strategy for onchocerciasis has recently been successfully piloted in a health area of Central Cameroon where community‐directed treatment with ivermectin had to be permanently halted after a series of SAEs occurred in 1999 This area of research is particularly important for interventions targeting onchocerciasis in Future economic analyses of alternative interventions need to be tailored to the key policy questions from the different decision makers and stakeholders. These different questions may require different methodological approaches and perspectives for the analyses. This further emphasises the need for transparent reporting of methodology in economic evaluations.Many older studies only quantified the health and economic benefits resulting from the number of blindness cases averted. More advanced disease models have been developed that account for averted visual impairment, skin disease, and excess human mortality. However, further refinements are needed to better capture the relationship between infection and skin disease When evaluating an intervention aimed at reducing morbidity, the number of DALYs averted is often the best effectiveness metric, as it allows cost‐effectiveness estimates to be directly compared to estimates relating to other interventions/diseases as well as to standardised cost‐effectiveness thresholds. This makes the results of economic evaluations easier to interpret by policymakers. However, DALYs do have limitations and there are controversies surrounding their calculation The universal disability weights do not account for how the local context may influence the burden of a disease. Consequently, the potential that the burden of a disease or its sequelae may be worse for those that are living in poverty is not accounted for. It has been argued that this aspect of DALY calculations may significantly underestimate the burden of poverty‐related diseases The DALY disability weights do not fully account for the psycho‐social implications of a disease or its sequelae Interestingly, the same age group (those aged below 20 years) for which there is a statistically significant higher risk of mortality for a given microfilarial load in comparison to those aged 20 years and older et al. Ivermectin is a broad‐spectrum antiparasitic drug that also has an impact on other co‐endemic parasitic infections . Krotneva et al. Dynamic transmission models have an important role, particularly for the evaluation of novel interventions and how they compare to the standard strategy of MDA with ivermectin. These models (reviewed in Basáñez The cost benefit and cost effectiveness of onchocerciasis interventions have consistently been found to be very favourable. This finding provides strong evidential support for the ongoing efforts to eliminate onchocerciasis from endemic areas.MDA against other NTDs has also been found to be cost effective Loa loa co‐endemic areas which will become more important in the end‐game for elimination. Finally, the need to increase the comparability of economic analyses. Greater adherence to standardised guidelines for reporting the results of economic evaluations (such as CHEERS for cost‐effectiveness analysis We identify three main research gaps in this area. First, the need to be more inclusive in quantifying burden. Originally, studies only quantified the benefits of preventing blindness, and then also captured onchocerciasis‐associated skin disease. An improved understanding of other factors, such as onchocerciasis‐associated epilepsy Programmes to eliminate onchocerciasis have always been in the vanguard of global efforts to eliminate diseases of poverty. Lessons learned here from the economic analysis of onchocerciasis programmes have direct relevance to the design of programmes addressing all the other NTDs.Appendix S1. PRISMA checklist.Click here for additional data file.


Our results provide evidence for a novel role of tau in the regulation of presynaptic function.Tauopathies are a class of neurodegenerative diseases that are characterized by pathological aggregation of tau protein, which is accompanied by synaptic disorders. However, the role of tau in endocytosis, a fundamental process in synaptic transmission, remains elusive. Here, we report that forced expression of human tau (hTau) in mouse cortical neurons impairs endocytosis by decreasing the level of the GTPase dynamin 1  Pathologically aggregated tau is recognized as the dominant component of neurofibrillary tangles (NFTs), which constitute the characteristic pathological hallmark of tauopathies, including Alzheimer's disease (AD). Under normal conditions, tau is predominantly distributed in the axon, the main presynaptic loci. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in a model of early AD ‐546 Figure a. We fouMethyl‐CpG‐binding protein 2 (MeCP2) was reported to bind to the promoter regions of dynamin 1  develop hyperphosphorylated, conformationally altered tau aggregates in the cell bodies and dendrites of neurons, a phenotype that is recognized to closely recapitulate a type of tau pathology found in early AD (Andorfer et al., Taken together, the results of our study demonstrate that tau interferes with neuronal endocytosis through the miR‐132‐MeCP2‐dynamin 1 pathway, and they provide a possible mechanism of tau‐induced neuronal dysfunction and neurodegenerative pathogenesis.None declared. Click here for additional data file.


Fish passage out of reservoirs is a critical issue for downstream movement of juvenile salmonids and other migratory species. Reservoirs can delay downstream migrations by juvenile salmon for months or years. Here, we examine whether a novel management activity implementing annual short‐term draining of a reservoir to streambed improves timely downstream migration of juvenile salmonids. We analyse 12 years of fish capture data from a screw trap located downstream of Fall Creek Reservoir  to examine changes in timing of passage out of the reservoir and to compare fish species composition pre‐ and post‐draining. We observed a contraction in the timing of downstream migration for juvenile Chinook Salmon and reduction of yearlings in years following draining. We suggest that briefly draining the reservoir to streambed leads to reduced abundance of warm‐water invasive fishes in the reservoir after it refills. These changes could decrease predation and shift competition between invasive and resident riverine‐adapted native fishes in the reservoir. Collectively, our findings suggest that this low‐cost reservoir management option may improve passage and connectivity for juvenile Chinook Salmon while also decreasing the abundance of invasive fish species in the reservoir. This case study underscores the crucial need for further evaluations of reservoir draining in other systems and contexts. Large dams serve as barriers to both up‐ and down‐stream migration, with severe consequences for migratory species  and crappie (Pomoxis sp.) that co‐occur with native juvenile salmonids  at some PNW dams  increase the effectiveness of downstream passage of juvenile salmon, improving numbers of individuals available to recruit to the adult population. We predict that more effective passage will be evidenced by a reduction in passage in the months after reservoir draining to streambed  and that adult numbers will increase in subsequent years. 2) We also hypothesize that reservoir draining to streambed will ultimately reduce abundances of warm‐water invasive species in the reservoir. We expect warm‐water species to be highly sensitive to the temporary lotic conditions experienced during draining, which might favour a transition to a community dominated by cool‐water riverine‐adapted native species in the reservoir over time. We expect a reduction in abundance of warm‐water invasive species will result in shifting composition from invasive–dominated catches to native–dominated catches in the downstream screw trap. This work is an important first step in evaluating a novel management activity that could serve as an alternative to modification of dam outlet structures and may offer a cost‐effective solution to downstream passage and invasive species management.22.13; Figure This study was conducted in Fall Creek Reservoir, which was constructed in 1966 on a tributary of the Willamette River, western Oregon , Black Crappie (Pomoxis nigromaculatus), and Largemouth Bass . The trap was generally deployed year‐round, although low discharge in summers frequently precluded operation between June and August , metrics that should be more robust to variability and data gaps than fish counts. For evaluation of timing of juvenile Chinook Salmon passage, we used data that included complete subyearling cohorts . Monthly and annual proportions and species–specific sizes were compared for years before and after reservoir draining to streambed using unpaired Wilcoxon tests implemented in R with the ggpubr package . Trends in downstream passage shifted towards the cold season . We also observed nonsignificant trends towards smaller Largemouth Bass and bullhead. Conversely, some native species including Cutthroat Trout (Oncorhynchus clarkii), Rainbow Trout (Oncorhynchus mykiss), and Longnose Dace (Rhinichthys cataractae) showed trends of larger maximum sizes over this same period . Returns were low in 2015; it was a drought year .Although reservoir draining appears to reduce mortality for juvenile Chinook as they pass through the dam, as well as provide ecological benefits, such as a reduction in the size and number of invasive predatory fish, it is unclear what the long‐term implications of this pulsed downstream migration will be for maintaining a diversity of Chinook Salmon life histories  outmigrant Chinook Salmon may not be enough to affect adult survivorship. The ratios of adults returning to Fall Creek did not increase relative to returns to the Willamette River basin, as measured at Willamette Falls, suggesting that ocean conditions may not fully explain the lack of response. Ocean conditions experienced by juveniles are known to be the main drivers of adult Chinook Salmon returns (Dale, Daly, & Brodeur, Cultural resource protection, reservoir‐based recreation, and safety are critical considerations for reservoir management practices. Additional challenges specific to the implementation of draining could be similar to dam decommissioning and would include short term changes to downstream water quality, export of sediment, and increases in downstream turbidity. Potential longer‐term consequences would occur for off‐channel habitats if sediments are deposited in the margins and not transported downstream by later high discharge conditions (Kondolf et al., New options for reservoir management are increasingly under consideration as managers work to reduce ecological impacts of the dam and reservoirs on native species (Chen & Olden, Figure S1. Water surface elevations in Fall Creek Reservoir through time highlighting timing and duration of draining to streambed.Figure S2. Annual maximum observed fish sizes by species before and after initiation of draining to streambed.Figure S3. Annual counts of juvenile Chinook Salmon and other species before and after initiation of draining to streambed.Click here for additional data file.


If therapy is ever interrupted, virus rapidly rebounds from persistent reservoirs of cells infected with HIV. A fundamental goal of HIV cure research is thus to develop novel therapies capable of targeting and eliminating viral reservoirs, which may allow individuals to stop ARV therapy without viral rebound. Here, we present a perspective on two key areas of challenge and advancement in relation to this goal.2The rational development and evaluation of interventions designed to reduce HIV reservoirs are currently impaired by limitations in our ability to measure these reservoirs both on a cellular level, and throughout the body. As an example of a specific challenge that has benefited from recent advances, some 98% of the HIV DNA as measured by conventional quantitative PCR methods represents defective proviruses that is viral genomes which are inactivated by large deletions or other mutations and thus have no ability to give rise viral rebound + T cells harbouring intact proviruses in lymph nodes, whereas perhaps defective proviruses in astrocytes in the brain may represent the latter.To contextualize the utility of these novel assays with respect to the broader reservoir, we propose that the landscape of the body‐wide cells infected with HIV can hypothetically by plotted against the following three dimensions: 1) anatomical site ; (2) cell type and state ; and (3) composition of HIV proviruses (intact or defective). As is depicted in Figure  anatomicin vivo with implications both for the appropriate targeting of interventions and for the measurement of any resulting perturbations.The novel assays described above, which distinguish intact from defective proviruses, substantially improve our ability to limit the “Composition of Provirus” dimension to the proviruses with the potential to cause viral rebound (as indicated by the dashed lines). There is an ongoing need for basic and translational science to continue to develop our understanding of how the HIV reservoir is distributed 3+ T cells simply persisted in a quiescent state.Since the early 2000s, it has been known that the replication‐competent HIV reservoir is remarkably stable, with a decay half‐life of approximately 43 months What we have learned recently is that cells infected with HIV actually divide and proliferate in people living with HIV, a process known as clonal expansion + T cells, by viral factors (e.g. intact vs. defective provirus), and perhaps, by changes arising from the proviral integration site in vivo have the potential to apply selective pressure to infected cells, perhaps most notably immune pressure such as that applied by cytotoxic T cells (CTL) (immune cells that kill virus infected cells). We propose that if infected cells differ in their intrinsic susceptibility to CTL, this may result in a reservoir that has been selected for cells that were CTL resistant. This could potentially underlie our recent study which reported that “Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells” A case can be made for the possibility that these newly appreciated dynamics open the door for HIV reservoirs to undergo Darwinian evolution within people living with HIV, considering the infected cells themselves (rather than virus) as the biological units. The requirements for evolution to occur over time are: (1) variation in a population; (2) replication and heritability; and (3) selective pressure ex vivo reservoir‐harbouring cells, which would be enabled by novel approaches to isolating these rare populations. The identification of novel host‐cell characteristics that support HIV persistence may offer novel therapeutic targets that could be exploited along with latency reversal to reduce HIV reservoirs and bring us closer to a cure for HIV.The question of whether or not long‐lived reservoir‐harbouring cells have been selected by evolutionary processes may be one of the more critical questions being asked by the field, with potentially profound implications for efforts to eliminate these cells. Some potential approaches to address this involve: (1) Studying changes in the reservoir landscapes that occur over time in individuals living with HIV following ARV initiation in relation to potential drivers of selection, and (2) additional functional characterization of RBJ declares that he is a member of the scientific advisory board of AbbVie Inc, and that he has no other potential conflicts of interest.


The sol–gel coating affected pore size distribution and cumulative pore volume of the shiv resulting in tailored porosity. The overall porosity of shiv decreased with a refinement in diameter of the larger pores. Thermal analysis was performed using TGA and stability of coated and uncoated hemp shiv have been evaluated. Hemp shiv modified with sol–gel coating can potentially develop sustainable heat insulating composites with better hygrothermal properties.For the first time, the hydrophilicity of hemp shiv was modified without the compromise of its hygroscopic properties. This research focused on the use of sol–gel method in preparation of coatings on the natural plant material, hemp shiv, that has growing potential in the construction industry as a thermal insulator. The sol–gel coatings were produced by cohydrolysis and polycondensation of tetraethyl orthosilicate (TEOS) using an acidic catalyst. Methyltriethoxysilane (MTES) was added as the hydrophobic precursor to provide water resistance to the bio-based material. Scanning electron microscopy (SEM) and focused ion beam (FIB) have been used to determine the morphological changes on the surface as well as within the hemp shiv. It was found that the sol–gel coatings caused a reduction in water uptake but did not strongly influence the moisture sorption behaviour of hemp shiv. Fourier transformed infrared (FTIR) spectroscopy shows that the coating layer on hemp shiv acts a shield, thereby lowering peak intensity in the wavelength range 1200–1800 cm Bio-bas control .Several studies have discussed the ability of bio-based materials used in construction to absorb and release moisture in response to changes in relative humidity (RH) in the surroundings which creates a breathable wall. These materials act as a hygric buffer and eventually reduce the energy demands for air conditioning . The resTowards the end of the 20th century, a bio-based building material was rediscovered which used the woody core or shiv of hemp (Cannabis Sativa L.) and lime based binders to produce hemp concrete. Hemp shiv has very low conductivity compared to lime due to its porous structure. Many studies have been conducted over the recent years to optimise the hemp characteristics, curing conditions and binder content during the production of hemp based concrete. Hemp insulation materials show good hygrothermal properties by regulating humidity inside buildings and has low environmental impact , 7. The Considering bio-based insulation material to be a part of a vapour permeable wall, significant benefits can be achieved such as better indoor air quality  and robuHemp shiv has tendency to absorb large amounts of water due to its highly porous structure and presence of hydrophilic hydroxyl groups in its structure. This leads to certain disadvantages of using bio-based materials making them incompatible with hydrophobic thermoset/thermoplastic polymers causing poor adhesion in the matrix interface of the composites . There iAs a result, during the manufacture of hemp concrete, water is added in significant excess amounts compared to what is actually needed for the hydration of lime. This leads to long drying times ranging from several months to over a year which are not acceptable to be employed at an industrial scale . Large wSeveral studies have reported the improvement in mechanical properties of natural-fibre composites through alkali , 15, aceThe objective of this work was to treat the hemp shiv with a silica sol–gel coating functionalised with a hydrophobic agent in order to foster hydrophobicity of the hemp shiv. Our work focuses on creating a breathable coating around the shiv and investigate how the change in surface chemistry can alter the physical properties of the hemp shiv.Hemp shiv used in this study was received from CAVAC, an agricultural cooperative based in northwest France. The sol–gel was synthesised by hydrolysis and condensation of tetraethyl orthosilicate (TEOS) in ethanol and water. The reaction was catalysed by nitric acid. 1 M of TEOS was added to a mixture of 8 M distilled water, 4 M of absolute ethanol and 0.005 M of nitric acid. 0.33 M of methyltriethoxysilane (MTES) was added to the above mixture as the hydrophobic agent. Finally, 0.33 M of drying control chemical additive N,N-dimethylformamide was added. The sol was vigorously stirred at 40 °C and atmospheric pressure for nearly 2 h. All the chemicals were obtained from Sigma-Aldrich.Gelation took place in situ in which pieces of hemp shiv were dipped in the sol for 10 min and then carefully removed and transferred onto a Petri dish. The samples were placed in an oven at 40 °C for 1 h and then dried at 80 °C for 2 h. The residual water content was calculated by sealing the oven dried samples in a glass tube under vacuum, heating them at 150°C overnight and then weighing the sample. The amount of residual water was 5 wt% for the sol–gel coated samples.For preparation of the silica the sol was allowed to age in a container to a gel state at room temperature for 48 h The gel underwent dehydration at 80 °C for 120 h to obtain the silica.Photomicrographs of coated and uncoated hemp shiv samples were captured using a dual beam focused ion beam (FIB) system model FEI Helios NanoLab 600. This system is equipped with an extremely high resolution Elstar scanning electron microscopy (SEM) column and a fine-probe ion source. A high beam current of gallium ions was used for site specific sputtering and milling to prepare a specific area within the sample. All the samples were gold coated using an Edwards Scancoat Gold Sputter Coater. A further layer of platinum was deposited on the areas where higher beam current of gallium ions was used.To eliminate initial moisture content, the hemp shiv samples were dried overnight in an oven at 80 °C and then weighed to the nearest 0.1 mg. The samples were then completely immersed in water without using any external force. Since the density of shiv is lower than water, the samples were expected to float. Hence most of the water uptake observed was due to capillary action. The samples were removed at frequent intervals, shaking off any visible surface water and weighed to the nearest 0.1 mg within 30 s of removal from water. Mass readings were taken regularly for the next 24 h and the water absorption was calculated by the mass change (%). The readings reported were average of three measurements.m/dt < 0.002%). However, it should be noted that the maximum time allowed for each RH step to reach stability was 360 min. Previous studies have established that this value allows for obtaining equilibrium moisture content (EMC) values within 0.1% of the true equilibrium value [Isotherm analysis of uncoated and coated hemp shiv was carried out using a dynamic vapour sorption apparatus . Hemp shiv samples were prepared weighing ~15 mg and placed on the sample holder, combined with a microbalance by a hanging wire. The instrument was maintained at constant temperature of 23 °C and the RH was increased in steps in the following sequence , before decreasing to 0% RH in the reverse order. Each RH step change was programmed to move to the next when the moisture content was stable for duration of at least 10 minutes  analysis on treated and untreated hemp shiv was carried out by using a PerkinElmer FTIR spectrometer model Frontier. Transmittance spectra were collected with 2 cm−1 from 25 to 800 °C under nitrogen atmosphere purged at 30 ml min−1 using an alumina crucible.Thermal analysis of the uncoated and sol–gel coated samples was conducted by thermogravimetric analysis (TGA) using equipment STA 449 F1 Jupiter . The samples were heated at a rate of 10 K min2 network which is linked to the raw material through the hydroxyl sites of cellulose present in the hemp shiv. On addition of MTES as a co-precursor during the sol–gel processing, the hydroxyl groups on the silica clusters are replaced by the –Si–CH3 groups through –O–Si–CH3 bonds as seen in Fig. 3 groups on the SiO2 network through oxygen bonds. Hence, by increasing the numbers of layers of the sol–gel coating a reduction of the hydroxyl sites on cellulose was obtained. Conversely the number of –SiCH3 groups increased, which provided increased performance of the substrate (shiv) against water repellence.The water-repellent sol–gel coatings were prepared using MTES as the additive during the sol synthesis. In the present work, the co-precursor method of sol–gel synthesis was followed based on the simplicity of the process. In the sol–gel process, TEOS is hydrolysed and condensed to form a SiOThe sol–gel coating affected the surface morphology of the hemp shiv. Figure The morphology of the sol–gel modified hemp shiv was determined from an FIB cross section. Figure The sol–gel coating increased the mass of the hemp shiv as seen in Fig. −1 in the coated shiv indicates that the coating has enhanced the water repellence of hemp shiv. Other wavenumbers that confirm the presence of sol–gel coating on the surface of shiv are 940 cm−1 corresponding to vibration of Si–OH bonds and 780 cm−1 associated with molecules due to incomplete hydrolysis of TEOS. It is also observed in Fig. −1 thereby masking the functional groups present on the surface of hemp shiv.Figure −1 highlight the presence of Si–OH and Si–O–Si bonds although this cannot prove the covalent grafting of sol–gel coating onto C–OH of cellulose or hemicellulose. From the FTIR signals, one can prove, at best, that silica has been added on to the hemp shiv surface. For confirmation of covalent bonding between hemp shiv and the sol–gel network, further analysis is recommended.The region below 1000 cmThe percentage of distilled water absorption (WA %) for hemp shiv was calculated using the following equation:It is a measure for percent relative increase in weight due to water retention within the sample. Figure It can be seen that hemp shiv absorbs a large amount of water within the first few minutes of dipping. Hemp shiv without any coatings shows the maximum water absorption with 400% increase in its original mass. This was mainly due to highly porous structure of hemp shiv as well as its tendency to absorb water due to its hydrophilic nature. A single coating layer on the hemp shiv reduces the water absorption by 200%. This proves the coating layer with hydrophobic functional groups provides water resistance to the hemp shiv. Further coating layers on the shiv show an increased water resistance which can be attributed to the decrease in porosity reported in the next section of this paper.a and b are constants that are determined by the curve fitting procedure and t is the time in hours. This two parameter equation did not fit well with our experimental data.Based on our experimental data, a water absorption model was used to determine the parameters reported in Table c is the third constant determined by the curve fitting procedureModifying Eq.  by an ada, b and c) for uncoated and coated hemp shiv samples were obtained from curve fitting using MATLAB. Figure R2 values varying between 0.9365 and 0.9975.The values of WA and the constants  of coated shiv calculated using Eq. (m1) is always higher than the mass of untreated hemp shiv (m0) due to coating layer. Therefore from Eqs. , uncoated hemp shiv reached a MC of 19.41% whereas the values obtained for the MC of the coated shiv with 1 and 10 layers were 12.28% and 8.06%, respectively. Considering the mass increased due the sol–gel coating on the hemp shiv, the MCFigure vol are different. The lower adsorption values in for the coated shiv in Fig. It can be seen from Figs. The high values of EMC can be explained by the fact that raw hemp shiv has a high content of cellulose with large number of accessible OH groups. However, modifying the hemp shiv surface with sol–gel coating blocks the free OH groups on the surface, thereby reducing the moisture adsorption capability to a certain extent but does not seal the pores.The porosity distribution of uncoated and coated shiv is given in Figs. Figure The TGA weight loss curves in a nitrogen atmosphere for silica, uncoated and sol–gel coated hemp shiv samples are shown in Fig. The second degradation stage occurs around 300 °C which is due to the thermal depolymerisation of hemicellulose. The third peak observed at 330 °C is mainly due to cellulose and lignin decomposition. It can be seen from Fig. Sol–gel technology has proved successful in modifying a highly hydrophilic bio-based material into a water-resistant building material. Deposited silica based sol–gel coating alters the morphology of hemp shiv, by penetrating the shiv structure thereby reducing the pore size and total pore volume of the hemp shiv. On one hand a cross linked network is formed between the silica (sol–gel coating) and the free hydroxyl groups on the surface of the shiv. On the other hand, the moisture sorption ability is not compromised which means the shiv retains its hygroscopic properties. Sol–gel coated hemp shiv showed improved thermal stability and good water resistance. It has also potential to be mixed with binders to produce composites with better interfacial adhesion, lower drying times, provide ease of handling during the manufacturing stage and ultimately a more robust bio-based thermal insulation building material.


Fall Detection System for the Elderly Based on the Classification of Shimmer Sensor Prototype Data” [A novel fall detection algorithm for elderly using SHIMMER wearable sensors” [This paper defines two major data sets 1) from wearable inertial measurement sensors and 2) wearable ECG SHIMMER™ sensors. The first dataset is devised to benchmark techniques dealing with human behavior analysis based on multimodal inertial measurement wearable SHIMMER™ sensors unit during research studies “sensors” . The SHIsensors”  and a dasensors” . Each record file contains attributes defined with examples in ECG data collection was collected using Android smartphone application, and data was saved in common separate vector (csv) file format. The ECG data acquired according to the Limb Lead I and limb Lead II configuration according to the Einthoven's triangle as shown in The column and row description were same as given in The Dataset was categorized by five age groups as aging is another critical factor that increases the probability of fall for a person as the age of a person increases, the chances of fall also increase. Hence the early fall detection in elderly may have a significant role in healthcare. The persons with age greater than 60 years are considered as elderly according to world health organization (WHO) report .2The Sensing Health with Intelligence, Modularity, Mobility and Experimental Reusability (SHIMMER)  mote is 2.1Most studies such as , suggest2.1.1Before data collection, the height was measure using height scale adjusted on the wall, and weight was measured using weight machine of each subject. Subjects were asked to perform these activities in controlled environment. A line on the floor was marked on a distance of 5 m from the chair. The armless chair was used for sitting and getting up activity. Each activity was followed according to the defined in TUG test.•Standing Posture: While collecting this posture, the subjects were asked to stand straight without any movement for 5 seconds. An example of data collection and raw data (in graph form) of standing position shown in •Sitting on chair and getup from chair: This activity is an example of merged activities. The person first stands and then eventually sits as shown in graph of •Walking: For this activity, subjects were asked to walk on a leveled surface for approximately 5 m, while the graph of walking pattern can be seen in •Fall: Four subjects were asked to perform fall event intentionally on a mattress. Since this is not an unintentional fall, but it shows a notable change from other collected ADLs as depicted in In Following, the experimental protocols for data collection are described for performing activities:Each and every activity has a unique pattern. It may very person-to-person but not that much. Therefore, for basic fall detection and behavioral analysis, this data set may be helpful. We will increase the number of fall and data set size in near future.2.2The ECG data collection was divided in six different steps which took approximately 10–15 minutes to complete the whole procedure. For corrected and proper ECG recordings, Blood Pressure and pulse rate from digital Bluetooth device , a digital Bluetooth thermometer and a weight machine were used to identify the body parameters of the subjects as shown in 2.2.1•Take Biography info using mobile application.•Take weight, height using weight machine & height scale.•Get body temperature using sensing thermometer.•Fix “iHealth” device to the subject.•Fix ECG 5 Electrodes leads to the subject chest and connect with SHIMMER Sensor.•Start test that will take reading from both devices.•After the procedure electrodes are removed and discharge.•Electrodes paste is wiped off with a damp cloth.An Android smartphone application was developed for recording the basic information of the subjects such as age, weight, history of heart disease, gender, married or unmarried etc. as shown in The study involves data collection of certain daily life activities through wearable SHIMMER sensor on normal human subjects during research studies . All pro


Prediction of ecosystem response to global environmental change is a pressing scientific challenge of major societal relevance. Many ecosystems display nonlinear responses to environmental change, and may even undergo practically irreversible ‘regime shifts’ that initiate ecosystem collapse. Recently, early warning signals based on spatiotemporal metrics have been proposed for the identification of impending regime shifts. The rapidly increasing availability of remotely sensed data provides excellent opportunities to apply such model‐based spatial early warning signals in the real world, to assess ecosystem resilience and identify impending regime shifts induced by global change. Such information would allow land‐managers and policy makers to interfere and avoid catastrophic shifts, but also to induce regime shifts that move ecosystems to a desired state. Here, we show that the application of spatial early warning signals in real‐world landscapes presents unique and unexpected challenges, and may result in misleading conclusions when employed without careful consideration of the spatial data and processes at hand. We identify key practical and theoretical issues and provide guidelines for applying spatial early warning signals in heterogeneous, real‐world landscapes based on literature review and examples from real‐world data. Major identified issues include (1) spatial heterogeneity in real‐world landscapes may enhance reversibility of regime shifts and boost landscape‐level resilience to environmental change (2) ecosystem states are often difficult to define, while these definitions have great impact on spatial early warning signals and (3) spatial environmental variability and socio‐economic factors may affect spatial patterns, spatial early warning signals and associated regime shift predictions. We propose a novel framework, shifting from an ecosystem perspective towards a landscape approach. The framework can be used to identify conditions under which resilience assessment with spatial remotely sensed data may be successful, to support well‐informed application of spatial early warning signals, and to improve predictions of ecosystem responses to global environmental change. Ongoing global change steadily increases pressure on ecosystems, to the point where a small additional change may cause a sudden ecosystem state shift and drastically modify ecosystem functioning. Predicting such generally undesired ‘regime shifts’ is crucial for timely management intervention. A promising prediction method is the translation of spatial vegetation patterns observed with, for example, satellite imagery into ecosystem resilience indicators. While these spatial indicators perform well in theory, we show how application to real‐world landscapes presents unexpected challenges and may even lead to misleading conclusions. Our study identifies the conditions for successful application of spatial indicators to real‐world landscapes. We employed a spatially explicit extension of the Noy‐Meir model following Guttal and Jayaprakash , high‐biomass sites thus remain high in biomass, whereas the biomass at low‐biomass sites reduces due to the low recovery rates. This phenomenon increases spatial variability (variance), often in combination with peaking spatial skewness   data from real‐world landscapes. The framework aims to move from an ecosystem approach towards a landscape approach, recognizing that ecosystem properties are partially imposed by geological  variation, and are affected by human activity. The novel framework Figure  builds o2The following section discusses prerequisites for the use of SEWS and links to Figure 2.1Before identifying impending regime shifts or underlying drivers by applying SEWS in for example space‐for‐time approaches, evidence for the potential occurrence of regime shifts, alternative states and hysteresis needs to be established empirically and/or using mechanistic models  , and are therefore easily overlooked in large‐scale studies. Nonetheless, human activity can have major impacts on surrounding vegetation patterns, and thus on conclusions drawn from SEWS in socio‐ecological landscapes  on such ecosystems in heterogeneous landscapes, we compared vegetation response to drought on a homogeneous straight slope and a rolling landscape in California, US Figure a using aIn summary, heterogeneity and connectivity at the landscape scale seemingly work in the direction of more gradual ecosystem responses to and recovery from stress, hence promoting resilience at the ecosystem level. It remains to be addressed to what extent such landscape‐level resilience affects the applicability of SEWS.44.1Two main approaches are adopted to translate a remotely sensed signal into indicators of ecosystem status: land cover classification  and the calculation of vegetation indices (continuous data)  allow for gradual changes of states in space, but do not provide a direct characterization of vegetation types or ecosystem states. Threshold values are needed to distinguish between vegetation types, but values of vegetation indices often overlap for different vegetation types, and cut‐off values may even be subjective , three land cover types occur with clearly distinct spectral properties Figure , about 3Alternatively, the herbaceous plant community may represent a third alternative stable state Figure b, as alsIn the examples above, different criteria to merge land cover types will result in different spatial patterns. Comparable issues with defining ecosystem states may appear in other patterned ecosystems around the world, for example, in northern peatlands  have coarser resolution than more recent imagery (e.g. Sentinel‐2). This implies that the required resolution will determine whether longer‐term datasets are available to reconstruct historical developments in SEWS and upcoming regime shifts over time.55.1Currently, not all types of impending regime shifts can be identified with SEWS due to for example limited applicability of critical slowing down (CSD) or occurrence of extreme events that are impossible to anticipate using contemporary SEWS  on spatial vegetation patterns cannot be ruled out in the Anthropocene Figure , and its5.3The use of categorical data introduces several challenges, ranging from reducing the applicability of spatial skewness and variance to difficulties with defining ecosystem states Figures  and 5. WThe potential of variograms as SEWS can be illustrated from spatial patterns generated with the Noy‐Meir model Box . The varcD), derived from the range parameter of theoretical variograms. With the Shannon Theorem stating that the sampling frequency needs to be higher than twice the maximal frequency of the signal logical heterogeneity and socio‐ecological interactions. This may lead to several complications when applying SEWS in real‐world landscapes Figure . The firMoving from an ecosystem towards a landscape approach, we hope the framework (1) enhances successful application of SEWS in real‐world landscapes, (2) prevents over‐interpretation of SEWS, (3) provides guidance in understanding relations between spatial vegetation patterns and environmental drivers in landscapes under pressure and (4) will stimulate further development of SEWS that can deal with the challenges outlined in this paper. Click here for additional data file.