Minimally invasive management of sleeve gastrectomy collection with a nasobiliary drainage tube.

A staple line leak is a feared complication of sleeve gastrectomy. Endoscopic methods have superseded surgical management of small leaks, however large collections often require surgical intervention. Here, we describe endoscopic management of large collection adjacent to the staple line with an 8Fr nasobiliary tube.

Hyperammonaemic encephalopathy: a remarkably rare complication after bariatric surgery.

Hyperammonaemia is a metabolic disorder with elevated blood ammonia levels. Here we describe a case of hyperammonaemia associated encephalopathy as an incredibly rare, potentially fatal and treatable complication associated with bariatric surgery. This case highlights the importance of longer-term follow-up after bariatric surgery.

Global phylogeography of ridley sea turtles (Lepidochelys spp.): evolution, demography, connectivity, and conservation.

Globally distributed marine taxa are well suited for investigations of biogeographic impacts on genetic diversity, connectivity, and population demography. The sea turtle genus Lepidochelys includes the wide-ranging and abundant olive ridley (L. olivacea), and the geographically restricted and 'Critically Endangered' Kemp's ridley (L. kempii). To investigate their historical biogeography, we analyzed a large dataset of mitochondrial DNA (mtDNA) sequences from olive (n = 943) and Kemp's (n = 287) ridleys, and genotyped 15 nuclear microsatellite loci in a global sample of olive ridleys (n = 285). We found that the ridley species split ~ 7.5 million years ago, before the Panama Isthmus closure. The most ancient mitochondrial olive ridley lineage, located in the Indian Ocean, was dated to ~ 2.2 Mya. Both mitochondrial and nuclear markers revealed significant structure for olive ridleys between Atlantic (ATL), East Pacific (EP), and Indo-West Pacific (IWP) areas. However, the divergence of mtDNA clades was very recent (< 1 Mya) with low within- clade diversity, supporting a recurrent extinction-recolonization model for these ocean regions. All data showed that ATL and IWP groups were more closely related than those in the EP, with mtDNA data supporting recent recolonization of the ATL from the IWP. Individual olive ridley dispersal between the ATL, EP, and IN/IWP could be interpreted as more male- than female-biased, and genetic diversity was lowest in the Atlantic Ocean. All populations showed signs of recent expansion, and estimated time frames were concordant with their recent colonization history. Investigating species abundance and distribution changes over time is central to evolutionary biology, and this study provides a historical biogeographic context for marine vertebrate conservation and management. Supplementary Information: The online version contains supplementary material available at 10.1007/s10592-022-01465-3.

Multivariate analysis of biologging data reveals the environmental determinants of diving behaviour in a marine reptile.

Diving behaviour of 'surfacers' such as sea snakes, cetaceans and turtles is complex and multi-dimensional, thus may be better captured by multi-sensor biologging data. However, analysing these large multi-faceted datasets remains challenging, though a high priority. We used high-resolution multi-sensor biologging data to provide the first detailed description of the environmental influences on flatback turtle (Natator depressus) diving behaviour, during its foraging life-history stage. We developed an analytical method to investigate seasonal, diel and tidal effects on diving behaviour for 24 adult flatback turtles tagged with biologgers. We extracted 16 dive variables associated with three-dimensional and kinematic characteristics for 4128 dives. K-means and hierarchical cluster analyses failed to identify distinct dive types. Instead, principal component analysis objectively condensed the dive variables, removing collinearity and highlighting the main features of diving behaviour. Generalized additive mixed models of the main principal components identified significant seasonal, diel and tidal effects on flatback turtle diving behaviour. Flatback turtles altered their diving behaviour in response to extreme tidal and water temperature ranges, displaying thermoregulation and predator avoidance strategies while likely optimizing foraging in this challenging environment. This study demonstrates an alternative statistical technique for objectively interpreting diving behaviour from multivariate collinear data derived from biologgers.

Age-specific growth and maturity estimates for the flatback sea turtle (Natator depressus) by skeletochronology.

To address a major knowledge gap for flatback sea turtles (Natator depressus), a species endemic to Australia and considered 'Data Deficient' for IUCN Red List assessment, we present the first-ever skeletochronology-derived age and growth rate estimates for this species. Using a rare collection of bone samples gathered from across northern Australia, we applied skeletochronology and characterized the length-at-age relationship, established baseline growth rates from the hatchling to adult life stages, and produced empirical estimates of age-at- and size-at-sexual-maturation (ASM, SSM). We analyzed humeri from 74 flatback sea turtles ranging in body size from 6.0-96.0 cm curved carapace length (CCL), and recovered from Western Australia (n = 48), Eastern Australia (n = 13), central Australia (n = 8; Northern Territory n = 3, the Gulf of Carpentaria n = 5), and unknown locations (n = 5). We identified the onset of sexual maturity for 29 turtles, based on rapprochement growth patterns in the bones. Estimates for ASM ranged from 12.0 to 23.0 years (mean: 16.3 ± 0.53 SE), SSM ranged from 76.1 to 94.0 cm CCL (mean: 84.9 ± 0.90 SE), and maximum observed reproductive longevity was 31 years for a 45-year old male flatback. Growth was modeled as a smoothing spline fit to the size-at-age relationship and at the mean SSM (84.9 cm CCL) corresponded with a spline-predicted maturity age of 18 years (95% CI: 16 to 24), while mean nesting sizes reported in the literature (86.4 to 94 cm CCL) corresponded to estimated ages of 24+ years. A bootstrapped von Bertalanffy growth model was also applied and showed consistencies with the spline curve, yielding an estimated upper size limit, Linf, at 89.2 ± 0.04 cm (95% CI: 85.5 to 95.9 cm) with the intrinsic growth rate parameter, k, at 0.185 ± 0.0004 (0.16 to 0.22); at the same mean SSM (84.9 cm CCL) the estimated ASM was 16.3 ± 0.05 years (95% CI: 12.8 to 27.7 years). Lastly, four of the samples analyzed were collected from deceased adult females that had previous sizes known from on-going mark/recapture studies at nesting sites in Western Australia. The paired CCL data (measured at nesting and back-calculated) did not significantly differ (p = 0.875). This first skeletochronology study for flatback sea turtles generates valuable empirical estimates for ongoing conservation and management efforts.

Catastrophic loss of tropical seagrass habitats at the Cocos (Keeling) Islands due to multiple stressors.

Seagrass habitats at the Cocos (Keeling) Islands (CKI), a remote atoll in the Indian Ocean, have suffered a catastrophic decline over the last decade. Seagrass monitoring (1996-2020) in relation to dredging and coastal development works (2009 to 2011) provide a historical baseline, and document the decline of mixed tropical seagrass Thalassia hemprichii and macroalgal (predominantly Caulerpa spp.) beds over a decadal scale time series. Attribution of loss to coastal development is confounded by lagoon-wide die-off events in 2007, 2009 and 2012 and high air and water temperatures from 2009 to 2016, with evidence of broad scale changes, visible in satellite imagery between 2006 and 2018. We conclude that up to 80% of seagrass habitats in the CKI lagoon (~1200 ha) have been lost due to multiple stressors including episodic die-off events related to high temperatures and calm conditions, and loss due to sediment disturbance and increased turbidity. Grazing pressure from the resident green sea turtles (Chelonia mydas) may have also exacerbated the loss of seagrass, which in turn poses a dire threat to their ongoing health and survival. This study highlights the fragility of tropical seagrass habitats and the cascading effect of system imbalance as a result of anthropogenic pressures and climate drivers. Although small in comparison to global estimates, the loss of seagrass habitats at CKI could change the entire ecosystem of a remote atoll. Due to the significance of the Thalassia beds for coastal stability, as food for an isolated population of green sea turtles and as a fish nursery, rehabilitation efforts are warranted.

Streptococcus iniae associated mass marine fish kill off Western Australia.

Streptococcus iniae causes high mortality in cultured and wild fish stocks globally. Since the first report in captive Amazon river dolphins Inia geoffrensis in 1976, it has emerged in finfish across all continents except Antarctica. In March 2016, an estimated 17000 fish were observed dead and dying along a remote 70 km stretch of the Kimberley coastline north of Broome, Western Australia. Affected species included finfish (lionfish Pterois volitans, angelfish Pomacanthus sp., stripey snapper Lutjanus carponotatus, sand bass Psammoperca waigiensis, yellowtail grunter Amniataba caudavittata, damselfish Pomacentridae sp.), flatback sea turtles Natator depressus, and olive (Aipysurus laevis) and black-ringed (Hydrelaps darwiniensis) sea snakes. Moribund fish collected during the event exhibited exophthalmia and abnormal behaviour, such as spiralling on the surface or within the water column. Subsequent histopathological examination of 2 fish species revealed bacterial septicaemia with chains of Gram-positive cocci seen in multiple organs and within brain tissue. S. iniae was isolated and identified by bacterial culture, species-specific PCR, Matrix-Assisted Laser Desorption Ionisation Time-Of-Flight (MALDI-TOF) and biochemical testing. This is the first report of S. iniae associated with a major multi-species wild marine fish kill in Australia. Extreme weather events in the region including a marked decrease in water temperatures, followed by an extended period of above-average coastal water temperatures, were implicated as stressors potentially contributing to this outbreak.

Radionuclides in sea turtles at the Montebello Islands former nuclear test sites: Current and historical dose rates for adults and embryos.

Radionuclides from 1950s weapons testing at the Montebello Islands, Western Australia, may impact sea turtle embryos incubating within eggs laid in contaminated sands or be taken up into adult body tissues where they can contribute to radiation dose over a turtles' 60+ year lifespan. We measured plutonium in all local samples including turtle skin, bones, hatchlings, eggshells, sea sediments, diet items and beach sands. The amount of Pu in developing embryos/hatchling samples was orders of magnitude lower than that in the surrounding sands. These contaminated sands caused most dose to eggs (external dose from 137Cs, 152Eu), while most of the dose to adults was from internalised radionuclides (98%). While current dose rates are relatively low, local dose rates were high for about ten years following the 1950s detonations and may have resulted in lethality or health impacts to a generation of turtles that likely carry biomarkers today.

A continuous-time state-space model for rapid quality control of argos locations from animal-borne tags.

BACKGROUND: State-space models are important tools for quality control and analysis of error-prone animal movement data. The near real-time (within 24 h) capability of the Argos satellite system can aid dynamic ocean management of human activities by informing when animals enter wind farms, shipping lanes, and other intensive use zones. This capability also facilitates the use of ocean observations from animal-borne sensors in operational ocean forecasting models. Such near real-time data provision requires rapid, reliable quality control to deal with error-prone Argos locations. METHODS: We formulate a continuous-time state-space model to filter the three types of Argos location data (Least-Squares, Kalman filter, and Kalman smoother), accounting for irregular timing of observations. Our model is deliberately simple to ensure speed and reliability for automated, near real-time quality control of Argos location data. We validate the model by fitting to Argos locations collected from 61 individuals across 7 marine vertebrates and compare model-estimated locations to contemporaneous GPS locations. We then test assumptions that Argos Kalman filter/smoother error ellipses are unbiased, and that Argos Kalman smoother location accuracy cannot be improved by subsequent state-space modelling. RESULTS: Estimation accuracy varied among species with Root Mean Squared Errors usually <5 km and these decreased with increasing data sampling rate and precision of Argos locations. Including a model parameter to inflate Argos error ellipse sizes in the north - south direction resulted in more accurate location estimates. Finally, in some cases the model appreciably improved the accuracy of the Argos Kalman smoother locations, which should not be possible if the smoother is using all available information. CONCLUSIONS: Our model provides quality-controlled locations from Argos Least-Squares or Kalman filter data with accuracy similar to or marginally better than Argos Kalman smoother data that are only available via fee-based reprocessing. Simplicity and ease of use make the model suitable both for automated quality control of near real-time Argos data and for manual use by researchers working with historical Argos data.

Microclimate modelling of beach sand temperatures reveals high spatial and temporal variation at sea turtle rookeries.

The continual development of ecological models and availability of high-resolution gridded climate surfaces have stimulated studies that link climate variables to functional traits of organisms. A primary constraint of these studies is the ability to reliably predict the microclimate that an organism experiences using macroscale climate inputs. This is particularly important in regions where access to empirical information is limited. Here, we contrast correlative models based on both ambient and sea surface temperatures to mechanistic modelling approaches to predict beach sand temperatures at depths relevant to sea turtle nesting. We show that mechanistic models are congruent with correlative models at predicting sand temperatures. We used these predictions to explore thermal variation across 46 mainland and island beaches that span the geographical range of sea turtle nesting in Western Australia. Using high resolution gridded climate surfaces and site-specific soil reflectance, we predict almost 9 °C variation in average annual temperatures between beaches, and nearly 10 °C variation in average temperatures during turtle nesting seasons. Validation of models demonstrated that predictions were typically within 2 °C of observations and, although most sites had high correlations (r2 > 0.7), predictive capacity varied between sites. An advantage of the mechanistic model demonstrated here is that it can be used to explore the impacts of climate change on sea turtle nesting beach temperatures as, unlike correlative models, it can be forced with novel combinations of environmental variables.

Translating Marine Animal Tracking Data into Conservation Policy and Management.

There have been efforts around the globe to track individuals of many marine species and assess their movements and distribution, with the putative goal of supporting their conservation and management. Determining whether, and how, tracking data have been successfully applied to address real-world conservation issues is, however, difficult. Here, we compile a broad range of case studies from diverse marine taxa to show how tracking data have helped inform conservation policy and management, including reductions in fisheries bycatch and vessel strikes, and the design and administration of marine protected areas and important habitats. Using these examples, we highlight pathways through which the past and future investment in collecting animal tracking data might be better used to achieve tangible conservation benefits.

Using sacral nerve modulation to improve continence and quality of life in patients suffering from low anterior resection syndrome.

BACKGROUND: Sphincter preserving surgery for the treatment of rectal cancer is very often feasible, avoiding a permanent colostomy. It is well recognized that a large proportion of patients will experience altered bowel habit following low anterior resection (LAR). Faecal incontinence is a common symptom associated with LAR syndrome. The aim of this study is to evaluate the long-term improvement in continence and quality of life (QoL) in LAR patients treated with sacral nerve modulation. METHODS: Patients with ongoing faecal incontinence for >1 year after reversal of diverting ileostomy post ultra-LAR were selected for the study. Eligible patients underwent sacral nerve modulator implantation as a two-stage procedure. Bowel diaries and the Cleveland Clinic Faecal Incontinence Score were used to measure faecal incontinence and QoL. RESULTS: Twelve patients underwent permanent implantation of a sacral nerve stimulator. Median follow-up was 34 months (interquartile range (IQR) 20.25-62.5 months). The median improvement in faecal incontinence was 90% (IQR 76.25-98.75%) and the median improvement in patient QoL was 80% (IQR 71.25-93.75%). Patients who had previously been treated with biofeedback showed a median improvement in incontinence of 75% compared to 90% which was found in patients who had not had prior biofeedback treatment. The mean percentage improvement in patients with an internal anal sphincter defect was 80% compared to 90% seen in patients with an intact sphincter. CONCLUSIONS: The results of this study suggest that sacral nerve modulation should be more widely considered as an effective treatment strategy for patients with faecal incontinence following LAR.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis.

BACKGROUND: In this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. PATIENTS AND METHODS: Quality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. RESULTS: In the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], -0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). CONCLUSION: In its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.

Measuring behavioral responses of sea turtles, saltwater crocodiles, and crested terns to drone disturbance to define ethical operating thresholds.

Drones are being increasingly used in innovative ways to enhance environmental research and conservation. Despite their widespread use for wildlife studies, there are few scientifically justified guidelines that provide minimum distances at which wildlife can be approached to minimize visual and auditory disturbance. These distances are essential to ensure that behavioral and survey data have no observer bias and form the basis of requirements for animal ethics and scientific permit approvals. In the present study, we documented the behaviors of three species of sea turtle (green turtles, Chelonia mydas, flatback turtles, Natator depressus, hawksbill turtles, Eretmochelys imbricata), saltwater crocodiles (Crocodylus porosus), and crested terns (Thalasseus bergii) in response to a small commercially available (1.4 kg) multirotor drone flown in Northern Territory and Western Australia. Sea turtles in nearshore waters off nesting beaches or in foraging habitats exhibited no evasive behaviors (e.g. rapid diving) in response to the drone at or above 20-30 m altitude, and at or above 10 m altitude for juvenile green and hawksbill turtles foraging on shallow, algae-covered reefs. Adult female flatback sea turtles were not deterred by drones flying forward or stationary at 10 m altitude when crawling up the beach to nest or digging a body pit or egg chamber. In contrast, flyovers elicited a range of behaviors from crocodiles, including minor, lateral head movements, fleeing, or complete submergence when a drone was present below 50 m altitude. Similarly, a colony of crested terns resting on a sand-bank displayed disturbance behaviors (e.g. flight response) when a drone was flown below 60 m altitude. The current study demonstrates a variety of behavioral disturbance thresholds for diverse species and should be considered when establishing operating conditions for drones in behavioral and conservation studies.

Artificial light on water attracts turtle hatchlings during their near shore transit.

We examined the effect of artificial light on the near shore trajectories of turtle hatchlings dispersing from natal beaches. Green turtle (Chelonia mydas) hatchlings were tagged with miniature acoustic transmitters and their movements tracked within an underwater array of 36 acoustic receivers placed in the near shore zone. A total of 40 hatchlings were tracked, 20 of which were subjected to artificial light during their transit of the array. At the same time, we measured current speed and direction, which were highly variable within and between experimental nights and treatments. Artificial lighting affected hatchling behaviour, with 88% of individual trajectories oriented towards the light and spending, on average, 23% more time in the 2.25 ha tracking array (19.5 ± 5 min) than under ambient light conditions (15.8 ± 5 min). Current speed had little to no effect on the bearing (angular direction) of the hatchling tracks when artificial light was present, but under ambient conditions it influenced the bearing of the tracks when current direction was offshore and above speeds of approximately 32.5 cm s(-1). This is the first experimental evidence that wild turtle hatchlings are attracted to artificial light after entering the ocean, a behaviour that is likely to subject them to greater risk of predation. The experimental protocol described in this study can be used to assess the effect of anthropogenic (light pollution, noise, etc.) and natural (wave action, current, wind, moonlight) influences on the in-water movements of sea turtle hatchlings during the early phase of dispersal.

Phylogeography, Genetic Diversity, and Management Units of Hawksbill Turtles in the Indo-Pacific.

Hawksbill turtle (Eretmochelys imbricata) populations have experienced global decline because of a history of intense commercial exploitation for shell and stuffed taxidermied whole animals, and harvest for eggs and meat. Improved understanding of genetic diversity and phylogeography is needed to aid conservation. In this study, we analyzed the most geographically comprehensive sample of hawksbill turtles from the Indo-Pacific Ocean, sequencing 766 bp of the mitochondrial control region from 13 locations (plus Aldabra, n = 4) spanning over 13500 km. Our analysis of 492 samples revealed 52 haplotypes distributed in 5 divergent clades. Diversification times differed between the Indo-Pacific and Atlantic lineages and appear to be related to the sea-level changes that occurred during the Last Glacial Maximum. We found signals of demographic expansion only for turtles from the Persian Gulf region, which can be tied to a more recent colonization event. Our analyses revealed evidence of transoceanic migration, including connections between feeding grounds from the Atlantic Ocean and Indo-Pacific rookeries. Hawksbill turtles appear to have a complex pattern of phylogeography, showing a weak isolation by distance and evidence of multiple colonization events. Our novel dataset will allow mixed-stock analyses of hawksbill turtle feeding grounds in the Indo-Pacific by providing baseline data needed for conservation efforts in the region. Eight management units are proposed in our study for the Indo-Pacific region that can be incorporated in conservation plans of this critically endangered species.

Accelerating Tropicalization and the Transformation of Temperate Seagrass Meadows.

Climate-driven changes are altering production and functioning of biotic assemblages in terrestrial and aquatic environments. In temperate coastal waters, rising sea temperatures, warm water anomalies and poleward shifts in the distribution of tropical herbivores have had a detrimental effect on algal forests. We develop generalized scenarios of this form of tropicalization and its potential effects on the structure and functioning of globally significant and threatened seagrass ecosystems, through poleward shifts in tropical seagrasses and herbivores. Initially, we expect tropical herbivorous fishes to establish in temperate seagrass meadows, followed later by megafauna. Tropical seagrasses are likely to establish later, delayed by more limited dispersal abilities. Ultimately, food webs are likely to shift from primarily seagrass-detritus to more direct-consumption-based systems, thereby affecting a range of important ecosystem services that seagrasses provide, including their nursery habitat role for fishery species, carbon sequestration, and the provision of organic matter to other ecosystems in temperate regions.

Quality-adjusted survival with combination nab-paclitaxel + gemcitabine vs gemcitabine alone in metastatic pancreatic cancer: a Q-TWiST analysis.

OBJECTIVES: To use the Quality-Adjusted Time Without Symptoms or Toxicities (Q-TWiST) methodology to compare the quality-of-life and survival benefits associated with the combination of albumin-bound (nab)-paclitaxel and gemcitabine vs gemcitabine alone in the first-line treatment of metastatic pancreatic adenocarcinoma. METHODS: Total survival time through 45 months was partitioned into time before disease progression without toxicity grade ≥3 (TWiST), time with adverse event grade ≥3 (TOX), and time of disease progression (REL). Mean Q-TWiST was calculated by multiplying time spent in each health state by its respective utility (i.e., TWiST = 1.00; TOX/REL = 0.50, 0-1 in sensitivity analyses). Non-parametric bootstrap 95% confidence intervals (CI) were derived to assess the significance of between-treatment differences in TOX, TWiST, REL, and Q-TWiST. A relative gain in Q-TWiST (vs mean overall survival of gemcitabine) of ≥10% and ≥15% was defined as clinically important and clearly clinically important, respectively. RESULTS: Patients on nab-paclitaxel + gemcitabine spent a significantly longer time in every state and experienced significantly greater overall Q-TWiST (+1.7 months [95% CI = 0.8, 2.7]) than those receiving gemcitabine alone (8.2 months [95% CI = 7.5, 8.9] vs 6.5 months [95% CI = 5.8, 7.0]), assuming base-case utilities of TOX/REL = 0.50. This Q-TWiST gain ranged from 1.0 month (95% CI = 0.1, 1.9), when REL/TOX utilities were both 0, to 2.5 months (95% CI = 1.3, 3.7), when REL/TOX utilities were both 1. Relative gains in Q-TWiST were 21% in favor of nab-paclitaxel + gemcitabine in the base case, and ranged from 12-30% in sensitivity analyses. CONCLUSIONS: There are limitations to Q-TWiST analyses, e.g., imprecision when defining duration/severity of TOX and lack of prospective collection of utilities. This analysis addressed these issues via sensitivity analyses and conservative assumptions to show that nab-paclitaxel + gemcitabine results in statistically significant and clinically important gains in quality-adjusted survival, when compared to gemcitabine alone, in treatment-naive metastatic pancreatic adenocarcinoma patients.