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Due to the prevalence of cardiovascular disease in the United States, small-caliber vascular grafts for coronary bypass surgery continue to be in high demand. Human umbilical arteries, an under-utilized resource, were decellularized using zwitterionic (CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate)) and ionic (SDS (sodium dodecyl sulfate)) detergents and evaluated as potential vascular grafts. Vessels were tested for decellularization efficacy, mechanical integrity and recellularization potential. Hematoxylin and eosin staining and DNA quantification revealed moderate to successful removal of cells in both conditions. While CHAPS-decellularized vessels displayed collagen structure most similar to intact tissue, both CHAPS- and SDS-decellularized vessels demonstrated burst pressures lower than that of intact tissue. Alcian blue staining and sulfated glucosaminoglycan (sGAG) quantification indicated the preservation of sGAG content after both decellularization pathways. Both conditions were also capable of recellularization with human umbilical vein endothelial cells and the use of a basic fibroblast growth factor treatment did not have a significant effect on the density of adhered cells after five days. Whole CHAPS-decellularized vessels were successfully recellularized. Additionally, an evaluation of the effects of freeze-thaw cycles was performed. In summary, human umbilical arteries present a promising alternative for small-caliber vascular grafts due to their high availability and ability to be decellularized and recellularized for safe and successful implantation.

To develop a system that is equivalent to the gold standard Douglas Bag (DB) technique for measuring oxygen consumption (V̇oThis was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Healthy volunteers and patients 18 years or older who received mechanical ventilation were enrolled.Data from 3 healthy volunteers and 7 patients were analyzed in this study. The interrater reliability between the automation device and DB methods were 0.999, 0.993, and 0.993 for V̇oWe developed an automation system that enables repeat measurements of V̇o

Peatlands store amongst the highest proportion of soil carbon in terrestrial ecosystems, but there is significant concern surrounding the effect climate change, and in particular, altered soil moisture regimes have on carbon cycling in these ecosystems. While greenhouse gas dynamics of boreal and high-elevation peatlands are well-studied in the northern hemisphere, less is known about peatlands in an Australian context. Soils were sampled from Lake Mountain, a sub-alpine peatland in south-eastern Australia at along a transect at four sites; sphagnum, wet peat, mid slope and woodland sites. The soils were incubated for 31 days to determine the effect of altered moisture content on CO2, CH4 and N2O fluxes under controlled conditions. Three moisture scenarios were assessed, a wet, dry and a 14-day wet-dry cycle examined over four sites, with three replicate cores per site. The Lake Mountain peatlands were estimated to store 114.52 Mg ha-1 in the top 20 cm, which is lower than other estimates of high elevation peatlands in south-eastern Australia. There was no effect of treatment on greenhouse gas fluxes, but higher carbon to nitrogen ratio was found to increase CO2 and CH4 fluxes. Some N2O sequestration was also identified. The results suggest that over the short term where soils do not dry out completely, site characteristics have a larger influence on GHG emissions compared to altered moisture availability.

Supplemental Methods and Materials. ACF Phospho-ERK and ERK Level Quantification.

Colorectal cancer progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal growth factor receptor (EGFR) inhibitors are efficacious in advanced tumors including colorectal cancer. There is significant evidence that EGFR also plays important roles in colorectal cancer initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to colorectal cancer, and normal rectal tissue. A total of 45 patients were randomized to one of three erlotinib doses (25, 50, and 100 mg) with randomization stratified by nonsteroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphorylated ERK (pERK), phosphorylated EGFR (pEGFR), and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional prescreening stratification or potentially longer duration of use. Cancer Prev Res; 8(3); 222–30. ©2015 AACR.

Supplementary Materials from Phase IIA Trial Testing Erlotinib as an Intervention against Intraductal Pancreatic Mucinous Neoplasms

Purine nucleotide adenosine triphosphate (ATP) is a source of intracellular energy maintained by mitochondrial oxidative phosphorylation. However, when released from ischemic cells into the extracellular space, they act as death-signaling molecules (eATP). Despite there being potential benefit in using pyruvate to enhance mitochondria by inducing a highly oxidative metabolic state, its association with eATP levels is still poorly understood. Therefore, while we hypothesized that pyruvate could beneficially increase intracellular ATP with the enhancement of mitochondrial function after cardiac arrest (CA), our main focus was whether a proportion of the raised intracellular ATP would detrimentally leak out into the extracellular space. Indicated by the increased levels in systemic oxygen consumption and brain ATP levels, intravenous administrations of bolus (500 mg/kg) and continuous infusion (1000 mg/kg/hr) of pyruvate successfully increased oxygen and energy metabolism in post 10-min CA rats. The plasma ATP levels increased significantly from 67 ± 11 nM before CA to 227 ± 100 nM 2 hours after the resuscitation, while the pyruvate injection did not affect post-CA ATP levels. Notably, the pyruvate injection improved post-CA cardiac contraction and acidemia (low pH). We also found that pyruvate increased systemic CO2 production post-CA. These data support that pyruvate has therapeutic potential for improving CA outcomes by enhancing oxygen and energy metabolism in the brain and heart, and attenuating intracellular hydrogen iron disorders, but does not exacerbate the death-signaling of eATP in the blood.

Background Oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), which is the ratio of VO2 to VCO2, are critical indicators of human metabolism. To seek a link between the patient’s metabolism and pathophysiology of critical illness, we investigated the correlation of these values with mortality in critical care patients. Methods This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older healthy volunteers and patients who underwent mechanical ventilation were enrolled. A high-fidelity automation device, which accuracy is equivalent to the gold standard Douglas Bag technique, was used to measure VO2, VCO2, and RQ at a wide range of fraction of inspired oxygen (FIO2). Results We included a total of 21 subjects including 8 post-cardiothoracic surgery patients, 7 intensive care patients, 3 patients from the emergency room, and 3 healthy volunteers. This study included 10 critical care patients, whose metabolic measurements were performed in the ER and ICU, and 6 died. VO2, VCO2, and RQ of survivors were 282 +/- 95 mL/min, 202 +/- 81 mL/min, and 0.70 +/- 0.10, and those of non-survivors were 240 +/- 87 mL/min, 140 +/- 66 mL/min, and 0.57 +/- 0.08 (p = 0.34, p = 0.10, and p p IO2p

Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications.To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes.We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints.Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis.This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.

Traditional cancer registries have often been siloed efforts, established by single groups with limited objectives. There is the potential for registry data to support a broad range of research, audit and education initiatives. Here, we describe the establishment of a series of comprehensive cancer registries across the spectrum of common solid cancers. The experience and learnings of each registry team as they develop, implement and then use collected data for a range of purposes, that informs the conduct and output of other registries in a virtuous cycle. Each registry is multi-site, multi-disciplinary and aims to collect data of maximal interest and value to a broad range of enquiry, which would be accessible to any researcher with a high-quality proposal. Lessons learnt include the need for careful and continuous curation of data fields, with regular database updates, and the need for a continued focus on data quality. The registry data as a standalone resource has supported numerous projects, but linkage with external datasets with patients in common has enhanced the audit and research potential. Multiple projects have linked registry data with matched tissue specimens to support prognostic and predictive biomarker studies, both validation and discovery. Registry-based biomarker trials have been successfully supported, generating novel and practice-changing data. Registry-based clinical trials, particularly randomised studies exploring the optimal use of available therapy options are now complementing the research conducted in traditional clinical trials. More recent projects supported by the registries include health economic studies, personalised patient education material, and increased consumer engagement, including consumer entered data.

Objectives The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. Study Design and Setting We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989–October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. Results We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). Conclusion A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

BACKGROUND Graduate medical education is being transformed from a time-based training model to a competency-based training model. While the application of ultrasound in the perioperative arena has become an expected skill set for anesthesiologists, clinical exposure during training is intermittent and nongraduated without a structured program. We developed a formal structured perioperative ultrasound program to efficiently train first-year clinical anesthesia (CA-1) residents and evaluated its effectiveness quantitatively in the form of a proficiency index. METHODS In this prospective study, a multimodal perioperative ultrasound training program spread over 3 months was designed by experts at an accredited anesthesiology residency program to train the CA-1 residents. The training model was based on self-learning through web-based modules and instructor-based learning by performing perioperative ultrasound techniques on simulators and live models. The effectiveness of the program was evaluated by comparing the CA-1 residents who completed the training to graduating third-year clinical anesthesia (CA-3) residents who underwent the traditional ultrasound training in the residency program using a designed index called a "proficiency index." The proficiency index was composed of scores on a cognitive knowledge test (20%) and scores on an objective structured clinical examination (OSCE) to evaluate the workflow understanding (40%) and psychomotor skills (40%). RESULTS Sixteen CA-1 residents successfully completed the perioperative ultrasound training program and the subsequent evaluation with the proficiency index. The total duration of training was 60 hours of self-based learning and instructor-based learning. There was a significant improvement observed in the cognitive knowledge test scores for the CA-1 residents after the training program (pretest: 71% [0.141 ± 0.019]; posttest: 83% [0.165 ± 0.041]; P < .001). At the end of the program, the CA-1 residents achieved an average proficiency index that was not significantly different from the average proficiency index of graduating CA-3 residents who underwent traditional ultrasound training (CA-1: 0.803 ± 0.049; CA-3: 0.823 ± 0.063, P = .307). CONCLUSIONS Our results suggest that the implementation of a formal, structured curriculum allows CA-1 residents to achieve a level of proficiency in perioperative ultrasound applications before clinical exposure.

B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.

Background Posaconazole is a triazole antifungal licensed for the prevention of invasive fungal infections (IFI) in haemato-oncology patients and treatment of IFI where first-line therapy has failed. In January 2020 COVID-19 hit the UK, with many NHS services reduced to meet the unprecedented challenges of the pandemic. We audited prescriptions and therapeutic drug monitoring (TDM) of posaconazole and compared the results with an audit conducted pre-COVID-19 to assess the impact of the pandemic on antifungal stewardship (AFS). Methods Inpatients prescribed posaconazole over two 3 month periods (1 October to 31 December 2019 and 2020) at Addenbrooke's Hospital, Cambridge, were identified using an electronic computer system and their records reviewed for demographic, diagnostic and therapeutic data. Posaconazole levels were performed at the national Mycology Reference Laboratory, Bristol, using guide levels of 0.7–3.75 mg/L (prophylaxis) and 1–3.75 mg/L (treatment). The first pre-dose level for each patient was used in analyses. Audit standards included (i) all inpatients on posaconazole to have an indication in local guidelines; (ii) to have the correct loading dose prescribed; (iii) to have a pre-dose level taken (iv) at the correct time (i.e. between Day 3–8) after commencing therapy or a dose change; (v) to have a turnaround time of ≤5 days; and (vi) to stop posaconazole appropriately. Results Forty-two 42 inpatients received posaconazole in 2020 (49, 2019). In total, 39/42 (93%) patients had an appropriate indication [46/49, (94%), 2019]: 38/40 (95%) for prophylaxis [45/45, (100%) 2019]; 1/2 (50%) for treatment [1/1, (100%) 2019]. In 2020, 34/42 (81%) of patients received the correct loading dose [41/46 (89%), 2019). TDM was performed on 33/42 (79%) patients [46/46 (100%), 2019], 18/42 (43%) 3–8 days after starting [25/46 (54%), 2019] and 3/13 (23%) after a dose change [9/10 (90%), 2019]; 32/33 (97%) of TDM results were reported in ≤5 days [32/46 (70%), 2019]. Posaconazole was stopped in 24/26 (92%) patients who were no longer receiving immunosuppression and/or neutropenia had resolved [23/23 (100%), 2019]. Conclusions Despite the pressures of COVID-19, there were good standards of care with only slight reductions in compliance, with the exception of TDM. This may have reflected the change from face-to-face to virtual meetings with haemato-oncology, as well as representing issues of staff shortages and changes in hospital priorities. Such data have highlighted the usefulness of technology to facilitate AFS, e.g. electronic prescribing order sets, which would provide us with quality assurance in a system that will be facing ongoing pressures from the pandemic for years to come.

Exchangeable sodium can have pronounced influences on physicochemical soil properties whereas the combined impact on microbial turnover of organic carbon (OC) remains elusive. In this work, we aimed to differentiate the effects of exchangeable sodium and soil pH on microbially mediated aggregate formation and turnover of cattle slurry. We incubated the soils under controlled laboratory conditions using artificial soil model minerals containing quartz grains, montmorillonite and goethite. The montmorillonite was pre-treated with NaCl solutions of sodium adsorption ratios (SAR) 0, 1 and 5 which resulted in exchangeable sodium percentages (ESP) of 1, 7 and 19 on average. The soil pH was adjusted within two treatments to 7.5 and 8.5 for each ESP at the start of the incubation. We incubated these six treatments with and without cattle slurry ground to < 200 µm after addition of a combined microbial inoculum, extracted from a Cambisol (pHH2O 7.5, Germany) and a Calcaric Solonchak (pHH2O 9.3, Spain) added to all samples. The microcosms were incubated with three replicates over a period of 30 days at constant pF of 2.2. The CO2 emission measurements of the microcosms with exchangeable sodium indicated a delayed respiration. The respiration under ESP 19 increased rapidly within the first days of incubation, whereas it was more delayed under ESP 7 until 15 days of incubation. The delayed CO2 respiration might be related to inhibited structural formation in treatments with higher exchangeable sodium. To test this, we are investigating the data on water-stable aggregation by wet sieving. The delayed CO2 respiration was reflected in lower microbial biomass, extracted after the incubation. The microbial biomass under ESP 19 and pH 8.5 was highest whereas the amount of leached C after two rainfall events (at day 7 and 15) was lowest, which could be related to a higher microbially mediated OC sequestration. The composition of exchangeable cations was monitored before and after the whole incubation which might help explaining the processes of microbially mediated aggregate formation and microbial carbon turnover under different levels of exchangeable sodium.

The diagnostic capabilities, palliative procedures, and critical care therapies for neonates with single ventricle heart disease have rapidly evolved. We aimed to review current trends for intensivists and cardiologists caring for this population. Enhanced diagnostics and 3-dimensional modeling can be instrumental in planning care pathways for these neonates. Additionally, the ability to palliate many of these patients with catheter-based therapies rather than traditional surgical approaches has allowed for reduced morbidity. There are significant improvements in the understanding of how critical care therapies affect survival and neurodevelopmental outcomes in this population. Despite advancements in the understanding of longer-term outcomes in this population, much remains to be discovered about how initial palliation, critical care strategies, surgical techniques, and extracorporeal support can be optimized for the most favorable neurodevelopmental outcomes, survival, and quality of life. This will be the major focus of future research through larger collaboratives.

Interactive online learning tools have revolutionized graduate medical education and can impart echocardiographic image interpretive skills. We created self-paced, interactive online training modules using a repository of echocardiography videos of normal and various degrees of abnormal left ventricles. In this study, we tested the feasibility of this learning tool. Thirteen anesthesia interns took a pre-test and then had 3 weeks to complete the training modules on their own time before taking a post-test. The average score on the post-test (74.6% ± 11.08%) was higher than the average score on the pre-test (57.7% ± 9.27%) (P P = 0.278) and post-test (P = 0.093). The interns scored higher on the post-test than the pre-test on both extreme (P = 0.0062) and non-extreme (P = 0.0083) questions. After using an online educational tool that allowed learning on their own time and pace, trainees improved their ability to correctly categorize left ventricular systolic function. Left ventricular systolic function is often a key echocardiographic question that can be difficult to master. The promising performance of this educational resource may lead to more time- and cost-effective methods for improving diagnostic accuracy among learners.

The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC.Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes.A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02).Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

Objective : To systematically survey the literature addressing the reporting of studies estimating anchor-based minimal important differences (MIDs) and choice of optimal MIDs. Study design and Setting : We searched Medline, Embase and PsycINFO from 1987 to March 2020. Teams of two reviewers independently identified eligible publications and extracted quotations addressing relevant issues for reporting and/or selecting anchor-based MIDs. Using a coding list, we assigned the same code to quotations capturing similar or related issues. For each code, we generated an ‘item’, i.e. a specific phrase or sentence capturing the underlying concept. When multiple concepts existed under a single code, the team created multiple items for that code. We clustered codes addressing a broader methodological issue into a ‘category’ and classified items as relevant for reporting, relevant for selecting an anchor-based MID, or both. Results : We identified 136 eligible publications that provided 6 categories (MID definition, anchors, patient-reported outcome measures, generalizability and statistics) and 24 codes. These codes contained 34 items related to reporting MID studies, of which 29 were also related to selecting MIDs. Conclusion : The systematic survey identified items related to reporting of anchor-based MID studies and selecting optimal MIDs. These provide a conceptual framework to inform the design of studies related to MIDs, and a basis for developing a reporting standard and a selection approach for MIDs.

Objective: We recently reported that post-resuscitation normoxic therapy attenuates oxidative stress in multiple organs and improves post-cardiac arrest (CA) organ injury, oxygen metabolism, and survival. Yet, detailed mechanisms of gene expression patterns and signaling pathways mitigated by normoxic therapy have not been elucidated. Therefore, we assessed post-resuscitation normoxic therapy-modified gene expression of oxidative stress-related signaling molecules. Methods: Rats were resuscitated from 10 minutes of asphyxial CA and divided into 2 groups: those that inhaled 100% supplemental O 2 (CA-FIO2 1.0) and those that inhaled 30% supplemental O 2 (CA-FIO2 0.3). Control groups were also prepared for comparison (control-FIO2 1.0, control-FIO2 0.3). At 2 hours after resuscitation, brain and heart tissues were collected, and mRNA purifications followed by real-time PCR measurements were performed to compare gene expression of hyperoxia-induced inflammatory and apoptosis-related signaling pathways amongst these groups. Results: In the brain, relative IL-1 beta mRNA gene expression levels, which represent inflammatory signaling pathways, increased post-CA (8.1±2.3 in CA-FIO2 1.0 and 1.0±0.4 in control-FIO2 0.3, p Conclusions: Post-CA normoxic therapy significantly attenuated the gene expression of oxidative stress-induced inflammation and apoptosis in the brain, while there were no remarkable changes in the heart. Therefore, it is inferred that the heart is more tolerant to hyperoxic injury compared to the brain.

To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019.We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors.The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT.This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor.Compared to resilient and non-stressed control mice, we found that in both the dorsal and ventral hippocampal CA1 regions, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells). The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD to reactivate social defeat-related but not neutral contextual stimuli-related CA1 engram cells decreased social interaction. Increased engram cells in susceptible mice were region specific and could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Together, our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal engrams for negative memory may underlie the vulnerability and expression of cognitive symptoms in depression.Significance statementWe provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.

Objective: Comprehensive educational initiatives in ultrasound for practicing physicians are lacking. We developed a perioperative ultrasound training program for faculty to offer a broad orientation to the principles and clinical applications of ultrasound.Design and Setting: The program consisted of two phases. Phase one, which introduced ultrasound via didactic and hands-on components, had six live sessions. At the end of each, participants completed a knowledge quiz. During the sixth session, faculty participated in an objective structured clinical examination (OSCE). For phase two, faculty attended two to three sessions (8-10 hours each) of in-depth individualized training and demonstrated supervised performance of ultrasound-related procedures of their choice.Participants: Participants included Anesthesia faculty at Beth Israel Deaconess Medical Center.Measurements and Main Results: On average 30 faculty members attended each live session for phase one; 12 completed phase two. There was a significant difference in quiz scores across the six sessions (p 10 blocks on patients over two days; 5 of the 7 participants who received training in transthoracic echocardiography each completed more than 15 examinations on simulators and 10 examinations on patients.Conclusion: It is possible to implement a departmental educational program for ultrasound to improve ultrasound knowledge and skills in practicing anesthesiologists.(C) 2018 Elsevier Inc. All rights reserved.

Objective Proficiency in the use of ultrasound is presently not an ACGME required core competency for accredited surgical training. There should be a basic unified ultrasound curriculum for surgical trainees. We developed a multimodal ultrasound-training program to ensure baseline proficiency and readiness for clinical performance without impacting trainee duty hours. Design We developed and implemented a multimodal curriculum for ultrasound education and its use as a supplement to clinical evaluation of unstable patients. Setting A single-center study was completed in a hospital setting. Participants Post-graduate year-1 surgical residents at our institution were invited to participate in a multimodal perioperative course. Results 51 residents attended the course over the three sessions. The vignette exam as a whole demonstrated a Cronbach's alpha of 0.819 indicating good internal reliability of the entire test. There was significant improvement in their knowledge in clinical vignettes (55% ± 12.4 on pre-test vs. 83% ± 13.2% on post-test, p Conclusion It is feasible to incorporate a focused ultrasound curriculum to assess clinically unstable patients. The multimodal nature of the course aid in the development of preclinical proficiency and decreased the orientation phase of ultrasound use.

Substantial adjuvant chemotherapy (AC) overtreatment for stage II colorectal cancer results in a health and financial burden. Circulating tumour DNA (ctDNA) can improve patient selection for AC by detecting micro-metastatic disease. We estimated the health economic potential of ctDNA-guided AC for stage II colorectal cancer.A cost-utility analysis was performed to compare ctDNA-guided AC to standard of care, where 22.6% of standard of care patients and all ctDNA-positive patients (8.7% of tested patients) received AC and all ctDNA-negative patients (91.3%) did not. A third preference-sensitive ctDNA strategy was included where 6.8% of ctDNA-negative patients would receive AC. A state-transition model was populated using data from a prospective cohort study and clinical registries. Health and economic outcomes were discounted at 5% over a lifetime horizon from a 2019 Australian payer perspective. Extensive scenario and probabilistic analyses quantified model uncertainty.Compared to standard of care, the ctDNA and preference-sensitive ctDNA strategies increased quality-adjusted life-years by 0.20 (95% confidence interval - 0.40 to 0.81) and 0.19 (- 0.40 to 0.78), and resulted in incremental costs of AUD - 4055 (- 16,853 to 8472) and AUD - 2284 (- 14,685 to 10,116), respectively. Circulating tumour DNA remained cost effective at a willingness to pay of AUD 20,000 per quality-adjusted life-year gained throughout most scenario analyses in which the proportion of ctDNA-positive patients cured by AC and compliance to a ctDNA-negative test results were decreased.Circulating tumour-guided AC is a potentially cost-effective strategy towards reducing overtreatment in stage II colorectal cancer. Results from ongoing randomised clinical studies will be important to reduce uncertainty in the estimates.

Graduate medical education is predominantly based on a time-based apprenticeship model, with implied acquisition of proficiency after a pre-set amount of clinical exposure. While motion metrics have been used previously to measure skill performance indicators, these assessments have largely been performed on a summative scale to describe the performance of complete tasks or procedures. By segmenting performances of interest and assessing the essential elements individually, a more comprehensive understanding of the aspects in need of improvement for a learner can be obtained. The purpose of this review is to discuss technologies applicable to motion tracking, their benefits and limitations, approaches to data processing, and potential applications based on recent improvements in this technology. Objective analysis of motion metrics may improve educational standards of learning and efficiency by both standardizing the feedback process for trainees and reducing the volume of instructors required to facilitate practice sessions. With rigorous validation and standardization, motion metric assessment may also prove useful to demonstrate competency in technical procedures as part of a comprehensive certification process.

International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear.To describe real-world practice of Australian breast oncologists.Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry.Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data.Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Introduction: The optimal management of isolated distant lymph node metastases (IDLNM) from a colorectal primary, is not clearly established. We aimed to analyze the outcomes of patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Materials & Methods: Clinical data were collected and reviewed from the Treatment of Recurrent and Advanced Colorectal Cancer registry, a prospective, comprehensive registry for metastatic colorectal cancer (mCRC) treated at multiple tertiary hospitals across Australia. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with disease at other sites. Results: Of 3408 mCRC patients diagnosed 2009 to 2020, with median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC at other sites, patients with IDLNM were younger (mean age: 62.1 vs. 65.6 years, P = .02), more likely to have metachronous disease (57.0% vs. 38.9%, P < .01), be KRAS wild-type (74.6% vs. 53.9%, P< .01) and BRAF mutant (12.9% vs. 6.2%, P = .01). Amongst mCRC patients with IDLNM, 24 (25.8%) received treatment with curative intent and had a significantly better overall median survival than those treated with palliative intent (73.5 months vs. 23.2 months, P = .01). These 24 patients had an overall median survival similar (62.7 months, P = .82) to patients with isolated liver or lung metastases also treated with curative intent. Conclusion: Curative treatment strategies (radiotherapy or surgery), with or without systemic therapy, should be considered for mCRC patients with IDLNM where appropriate as assessed by the multidisciplinary team.

BACKGROUND: Fiberoptic intubation (FOI) is key in managing difficult airways. Good scope control increases efficiency and patient safety. Understanding the gap between novices and experts in scope control would help medical educators develop a feedback-based teaching approach for novices. We designed and used a checklist for evaluating the gap in fiberoptic scope control between novices and experts. METHODS: Twelve first-year anesthesiology residents (novice group) attended a lecture, followed by hands-on practice with a fiberoptic scope on a manikin. Five staff anesthesiologists (expert group) only did the hands-on practice. After practice, each participant was video-recorded while conducting an FOI on the manikin. Two senior anesthesiologists developed and used a 7-item checklist to assess the FOIs. Checklist scores and total times for FOIs were compared between groups using the Mann-Whitney U test. Internal consistency of the checklist items, interrater reliability, and the relationship between checklist score and total time for FOI were assessed with Cronbach alpha, Cohen kappa, and the Pearson correlation coefficient, respectively. RESULTS: Experts had higher checklist scores than novices (P = .0016). The item with the lowest success rate for novices (50%) was keeping the scope straight. Novices spent more time on the FOI than experts (P = .0005). Cronbach alpha, Cohen kappa, and the Pearson correlation coefficient were 0.8699, 0.75, and −0.9454, respectively. CONCLUSIONS: Our checklist was used to detect differences in fiberoptic scope control skills between novices and experts. With a video-based assessment method, it can be used to develop a feedback-based teaching method for fiberoptic scope control.

Clinical trials have strict eligibility criteria, potentially limiting external validity. However, while often discussed this has seldom been explored, particularly across cancer types and at variable time frames posttrial completion. We examined comprehensive registry data (January 2014 to June 2019) for standard first-line treatments for metastatic colorectal cancer (CRC), advanced pancreatic cancer (PC), metastatic HER2-amplified breast cancer (BC) and castrate-resistant prostate cancer (CaP). Registry patient characteristics and outcomes were compared to the practice-changing trial. Registry patients were older than the matched trial cohort by a median of 2-6 years (all P =

Computed Tomography (CT) scans help diagnose and triage life-threatening and time-sensitive emergency conditions, but most rural hospitals in British Columbia do not have access to a local CT scanner. We investigate how many transfers from a rural British Columbia hospital were for CT scans and describe the time delays to emergent CT imaging.This was a prospective cohort study, over a 1-year period, on all patients requiring a transfer from the Golden and District Hospital, located 247 km from the closest CT scanner. Data collection forms were completed prospectively and the main measurements included age, transport triage level, reason for transfer, referral hospital, transfer request time, and CT scan time. The time interval between the CT request and CT imaging was calculated and represents the 'delay to CT scan' interval.The study hospital received 8672 emergency department (ED) visits and 220 were transferred to referral centres (2.5%). 61% of all transfers received a CT scan. Transfers for time-sensitive emergencies took an average of 6 h 52 min. Patients with acute stroke experienced a 4 h 44 min time interval. Less urgent and non-urgent conditions entailed an even greater time delay.This study highlights that the lack of a rural CT scanner is associated with increased transfers and significant time delays. Improving access to CT scanners for rural communities may be one of the many steps in addressing healthcare disparities between rural and urban communities.RéSUMé: OBJECTIFS: La tomodensitométrie (TDM) aide à diagnostiquer et à trier les situations d'urgence qui mettent la vie en danger et pour lesquelles le temps est compté, mais la plupart des hôpitaux ruraux de la Colombie-Britannique n'ont pas accès à un tomodensitomètre local. Nous enquêtons sur le nombre de transferts d’un hôpital rural de la Colombie-Britannique pour des tomodensitogrammes et nous décrivons les délais pour l’imagerie tomographique émergente. MéTHODES: Il s'agit d'une étude de cohorte prospective, sur une période d'un an, sur tous les patients nécessitant un transfert de l'hôpital de Golden and district, situé à 247 km du scanner le plus proche. Les formulaires de collecte de données ont été remplis de manière prospective et les principales mesures comprenaient l'âge, le niveau de triage de transport, la raison du transfert, l'hôpital de référence, le temps de demande de transfert et le temps de tomodensitométrie. L’intervalle de temps entre la demande de tomodensitométrie et l’imagerie par tomodensitométrie a été calculé et représente l’intervalle « retard au scanner». RéSULTATS: L’hôpital d’étude a reçu 8 672 visites aux services d’urgence (SU) et 220 ont été transférés aux centres d’aiguillage (2,5%). 61% de tous les transferts ont fait l'objet d'un scanner. Les transferts pour les urgences sensibles au facteur temps ont pris en moyenne 6 h 52. Les patients ayant subi un accident vasculaire cérébral aigu ont connu un intervalle de temps de 4 h 44. Des conditions moins urgentes et non urgentes ont entraîné un délai encore plus long. CONCLUSIONS: Cette étude met en évidence que l'absence de tomodensitomètre en milieu rural est associée à une augmentation des transferts et à des retards importants. L’amélioration de l’accès aux tomodensitomètres pour les communautés rurales peut être l’une des nombreuses étapes pour remédier aux disparités en matière de soins de santé entre les communautés rurales et urbaines.