Antioxidant peptides are gradually being accepted as food ingredients, supplemented in functional food and nutraceuticals, to positively regulate oxidative stress in the human body against lipid and protein oxidation. Meat muscle and meat by-products are rich sources of proteins and can be regarded as good materials for the production of bioactive peptides by use of enzymatic hydrolysis or direct solvent extraction. In recent years, there has been a growing number of studies conducted to characterize antioxidant peptides or hydrolysates derived from meat muscle and by-products as well as processed meat products, including dry-cured hams. Antioxidant peptides obtained from animal sources could exert not only nutritional value but also bioavailability to benefit human health. This paper reviews the antioxidant peptides or protein hydrolysates identified in muscle protein and by-products. We focus on the procedure for the generation of peptides with antioxidant capacity including the acquisition of crude peptides, the assessment of antioxidant activity, and the purification and identification of the active fraction. It remains critical to perform validation experiments with a cell model, animal model or clinical trial to eliminate safety concerns before final application in the food system. In addition, some of the common characteristics on structure-activity relationship are also reviewed based on the identified antioxidant peptides. At the karyotes . Oxidati smoking . Superfl smoking ,6.In the human body, the cell employs a panel of enzymatic and non-enzymatic defense mechanisms to counteract oxidative and nitrosative stresses. The endogenous enzymes of superoxide dismutase (SOD), catalase, peroxidases, and thioredoxin are responsible for scavenging free radicals and natural antioxidants and also play a vital role in oxidative defense systems such as ascorbate, glutathione, tocopherol, flavonoids, alkaloids, and carotenoids ,8,9. OncMeat protein is thought to be a good source from which to obtain antioxidant peptides, because meat proteins contain essential amino acids in high availability that are not usually found in plant proteins, such as methylhistidine and hydroxymethyllysine. The well-known antioxidant peptides of carnosine and anserine exist endogenously in muscle tissue, acting as free radical scavengers and metal ion chelators . In addiThe antioxidant hydrolysate and peptides generated from meat proteins are summarized in Raw meat of chicken could exert antioxidant capacity by direct extraction . The hydThe extraction buffer of Chinese Jinhua ham and Spanish dry-cured ham was 0.01 N HCl while the Xuanwei ham was extracted with 0.2 mM phosphate buffer at pH 7.2 . Crude eBacillus polymyxa [Enzymatic hydrolysis of target proteins is the most commonly used method for producing antioxidant peptides and hydrolysate. The mechanism is that hydrolysis releases the more active acid R groups which are inactive in parental proteins and promote hydrophobicity due to unfolding protein chains . Table 1polymyxa . Different enzymes have specificity for cleavage of individual patterns of the peptide bond . TherefoMeasuring the antioxidant capacity is an essential process in validating the functional property of enzymatic hydrolysates or crude solvent extracts in order to determine which fractions of the purification step would be subject to purification using mass spectrometry analysis and identification of amino acid sequence of peptides . MethodsGenerally, based on the chemical reaction involved, the aim of these assays is to relatively quantify the hydrogen atom donating, electron transferring, or metal ion chelating ability of the target substrate . The maj2•−), hydroxyl (•OH), peroxyl (ROO•), and alkyl radical scavenge capacity and is widely employed by researchers [2•−, and ROO•. The principle of ESR spectroscopy is that the electron subjected to an applied magnetic field causes the energy to decrease or increase correlated parallel or antiparalled to the direction of the magnetic field [Apart from the aforementioned methods, the ability of peptides to scavenge the individual ROS is also an alternative to evaluating the antioxidant capacity. This category of methods includes the superoxide anion  to subject to oxidant stress by incubating with 1 mM tert-butyl hydroperoxide (t-BHP) in the presence and the absence of purified peptides . MTT assd-galactose to determine in vivo antioxidant ability of chicken protein hydrolysate [d-galactose induced aging mice group thus indicating the antioxidant properties of purified peptides. The positive effect of antioxidant peptide on human health promotion concerns the following factors: intestinal digestion of peptide, absorbed into the intestinal lymphatic system and finally transported to the target sites . The anirolysate . PeptideProtein hydrolysates or crude peptide extracts possess antioxidant capacity to a limited extent and contain the various sizes of peptides and amino acid composition with either inactive or active activity. In order to get to know the structural characteristics of peptide mixtures and further increase the antioxidant capacity of end-products for application and commercialization, it is essential to isolate single bioactive peptides, which thus involves the purification and identification steps . The tecWe have used the above mentioned methods and successfully isolated a bioactive peptide with high antioxidant capacity from Xuanwei ham . A crudeIt is of great importance to extract all available information on the structure-activity relationship of antioxidative peptides derived from meat proteins, to provide guides and predictions for evaluating bioactive peptides from certain proteins based on the amino acid sequence and the cleavage bonds of the enzymes. Though the exact mechanism of the antioxidant activity of peptides has not yet been fully understood, several common characteristics of peptides that possess considerable antioxidant capacity have emerged. The peptide sequences and corresponding molecular weights derived from animal proteins and by-products are summarized in 50 value of 0.532 mg/mL. Wang et al. separated the porcine plasma albumin and globulin hydrolysate by Alcalase into five groups  according to the molecular weight by sequential ultrafiltration and assessed their antioxidant capacity [The common feature of the identified peptides shows a size of 4–16 amino acids, and a molecular weight of approximately 400–2000 Da . Escudercapacity . They cocapacity . Finallycapacity ,60,61. Fcapacity . The fracapacity . The molecular weight also affects the routes by which bioactive peptides transfer into target sites . Small mIt is noteworthy that free amino acids could also exhibit antioxidant capacity in the decreasing order of Trp, Tyr, Met, followed by Cys, His, Phe with no antioxidant property in the remaining amino acids . HoweverN-terminus of the sequence, with strong scavenging ability on DPPH, OH−, and superoxide. These also occur in the peptide of HFGDPFH purified from fermented marine blue mussel [N-terminus could contribute to the antioxidant capacity. In order to further observe the effect of His-containing peptide on peptide bioactivity, Chen et al. designed a total of 28 synthetic dipeptides, tripeptides, and tetrapeptides based on a pentapeptide of LLPHH isolated from soybean protein hydrolysate [N-terminal NRVY sequence had a predominant effect on determining the reactivity of His residue compared to the remaining tetrapeptides of IHPF [The category of aromatic amino acids contains tyrosine (Tyr), histidine (His), tryptophan (Trp), and phenylalanine (Phe). The amino acids can donate protons to the electron deficient radicals contributing to the radical-scavenging properties of the amino acid residue . The Hise mussel  and HGPLe mussel , suggestrolysate . In the rolysate . The ami of IHPF . In addi of IHPF . Hydrophobic amino acids include alanine (Ala), isoleucine (IIe), leucine (Leu), proline (Pro), Phe, Tyr, and Trp. Despite the priority of Phe, Tyr, and Trp as hydrogen donors, the hydrophobic amino acids could increase the presence of peptides at the water-lipid interface and then access to scavenge free radicals from the lipid phase . Ohata eThere are two acidic amino acids of aspartic acid (Asp), glutamic acid (Glu) and three basic amino acids of arginine (Arg), lysine (Lys), and His. They utilize carbonyl and amino groups in the side chain which function as chelators of metal ions . We puriThe main benefit of developing an innovative and safe antioxidant peptide is to use to protect the human body from damage of oxidative stress as well as the risk of various degenerative diseases. The commercialized uses of antioxidant peptides are spread over the fields of functional foods, nutraceuticals, and cosmeceuticals. There is already a range of antioxidant peptides which is allowed to be incorporated into foods in the form of additives in some countries such as Japan and USA. However, popularization of antioxidant peptides derived from animal proteins still has a long way to go. It has been confirmed that identified peptides can exhibit strong antioxidant capacity in vitro. The lack of animal model experiments and human clinical trials has limited the progress in testing the bioavailability and then application in the consumer market. Thus, further research should be conducted to investigate the potential effects of bioactive peptides in vivo. In addition, the structure-activity relationship of peptides has not been fully established and little is known at present of the structural information of antioxidant peptides from the various protein sources.


Poliovirus transmission has been eliminated in most of the world through the use of inactivated poliovirus vaccine (IPV) and live, attenuated oral poliovirus vaccine (OPV). In the United States, use of OPV was discontinued by the year 2000 because of the potential for vaccine-associated paralytic polio (VAPP); an average of eight cases were reported each year in the United States during 1980–2000  but is not used in the United States because of the low prevalence of TB in the general population and the fact that BCG vaccination complicates the interpretation of TB skin tests. However, OPV and BCG vaccine recipients who are in the United States as visitors or immigrants might present their health care providers with complex medical issues related to vaccines other than those recommended by CDC and the American Academy of Pediatrics.BCG, a live vaccine strain of A boy from India aged 7 months was brought to a community hospital emergency department in San Antonio, Texas, in early July 2013. His parents reported that he had a 6-week history of intermittent fever associated with a draining skin lesion over the left deltoid at the site of BCG vaccination. The child was diagnosed with acute lymphadenitis, prescribed trimethoprim/sulfamethoxazole, and sent home.The child again was brought to the emergency department with increased irritability and decreased movement of the left leg, and was admitted to the hospital for further evaluation. The child appeared tired and anxious but was responsive to touch. The physical examination was negative for meningeal signs, no evidence of respiratory distress was found. A firm, mobile, tender, 2×2-cm mass was palpated under the left axilla. The child did not move his left leg spontaneously or in response to pain. Deep tendon reflexes were absent in the left leg and diminished in the right. Decreased anal sphincter tone was noted. The rest of the physical examination was noted as normal for age.Laboratory, imaging, and microbiologic studies were conducted . ImmunolM. bovis, confirming a diagnosis of BCG-osis (disseminated BCG infection). Genetic studies eventually confirmed the diagnosis of RAG-1 deficient SCIDS with homozygous mutation. Family history revealed the child’s older sibling died in infancy after rotavirus vaccination. Parental consanguinity and recurrent pregnancy losses in the mother were also reported. Chromosome microarray yielded homozygosity for >10% of the genome. The child progressed to respiratory distress during further observation. After consultation with multiple specialist physicians and with ethics committee review, the family chose to withdraw support, and the child died shortly thereafter.With the history of two additional OPV vaccinations during national immunization days in India, a diagnosis of VAPP was considered. The stool culture was subsequently identified as iVDPV type 1 (iVDPV1). The nonrecombinant iVDPV1 isolates had 10- 12 nucleotide substitutions from Sabin 1 vaccine virus in the 906- nucleotide VP1 capsid protein coding region. This result is consistent with initiation of a period of prolonged virus replication after receipt of the first OPV dose, based on the rate of evolution of approximately 1% per year  infection (BCG-osis). The infant had been vaccinated with oral poliovirus vaccine and BCG in India.What are the implications for public health practice?Primary health care providers in the United States should recognize the potential for live viral vaccine diseases, such as vaccine-associated paralytic poliomyelitis and BCG-osis, in foreign-born children recently arrived from abroad. By being vigilant, vaccine-associated diseases can be diagnosed early, the spread of disease can be prevented by immunization of exposed persons in the community and among contacts, and appropriate treatment can be given in a timely manner to minimize suffering and reduce morbidity and mortality.


The objective of this study is to compare and evaluate the effectiveness of implant placement and patient appraisal for two sinus lift techniques using both crestal and lateral techniques for bilateral sinus left in a split-mouth design.All implants were successfully osseointegrated without any clinical complications or peri-implant radiolucency during the follow-up period of maximum 3 years.In terms of outcomes postoperative vertigo showed to be a major concern with the crestal approach, this approach is preferred over the lateral technique because of the reduced time required for the procedure and because it is less invasive.Most patients preferred the crestal approach over the lateral approach due to the delay in implant placement. The limitations of dental implant placement in the posterior maxilla, due to alveolar ridge resorption and excessive maxillary sinus pneumatization, can be overcome by maxillary sinus floor elevation .Split-mouth designs first appeared in dental clinical trials in the late sixties. The main advantage of this study design is its efficiency in terms of sample size as the patients act as their own controls. Cited disadvantages relate to carry-across effects, contamination or spilling of the effects of one intervention to another, period effects if the interventions are delivered at different time periods, difficulty in finding similar comparison sites within patients and the requirement for more complex data analysis. Although some additional thought is required when utilizing a split-mouth design, the efficiency of this design is attractive, particularly in oral implantology studies where carry-across, period effects and dissimilarity between intervention sites does not pose a problem. Patients requiring both crestal (osteotome sinus floor elevation) and lateral antrostomy procedures on either side of the maxilla, as per current practice guidelines, constitute a very rare group. The quality and quantity of the maxillary residual ridge is the key factor in deciding between the two techniques in all patients . ClinicaThe aim of this study was to compare and evaluate the effectiveness of implant placement and patient appraisal for two sinus lift techniques using both crestal and lateral techniques for bilateral sinus left in a split-mouth design by using the outcome variables for a visual analog scale (VAS) score for each question as patients’ symptoms, and peri-implant soft tissue conditions for both the lateral and crestal approaches.21, [An approval for the study was granted by the Hospital Ethics Committee with a protocol number: kfmmc-dd18/05/2011 The participants were informed about the aims and protocol of the study, and they provided proper consent. All bilateral sinus lift cases during the period from 2006 to 2012 were considered. Patients were selected according to the inclusion and exclusion criteria shown in Table 1, . Pre-ope1, . Patient3The analysis of the data was performed using SPSS software, version 20.0. The results of the numeric responses are presented as the means ± standard deviations. The average VAS score for each question as patients’ symptoms for both sides were calculated and analyzed using Mann Whitney test. A timeline which was comparable for each surgical procedure was also recorded. At the annual clinical examination following functional loading, the survival of the implants and reconstructions were evaluated. Using two tailed T test, the averages of peri-implant soft tissue conditions for both the lateral and crestal approaches were evaluated clinically and radiographically.4et al. criteria [A total of 20 sinuses lift procedures were performed in 10 patients. The mean follow-up period was 36 months after permanent prosthetic insertion. No complications with the surgical procedures were recorded, including infection of the maxillary sinus, loss of bone particles through the nose, wound dehiscence, and/or loss of the implants’ initial stability. All of the implants were stable at the latest follow-up, and all of the prostheses were functional. During the follow-up period, no pain or swelling were noted in any of the cases before or after prosthetic loading. All of the implants successfully fulfilled the Buser criteria .Apical elevation of the sinus floor for both approaches was observed. Conventional radiography proved bone/graft maturation around the implant apex in cases completed with the lateral approach, while for crestal (OSFE), no marked evidence was seen of bone formation between the lifted sinus membrane and the implant apex. There are no statistically significant differences in the marginal bone levels measured during radiological assessment between the lateral window and the OSFE implants. Pocket probing depth PPD is used to measure the distance between implant shoulder and mucosal margin DIM. Distance between implant shoulder and first visible bone implant contact DIB were analysed to compare the implant survival showed insignificant p values 0.0504, 0.7784, 0.1817 respectively.1). Radiological evidence of the presence of bone over the implant apex was proved by CT scans. On periapical radiographs, bone formation at the apex of the implant was not always confirmed in the OSFE cases, whereas with the lateral technique, sufficient bone could be observed above the implant apex. One of our ten cases had a membrane perforation during the lateral approach in this study. After three years of prosthetic loading, periapical radiographs showed a stable clinical situation in the area around the apices of the implants on both sides.CT scans were performed in all of the patients, confirming the amount of bone gained bilaterally by both techniques, as shown on right and left coronal CT scans . Because this was a split-mouth study, the comparison of both techniques in the same patient proved that the symptoms seen in the OSFE group alone may be specific to the technique. The crossover effect of learned memory in the split-mouth design was one of the limitations of this study [et al. [No peri-implant radiolucency was noted in any of the cases  based questionnaires listing the symptoms and complications in two stages, and the questionnaire was evaluated by a neutral analyst. As shown in Table et al. criteria [Patients who experienced OSFE-associated symptoms during and after the OSFE did not experience any of these symptoms with the lateral approach. However, all of the patients recovered from these symptoms after 30 to 60 minutes. It was interesting to note that none of the patients were concerned about this transient discomfort, based on their responses. Although a delay in implant placement was the main reason for preferring OSFE over the lateral approach, the lateral approach was the choice of patients who feared the development of such symptoms and of patients who could not tolerate the discomfort of hammering. This finding also emphasizes the importance of disclosing all vestibular symptoms when presenting the OSFE procedure to the patient. The quality of the bone formed when replacing the bone graft with the lateral approach was different from the bone formed around the implant with the OSFE approach , 15. Howcriteria . This wacriteria . This reMaxillary sinus floor elevation with both the crestal and OSFE techniques could be evaluated precisely when both techniques were performed in the same patient. Although the small sample size for a split-mouth study was a limitation, the specific advantages, disadvantages and indications for each technique could be distinguished. The split-mouth design is a popular design in oral health research. The attractiveness of the design is to remove a lot of inter-individual variability from the estimates of the treatment effect.


We present a case of a seventeen-year-old patient, admitted in the care of the surgical team following inhalation of nitrous oxide at high pressure, leading to extensive pneumomediastinum and surgical emphysema. We discuss the subsequent investigations and management for this patient. In the absence of history of airway injury and respiratory problems including asthma and with no oesophageal perforation on investigations, the diagnostic and management challenges encountered have been discussed which will help in future management of similar cases. Surgical emphysema is the presence of air in tissue. It is due to the breach of an air containing viscous which is in communication with soft tissue and the generation of positive pressure that pushes the air along the tissue plains. Causes of pneumomediastinum and surgical emphysema include iatrogenic airway injuries , asthma (ruptured bullae), oesophageal perforations (iatrogenic or spontaneous), and blunt or penetrating chest trauma –5. The mA case of surgical emphysema following high pressure ventilation with nitrous oxide and anaesthesia has previously been reported ; howeverA seventeen-year-old African American male was taking nitrous oxide under high pressure via balloon inhalation at the time of a music festival and also two days prior to the event. He admitted to inhaling approximately fifty balloons worth of gas in total. He had also taken one MDMA (ecstasy) tablet. He noted swelling of the neck with pain and discomfort and presented to the accident and emergency department of the local hospital. The patient denied dysphonia, shortness of breath, and chest pain. On examination his observations were stable. He was saturating at 98% on 2 litres of oxygen. There was marked bilateral neck swelling, extending to the right chest wall and his entire right arm down to his wrist. There was easily palpable crepitus of the aforementioned areas. The airway was central and patent, chest was clear, and there was equal bilateral air entry as well as normal chest wall expansion. Heart sounds were also normal.A chest X-ray demonstrated extensive pneumomediastinum of the chest wall and neck, affecting the anterior chest wall, and subcutaneous emphysema can outline the pectoralis major muscle, giving rise to the ginkgo leaf sign .A CT scan  with intThe patient was admitted for observation in case of clinical deterioration and potential infection. Although he remained stable and well in himself, the considerable pneumomediastinum seen on initial imaging, combined with concern that this young otherwise healthy patient might be compensating and hence masking a more serious underlying condition, in particular, oesophageal perforation, led to a water soluble (gastrografin) swallow being requested. This revealed no leak of contrast outside the gastrointestinal tract. Given the recent history, a diagnosis of barotrauma with subsequent pneumomediastinum secondary to nitrous oxide inhalation was established.The patient was discharged home under care of his parents three days after admission. He was strongly advised against future use of the gas for recreational purposes and was told to avoid any contact sports for a duration of six weeks. His subcutaneous emphysema got much better at day 3 on discharge. At 2-week clinic follow-up, it had completely resolved.Multiple causes of surgical emphysema and pneumomediastinum have been published –4. CauseSpontaneous pneumomediastinum commonly occurs when an increased intra-alveolar pressure leads to the rupture of the marginal pulmonary alveoli. The air released ascends along the bronchi to the mediastinum and the subcutaneous space of the neck causing cervicofacial subcutaneous emphysema . SurgicaHigh airway pressure could have resulted from copious balloon inhalation of nitrous oxide in our patient, leading to rupture of the marginal alveoli.Nitrous oxide inhalation is a well established anaesthetic technique. It has a long history of safety in medicine and dentistry. However, it is known to cause neurological deficit by reducing the activity of vitamin B12 dependent enzymes in long-term use. The minimum concentration and duration of exposure at which this influence becomes significant are at present not known . Pneumom


Soybean canopy outline is an important trait used to understand light interception ability, canopy closure rates, row spacing response, which in turn affects crop growth and yield, and directly impacts weed species germination and emergence. In this manuscript, we utilize a methodology that constructs geometric measures of the soybean canopy outline from digital images of canopies, allowing visualization of the genetic diversity as well as a rigorous quantification of shape parameters. Our choice of data analysis approach is partially dictated by the need to efficiently store and analyze large datasets, especially in the context of planned high-throughput phenotyping experiments to capture time evolution of canopy outline which will produce very large datasets. Using the Elliptical Fourier Transformation (EFT) and Fourier Descriptors (EFD), canopy outlines of 446 soybean plant introduction (PI) lines from 25 different countries exhibiting a wide variety of maturity, seed weight, and stem termination were investigated in a field experiment planted as a randomized complete block design with up to four replications. Canopy outlines were extracted from digital images, and subsequently chain coded, and expanded into a shape spectrum by obtaining the Fourier coefficients/descriptors. These coefficients successfully reconstruct the canopy outline, and were used to measure traditional morphometric traits. Highest phenotypic diversity was observed for roundness, while solidity showed the lowest diversity across all countries. Some PI lines had extraordinary shape diversity in solidity. For interpretation and visualization of the complexity in shape, Principal Component Analysis (PCA) was performed on the EFD. PI lines were grouped in terms of origins, maturity index, seed weight, and stem termination index. No significant pattern or similarity was observed among the groups; although interestingly when genetic marker data was used for the PCA, patterns similar to canopy outline traits was observed for origins, and maturity indexes. These results indicate the usefulness of EFT method for reconstruction and study of canopy morphometric traits, and provides opportunities for data reduction of large images for ease in future use. Glycine max (L.) Merr.] is a leguminous plant and an important source of protein and oil for a wide range of end users across the world. Given the recent rate of climatic change and predictions for worsening environmental conditions, coupled with a growing global population . The images produced 8 GB of data. We deployed the analysis framework to reduce the useful storage size required while retaining information related with canopy outline, and evaluate shape descriptors/traits to investigate shape diversity among the lines. This paper represents the first stage of our analysis program. After evaluating and quantifying the shape diversity exhibited by this set of lines, we envision (in subsequent work) utilizing this framework to analyze and evaluate time-dependent geometric canopy traits to isolate genetic pathways that control various stress adaptation mechanisms.http://soybase.org/).A total of 446 soybean PI lines from 25 different countries acquired from the USDA soybean germplasm collection, grown near Ames, IA, in 2015, were used for this study Figure  and was First, each image was segmented. Then they were converted from native RGB to hue-saturation-value format to efficiently segment the foreground (the plant) from the background. The background of an image (soil) contains more gray pixels than the foreground (plant) and lacks in green and yellow hue values; therefore, most of the background was removed by excluding pixels that had a saturation value below a predefined threshold and hue values outside of a predefined range. The saturation threshold value was obtained by identifying the saturation values of the background in 148 diverse images. The hue range was simply obtained from the hue color wheel, removing pixels that were neither green nor brown.Once segmentation was done, the connected components labeling method th and ith]. The x and y coordinates of any point, pth, were expressed asEach contour was chain coded following standard practice Freeman, . Then lixi and Δyi are the differences along the x and y axes between the (i−1)th and the ith points.where Δpth point and the perimeter of the contour are denoted by tp and T, respectively.The length of the contour from the starting point to the ti is the distance between i−1th and ith points, and s is the total number of the chain coded points on the contour.where ΔThe co-ordinates in Equation (1) were expressed using elliptic Fourier expansion asandNth harmonic werewhere the coefficients of the N harmonics, 4N coefficients were evaluated and were subsequently used as descriptors of the shape. The original shape of canopy outline was reconstructed using inverse Fourier transform from these shape descriptors. The accuracy of the reconstruction depends on the number of harmonics (N) used. We defined the deviation of the reconstructed shape from the original asFor a shape representation using xNp and yNp are the approximated co-ordinates using N harmonics, and L is half of the length of the major axis (semi-major axis) of the best-fitted ellipse to the shape (estimation of L is presented in the standardized shape descriptors section). As with any approximation scheme, increase in the number of harmonics results in high accuracy of reconstruction, but requires more processing time and storage. We next detail an approach of identification of the optimal number of harmonics to use that represents a balance between accuracy and computational requirement.where N, needed to represent this canopy and subsequently utilize this number N for all other canopy descriptors. This ensures consistency while ensuring that a desired threshold of accuracy is met. Figure We first identified the most complex canopy (that would require the most number of harmonics to accurately represent) from the set of all available canopies. We then evaluated the optimal number of harmonics, N = 500 as this is where the normalized error reaches around 1%. Thus, each canopy outline is subsequently represented using a 500 harmonic representation.To identify the most complex canopy, error between outline from each original image and the Fourier approximation using the first ten harmonics of that image was calculated using Equation 9. The canopy with the highest deviation exhibits the most complex shape  is the center of the ellipse,  is the location of modified starting point (point on the major axis of the ellipse), where After each canopy outline is represented using 500 Fourier shape descriptors, traditional morphometric traits are evaluated from the shape. For comparative assessment of the utility of Fourier shape descriptors, the traits obtained from EFD reconstructed canopy outlines are compared with traits obtained from the original images. Diversity of the traits among the lines/genotypes based on the country of origin is investigated. For visualization and interpretation of diversity, PCA on the EFD is next deployed. Data visualization based on the first two principle components is performed with a focus on four classifications including country of origin, maturity index, stem termination index and seed weight. Finally, the canopy descriptors that are suitable for genetic improvement were suggested.yik = μ + gi + bk + eik, where yik is the trait observation/estimate of the ith genotype at the kth block, μ is the total mean, gi is the genetic effect of the ith genotype, bk is the block effect, and eik, is a random error following N. Accordingly, the broad-sense heritability on an entry-mean basis of each trait was calculated as H2 = k], where k is the number of replications. The analysis of variance was implemented in R via the ANOVA function. The variance components were calculated with all effects considered to be random.The model for the phenotypic trait with a single trial of randomized complete block design was two orders of magnitude less memory with minimal computational overhead to evaluate traditional traits.The accuracy of reconstruction was checked by comparing traits obtained from original images and traits evaluated from the reconstructed outlines using 500 harmonics. Figure To investigate the shape diversity based on the traditional traits, the traits are grouped based the origin of the lines, and presented in box plots Figure . The ploTwo lines are outliers for solidity, and occur as outliers in two of three reps Figures , i.e., aWe perform principal component analysis (PCA) on the EFD. PCA facilitates dimension reduction of the data set and permits efficient summarization of the information contained by the coefficients. The first 30 principal components express around 90% of the total variability, and first and second components describe, respectively, around 17 and 10% of the total variability. These two components are used in the subsequent sections for diversity visualization and interpretation. Figure In Figure Genetic improvement of plant canopy has long been a challenge of soybean genetic improvement programs because of the complexity of the trait and the difficulty of measurement. We investigated the genetic effect underlying each of the four shape traits/descriptors. The analysis of variance implied that the genetic effect of all traits, except aspect ratio, were significant Table . FurtherCharacterizing and understanding canopy outline variations is important for breeding. This work discusses a framework for efficient representation of complex canopy outlines using EFD. We detail how the choice of the number of harmonics is made to ensure consistency while ensuing a balance with computational effort. We rigorously show that traditional traits/descriptors can be easily, and very accurately reconstructed from the elliptic Fourier representation of the canopy outline. We utilized this framework to explore the diversity in canopy outline using a diverse panel of soybean plants.In the near term, we envision that this approach will allow for design and utilization of a high throughput canopy morphology phenotyping platform. Such a platform will allow systematic canopy outline analysis while maintaining the integrity of the shape. The use of EFD provides an attractive alternative to conventional canopy phenotypes. Genotypic differences within a species, as well as morphological differences under differing environmental and management conditions, can be characterized without bias, allowing identification of desirable lines/genotypes, as well as providing a proxy for rapidly measuring important plant canopy and growth traits. The approach presented in our paper may also find applications in the hyperspectral and multispectral imaging of disease and other causal damage that is observable on canopy during the crop growing season , ISU Presidential Initiative for Interdisciplinary Research (PIIR) in Data Driven Science (DDS) project, Monsanto Chair in Soybean Breeding at ISU (AKS), R F Baker Center for Plant Breeding; USDA CRIS project #IOW04314, and the USDA NIFA grant “A multi-scale data assimilation framework for layered sensing and hierarchical control of disease spread in field crops.”The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer ML and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient’s health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer. This article examines topics that were discussed by the authors at a European Society of Digestive Oncology (ESDO) workshop convened at the 2016 World Congress on Gastrointestinal Cancer in Barcelona, Spain. The objectives of the workshop were to highlight the importance of health-related quality of life (HRQoL) to patients with colorectal cancer (CRC) and its impact on treatment evaluation and decisions, and to evaluate the challenges of using patient-reported outcomes (PROs)—including HRQoL—and particularly how they can be standardized and used to improve patient management.Worldwide, CRC is one of the most frequently diagnosed cancers and one of the most common causes of cancer-related death . In 2012The five-year prevalence of CRC  in Europe in 2012 was 1.2 million, demonstrating that a large number of patients survive with the disease. The Eurocare-5 study reported five-year survival rates of 57% for colon cancer and 56% for rectal cancer . Table 1Approximately 25% of patients with CRC have metastatic disease at initial diagnosis, and almost 50% will develop metastases during the course of their disease . AlthougStandard treatments for mCRC are mainly palliative, and are based on chemotherapy and biologically-targeted agents. While palliative treatment for mCRC aims to increase the duration and maintain or improve the quality of the patient’s remaining life, this can be difficult given the toxicity profiles of the treatments administered. When treatments for mCRC are palliative, HRQoL considerations are crucial to understanding the impact of cancer on the patient . Loss ofAdverse events during cancer treatment can have a negative effect on HRQoL, so optimal therapy involves a balance between efficacy and safety. The aim is to increase the patient’s lifespan by a continuum of care that uses all the available and suitable drugs while at the same time ensuring a good quality of life for the patient. This means using treatment strategies such as induction and de-escalation/maintenance strategies, drug holidays, and so on to ensure that overall survival is not compromised but that HRQoL is maximised. To this end, HRQoL and PROs should be considered as a clinical endpoint in mCRC clinical trials to demonstrate that new treatment strategies are providing clinical benefit for the patient, and ultimately to individualise treatment on the basis of HRQoL and PROs to achieve the paradigm of precision/personalised medicine .A PRO is defined as any report about a health condition and its treatment that comes directly from the patient using a self-reported measure, without interpretation of the patient’s response by a physician or anyone else . PRO datPatient involvement is increasingly being recognised as a component of healthcare, and PROs that quantify patients’ feelings or functions are now being considered as important endpoints in cancer clinical trials . Some daThe Effectiveness Guidance Document (EGD) from the Center for Medical Technology Policy (CMTP) provides recommendations for the appropriate inclusion of PRO measures in the design and implementation of prospective clinical comparative effectiveness research (CER) in adult oncology, including but not limited to registries, prospective observational studies, randomised controlled trials, and pragmatic clinical trials . PROs shEfforts to standardise the use of PROs in clinical trials are underway. Standards for the PROs to be measured, the content to be included in clinical trial protocols, and the reporting of clinical trial findings have recently been established ,24,25,26Two Phase III clinical trials investigating the effects of bevacizumab plus radiotherapy–temozolomide in patients with newly diagnosed glioblastoma provide an example of the problems associated with a lack of standardisation of PROs. The two trials used the same tools to assess HRQoL but used different statistical approaches, and they found different results ,30. The The inclusion of a patient-centred endpoint in mCRC clinical trials to reflect how a patient feels, functions, or survives may help to show that new treatment strategies are providing clinical benefit for the patient and ultimately to individualise treatment on the basis of HRQoL and PROs to achieve the paradigm of precision/personalised medicine . The ultKRAS wild-type, chemotherapy-refractory mCRC showed that the combination of cetuximab  plus brivanib alaninate  delayed disease progression compared with cetuximab plus placebo. However, this observation of delayed disease progression was not associated with a longer period of time before deterioration in HRQoL. In fact, the combination of the two drugs led to an accelerated deterioration of HRQoL compared with single-agent cetuximab. The researchers suggested that this could be a result of the increased toxicity of the combined therapy, with the side effects offsetting any potential HRQoL benefit of delayed disease progression [For example, the CO.2O Phase III randomised trial of patients with gression .The time until definitive deterioration (TUDD) in HRQoL score has been defined as a method of longitudinal analysis in oncology. This method allows patients’ data to be preserved for analysis even if some of their questionnaires are missing, and allows the production of clinically meaningful and readable results for clinicians. To investigate the applicability of this method to mCRC, the HRQoL longitudinal changes in mCRC patients treated with FOLFOX4 versus FOLFOX7-FOLFIRI were analysed using data from the MIROX randomised Phase III trial . The resKRAS tumours. Additionally, patients with wild-type tumours who received cetuximab in addition to best supportive care experienced significantly less HRQoL deterioration and a longer time before clinically significant deterioration occurred compared with those who received best supportive care alone [The CO.17 trial demonstrated that cetuximab improves overall and progression-free survival in patients with advanced chemotherapy-refractory CRC—particularly in patients with wild-type re alone .KRAS mCRC. However, analyses of the HRQoL assessments made during these studies showed no statistically significant or clinically meaningful overall differences in the change in HRQoL in patients treated with panitumumab–chemotherapy compared with those treated with chemotherapy alone [In two randomised Phase III trials, the addition of panitumumab  to FOLFOX4 (first line) or to FOLFIRI (second line) significantly increased progression-free survival in patients with wild-type py alone .HRQoL scores have the potential to be used not only as an endpoint in clinical trials, but also in routine practice to improve patients’ health during treatment. The results of the direct improvement of quality of life (DIQOL) randomised controlled trial in colorectal cancer patients using a tailored pathway with quality of life diagnosis and therapy will provide more information on whether a specific quality of life pathway improves patients’ HRQoL during follow-up care of their disease . This apUse of PROs in routine practice can confer clinical benefits. Among adults receiving outpatient chemotherapy for advanced solid tumours at a large specialty cancer centre, self-reporting of symptoms with automated clinician e-mail alerts resulted in better HRQoL, fewer emergency room visits, fewer hospitalizations, a longer duration of palliative chemotherapy, and superior overall and quality-adjusted survival . In anotCapturing patients’ subjective experience or HRQoL is a key endpoint in clinical trials of cancer therapy, including trials of CRC, and PROs are tools for achieving this. Self-reported symptoms can also be used in routine practice to help guide the management of patients with CRC. PRO data—including HRQoL—from clinical trials can be used to inform clinical decision making, health policy, and reimbursement decisions . The Cen


Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Colistin has been extensively used orally since the 1960s in food animals and particularly in swine for the control of Enterobacteriaceae infections. However, with the recent discovery of plasmid-mediated colistin resistance encoded by the mcr-1 gene and the higher prevalence of samples harboring this gene in animal isolates compared to other origins, livestock has been singled out as the principal reservoir for colistin resistance amplification and spread. Co-localization of the mcr-1 gene and Extended-Spectrum-β-Lactamase genes on a unique plasmid has been also identified in many isolates from animal origin. The use of colistin in pigs as a growth promoter and for prophylaxis purposes should be banned, and the implantation of sustainable measures in pig farms for microbial infection prevention should be actively encouraged and financed. The scientific research should be encouraged in swine medicine to generate data helping to reduce the exacerbation of colistin resistance in pigs and in manure. The establishment of guidelines ensuring a judicious therapeutic use of colistin in pigs, in countries where this drug is approved, is of crucial importance. The implementation of a microbiological withdrawal period that could reduce the potential contamination of consumers with colistin resistant bacteria of porcine origin should be encouraged. Moreover, the management of colistin resistance at the human-pig-environment interface requires the urgent use of the One Health approach for effective control and prevention. This approach needs the collaborative effort of multiple disciplines and close cooperation between physicians, veterinarians, and other scientific health and environmental professionals. This review is an update on the chemistry of colistin, its applications and antibacterial mechanism of action, and on Enterobacteriaceae resistance to colistin in pigs. We also detail and discuss the One Health approach and propose guidelines for colistin resistance management.Colistin (Polymyxin E) is one of the few cationic antimicrobial peptides commercialized in both human and veterinary medicine. For several years now, colistin has been considered the last line of defense against infections caused by multidrug-resistant Gram-negative such as  Colistieriaceae  and is ueriaceae . Recentleriaceae . Colistieriaceae .Enterobacteriaceae infections, particularly for those caused by Escherichia coli  and/or a 4-amino-4-deoxy-L-arabinose (L-Ara4N), which reduces its binding to colistin and leads to bacterial resistance , and colistin use and in swine .Paenibacillus polymyxa var colistinus  amino groups . These amino groups are responsible for the electrostatically interaction between colistin and the lipid A portion of LPS molecules of GNB and play a central role in the bactericidal activity of colistin  is a polymyxin antibiotic produced by listinus  consistio groups . The L-Dcolistin . The polcolistin . PolymyxEnterobacteriaceae infections in pigs  of GNB. The most documented steps of colistin antibacterial activity are described below .(1)Colistin initially binds to LPS and specifically to lipid A, a key component of the LPS, through electrostatic interaction between positively charged Dab residues of colistin and the negatively charged phosphate groups of lipid A. Lipid A plays a crucial role in the control of bacterial permeability .(2)2+) and magnesium (Mg2+) that normally stabilize the LPS and as a consequence the three-dimensional structure of the LPS is altered. In fact, colistin has affinities for LPS that are at least three times higher than those for divalent cations D-Leu6 -L-Leu7 segment into the OM.Colistin causes an expansion of the OM monolayer by the insertion of its hydrophobic terminal fatty acyl chain or the (4)Colistin leads to a permeabilization of the OM by the formation of destabilized areas through which colistin will transit the OM via a self-promoted uptake mechanism . This me(5)Colistin destroys the physical integrity of the phospholipid bilayer of the inner membrane (IM) through membrane thinning by straddling the interface of hydrophilic head groups and fatty acyl chains .(6)This leads to IM lysis, leakage of intracellular contents and cell death.Colistin also exerts an anti-endotoxin activity because it binds to the lipid A component of LPS . In thisA. baumannii and E. coli through hydroxyl radical production by the Fenton reaction (2+). The production of this reactive oxygen species (ROS) might lead to oxidative damage in the bacterial DNA, proteins, and lipids and cause cell death . These studies were performed using CS, since this is the only form of colistin approved in swine medicine, and were conducted in healthy pigs. It is reasonable to think that the PK can be different in sick animals. The oral CS PK data in pigs were obtained using either a high-pressure liquid chromatography (HPLC) assay (Table 1); these data should be viewed with caution because of the limited sensitivity of this method and the descriptions of the experiment conditions.Unlike for human medicine, only a few studies have been conducted in pigs to evaluate the PK of colistin following oral , 2016b oC) assay  or a LC C) assay , 2016b. C) assay ; Table 1After oral CS administration in pigs and despite the use of a very sensitive analytical method, CS plasma concentrations were very difficult to quantify in healthy pigs . A concuParenteral CS PK studies in pigs were mainly conducted to study the safety of IM CS administration. The CS intestinal concentrations through the biliary system elimination were not determined following IM administration to assess whether or not colistin exerts a selective pressure on pig’s intestinal microflora after its parenteral administration. There is no available data in the literature concerning the possible renal tubular reabsorption of CS in pigs as previously demonstrated in rats through a carrier-mediated process ; if thisE. coli experimental infection in pigs increased CS intestinal absorption , as demonstrated previously .While great advances in colistin research have occurred in the last decade in both human and veterinary medicine , colistimcr-1 gene encoding for Enterobacteriaceae colistin resistance in farm animals and in humans (Table 2).Furthermore, the recent discovery of a plasmid mediated n humans  has promn humans . More daIt should be stressed here again that the CS commercially available is obtained by a bacterial fermentation process . Consequmax concentrations of colistin were not determined after a repetitive CS oral treatment to justify the efficacy of this therapeutic regimen in the treatment of pig’s diseases associated with Enterobacteriaceae. The duration of CS oral treatment in pig farms is far longer than 3–5 days as recommended on product monographs , no study has demonstrated the effectiveness of such association and its role in colistin Enterobacteriaceae resistance occurrence.In swine, and despite the use of some combinations of colistin with other antimicrobial agents  producing E. coli isolates from pigs in Germany and in Vietnam . In fact, it has been shown that the combination of amoxicillin with colistin has a synergy and additive affect in vitro against pathogenic E. coli of avian origin, without antagonism between the two antibiotics (Table 3). Moreover, it has been reported that in the weaning period, colistin was frequently applied in combination therapy with amoxicillin against symptoms of arthritis and/or meningitis and PWD in pigs  were reduced in pigs treated with a combination of chlortetracycline, bacitracin zinc, and CS compared with the group treated only with chlortetracycline , there are other combinations with this antibiotic that have been used in several scientific studies to evaluate the efficacy of some colistin alternative substances (Table 4).In addition to colistin combination therapy used in field conditions (Table 4) that evaluated the therapeutic efficacy of colistin combination therapy in pigs were carried out in China and focused primarily on clinical effectiveness not the emergence of antimicrobial resistance. Therefore, no information was available concerning the evolution of colistin bacterial resistance subsequent to the use of these combination therapies in swine, and we do not know whether these combinations are used in practice on pig farms in China.These studies  and/or phosphoethanolamine (PEtn). These molecules reduce the net negative charge of LPS and as a consequence increase the resistance to colistin . Mutations in the PmrAB TCS are mostly involved in the development of resistance to colistin in E. coli .Of note, regardless of the mutation location in PmrA or PmrB genes, there was no association with a difference in MIC of these colistin resistant in vitro in Salmonella  with a G+C content of 42.7%. The plasmid pHNSHP45 carrying mcr-1 gene was initially isolated in July 2013 from an E. coli strain recovered from a pig farm  and showed resistance to most antibiotic families except the carbapenems , pVT553 (62 Kb), IncX4 (30 Kb), and IncP (79 Kb) plasmids in E. coli from broilers poultry, bovine, and swine origin  from colistin resistant E. coli of porcine origin. The pKP81-BE plasmid showed a G+C content of 44.9% and belonged to IncFII incompatibility type with 4% similarity compared to pHNSHP45. These findings showed that mcr-1 has horizontally transferred to other plasmid types, leading to an increase in its target bacterial range  ISApl1-mcr-1 (or an mcr-1-containing mobile element) located immediately upstream of mcr-1, as also reported in plasmid pHNSHP45 , Vietnam (22%), Belgium (13.2%), Brazil (2%), Spain (0.68%), Germany (0.51%), and France (0.50%)  . Most reCarolina . In thesmcr-1 gene presence in enterobacterial species reported that colistin resistant strains harboring this gene also showed resistance to one or several classes of antibiotics conventionally used in swine such as: Aminoglycoside, Sulfonamide, Trimethoprim, Tetracycline, Quinolone, Lincosamide, β-lactam, and third generation cephalosporin , aminoglycosides (aadA1a and aadA2), sulfonamides (sul3), and phenicols (cmlA1)  . FurtherBL genes .mcr-1 gene was screened and detected in three colistin resistant Salmonella strains isolated from 122 lymph nodes and in two colistin resistant E. coli strains isolated from 439 swine fecal samples. This study was the first in swine to demonstrate the existence of a plasmid carrying mcr-1 gene, in addition to a mutation in PmrAB TCS, in two colistin resistant E. coli strains. The coexistence of these two colistin resistance mechanisms in E. coli was not associated with a difference in the MIC of these strains compared to resistant Salmonella strains that expressed only the plasmid carrying mcr-1 gene   . FernandEnterobacteriaceae . In addition to their use in pigs, polymyxins and especially polymyxin B are used in some countries for the treatment of coliform and Pseudomonas mastitis in cows  in Lithuania (Larus dominicanus) in Argentina .In addition, the ork meat , ground ork meat , and retork meat . These fE. coli strains isolated from humans with gastroenteritis or wound infections . However this strain remained susceptible to several other antimicrobial agents . Therefore, the management of colistin resistance requires global and coordinated action between the different actors in order to intercept this resistance spread and preserve the efficacy of colistin for the treatment of MDR-GNB in human medicine.Transmission of Figure 3).We believe that the One Health concept is more important than ever to better manage the impact of colistin resistance in human and veterinary medicine. Such a concept needs a global strategy to develop collaborations and interdisciplinary communication between concerned specialists . This section will focus on interventions in swine medicine but is applicable to all animal productions where colistin is used.The use of colistin in swine has contributed to the intensification of modern pig productions by assuring successful weaning, higher animal densities, and most likely helped to reduce economic losses caused by  disease . Economierminant , hence tThis practice should be banned internationally. In addition to the fact that antimicrobials for growth promotion can generally be purchased without veterinary involvement, low subinhibitory concentrations of antibiotics used to improve animal growth has been shown to promote antibiotic resistance emergence . No receThis usage is involved in the increase of colistin quantities used in pigs and increases its presence as waste in the environment . Such usE. coli populations  is of paramount importance. Any deviations from the guideline recommendations must be justified and recorded. In this context, extra-label use of colistin in some countries where this antibiotic is not approved in swine such as in Canada, must take place within a valid veterinarian-client-patient relationship. An analysis of the specific situation at farms and a determination that there are no alternatives to this antibiotic for the treatment of this case is required. Research is very important in order to establish a microbiological withdrawal period that could reduce the risk that pigs sent to slaughter contain colistin resistant bacteria or Veterinarians should ensure that colistin use targets clinical disease, should consider reduction of its use whenever practical, and should direct management and husbandry issues at the same time. Veterinarians should also consider laboratory examination as a routine practice to evaluate the effectiveness of colistin treatment and to monitor the sensitivity of infectious strains on the farm. Educational and awareness campaigns for employers and pig farmers are essential to generate an understanding that can support the veterinarian to withhold colistin. The professional organization of each country should develop clinical-practice guidelines on the judicious use of colistin. Data on colistin usage in food animals are critically important because they provide a basis for the development of national policies and they guide the risk of colistin resistance management and assess the effect of possible interventions . At a miTable 6). Among the principles of the One Health approach is the improved use of existing natural resources and implementation, which includes the monitoring of colistin resistance spread in both human and veterinary medicine. However, regulations and practices vary widely between these surveillance programs and are influenced by the economic and social context of each country , is to strengthen the coordination and integration of antimicrobial resistance and antimicrobial use activities and information in Canada and to consolidate surveillance from seven existing systems .Governments should fund research to enhance our understanding of environmental and genetics factors that facilitate the development of infectious disease in food animals, and to examine alternative strategies for the use of antibiotics on farms. Financial assistance for farmers in the implementation of sustainable practices and interventions to prevent infections, such as sanitation, housing, improvement of nutritional programs, and immunization, is very important for the reduction of the use of colistin or other antibiotics on farms. In addition, the preparation of guides and educational material for veterinarians and farmers on appropriate disease management and treatment based on the recent results of research is crucial for the responsible use of antimicrobials in farms. Efforts to improve microbiological laboratories are vital to help veterinarians undertake rapid therapeutic action with the most appropriate antibiotic and at an early stage of the disease . FinallyEisenia fetida; colistin caused significant damage to its intestinal epithelium and caused the induction of stress-related gene expressions  and wild hares (Lepus europaeus) that have not been previously treated with colistin .This section will be devoted to the possible interventions to limit the spread of colistin resistant bacteria and genes in the environment via pig manure  genes in manure  more effectively than other ARG such as erm(F), erm(B), and tet(G), while mesophilic anaerobic digestion and lagoon storage reduced none of these AR genes .Colistin is currently considered to be one of the last-resort antibiotics used for the treatment of infections caused by MDR-GNB in humans . Maintaimcr-1 screening tests among admitted patients who needed colistin as a treatment.This step is crucial before undertaking a therapeutic intervention using colistin, and screening should be done in both patients with and without prior history of colistin usage . Hospitamcr-1 genes and NDM enzymes by the same colistin resistant isolates, as reported by Enterobacteriaceae, published in 2012 by the USA Centers for Disease Control and Prevention (CDC) and updated in 2015 (available from: http://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html), would be a very good tool to prevent contamination by colistin resistant strains in hospitals. In addition, the identification of a patient carrying isolates that produce mcr-1 gene in association with carbapenemases should be strictly considered a reason for patient isolation , mainly to target resistant gram-negative aerobic bacteria, along with a short course of a parenteral broad-spectrum antimicrobial such as cefotaxime  . This prisolates . The lonisolates .in vitro and in mouse model studies have shown that combination of colistin with other antimicrobials such as rifampicin and imipenem may be more effective than colistin monotherapy in the treatment of MDR-GNB (K. pneumoniae carbapenemases (KPCs) producers (Several  MDR-GNB . A revieroducers . Howeverroducers . This inE. coli and Salmonella. The recent discovery of a plasmid-mediated mcr-1 gene encoding for colistin resistance in Enterobacteriaceae has generated great concern about the possible loss of effectiveness of colistin for the treatment of MDR-GNB in humans. Because of the large amounts of colistin used in food animals and particularly in pigs, pig production has been pointed to as the greatest cause of colistin resistance amplification and spread. Consequently, experts, scientists, and government agencies have called for a reduction of colistin use in pigs and stressed that this antibiotic should be used only for the treatment of diseased animals as a last-resort treatment under strict circumstances. The mcr-1 gene has been isolated on four continents from sources other than food animals, such as the environment and human origins, and some E. coli isolates carrying a plasmid-encoded mcr-1 gene were associated with ESBL or carbapenemases enzymes. This highlights the need for an overarching approach on the judicious use of all antibiotics, especially those of critical importance for human health. The One Health concept is more important than ever to better manage colistin resistance at the human- animal-environment interface through the use of adequate science-based risk management policies that respect interdisciplinary regulations. Finally, we should start thinking beyond colistin therapy in swine and begin evaluating the effectiveness of other alternative strategies against infections caused by Enterobacteriaceae.Colistin is an antibiotic widely used in pigs for the oral control of bacterial infections caused by MR conceived and designed the study, wrote the paper; FB designed the study, revised the paper; WT designed the study, revised the paper; AL designed the study, participated in the drafting of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The biochemical recurrence after local treatment for prostate cancer is an often challenging condition of clinical management. The aim of this report is to demonstrate the importance of the association of various imaging methods in the identification and subsequent accurate percutaneous biopsy in patients with recurrence of prostate cancer, especially in unusual sites.68Ga uptaken, suggesting the recurrence. A percutaneous fusion biopsy with PET-MRI and ultrasound was performed using transrectal access using ultrasound confirming infiltrating adenocarcinoma of the wall of the vas deferens, compatible with neoplastic prostate recurrence.An 86 years old male with biochemical recurrence, during radiological investigation a PET-MRI was noted the presence of an asymmetry of the vas deferens with PSMA-The fusion image technique combines the real–time view of the US to the possibility of higher definition and higher specificity, methods more anatomical detail as tomography and magnetic resonance imaging, simultaneously.High resolution acquired in PET / MR associated with image fusion allows orientation procedures, even in areas of difficult access, with greater accuracy than conventional techniques. Up to 35% of patients with localized treatment for prostate cancer  ultimately present with a biochemical recurrence, which means a prostate specific antigen (PSA) elevation without abnormal conventional imaging studies. The biochemical recurrence after local treatment is an often challenging condition of clinical management .An emerging tool for the topographic diagnosis of lesions in patients with biochemical recurrence is the use of prostate-specific membrane antigen (PSMA) PET scan associated with the magnetic resonance imaging (MRI), promoting high tumor contrast associated with high resolution image , identifThe aim of this report is to demonstrate the importance of the association of various imaging methods in the identification and subsequent accurate percutaneous biopsy in patients with recurrence of prostate cancer, especially in unusual sites. Similarly, we aim to report an uncommon presentation of recurrence of prostate cancer in the vas deferens, location which particularly benefited from the above-mentioned imaging methods combination.A 86 years-old male has been followed for elevated PSA levels after his prostatectomy fifteen years ago. He has already undergone salvage external beam radiation therapy with no success and has been on different hormonal manipulations since then. His current PSA was 21 with a doubling time of 1 month with a testosterone level of 23ng/dl.68Ga uptake, suggesting recurrence  and probe with guide prostate biopsies. An 18G automatic needle (Acecut-TSK Laboratory-Japan) was positioned into the lesion guided by real time fusion images and confirmed the position by tomography  .Five samples were collected, with immediate analysis by the pathologist, confirming the presence of atypical cells.Control tomography and transrectal ultrasound showed no immediate complications and the patient was discharged after 4 hours of observation and micturition without hematuria.Final pathological analysis of the sample showed infiltrating adenocarcinoma of the wall of the vas deferens and the adjacent adipose tissue compatible with neoplastic prostate recurrence. Due to prior external beam radiation therapy, he was started on Enzalutamide in addition to androgen deprivation associated with radiation therapy directed at the focus of tumor recurrence.Institutional review board approval for case report is not required in our institution.The biochemical recurrence is challenging, the rising of PSA level is not necessary associated with imminent death from disease, but patients concern about this rising and eager may hinder treatment. Precipitated interpretations may cause prematurely administration of androgen deprivation therapy. It is known that androgen blockage is associated with side effects such as impotence, bone loss, metabolic syndrome and increased risk of cardiovascular disease; it is worsened if the evolution of the disease is not associated with changes in survival .Hence, there is the quest for new diagnostic methods with high specificity and sensitivity to locate and predict the extent of the disease in case of biochemical recurrence. Other methods associated with membrane receptors have already been tried, but did not achieve the expected result.Positron emission tomography-magnetic resonance imaging (PET-MRI) is an image of a hybrid technique that combines morphological and functional information with high accuracy in diagnosis of primary and metastatic tumors. The prostate specific membrane antigen (PSMA) is a transmembrane protein with increased expression in neoplastic prostate cells compared to benign glandular cells. Currently, some studies  have demThe fusion image technique combines the real-time view of the US to methods of higher definition and specificity with better anatomic detail. In addition, the detection of clinically significant prostate cancer in MRI helps to detect the same disease in biopsy results .Although Lee et al. did not find significant difference between the use of fusion biopsy and systematic biopsy in detection rate of any-grade prostate cancer , MariottOur experience is in accordance with the literature, where it is observed a 13.5% upgrade for MRI-US fusion biopsy over systematic biopsy , that shThis case demonstrates the effectiveness of PET-MRI/PSMA in identifying the location of probable recurrence and, in combination with fusion biopsy, allowed the accurate diagnosis of the site of recurrence, contributing to the better treatment of the condition.High resolution acquired in PET/MR associated with image fusion allows orientation procedures, even in areas of difficult access, with greater accuracy than conventional techniques.


The walking mechanism of a prosthetic leg user is a tightly coordinated movement of several joints and limb segments. The interaction among the voluntary and mechanical joints and segments requires particular biomechanical insight. This study aims to analyze the inter-relationship between amputees' voluntary and mechanical coupled leg joints variables using cyclograms. From this analysis, the critical gait parameters in each gait phase were determined and analyzed if they contribute to a better powered prosthetic knee control design. To develop the cyclogram model, 20 healthy able-bodied subjects and 25 prosthesis and orthosis users  walked at their comfortable speed in a 3D motion analysis lab setting. The gait parameters  were coupled to form 36 cyclograms relationship. The model was validated by quantifying the gait disparities of all the pathological walking by analyzing each cyclograms pairs using feed-forward neural network with backpropagation. Subsequently, the cyclogram pairs that contributed to the highest gait disparity of each gait phase were manipulated by replacing it with normal values and re-analyzed. The manipulated cyclograms relationship that showed highest improvement in terms of gait disparity calculation suggested that they are the most dominant parameters in powered-knee control. In case of transfemoral amputee walking, it was identified using this approach that at each gait sub-phase, the knee variables most responsible for closest to normal walking were: knee power during loading response and mid-stance, knee moment and knee angle during terminal stance phase, knee angle and knee power during pre-swing, knee angle at initial swing, and knee power at terminal swing. No variable was dominant during mid-swing phase implying natural pendulum effect of the lower limb between the initial and terminal swing phases. The outcome of this cyclogram adoption approach proposed an insight into the method of determining the causal effect of manipulating a particular joint's mechanical properties toward the joint behavior in an amputee's gait by determining the curve closeness, C, of the modified cyclogram curve to the normal conventional curve, to enable quantitative judgment of the effect of changing a particular parameter in the prosthetic leg gait. Human walking is typically characterized by plotting kinematics and kinetics curves as a function of time or percentage of gait cycle. These kinematics and kinetics curves became the primary guideline in the prosthetic leg design that would mimic the normal gait. These were done by ensuring that the prosthesis produces user gait performance that is close to the normal single-variable curve , and wavelet methods  toward the least error production from normal profile. The final parameter at each gait sub-phase was then determined by analyzing the effect of manipulating one parameter onto another parameter of the coupled variables at the most deviated cyclogram for different amputee's profile.This study consists of 3 phases. The first phase involved gait analysis and cyclogram model generation based on the leg joint parameters. Phase 2 verified the generated cyclogram models by determining the gait deviation at each sub phase throughout the gait cycle of participants with different pathological conditions. In the last phase, the modified cyclogram models were used to identify the most dominant parameter at each gait sub-phase in the case of transfemoral amputees.In this section, the data collection procedure was explained in detail. Then, the generation of cyclogram pairs from the voluntary and mechanical joints' parameters was described.Table The profile data for each of the transtibial, transfemoral and orthosis subjects and their respective pathological condition are presented in Table The experimental procedures of this study were conducted in a motion analysis lab on a 4 m straight walkway. The lab was equipped with an optical three-dimensional motion capture system, a 6-infrared camera Vicon Nexus 1.5  mounted strategically around the room, working at 50 Hz and integrated with two force plates  working at 200 Hz, located midway to obtain synchronized kinematic and kinetic data within a capture volume of approximately 4 × 4 × 2 m.The subjects' bilateral leg length , ankle width and knee width were measured and recorded to the system software for automated calculation of mass, center of mass and moment of inertia. The knee width of residual limb was considered as similar with the sound limb for transfemoral subjects. The ankle width for both transfemoral and transtibial subject residual limb were also considered to be similar to the sound limb measurement. Ground reaction force was obtained from the force plates for kinetic automated calculation by the Vicon software to obtain joint power and moment. Sixteen reflective markers of 14 mm diameter were attached bilaterally based on Helen Hayes marker placement.At least 20 trials were recorded for each subject and all the subjects were asked to rest in between the trial to prevent fatigue effect to the data collection. The gait data was analyzed with a conventional model Vicon Plug-In-Gait and filtered using second-order Butterworth filter. The ankle, knee and hip joint kinematics, moments and gait events as well as relevant markers' trajectories, Ground Reaction Force (GRF) and Center of Pressure (COP) data were imported into Matlab for extraction and further analysis. Linear interpolation was applied to the original data points to obtain data points for joint kinematics and kinetics data at every 2% of stride duration. The joint moment was computed by inverse dynamics, using subjects' measurements and anthropometric properties and normalized to body weight ,moment-moment across the two joints pair (3 pairs),power-power across the two joints pair (3 pairs),angle-moment within the joint and across the two joints pair (9 pairs),angle-power within the joint and across the two joints pair (9 pairs), and,moment-power within the joint and across the two joints pair (9 pairs).A total of 36 relationships were obtained by pairing the variables of the joint itself and across the two joints pair. The relationships can be classified into 6 groups, namely:Most of these relationships were not found in the literature except for angle-angle relationship across the two joints pair  that the subjects used for mobilizing or propulsion; while in contrast, the non-dominant limb is the non-preferred limb (trailing limb) that is used to support the actions, i.e., stability control. This support and mobility task performed by each leg was interpreted as gait asymmetry that is normal to occur even to healthy able-bodied subjects. All the normal subjects in this study were right limb dominant, therefore, right side served as the propulsion source during walking. The necessity of defining which limb contributes to propulsion or support task was important in this study in order to select the reference side of cyclograms that was identical to the functional role of the prosthetic and the intact side for amputees. It has been revealed in the study by Carpenter et al. that the transtibial amputees who undergone osteomyoplastic amputation  rely on the prosthetic side to support, while the intact side function to propel the body forward  , hidden layer (7 neurons) and output layer (3 neurons). The relationship between the input data and the output data was found linear, thus linear regression functions were employed. The input and target data arrangement was illustrated as in Figure The network was first trained with data of 100 trials that was randomly chosen from 10 healthy subjects as network input and average normal data of 200 trials from 20 healthy subjects as the network target in order for the NN to learn the outcome of different paired variables interactions of normal subject as the reference. A total of 36 NN were trained with 36 paired variables, i.e., cyclograms, respectively. During the training, default random division algorithm was used for the NN to divide the data randomly for training (60%), validation (20%), and testing (20%). The network weight was reinitialized if all the following criteria for the network performance were not met, and only network that fulfilled the following criteria were kept for simulation with prosthetic cyclograms: (1) final mean square error <0.9 at the final iteration, (2) the test set error and validation set error has similar characteristics, (3) the regression for all set was > 0.9.ep−c) were calculated for each subject as illustrated in Figure Before simulating the trained network with amputee's cyclograms, the network was first tested and validated with 5 random normal subjects and 25 different cases of amputees and orthosis subjects' pathological conditions. The predicted output of cyclogram's pair from the simulation was split into two variables curve as a function of gait cycle percentage. These two curves were then compared with the curves that used the conventional trials averaging method. The errors between the two curves , with whereep−c = Errors between predicted curve points and conventional curve points, with 1 being maximum (100%) error or difference between predicted and conventional curve points, and 0 to be no error at all.The validation percentage presented in Table In this phase, the results obtained from the previous phase were used to assess the effect of manipulating one variable toward the other variable of the cyclograms. At each of the gait sub-phase for each amputee, the cyclograms relationship that resulted in the largest deviation was then being input back into the linear network model. A modification of the variable values at the particular sub-phase with the highest mean normalized error was done by inserting the normal value  at one of the paired variables as illustrated in Figure The cyclograms relationship that contributed to the highest mean normalized error at each gait sub-phase for each subject was summarized in Table At mid-stance (MSt) phase, the result indicated that the kinematics-kinetics relationship has the highest mean normalized error for each of the subject, except for TT5 (AM-HP), TT6 (AM-HP), and TT8 (AM-HP), which shows the kinetics-kinetics relationship. Nevertheless, the variable of the pairs that contributes the highest mean normalized error at this phase were all originated from the kinetics variable (knee power/hip power/hip moment). Except for TT5, TT6, TF4, and TF5 which shows that kinetics-kinetics relationship has high mean normalized error at terminal-stance (TSt), the rest showed that the kinematics-kinetics pair exhibits high mean normalized error. Similar with the MSt phase, the kinetic variable (knee power/hip power/hip moment) of the pairs has the highest mean normalized error in TSt phase compared to the kinematic variable.Similar cyclograms' relationship profile as the aforementioned MSt and TSt were found for pre-swing (PSw), initial-swing (ISw) and mid-swing (MSw), whereby most of the relationships that yield the high mean normalized error were of kinematics-kinetics pair except for TF4 (AM-HP) in pre-swing and TT2 (AM-HP) in ISw. As for terminal-swing (Tsw), 10 out of the 15 amputee subjects showed unanimously that the kinematics of knee angle variable yield the highest mean normalized error. This contradicted with the results of previous gait sub-phases in which kinetics variable (ankle moment/ankle power/knee moment/knee power/hip moment/hip power) of the pair contributed to the highest mean normalized error.The results of the manipulated variable that showed the lowest mean normalized error were translated as the variable that induced closest-to-normal cyclograms curve compared to the after-effect of manipulating the other parameters. The overall results were summarized as in Table Manipulation of any one of the parameters at MSw does not improve the sub-phase normalized errors. Observation at this phase indicated that the manipulation of parameter at this phase consequently caused the neighboring phases to yield a large mean normalized error. Therefore, no parameter was selected for manipulation at this sub-phase. Finally, for the TSw, knee power parameter was selected as it demonstrated the lowest mean normalized error when being manipulated.All the dominant parameters identified through this method were of either hip, knee or ankle parameters. However, in case of minimizing gait disparity through optimization of the knee parameters only, results related to hip and ankle parameters were revisited to identify the dominant knee parameters in its place. This was done by referring to the values of mean normalized error at Phase 2 between hip and ankle variables paired with knee variables. The knee variables that yielded the least mean normalized error when paired with hip and ankle variables of the result as in Table This study modeled all cyclograms of lower limb joint's gait variables holistically and analyzed it to identify the gait disparity among prostheses users. It also identified the most dominant knee parameter at each gait sub-phase for a prosthetic knee design.The highlight of the finding was the results of MSw gait phase modified behavior. Manipulation of both parameters in the coupled pair that was found to have the largest mean normalized error in MSw phase did not improve the performance at that particular phase. Worse is, the manipulation of either parameter at the MSw phase caused the neighboring sub-phases (ISw and TSw) yield larger mean normalized error. This indicated biomechanical justification of the momentum and gravity influence during MSw. The prosthetic knee should be left independent to extend by the effect of momentum produced by its weight and the gravity at the mid-swing in order to connect the end of initial-swing phase with the beginning of terminal-swing as illustrated in Figure In this study, the results shown that altering one of the dominant parameter that was identified using manipulate cyclograms method yielded to a better performance in most of the gait sub-phases. However, it might be oversimplified considering the complexity in the dynamics of human gait. Therefore, the findings will need to be further verified by performing experiment using a micro-controller knee on a patient and the effect in the gait of the patient is analyzed.It has been recommended in a previous study that more prospective intervention studies that take into account the multifactorial nature on the amputees walking ability should be conducted  of Malaysia; grant no: UM.C/HIR/MOHE/ENG/10 and the first author's research work is supported by Ministry of Higher Education, Malaysia and International Islamic University Malaysia under SLAB/SLAI scholarship.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Here we present the Cancer Genome Interpreter, a versatile platform that automates the interpretation of newly sequenced cancer genomes, annotating the potential of alterations detected in tumors to act as drivers and their possible effect on treatment response. The results are organized in different levels of evidence according to current knowledge, which we envision can support a broad range of oncology use cases. The resource is publicly available at The online version of this article (10.1186/s13073-018-0531-8) contains supplementary material, which is available to authorized users. Nevertheless, none of these resources address the whole process of interpretation and researchers and clinicians thus face a challenging task to annotate the variants detected in a newly sequenced cancer genome with their collective information.The accumulation of so-called “driver” genomic alterations confers on cells tumorigenic capabilities . Thousang), PMKB , PCT (ht), CIViC , and JAXHere, we describe the Cancer Genome Interpreter (CGI), a platform that systematizes the interpretation of cancer genomes, the main hallmark of which is the streamlining and automatization of the whole process  and the International Cancer Genome Consortium [in silico prediction [https://www.cancergenomeinterpreter.org/genes).One of the main aims of the interpretation of cancer genomes is to identify the alterations responsible for tumorigenic traits. In the CGI, this process begins with a focus on alterations that affect the genes capable of driving the cancer hallmarks of a particular tumor type. Therefore, we compiled a catalog of genes involved in the onset and progression of different types of cancer, obtained via different methods and from different sources . Each oediction . The reshttps://www.cancergenomeinterpreter.org/mutations). Across a pan-cancer cohort of 6792 tumors sequenced at the whole-exome level (mostly at diagnosis) [n = 5314) and a collected set of likely neutral—i.e., non-tumorigenic—PAMs affecting cancer genes (n = 1676). We found that OncodriveMUT separated the variants of these two data sets with 86% accuracy , out-performing other methods employed for this goal  that occur in genes of the Catalog of Cancer Genes. First, validated tumorigenic mutations may confidently be labeled as drivers when detected in a newly sequenced tumor. We compiled an inventory that currently contains 5314 such validated mutations, including cancer-predisposing variants, from dedicated resources , 13, 16 agnosis) . Examplehttp://cancervariants.org/) under the umbrella of the Global Alliance for Genomics & Health [The second major aim of the effort to interpret cancer genomes is to identify which tumor alterations may shape the response to anti-cancer therapies. Knowledge on the influence of genomic alterations on drug response is continuously generated and reported through publications, clinical trials, and conference communications. Nevertheless, collecting and curating relevant information into an easy-to-use resource supporting the comparison with newly sequenced tumors and organize the results according to the needs of different users is challenging. The CGI employs two resources to explore the associations between gene alterations and drug response. The first is the Cancer Biomarkers database, an extension of a previous collection of genomic biomarkers of anti-cancer drug response  which cu& Health . Besideshttps://www.cancergenomeinterpreter.org/biomarkers, https://www.cancergenomeinterpreter.org/bioactivities).The second resource is the Cancer Bioactivities database, which currently contains information on 20,243 chemical compound–protein product interactions that may support novel research applications. We built this database by compiling a catalog of available results from bioactivity assays of small molecules interacting with cancer proteins. This information was obtained by querying several external databases , as expected of tumors with a higher proportion of recurrence/relapse patients  are distributed under an open license, and the resource can be accessed via its web site at In previous examples, the systematic analysis of large datasets was facilitated by the automatic classification of cancer variants that CGI provides. However, the detailed review of these results is empowered by the inclusion in the output reports of all the annotations employed by the CGI. The ability to review these data is especially critical in the clinical research setting. In this case, the use of the CGI to analyze the list of alterations detected in a patient’s tumor could support decision-making in multiple scenarios, assessing variants of unknown significance that may have implications for response to therapy. Early clinical adopters of the CGI have used the resource to support final decisions about the most appropriate genomic-guided clinical trial to enroll cancer patients or explore potential drug re-purposing opportunities for pediatric tumors unresponsive to standard-of-care therapy . With respect to the aggregation, curation, and interpretation of the relevance of cancer variants, our team follows the standard operating procedures developed under the umbrella of the H2020 MedBioinformatics (http://www.medbioinformatics.eu/) project, thus ensuring the mid-term maintenance of these resources. Feedback from the community is also facilitated through the CGI web interface. Access to this type of cancer data is crucial for the advance of precision medicine, but is highly complex for a single institution to comprehensively manage and update. We envision that individual databases will continue to be maintained to fulfill specific needs [Crucial to the performance of the CGI are the maintenance and further development of its two distinct types of resources: the repositories of accumulated knowledge, which are continuously generated, and the bioinformatics methods to estimate the relevance of those events that are not yet validated. As new tumor cohorts are re-sequenced and analyzed, more comprehensive catalogs of cancer genes and oncogenic mutations will be obtained, including both new malignancies and new genomic elements. In particular, the possibility to identify non-coding cancer drivers  from curic needs , but ourThe CGI is a versatile platform that automates the steps proposed here for the interpretation of cancer genomes. It annotates the alterations detected in human tumors with features that may inform about their involvement in tumorigenesis. It also highlights the alterations of the tumor that constitute biomarkers of response to anti-cancer drugs, according to current levels of evidence. The CGI is easy to use, and will improve with new knowledge extracted from the study of thousands of tumors. We envision that it will become established as a useful tool in both the basic and translational cancer research settings.Additional file 1:Table S1. The features provided by different resources/methods and details about which of them are employed by the CGI. (XLS 21 kb)Additional file 2:Table S2. and Figures S1–S3. (PDF 6267 kb)Supplementary methods, use cases description,