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The Newfoundland and Labrador Shelves Bioregion, located on the glaciated continental shelf and adjacent continental slope of eastern Canada, is classified into units that reflect its great physiographic diversity. There are ten shelf units: bedrock zone, fjord systems, major inlet, shelf-crossing troughs, four types of offshore banks, basin, and disturbed (glaciotectonic) terrain. There are three units on the continental slope: channelized areas, trough-mouth areas, and large sedimentary drifts. A series of vignettes illustrates both the distinguishing characteristics of the principal geomorphic units and the morphologic diversity within them. A sediment mobility analysis reveals that wave- and current-generated disturbances are dominant and largely depth-controlled within the shelf units, while the south-flowing Labrador Current impacts sediment transport and mobility along the continental slope.

Aim To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE). Methods A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35–71) years using a 20 mg/m2 test dose administered 1–3 days prior to HDM (predominantly 180 mg/m2). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann–Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined. Results Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p n = 5) was associated with significantly lower PE than administration times of 16–60 min (n = 22), p ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively). Conclusion Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.

The Highway Capacity Manual (HCM) 2016 recommends using right-turn-on-red (RTOR) volume for capacity and level of service analyses but provides very limited guidance for predicting the volume in the absence of field data. The signalized intersection methodology in the HCM computes capacity using only the green portion of the cycle, ignoring the additional capacity that may result from allowing RTOR. This leads to an overestimation of delay, and consequently a determination of level of service that is likely to appear worse than the actual performance. Therefore, it is essential to develop proper RTOR volume and capacity estimation models for correct estimation of the level of service at signalized intersections. In this study, regression models for RTOR volume were developed for intersections where the subject RTOR movement occurs from an exclusive right-turn lane. Data from 128 intersections across the United States was used for the analysis. Four different categories of regression model with three types of model under each category were developed and their performances were compared using a testing data set. Tobit regression performed better than other types of regression in predicting the RTOR volume. The model will be useful in predicting RTOR volumes in the absence of field data for accurate estimation of delay and level of service at a signalized intersection.

We investigate the interaction of fluvial and non-fluvial sedimentation on the channel morphology and kinematics of an experimental river delta. We compare two deltas: one that evolved with a proxy for non-fluvial sedimentation (treatment experiment) and one that evolved without the proxy (control). We show that the addition of the non-fluvial sediment proxy alters the delta's channel morphology and kinematics. Notably, the flow outside the channels is significantly reduced in the treatment experiment and the channels are deeper (as a function of radial distance) and longer. We also find that the treatment channels have the same width from the entrance to the shoreline, while the control channels get narrower as they approach the shore. Interestingly, the channel beds in the treatment experiment often exist below sea level in the terrestrial portion of the delta top creating a ~0.7 m reach of steady, nonuniform backwater flow. However, in the control experiment, the channel beds generally exist at or above relative sea level, creating channel movement resembling morphodynamic backwater kinematics and topographic flow expansions. Differences between channel and far-field aggradation produce a longer channel in-filling timescale for the treatment as compared to the control, suggesting that the channel avulsions triggered by a peak in channel sedimentation occur less frequently in the treatment experiment. Despite this difference, the basin-wide timescale of lateral channel mobility remains similar. Ultimately, non-fluvial sedimentation on the delta top plays a key role in the channel morphology and kinematics of an experimental river delta, producing channels which are more analogous to channels in global river deltas, and which cannot be produced solely by increasing cohesion in an experimental river delta.

Irreversible electroporation (IRE) is an ablation technology that uses electrical energy delivered between electrodes. If the electrodes are placed atraumatically, there is little to no risk of collateral injury, making IRE appealing for the treatment of pancreatic tumors.We report on 20 patients with pancreatic adenocarcinoma (PAC) who underwent 21 IRE in our center. There were 6 IRE for stage 2 PAC, 11 for stage 3 PAC, 1 for stage 4 PAC, and 2 patients treated with IRE for recurrence after pancreaticoduodenectomy. One patient had local progression 18 months after IRE and received a second IRE treatment. Using propensity score matching (age, sex, stage, tumor size, and chemotherapy), cases were matched 2 to 1 with patients from the Surveillance, Epidemiology, and End Results database.A total of 7 cases experienced 8 complications; 4 complications were mild, and 4 were severe. Significant survival benefit was seen for patients with stage 3 PAC (27.5 vs 14.6 months for the matched group, P = 0.003); for stage 2, median survival was 15 months, and the single stage 4 patient survived 9 months after IRE treatment.Pancreatic cancers were safely and effectively treated with image-guided IRE in our medium-sized center.

Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.

Limited evidence is available regarding the survival benefit of second-line therapy in real world patients with advanced biliary tract and gallbladder cancer. Until very recently, there was a lack of randomized clinical trials to address this important question. In this multicenter population-based cohort study, the authors evaluated whether second-line therapy improves the survival of real world patients with advanced biliary tract and gallbladder cancer.Patients with biopsy-proven advanced biliary tract and gallbladder cancer who were diagnosed during the period of 2006 to 2015 and had received first-line chemotherapy were assessed. Cox proportional multivariate analysis was performed to determine the survival benefit of second-line therapy.One hundred thirty-six eligible patients with a median age of 66 years and male:female ratio of 1:1.34 were identified. Sixty-eight percent of patients had metastatic disease. Primary tumor sites were as follows: gallbladder 31%, intrahepatic cholangiocarcinoma 36%, extrahepatic bile duct 23%, and ampullary cancer 10%. Overall, 37% of patients received second-line therapy. The median overall survival of the treatment group was 17 months (95% confidence interval [CI]: 12.5-21.5) compared with 7 months (95% CI: 5.3-8.7) in the control (P0.0001). Patients who received combination chemotherapy had a median overall survival of 20 months (14.0-26.1) compared with 17 months (13.5-20.5) if they received single-agent second-line therapy (P=0.73). Multivariate analysis of second-line therapy, hazard ratio: 0.55 (95% CI: 0.36-0.83) and neutrophil to lymphocyte ratio2, HR: 1.10 (1.05-1.15) showed a significant correlation with survival.This well-designed population-based retrospective cohort study suggests that second-line chemotherapy improves survival of real world patients with advanced biliary tract and gallbladder cancers and should be offered to the patients who are potential candidates for chemotherapy.

Ecologists have long sought to understand the controls of species’ geographic distributions. Two important hypotheses have been that range limits are determined 1) predominantly by climate or 2) by competition in addition to climate, with competitive interactions dominating where climate is benign. If the first hypothesis is correct, the effect of changing climate on species’ distributions should be adequately predicted by climate-only models. Here, we used demographic range models (DRMs) to evaluate the influence of climate and competition on the geographic distribution of Pinus edulis, a desert pine in the southwestern U.S. We parameterized DRMs with data on 23,426 trees in 1,941 forest inventory plots. Vital rate responses were consistent with the predictions of the second hypothesis: negative effects of warm-dry conditions at low-elevation sites and competition at cool-humid, high-elevation sites. Further, including both climate and competition in the DRM yielded a better fit of DRM-predicted population growth rate to the observed distribution than a climate-only DRM. However, at cool-humid sites, negative effects of competition were too weak to offset positive climate effects, resulting in a mismatch between predicted population growth rate and observed distribution. This result leads us to formulate a new hypothesis: climate has complex influences on species’ distributions through its effects on range-limiting processes at a variety of scales, for example, biotic and disturbance feedbacks at community, ecosystem, landscape, and macrosystem scales. The implications of this complex systems hypothesis are that range dynamics may be poorly predictable from static, climate-only models, and may be characterized by sudden changes in abundance, even distribution collapse, with climate change.

River deltas and the vast marshes that they host are impossible to separate. However, the sediment dynamics of rivers (channel- and lobe-based deposition) and marshes (elevation-based deposition) have not been investigated as a coupled system. We investigate this coupling by comparing a laboratory delta experiment with proxy marsh accumulation to a proxy-less control. The proxy adds just 8% mass to the system but clearly influences delta slopes and mass partitioning. Slopes in the marsh window (elevations around sea level where marsh accumulates) are reduced by 40%, as marsh deposition away from channels smooths topography. While riverine sedimentation continues to be 85% of the deposit in the marsh window, the reduced slopes increase the area in this zone such that 1.3 times more clastic volume is deposited in this window. The area above the marsh window and the mass fraction deposited at these high elevations is correspondingly reduced as if the marshes are “stealing” riverine sediment from upstream. Comparing experimental elevation distributions to the field, we show that large deltas might also exhibit this signature. Given that coastal risk is tied to elevation, these findings show that the coupling between marshes and deltas significantly impacts how they should be managed.

Patients with borderline resectable pancreatic cancer are at high risk of incomplete resection with upfront surgery. Currently, no standard induction chemotherapy regimen exists for these patients. Both FOLFIRINOX (5-FU, irinotecan, & oxaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have shown better efficacy than gemcitabine alone in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with borderline resectable pancreatic cancer who received induction FOLFIRINOX or GnP. In this population-based multicenter retrospective cohort study, patients with biopsy-proven borderline resectable pancreatic cancer diagnosed from 2011 to 2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses. Of 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with borderline resectable pancreatic cancer were identified. Ten patients each received FOLFIRINOX or GnP. Eleven patients had partial response (5, FOLFIRINOX; 6, GnP); 3 progressed during treatment. Five patients (4, FOLFIRINOX; 1, GnP; p = NS) underwent curative surgery. The median progression-free survival was 17 months in FOLFIRINOX (95% CI, 5.3–28.6) vs. 9 months (95% CI, 3.0–15) in GnP groups (p = 0.27). Overall, 80% patients in GnP vs. 40% in FOLFIRINOX died from progressive disease. The median overall survival has not been reached in FOLFIRINOX group versus 16 months (95% CI, 9.3–22.7) in GnP group (p = 0.15). The current study suggests that patients with borderline resectable pancreatic cancer who received FOLFIRINOX tend to have better outcomes. Future studies are warranted to establish a preferred systemic therapy for patients with borderline resectable pancreatic cancer.

Data from two surveys by multi-beam sonar and two by marine/terrestrial LiDAR are used to evaluate the geomorphology of the seafloor in littoral areas of the Canadian Arctic Channels, near King William Island, Nunavut. Submarine terrains show well-preserved glacial landforms (drumlins, mega-scale glacial lineations, iceberg-turbated terrain, recessional moraines, and glaciofluvial landforms) with only slight modification by modern processes (wave action and sea-ice activity). At Gjoa Haven the seafloor is imprinted by fields of pits 2 m wide and 0.15 m deep. They may result from gas hydrate dissolution triggered by falling relative sea levels. The Arctic Archipelago displays what might be termed inverted terrains: marine terrains, chiefly beach ridge complexes, exist above modern sea level and well-preserved glacial terrains are present below modern sea level. This is the inverse of the submerging regimes of Atlantic Canada, where glacial terrains exist on land, but below sea level they have been effaced and modified by marine processes down to the lowstand depth.

The inner shelf off southwest Newfoundland, bordering the Laurentian Channel, was mapped with multi-beam sonar between depths of 200 and ∼20 m, overlapping with coverage by marine/terrestrial LiDAR from maximum depths of 30 m to above sea level. The new data provide the first clear view of linkages between terrestrial and nearshore coastal systems and the inner shelf. Offshore sand reservoirs associated with adjacent sandy coastal barriers and spits are thin (∼2 m), and isolated from one another, so that bedrock is the dominant seafloor terrain on the inner most shelf. The offshore sand reservoirs link with complex nearshore bar systems, from which it is inferred that sediment exchange with terrestrial systems can occur. Several isolated sand bodies are interpreted as residuals from former coastal systems destroyed during the Holocene transgression. The new data reveal the unexpected existence of a submarine canyon that facilitates transport of sediment from the inner shelf into the deep glacial trough of the Laurentian Channel.

Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P =0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P P Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au ; Unique identifier: ACTRN12616000535471.

The precaecocolic fascia, previously known as Jackson's membrane, is a variable vascular peritoneal fold between the ascending colon and the right posterolateral abdominal wall. First described in 1913, it was originally thought to be of developmental or inflammatory origin and associated with abdominal pain. This investigation aimed to review its frequency, form and structure and look for evidence of association with malformation of the bowel, or previous inflammation. 26 dissecting room cadavers were studied to identify the precaecocolic fascia, any malrotation of the colon or signs of previous inflammation: adhesions, surgical scars, or absence of the appendix. Its structure was examined histologically and latex injections were used to trace the arteries. Membranes comparable with previous descriptions of the precaecocolic fascia occurred in 12 of 26 abdomens. They varied in form and size from long and translucent to short, thick, and opaque. In structure, the fascia resembled a fold of peritoneum containing a thickened fibrous lamina. Large thin-walled arteries in the fascia crossed the arteries in the wall of the colon at the point of attachment. No significant association with colonic malrotation or markers of previous inflammation were found. Attention should be paid to the definition of the precaecocolic fascia and "membrane" seems a more appropriate term than "fascia". It is one of a recognized group of peritoneal folds/bands, doubtful in origin but unlikely to be post-inflammatory. It may modify colonic mobility or complicate colonic operations.

Despite growing recognition of how curriculum modules can benefit child and adolescent psychiatry (CAP) training, there are few standardized teaching resources for pediatric consultation-liaison psychiatry (PCLP). A Special Interest Group (SIG) of the American Academy of Child and Adolescent Psychiatry Physically Ill Child Committee (PICC) conducted a needs assessment to establish interest in, and availability of, a library of online, self-paced learning modules specific to PCLP.An email needs assessment survey was distributed to the PICC listserv in the fall of 2019 with four core areas of inquiry: (1) clinical service description, (2) teaching barriers, (3) interest in curriculum resources, and (4) interest in evaluation resources.Respondents were representative of typical academic PCLP programs. The response rate was 28% (n = 39). Programs endorsed barriers to teaching including high service obligations and limited protected teaching time. All respondents indicated that they would utilize high-quality, online learning modules. Psychiatric complications of medical illness, catatonia, and delirium were identified as priority topics in the care of pediatric patients with comorbid medical conditions.There are currently no published educational studies regarding the training needs for PCLP programs, even among tertiary care academic facilities. This training needs assessment is the first step in establishing a national PCLP training curriculum. New paradigms to develop standardized curriculum resources for PCLP are needed.

Julia Kogan v (1) Nicholas Martin (2) Big Hat Stories Limited (3) Florence Film Limited (4) Pathe Productions Limited (5) Qwerty Films Limited [2019] EWCA Civ 1645 The dispute between Ms Kogan and Mr Martin (and various film companies) regarding the authorship (or joint authorship) of the screenplay for the film depicting socialite Florence Foster Jenkins has been granted a retrial following a decision by the Court of Appeal that included an explanation of the criteria for joint authorship under UK law.

The aim of this study was to compare the efficacy and safety of FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) in patients with advanced pancreatic cancer.Patients with newly diagnosed advanced pancreatic cancer in Saskatchewan, Canada, from 2011 to 2016, who received FOLFIRINOX or GnP were assessed. A Cox proportional multivariate analysis was performed to evaluate prognostic variables.One hundred nineteen eligible patients with median age of 61 years and male/female ratio of 70:49 were identified. Seventy-seven percent had metastatic disease. Of 119 patients, 86 (72%) received FOLFIRINOX and 33 (28%) were treated with GnP. Median progression-free survival of the FOLFIRINOX group was 6.0 months [95% confidence interval (CI), 4.5-7.5] versus 4.0 months (95% CI, 2.9-5.1) with GnP (P = 0.39). The median overall survival of the FOLFIRINOX group was 9.0 months (95% CI, 7-11) compared with 9.0 months (95% CI, 4.2-13.8) with GnP (P = 0.88). On multivariate analysis, albumin [hazard ratio (HR), 0.63; 95% CI, 0.41-0.97], male sex (HR, 0.65; 95% CI, 0.43-0.97), and second-line therapy (HR, 0.50; 95% CI, 0.28-0.86) were correlated with survival.Our results showed that real-world patients with advanced pancreatic cancer treated with FOLFIIRNOX or GnP had comparable survival with different safety profile.

Background Blood loss and transfusion remain a significant concern in liver resection (LR). Patient blood management (PBM) programs reduce use of transfusions and improve outcomes and costs, but are not standardized for LR. This study sought to create an expert consensus statement on PBM for LR using modified Delphi methodology. Methods An expert panel representing hepato-biliary surgery, anesthesiology, and transfusion medicine was invited to participate. 28 statements addressing the 3 pillars of PBM were created. Panelists were asked to rate statements on a 7-point Likert scale. Three-rounds of iterative rating and feedback were completed anonymously, followed by an in-person meeting. Consensus was reached with at least 70% agreement. Results The 35 experts panel recommended routine pre-operative transfusion risk assessment, and investigation and management of anemia with iron supplementation. Intra-operatively, restrictive fluid administration without routine central line insertion was recommended, along with intermittent hepatic pedicle occlusion and surgical techniques considerations. Specific criteria for restrictive intra-operative and post-operative transfusion strategy were recommended. Conclusions PBM for LR included medical and technical interventions throughout the perioperative continuum, addressing specificities of LR. Diffusion and adoption of these recommendations can standardize PBM for LR to improve patient outcomes and resource utilization.