Castor oil (CO) is an inedible vegetable oil (VO) that has been employed extensively as a bioresource material for the synthesis of biodegradable polymers, cosmetics, lubricants, biofuels, coatings and adhesives. It is used in medicine, pharmaceuticals and biorefineries, due to its versatile chemistry. However, there has been less focus on CO as an alternative to toxic and expensive solvents, and capping/stabilizing agents routinely used in nanoparticle syntheses. It provides a richer chemistry than edible VOs as a solvent for green syntheses of nanoparticles. CO, being the only rich source of ricinoleic acid (RA), has been used as a solvent, co-solvent, stabilizing agent and polyol for the formation of polymer–nanoparticle composites. RA is a suitable alternative to oleic acid used as a capping and/or stabilizing agent. Unlike oleic acid, it provides a facile route to the functionalization of surfaces of nanoparticles and the coating of nanoparticles with polymers. For applications requiring more polar organic solvents, RA is more preferred than oleic acid. In this review, we discuss the production, chemical and physical properties, triglyceride and fatty acid (FA) compositions and applications of CO, focusing on the use of CO and RA as well as other VOs and FAs in syntheses of nanoparticles and surface functionalization. However, the use of expensive and toxic materials for the syntheses of nanoparticles is becoming a critical concern. Many researchers have resorted to employing environmentally friendly renewable bioresource materials such as vegetable oils (VOs), carbohydrates and plant extracts in the syntheses of nanoparticles –15. CastOleum Palmae Christi (or CO) is a hydroxylated lipid obtained from the seed of the castor plant, Ricinus communis L. of the family Euphorbiaceae and native to tropical Asia and Africa [d Africa –18. It id Africa . The trid Africa ,20,21.FRA is a multifunctional compound, possessing a carboxylic acid, a double bond (between C9 and C10) and a secondary alcohol or hydroxyl (at C12) functional group. The hydroxyl group is beta to the double bond and protects that double bond from peroxide formation . These fCarboxylic acids such as oleic acid and stearic acid have been employed extensively as ligands or capping agents ,32. RA aThis review is split into four main sections: (i) facts about CO , (ii) composition and structure of CO and isolation of RA, (iii) application of CO in biomedicine, biopolymers, biochemicals, bioenergy, lubricants and coatings and (iv) utilization of CO (as well as other VOs) and RA (as well as other FAs) as capping ligands or solvents for nanoparticle syntheses and functionalization. The review is then concluded by highlighting the areas in nanoparticle syntheses where CO and RA can be used.2.2.1.2n=2x= 20) species within the family of Euphorbiaceae and the genus Ricinus. The castor plant is a coarse perennial crop that grows to approximately 10 ft in the tropics and has a stem diameter of 7.5–15 cm. In the temperate regions, the castor plant behaves as an annual crop with succulent stems and usually herbaceous [2, NaOH or NaOCl to remove the toxins [www.castoroil.in [Ethiopia (east Africa) is believed to be the most likely origin of castor in addition to places such as northwest and southwest Asia, the Arabian Peninsula and the subcontinent of India and China . The hisrbaceous . Picturee toxins ,38,44. Doroil.in .Figure 2.2.6 t [3 t of castor seeds annually, representing approximately 4.54% of the world's production. Mozambique produces approximately 3.01% of the world's annual production and is the leading producer of CO seed in Africa. Ethiopia, South Africa, Angola, Tanzania and Kenya are African countries also involved in castor production though their production figures are low. China, Brazil, Paraguay and Thailand are also noted for castor production [The oil content of the castor seed is approximately 45–50%, with a yield of 470 kg of oil per hectare ,45. The 6 t . The majoduction .Figure 2.3.et al. [−1 and 928.31 g mol−1, respectively. Salimon et al. [−1. Compared with olive oil, CO has a higher MW and thus has a higher viscosity. The density of CO is also reported to be 961 kg m−3 [The presence of the hydroxyl group on RA has a drastic effect on the viscosity, pour point, melting point, heat of fusion, solubility, crystal structure and polymorphism of CO . The hydet al.  analysedn et al.  also rep1 kg m−3 ,43. The 3.3.1.et al. [et al. [et al. [Most of the triglyceride molecules in CO consist of three molecules of RA connected to a glycerol moiety . Salimonet al.  identifi [et al. ; Plante  [et al.  and Lin  [et al. , however [et al.  found fo [et al.  found 40 [et al. . These a [et al. . Estolid [et al. .Figure 3.2.et al. [The uniqueness of CO compared with other VOs lies in its FA composition. Numerous groups have reported on CO FA composition from different countries . The FAset al.  also shoet al. [Alternanthera triandra, Lam Syn. Alternanthera sessilis (L.) R. Br. seed oil as another source of RA (contains approx. 22.1% of RA). However, despite the possibility that other seed oils may contain RA, CO remains the only reported rich source of RA to date.Although CO is known to contain RA, which is a monohydroxy FA, Lin  has idenet al.  also rep3.3.et al. [4. Clarification of the FAs is done by mixing with n-hexane (1 : 5 w/v) and keeping at −4°C for 72 h in darkness. Chromatographic analysis of the resultant FAs revealed the purity to be within 87.50–88.10% of RA and 12.5–11.9% of palmitic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid and linolenic acid. Solid residues found after clarification were identified to be 9-,10-dihydroxystearic acid [Several methods, including chemical and biochemical pathways, have been used to isolate RA from CO. The isolation occurs by hydroxylation of the ester linkages in the triglyceride molecules to yield RA and glycerol. The salt solubility-based fractionation method reported by Vaisman et al.  is an exric acid .et al. [Candida rugosa, Pseudomonas cepacia and Geotrichum candidum lipases for hydrolysis of CO. In a typical reaction, tubes containing 100 mg of oil, 0.6 ml of 0.5 M phosphate buffer (pH 7) and approximately 2–5 mg of free lipase were stirred at 500 r.p.m. at 30°C for 1–4 h. The extent of hydrolysis was determined by titrating the hydrolysis mixture (in 20 ml of diethyl ether/ethanol/water (3 : 3 : 2)) to pH 12 with 0.1 N NaOH solution. The P. cepacia lipase was found to be effective in hydrolysing CO to RA to the tune of 27% compared with 13% recorded for C. rugosa and G. candidum. Ozcan & Sagiroglu [C. rugosa, porcine pancreatic and castor bean lipases for lipolysis of CO and obtained a yield of RA within 20–40%, considering a number of parameters such as pH, temperature, amount of substrate and enzyme. Interestingly, Piazza & Farrell [Avena sativa L.) to hydrolyse CO and obtained approximately 90% yield of RA.Biocatalysts such as lipase  enzymes have been used to isolate RA from CO. Foglia et al.  employedagiroglu  also emp Farrell  used lipet al. [An eco-friendly approach by the use of microwave-assisted extraction of RA from CO has also been reported by Karpakavalli et al. . In thei4.CO has received much attention as a valuable commercial feedstock for production of a variety of products in a wide range of industries spanning pharmaceuticals to lubricants. 4.1.et al. [3 receptors.Historically, CO has been known as a medicinal oil and primarily used as a purgative or laxative to ease constipation . As far et al.  found thAdditionally, eye drops containing approximately 1.25% of homogenized CO are reported for the treatment of lipid-deficiency dry eye (i.e. meibomian gland dysfunction). The role of CO in treating dry eye is that it serves as a hydrophilic lipid that spreads over the human tear aqueous layer to correct the deficiency .et al. [Katzer et al.  have alset al. .4.2.et al. [in vitro studies showed that these biopolymers degrade rapidly via hydrolysis after 10 days, releasing RA and its counterparts [The use of CO as a raw material in the synthesis of polymeric materials is very well established. The hydroxyl functionality is more suitable for isocyanate reactions, yielding polyurethane, while the double bond is dehydrated to obtain dehydrated CO, which is applied in producing paints, enamels, lacquers and varnishes . Polymeret al.  reportedterparts . Table 54.3.et al. [Very important industrial chemicals such as γ-decalactone, sophorolipids, undecylenic acid, linoleic acid, sebacic acid, capryl alcohol, heptaldehyde, zinc ricinoleate, glyceryl ricinoleate and lithium 12-hydroxystearate are produced from CO ,77. Theset al.  synthesiet al. . Biodieset al. .5.(i) environmentally benign and inexpensive;(ii) suitable alternatives to some toxic and expensive solvents or ligands traditionally used in nanoparticle syntheses;(iii) renewable source of raw material;(iv) biodegradable and provide versatile chemistry-based opportunities;(v) a source of carboxylic acids suitable as ligands/capping agents or for synthesizing safe chemical precursors for metal oxide and sulfide nanoparticle syntheses; and(vi) biocompatible, ensuring dispersion of nanoparticles in non-polar solvents.For biomedical applications (e.g. staining of proteins), nanoparticles should be: (i) biocompatible, (ii) water soluble and (iii) easily functionalized or chemically modified at the surface to tailor the interaction of the nanoparticles with target biomolecules [(i) CO is inedible and obviates possible competition as raw material for the food industry;(ii) CO is a natural source of polyol and presents a simple avenue for versatile chemical reactions;(iii) CO is the only rich source of RA that has been used as a building block for synthesis of several biochemicals;(iv) RA due to the presence of the hydroxyl functional group on its hydrocarbon chain provides a facile route for chemical functionalization and manipulation of nanoparticle surfaces to tailor it to a specific application;(v) CO and RA are more suitable for applications requiring highly polar organic solvents; andCO and RA possess antimicrobial properties.Green syntheses of nanoparticles are strongly advocated worldwide because of the disadvantages of the use of toxic solvents and chemicals, especially the effects on human health and the environment. Green chemistry principles embody the (i) design of less hazardous chemical syntheses, (ii) use of safer chemicals and solvents, (iii) use of renewable feedstocks and (iv) design of degradation . Thus, rolecules ,83,84. Folecules . Thus, C5.1.et al. [Metal nanoparticles are synthesized either by wet chemical, laser ablation, sputtering deposition or sonochemical methods. Diphenylmethane is a common solvent used in sonochemical reactions. Diphenylmethane is, however, reported to decompose to toxic by-products . In addiet al.  have demet al. ,15,85–88et al. . Howeveret al. [et al. [4 in KOH solution), because several attempts to synthesize similar stable colloids with soya bean or cottonseed oils failed [As previously stated, CO is inedible and the seed oil is high yielding compared with most edible oils, and is found to be the best and inexpensive alternative to edible oils for metal nanoparticle syntheses . In addiet al.  combined [et al.  made cols failed .in situ by autoxidation of the drying oil [Interestingly, antimicrobial paints based on VOs and silver nanoparticles have been developed via a simple method centred on free radicals generated ying oil . Drying ying oil . Howeverying oil .5.2.Metal chalcogenide semiconductor nanoparticles are a useful class of inorganic materials that have received tremendous applications in solar cells and biomedical labelling . Some ke5.2.1.et al. [et al. [et al. [et al. [Xiao et al.  demonstr [et al.  prepared [et al.  and Hard [et al.  replicatet al. [Though olive oil was reported to be a suitable green solvent, Hardman et al.  noted th5.2.2.et al. [Solvents such as octadecene and TOPO are often used as co-solvents with VOs and FAs. The reasons for the co-solvent addition are to: (i) decrease the viscosity of the oil to ensure uniform nucleation of the nanoparticles and (ii) reduce the strong binding of the FAs to the nanoparticles or reduce the extent of inhibition of the nanoparticle growth ,105. Akhet al. [et al. [et al. [Nyamen et al.  thermoly [et al.  synthesi [et al.  also, apet al. [et al. [−1) and in TOPO (with molecular weight of 386.65 g mol−1) to be 0.56 and 0.95 eV molecule−1, respectively [−1, higher than the molecular weight of TOPO).Qu et al.  revealed [et al.  found thectively . Thus, t5.2.3.FAs are Lewis acids and have been extensively applied as capping agents and surfactants in the syntheses of nanoparticles. Oleic acid is known as a standard FA; the double bond and alkyl chain forming a ‘kink’ imparts colloidal stability . Oleic a5.2.4.et al. [Metal FA salts (MFASs) are polyvalent metal soaps, prepared by: (i) metathesis of a sodium or potassium FA salt with metal salts in aqueous or polar solvents, (ii) dissolution or fusion of metal oxides  in hot FAs, or (iii) direct reaction of metal with hot FAs . MFASs het al.  combinedet al. [et al. [Chen et al.  decompos [et al.  decomposMFASs decompose thermally through the formation of free radicals that combine, disintegrate into smaller molecules or react with other metal carboxylates to propagate to decompose metal carboxylates in MFASs .et al. [2S, MnS, PbS, CdS and ZnS nanocrystals by the solution-phase thermolysis of metal–oleate complexes in alkane thiol. This method was considered simple and general for the synthesis of metal chalcogenides. Specifically, the metal–oleate precursors were dissolved in solvent mixtures of oleylamine and dodecanethiol. The resultant mixtures were then heated to the required temperatures and maintained for a period. The reaction temperature, time and the molar ratio of the two solvents were varied to tune the sizes of the nanoparticles. The nanoparticle sizes were uniform and had average particle sizes of 18, 11, 47, 10 and 10 nm for Cu2S, MnS, PbS, CdS and ZnS nanocrystals, respectively. Similarly, Patel et al. [Choi et al.  synthesil et al.  obtained5.3.et al. [et al. [4:Yb/Er and obtained NaYF4:Yb/Er-C12 (Up-conversion nanoparticles (UCNps) have received considerable attention as fluorophores in bioimaging over organic fluorophores and semiconductor quantum dots. UCNps have high quantum yields, high photostability and narrow emission peaks. However, to efficiently use UCNps in bioimaging, the UCNps must be rendered water-dispersible and their surfaces functionalized . To rendet al.  as an ex [et al.  reacted b/Er-C12 . Interes5.4.3O4 nanoparticles, Lattuada & Hatton [The coating of surfaces of very small size monodispersed nanoparticles with polymers for specific application in biomedicine is a major challenge. Nanoparticle surfaces can be polymerized in various solvents with the appropriate polymer for a specific purpose if ligands on the surfaces are suitable for such polymerization reactions. RA (and CO) in this regard stands out as the most suitable ligand  compared to oleic acid. In an attempt to develop polymer-coated monodispersed Fe& Hatton  first (i3O4 nanoparticles composited with poly(lactic-co-glycolic) acid was reported by Furlan et al. [3O4 nanoparticles were synthesized using the Massart co-precipitation method. The RA played its role as a biocompatible ligand rendering the nanoparticles hydrophobic, which ensured their dispersibility in apolar and mildly polar organic solvents such as dichloromethane. Additionally, a wound healing bio-nanocomposite based on CO and chitosan-modified ZnO nanoparticles has also been reported [Similarly, RA stabilized Fen et al.  as a magreported . The CO reported  also pre6.CO has a useful versatile chemistry and has been reviewed as a valuable bioresource material for green syntheses of nanoparticles. It is used as a biocompatible solvent, co-solvent, and a capping and stabilizing agent in the syntheses of metal and metal chalcogenide nanoparticles, as well as a source of polyol for forming chemically bonded polymer–nanoparticle composites that are biodegradable. CO is distinct from other VOs and contains huge amounts of ricinoleic acid, which is isostructural to the traditional oleic acid for capping magnetic and luminescent nanocrystals ,100,112.Ricinoleic acid is a more suitable stabilizing and/or capping agent for applications requiring more polar organic solvents (e.g. in lubricants) . It provThough the utilization of CO and ricinoleic acid as solvent/capping/stabilizing agents for nanoparticle syntheses has substantial potential in expanding the spectrum of nanoparticle applications, it is somewhat limited. Ricinoleic acid is more suited for low-temperature organometallic synthesis because of the possible oxidation of the hydroxyl group on its hydrocarbon chain . However


The traditional healthcare industry is undergoing a major paradigm shift due to the rapid advances and developments of mobile, wearable, and other wireless technologies. These Mobile Health  technologies promise to bring tremendous benefits and opportunities to the diagnosis, prognosis, treatment, and prevention of human diseases for a better quality of life. In the meantime, mHealth also presents unprecedented performance and security challenges in the entire process of data collection, processing, analysis, synthesis, and visualization. For example, the advent of wearable technology has now made it possible to constantly monitor sophisticated biometrics for many people ranging from home athletes to chronic healthcare patients. A wide spectrum of devices are being designed as either a replacement of an existing healthcare monitor or a proposition for a new multifunction one. These devices typically require communication with a central healthcare system via cell phones or tablets, and thus, threats to the data at rest and in transit still exist, apart from a potential risk of misuse via patient profiling. Therefore, it is crucial to design and implement new mHealth technologies to build reliable, accurate, efficient, and secure healthcare environments for optimal patient care. The wide deployments of such wearable monitoring devices have also raised a critical issue to health informatics caused by the sheer volume and high complexity of health data collected anywhere and anytime. Machine learning and big data-oriented algorithms, models, systems, and platforms are needed to support the analysis, use, interpretation, and integration of diverse health data.This special issue includes 14 research articles, addressing various aspects of the recent mHealth advances and developments that use mobile and wireless devices to improve healthcare outcomes, services, and research. In the article titled “Mobile Aid to Assist with Care Decisions in Children with Autism Spectrum Disorder (ASD),” A. Khan et al. developed an autism spectrum disorder intervention application that provides an outlet for children to express their emotions while providing an uncomplicated environment. In the article titled “Systems and WBANs for Controlling Obesity,” M. S. Mohammed et al. explored the use of wireless body area networks (WBANs) and related systems for controlling obesity and proposed to integrate such technologies into an intelligent architecture. In the article titled “Indication of Mental Health from Fingertip Pulse Waves and Its Application,” M. Oyama-Higa and F. Ou explored the use of the largest Lyapunov exponent (LLE) of the attractor to provide an effective indicator of mental health. In the article titled “A New Remote Health-Care System Based on Moving Robot Intended for the Elderly at Home,” B. Zhou et al. developed specialized robotics technologies for remote geriatric care. In the article titled “A Mobile Multimedia Reminiscence Therapy Application to Reduce Behavioral and Psychological Symptoms in Persons with Alzheimer's,” D. Imtiaz et al. developed a mobile technology-based solution to address behavioral and psychological symptoms of dementia (BPSD) that occur in individuals with Alzheimer's dementia. In the article titled “QRS Detection Based on Improved Adaptive Threshold,” X. Lu et al. designed an adaptive threshold algorithm for QRS detection that can be used in mobile devices. In the article titled “Genuine and Secure Identity-based Public Audit for the Stored Data in Healthcare Cloud,” J. Zhang et al. constructed an identity-based data-auditing system where an algorithm is used to calculate an authentication signature. In the article titled “Modeling Medical Services with Mobile Health Applications,” Z. Wang et al. designed a medical service equilibrium model for evaluating the influence of mHealth applications on the medical service market to balance the supply of doctors and the demand of patients. In the article titled “Chinese Mobile Health APPs for Hypertension Management: A Systematic Evaluation of Usefulness,” J. Liang et al. conducted a study of Chinese mobile health APPs for hypertension management to investigate the difference and effectiveness of the APPs between mainland China and other places. In the article titled “Leveraging Multiactions to Improve Medical Personalized Ranking for Collaborative Filtering,” S. Gao et al. constructed a medical Bayesian personalized ranking (MBPR) over multiple users' actions based on a simple observation that users tend to assign higher ranks to healthcare services that are meanwhile preferred in users' other actions. In the article titled “A Systematic Review on Recent Advances in mHealth Systems: Deployment Architecture for Emergency Response,” E. Gonzalez et al. conducted a broad survey of recent advances in mHealth systems. In the article titled “An Ensemble Multilabel Classification for Disease Risk Prediction,” R. Li et al. explored the use of ensemble multilabel classification for disease risk prediction. In the article titled “Semiautomatic Segmentation of Glioma on Mobile Devices,” Y.-P. Wu et al. studied hard edge multiplicative intrinsic component optimization to preprocess glioma medical images. In the article titled “Handling Data Skew in MapReduce Cluster by Using Partition Tuning,” Y. Gao et al. explored the use of partition tuning-based skew handling (PTSH) to make improvements over the traditional MapReduce model in processing large healthcare datasets.


Ultrafast laser microfabrication is a very powerful method for producing integrated devices in transparent materials . This te(1)Ultrafast laser ablation. In this category, we include papers where laser ablation is used to microstructure transparent materials. Bettella et al. [a et al.  produceda et al.  used las(2)Femtosecond laser irradiation and chemical etching. Here we include papers that demonstrate the potential of the combined use of femtosecond laser irradiation and chemical etching. In fact, on suitable materials  the irradiated pattern is selectively removed by a subsequent chemical etching step in aqueous solutions of hydrofluoric acid or potassium hydroxide. The advantage of this approach with respect to ablation is an extended 3D structuring capability and much better surface quality, as widely demonstrated by Cheng [by Cheng  in his rby Cheng  showed f(3)Two-photon polymerization. In this category, we include papers that discuss the use of two-photon polymerization to directly write micro/nano structures with specific potential for lab-on-a-chip applications. Zandrini et al. [i et al.  showed ti et al.  reviewed(4)Combining subtractive and additive processes. In this category we include papers where the above processes are combined in order to provide more functionality on the same lab-on-a-chip. Sima et al. [a et al.  revieweda et al.  followeda et al.  discusseThe special issue is composed of nine papers, including original research and reviews. The different contributions can be organized into the following four categories:We would like to thank all the contributors for submitting their papers to this Special Issue. We also thank all the reviewers for dedicating their time to help improve the quality of the submitted papers.


Background: Metabolic syndrome increases the risk of cardiovascular disease (CVD) over and above that related to type 2 diabetes. The optimal diet for the treatment of metabolic syndrome is not clear. Materials and Methods: A review of dietary interventions in volunteers with metabolic syndrome as well as studies examining the impact of dietary fat on the separate components of metabolic syndrome was undertaken using only recent meta-analyses, if available. Results: Most of the data suggest that replacing carbohydrates with any fat, but particularly polyunsaturated fat, will lower triglyceride(TG), increase high density lipoprotein (HDL) cholesterol, and lower blood pressure, but have no effects on fasting glucose in normal volunteers or insulin sensitivity, as assessed by euglycemic hyperinsulinemic clamps. Fasting insulin may be lowered by fat. Monounsaturated fat (MUFA) is preferable to polyunsaturated fat (PUFA) for fasting insulin and glucose lowering. The addition of 3–4 g of N3 fats will lower TG and blood pressure (BP) and reduce the proportion of subjects with metabolic syndrome. Dairy fat (50% saturated fat) is also related to a lower incidence of metabolic syndrome in cohort studies. The metabolic syndrome is associated with an increased risk of cardiovascular disease and type 2 diabetes and enhances the risk of CVD in people with diabetes . There aTo systematically review meta-analyses of interventions that replace carbohydrates with fat in people with metabolic syndrome and interventions that examine these effects on the individual components of the syndrome. Pubmed was searched  with the terms “meta-analysis AND dietary fat AND carbohydrate AND intervention AND ”. We reviewed 102 titles.A large amount of evidence has accumulated that replacing carbohydrates  with fat of any sort will lower fasting triglyceride and increase HDL cholesterol. A meta-analysis by Mensink and Katan  found thThe relationship between carbohydrate intake and TG has been controversial for many years with arguments about the persistence of the TG elevation effect ,9, with p < 0.001) and a lower level of HDL-cholesterol (WMD: −2.57 mg/dL (−0.07 mmol/l); 95 % CI −3.85, −1.28; p < 0.001) after the low-fat diets, compared with high-fat diets in 20 studies with 2016 participants.In a meta-analysis of high-fat versus low-fat diets in people with obesity, but no overt metabolic disturbance, Lu et al. 2018) [ [18] foun-3 PUFAs was associated with a lower metabolic syndrome risk . The plasma/serum n-3 PUFAs in controls were significantly higher than in metabolic syndrome cases , especially docosapentaenoic acid and docosahexaenoic acid. Guo et al.  performeThe addition of fish oil fatty acids of at least 1 g/day lowers fasting TG and a metanalysis performed by Eslick et al.  of 47 stn trials = 99), but lowered fasting insulin . Replacing saturated fat with PUFA lowered fasting glucose . Thus, PUFA is clearly the better fat for replacing carbohydrates in normal people. In people with type 2 diabetes [Fasting glucose lowering by reducing carbohydrate and replacing it with fat is far more controversial. A recent meta-analysis by Wanders et al.  showed ndiabetes , high MUdiabetes . Surprisp = 0.02) and diastolic blood pressure  mm Hg; p = 0.05) than did diets rich in cis-monounsaturated fat. Huntress et al. [There are much less data on blood pressure and carbohydrate replacement with fat in non-diabetics and the effects are relatively small. A meta-analysis performed by Shah et al.  found ths et al.  examineds et al. , MUFA loMansoor et al.  performen = 21), ruminant TFA-rich lipids , or industrial TFA-rich lipids , no changes in peripheral insulin sensitivity were seen. Bendtsen et al. [p = 0.03) accompanied by a reduction in liver fat [Insulin resistance is a key and essential element of the metabolic syndrome (except the NCEP111 criteria), usually assumed on the basis of central adiposity. As noted by Wanders et al. , replacin et al.  found non et al.  found non et al.  found non et al.  showed tiver fat A contrary result was found in the Lipgene study  where 47p < 0.028).In another report from the same study, in 337 volunteers , the preMost meta-analyses show that replacement of carbohydrates with fat lowers fasting TG and glucose and blood pressure, and increases HDL cholesterol with some differences, depending on whether the population has type 2 diabetes or not. There are some large intervention and cohort studies that show the opposite results, but these are in the minority. PUFA is probably superior to MUFA, while fish oil is superior to both.


In the Funding section, the information provided is incomplete. The complete, correct Funding section is:http://www.isciii.es).This work was supported by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER). PI13/01668 (


We report a close replication but with measures of attachment that are considered superior in comparison to measures used by Van Lange et al., due to subsequent psychometric improvements. Psychometric analyses indeed showed that our attachment measures were reliable and valid, demonstrating theoretically predicted associations with other outcomes. With a sample (N = 879) sufficiently large to detect d = 0.19 , we failed to replicate the effect. Based on the available evidence, we interpret as there being no evidence for the link between attachment security and Social Value Orientation, but further replication research that uses solid measures and large samples can provide more definite conclusions about the association between attachment and SVO.We report a replication and extension of a finding from Studies 1 and 2 of Van Lange  Close, intimate relations are thought to be rooted in an attachment system that helped to solve basic evolutionary pressures related to survival, caregiving and procreation. Central to attachment behaviours is the regulation of proximity between carers and infants . For exaOne of the hallmark premises of attachment theory is that having a responsive and reliable carer (or not) causes greater (or lesser) confidence in others, forming the basis for how people interact later in life , modern dimensional approaches treat attachment style as consisting of two underlying dimensions: anxiety and avoidance. Note that in the latter framework, security is not a separate dimension but a combination of low levels of both anxiety and avoidance .1.2.As stated above, adult attachment is seen as the result of prior experiences with carers. Although the majority of attachment research has been conducted in the context of close relationships, some research indeed suggests that people who are securely attached are also more supportive towards strangers . Van Lanet al. [and individualists grouped together; hereafter referred to as ‘proselfs’) scored higher on this scale (i.e. security), but only marginally significantly lower on the scales measuring attachment anxiety and avoidance in their attachment towards a variety of close others. They continued to examine contrasts between prosocials versus competitors and individualist in terms of the latter two dimensions and found that these were statistically significant and supportive of their hypothesis. Moreover, in Study 2 they found that prosocials more strongly endorsed the secure prototype.Van Lange et al.  found th2.et al. measured attachment in two ways. In Study 1 (N = 573), they used a multi-item questionnaire that seems a precursor of 13 items published by Carnelley and Janoff-Bulman [Although the findings garnered considerable interest, they had considerable problems. First and foremost, Van Lange f-Bulman  that evef-Bulman . This meet al. [N = 136), they measured attachment styles using a Likert-scale endorsement of each of the three attachment prototypes. Indeed, the reliabilities of Van Lange et al.'s [p = 0.09 and p = 0.06, respectively) in a sample of 573 participants. These marginal differences were obtained while controlling for gender and after dropping items from the attachment scale related to feelings about one's partner, yet in Study 2 the effect was present for partner-specific attachment.The lack of dimensionality might be one of the reasons for the low reliability reported for this scale in the Van Lange et al.  paper. Iet al.'s [et al. [In terms of validity, there might also have been problems with the attachment measure's translation. In Van Lange et al.'s  paper, t [et al.  paper  among Tilburg University's first year bachelor students. The study was thus not planned as a pure replication, which partly explains why we did not implement Van Lange 4.4.1.a priori power analysis. A post hoc sensitivity analysis in G*Power [d = 0.19. In order to test as conservatively as possible, we excluded eight participants who had four duplicate subject IDs. We ran no further studies to test the effect. All participants were first year bachelor students who participated in exchange for course credit. All data and syntaxes needed for these attachment analyses are available at https://osf.io/6kqzy/.We report the descriptives in  G*Power  with 4994.2.4.2.1.The exact composition of the battery of questionnaires in our test-weeks varied throughout the four years. In each year SVO was assessed by the same nine-item triple dominance measure used in the original . The lack of unidimensionality is also apparent from the very low Omega reliability for the security scale in 2011 and 2014, see Attachment was assessed with one or two measures per assessment wave. The switch of these instruments occurred based on considerations unrelated to the current study and were thus not informed by any preliminary analysis (which we did not conduct). In all studies, attachment style was assessed in a dimensional fashion. In 2011 and 2014, we used the Adult Attachment Scale , which et al. [Importantly, our attachment measures differed from Van Lange et al.  in two w4.2.3.and to investigate whether our central measures (SVO and attachment) behaved like they are expected to behave on the basis of the existing literature.As noted, the data was collected in test-weeks. A full overview of relevant measures is reported in tables 4.2.4.SW = 0.98, p < 0.01; prosocial SW = 0.98, p < 0.01), once significant for anxiety , significant for security , the Central Limit Theorem prescribes that distributions of means approach normality as long as the sample is sufficiently large [https://osf.io/6kqzy/files/) so we proceeded with parametric testing, as was also done in the Van Lange et al. [We also tested the SVO-attachment data for normality via the Shapiro–Wilk test. Although this test was significant for avoidance (proself ly large . When we5.https://osf.io/6kqzy/).The following results were found with the merged datasets. Given that not all questionnaires were administered in each year, sample size varied per study. Furthermore, degrees of freedom varied per analysis. We will not list these descriptors for each analysis, but instead point the reader to the data and analysis scripts that are available online under the files at our Open Science Framework page  and 269 proselfs (35%) and 95 individuals who could not be classified. If participants answered more than six dilemmas in a prosocial manner, they were classified as being prosocial. Note that the number of prosocials are somewhat higher than reported in the Van Lange paper, where between 43% and 49% of the sample was classified as prosocial, 1 For sake of consistency, we report ANOVAs in all our replication analyses.Given that attachment measures were measured at different scales (from 1 to 5 for the AAS and 1 to 7 for the ECR-R) we standardized them within each year for our aggregate (cross-sample) analysis. In our 2014 sample, we furthermore aggregate across the avoidance and anxiety dimensions of both available measures. We also analyse all scales separately and report the results in footnotes.et al. [2 We did not find higher levels of attachment security for prosocials  than proselfs  in the combined 2011 or 2014 samples; however, Cohen's d = 0.15, .3 Van Lange et al. [M = 0.03, s.d. = 1.01) people are less anxious than proselfs , Cohen's d = 0.03, F1,764 = 0.11, p = 0.74, or that prosocials  are less avoidant in their attachment than proselfs , Cohen's d = 0.07, F1,763 = 0.86, p = 0.36. When we tested for the differences between prosocial  and proself  with the ECR reverse-scored and averaged as proxy for security, we also found no difference, Cohen's d = 0.03, F1,763 = 0.12, p = 0.73. We also considered testing the relationship between SVO using a continuous measure instead of a categorical measure. However, because the data were binomially distributed, we could not support analysing SVO as continuous.In the Van Lange et al.  paper, r6.N = 879) we found no relationship between social value orientation and attachment, and we could thus not replicate Van Lange et al. [N = 879 participants, we could not confirm the hypothesis that SVO is related to attachment security.In a large sample study from four years , the alpha of a security composite will necessarily be modest . From a measurement perspective, it is problematic that Van Lange et al. [There are three possible explanations for the discrepancy. First, it is possible that our study was not well conducted, including the fact that our attachment measures differed. This is of course possible, but we could not identify any psychometric indicators to support such a claim. Our measures were more reliable than Van Lange et al.'s  measureset al.'s . Moreove [et al.  measuredstill tested the relationship with more outdated scales and also found nothing.One could further discuss what constitutes a solid replication . These analyses clearly showed robust patterns  of attachment dimensions correlating in expected ways with theoretically related constructs. Reporting being less avoidant in one's attachment related to scoring higher on empathic concern, perspective taking, self-esteem, agreeableness and extraversion, and scoring lower on psychopathic tendencies. Reporting being less anxious in one's attachment related to scoring lower on behavioural inhibition and neuroticism, and higher on perspective-taking, self-esteem, openness to experience, extraversion and self-control. Importantly, we did not detect interaction effects between measures and assessment year. Note also that when we did use a measure that included a scale of attachment security, we also did not replicate the original Van Lange et al. [We think the soundness of our approach is evident from the fact that our attachment measures did not only have superior reliability as compared to the original study but also demonstrated construct validity in conducted auxiliary analyses , we did find that our sample was slightly more proself than Van Lange. It could be speculated that the urban versus provincial status of the samples might have contributed to this difference, but we should also note that Tilburg is itself a medium-sized (for Dutch standards) industrial town that is only a 1 h drive from Amsterdam. Variance restriction might have been an issue, although we do not think this accounts for the lack of replication. Finally, we note that our sample size was considerably larger than the original and our sensitivity analyses showed that we were well positioned to detect a small effect.et al.'s [p = 0.09 and p = 0.06, respectively) in a sample of 573 participants. These marginal differences were obtained while controlling for gender and after dropping items from the attachment scale related to feelings about one's partner (yet in Study 2 the effect was present for partner-specific attachment). In terms of validity, there might also have been problems with the attachment measure's translation. In Van Lange et al.'s [et al. [A final possibility is that the lack of replication of the original study was made possible by problems with the measurement of attachment. First and foremost, the reliabilities of Van Lange et al.'s  Study 1'et al. [Post hoc, after knowing the outcome of these replication studies, one could argue that Studies 1–3 are not vital to the 1997 paper , with w [et al.  for exam [et al. , p. 1082 [et al.  similarl [et al.  concludeWhere do we go from here? Going into this project, we did not think it was an unreasonable assumption that attachment was in some way related to SVO. After all, both relate to the honesty/humility factor of the HEXACO  and the et al.'s [What are then the developmental origins of SVO? Although we think this is an exciting question, we simply don't know. In any case, given that this paper was the bedrock of an entire literature and that Van Lange et al.'s  Studies


Cancer stem cells (CSCs) are a group of tumor cells with self-renewal property and differentiation potential. CSCs play a crucial role in malignant progression of several types of tumors. However, what is still controversial is the clinicopathological relationship between the Nanog marker and its prognostic value in the patients with breast cancer. The expression of Nanog in the patients with breast cancer and its correlation with clinicopathological prognostic factors was explored in the present study.A sample of 120 breast cancer tissues was obtained from the patients who referred to Imam Khomeini Hospital in Sari City, Iran during January 2012 and December 2016. The associations between Nanog expression and clinicopathological factors were analyzed based on immunohistochemical analysis.p = 0.001), lymph node metastasis (p = 0.01), and the stage of the disease (p = 0.003).The expression of Nanog was detected in 67 (55.8%) patients with a high expression rate in 24 (36%) cases (staining index ≥3). Moreover, there was a statistically significant relationship between Nanog expression and clinicopathological factors, including tumor grade (Findings of the study indicate that Nanog may act as a biomarker for prognostic prediction in patients with breast cancer. Breast carcinoma is the most common malignant tumor with the highest mortality rate in women. It involves more than 1.7 million cases around the world annually. Cancer Nanog is a key multidomain homeobox transcription factor for maintaining ESC pluripotency,12. HumaThe specimens of breast cancers were obtained from 120 patients referred to Imam Khomeini Hospital in Sari (Iran) during January 2012 and December 2016. Clinicopathologic parameters were age, tumor size, histological grade, perineural invasion, vascular invasion, lymph node metastasis, and tumor stage. Data were gathered using hematoxylin and eosin (H&E)-stained pathologic slides, pathological records, and hospital files. All the patients were women, with the mean age of 54.5 (ranging from 28 to 77) years. The samples were taken from the cancerous and adjacent normal tissues. For microscopic examination, the tissues were routinely fixed with formalin 10% before being embedded in paraffin.This research was performed using the samples stored after the pathological diagnosis. All the data were obtained from anonymous samples. Mazandaran University of Medical Science  approved the study .Participants of the study included patients diagnosed with invasive ductal carcinoma following the breast surgery and those who did not receive neoadjuvant treatment. The inappropriate paraffin tissue blocks for immunohistochemical staining as well as those samples with incomplete documents were excluded from the study.00 °C for 13 min and then removed and put aside to reach room temperature. The tissue was washed with both running water and wash buffer. Next, the slides were incubated at envision for 60 minutes using diagnostic kit for monoclonal Nanog with 1/500 dilution, and then they were washed twice with wash buffer. The DAB solution was added and after appearing brown color, the slides were placed again in wash buffer for two minutes. Finally, the washed slides were stained with Mayer's hematoxylin, rinsed in distilled water, fixed in xylol and mounted with Entellan. Positive control kit for Nanog was Seminoma tissue. Our negative control was the tissue that the primary antibody did not shed. The nuclear staining was observed and scored by two pathologists according to the published criteria using a semi-quantitative score), followed by 33 (27.5%) as grade I and 19 (15.8%) as grade III of the tumor. Sixty-seven of the breast cancer patients (55.8%) of the study exhibited lymph node involvement. The higher Nanog expression was observed in 44 lymph node positive samples (36.7%).p = 0.001), tumor stage (p = 0.003), and lymph node involvement (p = 0.01) in breast cancer samples. There was not any relationship between Nanog expression and age (p = 0.71), tumor size (p = 0.25), perineural invasion (p = 0.06), and vascular invasion (p = 0.27).et al.[et al.[et al.[In this study, 55.8% of tumoral sample have expressed Nanog marker. Finicelli et al. also repl.[et al. found lil.[et al. observedl.[et al.,19. In al.[et al., tumor al.[et al., hormonel.[et al., and chel.[et al..et al.[et al.[et al.[et al.[et al.[et al.[et al.’s[et al.[et al.[et al.[et al.[et al.[We identified Nanog protein to be predominately expressed in the nucleus of tumor cells. IHC analysis of Nanog in breast carcinoma tissues has shown both nuclear and cytoplasmic localization of this protein; a result that is compatible with ours,19. Our et al. and Wangl.[et al. have deml.[et al. and Wangl.[et al. did not l.[et al.,23. Withl.[et al.. Arif et[et al.’s results l.[et al. and Wangl.[et al. and Wanget al.[et al.[In this study, we found no significant link between perineural and vascular invasion. However, there is no study reporting these two prognostic factors. Nagata et al. have shol.[et al., no signSome limitations of this study include short follow-up period, evaluation of distant metastasis, and survival rate of the patients. This study found a strong connection between Nanog expression and some clinicopathologic features in the patients with breast cancer, which includes lymph node metastasis, stage of the disease, and grade of disease. Our findings indicate that there is an association between the expression of Nanog and prognosis of the breast cancer patients. Moreover, worse prognostic characteristics were observed in the patients with high expression of Nanog. However, controversies exist among the studies conducted to evaluate this relationship.


Neuroimage57, 1205–1211) investigated whether any regions activated more in response to passively viewing digits in contrast with letters and visually similar nonsense symbols and identified a region in the left angular gyrus. By contrast, Grotheer et al.  found bilateral regions in vOTC which were more activated in response to digits than other stimuli categories while performing a one-back task. In the current study, we aimed to replicate the findings reported in Grotheer et al. with Price & Ansari's passive viewing task as this is the most stringent test of bottom-up, sensory-driven, category-specific perception. Moreover, we used the contrasts reported in both papers in order to test whether the discrepancy in findings could be attributed to the difference in analysis.The influential triple-code model of number representation proposed that there are three distinct brain regions for three different numerical representations: verbal words, visual digits and abstract magnitudes. It was hypothesized that the region for visual digits, known as the number form area, would be in ventral occipitotemporal cortex (vOTC), near other visual category-specific regions, such as the visual word form area. However, neuroimaging investigations searching for a region that responds in a category-specific manner to the visual presentation of number symbols have yielded inconsistent results. Price & Ansari (Price, Ansari 2011  Arabic digits) was postulated by Dehaene , but onlThe extent to which category-specific regions in the ventral visual stream, such as the visual word form area (VWFA), are specialized for domain-specific processing remains debated e.g. –10). The. The10])An opposing view, the interactive account of vOTC function, proposes that object recognition is dependent on forward and backward feedback loops between visual cortices and higher-order semantic processing regions . Supportet al. proposed that to be considered an NFA, the region ‘should be anatomically consistent across subjects and should respond more to numerals than morphologically, semantically, or phonologically similar stimuli' [et al. [In order to resolve this debate, it is important to determine the criterion for a region to be considered functionally specific for number symbols. For example, Shum stimuli' , p. 6709stimuli'  further stimuli' . Notably [et al.  found thet al. [et al. [et al. [Price & Ansari  used a met al.  to test et al.  ran a co [et al.  ran a co [et al. . However [et al. . While P [et al.  used a p [et al.  used a o1.1.et al. [If an NFA can be reproducibly localized and is specific to Arabic numerals rather than familiar symbols more broadly, it should activate more strongly for Arabic numerals than other meaningful written symbols, regardless of task demands. The current study, therefore, aimed to replicate and extend the study by Price & Ansari  using upet al.  to deter2.https://osf.io/wz268/register/5a970dfec69830002df68ac2). This pre-registration was performed after data analysis. We had also previously registered our analysis plan on the OSF on 15 September 2017, before we completed data collection (https://osf.io/hcs7t).This article received results-blind in-principle acceptance (IPA) at Royal Society Open Science. Following IPA on 7 March 2019, the accepted Stage 1 version of the manuscript, not including results and discussion, was pre-registered on the OSF  recruited from the London, Ontario, region participated in the study, and 27 of them were female. An additional three adults completed the study but were excluded from data analysis for failing to disclose that they were left-handed in advance. All included participants were right-handed with normal or corrected to normal vision.Forty adults between 18 and 37 years of age . A whole-brain high-resolution T1-weighted anatomical scan was collected using an MPRAGE sequence with 176 slices, a resolution of 1 × 1 × 1 mm voxels and a scan duration of 5 min and 21 s . The in-plane resolution was 256 × 256 pixels. Functional MRI data were acquired during the change detection task using a T2*-weighted single-shot gradient-echo planar sequence . Forty-eight slices were obtained in an interleaved ascending order with a voxel resolution of 2.5 × 2.5 × 2.5 mm. A multiband acceleration factor of 4 was used. There were 4 runs of the change detection task with 335 volumes. Padding was used around the head to reduce head motion. The total scan duration was approximately 45 min.et al. [et al. [The aim of this study was to test whether an NFA region can be localized using the passive design used by Price & Ansari  and imaget al.  compensaet al.  but stil [et al.  also use2.4.p < 0.001. These maps were then corrected for multiple comparisons using the Monte Carlo simulation procedure to determine a minimum cluster threshold [α < 0.05. This cluster thresholding algorithm estimates and accounts for spatial smoothness and spatial correlations within the data . The functional images were corrected for head motion, low-frequency noise (high-pass filter with a cut point of two cycles per time point) and differences in slice time acquisition, and spatially smoothed with a 6 mm FWHM Gaussian kernel. The number of functional volumes acquired (335) exceeded the length of the behavioural task and was adjusted to 323 volumes for the second participant to match the duration of the task. However, this correction was not saved to the acquisition protocol and only that participant had this number of volumes acquired for functional runs. Therefore, the runs for the other 39 participants were trimmed to 323 volumes during pre-processing so that all runs had the same number of volumes. Three runs were excluded from further analysis because the participant's movement exceeded 3 mm over the total course of the run or 1 mm between volumes. An automatic alignment procedure using gradient-driven affine alignment in Brain Voyager was used to spatially align the functional data to the corresponding anatomical scan. Images were then spatially transformed to MNI-152 space. All contrast and conjunction analyses were run using voxel-wise general linear models and thresholded at an initial, uncorrected threshold of ata (see ).et al. [1.et al. [et al. [We ran a contrast similar to the one reported in Grotheer et al.  to test  [et al.  had addi2.To test whether there was a region in the ITG that is number-specific, we ran the more stringent conjunction analysis reported in Price & Ansari  to look 3.To test the alternative hypothesis that there is a region in the ITG that responds preferentially to familiar symbols, we ran a conjunction analysis to look for a region that responded to: (digits > scrambled digits) and (letters > scrambled letters).In order to resolve the discrepancy in the literature, we ran analyses reported previously in Price & Ansari  and Grotet al. . Therefo3.3.1.M = 99.12%, s.d. = 2.2%). We first ran the contrast reported by Grotheer et al. [Analysis of the behavioural results revealed that button press data were not recorded for three participants due to a technical error, so data from these participants were excluded from the analyses. Accuracy on the change detection task was high for all remaining participants  and (letters > scrambled letters). Results revealed bilateral clusters in the middle occipital gyrus that responded less to familiar characters than to scrambled symbols . This ag3.2.a priori region of interest (ROI) based on a recent meta-analysis by Yeo et al. [et al. which demonstrated significant activation in response to number symbols across studies, corresponding to the putative NFA , we ran additional analyses that were not included in the registered protocol to check the signal quality in our data. To investigate whether the absence of a region that responded specifically to viewing number symbols could be attributed to poor data quality and signal loss in the ITG, we took a two-step approach to determine the quality of data in an o et al. . A sphertive NFA . This ROtive NFA . To asseAs a second step, to determine the degree of signal dropout in this region, we employed a masking procedure using AFNI's 3dAutomask function to create a ‘brain-only' mask of each subject's mean functional image. We then determined the percentage of voxels within the NFA ROI that were excluded from the brain mask, serving as a measure of signal loss in this region. We assessed these data quantitatively by varying the signal intensity ‘clip fraction' parameter, from the default setting of 0.5  up to 0.75 (more conservative) . To summAs a final assessment, we sought to verify whether participants with a poor signal in the NFA ROI, relative to the group, influenced our activation results. We defined an exclusion criterion in which two conditions had to be true: (i) tSNR in the ROI was below 1 s.d. of the mean across our sample and (ii) the mean percentage of voxels excluded from the ROI was above 1 s.d. of the mean across our sample . Two participants met this criterion (P08 and P13). We then ran the same contrasts described above excluding these two participants from the analysis and the pattern of results remained the same . Figure 4.Despite mixed evidence for the existence of an NFA, it has been proposed that it is an important research direction for gaining insight into the organizing principles of vOTC, as well as mathematical learning and development ,5. The aImportantly, this study cannot rule out the possibility that a region in vOTC responds to numbers when participants are asked to engage in tasks that require identifying numbers. We used a passive viewing task because previous investigations successfully used similar tasks to locate other category-specific regions in the ventral visual stream, including the parahippocampal place area , the fuset al. [et al. [Goal-directed attention imposed by task demands may be required in order to engage neurons in vOTC in response to numbers. Recent studies have provided evidence that a region in vOTC activates preferentially to number symbols when participants are performing active numerical tasks –22. Resuet al.  probed t [et al.  systemat [et al. , but rat [et al. .Our results did not replicate Price & Ansari's  finding Future studies should investigate the modulation of vOTC by different task demands. There is mounting evidence that neural activation in response to number in vOTC seems to be engaged by semantic rather than perceptual processes (e.g. ,22,31,325.The results fail to support the theory that there exists a region in the vOTC that can be reproducibly localized and responds selectively to the visual presentation of number symbols during passive viewing. The current study failed to replicate previous reports of a putative NFA and corroborates a growing body of evidence that this region is not responsible for bottom-up visual processing of Arabic digits. Given that some reproducible localization is evident across active task paradigms, more work is needed to understand the function of this region and how it interacts with the network of regions involved in symbolic number processing.


Colorectal cancer (CRC) represents the second most common cancer worldwide and the third leading cause of cancer death. Most CRCs arise from premalignant colorectal lesions (mainly adenomas) that require years to develop an invasive disease. Early stage detection through the use of screening programs can sharply reduce CRC incidence and mortality allowing for better outcomes of the disease. The effectiveness of these programs may be strongly enhanced by targeting screening to individuals at higher risk.Tomlinson et al. [Gargallo et al. [CRC is a multifactorial disease resulting from complex interactions between environmental and genetic factors. A great progress in understanding the underlying genetic factors of CRC has been made in the past two decades. Since the first genome-wide association study (GWAS) on CRC risk published in 2007 by n et al. , more thDunlop et al. [Yarnall et al. [Jung et al. [Hsu et al. [. They observed that adding the GRS to prediction models increased discriminatory accuracy from 0.51 to 0.59 (P = 0.0028) in men and from 0.52 to 0.56 (P = 0.14) in women, compared to risk models based only on family history. Subsequent studies show similar results. Ibáñez-Sanz et al. reported a discriminatory accuracy value of 0.63 for CRC risk prediction model combining some modifiable risk factors , family history of CRC, and a GRS based on 21 susceptibility SNPs [Weigl et al. [Jeon et al. [Balavarca et al. [p = 0.0002).Nowadays CRC screening guidelines are based mainly on age and family history. However, the elaboration of prediction risk models including environmental and genetic risk factors may allow a more accurate selection of low-and high-risk patients. Improving risk stratification will optimize the use of invasive technology and increase adherence to screening programs. The first risk prediction models for CRC were performed based on family history, lifestyle factors, and environmental risk factors. However, recent studies showed an increasing interest in developing genetic risk scores (GRS), combining common genetic variants associated with CRC for a more personalised risk assessment. In this context, p et al. , Yarnalll et al. , and Jung et al.  developeu et al.  developeity SNPs . More reP = 0.002 in men aa et al.  after evAll these studies support the idea that adding genetic, environmental and lifestyle information into a CRC risk prediction model may significantly increase the discriminatory accuracy over models using only age and family history. Risk stratification could still be improved by integrating new discovered susceptibility SNPs to GRS as well as other relevant biomarkers such as epigenetic markers. Combining environmental, lifestyle factors and GRS in risk prediction models can help to tailor CRC prevention measures by adapting the onset age, nature and the intensity of CRC screening strategies.


Critical Care concluding that, while both plasma citrulline concentrations and glucose absorption were reduced in critical illness, fasting plasma citrulline concentrations were not predictive of subsequent glucose absorption and therefore do not appear to be a marker of small intestinal absorptive function [Poole et al. published in a relatively recent paper in function . It is afunction  demonstrfunction . Approxifunction . Synthesfunction . In the function  describefunction  that, defunction . In one function . Continu


An increased understanding of the biology of colorectal cancer (CRC) has fuelled identification of biomarkers with potential to drive a stratified precision medicine care approach in this common malignancy.We conducted a systematic review of health economic assessments of molecular biomarkers (MBMs) and their employment in patient stratification in CRC. Our analysis revealed scenarios where health economic analyses have been applied to evaluate the cost effectiveness of MBM-guided clinical interventions: (i) evaluation of Dihydropyrimidine dehydrogenase gene (DPYD) status to identify patients susceptible to 5-Fluouracil toxicity; (ii) determination of Uridine 5′-diphospho- glucuronosyltransferase family 1 member A1 gene (UGT1A1) polymorphism status to help guide irinotecan treatment; (iii) assessment of RAS/RAF mutational status to stratify patients for chemotherapy or Epidermal Growth Factor Receptor (EGFR) therapy and (iv) multigene expression analysis (Oncotype Dx) to identify and spare non-responders the debilitating effects of particular chemotherapy interventions.Our findings indicate that Oncotype Dx is cost-effective in high income settings within specific price points, by limiting treatment toxicity in CRC patients. DPYD status testing may also be cost effective in certain settings to avoid specific 5-FU toxicities post treatment. In contrast, current research does not support UGT1A1 polymorphism status as a cost-effective guide to irinotecan dosing, while the health economic evidence to support testing of KRAS/NRAS mutational status and chemo/EGFR therapy choice was inconclusive, despite its widespread adoption in CRC treatment management. However, we also show that there is a paucity of high-quality cost-effectiveness studies to support clinical application of precision medicine approaches in CRC. Within the UK, in 2015, almost 42,000 new cases of CRC were documented [et al Manuscript in Preparation).Globally, colorectal cancer (CRC) is the second most common cancer in women , and third most common in men ; and the annual number of deaths approaches 700,000  identifiAn increased understanding of the biology underpinning malignancy has indicated that many cancers, including CRC, are composed of a number of different molecular disease subtypes, which may show differing responses to therapeutic intervention. Identification of appropriate prognostic and predictive molecular biomarkers (MBMs), which can distinguish between these different subtypes, can assist clinical decision-making, such that patients receive the most appropriate treatment based on their molecular profile. This stratified or precision medicine approach has the potential to contribute to enhanced therapeutic efficacy, while minimising treatment-related toxicity.To identify MBMs of the required clinical utility, e.g. diagnostic (identifying cancer subtype), predictive (determining likelihood of response to therapy), or prognostic (indicating course of disease), analytical platforms are becoming more sophisticated, incorporating technologies such as gene expression profiling and next-generation sequencing. Interpretation of data generated from these platforms is performed using different bioinformatics approaches, adding to overall complexity . The Natet al. [BRAF and DNA mismatch repair status) and predictive (KRAS and NRAS) utility [et al. [For researchers and clinicians to embrace a MBM test, it must demonstrate analytical validity, clinical validity, and, most importantly, clinical utility . These pet al.  examined utility . Sepulve [et al.  also notDecision makers such as healthcare payers need to know both the financial and the health-related implications of introducing MBM testing. Limited information on the contribution to patient outcomes and societal benefit is often cited as the basis for lack of reimbursement for a particular MBM test . TherefoFollowing Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, this review is registered with PROSPERO (registration number: CRD42016038046) and the findings conform to that registration .5-Fluorouracil (5-FU) has been the backbone of chemotherapeutic regimens for CRC since the late 1950s. As part of our initial scoping search, we identified thirteen other drugs that have been approved by the Food and Drug Administration (FDA) for treatment of CRC since 1996 see .Our research question, formulated using the PICOS framework  was “What is the cost-effectiveness of using a MBM test for predicting response to therapy in CRC?”. PICOS was employed to develop a search limited to studies that performed economic evaluation of patients diagnosed with CRC, who were subsequently stratified for treatment selection by the result of a MBM test. Initially, a scoping search was performed to identify keywords and MeSH headings. Articles were identified by systematic literature search if they were published between 1 January 2006 and 31 December 2016. We searched MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, Econlit and SCHARR. Meeting presentations were also searched for the same time period in the American Society of Clinical Oncology (ASCO) and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) websites. Boolean operators were used to set up weekly searches of the above databases throughout the preparation of the review to keep it current, with the addition of Google Scholar alert searches at least 3 times per week until the end of 2018. All bibliographic references retrieved via the searches were exported to reference management software, and duplicates were removed before the study selection step.Articles were screened for eligibility based on the following criteria :Titles and abstracts of all articles were reviewed for eligibility and only accepted if the above criteria were met. Four reviewers  independently evaluated the full text of potentially eligible articles to determine whether to include these articles in this review. A lack of consensus over eligibility was resolved between the four reviewers. If doubts remained about the suitability of the study (such as academic posters which lack full peer review), we took the conservative approach of including these studies, so as to avoid missing potentially informative studies, while noting that they had not undergone full peer review.The integrity of each study was assessed according to a checklist developed by the ISPOR Consolidated Health Economic Evaluations Reporting Standards (CHEERS) Task Force Report . This unIn cases where more than one therapy were modelled, the reported ICER might not be compared to the base case, e.g. best supportive care (BSC). In these instances, we calculated the ICER based on reported costings and QALYs for the MBM test using the following formula:Where LYGs were reported, but not QALYs, and no health utility was reported then:The baseline health utility score of 0.8 was calculated from studies identified in our systematic review, which ranged from 0.71 to 0.87 for progression-free survival in CRC patients, which conforms with a published systematic review of health utility values for CRC . ConversFor each therapeutic intervention indicated, we listed the dates of FDA, European Medicines Agency, and National Institute for Health and Care Excellence (NICE) approval. We have identified the annual costs for each of these therapies, adjusted to 2016 £GBP and Euros using the CCEMG (Campbell and Cochrane Economics Methods Group) - EPPI (Evidence for Policy and Practice Information) - Centre Cost Converter . We haveCosts listed in n = 25) were removed. A total of 121 articles were then screened for eligibility. After full text examination, 25 articles were excluded as these reported CEAs that related to screening of families for hereditary CRC, which is not relevant to the research question being posed in this systematic review. A further 16 articles were either reviews or systematic reviews which were retained for reference, and 5 articles did not mention the terms LYG, QALY, or ICER. A total of 12 other articles did not include CBAs, CEAs, CMAs, or CUAs and 12 articles focused on CRC therapy alone, not taking into account the use of MBM tests to help guide therapy. On further examination, 7 articles were identified as duplicate studies (earlier abstract reports of the same study or versions of the same study published in other languages), a further 7 were abstracts without sufficient information, 3 articles involved a mixed population of cancer types which either included data already captured or aggregated data from which CRC-specific data could not be extracted, 1 study was an incomplete trial with insufficient data, and 5 were letters with insufficient detail for inclusion. In total, 14 eligible studies remained which involved economic evaluation of a MBM test for guiding therapeutic intervention in CRC.The Study Selection Workflow is outlined in We extracted empirical and methodological data and imported the data into Microsoft Excel. Extracted features included: author, year, country of study, CRC stage/metastases/not described, therapy, biomarker utilised, LYG, QALY, and ICER employed –2C. We aA quality rating for each study was determined (see Methods) which allowed us to assign a level of confidence in the strength of evidence for each study. The quality assessment was performed by one reviewer, checked by a second reviewer and any disagreement was resolved by the third and fourth reviewers.Data capture and quality analysis for each study of cost-effectiveness were represented in DPYD gene status in relation to 5-FU toxicity [DPYD gene. More than 80% of administered 5-FU is detoxified in the liver by DPD metabolism [toxicity . 5-FU istabolism .UGT1A1 testing to guide irinotecan dosing [n dosing –26. The n dosing .RAS (KRAS and NRAS) and BRAF, ) in relation to their use as prognostic/predictive MBMs in CRC. Tumours harbouring mutated forms of these genes are resistant to anti-epidermal growth factor receptor (EGFR) therapy [RAS (KRAS and NRAS) mutations occur in 53% of CRC patients [BRAF mutations in approximately 10% [RAS mutational status (KRAS and NRAS) before either treatment with an EGFR monoclonal antibody or chemotherapy treatment. therapy . RAS (KRpatients  and BRAFtely 10% . Most ofN = 8) involved RAS and BRAF testing prior to CRC treatment with cetuximab and panitumumab [The majority of health economic evaluations . The second HQO CEA for KRAS screening prior to panitumumab treatment (compared to BSC) came very close to the NICE threshold with an ICER of £30,607  and over 82 QALDs. The third HQA CEA for KRAS screening before cetuximab monotherapy (compared to BSC) generated an ICER above NICE’s threshold at £35,095  with 112 QALDs; however, these 3 studies were rated as medium-quality studies, as the report did not outline a structured summary, describe its analytical methods, or mention funding sources and conflicts of interest. The CEA from the Westwood et al. [et al. [et al. [KRAS testing prior to cetuximab treatment) and £48,999  (over 179 QALDs for combined KRAS and BRAF screening prior to cetuximab treatment), respectively. These ICERS were above the NICE threshold of £30,000 . The remaining studies were of medium to poor quality, missing important details when applying the CHEERS checklist.The results in l. study  both yied et al.  study re [et al.  and Blan [et al. , produceIn All studies undertaken were CEAs.Incremental costs relating to toxicities following 5-FU administration are indicated in UGT1A1 genotyping to guide irinotecan dosing, one study [et al. [In the CEAs detailing ne study  reportedne study , 24 repo [et al.  based thRAS (KRAS and NRAS) and BRAF testing utilised QALYs to calculate their ICERs. The exceptions are Behl et al. [et al, [In l et al.  and Vija [et al,  which emet al. [In et al.  calculatet al. [DPYD testing CEA. A decision analytic approach in combination with a Markov model was employed to assess resource use and health outcomes. The time horizon was 2 cycles of chemotherapy.Traoré et al.  did not UGT1A1 genotyping to guide irinotecan dosing was described from the perspective of the healthcare payer in 3 studies [et al. [et al. [The healthcare perspective for CEAs for  studies –25, wher [et al.  focussed [et al.  employed [et al. –26, withRAS (KRAS and NRAS) and BRAF BM testing to inform anti-EGFR therapy was modelled in 6 of 8 studies from the healthcare payer perspective  of 4  studies , 24 empl [et al.  while GoRAS/BRAF studies employed a discount rate, which ranged from 3-5%. Five (5) of 8 studies employed a health utility questionnaire; in 4 cases [Six (6) of 8  4 cases , 36, 38 Oncotype DX study employed a discount rate of 3% and used a health utility questionnaire, but the type of questionnaire was not specified  threshold was not employed.Three (3) out of 4 studies reported WTP thresholds, which range from €50,000 in 2013   to US$10et al. [et al. [Six (6) of 8 studies used a WTP threshold which ranged from a Canadian study  which seet al.  utilised [et al.  did not et al. [Alberts et al.  limited Sensitivity analyses were performed to test the degree of uncertainty in health benefits and costs. DSA tested parameters such as clinical effects, disease progression, QALYs and costs one at a time, while the superior PSA tested these parameters in combination.et al. [Traoré et al.  conducteet al. [et al. [et al. [et al. [UGT1A1 BM test.Gold et al.  and Butz [et al.  performe [et al.  and Pich [et al.  only perKRAS testing, cetuximab plus irinotecan was the most cost-effective therapy when compared to BSC. The DSA from Vijayaragharan et al. [KRAS WT patients in the population. The DSA used by Shiroiwa et al. [KRAS testing to be 62% cost-effective at a WTP threshold of ¥20 million . The PSA from Westwood et al. [KRAS testing strategies were almost equal.The PSA in the HQO paper  showed tn et al.  indicatea et al.  did not d et al.  did not et al. [et al. [KRAS and BRAF testing to be the dominant strategy at a WTP threshold of €10,000 to €40,000 , whilst at a WTP threshold greater than €40,000 , KRAS testing was dominant. The tornado plot by Harty et al. [et al. [The scenario analysis performed by Blank et al.  describe [et al.  also noty et al.  indicate [et al.  revealed [et al.  DSA detaMost studies which used a PSA approach , 36, 38 The DSA and PSA indicated that QALYs were sensitive to: (1) benefit of fluoropyrimidine monotherapy over surgery alone, (2) benefit of FOLFOX over fluoropyrimidine monotherapy, and (3) time preference discount rate.KRAS/BRAF test result. For panitumumab therapy, the average cost saving is £41,159  per patient per year.UGT1A1, which is used to guide the reduction of irinotecan dosing.KRAS MBM reduced the ICER for cetuximab from £142,515  to £109,452  in the Shiroiwa et al. study [As shown in l. study  and for l. study . HoweverKRAS (or BRAF) mutations. Two studies [et al. [From reported costs and positive effects  in three studies 32, 33, 35), we were able to generate ICERs  for chem, 33, 35, studies  resulted [et al.  while brUGT1A1*28 polymorphism occurs with higher prevalence in the African (42–56%) and Caucasian (26–31%) populations, than in Asian populations (9–16%). Consequently, the use of this biomarker leads to a ten-fold increase in Africans LYGs compared to Asian LYGs, when used to guide irinotecan treatment. However, even with this increase in LYG, this MBM is still not cost-effective [It is important to note that the ICERs for the MBMs evaluated in this systematic review are susceptible to the frequency of mutations in the general population. The ffective .The economic impact of MBM testing to guide therapy in CRC depends upon the cost of the therapeutic intervention and the price of the test, balanced against the clinical impact of the intervention and the degree of toxicity to the patient. So, if the net savings and QALYs are within a specific country’s WTP threshold, the value-based reimbursement of the MBM may help justify a stratified/precision medicine approach to cancer treatment .et al. [DPYD*2A screening prior to treatment, showed that genotyping marginally improves patient outcomes, and is also cost saving . The CEA by Traoré et al. [et al.’s study demonstrates that establishing DPYD screening in clinical practice in advance of 5-FU or capecitabine treatment may be cost-effective. On the evidence that we have presented and evaluated in this systematic review, DPYD screening is not only cost saving, but also spares patients the associated toxicities, although the overall net monetary benefit may be minimal.Deenen et al. , in a saé et al.  and DeenUGT1A1 may be cost saving, but our systematic review is inconclusive as to whether testing improves patient outcomes, with both positive [et al. [UGT1A1 genotyping to guide irinotecan dosing, and that any dose reduction should be based on clinical parameters, rather than UGT1A1 status.Three of the irinotecan studies –25 identpositive  and negapositive  QALYs be [et al.  stated tet al. [UGT1A1*1 homozygotes and UGT1A1*28 heterozygotes, with positive therapeutic results without the development of adverse effects; a RCT of this approach is ongoing [UGT1A1 status has yet to be defined [UGT1A1 genotyping to guide irinotecan dosing will most likely need to be revisited following the availability of results from RCTs such as the one highlighted above in order to determine its efficacy and cost-effectiveness.Lu et al.  attempte ongoing . As the  defined , UGT1A1 RAS (KRAS and NRAS) and BRAF mutations before anti-EGFR or chemotherapy administration has informed clinical decision making in CRC. Of the articles we identified, both the Canadian study by the HQO [et al. [KRAS WT guided therapy compared to BSC and chemotherapy respectively. However, where RAS (and BRAF) testing were used to select chemotherapy for patients with the mutated form of these genes [et al. [RAS family and BRAF mutation testing, the results overall were inconclusive as to whether precision medicine strategies are cost-effective when selecting CRC patients for anti-EGFR therapy. Although NICE’s WTP is set at £30,000, technology appraisals performed for end-of-life treatment guidance, have permitted costs to breach this threshold at an average of £49,000, implicitly suggesting a £50,000 WTP when end-of-life criteria are met. If this figure had been used as our benchmark in this metastatic CRC setting, then half of the studies would be classed as cost-effective [RAS/BRAF testing did prove to be cost-effective. The cost savings can be significant. For example, given that more than one million CRC patients in Europe are expected to develop metastatic CRC [RAS mutations, there is the potential to save £3 billion (€3.5 billion) over the lifetime of this patient cohort.Testing of patients with  the HQO  and the  [et al.  generatese genes , 34, ICE [et al.  resulted [et al.  but reco [et al. . From thatic CRC , 51, witRAS (and BRAF) testing can only be cost-effective when selecting patients who should receive chemotherapy, but not those who receive EGFR therapy, based on the result of their molecular assay.When MBM guided anti-EGFR therapy is compared to anti-EGFR therapy alone, there is a pronounced increase in the ICER values, but the QALYs produced are only marginally different. Thus, et al. [et al. CEA [The initial economic analysis of the Oncotype DX assay was generated by data from the National Comprehensive Cancer Network and concluded that the assay would improve patient outcomes (QALY = 0.035), and decrease costs by $3,000 for stage II, T3, proficient DNA mismatch repair CRC patients . In the et al. , a largeet al.  and a QAet al. , and altet al. , the laret al. . An econet al. . Althoug al. CEA  was base al. CEA , and fav al. CEA –56 indicUGT1A1 MBM, while the remaining 4 investigated the KRAS MBM. We captured all 7 of these articles but excluded the study by Mittman et al. [UGT1A1 testing prior to irinotecan administration remains unresolved, whilst using KRAS genotyping to stratify patients before anti-EGFR treatment was cost-effective. The second systematic review, by Westwood et al. in 2014 [KRAS testing of CRC tumours. Its literature search found 5 articles, which we also identified, and the authors concluded that the ICER for KRAS mutation testing to guide anti-EGFR therapy was large. However, although they performed a CEA and found KRAS testing to be cost-effective, their results should be interpreted with caution as a number of assumptions were made in relation to resection rates, MBM test use, etc. The third paper by Guglielmo et al. [et al. [KRAS testing to guide anti-EGFR therapy were inconclusive. The fourth review by Seo and Cairns [et al. [KRAS testing is always more cost-effective, even if this is not always the case for anti-EGFR therapies. However, we draw different conclusions from the data for the irinotecan studies, finding UGT1A1 testing not to be cost-effective.There have been four previous systematic reviews on the economic analysis of MBM approaches in CRC in the personalised/precision medicine setting. The first was performed by Frank and Mittendorf in 2013 . They idn et al.  because  in 2014 , was a ho et al.  identifi [et al.  which th [et al.  or Japan [et al.  studies d Cairns  identifi [et al. . Our finUGT1A1, because our analysis indicates that there is enough evidence to support the assertion that the use of UGT1A1 genotyping to reduce irinotecan dosing is not cost-effective. Despite being able to select patients to receive chemotherapy, our findings suggest that there is insufficient evidence to indicate KRAS (and BRAF) testing is cost-effective, in the context of EGFR therapy.We disagree with the Frank and Mittendorf systematic review on the lack of evidence to make a decision on the cost-effectiveness of PIK3CA mutated tumours benefit from exposure to aspirin, whereas PIK3CA wild-type patients do not [Fusobacterium nucleatum may counteract MSI-H positivity with associated immunosuppressive effects [RAS, BRAF, PIK3CA, MSI-H, and F.nucleatum positivity in a cost effective manner to precisely guide anti-EGFR therapy, aspirin therapy, and immunotherapy in mCRC. This challenge is becoming increasingly relevant as treatment algorithms incorporating multiple biomarkers become more common place and techniques such as whole genome sequencing enters clinical practice.It is evident that not all CRC patients currently benefit from precision medicine MBM-informed therapy, as is the case for the 53% of RAS mutant mCRC patients not eligible for anti-EGFR treatment . The emes do not . Microsa effects , 65. TheDPYD screening could be cost-effective in high-income settings, if it is implemented before 5-FU therapy. Likewise, Oncotype DX assay is likely to be cost-effective in identifying patients who will not benefit from chemotherapy. We were unable to find evidence to support UGT1A1 testing to guide irinotecan dosing. Perhaps more controversially, despite its adoption in many countries globally, we found that the cost-effectiveness data currently available to support anti-EGFR treatment based on RAS/BRAF mutational status is inconclusive.There is a paucity of high-quality CEAs that evaluate MBM in CRC. Unless CEA is incorporated prospectively into clinical trial design, economically unsubstantiated results can obscure the best available evidence, undermining both methodological approaches and resources. In summary, we found that the cost-effectiveness of MBM approaches to guide CRC therapy is highly variable. The evidence from our review suggests that The evidence presented here reflects a need for a more rigorous methodological CEA-driven approach to be prospectively employed. There also needs to be greater transparency on prices used in CEA, so as to ensure the delivery of value-based care in a disease that kills nearly 170,000 Europeans every year.


Methylococcus capsulatus (Bath)’ by Hannah R. Adams et al., Chem. Sci., 2019, DOI: ; 10.1039/c8sc05210g.Correction for ‘One fold, two functions: cytochrome P460 and cytochrome c′-β from the methanotroph  The authors regret an error in the listing of one of the authors, Tadeo Moreno-Chicano, in the original manuscript. The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Endoscopic video sequences provide surgeons with direct surgical field or visualisation on anatomical targets in the patient during robotic surgery. Unfortunately, these video images are unavoidably hazy or foggy to prevent surgeons from clear surgical vision due to typical surgical operations such as ablation and cauterisation during surgery. This Letter aims at removing fog or smoke on endoscopic video sequences to enhance and maintain a direct and clear visualisation of the operating field during robotic surgery. The authors propose a new luminance blending framework that integrates contrast enhancement with visibility restoration for foggy endoscopic video processing. The proposed method was validated on clinical endoscopic videos that were collected from robotic surgery. The experimental results demonstrate that their method provides a promising means to effectively remove fog or smoke on endoscopic video images. In particular, the visual quality of defogged endoscopic images was improved from 0.5088 to 0.6475. The endoscope provides surgeons with real-time endoscopic video sequences that are shown on medical displays. On the basis of endoscopic vision or surgical field from these images, surgeons can directly visualise and examine abnormal tissues and treat or resect tumours in the body.Unfortunately, the visual quality of endoscopic video images is unavoidably degraded because of surgical smoke or fog during robotic surgery. These endoscopic foggy images Fig.  are geneEndoscopic field defogging methods generally consists of hardware- and software-based strategies. While the former uses typical devices to remove smoke, the latter is algorithmic, i.e. computational photography techniques. This work develops a new luminance blending strategy for surgical video defogging. It combines a contrast enhancement procedure with a fast visibility recovery method to remove fog or smoke on endoscopic video sequences. We also quantitatively and objectively evaluate the experimental results of using our proposed method and others. The main contributions of this work are two-fold: (i) a new luminance blending approach with better performance than other defogging approaches and (ii) an objective image quality metric for quantitative assessment of dehazed images.The remainder of this Letter is organised as follows. Section 2 briefly reviews work related to current dehazing methods. Our hybrid luminance blending-based dehazing method for vision augmentation is presented in Section 3, followed by the experiment settings in Section 4. Sections 5 shows and discusses the validation results before concluding this work in Section 6.2Real-world natural image and video dehazing or defogging techniques are widely discussed in computer vision and computational photography in the literature. Fattal  presenteet al. [et al. [et al. [et al. [et al. [While He et al.  proposed [et al.  employed [et al.  estimate [et al.  discusse [et al.  proposed [et al.  presente [et al. .et al. [et al. [et al. [et al. [More recently, deep learning-driven methods are increasingly developed for single image dehazing. While Ren et al.  employed [et al.  proposed [et al.  develope [et al.  introducAlthough these methods work well on natural images, they remain challenging to deal with surgical endoscopic video image fog or smoke, particularly in the case of inhomogeneous or thick haze. This work aims to address the problem of hazy images or videos with inhomogeneous or thick haze, particularly foggy endoscopic videos.3This section details our luminance blending framework for surgical endoscopic video defogging. Our method contains several steps: (i) contrast enhancement, (ii) visibility recovery, and filtering, and (iii) luminance blending. Fig. 3.1Surgical foggy images are of low-contrast and limited illumination, especially in hazy regions. The goal of contrast enhancement is to improve the contrast of hazy-less regions on the endoscopic image and calculate the luminance The contrast enhancement step assumes (i) most regions on the foggy image are hazy pixels that critically affect the mean of the foggy image and (ii) the level of haze in these regions depends on the distance between the atmospheric light and the scene, as discussed in . On the lated by (2)\docu3.2k and A widely used physical imaging model is established for hazy images by Koschmieder's law (3)\docuOn the basis of , we aim entclass1pt{minimaA∞.Then,  can be rmulation . The metentclass1pt{minimaSince the result The bilateral filter is an edge-aware image processing method to denoise and simultaneously preserve edge information , 16. Thectively) (7)\docu3.3This step is to estimate illumination on image Y-component or luminance component of them, we used recursive filtering [Y-component We transfer the images iltering  to estim4Foggy endoscopic videos were acquired from robotic surgery. All the experiments were executed on a laptop installed with Windows 8.1 Professional 64 bit system, 32.0 GB memory, and processor Intel(R) Xeon(R) CPU et al. [et al. [et al. [et al. [et al. [We compare the proposed method with the following approaches: (i) M1, Tarel et al. , (ii) M2 [et al. , (iii) M [et al. , (iv) M4 [et al. , (v) M5, [et al. , and (viWe introduce a naturalness metric to depict how natural surgical images appear based on statistically analysing thousands of images . On the 5Fig. Table Additionally, the computational times of the methods M1, M3, M4, M5, M6, and M7 were 31.3, 62.3, 1.3, 5.2, 75.6, and 1.1 s/frame, respectively. Method M2 deals with an image in more than 2700 s since soft editing was extremely slow [This work aims to enhance the surgical field visualisation of endoscopic surgery. We developed a new luminance blending defogging algorithm. The experimental results demonstrate that our algorithm outperforms others from subjective and objective evaluations. The effectiveness of our algorithm lies in fusing the advantages of the enhancement and restoration dehazing methods. Our method has several potential limitations including unclear parameter sensitivity, effective enhancement, quality assessment, and heavy processing time. These limitations will be further investigated in the future. In addition, though our method works better than other approaches, it still introduces colour distortion, which will be further investigated.6We proposed a new luminance blending defogging framework that integrates contrast enhancement, joint bilateral filtering, and visibility recovery to remove smoke in endoscopic videos from robotic surgery. We evaluated our method on endoscopic video sequences acquired from robotic prostatectomy. The experimental results demonstrate the effectiveness of our proposed method, which outperforms other approaches. In particular, our method improved the hybrid quality of the dehazed results from 0.5088 to 0.6475.


Frontotemporal dementia (FTD) is a neurodegenerative disorder clinically characterised by progressively worsening deficits in behaviour, personality, executive function and language . Clinicaper se from those that may be responsible for parkinsonian symptoms, Di Stasio et al. (2018) [The pathophysiological mechanisms responsible for parkinsonism in FTD were specifically investigated in a transcranial magnetic stimulation (TMS) study by Di Stasio et al. (2018)  that was. (2018)  examined. (2018) . By contSeveral research issues in the pathophysiology of FTD have yet to be fully investigated and clarified. The neurophysiological abnormalities reported in the FTD patients studied by Di Stasio et al. (2018)  are not


There are errors the Funding statement. The correct Funding statement is as follows:RN is a Ph.D. grant holder from FRIA-FNRS (Fond pour la Formation et la Recherche dans l’Industrie et dans l’Agriculture). MM is a "Maître de Recherche" at the "Fonds National de Recherche Scientifique". This study was supported by ULiège-ARC program  as well as the University Foundation of Belgium (AS-0265). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


In the field of artificial intelligence (AI), developments are leading to a new era involving its social implementation. In 2006, Hinton et. al. reported that high-dimensional data can be converted into low-dimensional codes by training a multilayer neural network with a small perceptron . This di