Global collaborative healthcare: assessing the resource requirements at a leading Academic Medical Center.

INTRODUCTION: Academic Medical Centers ("AMCs") have served as a hub of the United States ("US") health system and represented the state-of-the art in American health care for well over a century. Currently, the global healthcare market is both massive and expanding and is being altered by the unprecedented impact of technological advances and globalization. This provides AMCs a platform to enter into trans-national collaborative partnerships with healthcare organizations around the world, thus providing a means to deliver on its promise globally while also expanding and diversifying its resources. A number of leading US AMCs have engaged in global collaborative healthcare, employing different models based on services offered, global distribution, and inclination to assume risk. Engaging in these collaborations requires significant effort from across the health system, and an understanding of the resources required is paramount for effective delivery and to avoid overextension and diversion from the primary mission of these organizations. The goal of this paper is to discuss the role of US AMCs in this current global healthcare landscape and to also investigate our institutional faculty and staff resource requirements to support the operating model. METHODOLOGY: We extracted and retrospectively analyzed data from the JHI Global Services database for a 3-year period (Jan, 2013-Dec, 2015) to determine total utilization (hours and full time equivalent (FTE)), utilization by profession, and clinical and non-clinical areas of expertise. RESULTS: JHI utilized on average 21,940 h annually, or 10.55 FTEs of faculty and staff subject matter experts. The majority of the hours are for work performed by physician faculty members from 23 departments within the School of Medicine, representing 77% percent or on average 16,894 h annually. Clinical and allied health departments had an average annual utilization of 17,642 h or 7.8 FTEs, while non-clinical departments, schools and institutes averaged 4298 h or 1.9 FTEs, representing 80.4% and 19.6% respectively. CONCLUSION: We found that significant human resources are required within a broad range of AMC subject matter expertise across multiple disciplines, and that with adequate forecasting AMCs can successfully engage in these collaborations while continuing to fulfill their core mission.

Acute kidney injury is surprisingly common and a powerful predictor of mortality in surgical sepsis.

BACKGROUND: Acute kidney injury (AKI) is a common and often catastrophic complication in hospitalized patients; however, the impact of AKI in surgical sepsis remains unknown. We used Risk, Injury, Failure, Loss, End stage (RIFLE) consensus criteria to define the incidence of AKI in surgical sepsis and characterize the impact of AKI on patient morbidity and mortality. METHODS: Our prospective, institutional review board-approved sepsis research database was retrospectively queried for the incidence of AKI by RIFLE criteria, excluding those with chronic kidney disease. Patients were grouped into sepsis, severe sepsis, and septic shock by refined consensus criteria. Data including demographics, baseline biomarkers of organ dysfunction, and outcomes were compared by Student's t test and χ test. Multivariable regression analysis was performed for the effect of AKI on mortality adjusting for age, sex, African-American race, elective surgery, Acute Physiology and Chronic Health Evaluation II score, septic shock versus severe sepsis, and sepsis source. RESULTS: During the 36-month study period ending on December 2010, 246 patients treated for surgical sepsis were evaluated. AKI occurred in 67% of all patients, and 59%, 60%, and 88% of patients had sepsis, surgical sepsis, and septic shock, respectively. AKI was associated with Hispanic ethnicity, several baseline biomarkers of organ dysfunction, and a greater severity of illness. Patients with AKI had fewer ventilator-free and intensive care unit-free days and a decreased likelihood of discharge to home. Morbidity and mortality increased with severity of AKI, and AKI of any severity was found to be a strong predictor of hospital mortality (odds ratio, 10.59; 95% confidence interval, 1.28-87.35; p = 0.03) in surgical sepsis. CONCLUSION: AKI frequently complicates surgical sepsis, and serves as a powerful predictor of hospital mortality in severe sepsis and septic shock. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.

Single-stage repair of a complex type B aortic dissection associated with a pressurized infrarenal abdominal aortic aneurysm.

The decision-making involved in managing type 2 aortic dissections remains challenging despite the advances in endovascular technology. We report a challenging case of a patient presenting with a type 2 aortic dissection and false lumen extension into an infrarenal abdominal aortic aneurysm (AAA). Severe back pain and hypertension were the patient's initial complaints, and dynamic magnetic resonance angiography revealed 1-way pulsatile flow into the AAA sac from the false lumen. This patient underwent endovascular repair with a thoracic and infrarenal aortic endograft, successfully excluding the false lumen and decompressing the infrarenal aneursymal sac. This is a unique presentation of total endovascular repair of a symptomatic type B aortic dissection with a pressurized infrarenal AAA sac from false lumen flow into the sac.

Lung T lymphocyte trafficking and activation during ischemic acute kidney injury.

Despite advances in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely owing to extrarenal organ dysfunction. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that facilitate organ crosstalk and induce caspase-dependent lung apoptosis and injury through a TNFR1-dependent pathway. Given that T lymphocytes mediate local IRI in the kidney and are known to drive TNFR1-mediated apoptosis, we hypothesized that T lymphocytes activated during kidney IRI would traffic to the lung and mediate pulmonary apoptosis during AKI. In an established murine model of kidney IRI, we identified trafficking of CD3+ T lymphocytes to the lung during kidney IRI by flow cytometry and immunohistochemistry. T lymphocytes were primarily of the CD3+CD8+ phenotype; however, both CD3+CD4+ and CD3+CD8+ T lymphocytes expressed CD69 and CD25 activation markers during ischemic AKI. The activated lung T lymphocytes did not demonstrate an increased expression of intracellular TNF-α or surface TNFR1. Kidney IRI induced pulmonary apoptosis measured by caspase-3 activation in wild-type controls, but not in T cell-deficient (T(nu/nu)) mice. Adoptive transfer of murine wild-type T lymphocytes into T(nu/nu) mice restored the injury phenotype with increased cellular apoptosis and lung microvascular barrier dysfunction, suggesting that ischemic AKI-induced pulmonary apoptosis is T cell dependent. Kidney-lung crosstalk during AKI represents a complex biological process, and although T lymphocytes appear to serve a prominent role in the interorgan effects of AKI, further experiments are necessary to elucidate the specific role of activated T cells in modulating pulmonary apoptosis.

Lung endothelial cell apoptosis during ischemic acute kidney injury.

Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that drive lung inflammatory cascades, tumor necrosis factor receptor 1 (TNFR1)-mediated programmed cell death, and microvascular barrier dysfunction, leading to acute lung injury. We hypothesized that lung microvascular endothelial cells (ECs), with their integral role in maintaining the lung-semipermeable barrier, were key cellular targets of TNFR1-mediated apoptosis during ischemic AKI. Male C57/BL6 mice and Sprague-Dawley rats underwent 60 min of bilateral renal pedicle occlusion (IRI) or sham laparotomy (sham) and were killed at 4 or 24 h. Colocalization with TUNEL, DAPI, and CD34 was performed to identify EC-specific apoptosis. Mouse ECs (CD45/CD31) isolated with novel tissue digestion techniques and magnetic microbead sorting underwent quantitative real-time polymerase chain reaction SuperArray analysis with 84 apoptosis-related genes. In parallel, rat lung microvascular ECs grown to confluence were treated with serum from rats obtained following sham or kidney IRI. Rat lung microvascular ECs treated +/- etanercept, a TNF-α/TNFR1 signaling inhibitor, underwent custom real-time polymerase chain reaction analysis for proapoptotic and TNF superfamily transcriptional events, and apoptosis was identified with caspase 3 and poly(ADP-ribose) polymerase activity assays. In vivo, TUNEL-positive cells colocalized with CD34 in whole-lung tissue and isolated lung ECs demonstrated a proapoptotic transcriptome during ischemic AKI. In vitro, ischemic AKI incited proapoptotic (FasL, Dapk1, Bcl10) and TNF superfamily (TNFR1, TNFR2, TNF-α) gene activation and increased caspase 3 and poly(ADP-ribose) polymerase activity at 24 h versus sham. Compared with vehicle, treatment of rat lung microvascular ECs with etanercept inhibited proinflammatory gene activation (E-selectin, intercellular adhesion molecule 1, interleukin 6, RhoB) and apoptosis during ischemic AKI. Ischemic AKI drives distinct proinflammatory and proapoptotic changes in the pulmonary EC transcriptome with TNFR1-dependent caspase activation and programmed cell death. Further investigation of potential EC mechanisms of kidney-lung crosstalk during AKI may identify potential therapeutic targets for this deadly disease.

TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury.

Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

Endovascular management of carotid artery stenosis secondary to sclerosing mediastinitis.

Sclerosing mediastinitis is a rare, progressive condition characterized by extensive fibrotic reaction. We report the first known case of symptomatic, extrinsic compression of the carotid artery by fibrotic extension of sclerosing mediastinitis. A 54-year-old woman began experiencing neurologic symptoms from extension of a known mediastinal mass resulting in 70% to 79% stenosis of the right internal carotid artery. The stenosis was treated with endovascular stenting. Completion angiogram revealed a good result with <10% residual stenosis. At 18-month follow-up, the patient was symptom free without evidence of re-stenosis. Endovascular therapy provides a novel and durable solution in the midterm to this very rare problem.

Inflammatory Mechanisms of Organ Crosstalk during Ischemic Acute Kidney Injury.

Acute kidney injury (AKI) is a common complication during inpatient hospitalization, and clinical outcomes remain poor despite advancements in renal replacement therapy. AKI in the setting of multiple organ failure (MOF) remains a formidable challenge to clinicians and incurs an unacceptably high mortality rate. Kidney ischemia-reperfusion injury (IRI) incites a proinflammatory cascade and releases cellular and soluble mediators with systemic implications for remote organ injury. Evidence from preclinical models cites mechanisms of organ crosstalk during ischemic AKI including the expression of cellular adhesion molecules, lymphocyte trafficking, release of proinflammatory cytokines and chemokines, and modification of the host innate and adaptive immune response systems. In this paper, the influence of kidney IRI on systemic inflammation and distant organ injury will be examined. Recent experimental data and evolving concepts of organ crosstalk during ischemic AKI will also be discussed in detail.

Endovascular repair of ruptured abdominal and thoracic aortic aneurysms.

Management of acute pathology remains one of the most challenging clinical entities, with a persistently high mortality rate both prior to and upon arrival to a hospital. Responding to the distinct advantages of endovascular approaches to aortic disease, many high-volume cardiovascular centers have focused on endovascular therapies for managing patients with ruptured or leaking aortic aneurysms and other acute aortic syndromes. Nonetheless, similar to outcomes for other surgical emergencies, time and efficiency are critical in managing these conditions. Early diagnosis, transport to an appropriate acute care facility, rapid institution of optimal medical management, availability of cardiovascular anesthesia and intensive care, and appropriate and timely surgical intervention continue to be the keys to success. This article discusses the endovascular approach to ruptured abdominal and thoracic aortic aneurysms.

Pulmonary endothelial cell activation during experimental acute kidney injury.

Acute kidney injury (AKI) leads to increased lung microvascular permeability, leukocyte infiltration, and upregulation of soluble inflammatory proteins in rodents. Most work investigating connections between AKI and pulmonary dysfunction, however, has focused on characterizing whole lung tissue changes associated with AKI. Studies at the cellular level are essential to understanding the molecular basis of lung changes during AKI. Given that the pulmonary microvascular barrier is functionally abnormal during AKI, we hypothesized that AKI induces a specific proinflammatory and proapoptotic lung endothelial cell (EC) response. Four and 24 h after kidney ischemia/reperfusion injury or bilateral nephrectomy, murine pulmonary ECs were isolated via tissue digestion followed by magnetic bead sorting. Purified lung ECs were analyzed for changes in mRNA expression using real-time SuperArray polymerase chain reaction analysis of genes related to EC function. In parallel experiments, confluent rat pulmonary microvascular ECs were treated with AKI or control serum to evaluate functional cellular alterations. Immunocytochemistry and FACS analysis of Annexin V/propidium iodide staining were used to evaluate cytoskeletal changes and promotion of apoptosis. Isolated murine pulmonary ECs exhibited significant changes in the expression of gene products related to inflammation, vascular reactivity, and programmed cell death. Further experiments using an in vitro rat pulmonary microvascular EC system revealed that AKI serum induced functional cellular changes related to apoptosis, including structural actin alterations and phosphatidylserine translocation. Analysis and segregation of both upregulated and downregulated genes into functional roles suggest that these transcriptional events likely participate in the transition to an activated proinflammatory and proapoptotic EC phenotype during AKI. Further mechanistic analysis of EC-specific events in the lung during AKI might reveal potential novel therapeutic targets for the deleterious kidney-lung crosstalk in the critically ill patient.

Surgical sepsis and organ crosstalk: the role of the kidney.

Acute kidney injury (AKI) is a common complication of hospitalized patients, and clinical outcomes remain poor despite advances in renal replacement therapy. The accepted pathophysiology of AKI in the setting of sepsis has evolved from one of simple decreased renal blood flow to one that involves a more complex interaction of intra-glomerular microcirculatory vasodilation combined with the local release of inflammatory mediators and apoptosis. Evidence from preclinical AKI models suggests that crosstalk occurs between kidneys and other organ systems via soluble and cellular inflammatory mediators and that this involves both the innate and adaptive immune systems. These interactions are reflected by genomic changes and abnormal rates of cellular apoptosis in distant organs including the lungs, heart, gut, liver, and central nervous system. The purpose of this article is to review the influence of AKI, particularly sepsis-associated AKI, on inter-organ crosstalk in the context of systemic inflammation and multiple organ failure (MOF).

Secondary stroke prevention in the era of carotid stenting: update on recent trials.

Stroke is a leading cause of morbidity and mortality worldwide. Traditional therapy for extracranial carotid artery occlusive disease, a significant risk factor for stroke, consists of optimal medical management and selective surgical treatment with carotid endarterectomy (CEA) for stroke risk reduction. Buoyed by the widespread application of percutaneous interventions for the treatment of coronary artery disease, carotid artery stenting (CAS) has steadily developed during the past decade as an alternative to CEA for patients who might benefit from surgical treatment. With greater operator experience have come advances in CAS techniques and patient selection criteria, and several single-center studies and industry-sponsored stent registries have demonstrated excellent results for CAS, especially compared with the landmark randomized CEA trials of the 1980s. Nevertheless, CAS has emerged as one of the most controversial procedures in the era of modern medicine, and recently published randomized trials from Europe have only stoked the fires of controversy. This study reviews the best available data for CAS as an alternative therapy to CEA for stroke risk reduction and gives an overview of eagerly anticipated large randomized trials.

Therapeutic distant organ effects of regional hypothermia during mesenteric ischemia-reperfusion injury.

INTRODUCTION: Mesenteric ischemia-reperfusion injury (IRI) leads to systemic inflammation and multiple organ failure in clinical and laboratory settings. We investigated the lung structural, functional, and genomic response to mesenteric IRI with and without regional intraischemic hypothermia (RIH) in rodents and hypothesized that RIH would protect the lung and preferentially modulate the distant organ transcriptome under these conditions. METHODS: Sprague-Dawley rats underwent sham laparotomy or superior mesenteric artery occlusion (SMAO) for 60 minutes with or without RIH. Gut temperature was maintained at 15°-20°C during SMAO, and systemic normothermia (37°C) was maintained throughout the study period. At 6 or 24 hours, lung tissue was collected for (1) histology, (2) myeloperoxidase activity, (3) bronchoalveolar lavage (BAL) fluid protein concentrations, (4) lung wet/dry ratios, and (5) total RNA isolation and hybridization to Illumina's Sentrix BeadChips (>22,000 probes) for gene expression profiling. Significantly affected genes (false discovery rate <5% and fold change ≥1.5) were linked to gene ontology (GO) terms using MAPPFinder, and hypothermia-suppressed genes were further analyzed with Pubmatrix. RESULTS: Mesenteric IRI-induced lung injury, as evidenced by leukocyte trafficking, alveolar hemorrhage, and increased BAL protein and wet/dry ratios, and activated a proinflammatory lung transcriptome compared with sham. In contrast, rats treated with RIH exhibited lung histology, BAL protein, and wet/dry ratios similar to sham. At 6 hours, GO analysis identified 232 hypothermia-suppressed genes related to inflammation, innate immune response, and cell adhesion, and 33 hypothermia-activated genes related to lipid and amine metabolism and defense response. Quantitative real-time polymerase chain reaction validated select array changes in top hypothermia-suppressed genes lipocalin-2 (lcn-2) and chemokine ligand 1 (CXCL-1), prominent genes associated with neutrophil activation and trafficking. CONCLUSIONS: Therapeutic hypothermia during SMAO provides distant organ protection and preferentially modulates the IRI-activated transcriptome in the rat lung. This study identifies potential novel diagnostic and therapeutic targets of mesenteric IRI and provides a platform for further mechanistic study of hypothermic protection at the cellular and subcellular level.

Academic needs in developing countries: a survey of the West African College of Surgeons.

BACKGROUND: The inaugural Fundamentals of Surgical Research Course was held in Sierra Leone in conjunction with the West African College of Surgeons (WACS). We subsequently performed a formal assessment of the academic needs of West African surgeons to plan for future courses, and hypothesized that they would differ from the goals of the U.S. course. METHODS: A survey was distributed via email to members of the WACS and returned by the same mechanism. It consisted of 6 questions addressing specific elements of the inaugural course, and potential new topics for future courses. RESULTS: Over half (53%, 25/47) of the respondents had not attended the inaugural course, while 85% (40/47) planned on attending the next course. Respondents identified least useful topics from the initial course as "Molecular Biology: Tools of the Trade" (45%, 21/47) and "Getting Promoted" (23%, 11/47). The least popular potential new topics were "Use and Abuse of Administrative Databases" (9%, 4/47), "Animal Models" (21%, 10/47), and "Genomics and Proteomics" (21%, 10/47). CONCLUSIONS: The self-reported academic needs of West African surgeons are oriented toward clinical research. Basic and translational research topics are of secondary interest to the majority of respondents. Future courses in this region must address specific local needs.

Organ crosstalk: the role of the kidney.

PURPOSE OF REVIEW: Acute kidney injury (AKI) continues to contribute significantly to morbidity and mortality in the ICU setting, especially when associated with distant organ dysfunction. There is increasing evidence that AKI directly contributes to organ dysfunction in lung, brain, liver, heart and other organs. This review will examine our current understanding of the deleterious organ crosstalk in the critically ill, which can provide a framework for developing novel therapeutics. RECENT FINDINGS: The majority of studies correlating AKI with distant organ dysfunction have demonstrated the pathophysiological importance of proinflammatory and proapoptotic pathways as well as oxidative stress and reactive oxygen species (ROS) production. Leukocyte activation and infiltration, changes in levels of soluble factors such as cytokines and chemokines, and regulation of cell death in extra-renal organs are potentially important mechanisms by which AKI modulates multiorgan dysfunction. SUMMARY: There is increasing knowledge of AKI and deleterious interorgan crosstalk that arises, at least in part, due to the imbalance of immune, inflammatory, and soluble mediator metabolism that attends severe insults to the kidney. Further studies can build on these new mechanistic observations to develop strategies to improve outcomes in the critically ill patient.

Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis.

Distant organ effects of acute kidney injury (AKI) are a leading cause of morbidity and mortality. While little is known about the underlying mechanisms, limited data suggest a role for inflammation and apoptosis. Utilizing a lung candidate gene discovery approach in a mouse model of ischemic AKI-induced lung dysfunction, we identified prominent lung activation of 66 apoptosis-related genes at 6 and/or 36 h following ischemia, of which 6 genes represent the tumor necrosis factor receptor (TNFR) superfamily, and another 23 genes are associated with the TNFR pathway. Given that pulmonary apoptosis is an important pathogenic mechanism of acute lung injury (ALI), we hypothesized that AKI leads to pulmonary proapoptotic pathways that facilitate lung injury and inflammation. Functional correlation with 1) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and 2) active caspase-3 (aC3) activity, immunoblotting, and immunohistochemistry (IHC) identified kidney IRI-induced pulmonary apoptosis at 24 h, and colocalization studies with CD34 identified predominantly endothelial apoptosis. Mice were treated with the caspase inhibitor Z-VAD-FMK (0.25 mg ip) or vehicle 1 h before and 8 h after sham or kidney IRI, and bronchoalveolar lavage fluid protein was measured at 36 h as a surrogate for lung leak. Caspase inhibition reduced lung microvascular changes after kidney IRI. The pulmonary apoptosis seen in wild-type control mice during AKI was absent in TNFR(-/-) mice. Using an initial genomic approach to discovery followed by a mechanistic approach to disease targeting, we demonstrate that pulmonary endothelial apoptosis is a direct mediator of the distant organ dysfunction during experimental AKI.