To empirically explore the level of agreement of the treatment hierarchies from different ranking metrics in network meta-analysis (NMA) and to investigate how network characteristics influence the agreement.Empirical evaluation from re-analysis of NMA.232 networks of four or more interventions from randomised controlled trials, published between 1999 and 2015.We calculated treatment hierarchies from several ranking metrics: relative treatment effects, probability of producing the best value Overall, the pairwise agreement was high for all treatment hierarchies obtained by the different ranking metrics. The highest agreement was observed between SUCRA and the relative treatment effect for both correlation and top-weighted measures whose medians were all equal to 1. The agreement between rankings decreased for networks with less precise estimates and the hierarchies obtained from Different ranking metrics address different treatment hierarchy problems, however they produced similar rankings in the published networks. Researchers reporting NMA results can use the ranking metric they prefer, unless there are imprecise estimates or large imbalances in the variance estimates. In this case treatment hierarchies based on both probabilistic and non-probabilistic ranking metrics should be presented. To our knowledge, this is the first empirical study exploring the level of agreement of the treatment hierarchies from different ranking metrics in network meta-analysis (NMA).The study also explores how agreement is influenced by network characteristics.More than 200 published NMAs were re-analysed and three different ranking metrics calculated using both frequentist and Bayesian approaches.Other potential factors not investigated in this study could influence the agreement between hierarchies.Network meta-analysis (NMA) is being increasingly used by policymakers and clinicians to answer one of the key questions in medical decision-making: ‘what treatment works best for the given condition?’.3 4non-probabilistic ranking metric such as the treatment effect against a common comparator considers only the mean effect ) and ignores the uncertainty with which this is estimated. In contrast, the probability that a treatment achieves a specific rank (a probabilistic ranking metric) considers the entire estimated distribution of each treatment effect. However, it is important to understand why and how rankings based on different metrics differ.Despite the importance of treatment hierarchies in evidence-based decision-making, various methodological issues related to the ranking metrics have been contested.There are network characteristics that are expected to influence the agreement of treatment hierarchies from different ranking metrics, such as the precision of the included studies and their distribution across treatment comparisons.nmadb R package.11We re-analysed networks of randomised controlled trials from a database of articles published between 1999 and 2015, including at least four treatments; details about the search strategy and inclusion/exclusion criteria can be found in.netmeta R package.https://github.com/esm-ispm-unibe-ch/NMAJags). To obtain probabilistic ranking metrics in a frequentist setting, we used parametric bootstrap by producing 1000 data sets from the estimated relative effects and their variance-covariance matrix. By averaging over the number of simulated relative effects we derived the probability of treatmentto produce the best valueAll networks were re-analysed using the relative treatment effect that the original publication used: OR, risk ratio (RR), standardised mean difference (SMD) or mean difference (MD). We estimated relative effects between treatments using a frequentist random-effects NMA model using the where where F of average efficacy To obtain the non-probabilistic ranking metric we fitted an NMA model and estimated related treatment effects. To obtain estimates for all treatments we reparametrise the NMA model so that each treatment is compared with a fictional treatment of average performance.To estimate the level of agreement between the treatment hierarchies obtained using the three chosen ranking methods we employed several correlation and similarity measures.To assess the correlation between ranking metrics we used Kendall’s 10.1136/bmjopen-2020-037744.supp1Supplementary datanon-conjoint when a ranking is truncated to a certain depth k with such lists called top-k rankings. We calculated the Average Overlap,overlap) between the two lists and averages it over a specified depth (cut-off point) k .The measures described so far can only be considered for conjoint rankings, that is, for lists where each item in one list is also present in the other list. Rankings are We calculated the four measures described above to assess the pairwise agreement between the three ranking metrics within the frequentist setting and summarised them for each pair of ranking metrics and each agreement measure using the median and the first and third quartiles. The hierarchy according to The main network characteristic considered was the amount of information in the network (reflected in the precision of the estimates). Therefore, for each network we calculated the following measures of information:The average variance, calculated as the mean of the variances of the estimated treatment effects The relative range of variance, calculated as The total sample size of a network over the number of interventions.These measures are presented in scatter plots against the agreement measurements for pairs of ranking metrics.https://github.com/esm-ispm-unibe-ch/rankingagreementAll the codes for the empirical evaluation are available at Patients and the public were not involved in this study.To illustrate the impact of the amount of information on the treatment hierarchies from different ranking metrics, we used a network of nine antihypertensive treatments for primary prevention of cardiovascular disease that presents large differences in the precision of the estimates of overall mortality.The reason for this disagreement is explained by the differences in precision in the estimated effects . These RTo explore how the hierarchies for this network would change in case of increased precision, we reduced the standard error (SE) of the conventional versus ARB treatment effect from the original 0.7 to a fictional value of 0.01 resulting in a CI 0.77 to 0.96. The columns in the right-hand side of A total of 232 networks were included in our data set. Their characteristics are shown in The majority of networks  did not report any ranking metrics in the original publication. Among those which used a ranking metric to produce a treatment hierarchy, the probability of being the best was the most popular metric followed by the SUCRA with 35.8% and 6.9% of networks reporting them, respectively.The SUCRAs from frequentist and Bayesian settings (s (IQRs) . Neverth22The association between Spearman’s The total sample size in a network over the number of interventions has a similar impact on the level of agreement between hierarchies. This confirms that the agreement between hierarchies increases for networks with a large total sample size compared with the number of treatments and, more generally, it increases with the amount of information present in a network .Our empirical evaluation showed that in practice the level of agreement between treatment hierarchies is overall high for all ranking metrics used. The agreement between treatment hierarchies from Simulation studiesSeveral factors can be responsible for imprecision in the estimation of the relative treatment effects in a network:Large sampling error, determined by a small sample size, small number of events or a large standard deviation;Poor connectivity of the network, when only a few links and few closed loops of evidence connect the treatments;Residual inconsistency;Heterogeneity in the relative treatment effects.Random-effects models tend to provide relative treatment effects with similar precision as heterogeneity increases. In contrast, in the absence of heterogeneity when fixed-effects models are used, the precision of the effects can vary a lot according to the amount of data available for each intervention. In the latter case, the ranking metrics are likely to disagree. Also, the role of precision in ranking disagreement is more pronounced in cases where the interventions have similar effects.Our results also confirm that a treatment hierarchy can differ when the uncertainty in the estimation is incorporated into the ranking metric We acknowledge that there could be other factors influencing the agreement between hierarchies that we did not explore, such as the chosen effect measures.To our knowledge, this is the first empirical study assessing the level of agreement between treatment hierarchies from ranking metrics in NMA and it provides further insights into the properties of the different methods. In this context, it is important to stress that neither the objective nor the findings of this empirical evaluation imply that a hierarchy for a particular metric works better or is more accurate than one obtained from another ranking metric. The reason why this sort of comparison cannot be made is that each ranking metric address a specific treatment hierarchy problem. For example, the if the NMA estimated effects are precise, to use the ranking metric they prefer; if at least one NMA estimated effect is imprecise, to refrain from making bold statements about treatment hierarchy and present hierarchies from both probabilistic  and non-probabilistic metrics .Our study shows that, despite theoretical differences between ranking metrics and some extreme examples, they produce very similar treatment hierarchies in published networks. In networks with large amount of data for each treatment, hierarchies based on SUCRA or the relative treatment effect will almost always agree. Large imbalances in the precision of the treatment effect estimates do not occur often enough to motivate a choice between the different ranking metrics. Therefore, our advice to researchers presenting results from NMA is the following:


The development of novel polymeric composites based on cellulose derivatives and hydroxyapatite represents a fascinating and challenging research topic in membranes science and technology. Cellulose-based materials are a viable alternative to synthetic polymers due to their favorable physico-chemical and biological characteristics. They are also an appropriate organic matrix for the incorporation of hydroxyapatite particles, inter and intramolecular hydrogen bonds, as well as electrostatic interactions being formed between the functional groups on the polymeric chains surface and the inorganic filler. The current review presents an overview on the main application fields of cellulose derivatives/hydroxyapatite composite membranes. Considering the versatility of hydroxyapatite particles, the hybrid materials offer favorable prospects for applications in water purification, tissue engineering, drug delivery, and hemodialysis. The preparation technique and the chemical composition have a big influence on the final membrane properties. The well-established membrane fabrication methods such as phase inversion, electrospinning, or gradual electrostatic assembly are discussed, together with the various strategies employed to obtain a homogenous dispersion of the inorganic particles in the polymeric matrix. Finally, the main conclusions and the future directions regarding the preparation and applications of cellulose derivatives/hydroxyapatite composite membranes are presented. Among the functional materials currently known, membranes possess a unique characteristic and that is selectivity . AnotherDue to the porosity and semi-permeable properties, polymeric membranes are also used in the development of controlled drug delivery devices , in an aPure cellulose is frequently turned into cellulose derivatives to overcome the drawbacks related to its poor solubility in common organic solvents . Due to 2/CH4 natural gas separations. The hydrophilic nature of cellulose acetate makes the membranes suitable for assisting chemical and biochemical reactions as well as for the removal of polar compounds or specific organic–organic separations using pervaporation. The separation of helium particularly is of great interest in the natural gas purification process, due to its high added value. Asymmetric CA membranes presented an acceptable permeability for He and a good He/N2 and He/CH4 selectivity, being considered economically feasible for usage in three stage membrane processes with recycle streams . In. In52]. Despite the sonication treatment, high amounts of filler cannot be dispersed uniformly throughout the membrane and hydroxyapatite clusters with high concentrations are formed. Another dispersion improvement strategy was reported by Ohland et al. and it is represented by the functionalization of the hydroxyapatite particles in a methanol plasma atmosphere, prior to their ultrasound-assisted incorporation in the polymeric solution. X-Ray Photoelectron Spectroscopy (XPS) analysis of the functionalized hydroxyapatite revealed an increase in the oxygen atomic percentage and also in the oxygen/carbon ratio, this indicating that the methanol plasma precursor successfully provided hydroxyl groups that were further transferred to the particles surface, this increasing their hydrophilicity and compatibility with the polymeric matrix. The composite membranes prepared using phase inversion with partial solvent evaporation before precipitation presented an anisotropic morphology a. The pl2 h bar) and fouling resistance compared to previously reported studies [High performance ultrafiltration membranes based on cellulose acetate and nano-hydroxyapatite were prepared using the surfactant assisted phase inversion method to prevent particle agglomeration. The nano-powder was first dispersed in 12-hydroxystearic acid, an amphiphilic surfactant, and then mixed homogenously with the polymeric solution, acetone being used as solvent in both cases. The filler loading percentage was varied between 10 and 30 wt. %, the best results being obtained for the membrane containing 30 wt. % hydroxyapatite. The higher water flux values and the increase in salt rejection capability of the composite membranes were attributed to the formation of hydrophilic nano-pores in the top layer and in the pore walls of the middle layer, coupled with the negative surface charge. These characteristics are thought to also be involved in the modification of the fouling behavior . Overall studies ,56,75.®® adsorbent for chromatography, notably in the case of the 30/60/10 CA/HA/PEG composite  1000 as surfactant, during the hydroxyapatite synthesis stage, to obtain highly dispersed particles that were further incorporated into cellulose acetate  or hydroomposite . The stuOther examples of toxic compounds in water include heavy metals, pesticides, polychlorinated biphenyls, and inorganic and organic poisons . Nanofib3).4H20 and (NH4)2HPO4 were precipitated in an aqueous CMC solution and lysine, an essential amino acid with antibacterial activity due to its amine group [Candida albicanis, Gram-positive Bacillus subtillus and Gram-negative Escherichia coli, this indicating their multi-functionality and potential to be used for both water purification and biomedical applications [Carboxymethylcellulose was also used in combination with hydroxyapatite to prepare biodegradable nanocomposite membranes for the removal of bisphenol-A from water. The membranes were fabricated by two different methods, the conventional solution casting and the double decomposition procedure. Double decomposition is a common method used for the synthesis of hydroxyapatite. It consists of the decomposition of both calcium and phosphate sources in an aqueous solution to form hydroxyapatite precipitates . In thisne group , was useications .The use of cellulose derivatives/hydroxyapatite composite membranes as artificial scaffolds for in vitro regeneration of bone tissue was reported in several studies. Osteoblasts are anchorage dependent cells whose attachment on scaffolds depends on the surface area and porosity. Electrospinning cellulose acetate results in biocompatible membranes, with appropriate structural characteristics for cellular attachment and migration. The thin fibers serve as attachment sites for cells while the interconnected porosity allows the cellular migration inside the membrane. Studies showed that the fibrous cellulose acetate membranes are very flexible and the pores can dynamically expand to accommodate growing cells a. The biSurface modifications via oxygen plasma or alkaline treatments were reported for the improvement of the membranes biological activity by mechanisms such as migration of the hydroxyapatite filler towards the fiber surface or the increase in hydrophilicity and deacetylation of cellulose acetate . Accordi3−) density had an important influence on the hydroxyapatite crystals formation and growth. At higher NaOH and HCO3− concentrations, a large number of fine hydroxyapatite crystals were formed on the nanofibers probably due to the increased substitution degree of the carboxyl groups and the intermolecular interactions between HA particles and HCO3− ions. A longer biomineralization time lead to crystal growth and formation of aggregates in the hollow spots between the nanofibers  prior to their dispersion in the cellulose acetate solution using cetrimonium bromide (CTAB) as surfactant. The thin membranes obtained after solvent evaporation presented a porous morphology, favorable for osseointegration and were flexible enough to be rolled and stacked, if required, to increase their mechanical strength and anisotropy . Hydroxynofibers . A miner2+ complexes. The thermal and mechanical properties were remarkably improved after mineralization, especially in the case of EC/PAA composites that presented a higher percentage of deposited inorganic compounds [Other cellulose based matrices reported in literature for biomimetic mineralization include composites of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) with polyacrylic acid (PAA). The composites were soaked in salt solutions containing small amounts of PAA to prevent mineral precipitation and thermostated at 30 °C for 5 days, the solutions being frequently changed to maintain an optimal pH value (8.5–9). The mineralization rate was proportional to the content of PAA that served as an ion adsorbent. XRD and EDS analysis revealed that the minerals were incorporated in the polymeric matrix in the form of amorphous calcium phosphate, hydroxyapatite, and PAA-Caompounds .Recent studies showed that carboxymethylcellulose stimulates adhesion, spreading, and migration of mouse fibroblasts in vitro and also has the potential to induce osteogenic differentiation. These findings support its use in the fabrication of materials for bone tissue regeneration . Carboxy2/Tris-HCl and NaH2PO4 to obtain flexible and easy to handle scaffolds for bone regeneration. XRD spectra showed that the deposited calcium phosphate was a mixed phase of brushite  and hydroxyapatite. The highly soluble brushite could act as a calcium resource and promote mineralization during osteogenesis while hydroxyapatite contributes to osteoconductivity. Further analysis indicated that a higher protonation degree determined a more effective loading due to the suppression of the fibers swelling during the soaking process, this leaving the fiber gaps open for calcium phosphates deposition. Also, the sheet dissolution time can be adjusted according to the desired application by modifying the protonation degree [Polyethylene oxide (PEO) was also found to be an effective additive for the improvement of CMCs electrospinnability, the emergence of hydrogen bonds between the macromolecules of CMC and PEO, combined with the polymeric chains entanglement, resulting in a crosslinked structure which allows the spinning of nanofibers. A detailed study on the influence of the electrospinning parameters on the formation of nanofibers from aqueous mixtures of carboxymethylcellulose/polyethylene oxide/nano-hydroxyapatite was performed by Gasparic et al. It was found that a blend of 7 wt. % CMC and 5 wt. % PEO (CMC:PEO 1:1 wt./wt.), electrospun using a voltage of 60–65 kV and a distance of 150 mm between electrodes, at a relative humidity lower than 50% at 20 °C, produced high quality nanofibrous membranes. The addition of hydroxyapatite nanoparticles broadened the size distribution of the fibers but their diameter remained on the nanoscale. Additionally, the prepared membranes were hydrophobized by impregnation with alkenyl succinic anhydride, to extend their range of applications by making them insoluble in water. Cellular viability results were similar to the ones obtained for commercial collagen/apatite scaffolds. Osteoblasts grown on the hydrophobized membranes presented similar viability but reduced cellular attachment compared to the commercial substrates . Anothern degree .Guided bone regeneration is a surgical procedure that uses barrier membranes, with or without bone substitution materials, to avoid the interfering of non-osteogenic components in tissue regeneration, prior to the installment of metallic implants. The barrier membrane plays a vital role in the guided bone regeneration process, therefore, the optimization of membrane materials, both in terms of barrier and bioactive properties, represents an important research topic . Composi2. However, SEM analysis showed that the chitosan solution did not penetrate into the NaCMC/n-HA liquid membrane and the electrostatic interactions were limited only at the interface between the two phases [Carboxymethylcellulose/chitosan blends were also studied in combination with nano-hydroxyapatite (n-HA) for the preparation of membranes with applications in guided bone regeneration. Different techniques were employed for the preparation of such membranes but gradual electrostatic assembly was found to be the most effective for obtaining a uniform, homogenous structure. Jiang et al. studied three types of blending methods to determine which one is optimal for the electrostatic self-assembly of sodium carboxymethyl cellulose (NaCMC) and chitosan (CS) without phase separation or aggregation of the nano-hydroxyapatite particles or polymeric components. Layered casting was used in early studies, more specifically, a certain amount of nano-hydroxyapatite was homogenized into an aqueous NaCMC solution and the mixture was poured in a Petri plate. Afterwards, a chitosan solution in acetic acid was casted slowly on the NaCMC/n-HA wet membrane and the tri-composite material was dried at room temperature and crosslinked with CaClo phases . To avoio phases . This opo phases .Multiple studies emphasized the important role of calcium in the normal homeostasis of the skin and keratinocyte proliferation and differentiation . Nano-hyStreptomyces noursei bacterial strain, was used as model drug to evaluate the controlled drug delivery ability of cellulose acetate/hydroxyapatite membranes. The composites were obtained by adding calculated amounts of hydroxyapatite and nystatin in the cellulose acetate solution (CA/Nys mass ratio ~3.34), followed by casting on Petri plates and solvent evaporation [Drug delivery systems are gaining momentum in the biomedical field due to their advantages such as controlled release of the therapeutic substance, which ensure the maintenance of its level within a desired range and the need for fewer administrations associated with an increased patient comfort . Nystatiporation . The relporation . Anotherporation . Chitosaporation  and polyporation  were alsHemodialysis is the process of removal of waste and extra water from blood using an external filter called a dialyzer, which contains a semipermeable membrane . CelluloThe present review was focused on the systematical presentation of the preparation methods and functional applications of cellulose derivatives/hydroxyapatite composite membranes. The manufacturing techniques varied from phase inversion by immersion precipitation or solvent evaporation to electrospinning and gradual electrostatic assembly, the optimal method being selected depending on the type of cellulose derivative used as an organic matrix. For example, cellulose acetate was found to be appropriate especially for electrospinning and phase inversion while the anionic nature of carboxymethylcellulose recommended it for gradual electrostatic assembly in combination with oppositely charged polymers. The reviewed studies showed that the addition of hydroxyapatite can impart desired characteristics to the surface and structure of the membrane thus improving its performance. However, an important issue is represented by the aggregation tendency of the hydroxyapatite particles especially when phase inversion is used for membrane preparation. Various strategies were employed to obtain a homogenous filler dispersion, the addition of surfactants, plasma modification of the inorganic particles, and ultrasound assisted mixing showing promising results. Regarding the application fields of the hybrid cellulose derivatives/hydroxyapatite membranes, water purification, hemodialysis, and tissue engineering are among the domains intensively researched.Future perspectives are mainly related to the biomedical applications of composite membranes with hydroxyapatite, particularly osseointegration combined with the controlled release of therapeutic agents. The synthesis of hydroxyapatite with controlled particle dimensions to favor an optimal osseointegration represents one of the challenges of the near future. Too large dimensions hinder the development of pre-osteoblasts, while too small ones are characterized by an inefficient activity of these particles. Another future direction is represented by the obtainement of hydroxyapatite from natural sources, other than bone  as well as its wide scale synthesis from anorganic precursors. A domain that will know an explosive development will be the one of controlled release of pharmaceutically active substances from hydroxyapatite particles, antibiotics and cytostatics being the main classes of drugs that will be studied for such applications. In the dental field, composite membranes are already used to favor osseointegration. The capacity of the membrane to release antibiotics, locally, from particles of hydroxyapatite will enhance both quality and efficiency of the medical act and will also improve the patient’s life. The utilization of composite membranes with hydroxyapatite for such applications will provide multiple simultaneous advantages—the membrane will favor implant osseointegration in the case of major bone defects generated by the extraction of the tumoral mass and the targeted release of cytostatics will be associated with an augmented treatment efficiency and with the minimization of the toxic impact of these drugs on the human body.Principle practical gaps are related to the control of porosity for both components—hydroxyapatite and the membrane. New methods for hydroxyapatite production will be accompanied by processing steps like controlled milling or sintering in order to provide the desired porosity for the required application. In the domain of membranes the porosity can be easily controlled, but a major challenge will be the synthesis of membranes with macroporosity and nanoparticles in their structure. Most probably, the easiest way to address this problem will be the chemical bonding between hydroxyapatite and the cellulose derivative, which will remain a future challenge.


While filters with micrometer-sized pores caught larger masses and total proportions of fibres than filters with millimeter-sized pores, the differences were only significant for the total proportions of cotton . For tests with garments of either types of polymer, the filtered effluent still contained up to a third of the original masses of fibres released from the garments. Given the diversity of clothes, polymers, appliances and filters currently sold to consumers, our work shows the value of increasing the rigour (e.g. more levels of replication) when testing filters and the need for further studies that test an even greater diversity of materials and methods in order to meet the growing demand for knowledge from governments, industry and the public.When clothes are worn and washed, they emit fibres into the ecosystem via discharges of sewage that have been linked to the global dispersion of clothing fibres. Facilities that treat sewage divert some fibres from sewage effluent to sludge, but no current methods of filtration eliminate their environmental release. While filters for washing-machines are sold to consumers with the argument they will reduce the emissions of fibres from clothes to the environment, there is insufficient scientific peer-reviewed evidence assessing their ability to retain fibres from washed clothes and reduce environmental contamination. To improve our understanding and develop more realistic methods to assess the efficiency of filters, we washed replicate cotton and polyester garments in replicate domestic front-loaded washing-machines with and without replicate filters (micro- and milli-meter-sized pores), and then quantified the masses of the fibres retained by the filters and those released in the effluent. Here we show micrometer-sized filters significantly reduced the mass of cotton by 67% (F Globally over 50 billion apparel items per annum are reportedly made from 70 million tons of fibre –3. When Fibre-sized polymers are problematic because they are ingested by organisms and can accumulate in guts, ,12 transProducts are beginning to be sold to consumers with the argument they will reduce the emissions of fibres from clothes to the environment –24. ThesThere are currently no standardized methods or metrics for assessing the effectiveness of washing-machine filters or the emissions of fibres from clothes to sewage; however, a number of studies have shed light on these important topics . SeveralHere we developed and tested a novel protocol to assess the capacity of two commercially available washing-machine filters with either mili- or micro-meter-sized pores to trap and reduce emissions of fibres by mass (here after referred to as debris) from clothing  to sewage. In order to provide translatable and rigorous testing of the washing-machine filters our experiments (i) washed whole garments in domestic appliances; (ii) used common garments made from natural and synthetic fibres washed according to their care instructions ; (iii) used replicate and independent garments and filters to improve the independence of data; (iv) used multiple domestic washing-machines across brands so that results can be more easily generalised; (v) removed fibres from effluent using membranes with smaller pores that catch all of the micron-sized fibres of interest; (vi) quantified fibres trapped and not trapped by the filter in terms of their actual and relative mass; (vii) used parametric statistical analyses to improve certainty about how washing-machine filters with different sized pores affect emissions of fibres.To test the capacity of a commercially available washing-machine filter (Lint-luver ) to trapwww.peopleinplastic.com.au) and the filter-case. The volumes of effluent in the filter-case and drum were then determined using electronic balances (Mettler Toledo MS). The total volume of water in the filter-case was collected in metallic flasks and then effluent in the drum was stirred for 30 seconds (to help ensure the fibres were evenly distributed) and then triplicate samples of water (each 100 mL for cotton or 200 mL for polyester) were collected in more metal flasks. Drum and filter-case samples were then vacuum filtered onto 47 mm glass fibre filters  and placed in petri dishes to determine the total mass of debris. The metallic core of the filter was then removed from the filter-unit, wrapped in aluminium foil, dried at  in an oven (Labec) and then the mass of debris on the metallic core quantified using an electronic balance (Mettler Toledo MS). This temperature is cooler than those used to make garments  and even if the temperatures of the washes did evaporate compounds from the fibres and yarns, it would occur for all treatments and experimental units so is less likely to affect the pattern of results. To reduce cross-contamination by fibres we used cleaned and new containers, petri dishes, laboratory coats and we filtered the effluent in a glass cabinet inside a large closed polyethylene tent. For each wash, data about the volumes of effluent and the mass of debris in the drum and filter-cases were combined to determine the total mass of debris in the effluent of the drum and filter-case. Then the debris trapped on metallic core of each filter was also determined. This provided replicate data about the debris for each wash with cotton (n = 3) or polyester (n = 5) clothes in terms the quantities of debris entering sewage, the quantities of debris prevented from entering sewage by the filter, and the net-reductions (%) in debris entering sewage. Each metric for each polymeric material (i.e. cotton or polyester) was analysed using a balanced one-factor analysis of variance (Fixed: 3 levels of filtration) with 3 replicates for cotton and 5 replicates for polyester followed by post-hoc SNK tests .To quantify fibres discharged from each wash the effluent was collected in a 200 L polyethylene drum  and the second factor ‘Filtration’ (Random with 3 levels of filtration) followed by post-hoc pooling and SNK tests .2,6 = 11.69, P<0.01), while millimeter-sized filters had no significant effect .Adding micron-sized filters to washing-machines reduced the mass of cotton in their effluent by 67% compared to appliances with no filters  and polyester  with no difference between the two types of filter . When th2,12 = 5.20, P<0.01; Washing synthetic garments (49.4±4.52 L per wash) used 167% more water than washing cotton garments (29.64±4.52 L per wash)  domestic appliances, filters and the quantification of the masses and proportions of micron-sized fibres trapped both in the filters and in the effluent builds on previous laboratory work  to proviOur study showed filters with smaller pores trapped larger masses and proportions of fibres, however, the significance of patterns varied in relation to the type wash/garment. Therefore further work is needed to distinguish the features of clothing and/or the wash that cause these differences in the performance of the filter. Because synthetic and natural fibre clothing vary by polymer and in their construction  more complicated multifactorial experiments  than havIn our study limited resources meant we could only estimate the mass of fibres. We considered mass as the most relevant metric for assessing the efficiency of filters because it can be related to the total mass of garments and the polymers used in manufacture. Even so further work would also benefit from characterising emissions of fibres by size, shape and number, as it would enable tests to determine if variations in the significance of the patterns observed by the mass of fibres in the effluent and trapped on filters  could be generalised to numbers and particular sizes and shapes of fibres in the effluent and trapped on filters. This would yield useful information about the types of fibres trapped by filters which would enable engineers to reengineer features of the filter so scientists can test whether they can trap a broader range of shapes and sizes of fibres. Whilst it is tempting to use filters with even smaller pore-sizes, these could alter the efficiency of appliances and/or damage the motor, pump, valves, drum, agitator, paddles, electrical circuits and the heating elements of appliances. So any changes to the design of the filters needs to be based on experiments that provide robust information about how features of the filter interact with the type of appliance, wash and garment to affect emissions of fibres and the performance, durability and safety of appliances.The limited budget and number of independent filters also meant it was not possible to test potential sources of variation attributable to the machines and further studies should assess this by having replicate washes of each treatment done using each machine. The importance of replication and statistical tests are well established –49 and eWhile it is tempting to combine data from small-scale experiments and surveys to estimate the potential environmental impact of a whole city using washing-machine filters , such esOur study provides insights from replicated and more realistic testing of two washing-machine filters used on whole garments of clothing. This information contributes to our growing understanding of the critical need for, and effectiveness of, technologies that can reduce contamination and pollution by fibres and yarns. While products to mitigate pollution are already available for purchase in some countries, insufficient peer-reviewed information is available to understand the effectiveness of these products. We provide evidence that one filter-design may more than halve emissions of fibres to effluent but the metric, pore-size and polymer chosen can affect the ability of filters to reduce domestic emissions of fibres to sewage. Given that three different measures of the performance of a filter resulted in different patterns of results for each type of garment has important implications for this field of research and innovation. Previous studies used one top-loader machine to wash replicate garments with and without one of the same models of external micron-sized filter . ThroughS1 Data(XLSX)Click here for additional data file.


Many healthcare facilities in low-income and middle-income countries are inadequately resourced and may lack optimal organisation and governance, especially concerning surgical health systems. COVID-19 has the potential to decimate these already strained surgical healthcare services unless health systems take stringent measures to protect healthcare workers (HCWs) from viral exposure and ensure the continuity of specialised care for patients. The objective of this broad evidence synthesis is to identify and summarise the available literature regarding the efficacy of different personal protective equipment (PPE) in reducing the risk of COVID-19 infection in health personnel caring for patients undergoing trauma surgery in low-resource environments.We will conduct several searches in the L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs automated regular searches in PubMed, Embase, Cochrane Central Register of Controlled Trials and over 30 other sources. The search results will be presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. This review will preferentially consider systematic reviews of experimental and quasi-experimental studies, as well as individual studies of such designs, evaluating the effect of different PPE on the risk of COVID-19 infection in HCWs involved in emergency trauma surgery. Critical appraisal of eligible studies for methodological quality will be conducted. Data will be extracted using the standardised data extraction tool in Covidence. Studies will, when possible, be pooled in a statistical meta-analysis using JBI SUMARI. The Grading of Recommendations, Assessment, Development and Evaluation approach for grading the certainty of evidence will be followed and a summary of findings will be created.Ethical approval is not required for this review. The plan for dissemination is to publish review findings in a peer-reviewed journal and present findings at high-level conferences that engage the most pertinent stakeholders.CRD42020198267. To the best of our knowledge this protocol provides a detailed description of the first systematic review on the effects of personal protective equipment in protecting emergency trauma surgery staff against COVID-19 infection.The protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines for reporting a systematic review protocol.The protocol is being conducted by a multidisciplinary team with extensive experience in conducting high-quality systematic reviews.Given the rate at which new COVID-19-related studies are being published, there is the possibility that new studies will have been published at the time of review publication that were not available at the time of writing the review.Many healthcare facilities in low-income and middle-income countries (LMICs) are inadequately resourced. COVID-19 has the potential to decimate these already strained surgical healthcare services unless health systems take stringent measures to protect healthcare workers (HCWs) from viral exposure. A recent study showed that 15.6% of confirmed patients with COVID-19 are symptomatic and that nearly half of patients with no symptoms at detection time will develop symptoms later.To take care of patients, providers must first take care of themselves. Personal protective equipment (PPE) is paramount to protect HCWs from contracting the virus and becoming disease carriers. Basic recommended PPE for trauma surgery staff of high-income country facilities include (1) a surgical mask or better for all personnel interacting with patients and in the operating room (including cleaning staff); 2) N95 or better mask for all staff in close contact with the patients (<6 feet away); 3) powered air-purifying respirator for aerosolising and high-risk procedures ; (4) universal testing of patients preoperatively to enable appropriate PPE use; and (5) changing scrubs after every procedure. N95 or b powered Some resource-adjusted recommendations include the use of cloth masks and bandanas. While innovative, their moisture retention, reusability and filtration are considered very inferior to N95 and other masks.A preliminary search of PROSPERO , MEDLINE, Cochrane Database of Systematic Reviews, and JBI Database of Systematic Reviews and Implementation Reports was conducted, and no current or underway systematic reviews on the topic were identified.The primary objective of the review is to summarise the effects of different PPE in reducing the risk of COVID-19 infection among health personnel caring for patients undergoing trauma surgery. There is a need for high-quality evidence in this area, and a well-constructed systematic review can help provide a higher level of evidence.A protocol of this review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was registered in PROSPERO. Any changes to the protocol will be amended in PROSPERO and reported in the final review. This review was conducted following the JBI methodology for systematic reviews.7Patients and the public were not involved in the design of this systematic review protocol.et alA systematic review of peer review and grey literature following the PRISMA approach by Moher We will conduct several searches in the L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs automated regular searches in PubMed, Embase, Cochrane Central Register of Controlled Trials and over 30 other sources. When compared with manual searches, this platform consistently identifies all the available studies associated with the terms of interest. It allows for a fast (automated) search that is easy to update—a crucial element given the urgent need to answer the research question rapidly and thoroughly. We will search for systematic reviews and randomised trials evaluating the effect of different PPE on the risk of COVID-19 infection in personnel involved in emergency trauma surgery during the pandemic. Other in-hospital clinical settings will be considered for inclusion and synthesis if evidence for trauma surgery setting is not available. Different clinical settings will be treated as subgroups from which extrapolation will be possible when considered adequate. Non-randomised studies will be considered if systematic reviews and randomised controlled trials (RCTs) are not available or are scarce and of low quality. We will include preprint studies identified in our searches, but no ongoing studies will be considered. Ongoing studies will be counted as excluded studies in the corresponding tables and PRISMA diagram. An example search for studies involving HCWs and N95 masks is provided in 10.1136/bmjopen-2020-045598.supp1Supplementary dataFollowing the search, all identified citations will be collated and uploaded into EndNote V.X9 . The citations will then be imported into the JBI System for the Unified Management, Assessment and Review of Information (SUMARI) for review process. Two independent reviewers will examine titles and abstracts for eligibility. The full text of selected studies will be retrieved and assessed. Full-text studies that do not meet the inclusion criteria will be excluded, and a list of such excluded studies will be provided. Disagreements between the reviewers during title and abstract screening or full-text screening will be resolved by consensus or with a third reviewer. The results of the search will be reported in full in the final report and presented in a PRISMA flow diagram.8The review will preferentially include studies involving HCWs in emergency trauma surgery during the COVID-19 pandemic. Given the likelihood that reports on this specific population are scarce or even non-existent, if not available or insufficient we will consider studies of HCWs in any procedural and in-hospital setting such as emergency room and critical care management in COVID-19. Studies summarising the available evidence for other viral respiratory illnesses will be considered if COVID-19 evidence is not available and the setting reported is trauma surgery.The intervention will be different types of PPE used when treating patients requiring emergency trauma surgery.Comparators of interest will be no PPE use and different types of PPE.This review will consider studies that include the following outcomes: risk of contagion to health personnel involved in the care of the described population during the COVID-19 pandemic; differences in surgical field vision; and expressed as incidence differences, risk ratios or ORs. All outcomes will be summarised narratively.This review will consider systematic reviews of experimental and observational studies, and experimental or observational studies if not included in systematic reviews that fulfilled the population and intervention criteria. We will also include reports on implementation strategies that could inform recommendations for variable resource settings. Only studies published in English or Spanish will be included. We will include preprint studies identified in our search, but no ongoing studies will be considered.The PICOS  inclusion criteria is summarised in Eligible studies will be critically appraised by one reviewer and verified with the other. We will use the AMSTAR tool to assess the risk of bias in systematic reviews, the Cochrane Risk of Bias-2 tool for RCTs and the ROBINS-I tool for non-randomised studies.Data will be extracted from the included studies by a reviewer and verified by a second reviewer using a data extraction tool from JBI SUMARI.Studies will be summarised narratively. Effect sizes from systematic reviews and from individual studies not included in them will be expressed as ORs (for dichotomous data) with their 95% CIs. Decision rules regarding data extraction for situations where data are:Reported at multiple time points: include all and note the time of measurement for each.Multiple ‘doses’: not applicable .Multiple exposures are compared : as mentioned before, exposure will relate to the clinical setting of HCWs studied and will be classified accordingly.For summarising results from other settings different from trauma surgery, the effect of PPE will be summarised by subgroups according to different clinical settings.The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed, and an SoF will be created using online software GRADEPro GDT 2020 .No ethical approval will be required as this review is based on already published data and does not involve interaction with human subjects. The plan for dissemination, however, is to publish the findings of the review in a peer-reviewed journal and present findings at high-level international conferences that engage the most pertinent stakeholders. The proposed systematic review will provide a detailed summary of available evidence on the effects of different PPE in reducing the risk of COVID-19 infection of health personnel caring for patients undergoing trauma surgery. The purpose of the review is to inform recommendations for the rational use of PPE in emergency surgery staff, particularly in low-resource environments where PPE shortages and high costs are expected to hamper the safety of HCWs and affect the care of trauma patients.This protocol has been rigorously developed and designed specifically to assess the effects of different PPE in reducing the risk of COVID-19 infection among health personnel caring for patients undergoing trauma surgery. Given the limited recent evidence associated with the primary objective, findings from the review will be critical to researchers, policymakers, and government and non-governmental organisations in planning and developing guideline recommendations for PPE use in emergency trauma surgery settings, especially in LMICs. If protocol modifications are required, the authors will include the detailed description of any changes along with a justification during the publication of the review.Clearly, in the era of COVID-19, where protecting HCWs from infection is essential, up-to-date information on the effects of PPE in protecting against COVID-19 infection is essential. This review will serve an important role as a repository of available evidence for the purpose of setting effective policy and clinical guideline recommendations.


Phlebovirus. Since it was firstreported, RVFV has spread to western Africa, Egypt and Madagascar from itstraditional endemic region, and infections continue to occur in new areas. Inthis study, we analyzed genomic patterns according to the infection propertiesof RVFV. Among the four segments of RVFV, the nucleotide composition, overall GCcontent and the difference of GC composition in the third position of the codons(%GC3) between groups were the largest in the S (NP) segment, showing that morediverse codons were used than in other segments. Furthermore, the results of CAIanalysis of the S (NP) segment showed that viruses isolated from regions whereno previous infections had been reported had the highest values, indicatinggreater adaptability to human hosts compared with other viruses. This resultsuggests that mutations in the S (NP) segment co-evolve with the infected hostsand may lead to expansion of the geographic range. The distinctive codon usagepatterns observed in specific genomic regions of a group with similar infectionproperties may be related to the increasing likelihood of RVFV infections in newareas.Rift Valley fever virus (RVFV) is a vector-borne pathogen and is the most widelyknown virus in the genus  Recently, infection with Rift Valley fever virus (RVFV) was reported for the firsttime in China   . RVFVis., etc.) . The M s., etc.) . The S s., etc.) . Infectihttps://www.ncbi.nlm.nih.gov/genbank/) in order to compare thegenetic characteristics of RVFVs that infect humans. RVFV sequences isolatedfrom infected humans were studied in this analysis. Sequence datasets (in FASTAformat) for the four coding-sequence (CDS) regions  withineach segment of the virus were grouped based on the region of collection(country) GenBank database (country) .http://www.megasoftware.net) to examine the evolutionaryrelationships among RVFVs by region and time (year)  segments usingthe program MEGA7 (http://www.geneinfinity.org/sms/sms_codonusage.html), and codonadaptation index (CAI) values were calculated for comparison of general codonusage patterns among the virus and its hosts, human and mosquito, using theCAIcal program .Analysis of codon usage bias in viruses provides information on molecularevolution; it can also improve understanding of the regulation of viral geneexpression and help to identify the efficient expression process of viralproteins required to evade immune responses . There iPhylogenetic trees were constructed for each segment  ofthe RVFV genome. RVFVs were grouped according to the infected region (country)and time (year) in the constructed trees . This reFour CDS regions were analyzed for each segment to compare the nucleotidecompositions of the five groups identified in phylogenetic analysis . In the Aedesaegypti), a representative vector of RVFV, and the infected host(Homo sapiens) for comparison of general codon usagepatterns. As the CAI value approaches one, the codon usage pattern becomes moresimilar to that of the reference individual. Overall, the CAI value with humans(Homo sapiens) as a reference was higher than that withmosquitos (Aedes aegypti). Remarkably, the CAI value of the S(NP) segment is highest in Group 5. In this study, all viral data for Group 5were obtained from RVFVs collected in 2016. These viruses were isolated from newregions (Angola and China) where no previous cases of infection were reported,and the viral data used for analysis is the most recent data among the fivegroups. These results suggest that mutations in the S (NP) segment co-evolvewith the hosts (mosquitoes and humans) and may allow the virus to expand itsgeographic range.The %GC, %GC3, ENC, and CAI values were calculated for each group in order toanalyze codon usage patterns in RVFVs. The %GC and %GC3 values showed the mostsignificant differences between groups within the S (NP) segment . The %GCIn addition, ENC plots were generated for each CDS region in order to determinethe degree of compositional constraints on codon usage bias in the RVFVs . The ENCRSCU analysis was performed to determine whether group-specific properties couldbe discriminated from differing codon preferences in each CDS region . In the Various factors allow viruses to expand their range and rapidly evolve pathogenicitywhen adapting to new environments and hosts, including natural environmental factorsand anthropogenic factors, such as climate change and the development ofinternational trade and transportation. Surveillance of the emergence of viruses isimportant, as an unexpected influx of new infectious agents into a new area cancause serious illnesses in unimmunized populations. RVFV infections are beingreported in new areas continuously and constant monitoring for the emergence of thevirus is required. This study investigated whether the effects of RVFV on hostsdiffered among epidemic periods and whether evolutionary changes in viruses areinvolved in the expansion of the affected area. RVFVs were grouped based on thecollection time and region through phylogenetic analysis. Based on the sampleclusters, nucleotide composition and codon usage were analyzed. The nucleotidecomposition, overall GC content, and differences in GC content in the third codonposition (%GC3) between groups were greatest in the S (NP) segment, confirming thatmore diverse codons were used there than in other segments. Remarkably, in CAIanalysis of the S (NP) segment, Group 5 had the highest value, indicating that Group5 viruses have the greatest similarity to the reference data in terms of codon usagepatterns and expression levels, and that they are better adapted to human hostscompared with other groups. Group 5 consisted of the most recent viral samples amongthe five groups, and all Group 5 viruses were isolated from new regions (Angola andChina) where no previous cases of infection had been reported. These results suggestthat mutations in the S (NP) segment co-evolve with infected hosts, i.e., mosquitoesand humans, and may lead to expansion of the areas where viral infection occurs. Dueto the limitations of the published data, we could not analyze some recentlyisolated RVFV sequence data, other than data for Group 5 collected in Angola andChina. Sufficient genetic data can reduce the bias that can occur during theanalysis, so if a future analysis is performed using additional public data, it mayprovide important information to confirm the relationship between evolutionaryvariation in the patterns of RVFV and the incidence of infection. RVFV viruses havea relatively large number of conserved genomic regions, and infection has occurredmainly in limited areas due to the geographically limited habitat of its vectors.However, the results of this study showed distinct codon usage patterns in specificgenomic regions and identified a group of RVFVs that might have an increasedpossibility of causing infections in new areas based on genetic mutations.Therefore, continuous monitoring of RVFV is necessary to prevent an epidemic of thisinfectious disease. The codon usage patterns of RVFVs demonstrated in the presentstudy suggest the need for continuous monitoring of RVFV infections, particularlywith regard to mechanisms of viral evolution and adaptation to new environmentalconditions and to human hosts.


Health information systems (HIS) are expected to be effective and efficient in improving healthcare services, but empirical observation of HIS reveals that most perform poorly in terms of these metrics. Theoretical factors of HIS performance are widely studied, and solutions to mitigate poor performance have been proposed. In this paper we implement effective methods to eliminate some common drawbacks of HIS design and demonstrate the synergy between the methods. JointCalc, the first comprehensive patient-facing web-based decision support tool for joint replacement, is used as a case study for this purpose.User-centred design and thorough end-user involvement are employed throughout the design and development of JointCalc. This is supported by modern software production paradigms, including continuous integration/continuous development, agile and service-oriented architecture. The adopted methods result in a user-approved application delivered well within the scope of project.This work supports the claims of high potential efficiency of HIS. The methods identified are shown to be applicable in the production of an effective HIS whilst aiding development efficiency. A patient's post-operative PROM score is an integer quantity and is estimated as a function of the patient's attributes using a regression model. The risks of death and revision are the conditional probabilities of an event as a function of time and the patient's attributes, computed using survival analysis models.The software delivered within the project is required to be scalable, easily accessible to a heterogeneous audience and future-proof beyond the initial development stage. A web-based solution has the potential to satisfy these needs with minimal overhead costs.In spite of the high potential benefit of HIS implementation, poor usability of a deployed application is a common reason for its poor performance This work aims to describe the novel implementation of a personalised risk estimation methodology integrated in a HIS that is focussed on its end user, the patient. The algorithm framework that drives the web-enabled HIS interface incorporates personalised information and treatment choices. We achieved this aim by: (1) developing a web-enabled HIS that is centred on utility for the end user; (2) showing the integration of HIS development techniques that minimises common drawbacks of the established state-of-art methods, using JointCalc as a practical example; and (3) evaluating the performance of the tool in respect of its utility and usability, as assessed by end-user feedback.22.1Health information systems (HIS) are proven to enhance the efficiency of a healthcare service by providing clinicians with timely and detailed information about the patient and serving the patient with a better understanding of the disease Approximately 80% of HIS maintenance costs are attributable to usability and user interface improvements Black et al. 1.How much better will my pain and function be after the operation?2.What is my risk of dying after the operation?3.What is my risk of needing revision surgery?4.How does each risk vary with my personal biometric characteristics and the surgical choices that I make as a patient?The underlying health need that JointCalc aims to address is the provision of personalised estimated outcome information for patients considering joint replacement. Patient consultation exercises conducted during the design phase of the tool showed that the key questions of interest to patients were:In order to develop algorithms that reliably underpin these questions across a broad patient demographic and a similarly large range of intervention choices, a large and detailed dataset of individual patient procedure episodes and their outcomes is required. This must then be integrated into a patient-facing tool that presents the choices in an accessible manner in order to achieve the required end-user utility.2.2A PROM is a quantitative metric of a patient's perception of the pain and function of their affected joint. JointCalc provides the user with a comparison of their pre- and post-surgery PROM scores. The post-operative score is estimated using a linear regression model where the input variables are the patient's current biometrics and the pre-operative PROM score.The patients are divided into two groups based on the joint surgery type: hip or knee. For each group, two models are constructed with different variable selections: a community-based model that uses basic biometric data of the patient, and a clinic-based model that includes potential surgical choices but necessitates assistance from a healthcare professional for data input.2.3Two different events are studied in the experimental scenario for the JointCalc model: death and revision surgery following the initial surgical episode. Since the two events are not considered to be causally correlated, each are expressed separately, considering the other event as censored, which makes this choice equivalent to the assumption made in •hip replacement;•total knee replacement;•patellofemoral knee replacement;•unicompartmental knee replacement.Different mortality and revision models are used based on the type of operation and variable selection. Surgical operations reported in data from the National Joint RegistryFor each group, both a community-based and a clinic-based model are built. The models developed include: revision risk modelling after total, patellofemoral or unicompartmental knee replacement 3The PROM modelling used patient questionnaire data from NHS-Digital, including 319,030 hip and 338,672 knee replacement surgeries performed between May 2009 and February 2018. Modelling was performed using minimum mean square error estimation. The square of the age was included as part of the inputs in this model, resulting in the following formulation:The estimations for the risks of death and revision were built using data from the National Joint Registry for England and Wales (NJR). After pre-processing and removal of procedures with incomplete records, the data includes 327,238 hip and 430,455 knee replacement surgeries performed between April 2003 and September 2015. The hip replacement data was used in a single model, whilst the knee replacement data were divided into 387,459 total; 37,693 unicompartmental; and 5,303 patellofemoral knee replacements, with a different revision model for each knee replacement type. The survival modelling was performed with the proportional hazards version of the flexible parametric model Algorithm 1JointCalc PROM and risks calculation algorithmEach model was validated with 50 repetitions of a fivefold cross validation procedure. In each repetition, the data was randomly partitioned into 5 subsets and estimation was performed with each combination of 4 subsets, with the remaining subset being used to compute the performance metrics. The performance metrics at each repetition was given by the average over the 5 different combinations, and the results for each repetition were used to compute their overall average with the 95% confidence interval. The results of the validation are presented in 4The design of the JointCalc application follows the user-centred design paradigm. It is based on detailed interactions with patients and their supporting clinicians, and further analysis and conversion of the received user feedback into user-friendly design. This joint work heavily influenced the design, content and architecture of the decision support system.The end-users of JointCalc were involved in early A/B testing of the overall web-tool layout and interface design via a series of patient panel meetings. Participants included both patients that were considering, or had previously undergone, joint replacement surgery and clinicians working in the field of arthritis care. Participants provided feedback both within the group meetings and remotely, following each meeting. The patient panel were initially presented with a number of patient- and clinician-centric decision support and calculator websites for other medical problems, including diabetes and fracture risk. The websites were assessed on their aesthetics, ease of understanding the language used, data entry methods, and how results were conveyed. Feedback was scored into three broad categories: “disliked”, “indifferent”, and “liked”. Four mock websites were then constructed based on the feedback, focussing on maximising the features that the patient panel liked and minimising those features that they disliked. The websites lacked core functionality and, instead, only served to demonstrate the appearance, example text and questions, and type of data entry methods available.Based on the patient panel feedback, two website designs were discarded. The remaining two were further developed, introducing functionality, incorporating feedback, and including a preliminary version of the results page. Additional iterations of development and patient panel feedback sessions were conducted, with comments broadened to include criteria such as site responsiveness.4.1Many users feel burdened when tasked with filling a form, with services observing high user drop-out rates on such activities 4.2Accessibility facilitates adoption, particularly in an older adult target demographic, and was therefore a focal point during JointCalc design. Patient panel feedback was invaluable for improving readability and usability of the interface materials. The various viewpoints were integrated to formulate the text in an optimally comprehensible manner for readers across different backgrounds and educational level. JointCalc also hosts functionality aimed at users with disabilities, including options that control font size and contrast of the colour scheme see .Fig. 2Jo4.3Sillence et al. 5JointCalc development had to accommodate both the chosen iterative design and the long-term implementation goals. These implications conform to many modern software implementation requirements and are largely tackled through an agile Automated testing is the main tool that enables agile development for JointCalc. Automated tests cover the key functional  and usability  features of the tool and are executed after every code modification. This achieves an increase in the robustness of service quality, whilst simultaneously focussing the development effort on enhancement rather than maintenance. Container management automation also further reduces project costs by streamlining the creation, updating and deployment of test and development servers. An approximation based on the number of commits and live releases yields an efficiency gain of 334 h (more than eight full-time weeks at 40 h effort per week) during one year of development due to test automation.The flexible development approach could be partly inhibited by a monolithic application architecture, as small adjustments to the code base produce significant overheads, as for example, in large amounts of regression testing. Moreover, the upgrades of a single large application typically take more time than atomic updates of smaller components, resulting in higher application downtime. A service-oriented architecture (SOA) is an application architecture approach that addresses the issues stated above, and promotes segregation of application functionality into loosely coupled parts where each functional module is considered a service. Such a modular architecture aims to divide the code base into more manageable pieces and reduce the interdependence between the application's functional parts, thus enabling desynchronised and incremental upgrades of the separated services The JointCalc application architecture design is guided by the application requirements and development processes with future scalability and maintainability being the prime drivers. To meet these requirements, JointCalc adopts the microservices architecture design approach. The application is split into services based on the maintained functional areas.•Load-balancer receives external requests over HTTPS and distributes them among available service instances that execute the relevant functionality.•Web server handles the incoming HTTP requests and serves either HTML pages or Application programming interface (API) response messages depending on the content of the received HTTP request.•Front-end service produces the HTML pages served to a user's device.•API service exposes the back-end services for programmatic access.•The calculation module encapsulates the implementation logic of the models that produce the risk and patient outcome estimates.•The database service accompanies the web server and provides data storage and retrieval functionality.•Web analytics service generates insights from the web server access logs.•Test automation service executes the automated test suites and produces testing reports.•Container registry is used to share the containerised environment configurations.•Version control system provides version tracking and general project planning features.The following list presents a brief enumeration of the components of JointCalc architecture depicted in In addition to the previously highlighted efficiency benefits for agile development, the modularity of microservices significantly enhances the maintainability of the code base. Meaningful distribution of code among the services provides the developers with a clear map of application functionalities with reduced amount of documentation, thus easing both new developer onboarding and routine debugging. The choice of specific technologies used for JointCalc is primarily guided by domain-specific requirements, taking into account component performance estimates and project cost optimisation.6The success of the implementation is reflected in JointCalc usage and the feedback from its users recorded to date of writing (the first nine months after public deployment). From a total of 15,372 unique visitors to the website, 5120 have viewed the results. 8375 of the unique visitors were from the UK and the rest were from 110 other countries around the world.33,103 non-unique visits to the results page resulted in 2994 feedback submissions via the feedback form . From th7JointCalc is a practical example of an effective software implementation of a HIS, and represents the first comprehensive web-based patient decision support tool for joint replacement. The developers utilise existing knowledge of pitfalls common in HIS implementations and leverage the solutions proposed by the scientific community to avoid them. This approach impacts the design and development paradigms followed throughout the project, resulting in an application design that supports presentation of information in a comprehensive manner that demands neither prior understanding of the problem nor training in application use. The tool thus exposes the complexity of a novel computational framework in a user-friendly way available to a wide audience. The chosen approach also shapes the production process, demanding high efficiency that takes form in an automated testing system. This not only makes the project more cost-effective, but also enables the fast and efficient processing of acquired feedback.•Health information systems are expected to be effective and efficient in improving healthcare services.•However, most perform poorly either in terms of efficiency or effectiveness, or both. The main causes of this inefficiency have been established.•User-centred design is an application design approach that may counter the known drawbacks of traditional application design methods.What was already known on the topic?•We describe the development of the first web-enabled, personalised, patient-centred decision support tool of user-centred design.•We show that user-centred design can be practically applied to produce an effective health information system, while also improving its development efficiency.•Modern software design paradigms, such as agile and service-oriented architecture, organically fit the processes implied by adoption of user-centred design approach.What did this study add to our knowledge?JMW and EVM initiated the JointCalc concept, JMW led the development process. EZ and AFH developed the application throughout the case study, supervised by VK and JMW. AFH architected the application and administrates the system. EZ developed the application monitoring and CI/CD stacks. PA and AS worked on the risk modeling methodology, supported by JMW and AB. EZ wrote the initial version of the paper and edited it after review, AFH wrote the initial application design, FLM added the background on risk modelling methodology. All authors reviewed and edited the paper prior to submission.None declared.


Complex interaction of rheologically contrasting layers within the lithosphere during the collision of continental plates leads to active faulting, which represents a serious hazard to the population and infrastructure. One of the collision scenarios presumes the existence of a middle-lower crustal channel composed of subducted silicic upper crustal rocks, which is thought to exist in the Tibetan-Himalayan system. Based on the results of seismic tomography, we argue that a similar mechanism of crustal channeling takes place beneath the Zagros mountain system in southwestern Iran. The 3D seismic velocity model reveals an inverted crustal architecture of the collision zone, in which the low-velocity felsic (granitic and sedimentary) upper crustal rocks of the Arabian plate form a seismically inactive lower crustal channel below the higher-velocity mafic  middle-upper crustal layer of the Iranian crust. Based on existing numerical models, we suggest that the formation of the felsic channel is likely governed by separation (delamination) of the weak felsic upper crust of the subducting Arabian lithosphere and its ductile underplating under rheologically stronger upper-middle crust of the Iranian plate. The continental lithospheric plates consist of multiple compositionally contrasting crustal layers and the mantle lithosphere contains strongly variable rheological properties. Understanding the mechanisms of the interaction between the lithosphere layers during collision and shortening of continental plates is an on-going challenge that is actively discussed in the scientific literature4. However, the physical mechanism and the dynamics of formation of such channels remain enigmatic and have, so far, only been investigated on the basis of numerical modeling4. These models show that the formation of the felsic channel is likely governed by separation (delamination) of the weak felsic upper crust of the subducting plate and its ductile underplating under rheologically stronger upper-middle crust of the overriding plate. However, there are few areas in the world where such a mechanism can be directly observed in geophysical images6.The existence of rheologically weak partially molten middle-lower crustal channels composed of subducted silicic upper crustal rocks has been proposed based on geological-geophysical data from modern and ancient continental collision zones such as the Tibetan-Himalayan system or Variscan orogenyWe propose that the mechanism of crustal channeling may take place beneath the Zagros mountain belt in the collision zone between the Arabian Plate and Central Iran. To investigate this hypothesis, we create a new 3D seismic velocity model of the crust and uppermost mantle beneath the southwestern part of Iran that reveal the details of the lithosphere structures in the colliding plates.9, the Zagros is categorized as one of the youngest such settings on Earth, at an early stage of collision10.The Zagros orogenic belt was formed approximately 12 million years ago due to the convergence between the Arabian and Eurasian plates upon the closing of the Neo-Tethys Ocean. Although the precise time of the final phase of oceanic closure or initiation of collision is controversial11. Geological observations show that the Zagros experienced complex deformation that formed several parallel tectonic structures12. From southwest to northeast (perpendicular to the main trend) the Zagros belt can be subdivided into three elongated zones: 1- the Zagros Fold and Thrust Belt (ZFTB); 2- the Sanandaj–Sirjan Metamorphic Zone (SSZ); and 3- the Urumieh–Dokhtar Magmatic Arc (UDMA)  Fig. . In the 17. The SSZ consists of sedimentary and Paleozoic to Cretaceous metamorphic rocks created in the previous active margin of an Iranian microplate which drifted during the Late Jurassic7. These metamorphics are overlain by unconformable Barremo–Aptian Orbitolina limestones typical of Central Iran sedimentation. During most of the second half of the Mesozoic, the SSZ represented an active Andean-like margin whose calc–alkaline magmatic activity progressively shifted northward14. It is today moving northward at 14 mm/year with respect to stable Eurasia as a fairly rigid block10. From another point of view the SSZ can be regarded as the metamorphic core of the larger Zagros accretionary complex which formed by the thickening of distal crustal segments of the Arabian margin19. The UDMA, which is situated between the SSZ and Central Iran, is thought to be mostly composed of Andean-type structures and is related to the magmatic activity from Eocene to the present20.The SSZ is mainly composed of Precambrian metamorphic rocks. The presence of ophiolite sequences along the MZT shows that the SSZ experienced various metamorphic processes during the subduction of the Tethyan Ocean beneath the Iranian microplatew, represent a serious hazard to the population and infrastructure of densely populated areas of Iran.The ongoing collisional processes cause high seismicity in this region; the majority of earthquakes recorded in Iran occur in the Zagros. The strongest events, like the earthquake of Sare-Pol-Zahab on November 12, 2017 with magnitude 7.3 M27. Based on these studies, it can be concluded that the ZFTB has a crustal thickness of 45 ± 3 km, whereas beneath the SSZ, the Moho depth significantly increases up to et al.28 who observed thickening of the crust in the SSZ (front of the MZT) and explained it as a signature of crustal doubling due to underthrusting the Arabian crust underneath Central Iran.The deep structure of the crust and mantle is a key element to understand the geodynamic framework of regional collisional processes. Many geophysical multiscale studies have been performed in the Zagros region based on different seismic and non-seismic data. Numerous studies based on receiver function analysis have provided generally consistent information about the crustal thickness beneath Zagros and surrounding areas31. Hafkenscheid et al.32 and Mohammadi et al.33 found a thick lithosphere beneath the Zagros which they considered as an indication of oceanic slab break-off in the Zagros collision zone. The regional travel time tomography studies by Alinaghi et al.34 and Koulakov35 revealed a subducting slab beneath Zagros turning to a nearly 900 dip angle across the upper/lower mantle boundary.The mantle structures beneath the Zagros have been studied using regional tomography methods based of body and surface wave dataAmong the many geophysical studies of Zagros and surrounding areas, local earthquake tomography (LET), which uses travel time data of both stations and earthquakes located in the study area, has never been performed for the entire Zagros. This method, which provides information on seismic structures down to ~100 km depth, appears to be complementary to the previously derived results of regional tomography and receiver function analysis and can help us to answer some questions related to the lithospheric structure of the Zagros collision zone.37. The distributions of earthquakes and stations used in the analysis are shown in Fig. In this study, we use arrival time data from 2006 to 2018 which have been collected by the Iranian Seismological Center as well as International Institute of Earthquake Engineering and Seismology seismic networks. The dataset used for tomography consists of 123,575 P- and 11,520 S-picks from 7783 events with magnitude 38, developed for simultaneous inversion for the 3D distributions of the P and S wave velocity anomalies and source locations. In the first step, LOTOS determines initial source locations using tabulated values of travel times previously calculated in a 1-D velocity model. The iterative algorithm of tomographic inversion includes the following steps: (1) Source relocations in the updated 3-D velocity structure based on the ray tracing bending method, (2) calculation of the first derivative matrix and (3) simultaneous inversion for P and S wave velocity anomalies, earthquake source parameters (4 parameters for each source), and station corrections. The inversion uses the LSQR method39. Further details regarding the data and inversion procedure are described in the Supplementary Information.We used the LOTOS code, KoulakovThe resulting 3-D distributions of the P wave velocity (Vp) anomalies are presented in two horizontal sections Fig.  and four27.The most important structures related to the architecture of the colliding plates can be revealed in vertical sections in Fig. et al.35 and Koulakov35 clearly show that the Arabian Plate deepens beneath the Zagros becoming nearly vertical. This seems to contradict the observation in our model of a nearly horizontal anomaly that propagates beneath the ZFTB and SSZ and almost reaches Central Iran. Second, the high-velocity anomaly located below the “crust-related” low-velocity anomaly appears to be narrower than would be expected if it was associated with the mantle lithosphere. This might be explained as a result of limited resolution of the tomographic inversion at this depth. However, the synthetic test with realistic configurations of anomalies  upper crustal rocks of Arabian plate form a narrow, seismically inactive39 lower crustal channel below the higher-velocity mafic  middle-upper crustal layer of the thickening Iranian crust. Based on existing numerical models40, we suggest that the felsic channel formation is likely produced by separation (delamination) of the rheologically weak felsic upper crust of the subducting Arabian plate and its ductile propagating under rheologically stronger upper-middle crust of the Iranian plate. This intra-crustal relamination process is likely enabled by the hot thermal structure of the upper plate that creates conditions for rheological decoupling at the Moho40.We propose that these structures represent the ongoing process of relamination of the low-density Arabian continental crust, which was detached from the high-density mantle lithosphere and propagates underneath rheologically stronger crust of the Iranian plate. A similar scenario has been used to explain the presence of felsic channels presumed to exist in some modern and ancient continental collision zones, such as the Tibetan-Himalayan system or the Variscan orogenyA shallow high-velocity anomaly beneath the SSZ can be interpreted as an exhumed mafic part of the Iranian crust. The fact that this shallow high-velocity anomaly looks non-continuous and seems to be separated in several parts can be explained by alternation of the uplifts and subsidence areas, as schematically illustrated in Fig. 27. A key structure for understanding the crust-mantle transition is the narrow high-velocity anomaly, which is marked with 3 in Fig. The interpretation of the Moho interface appears to be more complicated, as was suggested in previous studies. Doubled crust beneath the Zagros and SSZ causes an unusual structural inversion: the exhumed mafic crust of the central Iranian microplate is observed in the upper part, whereas felsic crust of the underthrusted Arabian Plate is dominant in the lower part. In Fig. 44, active crustal shortening causes delamination of the mantle lithosphere45. As a result, beneath the collision belts the mantle lithosphere layer is either strongly thinned or absent. The delaminated mantle lithosphere is then replaced by hot asthenosphere, which may appear directly beneath the crust and transport heat from the mantle to the surface. In turn, this may cause overheating of the crust and the formation of volcanic fields such as the UDMA in the Zagros collision zone.Finally, beneath the UDMA at mantle depths, we observe prominent low-velocity anomalies. As was proposed for other similar collision zones, such as the CaucasusIn this study, we have performed the travel time tomography for the entire Zagros using available data on regional seismicity. The derived models of Vp and Vs anomalies were carefully verified using a set of synthetic tests, as well as by independent inversions of separate data subsets (odd/even test).The main feature resolved in the tomography model is a gently sloping inclined low-velocity anomaly that dips to the northeast. This anomaly is interpreted as the felsic crust of the continental Arabian Plate that propagates underneath the rheologically stronger crust of the central Iranian plate. This anomaly seems to be overlain by a high-velocity anomaly that may represent the exhumed mafic part of the Iranian crust. On the surface, this high-velocity anomaly coincides with metamorphic complexes within the Sanandaj–Sirjan Zone and ophiolites. The process of underplating of a silicic upper-crustal layer underneath the mafic lower crust during collision, called relamination, was previously presumed for some modern and ancient collision zones. In this study, we present a tomographic model that clearly images the crustal channeling beneath the Zagros.Beneath the Zagros we observe a paradoxical situation: the felsic crust, which normally should be above, is located below the mafic crustal layer. This complex doubling of the crust makes it difficult to estimate the crustal thickness beneath the Zagros. We propose that the interface, which is interpreted as Moho in the existing receiver function studies, actually represents the boundary between the felsic and mafic crustal layers in the subducting Arabian Plate, and the actual crust-mantle interface is considerably deeper.Supplementary Information.


Dieulafoy's disease is a rare vascular lesion characterized by presence of large aberrant arteries within the submucosa of gastrointestinal tract or respiratory tract with a potential to cause life-threatening hemorrhage. Treatment includes bronchoscopy ablation, angiographic embolization or surgery. We report management of 7-year old girl with Dieulafoy's disease in the airway who presented with recurrent hemoptysis. Bronchial angiography revealed multiple feeding vessels to the lesion. Considering the potential risk of recurrence with embolization, sleeve resection of bronchus offered complete resolution. This case demonstrates the usefulness of bronchial angiography as part of multi-faceted approach before surgery in the management of Dieulafoy's disease. Dieulafoy's disease (DD) is a distinct pathologic condition characterized by presence of large aberrant arteries within the submucosa of the gastrointestinal tract . Most coOur patient was a 7-year old girl who presented with frequent episodes of unprovoked massive hemoptysis for 5 months. She was referred to us after a bronchoscopic finding of a polypoid lesion in her bronchus intermedius (RBI). On admission to our hospital, she appeared well but continued to have small-volume hemoptysis. Physical examination was essentially normal, especially with no cutaneous telangiectasia.Computer tomography angiography (CTA) and a repeat bronchoscopy revealed an abnormal vascular lesion in her RBI . To furtHistopathology revealed increased number of thick-walled vessels with prominent intimal thickening within submucosa and peri-bronchial connective tissue of the resected specimen. Places of erosion of the respiratory epithelium close to these thick-walled vessels could be found. Patchy chronic inflammation in the submucosa and patchy hypertrophy of the sub-epithelial connective tissue were also present . CurrentDieulafoy's disease of the bronchus was first described in 1995 by Sweerts et al.  and to dIts pathogenesis is hypothesized to be a hypertrophic response to chronic inflammation in a background of a possible congenital malformation. Patients in reported series are mostly middle-aged individuals with a male preponderance and with a history of smoking . PediatrRecurrent massive hemoptysis was the most common cause of hospitalization of those children described in the literature. Bronchoscopy in all these patients showed polypoid and non-pulsatile lesions in their airways. A white cap was described in one patient. The vascular lesions were able to be identified by CTA in three cases. It was non-diagnostic in the fourth patient, in whom an endobronchial ultrasound revealed the underlying lesion.n = 2) underwent bronchial artery embolization (BAE) with initial success in one of them (50%). Lobectomy was performed in one patient after failure of BAE (50%). Recurrence after initial treatment was reported in two patients  of which one underwent lobectomy and the other, continued with conservative management. Histological examination of all those published cases showed dilated tortuous branches of bronchial artery in the submucosa of the respiratory tract in association with mucosal erosion.One patient underwent upfront segmentectomy due to lack of expertise in interventional radiology in their facility. Rest of the patients  can be more appropriate in selected scenarios where definitive treatment with lower risk of recurrence is preferred.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.Written informed consent was obtained for the publication of this case report from the parents of the child treated for such condition while in hospital and they are fully aware of the images as well as the report sent across to the journal.Y-TY and MR prepared the initial draft. SC, DM, and NMc worked on editing the pictures. JS, J-NR, SS, and SC contributed to interventional radiology component. NMu edited the final version and approved for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2018, colon cancer (CC) is the third most common cancer in men and second in women worldwide , destined to accumulate within tumor regions. However, i.v. administration causes significant distribution in highly perfused organs  compared to tumor sites. This untoward deployment of the i.v. administered chemotherapeutics may impair the functionality of said organs upon long-term exposure  or polymers  and dextran)  imparts selectivity to the delivery system for cancer tissue and reduces sporadic therapeutic effects of the anticancer agent on normal tissue. Pharmacogenomics backed by combinatorial anti-colon cancer therapeutics has immerged as the prospective frontier in the management of colon cancer. Along with the formulation of intelligent delivery systems administrable orally, we will be traversing a significant threshold in the treatment of colon cancer.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.