Insufficient oxygen inhalation during cardiopulmonary resuscitation induces early changes in hemodynamics followed by late and unfavorable systemic responses in post-cardiac arrest rats.

Cardiac arrest (CA) and concomitant post-CA syndrome lead to a lethal condition characterized by systemic ischemia-reperfusion injury. Oxygen (O2 ) supply during cardiopulmonary resuscitation (CPR) is the key to success in resuscitation, but sustained hyperoxia can produce toxic effects post CA. However, only few studies have investigated the optimal duration and dosage of O2 administration. Herein, we aimed to determine whether high concentrations of O2 at resuscitation are beneficial or harmful. After rats were resuscitated from the 10-min asphyxia, mechanical ventilation was restarted at an FIO2 of 1.0 or 0.3. From 10 min after initiating CPR, FIO2 of both groups were maintained at 0.3. Bio-physiological parameters including O2 consumption (VO2 ) and mRNA gene expression in multiple organs were evaluated. The FIO2 0.3 group decreased VO2 , delayed the time required to achieve peak MAP, lowered ejection fraction (75.1 ± 3.3% and 59.0 ± 5.7% with FIO2 1.0 and 0.3, respectively; p < .05), and increased blood lactate levels (4.9 ± 0.2 mmol/L and 5.6 ± 0.2 mmol/L, respectively; p < .05) at 10 min after CPR. FIO2 0.3 group had significant increases in hypoxia-inducible factor, inflammatory, and apoptosis-related mRNA gene expression in the brain. Likewise, significant upregulations of hypoxia-inducible factor and apoptosis-related gene expression were observed in the FIO2 0.3 group in the heart and lungs. Insufficient O2 supplementation in the first 10 min of resuscitation could prolong ischemia, and may result in unfavorable biological responses 2 h after CA. Faster recovery from the impairment of O2 metabolism might contribute to the improvement of hemodynamics during the early post-resuscitation phase; therefore, it may be reasonable to provide the maximum feasible O2 concentrations during CPR.

Pulmonary embolism response teams. A description of the first 36-month Australian experience.

BACKGROUND: High/intermediate-risk pulmonary embolism (PE) confers increased risk of cardiovascular morbidity and mortality. International guidelines recommend the formation of a PE response team (PERT) for PE management because of the complexity of risk stratification and emerging treatment options. However, there are currently no available Australian data regarding outcomes of PE managed through a PERT. AIMS: To analyse the clinical and outcome data of patients from an Australian centre with high/intermediate-risk PE requiring PERT-guided management. METHODS: We performed a retrospective observational study of 75 consecutive patients with high/intermediate-risk PE who had PERT involvement, between August 2018 and July 2021. We recorded clinical and interventional data at the time of PERT and assessed patient outcomes up to 30 days from PERT initiation. We used unpaired t tests to compare right to left ventricular (RV/LV) ratios by computed tomography criteria or transthoracic echocardiogram (TTE) at baseline and after interventions. RESULTS: Data were available for 74 patients. Initial computed tomography pulmonary angiography RV/LV ratio was increased at 1.65 ± 0.5 and decreased to 1.30 ± 0.29 following PERT-guided interventions (P < 0.001). TTE RV/LV ratio also decreased following PERT-guided management (1.09 ± 0.19 vs 0.93 ± 0.17; P < 0.001). 20% of patients had any bleeding complication, but two-thirds were mild, not requiring intervention. All-cause mortality was 6.8%, and all occurred within the first 7 days of admission. CONCLUSION: The PERT model is feasible in a large Australian centre in managing complex and time-critical PE. Our data demonstrate outcomes comparable with existing published international PERT data. However, successful implementation at other Australian institutions may require adequate centre-specific resource availability and the presence of multispeciality input.

Low respiratory quotient correlates with high mortality in patients undergoing mechanical ventilation.

OBJECTIVE: 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 < 0.01), respectively. The difference of RQ was statistically significant (p < 0.01) and it remained significant when the subjects with FIO2 < 0.5 were excluded (p < 0.05). CONCLUSIONS: Low RQ correlated with high mortality, which may potentially indicate a decompensation of the oxygen metabolism in critically ill patients.

Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Systematic analytical workflow for characterisation and identification of partially reduced species in monoclonal antibody manufacturing.

Fragmentation is a major degradation pathway ubiquitous to all therapeutic monoclonal antibody (mAb) and therefore, monitored throughout the manufacturing process. Here, we describe a three-step approach to 1) detect, 2) confirm and 3) characterize partially reduced fragment species in an immunoglobulin G1 (IgG1) mAb with prolonged hold time of harvested cell culture fluid (HCCF). Microchip capillary electrophoresis (MCE) and high-performance size exclusion chromatography (HPSEC) were used as fast and efficient screening methods to detect fragmentation. HPSEC was found to be underestimating fragmentation levels. To confirm and characterize the fragments, capillary electrophoresis-sodium dodecyl sulphate (CE-SDS) was employed. Interestingly, the absence of fragments in the reduced CE-SDS analysis suggested partial reduction of disulphide bonds contributing to fragmentation in this mAb lot. This was further confirmed using reverse phase high performance liquid chromatography (RP-HPLC) coupled with mass spectrometry, which established the presence of heavy-heavy-light (HHL), heavy-heavy (HH), light-light dimer (LL), light chain (LC) and half antibody (HL) fragments with good mass accuracy. In this study, we demonstrated a readily applicable systematic strategy to support process development and investigate anomalous events in manufacturing. An additional highlight of this work is the data-driven comprehensive comparison of modern and conventional analytical techniques for fragment analysis.

The role of pyruvate-induced enhancement of oxygen metabolism in extracellular purinergic signaling in the post-cardiac arrest rat model.

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. As indicated by the increased levels in systemic oxygen consumption, intravenous administrations of bolus (500 mg/kg) and continuous infusion (1000 mg/kg/h) of pyruvate successfully increased oxygen metabolism in post 10-min CA rats. Plasma ATP levels increased significantly from 67 ± 11 nM before CA to 227 ± 103 nM 2 h after the resuscitation; however, pyruvate administration did not affect post-CA ATP levels. Notably, pyruvate 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 ion disorders, but does not exacerbate the death-signaling of eATP in the blood.

Compliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer.

BACKGROUND: 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. AIM: To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS: 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. RESULTS: Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% 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. CONCLUSION: 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.

Continuous and repeat metabolic measurements compared between post-cardiothoracic surgery and critical care patients.

OBJECTIVE: Using a system, which accuracy is equivalent to the gold standard Douglas Bag (DB) technique for measuring oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ), we aimed to continuously measure these metabolic indicators and compare the values between post-cardiothoracic surgery and critical care patients. METHODS: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital. Age 18 years or older patients who underwent mechanical ventilation were enrolled. RESULTS: We included 4 post-surgery and 6 critical care patients. Of those, 3 critical care patients died. The longest measurement reached to 12 h and 15 min and 50 cycles of repeat measurements were performed. VO2 of the post-surgery patients were 234 ± 14, 262 ± 27, 212 ± 16, and 192 ± 20 mL/min, and those of critical care patients were 122 ± 20, 189 ± 9, 191 ± 7, 191 ± 24, 212 ± 12, and 135 ± 21 mL/min, respectively. The value of VO2 was more variable in the post-surgery patients and the range of each patient was 44, 126, 71, and 67, respectively. SOFA scores were higher in non-survivors and there were negative correlations of RQ with SOFA. CONCLUSIONS: We developed an accurate system that enables continuous and repeat measurements of VO2, VCO2, and RQ. Critical care patients may have less activity in metabolism represented by less variable values of VO2 and VCO2 over time as compared to those of post-cardiothoracic surgery patients. Additionally, an alteration of these values may mean a systemic distinction of the metabolism of critically ill patients.

Novel Three-Dimensional Printed Human Heart Models and Ultrasound Omniplane Simulator for Transesophageal Echocardiography Training.

Simulation-based training plays an essential role in transesophageal echocardiography (TEE) education. Using 3-dimensional printing technology, the authors invented a novel TEE teaching system consisting of a series of heart models that can be segmented according to actual TEE views, and an ultrasound omniplane simulator to demonstrate how ultrasound beams intersect the heart at different angles and generate images. This novel teaching system is able to provide a more direct way to visualize the mechanics of obtaining TEE images than traditional online or mannequin-based simulators. It can also provide tangible feedback of both an ultrasound scan plane and a TEE view of the heart, which has been proven to improve trainees' spatial awareness and can significantly help in understanding and memorizing complex anatomic structures. This teaching system itself is also portable and inexpensive, making it conducive to teaching TEE in regions of diverse economic status. This teaching system also can be expected to be used for just-in-time training in a variety of clinical scenarios, including operating rooms, intensive care units, etc.

Insufficient Oxygen Supplementation During Cardiopulmonary Resuscitation Leads to Unfavorable Biological Response While Hyperoxygenation Contributes to Metabolic Compensation.

Sudden cardiac arrest (CA) is the third leading cause of death. Immediate reoxygenation with high concentrations of supplemental oxygen (O2) during cardiopulmonary resuscitation (CPR) is recommended according to the current guidelines for adult CA. However, a point in controversy exists because of the known harm of prolonged exposure to 100% O2. Therefore, there have been much debate on an optimal use of supplemental O2, yet little is known about the duration and dosage of O2 administration. To test whether supplying a high concentration of O2 during CPR and post resuscitation is beneficial or harmful, rats subjected to 10-minute asphyxia CA were administered either 100% O2 (n = 8) or 30% O2 (n = 8) for 2 hours after CPR. Two hours after initiating CPR, the brain, lung, and heart tissues were collected to compare mRNA gene expression levels of inflammatory cytokines, apoptotic and oxidative stress-related markers. The 100% O2 group had significantly shorter time to return of spontaneous circulation (ROSC) than the 30% O2 group (62.9 ± 2.2 and 77.5 ± 5.9 seconds, respectively, P < 0.05). Arterial blood gas analysis revealed that the 100% O2 group had significantly higher PaCO2 (49.4 ± 4.9 mmHg and 43.0 ± 3.0 mmHg, P < 0.01), TCO2 (29.8 ± 2.7 and 26.6 ± 1.1 mmol/L, P < 0.05), HCO3- (28.1 ± 2.4 and 25.4 ± 1.2 mmol/L, P < 0.05), and BE (2.6 ± 2.3 and 0.1 ± 1.4 mmol/L, P < 0.05) at 2 hours after initiating CPR, but no changes in pH (7.37 ± 0.03 and 7.38 ± 0.03, ns). Inflammation- (Il6, Tnf) and apoptosis- (Casp3) related mRNA gene expression levels were significantly low in the 100% O2 group in the brain, however, oxidative stress moderator Hmox1 increased in the 100% O2 group. Likewise, mRNA gene expression of Icam1, Casp9, Bcl2, and Bax were low in the 100% O2 group in the lung. Contrarily, mRNA gene expression of Il1b and Icam1 were low in the 30% O2 group in the heart. Supplying 30% O2 during and after CPR significantly delayed the time to ROSC and increased inflammation-/apoptosis- related gene expression in the brain and lung, indicating that insufficient O2 was associated with unfavorable biological responses post CA, while prolonged exposure to high-concentration O2 should be still cautious in general.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Preclinical Proficiency-Based Model of Ultrasound Training.

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.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: 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. AIM: To describe real-world practice of Australian breast oncologists. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Motion-Tracking Machines and Sensors: Advancing Education Technology.

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.

National Delphi Survey on Anesthesiology Resident Training in Perioperative Ultrasound.

OBJECTIVE: To establish agreement among nationwide experts through a Delphi process on the key components of perioperative ultrasound and the recommended minimum number of examinations that should be performed by a resident upon graduation. DESIGN: A prospective cross-sectional study. SETTING: A survey on multiinstitutional academic medical centers. PARTICIPANTS: Anesthesiology residency program directors and/or experts in perioperative ultrasound. INTERVENTIONS: A list of components and examinations recommended for anesthesiology resident training in perioperative ultrasound was developed based on guidelines and 2 survey rounds among a steering committee of 10 experts. A questionnaire asking for a rating of each component on a 5-point Likert scale subsequently was sent to an expert panel of 120 anesthesiology residency program directors across the United States. An agreement of at least 70% of participants, rating a component as 4 or 5, was compulsory to list a component as essential for anesthesiology resident training in perioperative ultrasound. MEASUREMENTS AND MAIN RESULTS: The nationwide survey's response rate was 62.5%, and agreement was reached after 2 Delphi rounds. The final list included 44 essential components for basic ultrasound physics and knobology, cardiac ultrasound, lung ultrasound, and ultrasound-guided vascular access. Agreement was not reached for abdominal ultrasound, gastric ultrasound, and ultrasound-guided airway assessment. Agreement for the recommended minimum number of examinations that should be performed by a resident upon graduation included 50 each for transthoracic and transesophageal echocardiography, and 20 each for lung ultrasound, ultrasound-guided central line, and ultrasound-guided arterial line placements. CONCLUSIONS: The recommendations outlined in this survey can be used to establish standardized training for perioperative ultrasound by anesthesiology residency programs.

Assessing Skill Acquisition in Anesthesiology Interns Practicing Central Venous Catheter Placement Through Advancements in Motion Analysis.

OBJECTIVES: The study authors hypothesized that a combination of previously used (path length, translational motions, and time) and novel (rotational sum) motion metrics could be used to analyze learning curves of anesthesiology interns (postgraduate year 1) practicing central venous catheter placement in the simulation setting. They also explored the feasibility of using segmented motion recordings to inform deliberate practice. DESIGN: A prospective cohort study. SETTING: A single academic medical center. PARTICIPANTS: Anesthesiology interns (postgraduate year 1). INTERVENTIONS: Anesthesiology interns underwent a 2-day training course in which they performed 9 central venous catheter placements, while attached to motion sensors on the dorsum of their dominant hand and ultrasound probe. MEASUREMENTS AND MAIN RESULTS: Motion metrics were analyzed using generalized estimating equations for both the overall procedure and predefined segments. Five attending anesthesiologists performed 3 trials each for comparison. Overall, there was a negative trend in path length, translational motions, rotational sum, and time (p < 0.001), with the exception of translational motions of the ultrasound probe. Interns reached within 1 standard deviation of the attending anesthesiologists by trials 7-to-8 for most metrics. Segmentation identified specific components of the procedure that were either significantly improved upon or required deliberate practice. The novel metric of rotational sum exhibited a moderate-to-strong positive correlation with other metrics (p < 0.001). CONCLUSIONS: A comprehensive series of motion metrics was able to describe the learning curves of novices training to perform central venous catheter placement in the simulation setting. Furthermore, it was determined that segmentation may provide additional insight into skill acquisition and inform deliberate practice.

Cancer clinical trial vs real-world outcomes for standard of care first-line treatment in the advanced disease setting.

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 = <.01) for the CRC, BC and PC cohorts. The proportion of Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 patients was lower for CRC (94.1% vs 99.2%, P = .001) and BC (94.9% vs 99.3%, P = .001). Progression-free survival (PFS) for registry patients was similar to the trial patients or significantly longer (CaP, Hazard Ratio [HR] = 0.65, P = <.001). Overall survival (OS) was also similar or significantly longer (CaP, HR 0.49, P = <.001). In conclusion, despite real-world patients sometimes being older or having inferior PS to trial cohorts, the survival outcomes achieved were consistently equal or superior to those reported for the same treatment in the trial. We suggest that this is potentially due to optimised use of each treatment over time, improved multidisciplinary care and increased postprogression options. We can reassure clinicians and patients that outcomes matching or exceeding those reported in trials are possible. The potential for survival gains over time should routinely be factored into future trial statistical plans.

Cardiac and lung endothelial cells in response to fluid shear stress on physiological matrix stiffness and composition.

OBJECTIVE: Preconditioning of endothelial cells from different vascular beds has potential value for re-endothelialization and implantation of engineered tissues. Understanding how substrate stiffness and composition affects tissue-specific cell response to shear stress will aid in successful endothelialization of engineered tissues. We developed a platform to test biomechanical and biochemical stimuli. METHODS: A novel polydimethylsiloxane-based parallel plate flow chamber enabled application of laminar fluid shear stress of 2 dynes/cm2 for 12 hours to microvascular cardiac and lung endothelial cells cultured on cardiac and lung-derived extracellular matrix. Optical imaging of cells was used to quantify cell changes in cell alignment. Analysis of integrin expression was performed using flow cytometry. RESULTS: Application of fluid shear stress caused the greatest cell alignment in cardiac endothelial cells seeded on polystyrene and lung endothelial cells on polydimethylsiloxane. This resulted in elongation of the lung endothelial cells. αv and ß3 integrin expression decreased after application of shear stress in both cell types. CONCLUSION: Substrate stiffness plays an important role in regulating tissue-specific endothelial response to shear stress, which may be due to differences in their native microenvironments. Furthermore, cardiac and lung endothelial cell response to shear stress was significantly regulated by the type of coating used.

Emergence of dominant multidrug-resistant bacterial clades: Lessons from history and whole-genome sequencing.

Antibiotic resistance in bacteria has emerged as a global challenge over the past 90 years, compromising our ability to effectively treat infections. There has been a dramatic increase in antibiotic resistance-associated determinants in bacterial populations, driven by the mobility and infectious nature of such determinants. Bacterial genome flexibility and antibiotic-driven selection are at the root of the problem. Genome evolution and the emergence of highly successful multidrug-resistant clades in different pathogens have made this a global challenge. Here, we describe some of the factors driving the origin, evolution, and spread of the antibiotic resistance genotype.