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The Cretaceous Dunvegan Formation in the Western Canada Sedimentary Basin is a well-characterized source-to sink system that extends for about 1000 km from proximal gravelly alluvial systems in the Liard Basin, Northwest Territories, to well-developed sandy deltaic and prodelta muddy shelf systems in Alberta. The mud to sand transition has been well-documented and the sandy deltas have been shown to be fed by tributive incised valley systems driven by cycles of high frequency sea-level change. These incised valleys in turn pass landward into the conglomerate alluvial systems, but the nature of these conglomerates and the controls on the gravel-sand transition have not been well examined.Dunvegan conglomerates in outcrops in the Liard Basin are moderately-sorted and well- rounded reaching up to small cobbles in size. These have previously been interpreted as alluvial fans; however, our investigations show a domination of sharp to scoured based meters-thick fining upward facies successions consisting of dune- and bar- scale cross stratification. The conglomeratic units comprise highly amalgamated channel belt deposits that form cliff exposures that are about 70 m high. There is an absence of debris flows or of sedimentary structures characteristic of supercritical flows, and we thus interpret these as likely deposited by meters-deep lower-gradient gravel-bed streams, rather than steep-gradient, sheet-flood dominated alluvial fans.Trunk channels in the sink area, farther to the southeast are associated with incised valleys and have a mean bankfull depth of 10-15 m, carry medium sand (< 200 microns) with slopes estimated to be on the order of 6x 10-5. Source to sink calculations indicate a back-water length of around 200 kilometers. Based on paleogeographic reconstructions, the conglomerates appear to have been deposited 300 to 500 km from the mapped deltaic shorelines, indicating that the gravel sand transition is not related to the back water and is likely not controlled by sea-level changes, thought to be important in generating the incised valleys in the sink area. The conglomerates appear to be confined within the Liard Basin, which is bounded to the east by the Bovie Fault, expressed as a major kilometer-throw normal fault. The Bovie structure was long-lived and may have been active throughout Dunvegan time. Hence, excess accommodation, driven by movement on the Bovie Fault may have prevented gravel from escaping into the more distal parts of the Western Canada Sedimentary basin. This is in contrast to other clastic wedges in the Cretaceous Interior Seaway, such as the Frontier and Cardium formations, that contain conglomeratic shoreline and shelf deposits and may indicate steeper gradient S2S systems.Tectonics and climate in the Dunvegan drainage basin may not have been linked to processes downstream because of the Bovie Fault. Despite clear evidence of downstream sea-level controls in the Dunvegan sink, it does not appear that these signals were able to propagate upstream.

Background/Aims A female acute inpatient mental health ward developed a care pathway to support women who self-harm during their admission. This service evaluation was the first to explore staff and patients' experiences of the care pathway using qualitative methods. Methods Semi-structured interviews were completed with eight staff members and five patients. Thematic analysis was used to analyse the interview data. Results Themes that developed from staff interviews were about effects on staff and staff support, enabling patients to manage self-harm autonomously and the ward environment. Themes developed from patient interviews included enabling engagement, putting skills into practice and least restrictive practice. Staff and patients viewed the pathway as effective in reducing self-harm incidents and levels of restriction on the ward. Conclusions The pathway was viewed positively by staff and patients, although improvements could be considered to increase its efficacy.

Septic systems are a common contributor of contaminants to groundwater that have implications for source water protection, particularly in fractured sedimentary bedrock environments. Two 24-h tracer experiments were performed that applied (1) the dye Lissamine Flavine FF and (2) three artificial sweeteners (acesulfame, sucralose, and cyclamate) in the leaching bed to examine solute transport from a single-family septic bed to a multilevel monitoring well installed in fractured sedimentary bedrock on a First Nation reserve in Southern Ontario, Canada. Tracer was first observed 3 h and 20 min after deployment, and breakthrough curves showed that multiple pathways likely exist between the septic bed and the monitoring well. Cyclamate concentrations were more elevated than expected compared to other studies that examined cyclamate’s attenuation in the laboratory and in porous media aquifers. Solute transport through the septic bed was analyzed with the numerical modeling software Hydrus 1D, which indicated that the septic bed may be too thin, located directly on bedrock, underlain by fractured soils, or bypassed through a short-circuit. The rapid transport of septic leachate to fractured sedimentary aquifers is problematic for First Nation and rural communities. More stringent regulations are needed for the design and use of septic systems in these environments.

In 2020, toward the end of the Winter semester, the COVID-19 pandemic disrupted life across the globe. Institutions, including law schools, felt the widespread effects of this public health crisis. Law schools were forced to move entire curriculums online in record time and consider how they were going to administer final exams. There is no precedent or manual for how to do this successfully. The pressure of the high stakes law school final exam that the law student’s entire grade and ranking rest upon is stressful, to say the least. Law students are on edge during final exams during normal times, but as the United States became overwhelmed by the COVID-19 pandemic, universities sent students, faculty, and staff home to finish the semester online and were left with a myriad of issues to address. One issue that arose was how to deliver final exams in a completely online format while maintaining the integrity of the law school exam. This article discusses the pivot to flexibility that one law school had to make, under emergency conditions, and with limited resources. Part I describes the law school final exam pre-COVID 19, Part II describes the pre-planning process, Part III discusses the building process, Part IV discusses the administrating process, and Part V explores some of the lessons learned from the experience with exams and suggests how to move forward in an uncertain world.

Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo-controlled, three-arm trial where eligible subjects were randomized to 8g PEG-3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. Trial registration: ClinicalTrials.gov NCT00828984

Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.

A one-pot reaction of carboxylic acids with sulfonamides to afford sulfonylureas is described.

Neonatal arch reconstructions present a challenge for myocardial protection. We report our results for eight patients treated with intermittent cold all blood retrograde cardioplegia during arch reconstruction using continuous selective normothermic cerebral perfusion. Over a 10-month period eight consecutive neonates underwent complex arch reconstruction. Mean age was 8.4 days (range 2-23); weight 3.1 kg (range 2.7-3.8). Diagnosis was hypoplastic left heart syndrome (5), interrupted aortic arch/ventriculoseptal defect (2), and complex AP window (1). Mean cardiopulmonary bypass time was 149 minutes (range 80-201), mean cross-clamp time was 74 (range 51-101). All patients had primary chest closure and none required extra-corporeal membrane oxigenation. One patient (12%) had a period of low cardiac output syndrome, which resolved with high dose inotropes. All patients were discharged alive and well. Intermittent all blood retrograde microplegia is an effective myocardial protection strategy for complex neonatal arch reconstruction. Postoperative myocardial function is very good. This protection approach facilitates continuous selective normothermic cerebral perfusion.

Accurate characterization of contaminant mass in zones of low hydraulic conductivity (low k) is essential for site management because this difficult-to-treat mass can be a long-term secondary source. This study developed a protocol for the membrane interface probe (MIP) as a low-cost, rapid data-acquisition tool for qualitatively evaluating the location and relative distribution of mass in low-k zones. MIP operating parameters were varied systematically at high and low concentration locations at a contaminated site to evaluate the impact of the parameters on data quality relative to a detailed adjacent profile of soil concentrations. Evaluation of the relative location of maximum concentrations and the shape of the MIP vs. soil profiles led to a standard operating procedure (SOP) for the MIP to delineate contamination in low-k zones. This includes recommendations for: (1) preferred detector (ECD for low concentration zones, PID or ECD for higher concentration zones); (2) combining downlogged and uplogged data to reduce carryover; and (3) higher carrier gas flow rate in high concentration zones. Linear regression indicated scatter in all MIP-to-soil comparisons, including R(2) values using the SOP of 0.32 in the low concentration boring and 0.49 in the high concentration boring. In contrast, a control dataset with soil-to-soil correlations from borings 1-m apart exhibited an R(2) of ≥ 0.88, highlighting the uncertainty in predicting soil concentrations using MIP data. This study demonstrates that the MIP provides lower-precision contaminant distribution and heterogeneity data compared to more intensive high-resolution characterization methods. This is consistent with its use as a complementary screening tool.

Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles.

Infants with heparin-induced thrombocytopenia (HIT) represent a challenging and high-risk group of patients when they require cardiopulmonary bypass (CPB). Bivalirudin offers many potential pharmacologic advantages over other nonheparin anticoagulants for such patients. We describe our protocol for the use of bivalirudin in a 5-month-old infant undergoing stage 2 Norwood for hypoplastic left heart syndrome. The patient was a 5- month-old, 6-kg infant who developed HIT after a bowel resection complicating initial Norwood stage 1. After sternotomy and dissection had been redone, the child received an initial dose of bivalirudin of 1.0 mg/kg and 0.5 mg/kg 5 min later. The CPB circuit was primed with 50 mg/kg bivalirudn/400 cc volume. With the initiation of CPB, a continuous infusion of 2.5 mg/kg bivalirudin was begun. Activated clotting time (ACT) was targeted for over 400 s, with an examination prior to bypass and each 15 min thereafter. Bivalirudin was discontinued with separation from bypass and during modified ultrafiltration (MUF). The ACT was 286 s after the initial 1 mg/kg bolus and 597 s after the second 0.5 mg/kg bolus and initiation of CPB. At a rate of 2.5 mg/kg/min, ACT ranged between 461 and 597 s. At the completion of MUF, the ACT was 316 s. The ACT was 214 s 20 min after MUF. No clots were noted in the CPB circuit, and good hemostasis was achieved within 10 min after MUF was completed. Incision to closure time was 160 min; time from completion of MUF to sternal closure was 30 min. Post-MUF, 60 cc of processed cell saver blood was reinfused, and no clotting factors were required. Chest tube output was 10, 10, 3, and 4 ccs, respectively, at hours 1-4 post operation. Bivalirudin provides effective anticoagulation in infants requiring CPB in the presence of HIT. Bivalirudin's efficacy is effectively monitored by ACT, and, after CPB, its short half-life and ability to be ultrafiltered facilitate the ability to achieve hemostasis in a timely fashion.

A one-pot reaction of carboxylic acids with sulfonamides to afford sulfonylureas is described.

The Norwood procedure is commonly performed using either circulatory arrest or deep hypothermia with low-flow cardiopulmonary bypass. We describe our technique for the Norwood procedure using selective cerebral perfusion with corporeal normothermia (> 32 degrees C). A right radial artery catheter was placed and cerebral NIRS applied. A C-clamp was placed upon the innominate artery and gortex shunt placed. Cardiopulmonary bypass was established through the shunt. A 7.0 purse-string was placed at the beginning of the arch and a cross-clamp applied superior to this and cold cardioplegia was given by hand. The left carotid and subclavian were snared and a C-clamp was placed on the distal descending aorta. The cross-clamp was then repositioned across the base of the innominate and pump flow was reduced. This resulted in arch isolation with a bloodless field. Perfusion was then transferred to a neo-artic cannula and the central shunt completed. Cardiopulmonary bypass time was approximately 60 minutes and cardiac arrest time was approximately 20 minutes; core temperature had not dropped below 32 degrees C. The Norwood procedure can be successfully performed with normothermic selective cerebral perfusion thereby offering the theoretical benefit of avoiding deep hypothermia with or without circulatory arrest.

All blood cardioplegia delivery units offer the advantage of removing additional crystalloid volumes associated with multidose crystalloid or 4:1 blood cardioplegia. Further reductions in crystalloid and prime volumes can be achieved if the cardioplegia delivery unit can be integrated as the modified ultrafiltration (MUF) unit as well. This article reports our technique and results for integration of the Quest MPS all-blood cardioplegia delivery unit (Quest Medical, Allen, TX) for modified ultrafiltration. The charts of 50 consecutive patients were reviewed. Patient age ranged from 3 days to 5 years. There were nine neonates. Patient weight ranged from 1.7 to 20.4 kg. Standard prime volumes were 400 cc for patients weighing less than 12 kg, and 800 cc for patients weighing more than 12 kg. Cardiopulmonary bypass time ranged from 32 to 231 minutes. All patients were perfused with corporeal temperatures above 31 degrees C except Norwood cases. MUF time ranged from 5 to 15 minutes with an average of 10.2 minutes. Volume removed ranged from 100 to 600 cc with an average of 239 cc. There was one mortality (2%), which was unrelated to MUF. Additional prime volume was not required to initiate MUF through the MPS cardioplegia unit. The Quest MPS all-blood CPG unit can be safely and effectively integrated as a MUF unit without additional prime volumes. This approach allows for mild hypothermic cardiopulmonary bypass, multidose all-blood CPG, and MUF to be used with tremendous limitation of crystalloid usage.

BACKGROUND AND AIM: Endoscopy is the first level procedure in the diagnosis of gastrointestinal (GI) masses. However gastro-duodenal or colonic lesions which mainly involve submucosa or subserosa as well as small bowel's lesions may be difficult to diagnose. The present study aimed to evaluate the role of ultrasound (US)-guided percutaneous biopsy in diagnosing GI tract lesions. PATIENTS AND METHODS: 114 patients (63 male 51 female patients, age range 55-80 years, median age 68 years) underwent US-guided biopsy of GI lesions from 2000 to 2012. In 36 patients the lesion was in the small bowel, thus endoscopically inaccessible; in 50 patients previous histology of endoscopic biopsies was repeatedly negative; in 18 patients, stenosis did not allow bioptic sampling and in 10 patients age, severe cardiological disease and sepsis prevented endoscopy. We used multi-frequency convex probes with side adapters and 18G cutting needle for histological sampling. After biopsy, patients were monitored by measuring blood pressure and pulse rate during the following 3-4 hours to evaluate possible complications. Histology was compared with postsurgery histological evaluation in 73 cases. In the remaining, histology of US-guided biopsy was the only clue to diagnosis. RESULTS: Biopsy specimens were taken from stomach in 38 cases, small bowel in 36 cases and colon-sigma in 40 cases. Final diagnosis was malignant lesions in all but three cases. One case was intestinal endometriosis, the second was bowel duplication, whereas in the third case it was a false-negative result, the correct diagnosis being gastric adenocarcinoma. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of biopsy were respectively 99%, 100%, 100%, 66%, 99%.We observed no mortality and one complication: A case of melena due to bleeding from gastric gastrointestinal stromal tumor that was effectively controlled by positioning of metal clips. CONCLUSION: US-guided percutaneous biopsy of GI tract lesions may be an alternative, safe and effective procedure for diagnosis of GI tract lesions in those cases where conventional diagnostic approach is not feasible or successful.

Releases of mixed organic solvent DNAPL occurred before 1970 at an industrial site. The DNAPL migrated through glacial sediments and shallow bedrock, accumulated between 45 and 55 m bgs in a fractured sandstone, and is a persistent source for a large groundwater plume. Here, the contaminant mass variability is characterized using five cored holes along a 238 m long transect orthogonal to groundwater flow and immediately downgradient of the source. Average sample frequency was 4.7 samples per metre. Results show distinct and sometimes unpredictable spatial variability of concentration and composition. One core was located 13 m from a hole cored and sampled in a similar manner 10.5 years earlier. Comparison of results shows an 85% reduction in total VOC mass, attributed mostly to groundwater flushing above the known DNAPL accumulation with evidence for some microbial degradation. These data are foundational to future mass flux estimates and source zone longevity calculations. Dr. Beth Parker’s NSERC IRC and Hydrite Chemical Co.