Using Machine Learning (XGBoost) to Predict Outcomes After Infrainguinal Bypass for Peripheral Artery Disease.

OBJECTIVE: To develop machine learning (ML) algorithms that predict outcomes after infrainguinal bypass. BACKGROUND: Infrainguinal bypass for peripheral artery disease carries significant surgical risks; however, outcome prediction tools remain limited. METHODS: The Vascular Quality Initiative database was used to identify patients who underwent infrainguinal bypass for peripheral artery disease between 2003 and 2023. We identified 97 potential predictor variables from the index hospitalization [68 preoperative (demographic/clinical), 13 intraoperative (procedural), and 16 postoperative (in-hospital course/complications)]. The primary outcome was 1-year major adverse limb event (composite of surgical revision, thrombectomy/thrombolysis, or major amputation) or death. Our data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, we trained 6 ML models using preoperative features. The primary model evaluation metric was the area under the receiver operating characteristic curve (AUROC). The top-performing algorithm was further trained using intraoperative and postoperative features. Model robustness was evaluated using calibration plots and Brier scores. RESULTS: Overall, 59,784 patients underwent infrainguinal bypass, and 15,942 (26.7%) developed 1-year major adverse limb event/death. The best preoperative prediction model was XGBoost, achieving an AUROC (95% CI) of 0.94 (0.93-0.95). In comparison, logistic regression had an AUROC (95% CI) of 0.61 (0.59-0.63). Our XGBoost model maintained excellent performance at the intraoperative and postoperative stages, with AUROCs (95% CI's) of 0.94 (0.93-0.95) and 0.96 (0.95-0.97), respectively. Calibration plots showed good agreement between predicted and observed event probabilities with Brier scores of 0.08 (preoperative), 0.07 (intraoperative), and 0.05 (postoperative). CONCLUSIONS: ML models can accurately predict outcomes after infrainguinal bypass, outperforming logistic regression.

GLP-1 receptor agonists and atherosclerosis protection: the vascular endothelium takes center stage.

Atherosclerotic cardiovascular disease is a chronic condition that often copresents with type 2 diabetes and obesity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetics endorsed by major professional societies for improving glycemic status and reducing atherosclerotic risk in people living with type 2 diabetes. Although the cardioprotective efficacy of GLP-1RAs and their relationship with traditional risk factors are well established, there is a paucity of publications that have summarized the potentially direct mechanisms through which GLP-1RAs mitigate atherosclerosis. This review aims to narrow this gap by providing comprehensive and in-depth mechanistic insight into the antiatherosclerotic properties of GLP-1RAs demonstrated across large outcome trials. Herein, we describe the landmark cardiovascular outcome trials that triggered widespread excitement around GLP-1RAs as a modern class of cardioprotective agents, followed by a summary of the origins of GLP-1RAs and their mechanisms of action. The effects of GLP-1RAs at each major pathophysiological milestone of atherosclerosis, as observed across clinical trials, animal models, and cell culture studies, are described in detail. Specifically, this review provides recent preclinical and clinical evidence that suggest GLP-1RAs preserve vessel health in part by preventing endothelial dysfunction, achieved primarily through the promotion of angiogenesis and inhibition of oxidative stress. These protective effects are in addition to the broad range of atherosclerotic processes GLP-1RAs target downstream of endothelial dysfunction, which include systemic inflammation, monocyte recruitment, proinflammatory macrophage and foam cell formation, vascular smooth muscle cell proliferation, and plaque development.

Using machine learning to predict outcomes following suprainguinal bypass.

OBJECTIVE: Suprainguinal bypass for peripheral artery disease (PAD) carries important surgical risks; however, outcome prediction tools remain limited. We developed machine learning (ML) algorithms that predict outcomes following suprainguinal bypass. METHODS: The Vascular Quality Initiative database was used to identify patients who underwent suprainguinal bypass for PAD between 2003 and 2023. We identified 100 potential predictor variables from the index hospitalization (68 preoperative [demographic/clinical], 13 intraoperative [procedural], and 19 postoperative [in-hospital course/complications]). The primary outcomes were major adverse limb events (MALE; composite of untreated loss of patency, thrombectomy/thrombolysis, surgical revision, or major amputation) or death at 1 year following suprainguinal bypass. Our data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, we trained six ML models using preoperative features (Extreme Gradient Boosting [XGBoost], random forest, Naïve Bayes classifier, support vector machine, artificial neural network, and logistic regression). The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). The best performing algorithm was further trained using intra- and postoperative data. Model robustness was evaluated using calibration plots and Brier scores. Performance was assessed on subgroups based on age, sex, race, ethnicity, rurality, median Area Deprivation Index, symptom status, procedure type, prior intervention for PAD, concurrent interventions, and urgency. RESULTS: Overall, 16,832 patients underwent suprainguinal bypass, and 3136 (18.6%) developed 1-year MALE or death. Patients with 1-year MALE or death were older (mean age, 64.9 vs 63.5 years; P < .001) with more comorbidities, had poorer functional status (65.7% vs 80.9% independent at baseline; P < .001), and were more likely to have chronic limb-threatening ischemia (67.4% vs 47.6%; P < .001) than those without an outcome. Despite being at higher cardiovascular risk, they were less likely to receive acetylsalicylic acid or statins preoperatively and at discharge. Our best performing prediction model at the preoperative stage was XGBoost, achieving an AUROC of 0.92 (95% confidence interval [CI], 0.91-0.93). In comparison, logistic regression had an AUROC of 0.67 (95% CI, 0.65-0.69). Our XGBoost model maintained excellent performance at the intra- and postoperative stages, with AUROCs of 0.93 (95% CI, 0.92-0.94) and 0.98 (95% CI, 0.97-0.99), respectively. Calibration plots showed good agreement between predicted and observed event probabilities with Brier scores of 0.12 (preoperative), 0.11 (intraoperative), and 0.10 (postoperative). Of the top 10 predictors, nine were preoperative features including chronic limb-threatening ischemia, previous procedures, comorbidities, and functional status. Model performance remained robust on all subgroup analyses. CONCLUSIONS: We developed ML models that accurately predict outcomes following suprainguinal bypass, performing better than logistic regression. Our algorithms have potential for important utility in guiding perioperative risk mitigation strategies to prevent adverse outcomes following suprainguinal bypass.

STOP Signs: A Population-based Interrupted Time Series Analysis of Antibiotic Duration for Complicated Intraabdominal Infection Before and After the Publication of a Landmark RCT.

OBJECTIVE: To determine if the STOP-IT randomized controlled trial changed antibiotic prescribing in patients with Complicated Intraabdominal Infection (CIAI). SUMMARY OF BACKGROUND DATA: CIAI is common and causes significant morbidity. In May 2015, the STOP-IT randomized controlled trial showed equivalent outcomes between four-day and clinically determined antibiotic duration. METHODS: This was a population-based retrospective cohort study using interrupted time series methods. The STOP-IT publication date was the exposure. Median duration of inpatient antibiotic prescription was the outcome. All adult patients admitted to four hospitals in Calgary, Canada between July 2012 and December 2018 with CIAI who survived at least four days following source control were included. Analysis was stratified by infectious source as appendix or biliary tract (group A) versus other (group B). RESULTS: Among 4384 included patients, clinical and demographic attributes were similar before vs after publication. In Group A, median inpatient antibiotic duration was 3 days and unchanged from the beginning to the end of the study period [adjusted median difference -0.00 days, 95% confidence interval (CI) -0.37 - 0.37 days]. In Group B, antibiotic duration was shorter at the end of the study period (7.87 vs 6.73 days; -1.14 days, CI-2.37 - 0.09 days), however there was no change in trend following publication (-0.03 days, CI -0.16 - 0.09). CONCLUSIONS: For appendiceal or biliary sources of CIAI, antibiotic duration was commensurate with the experimental arm of STOP-IT. For other sources, antibiotic duration was long and did not change in response to trial publication. Additional implementation science is needed to improve antibiotic stewardship.

Characterizing the Impact of Procedure Funding on the Covid-19 Generated Procedure Gap in Ontario: A Population-Based Analysis.

BACKGROUND: Surgical procedures in Canada were historically funded through global hospital budgets. Activity-based funding models were developed to improve access, equity, timeliness, and value of care for priority areas. COVID-19 upended health priorities and resulted in unprecedented disruptions to surgical care, which created a significant procedure gap. We hypothesized that activity-based funding models influenced the magnitude and trajectory of this procedure gap. METHODS: Population-based analysis of procedure rates comparing the pandemic (March 1, 2020-December 31, 2021) to a prepandemic baseline (January 1, 2017-February 29, 2020) in Ontario, Canada. Poisson generalized estimating equation models were used to predict expected rates in the pandemic based on the prepandemic baseline. Analyses were stratified by procedure type (outpatient, inpatient), body region, and funding category (activity-based funding programs vs. global budget). RESULTS: In all, 281,328 fewer scheduled procedures were performed during the COVID-19 period compared with the prepandemic baseline (Rate Ratio 0.78; 95% CI 0.77-0.80). Inpatient procedures saw a larger reduction (24.8%) in volume compared with outpatient procedures (20.5%). An increase in the proportion of procedures funded through activity-based programs was seen during the pandemic (52%) relative to the prepandemic baseline (50%). Body systems funded predominantly through global hospital budgets (eg, gynecology, otologic surgery) saw the least months at or above baseline volumes, whereas those with multiple activity-based funding options (eg, musculoskeletal, abdominal) saw the most months at or above baseline volumes. CONCLUSIONS: Those needing procedures funded through global hospital budgets may have been disproportionately disadvantaged by pandemic-related health care disruptions.

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Using machine learning to predict outcomes following open abdominal aortic aneurysm repair.

OBJECTIVE: Prediction of outcomes following open abdominal aortic aneurysm (AAA) repair remains challenging with a lack of widely used tools to guide perioperative management. We developed machine learning (ML) algorithms that predict outcomes following open AAA repair. METHODS: The Vascular Quality Initiative (VQI) database was used to identify patients who underwent elective open AAA repair between 2003 and 2023. Input features included 52 preoperative demographic/clinical variables. All available preoperative variables from VQI were used to maximize predictive performance. The primary outcome was in-hospital major adverse cardiovascular event (MACE; composite of myocardial infarction, stroke, or death). Secondary outcomes were individual components of the primary outcome, other in-hospital complications, and 1-year mortality and any reintervention. We split our data into training (70%) and test (30%) sets. Using 10-fold cross-validation, six ML models were trained using preoperative features (Extreme Gradient Boosting [XGBoost], random forest, Naïve Bayes classifier, support vector machine, artificial neural network, and logistic regression). The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). Model robustness was evaluated with calibration plot and Brier score. The top 10 predictive features in our final model were determined based on variable importance scores. Performance was assessed on subgroups based on age, sex, race, ethnicity, rurality, median area deprivation index, proximal clamp site, prior aortic surgery, and concomitant procedures. RESULTS: Overall, 12,027 patients were included. The primary outcome of in-hospital MACE occurred in 630 patients (5.2%). Compared with patients without a primary outcome, those who developed in-hospital MACE were older with more comorbidities, demonstrated poorer functional status, had more complex aneurysms, and were more likely to require concomitant procedures. Our best performing prediction model for in-hospital MACE was XGBoost, achieving an AUROC of 0.93 (95% confidence interval, 0.92-0.94). Comparatively, logistic regression had an AUROC of 0.71 (95% confidence interval, 0.70-0.73). For secondary outcomes, XGBoost achieved AUROCs between 0.84 and 0.94. The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.05. These findings highlight the excellent predictive performance of the XGBoost model. The top three predictive features in our algorithm for in-hospital MACE following open AAA repair were: (1) coronary artery disease; (2) American Society of Anesthesiologists classification; and (3) proximal clamp site. Model performance remained robust on all subgroup analyses. CONCLUSIONS: Open AAA repair outcomes can be accurately predicted using preoperative data with our ML models, which perform better than logistic regression. Our automated algorithms can help guide risk-mitigation strategies for patients being considered for open AAA repair to improve outcomes.

Machine learning to predict outcomes following endovascular abdominal aortic aneurysm repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) carries important perioperative risks; however, there are no widely used outcome prediction tools. The aim of this study was to apply machine learning (ML) to develop automated algorithms that predict 1-year mortality following EVAR. METHODS: The Vascular Quality Initiative database was used to identify patients who underwent elective EVAR for infrarenal AAA between 2003 and 2023. Input features included 47 preoperative demographic/clinical variables. The primary outcome was 1-year all-cause mortality. Data were split into training (70 per cent) and test (30 per cent) sets. Using 10-fold cross-validation, 6 ML models were trained using preoperative features with logistic regression as the baseline comparator. The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). Model robustness was evaluated with calibration plot and Brier score. RESULTS: Some 63 655 patients were included. One-year mortality occurred in 3122 (4.9 per cent) patients. The best performing prediction model for 1-year mortality was XGBoost, achieving an AUROC (95 per cent c.i.) of 0.96 (0.95-0.97). Comparatively, logistic regression had an AUROC (95 per cent c.i.) of 0.69 (0.68-0.71). The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.04. The top 3 predictive features in the algorithm were 1) unfit for open AAA repair, 2) functional status, and 3) preoperative dialysis. CONCLUSIONS: In this data set, machine learning was able to predict 1-year mortality following EVAR using preoperative data and outperformed standard logistic regression models.

Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease.

Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin-angiotensin-aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium-glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury.

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control.

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

History of the Department of Surgery at the University of Toronto: celebrating a centennial of progress and innovation.

Now in its centennial year since inauguration, the Department of Surgery at the University of Toronto lays claim to more than 500 faculty, 270 residents, and 250 clinical fellows. There are 7 direct entry residency training programs, and 4 subspecialty programs accredited by the Royal College of Physicians and Surgeons of Canada. There have been 10 chairs of the department since 1921. This article chronicles the life and times of the previous chairs in sequence; the success of the department originates from its many talented and luminary surgeons who have innovated and shaped their fields of surgery. In recent years, the department's academic productivity has been characterized by more than 1400 peer-reviewed publications per year, and annual research grant capture in excess of $90 million. Since the time of William Gallie, surgical trainees have been enabled to develop careers in surgery and science through the Gallie Program and, more recently, the Surgeon Scientist Training Program (SSTP) to attain higher graduate degrees. Providing quaternary surgical care at multiple hospital sites in Toronto, the Department of Surgery takes great pride in its robust clinical fellowship programs across all specialties that continue to attract trainees from around the world.

Lessons from bariatric surgery: Can increased GLP-1 enhance vascular repair during cardiometabolic-based chronic disease?

Type 2 diabetes (T2D) and obesity represent entangled pandemics that accelerate the development of cardiovascular disease (CVD). Given the immense burden of CVD in society, non-invasive prevention and treatment strategies to promote cardiovascular health are desperately needed. During T2D and obesity, chronic dysglycemia and abnormal adiposity result in systemic oxidative stress and inflammation that deplete the vascular regenerative cell reservoir in the bone marrow that impairs blood vessel repair and exacerbates the penetrance of CVD co-morbidities. This novel translational paradigm, termed 'regenerative cell exhaustion' (RCE), can be detected as the depletion and dysfunction of hematopoietic and endothelial progenitor cell lineages in the peripheral blood of individuals with established T2D and/or obesity. The reversal of vascular RCE has been observed after administration of the sodium-glucose cotransporter-2 inhibitor (SGLT2i), empagliflozin, or after bariatric surgery for severe obesity. In this review, we explore emerging evidence that links improved dysglycemia to a reduction in systemic oxidative stress and recovery of circulating pro-vascular progenitor cell content required for blood vessel repair. Given that bariatric surgery consistently increases systemic glucagon-like-peptide 1 (GLP-1) release, we also focus on evidence that the use of GLP-1 receptor agonists (GLP-1RA) during obesity may act to inhibit the progression of systemic dysglycemia and adiposity, and indirectly reduce inflammation and oxidative stress, thereby limiting the impact of RCE. Therefore, therapeutic intervention with currently-available GLP-1RA may provide a less-invasive modality to reverse RCE, bolster vascular repair mechanisms, and improve cardiometabolic risk in individuals living with T2D and obesity.

Embryonic-Derived Myb- Macrophages Enhance Bacterial Clearance and Improve Survival in Rat Sepsis.

Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb- "peritoneal-like" macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large "peritoneal-like" macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.

ndufa7 plays a critical role in cardiac hypertrophy.

Cardiac hypertrophy is a common pathological change in patients with progressive cardiac function failure, which can be caused by hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) or arterial hypertension. Despite years of study, there is still limited knowledge about the underlying molecular mechanisms for cardiac hypertrophy. NDUFA7, a subunit of NADH:ubiquinone oxidoreductase (complex I), has been reported to be a novel HCM associated gene. However, the biological role of NDUFA7 in heart remains unknown. In this study, we found that NDUFA7 exhibited high expression in the heart, and its level was significantly decreased in mice model of cardiac hypertrophy. Moreover, we demonstrated that ndufa7 knockdown in developing zebrafish embryos resulted in cardiac development and functional defects, associated with increased expression of pathological hypertrophy biomarkers nppa (ANP) and nppb (BNP). Mechanistic study demonstrated that ndufa7 depletion promoted ROS production and calcineurin signalling activation. Moreover, NDUFA7 depletion contributed to cardiac cell hypertrophy. Together, these results report for the first time that ndufa7 is implicated in pathological cardiac hypertrophy.

GPIbα is required for platelet-mediated hepatic thrombopoietin generation.

Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα-/- mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα-/- platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα-/-, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα-/- mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα-/- platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα-/- platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbα-transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias.

Humanistic education in surgery: a "patient as teacher" program for surgical clerkship.

Summary: Surgeons are frequently perceived by medical students to be uncompassionate, resolute and individualistic. Surgical education often prioritizes teaching and learning approaches that perpetuate these perceptions. In other specialties, engaging patients in education has shown promise in refocusing attention from the technical and procedural aspects of care toward the humanistic and social aspects. Despite proven favourable outcomes for both patients and students in many clinical areas, a "patient as teacher" approach to surgical education has yet to be adopted widely in Canada. A patient as teacher program was developed for surgical clerks at the University of Toronto with the goal of emphasizing the humanity of the patient, the psychosocial impact of a surgical diagnosis of breast cancer on patients and their families, and the social and humanistic roles for surgeons in providing patient-centred care. We report on the program's development process and pilot session.

Cell confluence regulates claudin-2 expression: possible role for ZO-1 and Rac.

Claudin-2 (Cldn-2) is a channel-forming tight junction (TJ) protein in the proximal tubules that mediates paracellular Na+ transport and has also emerged as a regulator of proliferation and migration. Expression of Cldn-2 is altered by numerous stimuli, but the underlying mechanisms remain incompletely understood. Here we show that Cldn-2 protein and mRNA expression were low in subconfluent tubular cells and increased during junction maturation. Cldn-1 or occludin did not exhibit similar confluence-dependence. Conversely, disruption of TJs by Ca2+ removal or silencing of zonula occludens-1 (ZO-1) or ZO-2 induced a large drop in Cldn-2 abundance. Immunofluorescent staining revealed a more uneven Cldn-2 staining in nascent, Cldn-1-positive TJs. Subconfluence and ZO-1 silencing augmented Cldn-2 degradation and reduced Cldn-2 promoter activity, suggesting that insertion into the TJs slows Cldn-2 turnover. Indeed, blocking endocytosis or lysosomal degradation increased Cldn-2 abundance. Cell confluence increased expression of the junctional adapters ZO-1 and -2, and the small GTPase Rac, and elevated Rac activity and p21-activated kinase (Pak) phosphorylation, suggesting that they might mediate confluence-dependent Cldn-2 regulation. Indeed, Rac silencing or Pak inhibition strongly reduced Cldn-2 protein abundance, which was likely the combined effect on turnover, as these interventions reduced Cldn-2 promoter activity and augmented Cldn-2 degradation. Taken together, our data suggest that TJ integrity and maturity, ZO-1 expression/TJ localization, and Rac/Pak control Cldn-2 degradation and synthesis. A feedback mechanism connecting Cldn-2 expression with junction remodeling, e.g., during wound healing, epithelial-mesenchymal transition, or tumor metastasis formation, may have important downstream effects on permeability, proliferation, and migration.

Postoperative ERAS Interventions Have the Greatest Impact on Optimal Recovery: Experience With Implementation of ERAS Across Multiple Hospitals.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs incorporate evidence-based practices to minimize perioperative stress, gut dysfunction, and promote early recovery. However, it is unknown which components have the greatest impact. OBJECTIVE: This study aims to determine which components of ERAS programs have the largest impact on recovery for patients undergoing colorectal surgery. METHODS: An iERAS program was implemented in 15 academic hospitals. Data were collected prospectively. Patients were considered compliant if >75% of the preoperative, intraoperative, and postoperative predefined interventions were adhered to. Optimal recovery was defined as discharge within 5 days of surgery with no major complications, no readmission to hospital, and no mortality. Multivariable analysis was used to model the impact of compliance and technique on optimal recovery. RESULTS: Overall, 2876 patients were enrolled. Colon resections were performed in 64.7% of patients and 52.9% had a laparoscopic procedure. Only 20.1% of patients were compliant with all phases of the pathway. The poorest compliance rate was for postoperative interventions (40.3%) which was independently associated with an increase in optimal recovery (RR = 2.12, 95% CI 1.81-2.47). Compliance with ERAS interventions remained associated with improved outcomes whether surgery was performed laparoscopically (RR = 1.55, 95% CI 1.23-1.96) or open (RR = 2.29, 95% CI 1.68-3.13). However, the impact of ERAS compliance was significantly greater in the open group (P < 0.001). CONCLUSIONS: Postoperative compliance is the most difficult to achieve but is most strongly associated with optimal recovery. Although our data support that ERAS has more effect in patients undergoing open surgery, it also showed a significant impact on patients treated with a laparoscopic approach.

Trial of short-course antimicrobial therapy for intraabdominal infection.

BACKGROUND: The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS: We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).