Surgical resection is the only potential cure for colorectal cancer with synchronous liver metastases (SLM). Simultaneous resection of colorectal cancer and SLM using robotic‐assistance has been rarely reported. We demonstrate that robotic‐assisted simultaneous resection of colorectal cancer and SLMs is feasible, safe, and has potential to demonstrate good oncologic outcomes. Several retrospective studies comparing these approaches have demonstrated that simultaneous hepatic and colorectal resections are safe in select patients A 59‐year‐old man with a history of hypertension, diabetes, and dyslipidemia presented with occasional bright red blood per rectum and anemia. The patient did not endorse any personal or family history of malignancy, and denied all constitutional or dysenteric symptoms. Physical examination, including a digital rectal examination, was unremarkable. A subsequent diagnostic colonoscopy revealed a mass 12 cm from the anal verge, which was tattooed and biopsied. Histological examination revealed a moderately differentiated adenocarcinoma. Staging MRI demonstrated a T2 or possibly early T3 lesion above the peritoneal reflection with one indeterminate 5 mm lymph node within the sigmoid mesocolon  at the half‐way point between a line from the umbilical port to the anterior superior iliac spine (ASIS). Similarly, an 8‐mm robotic port was placed in the left lower‐quadrant (LLQ). A third 8‐mm robotic port was placed in the LLQ lateral and superior to the previous port. Two 5‐mm laparoscopic ports were subsequently inserted, one in the right midabdomen and one in the epigastric area Fig. .®  surgical system model S  was docked on the inferior left side of the patient, with an approximate docking time of 15 min , our tumor‐specific TME, and the potential morbidity with an anastomotic leak, it was decided to undergo proximal diversion. A loop ileostomy was fashioned in the usual manner using laparoscopic assistance. The patient was subsequently awoken from anesthesia and extubated. Blood loss was estimated to be approximately 300 cc. Total operative time was approximately 390 min. The patient was discharged on postoperative day six, tolerating a full diet. The final pathology showed a moderately differentiated adenocarcinoma with 2/36 positive nodes and clear microscopic margins at both the LAR and liver specimens. No lymph‐vascular or perineural invasion was reported. Final staging was determined to be pT3N1bM1a.Upon completion of pseudo‐adjuvant systemic therapy, the patient underwent a hypaque enema prior to reversal of his ileostomy. This revealed no evidence of an anastomotic leak; a subsequent flexible sigmoidoscopy, however, revealed a low‐grade stricture at the colorectal anastomosis requiring balloon dilatation. The patient went on to receive an uncomplicated reversal of his ileostomy followed by scheduled outpatient surveillance. At the 20‐month mark, the patient demonstrated no clinical or radiographic signs of recurrence. They were tolerating a normal diet and slowly regaining regularity in bowel movements, without any evidence of LAR syndrome on clinical assessment.® application to colorectal and liver procedures has been driven in part by the advantages it has over conventional laparoscopy, including greater range of articulation, tremor reduction, as well as improved depth perception and ergonomics. As demonstrated in this case, robot‐assisted simultaneous resection of both CRC and CRLM is feasible and safe.Interest in expanding the da Vinci'sTotal mesorectal excision, the gold standard procedure for rectal cancer, requires meticulous and precise dissection under direct vision. The complex anatomy of the pelvis, restricted space and visibility, together with diminished dexterity with laparoscopic instruments makes laparoscopic TME one of the most challenging of minimal access procedures. A robotic approach may offer a solution to some of these challenges Minimally invasive approaches in liver surgery have the potential to offer many of the same benefits as in colorectal surgery. There have been two published systematic reviews examining RALS for liver resections. Mean operative times ranged from 200 to 507 min between both reviews. The mean LOS ranged from 5.5 to 11.7 days and the conversion rates were between 4.6% and 6.6%. No perioperative mortalities were reported in any of the studies in either review ® application to colorectal and procedures has been driven in part by the advantages it has over conventional laparoscopy, including greater range of articulation, tremor reduction, as well as improved depth perception and ergonomics.A minimally invasive approach for primary CRC and liver metastasis allows for a complex operation with faster recovery and better outcomes compared to a conventional open approach. A recent systematic review by Lupinacchi et al. identified 14 studies involving laparoscopic simultaneous resections of both the primary colorectal lesion and the CLRM. There was no conversion to open resection, and mortality was null. Estimated blood loss varied between 10 and 650 mL and was not related to the type of liver or colorectal resection preformed. Length of hospital stay ranged from 4 to 54 days with an average of 9 days ®‐assisted left lateral sectionectomy and low anterior resection for a rectosigmoid primary with an associated 1.5 cm mass on segment 3 of the liver ®‐assisted resection of a primary rectal cancer 13 cm from the anal verge with liver and lung metastases Given the potential benefits of the da Vinci system over laparoscopic surgery at the operator level, its application to complex simultaneous resections could potentially be advantageous. There are case reports of combined colorectal and prostate or uterine procedures We believe this case highlights several important points. Firstly, application of the robot‐assisted daVinci system is feasible in the hands of well‐trained surgeons. Secondly, this report demonstrates that highly complex robotic‐assisted surgery can be conducted safely with regard to the intraoperative and postoperative management of patients with CRC and CRLM. Finally, this case also demonstrates that a robotic‐assisted simultaneous resection for CRC and CRLM has the potential for demonstrating good short‐ and long‐term oncologic outcomes with the potential for shorter length of stay. Further research involving larger cohort of patients is needed to confirm the efficacy of simultaneous robot‐assisted surgery with regard to both short and long‐term metrics.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.SS, JR, AA, and DH: participated in the acquisition and analysis of data, literature review, and writing of the manuscript. SC and FAQ: were involved in the medical care of the patient, drafting of the manuscript, and acquisition and analysis of data. All authors approved the final version of the manuscript.None declared.


Falco peregrinus). We examined the reestablishment of peregrine falcons on Kasatochi by evaluating the genetic relatedness among legacy samples collected in 2006 to those collected posteruption and to other falcons breeding along the archipelago. No genotypes found in posteruption samples were identical to genotypes collected from pre‐eruption samples. However, genetic analyses suggest that individuals closely related to peregrine falcons occupying pre‐eruption Kasatochi returned following the eruption and successfully fledged young; thus, a genetic legacy of pre‐eruption falcons was present on posteruption Kasatochi Island. We hypothesize that the rapid reestablishment of peregrine falcons on Kasatochi was likely facilitated by behavioral characteristics of peregrine falcons breeding in the Aleutian Islands, such as year‐round residency and breeding site fidelity, the presence of an abundant food source (seabirds), and limited vegetation requirements by seabirds and falcons.How populations and communities reassemble following disturbances are affected by a number of factors, with the arrival order of founding populations often having a profound influence on later populations and community structure. Kasatochi Island is a small volcano located in the central Aleutian archipelago that erupted violently August 8, 2008, sterilizing the island of avian biodiversity. Prior to the eruption, Kasatochi was the center of abundance for breeding seabirds in the central Aleutian Islands and supported several breeding pairs of peregrine falcons ( Biologis Figure . In partFalco peregrinus) nested on Kasatochi , are nonmigratory and remain close to their breeding islands throughout the year  found on beaches or near eyries and eggshell membranes  were collected at peregrine falcon eyries posteruption (2009–2011) of Kasatochi Island. It should be noted that juvenile feathers were molted from adult (after hatch year) birds. Posteruption feather samples were collected during the 1‐ to 3‐day field activities on the island . Legacy samples  consisted of feathers collected from two of the four active eyries or within the territories of known pairs from perches and plucking stations in 2006. Therefore, our legacy sample size represents between 25% (n = 2/8) and 87.5% (n = 7/8) of the peregrine falcons breeding in 2006. We assumed that molted feathers came from individuals that were residents of Kasatochi and not peregrines from nearby islands or nonbreeders, given their breeding site fidelity and territorial behavior , collected as part of a larger regional study from peregrine falcons breeding throughout the Aleutian Islands, were included to derive insight into the contributions of islands in the reestablishment of falcons on Kasatochi Island .DNA was extracted using a salt extraction following Talbot et al. . Genotyp2.3rxy) was calculated among pairs of peregrine falcons on Kasatochi Island within and across years and among individuals sampled throughout the archipelago, as well as averaged across all individuals within an island in a given year, using Identix 1.1  relationships, 0.25 for second‐order  relationships, 0 for unrelated individuals, and −1 for outbred individuals. Isolation‐by‐distance (IBD) analyses were conducted to determine whether islands in closer geographic proximity were also more genetically similar (FST) using Isolation by Distance web service version 3.23 . Among the posteruption samples, the genotype obtained from this same sample (Kas09‐003) was identical at all 11 loci to the genotype obtained from an eggshell membrane collected in 2010 (Kas10E02E). It is not possible that the feather and the egg shell membrane represent the same individual; rather this match likely represents a parent and its offspring, suggesting that at least one individual present on posteruption Kasatochi during 2009 returned the following year to Kasatochi Island to breed. Few first‐order familial relationships were observed between the remaining two comparisons  with a greater proportion of second‐order relationships observed  and the proportion of familial relationships decreased each subsequent year . Despite negative rxy values, greater than 66% of the comparisons indicated either a first‐ or second‐order familial relationship in 2006 and 2011  or posteruption . However, the percentage of first‐ and second‐order familial relationships among Kasatochi Island and Amatignak Island  are present on Motmot  to become established in 1985 on Anak Krakatau; the hobby was later displaced by peregrine falcon. Presumably on the Krakataus, the arrival of passerines was dependent on the presence of suitable vegetation and accompanying food source. In contrast, common avian prey species are ubiquitous  throughout the Aleutian Islands  of all the falcons that colonized Kasatochi Island following the 2008 eruption, aside from the lineage considered to have derived from temporarily displaced Kasatochi peregrines. The correlation between genetic and geographic distance increased from the pre‐eruption to the posteruption time periods, albeit not significantly, is likely due to sample size limitations. These trends suggest early posteruption recruitment from displaced prior residents occupying nearby islands, augmented in subsequent years by immigrants from other islands. Dispersal propensity would likely be a beneficial evolutionary strategy for species occupying this highly dynamic landscape. Therefore, species, such as peregrine falcons, that have rapidly colonized (or recolonized) novel habitats in this region may be predisposed to exhibit a metapopulation dynamic and possess (or evolved) characteristics that exploit this interplay of source and sink dynamics among neighboring islands. Indeed, source sink dynamics have also been characterized for mainland peregrine falcons (e.g., Kauffman, Pollock, & Walton, The authors have no conflict of interest to declare.


Azoarcus sp. CIB strain harbouring the bzd cassette was shown to behave as a valuable biocatalyst for anaerobic toluene valorization towards the synthesis of poly‐3‐hydroxybutyrate (PHB), a biodegradable and biocompatible polyester of increasing biotechnological interest as a sustainable alternative to classical oil‐derived polymers.Microorganisms able to degrade aromatic contaminants constitute potential valuable biocatalysts to deal with a significant reusable carbon fraction suitable for eco‐efficient valorization processes. Metabolic engineering of anaerobic pathways for degradation and recycling of aromatic compounds is an almost unexplored field. In this work, we present the construction of a functional bzd cassette encoding the benzoyl‐CoA central pathway for the anaerobic degradation of benzoate. The bzd cassette has been used to expand the ability of some denitrifying bacteria to use benzoate as sole carbon source under anaerobic conditions, and it paves the way for future pathway engineering of efficient anaerobic biodegraders of aromatic compounds whose degradation generates benzoyl‐CoA as central intermediate. Moreover, a recombinant  Due to the thermodynamic stability of the aromatic ring, aromatic compounds are difficult to degrade and they tend to persist in the environment for long periods of time. Many of these compounds are toxic and/or carcinogenic thus representing major persistent environmental pollutants. Therefore, removal of aromatic compounds is very important both for a balanced global carbon budget and to protect wildlife and human health. Some specialized microorganisms  have adapted to use aromatic compounds as sole carbon and energy source  or, at least, partially degrade these molecules to less‐toxic and persistent compounds , the aromatic ring is de‐aromatized by reductive reactions . The different peripheral pathways converge into a few central pathways that carry out the reductive de‐aromatization and further conversion of the central intermediates to compounds of the central metabolism of the cell. Most monocyclic aromatic compounds are channelled and activated to benzoyl‐CoA. The catabolic genes encoding the benzoyl‐CoA central pathway enzymes are usually arranged in large chromosomal clusters that also contain the specific transcriptional regulators  a wide range of aromatic compounds including some toxic hydrocarbons such as toluene , have been characterized at the molecular level in strain CIB , a biodegradable and biocompatible polyester of increasing biotechnological interest as a sustainable alternative to classical oil‐derived polymers  from plasmid pECOR8 (Table bzd cluster (genes bzdRbzdNOPQMSTUVWX) was cloned as a XbaI/NcoI‐double digested fragment from the recombinant λBzd1 phage  to Azoarcus sp. CIBdbzdN (recipient strain) as previously described  (Table −1)‐containing MC medium with 10 mM glutarate as sole carbon source for counterselection of donor cells. The presence of plasmid pLB1 in Azoarcus sp. CIBdbzdN cells restored their anaerobic growth on benzoate and caused the consumption of this carbon source, as in the case of the wild‐type CIB strain containing plasmid pIZ1016 as control  strain was able to grow anaerobically using benzoate as sole carbon and energy source (doubling time of about 15 h), confirming that the bzd cassette was functional in heterologous hosts and conferred the ability to degrade benzoate in anoxic conditions  (PHB) up to 5.2% of the cell dry weight (CDW) during anaerobic growth on toluene using nitrate as final electron acceptor  of the methanolysed polyester as previously described  cells were compared with those in the wild‐type Azoarcus sp. CIB cells. As shown in Fig. bzd gene dosage enhances the anaerobic degradation of benzoate in Azoarcus sp. CIB. Then, we monitored the accumulation of PHB in Azoarcus sp. CIB (pLB1) cells grown anaerobically on 400 mM toluene supplied in 2,2,4,4,6,8,8‐heptamethylnonane carrier phase. PHB production was quantified from cells harvested at mid‐exponential phase, as previously done with the wild‐type CIB strain. Interestingly, the bzd cassette caused accumulation of PHB up to 35% CDW in Azoarcus sp. CIB (pLB1)  cells grow anaerobically on toluene, the bzd cassette enhances 2.7‐fold the bio‐production of PHB with respect to that observed in wild‐type cells. The higher conversion of toluene into PHB was also confirmed by transmission electron microscopy, which revealed an increase in number and size of PHB granules in recombinant cells    cells grown on m‐xylene (Fig. Azoarcus sp. CIB strain harbouring the bzd cassette as a valuable environmentally friendly strategy for the efficient anaerobic conversion of some petrochemical waste into added value products, such as bioplastics, relevant to the circular economy.This work is a proof of concept of the potential of metabolic engineering for the anaerobic bioconversion of aromatic compounds towards the production of valuable products. We have engineered the first broad‐host range metabolic bzd cassette for the anaerobic degradation of benzoate. The bzd cassette has been used to expand the ability of some denitrifying bacteria to use benzoate as sole carbon source under anaerobic conditions, and it paves the way for future pathway engineering of efficient anaerobic biodegraders of aromatic compounds. Moreover, we have developed a recombinant The authors declare no conflict of interest.


Sternula antillarum athalassos) and piping plover (Charadrius melodus) in the Platte River basin in Nebraska, USA, have embraced the idea that these species are physiologically adapted to begin nesting concurrent with the cessation of spring floods. Low use and productivity on contemporary Platte River sandbars have been attributed to anthropomorphically driven changes in basin hydrology and channel morphology or to unusually late annual runoff events. We examined distributions of least tern and piping plover nest initiation dates in relation to the hydrology of the historical central Platte River (CPR) and contemporary CPR and lower Platte River (LPR). We also developed an emergent sandbar habitat model to evaluate the potential for reproductive success given observed hydrology, stage–discharge relationships, and sandbar height distributions. We found the timing of the late‐spring rise to be spatially and temporally consistent, typically occurring in mid‐June. However, piping plover nest initiation peaks in May and least tern nest initiation peaks in early June; both of which occur before the late spring rise. In neither case does there appear to be an adaptation to begin nesting concurrent with the cessation of spring floods. As a consequence, there are many years when no successful reproduction is possible because emergent sandbar habitat is inundated after most nests have been initiated, and there is little potential for successful renesting. The frequency of nest inundation, in turn, severely limits the potential for maintenance of stable species subpopulations on Platte River sandbars. Why then did these species expand into and persist in a basin where the hydrology is not ideally suited to their reproductive ecology? We hypothesize the availability and use of alternative off‐channel nesting habitats, like sandpits, may allow for the maintenance of stable species subpopulations in the Platte River basin.Investigations of breeding ecology of interior least tern ( The Pla) Figure . The decThe first investigation of breeding ecology of least tern and piping plover along the CPR was conducted in 1979 Faanes, . Faanes The hydrology of the CPR and LPR is characterized by two spring rises, one in early spring due to localized snowmelt and one in the late spring due to snowmelt and precipitation runoff from basin headwaters in the high plains and Rocky Mountains in Colorado and Wyoming, USA  were of specific interest in this study. However, with the exception of a 5‐year period from 1902 to 1906, they were unavailable prior to 1915  controlling the height of sandbars in the analysis year. The 1.5‐year period for identification of DISCHHAB allowed for sandbar persistence through two nesting seasons.Identify maximum daily discharge for the period from 1 January the year prior to each analysis year and ending 1 July of the analysis year (hydrology methods presented in Section HAB) of the habitat‐forming discharge for each year using DISCHHAB and gage stage–discharge relationship  for each nesting season by subtracting sandbar height (BAR HEIGHT) relative to peak stage  during the least tern and piping plover nesting and brood rearing seasons of each year using mean daily discharge and stage–discharge relationships.Calculate daily stage (STAGEDAILY) to sandbar stage (STAGEBAR) to determine whether bar height exceeded river stage .Compare daily river stage  to be highest in the LPR reach and lowest in the historical AHR Table . However3.3Sandbar model performance in predicting the potential for nest inundation was assessed through examination of observed nest losses in relation to habitat forming and inundating flows. In 1947, a mean daily peak discharge of 394 cm occurred in the AHR on 23 June. On‐channel nests observed in 1948 were inundated twice even though the highest mean daily peak discharge during the 1948 nesting season was 127 cm which is well below the previous year peak of 394 cm. This indicates that sandbars used by the species in 1948 were formed to an elevation well below the stage associated with the previous year peak.In 1978, discharge in the AHR peaked at 297 cm. Faanes  reportedSimilarly, a discharge of 2,379 cm within the LPR at Louisville in 2008 produced sandbar habitat inundated by a discharge of 595 cm in 2009, flooding 50 least tern and 14 piping plover nests  channel supports least tern and piping plover reproductive levels that are sufficient to maintain species subpopulations. Within the contemporary AHR and LPR, piping plovers nest from late April to early August with the highest proportion of nests being initiated during May. Least terns breed and nest from mid‐May to early August with the highest nesting incidence occurring in early June. As a result, a preponderance of nests is often initiated prior to the late spring rise and is lost to inundation. The potential for successful reproduction is then dependent upon renesting. The timing of the late spring rise in relation to the piping plover nesting season severely limits the potential for successful reproduction as chicks from nests initiated in late June or early July would not fledge until September. Least terns have a greater potential for successful renesting given their incubation and brood rearing period is about 2 weeks shorter than piping plovers.Three‐year running average fledge ratios of 1.13 fledglings/pair for piping plovers and 0.70 fledglings/pair for least terns have been proposed as necessary to maintain a stable to growing piping plover and least tern populations in the AHR Lutey, . The hisThe potential for maintenance of stable on‐channel piping plover subpopulations in the contemporary AHR and LPR segments is also low. During years that have a potential for reproductive success, average piping plover fledge ratios required to maintain a stable subpopulation within the contemporary AHR (1.95 fledglings/pair) and LPR (2.40 fledglings/pair) are substantially higher than average fledge ratios observed on constructed habitats within the AHR, 2010–2015 (Cahis & Baasch, Why then, do these species occur along the Platte River? An alternative view is suggested by historical and contemporary species use of both in‐ and off‐channel habitats. The earliest species observations in the AHR include documentation of nesting on natural sandbars, artificially created on‐channel islands comprised of spoil from a sandpit operation, and at an off‐channel sandpit Wycoff, . In the In the contemporary LPR and AHR, these species routinely make use of off‐channel habitats regardless of whether on‐channel habitat is available or not Baasch, , 2013. TSince 2007, the program has implemented an Adaptive Management Plan to explore key uncertainties related to the response of least tern and piping plover to management actions on the CPR PRRIP, . A primaThe authors are unaware of any real or perceived conflicts of interest.


In the version of this article that was originally published , most have focused on identifying its plant origin. Past studies have often relied upon diagnostic phytochemicals  or the study of pollen in honey  (Alves and Santos 2014). Although the latter approach requires considerable expertise and cannot distinguish many plant species (Kaškonienė and Venskutonis 2010), yet it is a powerful diagnostic tool, especially when used with other methods . However, melissopalynology is ineffective in cases where low value honey is filtered to remove its source pollen and spiked with pollen from the desired monoflora (Kaškonienė and Venskutonis 2010).”The authors wish to acknowledge the article “Rapid identification of the botanical and entomological sources of honey using DNA metabarcoding” by Sean W.J. Prosser and Paul D.N. Hebert as reference for this paragraph (Prosser and Hebert


Segmentation of the spinal cord was poor (Dice coefficient 0.37). The process of automatic segmentation was significantly better on MRI compared to CT for orbits, parotid glands, brainstem, and left lymph node level II by multiple positional metrics; spinal cord segmentation based on MRI was inferior compared with CT. Accurate atlas‐based automatic segmentation of OAR and lymph node levels is feasible using T1‐MRI; segmentation of the spinal cord was found to be poor. Comparison with CT‐based automatic segmentation suggests that the process is equally as, or more accurate, using MRI. These results support further translation of MRI‐based segmentation methodology into clinical practice.Atlas‐based autosegmentation is an established tool for segmenting structures for CT‐planned head and neck radiotherapy. MRI is being increasingly integrated into the planning process. The aim of this study is to assess the feasibility of MRI‐based, atlas‐based autosegmentation for organs at risk (OAR) and lymph node levels, and to compare the segmentation accuracy with CT‐based autosegmentation. Fourteen patients with locally advanced head and neck cancer in a prospective imaging study underwent a T1‐weighted MRI and a PET‐CT (with dedicated contrast‐enhanced CT) in an immobilization mask. Organs at risk  and the left level II lymph node region were manually delineated on the CT and MRI separately. A ‘leave one out’ approach was used to automatically segment structures onto the remaining images separately for CT and MRI. Contour comparison was performed using multiple positional metrics: Dice index, mean distance to conformity (MDC), sensitivity index (Se Idx), and inclusion index (Incl Idx). Automatic segmentation using MRI of orbits, parotids, brainstem, and lymph node level was acceptable with a DICE coefficient of PACS number(s): 87.55.de Intensity‐modulated radiotherapy (IMRT) for the treatment of head and neck cancers is now established as a standard of care.Data suggest that head and neck cancer target volumes are difficult to contour with higher interobserver variation by comparison with other anatomical sites.Currently radiotherapy dose calculation is based upon CT imaging. However, the accuracy of target delineation for head and neck cancers is limited by the lack of soft‐tissue contrast on CT. We have conducted a prospective imaging study evaluating multimodality imaging in radiotherapy planning.≥18 years old; WHO performance status of 0−2; histologically proven stage III or IV nonnasopharyngeal locally advanced squamous cell carcinoma of the head and neck region; and a clinical decision to treat with a course of radiotherapy or concurrent chemoradiotherapy with curative intent, and fully informed consent. This study was approved by the Research Ethics Committee ; ISRCTN Registry: ISRCTN34165059.Fifteen patients entered this single‐center prospective study; one patient withdrew consent prior to imaging. The eligibility criteria for the study were: aged B.1FDG PET‐CT imaging was performed on a 64‐section GE Discovery 690 PET‐CT system , as previously described.B.2TR=831ms, TE=8.6 ms, 105×2 mm thick contiguous slices, acquired voxel size=0.9×0.9×2.0 mm) was performed.Images were acquired on a 1.5 T Siemens Magnetom Avanto , as previously described.Manual delineation was performed by a medical student and checked by a senior clinical oncologist on the MRI T1 postcontrast sequence and on the contrast‐enhanced CT images separately. OAR delineated were left and right parotid glands, left and right orbits, brainstem, and spinal cord in all patients. Brainstem was delineated from the junction of pons and medulla down to the foramen magnum. Spinal cord was delineated from below foramen magnum down to the inferior aspect of the C6 vertebral body. As a proof of principle the left nodal level II was delineated in all patients with no radiological evidence of lymph node in the left neck according to the 2013 DAHANCA, EORTC, HKNPCSG, NCIC CTG, NCRI, RTOG, TROG consensus guidelines.Contours were generated for OAR  in all patients and for the left lymph node level II in patients with no radiological evidence of lymph node disease in the left neck using a ‘leave‐one‐out’ multiatlas method of automatic segmentation. For each patient the leave‐one‐out approach selected each patient in turn as a target patient and used all other patients in the study as atlas patients. A deformable image registration was then performed between each atlas patient to the target patient. Registrations were performed using commercial image registration software , using standard registration presets intended for same‐patient registrations. Once registered, structures were transposed from each atlas patient to the target patient using the deformation vector field. A form of majority voting was used to combine structures from each atlas to leave one automated structure. This was performed on MRI and CT separately.Vtest is the volume of the test structure and Vreference is the volume of the reference structure:Accuracy of the automatic contours was determined by comparing them to the manual contours, regarded as the gold standard in this study. This is because delineation of OAR remains the ‘gold standard’ in terms of accuracy.Se Idx is a measure of the probability that the automatic contour matches the reference manual contour. The Incl Idx is the probability that a voxel of the autocontour is really a voxel of the reference manual contour.The Se Idx and Incl Idx calculate the overlap volume between the test and reference contours as a percentage of either the test or reference contours for Incl Idx and Se Idx, respectively see Eqs. . Both int‐test was used for significance testing between volume and positional metrics. Results were considered significantly different if the p‐value was <0.05.A two‐tailed paired Fourteen patients with nonnasopharyngeal squamous cell carcinoma underwent pretreatment MRI and PET‐CT imaging in an immobilization mask. Median age was 56 yr (range 39–69). Eleven patients had oropharyngeal carcinoma and three patients had laryngohypopharyngeal carcinoma. One had stage III and 13 patients had IV disease . Nine patients had no radiological evidence of nodal disease in the left neck; scans from these nine patients were used for contouring the left level II nodal structure. Mean volumes of each OAR and the left level II structures both manually and automatically delineated on MRI and CT are shown in Significant differences were found in the volume of manually delineated orbits and brainstem on MRI compared with CT. Automatically segmented volumes for the orbits and parotids were significantly larger for MRI compared with CT, whilst the spinal cord was significantly smaller.The mean positional contour comparison metrics are shown in Atlas‐based segmentation is a method by which a reference or atlas image is registered to a new image and the corresponding structures transposed on the new image. The quality of structure segmentation is dependent upon multiple factors, including the quality of the atlas, the similarity of the structure in the atlas and the new image, and the contrast within the images by which the structure can be defined.There is considerable enthusiasm to increase the role of MRI in head and neck radiotherapy planning, making use of superior soft‐tissue contrast to improve target volume and OAR delineation; in addition, functional MRI sequences may allow individualization/adaptation of treatment approaches.0.73−0.91. By contrast, the data clearly show that the methodology failed to accurately segment the spinal cord. A potential reason for this may be that the spinal cord is a long structure and registration on MRI may not be as accurate over such a length. An alternative explanation may be to do with image registration algorithms having a capture range;Our data have demonstrated that atlas‐based automatic segmentation based on MRI is able to accurately segment multiple OAR  and a lymph node level, based on multiple metrics of volume and positional analysis. For example, the DICE index for these structures was high, ranging between For comparative purposes, we have performed a similar atlas‐based automatic segmentation on the same structures delineated on CT. This method is comparative and the ‘gold standard’ for CT and MRI are separately defined, in the absence of an absolute ground truth that can be derived from CT or MRI. However, this method is instructive to compare the accuracy of the automatic segmentation process on MRI with a method that is already in clinical use for CT‐based radiotherapy planning. It is interesting to note that, on multiple positional parameters for structures other than the spinal cord, the process appears similar or more accurate when performed MRI. This not only validates the feasibility of MRI‐based, atlas‐based automatic segmentation, but additionally provides encouragement that the process has the potential to harness the soft‐tissue contrast of MRI to come closer to the ground truth.There are several limitations to this study. There is no consensus on the appropriate size or inclusion criteria of atlas for atlas‐based segmentation.These data demonstrate the feasibility of accurate atlas‐based automatic segmentation of OAR and lymph node levels using T1‐weighted MRI; segmentation of the spinal cord was found to be inaccurate. Comparison with CT‐based automatic segmentation suggests that the process is equally or more accurate using MRI. These results support further translation of MRI‐based segmentation methodology into clinical practice.This work is licensed under a Creative Commons Attribution 3.0 Unported License.Supplementary MaterialClick here for additional data file.


HC) and biparietal diameter (BPD) (outer‐to‐outer (BPDoo) vs outer‐to‐inner (BPDoi) caliper placement), and compare acquisition of these measurements in transthalamic (TT) vs transventricular (TV) planes.To compare the standard methods for ultrasound measurement of fetal head circumference  and HC in TT and TV planes were obtained by pairs of sonographers. Reproducibility of measurements made by the same (intraobserver) and by different (interobserver) sonographers, as well as the reproducibility of caliper placement and measurements obtained in different planes, was assessed using Bland–Altman plots.This study utilized ultrasound images acquired from women participating in the Oxford arm of the BPDoo and BPDoi. Neither method for measuring BPD showed consistently better reproducibility. In Phase II, we analyzed ultrasound images of 100 different singleton fetuses. The mean intraobserver and interobserver differences were < 1% (2.26 mm) and the 95% limits of agreement were < 8% (14.45 mm) for all fetal head measurements obtained in TV and TT planes. Neither plane for measuring fetal head showed consistently better reproducibility. Measurement of HC using the ellipse facility was as reproducible as HC calculated from BPD and OFD. OFD by itself was the least reproducible of all fetal head measurements.In Phase I, we analyzed ultrasound images of 108 singleton fetuses. The mean intraobserver and interobserver differences were < 2% (1.34 mm) and the 95% limits of agreement were < 5% (3 mm) for both BPDoi and BPDoo are equally reproducible; however, we believe BPDoo should be used in clinical practice as it allows fetal HC to be measured and compared with neonatal HC. For all head measurements, TV and TT planes provide equally reproducible values at any gestational age, and HC values are similar in both planes. Fetal head measurement in the TT plane is preferable as international standards in this plane are available; however, measurements in the TV plane can be plotted on the same standards. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.Measurements of  Linked Comment: Ultrasound Obstet Gynecol 2016; 48: 26–26 Unfortunately, even after decades of clinical practice, guidelines still vary as to how the measurements should be taken, i.e. whether the biparietal diameter (BPD) should be measured by outer‐to‐outer (BPDoo) or outer‐to‐inner (BPDoi) caliper placementellipsevs HCcalculated) and BPD  on ultrasound and (ii) the effect of acquiring head measurements in TT vs TV planes, so as to make recommendations regarding best practice.In this study, we aimed to compare (i) the standard methods for measuring fetal HC (HCst Project (www.intergrowth21.org.uk), a multicenter, multiethnic, population‐based project, conducted between 2008 and 2014 across eight countriesst Project, which aimed to construct international standards for fetal growth. All women included in our study were part of the FGLS. In the FGLS, serial two‐dimensional ultrasound scans were performed every 5 ± 1 weeks, from 14 + 0 to 41 + 6 weeks' gestation, and images were stored for later analysis. Inclusion criteria for the FGLS were pregnant women with a known, certain last menstrual period, who had regular menstrual cycles and were not taking hormonal contraceptives or breastfeeding in the 2 months before they conceived naturally. Gestational age was calculated using the last menstrual period, with ultrasound confirmation based on a crown–rump length measurement at 9 + 0 to 13 + 6 weeks' gestation that was in agreement by ≤ 7 daysThis study involved women at low risk of adverse pregnancy outcome who were recruited into the Oxford arm of the INTERGROWTH‐21ellipse were acquired in triplicate in the TT plane. The same commercially available ultrasound machine  with curvilinear abdominal transducers  was used at all study sites. For the purposes of the INTERGROWTH‐21st Project, the manufacturer reprogrammed the machine's software to ensure that measurement values did not appear on the screen, so as to reduce operator ‘expected value’ biasst Project was approved by the Oxfordshire Research Ethics Committee ‘C’ (reference: 08/H0606/139) and all participants gave written informed consent.All ultrasound scans in the FGLS were performed by sonographers who were trained, standardized and regularly auditedUsing the stored ultrasound images acquired in the FGLS, two sonographers twice measured the BPD using two methods . Sonographer B repeated the caliper placements on the images acquired by Sonographer A, resulting in a total of 36 measurements. HC was also calculated from BPD and OFD  for each image.Each sonographer placed the calipers once on each of the four images acquired per participant  intraobserver reproducibility of caliper placement for measurement of BPD using the BPDoo and BPDoi method, calculated for Sonographers A and B; and (ii) interobserver reproducibility of caliper placement for measurements of BPD using the BPDoo and BPDoi method, comparing the first measurements of Sonographer A with those of Sonographer B, and the second measurements of Sonographer A with those first obtained by Sonographer B.In Phase II, the following analyses were performed: (i) intraobserver reproducibility of plane acquisition and caliper placement for TT and TV planes, comparing each sonographer's first and second measurements in the same plane; (ii) interobserver reproducibility of plane acquisition and caliper placement for TT and TV planes, comparing measurements of Sonographers A and B in the same plane; (iii) caliper replacement reproducibility, based on Sonographer B replacing the calipers on the images acquired by Sonographer A in the TT and TV planes (interobserver reproducibility); (iv) intraobserver reproducibility of plane acquisition and caliper placement between TT and TV planes, comparing the measurements of Sonographer A acquired in the TT plane with those acquired by Sonographer A in the TV plane ; and (v) interobserver reproducibility for plane acquisition and caliper placement between TT and TV planes, comparing the measurements of Sonographer A acquired in the TT plane with those acquired by Sonographer B in the TV plane, and then the measurements of Sonographer B acquired in the TT plane with those acquired by Sonographer A in the TV plane.Intraobserver and interobserver variability were expressed as a percentage to account for increasing fetal head size with gestational age. Percentages were calculated as the difference between two measurements divided by the average of the two measurements, multiplied by 100. Reproducibility was assessed using Bland–Altman plots. All plots and analyses were performed using STATA 11 .t‐tests, as appropriate, were performed to assess mean differences between measurements obtained by the same sonographer (intraobserver reproducibility) and different sonographers (interobserver reproducibility), and those obtained in two different planes (between‐plane reproducibility). A P‐value of < 0.05 was considered statistically significant.Paired or unpaired Four women were included in the study at each gestational week, from 15 to 41 weeks in Phase I (108 women) and from 16 to 40 weeks in Phase II (100 women), resulting in a total of 4464 measurements. The demographic characteristics of the 208 participants are shown in Table  A total of 864 measurements were obtained in Phase I. Intraobserver and interobserver reproducibility was very good overall. The mean differences were < 2% (1.34 mm) and the 95% limits of agreement were < 5% (3 mm) for both BPDoo and BPDoi (Table  ellipse) were obtained in Phase II. HCellipse was marginally larger, by 0.09% , when measured in the TV than when measured in the TT plane. However, no such difference was observed for BPD or OFD. In terms of overall reproducibility, the mean differences in fetal head measurements were < 1% (2.26 mm) and the 95% limits of agreement were < 8% (14.45 mm) for both TV and TT planes .A total of 3600 measurements  were only slightly wider than the limits of agreement between TV and TT planes acquired and measured by the same sonographer (intraobserver reproducibility between TT and TV planes). This suggests that the effect of two sonographers measuring in the same plane is similar to that of the same sonographer measuring in different planes. The 95% limits of agreement were highest when two sonographers measured in different planes (interobserver reproducibility between TT and TV planes)  to measure HC was marginally more reproducible than using the two‐diameters method , with the former having interobserver 95% limits of agreement of just below 5% and the latter having interobserver 95% limits of agreement of just above 5%. This is probably due to the contribution of the OFD, which is the least reproducible head measurement in the two‐diameters method.We found no major differences in the reproducibility of caliper placement for measuring BPDoo or BPDoi. Similarly, there was no difference in the reproducibility of measuring HC in the TV or TT planes. Using the ellipse facility . Furthermore, when comparing the reproducibility of measuring HC in the TT and TV planes, the difference between sonographers measuring in the same plane was similar to that of the same sonographer measuring in different planes.There are some limitations to our study. It can be argued that the use of six different sonographers working in pairs (rather than one pair) might have had an impact on the results. However, we feel that the study design more accurately reflects clinical practice, as most units have several qualified sonographersellipse were reproducible, with a mean difference of 3.5 mm and limits of agreement of < 12 mm (5%), in line with our resultsvs TT) in the same population.A literature search was performed to identify all publications reporting reproducibility in the evaluation of fetal head biometry. We searched MEDLINE using the following keywords: biparietal diameter OR BPD OR occipitofrontal diameter OR OFD OR head circumference OR HC AND fetal OR foetal OR fetus OR foetus AND ultrasound OR ultrasonogra* OR ultra‐sonogra* OR sonic* OR scan* AND reproducibility OR variability OR repeatability. Restrictions that were applied were studies in humans, in the English language and published after 1970. Additional references were added from an important articlecalculated) for monitoring growth from the ‘womb to the classroom’ellipse were associated with slightly better interobserver reproducibility than using HCcalculated, based on BPD and OFD. However, there was no large difference in reproducibility of BPD, OFD or HCellipse measured in the TV compared with TT plane. The mean difference in head size between these two planes was also minimal (< 1%) at every gestational age.In conclusion, using modern ultrasound equipment, measurement of BPD is equally reproducible irrespective of whether calipers are placed BPDoo or BPDoi. However, BPDoo can be used for both BPD and HC measurements and is also the method to measure OFD. It therefore seems simplest to use BPDoo as a conceptually similar methodological approach for all head measurements. BPDoo is also clinically useful (as part of the HCellipse, all measured in the TT plane, based on the reproducibility evidence presented in this study and the existence of international standards based on these methods. In centers in which HC is measured in the TV plane, use of the international standards is still appropriateWe therefore recommend that standard fetal head biometry measurements are performed using the BPDoo, OFD and HCTable S1 and Figures S1–S7 may be found in the online version of this article.Click here for additional data file.


PHIs) that enable viruses to enter into the host cells and manipulate the cellular mechanisms to their own advantage. Experimentally‐verified protein–protein interaction (PPI) data of pathogen–host systems only became available at large scale within the last decade. In this study, we comparatively analyzed the current PHI networks belonging to DNA and RNA viruses and their human host, to get insights into the infection strategies used by these viral groups. We investigated the functional properties of human proteins in the PHI networks, to observe and compare the attack strategies of DNA and RNA viruses. We observed that DNA viruses are able to attack both human cellular and metabolic processes simultaneously during infections. On the other hand, RNA viruses preferentially interact with human proteins functioning in specific cellular processes as well as in intracellular transport and localization within the cell. Observing virus‐targeted human proteins, we propose heterogeneous nuclear ribonucleoproteins and transporter proteins as potential antiviral therapeutic targets. The observed common and specific infection mechanisms in terms of viral strategies to attack human proteins may provide crucial information for further design of broad and specific next‐generation antiviral therapeutics.Viruses are obligatory intracellular pathogens and completely depend on their hosts for survival and reproduction. The strategies adopted by viruses to exploit host cell processes and to evade host immune systems during infections may differ largely with the type of the viral genetic material. An improved understanding of these viral infection mechanisms is only possible through a better understanding of the pathogen–host interactions ( DNAdeoxyribonucleic aciddsDNAdouble‐stranded DNAdsRNAdouble‐stranded RNAEBVEpstein–Barr virusGOgene ontologyHNRPheterogeneous nuclear ribonucleoproteinKEGGKyoto Encyclopedia of Genes and GenomeskobasKEGG Orthology Based Annotation SystemPHIpathogen–host interactionphistopathogen–host interaction search toolPPIprotein–protein interactionRNAribonucleic acidssDNAsingle‐stranded DNAssRNA(−)negative‐sense single‐stranded RNAssRNA(+)positive‐sense single‐stranded RNAssRNAsingle‐stranded RNAViral infections pose ever‐increasing danger to the human beings because of emerging and reemerging diseases. Their high mutation rates enable viruses to easily develop drug resistance towards the conventional therapeutics, which mainly inhibit essential viral proteins. This makes the problem more serious, since most of the current antiviral drugs are hardly effective to the resistant virus strains. Therefore, the efforts on the next‐generation antiviral drug discovery have been focused on finding host‐oriented drug targets, which act on cellular functions essential in the virus life‐cycle Viral families are grouped based on their type of nucleic acid as genetic material, DNA or RNA Owing to their very small genome sizes, viruses have restricted life capabilities and must enter into the host cells to replicate, assemble and propagate. They have evolved to develop strategies to manipulate host cell mechanisms to control their own life cycles and also to disable antiviral responses of host immune systems et al. (2012) experimentally found 1681 PHI data between 70 viral proteins and 579 human proteins and then comparatively analyzed this dataset in terms of common and specific infection strategies used by DNA and RNA viruses. Here, we comparatively analyzed the current experimental PHI data belonging to DNA and RNA viruses, covering 19 033 PHIs between 1061 viral proteins and 4943 human proteins. The PHI data were obtained from phisto which is a comprehensive database of pathogen–human PPIs Despite the availability of detailed models of virus structures, replication machineries, and patho‐physiologies, a more functional analysis of virus–host molecular interactions is required to capture a systems view of viral infection mechanisms in host cells. Considering the preliminary efforts on the high‐throughput experimental studies phisto) was developed by our group due to the lack of a comprehensive PHI database in the Web phisto also provides integrated bioinformatic tools for visualization of PHI networks and topological/functional analysis of pathogen‐targeted human proteins through its user‐friendly interface (www.phisto.org). Ongoing studies on phisto are for covering experimental PHI data belonging also to other mammalian species as host organism.Pathogen–host interaction search tool , RNA viruses (RNA viruses‐targeted set), only DNA viruses, i.e. not targeted by any RNA viruses (only DNA viruses‐targeted set), and only RNA viruses, i.e. not targeted by any DNA viruses (only RNA viruses‐targeted set) were constructed to observe the characteristics specific to DNA and RNA viruses with respect to their interactions with human proteins. For a deeper comparison between DNA and RNA viral infections, human proteins interacting with at least four DNA virus families (4‐DNA viruses‐targeted set), as well as human proteins interacting with at least four RNA virus families (4‐RNA viruses‐targeted set) were used. On the other hand, to obtain the common infection strategies of viral pathogens, sets of human proteins targeted by all viruses, i.e. targeted by DNA and/or RNA viruses (viruses‐targeted set) and the ones targeted by both DNA and RNA viruses together (DNA‐RNA viruses‐targeted set) were also analyzed. The number of virus‐targeted human proteins covered by each set is tabulated in Table bingo plug‐in of Cytoscape P‐value of at most 0.05 were considered after an enrichment calculation with hypergeometric test and then Benjamini and Hochberg false discovery rate correction. All three GO terms  were scanned to identify the terms having significant association with each virus‐targeted human protein set studied.Gene ontology (GO) kobas (ver. 2.0) kobas platform uses hypergeometric test and Benjamini and Hochberg correction method. In this study, P‐value was set to 0.05 to obtain enriched human pathways for the virus‐targeted protein sets.Pathway enrichment analysis of the human protein sets was performed using the Web‐based tool, The visualization of virus–human networks Fig.  providesThe distribution of 4943 viruses‐targeted human proteins based on their attacking virus types can be observed from the number of proteins in the human protein sets  in the highly targeted human proteins list . HNRPs are RNA‐binding proteins, which function in processing heterogeneous nuclear RNAs into mature mRNAs and in regulating gene expression. Specifically, they take role in the export of mRNA from the nucleus to the cytoplasm. They also recruit regulatory proteins associated with pathways related to DNA and RNA metabolism Moreover, our analyses also reflected that proteins functioning in transport and localization related processes within the cell are targeted highly by both DNA and RNA viruses, i.e. IMA1, ADT2, TCPG, and TCPE. IMA1  functions mainly in nuclear import as an adapter protein for nuclear receptor KPNB1 (Karyopherin beta 1). Interacting with IMA1 enables viruses to enter the nucleus and consequently to use the host's transcriptional machinery. Besides, viruses may interact with IMA1 in order to inhibit the host antiviral response, since nuclear import factors regulate the transport of innate immune regulatory proteins to the nucleus of cells to activate the antiviral response EF1A1 and EF1A3 function as translation elongation factors in protein biosynthesis. EF1A proteins promote the GTP‐dependent binding of aminoacyl‐tRNA to the A‐site of ribosomes during protein biosynthesis with a responsibility of achieving accuracy of translation Interacting with human transcription factors was reported as one of the main viral infection strategies Among the highly targeted human proteins in Table Gene ontology and pathway enrichment analyses of pathogen‐targeted host proteins are widely used in bioinformatic analysis of PHI networks to understand the attack strategies of pathogens Our observation of the enriched GO process terms for human proteins targeted by only DNA viruses Table  may leadFurther investigation of the enriched processes of human proteins attacked by multiple DNA viruses Table  pointed P‐values of the enriched GO process terms are very low, indicating statistically strong results (Table In the case of human proteins targeted by both DNA and RNA viruses, the ts Table . The mosP‐value (Table A comparative investigation of the enriched pathway terms for human protein sets targeted by only DNA viruses and by only RNA viruses Table  reveals ue Table . Both viIn this study, an initial system‐level understanding of viral infection mechanisms through PHI networks was pursued by comparing DNA and RNA viruses, aiming to provide a framework for further investigations of infection mechanisms in the light of more precise information on pathogen–host systems in the near future. Ongoing studies and increasing amounts of experimentally‐verified PHI data will further improve our understanding of the interplay between pathogens and human and hopefully identify novel and effective therapeutics for infectious disesases.SD and KÖÜ conceived the study. SD performed the study. SD and KÜÖ prepared the manuscript.Data S1. DNA viruses–human PHI data.Click here for additional data file.Data S2. RNA viruses–human PHI data.Click here for additional data file.Data S3. Number of targeting DNA/RNA virus families for each targeted human proteins.Click here for additional data file.Data S4. GO enrichment results for the human protein sets.Click here for additional data file.Data S5. Pathway enrichment results for the human protein sets.Click here for additional data file.


Puma concolor) movement across the state of Arizona in the American Southwest and to identify those most likely to be impacted by current and future human land uses, particularly expanding urban development and associated increases in traffic volume. Human populations in this region are expanding rapidly, with the potential for urban centers and busy roads to increasingly act as barriers to demographic and genetic connectivity of large‐bodied, wide‐ranging carnivores such as pumas, whose long‐distance movements are likely to bring them into contact with human land uses and whose low tolerance both for and from humans may put them at risk unless opportunities for safe passage through or around human‐modified landscapes are present. Brownian bridge movement models based on global positioning system collar data collected during bouts of active movement and linear mixed models were used to model habitat quality for puma movement; then, a wall‐to‐wall application of circuit theory models was used to produce a continuous statewide estimate of connectivity for puma movement and to identify pinch points, or bottlenecks, that may be most at risk of impacts from current and future traffic volume and expanding development. Rugged, shrub‐ and scrub‐dominated regions were highlighted as those offering high quality movement habitat for pumas, and pinch points with the greatest potential impacts from expanding development and traffic, although widely distributed, were particularly prominent to the north and east of the city of Phoenix and along interstate highways in the western portion of the state. These pinch points likely constitute important conservation opportunities, where barriers to movement may cause disproportionate loss of connectivity, but also where actions such as placement of wildlife crossing structures or conservation easements could enhance connectivity and prevent detrimental impacts before they occur.This study sought to identify critical areas for puma ( Here, habitat quality refers not to the general condition of the landscape, but to the relative frequency or probability of use for puma movement . A wide variety of vegetation communities was present, including ponderosa pine (Pinus ponderosa)‐dominated forest types across the north and desert scrub and shrub and woodland across much of the rest of state. The topography of the state was rugged, and elevations ranged from 25 m in the southwest to 3,851 m at the top of Humphreys Peak in the north . Numerous, isolated mountain ranges (“Sky Islands”) were present throughout the southern portion of the state, which were dominated by mixed‐coniferous and deciduous forests at elevations >2,000 m. This diversity of natural cover and terrain types supported the movement patterns of pumas and their primary prey, mule deer. Most (>82%) of Arizona's land was publicly owned  collar location data from 28 pumas captured and monitored by the Arizona Game and Fish Department (AGFD) between August 2005 and March 2008 in the areas surrounding Payson, Prescott, and Tucson, Arizona  from 30‐m resolution USGS digital elevation models USGS . RuggednUsing the National Hydrography Dataset USGS , water fVariables representing availability of forest and woodland cover, riparian cover, and shrub and scrub cover were derived from the Southwest Regional Gap Analysis Project dataset , unconditional standard errors, and (w+) as a measure of the weight of evidence in favor of a given variable  for use in modeling connectivity, after assigning the minimum habitat quality value to the Colorado River, the Central Arizona Project canal, and open water bodies, including lakes and reservoirs. The assumption of a simple inverse relationship between habitat quality and resistance has been questioned, and exploration of alternative transformations of quality to resistance has been encouraged  strips along the east and west boundaries of the rectangular map extent encompassing the state of Arizona as parallel source and destination regions, then designating the north and south rectangular extent boundaries as the source‐destination pair. Cells in the areas between the rectangular map extent and the irregular state boundary were randomly filled with values from a normal distribution approximating the observed distribution of modeled conductance values , in the context of (1) projected change in the prevalence of impervious surface  and (2) current and projected change in vehicle traffic on roads.Data representing the extent of impervious surface in 2010 and projections for 2030, generated by the Integrated Climate and Land Use Scenarios (ICLUS) model  data for 2013 were also obtained, as well as projections for 2030 from the Arizona Department of Transportation. 2013 traffic volume was overlaid on our statewide connectivity layer to identify mile‐marker locations where pinch points are intersected by roads with high traffic volumes that may be expected to deter or present a barrier to puma movement   or were expected to be marginally impacted , but where these threshold traffic volumes are expected to be exceeded in the future , followed by decreasing degree of human modification (w+ = .728) (Table w+ = .375). There is also some evidence that movement habitat quality may increase with greater riparian cover (w+ = .396) and closer to reliable sources of water (w+ = .339). Forest/woodland cover and topographic position were less important in predicting habitat quality for movement .The global model had an AIC value 35 units lower  than the null model, suggesting that it approximated the data well. Weights of evidence indicated that increasing terrain ruggedness and increasing shrub/scrub cover were the strongest predictors of puma habitat quality for movement (8) Table . However3.3As expected, omnidirectional patterns of connectivity across the state closely mirror patterns of movement habitat quality Figure , with br3.42), as well as in and adjacent to other urban centers, particularly as development increases along major highways extending out of cities , but are also heavy along many interstate, U.S., and state highways that connect these urban centers and cross potential connectivity pinch points throughout the state Figures . Traffic4The model of puma habitat connectivity presented here identified large, contiguous areas of high connectivity across the state of Arizona, but also numerous movement and dispersal pinch points. These results are based on contemporary estimates of vegetation cover and the level of human influence on the region. Still, many areas were identified where an increase in the amounts of impervious surface and traffic volume are likely to create new or more expansive barriers, which may reduce connectivity. For example, although the natural areas between Phoenix, Prescott, and Payson exhibited some of the highest potential connectivity, these places may also be the most likely to experience intensified use by a growing human population. In fact, Maricopa County, which includes large portions of north and east Phoenix and its suburbs, as well as Yavapai County, which includes the city of Prescott, were two of the fastest growing counties in the U.S. in 2014  are an important source of mortality for pumas. Beier and Barrett  found thIn addition to WVC mortality, roads also have indirect effects on puma habitat connectivity. Pumas have been observed to avoid paved roads with two or more lanes , which have been demonstrated to promote demographic and genetic connectivity of large‐bodied, wide‐ranging mammals  and permission to archive these data publicly has not been granted to the authors due to sensitivities surrounding the whereabouts of a large, predatory game species occupying home ranges adjacent to urban centers.None declared. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Gradients in χ across the ESA‐EA drainage divide imply an ongoing, north directed shift of the Danube‐ESA watershed that is most likely driven by a base level rise in the northern Molasse basin. We conclude that the regional uplift pattern controls the geometry of ESA‐EA channels, while base level changes in the far field control the overall architecture of the orogen by drainage divide migration.The topography of the eastern Southern Alps (ESA) reflects indenter tectonics causing crustal shortening, surface uplift, and erosional response. Fluvial drainages were perturbed by Pleistocene glaciations that locally excavated alpine valleys. The Late Miocene desiccation of the Mediterranean Sea and the uplift of the northern Molasse Basin led to significant base level changes in the far field of the ESA and the Eastern Alps (EA), respectively. Among this multitude of mechanisms, the processes that dominate the current topographic evolution of the ESA and the ESA‐EA drainage divide have not been identified. We demonstrate the expected topographic effects of each mechanism in a one‐dimensional model and compare them with observed channel metrics. We find that the normalized steepness index increases with uplift rate and declines from the indenter tip in the northwest to the foreland basin in the southeast. The number and amplitude of knickpoints and the distortion in longitudinal channel profiles similarly decrease toward the east. Changes in slope of  Channels of the eastern Southern Alps reveal information on tectonics and base level changesA NW‐SE decrease in normalized steepness index coincides with decreasing uplift rates and level of exhumationBase level changes in the far field control the north directed migration of major watershed The topographic evolution of the Eastern Alps (EA) and eastern Southern Alps (ESA) is controlled by the Late Oligocene–Early Miocene indentation [Dunkl et al., Kuhlemann et al., Robl et al., Monegato and Stefani, Monegato et al., Monegato and Vezzoli, Castellarin and Cantelli, Zattin et al., Roveri et al., Willett et al., Mancin et al., Gusterhuber et al., Baran et al., Drainage systems of the ESA and EA are known to have reacted sensitively to tectonic and climatic signals of the last few million years as indicated by the migration of drainage divides, river capture events, and knickpoints [Robl et al., Hergarten et al., Wagner et al., Legrain et al., Robl et al., Dixon et al., Frisch et al. [Szekely et al. [The topography of the ESA has not been studied with respect to the interplay of crustal deformation, base level changes, and erosional surface processes. This is in contrast to the Eastern Alps, north of the Periadriatic fault, where geomorphological studies [e.g., h et al.  and Szeky et al. .In this study, we contribute to closing this knowledge gap and systematically analyze characteristic metrics of four major catchments draining the eastern Adriatic indenter east of the Giudicarie fault Figure  and disc2Handy et al. [Cotton, Stüwe et al., Bonnet, Willett et al., Yang et al., Roveri et al., Manzi et al., Loget et al., Willett et al., Robl et al., Monegato et al., Preusser et al., The study region encompasses four major rivers draining the eastern Adriatic indenter , i.e., 2.1The Adige, Brenta, Piave, and Tagliamento Rivers drain the largest part of the ESA. In the eastern sector of the study region, the watershed separating the Mediterranean Sea and the Black Sea base levels roughly follows the Pustertal‐Gailtal segment of the Periadriatic fault system but is offset by several kilometers to the south Figures  and 2. ORobl et al., Wagner et al., Monegato and Vezzoli, Benedetti et al., Delcaillau et al., Sakai et al., Monegato et al. [Orogen‐parallel flow is prominent within the eastward extruding wedge north of the indenter  indicate that the Pleistocene glaciations have reshaped the preglacial alpine landscape by the formation of glacial landforms and even reorganized the course of ESA rivers [e.g., 2.2Castellarin et al., Caputo et al., Castellarin and Cantelli, Zattin et al., In general, alpine topography and the position and orientation of valleys drained by major rivers are controlled by brittle structures that have accommodated shortening of the ESA since Middle Miocene–Late Miocene times [The eastern sector of the ESA is also characterized by a distinct transition from the foreland basin to mountainous topography  and uplift beyond 2 mm yr−1 in the headwaters of the Adige River, Piave River, and Tagliamento River [Cenni et al., Serpelloni et al., Cheloni et al., Gradients in the horizontal and vertical velocity field are responsible for the advection of rivers and alter the geometric properties of drainage basins, which in turn trigger landscape adjustment [e.g., Reiners and Brandon, Zattin et al., Heberer et al., Zattin et al., Emmerich et al., Heberer et al., Emmerich et al., Zattin et al., Galadini et al., Willingshofer and Sokoutis, Heberer et al., Benedetti et al., Monegato and Stefani, Low‐temperature thermochronology yields rates and duration of cooling and exhumation and can thus be used to constrain timing and rates of erosional surface processes [e.g., Despite this wealth of information on the geodynamic evolution and the present tectonic regime of the EA‐ESA realm, a number of questions regarding the interaction of crustal deformation, erosion, and climate in shaping the present‐day topography remain: (1) Which processes shaped the present‐day topography of the Adriatic indenter and adjacent domains? (2) How are ESA channel metrics related to uplift rates, lithology, and glaciation? (3) How did base level changes in the Mediterranean and the northern foreland basin affect the ESA channels and the EA‐ESA drainage divides?3Tarquini et al., Our morphometric approach uses the TINITALY digital elevation model (DEM) that covers the entire Italian territory [3.1Neteler et al., 2. Based on DEM cells exceeding this threshold, longitudinal channel profiles and the topology of the drainage network were calculated individually for all large catchments of the study area. To include tributaries draining the southern fringe of the ESA, coordinates of outlet points for all large north‐south draining channels were defined some tens of kilometers south of the orogenic front. We did not consider streams draining the southern foreland basin as low topographic gradients, and strong anthropogenic impact leads to the calculation of ambiguous flow directions.Data preprocessing included the per cell computation of flow direction (D8) and contributing drainage area, as well as the determination of drainage divides, and was based on standard methods of GRASS GIS [x = 0 km at the origin of the rivers. To reduce the noise introduced by the digital elevation model and to obtain exclusively monotonous profiles, we resample the raw channel profiles to a minimum vertical distance of 5 m between individual vertices. The computation of characteristic channel metrics  is based on these smoothed channel profiles.To obtain channel profiles we follow the main channel (Hack's Order 0), defined by the largest contributing drainage area, in the upstream direction and store the three‐dimensional geometry of the channel. Starting from the main channel, we mark each river confluence as outlet point of the channel of higher Hack Order and iteratively repeat this approach until the topology of the entire drainage system is resolved. In consequence of our approach for extracting channel profiles, the flow path with Hack's channel order 0 does not necessarily coincide with the eponymous river of the catchment . For better comparison, channel profiles are reversed and presented as downstream profiles with channel distance 3.2Howard, Hergarten, H is elevation, t is time, and x is the longitudinal coordinate along the river profile increasing in the upstream direction. U and K stand for uplift rate and rock erodibility, respectively. A represents the contributing drainage area as proxy for the discharge of a river, and ∂H∂x is the channel slope where m and n are exponents describing the nonlinear contribution of channel slope and drainage area to river incision. This mathematical description for fluvial incision roots on the empirical relationship discovered by Hack [θ, where θ is the concavity index, equal to m/n [Flint, In order to explore deviations of the drainage system from an equilibrium state defined by constant rock uplift rates and erosional response in a uniform lithology, we apply the most frequently used detachment‐limited model for bedrock channel incision [ by Hack  that then Flint, .∂H∂t=0 and equation In our morphometric approach, we compare natural drainage systems with a topographic steady state where If uplift rate and bedrock erodibility are constant, we getsk is the steepness index [e.g., Snyder et al., Wobus et al., U and K for n = 1. As even the physical dimension of sk depends on the value of θ, steepness indices of different rivers or river segments can only be compared if the same reference value θref is used for all channels of the investigated area. The respective values of ks are denoted normalized steepness index ksn and can be interpreted in terms of variable uplift rates, contrasting lithology, or time‐dependent reorganization of the drainage system toward a new equilibrium [Whipple and Tucker, Whipple et al., θ was determined by Hack [θ = 0.5 or slightly below (θ = 0.45) is expected for bedrock channels in fluvial equilibrium [e.g., Whipple and Tucker, Wobus et al., ksn, we employ θref = 0.5.Under these assumptions the product by Hack  with lowχ transformation [Perron and Royden, Royden and Perron, x is transformed to a new coordinate χ so that the curvature of the equilibrium channel profile vanishes. Contributing drainage area can be eliminated from Flint's law if the transformation satisfies the conditionx0 is an arbitrary reference point, and A0 is an arbitrary reference catchment size (A0 = 1 km2) introduced to avoid odd physical dimensions for χ.Changes in uplift rate or contributing drainage area recorded in the channel geometry are obscured by the curvature of the channel profile that is introduced by the nonlinear decrease of contributing drainage area (being a proxy of discharge) with the upstream distance. To overcome this problem, we apply the recently introduced χ versus H with the slope of the line proportional sk. Deviations can therefore be interpreted in terms of temporal or spatial variations of climatic conditions or tectonic forcing [e.g., Whipple et al., Goren et al., χ values for all channels with a contributing drainage area > 1 km2 by employing a novel numerical tool [Hergarten et al., χ space and present channel segments color coded according to their χ values. Such χ maps are useful indicators to constrain the stability of drainage divides and the direction of drainage divide migration [Willett et al., χ values at both sides of a drainage divide indicate either a spatial variation in uplift rate (or erodibility) or a disequilibrium where the drainage divide migrates. Willett et al. [χ method toward inhomogeneous uplift rates, but this extended transform requires that the uplift rate is known within the entire region or at least along a river profile. If the uplift is not known, differences in χ across a drainage divide can be directly interpreted in terms of different mean erosion rates using the following approach. According to equations Equilibrium channel profiles under spatially uniform climatic and tectonic conditions are straight lines in the coordinate system t et al.  presenteIntegrating this equation from a given base level leads toχ at both sides of a drainage divide in terms of the mean ratio K/E. Averaging is performed along the vertical axis (integration over H instead of x or χ). For a nonlinear stream power law (n ≠ 1) the average of the function KE1n is taken. The side of the drainage divide where χ is larger must be characterized either by higher erodibilities or by lower actual erosion rates in the mean, regardless of whether the latter arise from lower uplift rates or from disequilibrium.This relationship allows for a direct interpretation of differences in 4n = 1 and an additional diffusion term for various initial and boundary conditions. As a one‐dimensional model does not allow for the computation of catchment sizes, we used the power law relationship between catchment size and upstream length toward the drainage divide l originally found by Hack [l ∝ Ah, with h = 0.56. Then the term θA in equation lθh except for a constant factor, which can be included in the erodibility K.In order to disentangle various processes that drive ESA‐EA landscape evolution by geomorphic properties, we demonstrate the impact of lithology, uplift rate, base level change, and glacial erosion on a simplified one‐dimensional orogen. The simplified orogen consists of two channels separated by a drainage divide that can migrate toward the steeper channel as a consequence of hillslope diffusion. To describe the time‐dependent evolution of channels characterized by a detachment‐limited regime, we numerically solve equation  by Hack , l ∝ AhU) and bedrock erodibility (K), neglecting precipitation contrasts, the channels are symmetric on both sides of a watershed at middistance between the stable base levels at the southern and northern boundary of the model domain  is a measure of the ability of a river to incise into its bedrock. Consequently, channels in steady state characterized by uniform uplift rates and bedrock erodibility should show constant ksn values along their course. Variations in the ksn values can be interpreted in terms of (a) erodibility contrast, (b) variable uplift rates, or (c) non–steady state drainage systems  to the cover units  and a decrease in uplift rate  and are less frequently observed in the eastern catchments  and thus also show a northwest‐southeast trend. The Adige main channel is characterized by very low ksn values with some high ksn segments between the headwaters and the city of Meran/Merano. Downstream of Meran/Merano the channel gradient and thus ksn values of the Adige main channel are very low compared to the ksn values of adjacent tributaries. These low ksn values spatially correspond to the occurrence of unconsolidated Quaternary sediments forming the river bed indicating that alluviation has been the dominant fluvial process since the glacial retreat  along a short channel segment upstream of Trento. Some tens of kilometers south of Trento, a channel segment of increased ksn values tends toward the city of Verona. Compared to the receiving Adige River, the ksn values of its largest tributary, the Eisack River, are increased by several orders of magnitude near their confluence. The same peculiarity is also observed at the confluences of the Adige River with the nearby Talferbach , the Torrente Avisio, and several smaller tributaries. Clearly, the highest ksn values coincide with the occurrence of metamorphic and volcanic rocks from the Southalpine basement /He ages from apatite were found [Zattin et al., Heberer et al., ksn values are also determined in tributaries draining carbonatic units featuring plateaus with reduced surface runoff due to extensive karstification . In the Brenta catchment, high‐uplift rates are coincident with high ksn values. This trend is best observed at the tributaries north of the main stream  but perturbed by a series of knickpoints. While we did not observe a coincidence between uplift rate and ksn in the low‐gradient Sugana valley (upper reach of the Brenta), the lower reach of the Brenta features ksn values that roughly reflect the GPS‐measured vertical velocity field.The Brenta River shows very low y Figure a. This lp Figure a at the ksn values south of the Valsugana thrust and larger fluctuations north of it  or convex (too large θ) deviation from a straight line in the χ space. Several methods to determine the best fit θ using the χ transform are reported in the literature [Perron and Royden, Mudd et al., Hergarten et al., χ and the slope of channel profiles in the χ space for rivers draining different Southalpine catchments, we define θref = 0.5 and compute in analogy to the ksn the χn  for the receiving stream and one major tributary of each investigated catchment.To highlight spatial variations in uplift rate and lithology and to identify temporal effects disturbing the 3D geometry of major Southalpine drainages, we employed the  Figures  and 7. Bχ space reveals a clear trend of decreasing average slopes from the west to the east, with lowest average gradients in the easternmost Tagliamento catchment  and the Brenta Rivers   that the GPS‐derived, short‐term uplift pattern is consistent with long‐term topography formation (despite a difference in absolute rates), and (b) that the drainage system generally reflects variations in uplift and lithology  [e.g., Robl et al., Valla et al., Shuster et al., Wobus et al., −1 as determined by Serpelloni et al. [Muttoni et al., −1.Major knickpoints in channels of the European Alps originated after the Middle Pleistocene climate transition by the development of characteristic glacial landforms such as overdeepened and hanging valleys [e.g., i et al.  for the Furthermore, buried Messinian knickpoints could be partially revived by Pleistocene glacial sediment excavation. We speculate that glaciers overdeepened alpine valleys preconditioned by Messinian incision, and that major knickpoints observed in streams of the Adige catchment originate from relic Messinian channels exposed by repeated glacial erosion. The excavation of rocks during the Pleistocene glaciations is most spectacularly observed at the overdeepening of Lake Garda but is also consistent with the low lying and more or less flat valley floor of the Adige River downstream of Meran/Merano.ksn values at this section, although the main channel of the Piave River was deflected in post‐Messinian times by the growing Monte Grappa anticline . We suggest that the adjustment of the Piave River to uplift and deflection is already accomplished in this channel segment due to its larger contributing drainage area (and hence a higher discharge) compared to the Brenta River. We further suggest that deflection might be unlikely for the Piave River featuring high discharge in a steep, deeply incised channel as proposed for post‐Messinian times [Monegato et al., The Brenta River shows a low‐gradient section at the Sugana valley confined by a distinct knickpoint followed by downstream steepening Figures , 6, 7. T6.4Monegato and Stefani, Monegato et al., χ maps for drainages of the Southern and adjacent Eastern Alps. It is easily recognized from equation E, e.g., due to low‐uplift rates, should feature high χ values. If such regions are far away from the considered drainage divide, the resulting high χ values may be misinterpreted in terms of migrating drainage divides. A strong increase in χ is observed in the orogen‐parallel, low‐gradient valleys of the EA with valley floors located at an elevation roughly between 400 and 500 m. These valleys are filled by thick layers of Miocene to Quaternary sediments [e.g., Preusser et al., χ maps. We note that by defining base levels below 500 m and considering all orogen‐parallel river segments of the EA, the χ pattern is qualitatively the same but the differences in χ across the EA‐ESA watersheds increase dramatically.Migration of watersheds and stream captures are documented in the ESA. For example, the orogen‐parallel channel segment of the Fella River, a former tributary of the Sava River, was captured by the Tagliamento River in post‐Miocene times Figure . This evχ map for drainages of the Southern and adjacent Eastern Alps computed for a 500 m base level is consistent with the observed trend of north directed drainage divide migration [Monegato and Stefani, Monegato et al., χ across watersheds of the ESA rivers, large gradients still occur across watersheds separating streams from the ESA  and the EA . The χ map implies that the westernmost branch of the Adige headwaters is expected to grow toward the west and north by capturing tributaries of the Inn catchment  from the southern foreland toward the ESA‐EA drainage divide. However, GPS‐based uplift rates [Serpelloni et al., χ values than the Rhine River in the west, the Adda River in the south, and the Adige River in the east. Interpreting this χ pattern in term of spatial variations in uplift rate would mean that the Inn catchment occupies a low‐uplift corridor, surrounded by catchments draining higher uplift areas, which seems very unlikely and is not supported by the present vertical velocity field. Furthermore, it is common knowledge that the Rhine catchment is growing at the expense of the Danube catchment [e.g., Berendsen and Stouthamer, Kuhlemann and Rahn, Monegato et al., χ maps in terms of a north directed migration of ESA‐EA watersheds.In principle, gradients in Castellarin and Cantelli, Zattin et al., Shortening of the Adriatic indenter accompanied by the southward propagation of thrusts induces surface uplift and controls the lateral growth of the Southern Alps [e.g., Willett et al., The Messinian incision wave triggered by the desiccation of the Mediterranean Sea exclusively affected drainages of the ESA [e.g., Hergarten et al., Legrain et al., Robl et al., Genser et al., Gusterhuber et al., Baran et al., The EA experienced Late Miocene relief rejuvenation [Localized erosion during the Pleistocene glaciations may have affected the state of drainage divides as well Figure f, but weSeveral counteracting processes may be responsible for an expected shift of the drainage divide separating the EA from the ESA Figure .Shortenχ maps indicate that the Adda‐Rhine watershed is stable with similar χ on both sides of the watershed, while the Rhine catchment grows at the expense of the Danube drainage system (Inn catchment) , the shift of the divide would be reversible and should affect the entire ESA‐EA watershed. In contrast, (3) can be expected to lead to a permanent north directed migration of the watershed which should be restricted to the ESA‐Danube drainage divide. Spectacularly,  Figures b, and 8dThe observations reported above imply that the Periadriatic fault system no longer represents a strong tectonic discontinuity with respect to the present and future evolution of drainage systems. Thus, the drainage divide tracing the Adriatic indenter may vanish as watersheds rearrange according to the long‐term vertical velocity field and base level changes in the far field.7Fault zones control the flow direction of major rivers in the ESA, deform the drainage pattern, and advect streams horizontally and vertically.ksn) indicating a stable uplift and erosion pattern since Miocene times. Uplift rates and ksn decrease from the indenter tip in the northwest toward the southeast, which is probably not a result of crustal shortening due to the kinematics of indentation alone.Modern uplift rates are largely consistent with long‐term exhumation in the ESA and with variations in normalized steepness index  and adjacent domains of the Eastern Alps (EA) based on drainage pattern indices and their relation to regional tectonic and climatic characteristics and found strong evidence for a northward shift of the ESA‐EA drainage divide. We conclude the following.This study contributes to an enhanced understanding of the complex topographic evolution of the ESA controlled by the interplay of continental collision and indenter tectonics, Late Miocene base level changes, and Pleistocene glaciations. Future research should focus on constraining the pace and the direction of drainage divide migration in the entire European Alps to further disentangle processes and drivers of alpine landscape evolution.