Adjusting the Split: Examining Complications After Emergency Exploratory Laparotomy in Older Adults.

INTRODUCTION: Older adults experience higher rates of complications after an emergency exploratory laparotomy (EEL). To better understand the shift to an aging population in the United States, identifying how age may influence these complications in older patients is important. The current standard age category for older adult patients is ≥65. We analyzed postlaparotomy complications using a lower age split. METHODS: A retrospective analysis was done on patients who required an EEL from October 2015 to December 2019 at an academic medical center. Patient demographics and hospital course variables were collected. Differences in complications in patients aged ≥/<55 y and ≥/<65 y were measured using univariate and multivariable analyses. RESULTS: A total of 481 patients were reviewed. Both patient groups of ≥55 and ≥65 were typically male, White, had 3+ comorbidities, Medicare insurance, were retired, and presented in extremis to the emergency department. Patients aged ≥55 y had significant rates of pulmonary complications and inpatient mortality (odds ratio 2.2, 2.7, respectively). Patients aged ≥65 y had significant rates of genitourinary and cardiac complications (odds ratio 2.3, 1.8, respectively). CONCLUSIONS: Patients aged ≥55 y undergoing EEL had higher odds of experiencing pulmonary complications and death during their index hospitalizations, which was not present with the standard ≥/<65-y-old patient analysis. Those aged ≥65 y experienced index genitourinary and cardiac complications. The ≥/<55 age split has a unique set of complications that should be considered. Given the increased odds of inpatient mortality and types of complications in patients aged ≥55 y, the current age split for older adults should be reconsidered.

Identifying Factors Associated With Code Status Changes After Emergency General Surgery.

INTRODUCTION: Surgical emergencies are time sensitive. Identifying patients who may benefit from preoperative goals of care discussions is critical to ensuring that operative intervention aligns with the patient's values. We sought to identify patient factors associated with acute changes in a patient's goals using code status change (CSC) as proxy. METHODS: A retrospective analysis of single-institution data for patients undergoing urgent laparotomy was performed. Patients were stratified based on whether a postoperative CSC occurred. Parametric, nonparametric, and regression analyses were used to identify variables associated with CSC. RESULTS: Of 484 patients, 13.8% (n = 67) had a postoperative CSC. Patients with postoperative CSC were older (65 versus 60 years, P < 0.001). Odds of CSC were significantly higher in patients who were transferred between facilities (odds ratio [OR] 2.1), had a higher Charlson Comorbidity Index (3-4: OR 3.9, 5+: OR 6.8), and had a higher quick sequential organ failure assessment score (2: OR 5.0; 3: OR 38.7). Patients with anemia (OR 1.9) and active cancer (OR 3.0) had higher odds of CSC. CONCLUSIONS: Timely intervention in emergency general surgery may result in high-risk interventions and subsequent complications that do not align with a patient's goals and values. Our analysis identified a subset of patients who undergo surgery and have a postoperative CSC leading to transition to comfort-focused care. In these patients, a pause in clinical momentum may help ensure operative intervention remains goal concordant.

Comorbidities Matter as Distressed Communities Index Fails to Predict Mortality in Necrotizing Soft Tissue Infection.

Background: Necrotizing soft tissue infections (NSTIs) are life-threatening infections requiring prompt intervention. The Distressed Communities Index (DCI) is a comprehensive ranking of socioeconomic well-being based on zip code. We sought to identify the role of DCI in predicting mortality in NSTI, because it remains unknown. Patients and Methods: A retrospective, single-institution analysis of patients diagnosed with NSTI (2011-2020) requiring surgical intervention. The DCI is a composite score based on community-level factors: unemployment, education level, poverty rate, median income, business growth, and housing vacancies. The DCI scores were matched to the patient's zip code and stratification was performed using quintiles. Parametric and non-parametric analyses were performed to evaluate both the demographic and clinical characteristics. Multivariable regression analyses were performed to identify independent variables associated with outcomes. Results: Six hundred twenty patients met inclusion criteria. Ninety-day mortality was 12.4% (n = 77). Patients who died were more likely to be female (58.4%), older (median age 60.5 ± 11.3 years), have a body mass index (BMI) ≥30 (61.5%), have a higher Charlson Comorbidity Index (3; interquartile range [IQR], 2-7). After regression analysis, neither the composite DCI by quintile, nor the individual component scores, were found to correlate with mortality. Interestingly, underlying heart disease, hepatic dysfunction, and renal disease at baseline were found to significantly correlate with mortality from NSTI with p values <0.05. Conclusions: Socioeconomic status and insurance payer are championed for inclusion when constructing risk models, evaluating resource utilization, comparing hospitals, and determining patient management. The severity of community distress measured by DCI did not correlate with mortality for NSTI, despite contrasting evidence in other diseases. This finding is likely caused by a combination of both individual and community-level resources. This is highlighted by the recognition that comorbidities did correlate with mortality. The absence of DCI-related associations observed in this study warrants further investigation, as do mechanisms for the prevention of further organ dysfunction.

Using State Data to Predict a Single Institution Mortality for Patients That Fall.

BACKGROUND: Falls are the most common cause of injury-related death for patients older than 45.  We hypothesized that a machine learning algorithm developed from state-level registry data could make accurate outcome predictions at a level 1 trauma hospital. METHODS: Data for all patients admitted for fall injury during 2009 - 2019 in the state of Pennsylvania were derived from the state trauma registry.  Thirteen variables that were immediately available upon patient arrival were used for prediction modeling.  Data for the test institution were withheld from model creation.  Algorithms assessed included logistic regression (LR), random forest (RF), and extreme gradient boost (XGB).  Model discrimination for mortality was assessed with area under the curve (AUC) for each algorithm at our level 1 trauma center. RESULTS: 180,284 patients met inclusion criteria.  The mean age was 69 years ± 18.5 years with a mortality rate of 4.0%.  The AUC for predicting mortality in patients that fall for LR, RF, and XGB were 0.797, 0.876, and 0.880, respectively.  The variables which contributed to the prediction in descending order of importance for XGB were respiratory rate, pulse, systolic blood pressure, ethnicity, weight, sex, age, temperature, Glasgow Coma Scale (GCS) eye, race, GCS voice, GCS motor, and blood alcohol level. CONCLUSIONS: An extreme gradient boost model developed using state-wide trauma data can accurately predict mortality after fall at a single center within the state.  This machine learning model can be implemented by local trauma systems within the state of Pennsylvania to identify patients injured by fall that require greater attention, transfer to a higher level of care, and higher resource allocation.

Thrombospondin-5 and fluvastatin promote angiogenesis and are protective against endothelial cell apoptosis.

The thrombospondins (TSPs), multifunctional matricellular proteins, are known mediators of endothelial cell (EC) angiogenesis and apoptosis. TSP-1, an antiangiogenic molecule, is important in the progression of vascular disease, in part by inducing EC apoptosis. TSP-2, although less studied, also induces EC apoptosis and inhibits angiogenesis. The effects of TSP-5 are largely unexplored in ECs, but TSP-5 is believed to be protective against arterial disease. Statin drugs have been shown to have beneficial pleiotropic effects, including decreasing EC apoptosis, increasing angiogenesis, and blocking TSP signaling. We hypothesized TSP-5 will be proangiogenic and antiapoptotic, and statin pretreatment would reverse the proapoptotic and antiangiogenic phenotype of TSP-1 and TSP-2. ECs were exposed to serum-free medium, TSP-1, TSP-2, or TSP-5 with or without fluvastatin pretreatment. Quantitative real-time polymerase chain reaction was performed on 96 apoptosis and 96 angiogenesis-related genes using microfluidic card assays. Angiogenesis was measured using Matrigel assays, while apoptosis was measured by fluorescent caspase assay. TSP-5 suppressed apoptotic genes and had a mixed effect on the angiogenic genes; however, TSP-5 did not alter apoptois but was proangiogenic. Pretreatment with fluvastatin downregulated proapoptotic genes and apoptosis and upregulated proangiogenic genes and angiogenesis. Findings indicate TSP-5 and fluvastatin have a protective effect on ECs, being proangiogenic and reversing the antiangiogenic effects of TSP-1 and TSP-2. In conclusion, TSP-5 and fluvastatin may be beneficial for inducing angiogenesis in the setting of ischemia.

Intraluminal Delivery of Simvastatin Attenuates Intimal Hyperplasia After Arterial Injury.

INTRODUCTION: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid-polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. METHODS: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy-intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the -intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. RESULTS: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. CONCLUSIONS: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

Impact of ASA score misclassification on NSQIP predicted mortality: a retrospective analysis.

BACKGROUND: The ASA physical classification score has a major impact on the observed/expected (O/E) mortality ratio in the NSQIP General Vascular Mortality Model. The difference in predicted mortality is greatest between ASAs 3 and 4. We hypothesized under-classified ASA scores significantly affect the O/E mortality. METHODS: We conducted a retrospective review of NSQIP essential surgery cases from January 2014 to December 2014 (n = 1264) with mortality sub-analysis (n = 33) at our institution. We recorded transfer and emergency status and independently calculated the ASA score for mortalities using published definitions. A random sample of 50 survivors and 10 emergency survivors were reviewed and ASA recalculated. We performed statistical modeling to simulate the effects of ASA misclassifications. Statistical analysis was performed using JMP 10 and SAS 9.4. RESULTS: ASA was under-classified in 18.2% of mortalities, most commonly ASAs 3 and 4. Sixteen percent of ASA 3 survivors were misclassified, including 60% in the emergency subgroup (p < 0.05 vs. elective cases). Patients transferred from other institutions were more likely to be emergency cases than non-transferred patients (43.5 vs. 7.84%, p < 0.05). Transferred patients had a higher proportion of ASAs 3-5 vs. ASAs 1-2 compared with non-transfers (84.38 vs. 49.76%, p < 0.05) Simulation data showed ASA misclassification underestimated predicted mortality by 2.5 deaths on average. CONCLUSION: ASA misclassification significantly impacts O/E mortality. With accurate ASA classification, observed mortality would not have exceeded expected mortality in our institution. Education regarding the impact of ASA scoring is critical to ensure accurate O/E mortality data at hospitals using NSQIP to assess surgical quality.

Fluvastatin inhibits intimal hyperplasia in wild-type but not Thbs1-null mice.

BACKGROUND: Thrombospondin-1 (TSP-1) is functionally important to intimal hyperplasia (IH) development. Statin drugs have beneficial pleiotropic effects, including reduced IH; however, the effect of statins on IH in a TSP-1-independent setting is unknown. HYPOTHESIS: Statins will be less effective in attenuating IH after vascular injury in TSP-1-null (Thbs1-/-) mice compared with wild-type (WT) mice. MATERIALS AND METHODS: Carotid artery ligation was performed on WT and Thbs1-/- mice. Each strain was divided into two groups: no statin control or standard chow containing fluvastatin (10 or 40 mg/kg/d). After 28 d, analysis included morphometric analysis and real-time quantitative reverse transcription polymerase chain reaction on the arteries and enzyme-linked immunosorbent assay on plasma (TSP-1 WT, TSP-2 WT, and Thbs1-/-). Comparisons were made by analysis of variance, with P < 0.05 considered significant. RESULTS: In no statin controls, WT mice had more IH than Thbs1-/- mice (0.46 ± 0.09 versus 0.15 ± 0.04). Fluvastatin reduced IH in the WT (0.46 ± 0.09 versus 0.23 ± 0.06), but not in Thbs1-/- groups (0.15 ± 0.04 versus 0.22 ± 0.07). No difference in IH existed between Thbs1-/- no statin controls and fluvastatin WT and Thbs1-/- groups. Statin dose did not affect IH. TSP-1 plasma levels were increased in fluvastatin WT. TSP-2 levels were decreased in fluvastatin WT and elevated in fluvastatin Thbs1-/-. Fluvastatin had no effect on tissue Thbs1 or Thbs2 gene expression. CONCLUSIONS: TSP-1 is necessary for robust IH after arterial injury. Because fluvastatin had no effect on IH in Thbs1-/-, the data suggest that the statin effect on IH may be largely TSP-1 dependent. Both statins and the presence of TSP-1 affect TSP-1 and TSP-2 plasma levels.

Dyslipidemia Part 2: Review of Dyslipidemia Treatment in Patients With Noncoronary Vascular Disease.

Dyslipidemia is one of the major modifiable risk factors associated with atherosclerotic cardiovascular disease. Appropriate modification of lipid profiles reduces the progression of atherosclerosis in vessel walls across all vascular beds. The management of dyslipidemia has evolved over the last several decades, especially since the discovery of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins. Statin use in atherosclerotic heart disease is well described in observational and prospective placebo-controlled studies, citing both lipid-lowering and pleiotropic effects. However, the effect of statins and other lipid-lowering agents on noncoronary arterial beds (the aorta, arteries to the extremities, renal, and carotid arteries) is less understood. This article is part 2 of a 2-part review, with part 1 having focused on lipid metabolism and the downstream effects of lipids on the development of atherosclerosis. The current review (part 2) will discuss trials, retrospective reviews, and observational cohort studies regarding the use of statins and/or other lipid-lowering drugs for primary and secondary prevention of peripheral noncoronary atherosclerotic disease.

Dyslipidemia Part 1--Review of Lipid Metabolism and Vascular Cell Physiology.

Dyslipidemia, more specifically, high-serum low-density lipoproteins and low-serum high-density lipoproteins, are known risk factors for cardiovascular disease. The current clinical treatment of dyslipidemia represents the outcome of a large body of fundamental basic science research on lipids, lipid metabolism, and the effects of different lipids on cellular components of the artery, inflammatory cells, and platelets. In general, lower density lipids activate intracellular pathways to increase local and systemic inflammation, monocyte adhesion, endothelial cell dysfunction and apoptosis, and smooth muscle cell proliferation, resulting in foam cell formation and genesis of atherosclerotic plaque. In contrast, higher density lipids prevent or attenuate atherosclerosis. This article is part 1 of a 2-part review, with part 1 focusing on lipid metabolism and the downstream effects of lipids on the development of atherosclerosis, and part 2 on the clinical treatment of dyslipidemia and the role of these drugs for patients with arterial disease exclusive of the coronary arteries.

MT1-MMP Activation of TGF-ß Signaling Enables Intercellular Activation of an Epithelial-mesenchymal Transition Program in Cancer.

Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) is associated with cancer invasion and metastasis leading to poor patient prognosis. MT1-MMP mediates cancer cell invasion via degradation of basement membrane and extracellular matrix, and induction of cell migration. However, MT1-MMP expression in the cancer stroma can drive invasion of carcinoma cells in vivo, suggesting MT1-MMP may also promote cancer invasiveness via paracrinemediated mechanisms. A major step in cancer cell metastasis is thought to be an epithelial-mesenchymal transition (EMT), in which carcinoma cells evolve from a stationary epithelial phenotype to a more motile mesenchymal phenotype. We demonstrate here that EMT is triggered by MT1-MMP-mediated activation of TGF-. signaling, involving induction of CUTL1 and subsequently, of Wnt5a. Mesenchymal-like cancer cells expressing endogenous MT1-MMP reverted to an epithelial phenotype when MT1-MMP, SMAD4, CUTL1, or Wnt5a expression or TGF-. activity was inhibited. Wnt5a knockdown in MT1- MMP expressing LNCaP cells caused decreased cell migration and cell growth in soft agar. While MT1-MMP expression did not affect total TGF-. level, MT1-MMP catalytic activity increased the availability of active TGF-., enabling MT1-MMP-expressing cells to activate the EMT in nearby cells. MT1-MMP-expressing cells induced co-cultured non-MT1-MMP-expressing cells to undergo EMT by a TGF-.-dependent process. These results highlight a pathway by which tumor invasiveness may be expanded via MT1-MMP-mediated activation of TGF-. signaling, enabling autocrine and paracrine-mediated induction of EMT.

Thrombospondin-1, -2 and -5 have differential effects on vascular smooth muscle cell physiology.

INTRODUCTION: The thrombospondins (TSPs) are matricellular proteins that exert multifunctional effects by binding cytokines, cell-surface receptors and other proteins. TSPs play important roles in vascular pathobiology and are all expressed in arterial lesions. The differential effects of TSP-1, -2, and -5 represent a gap in knowledge in vascular smooth muscle cell (VSMC) physiology. Our objective is to determine if structural differences of the TSPs imparted different effects on VSMC functions critical to the formation of neointimal hyperplasia. We hypothesize that TSP-1 and -2 induce similar patterns of migration, proliferation and gene expression, while the effects of TSP-5 are different. METHODS: Human aortic VSMC chemotaxis was tested for TSP-2 and TSP-5 (1-40 µg/mL), and compared to TSP-1 and serum-free media (SFM) using a modified Boyden chamber. Next, VSMCs were exposed to TSP-1, TSP-2 or TSP-5 (0.2-40 µg/mL). Proliferation was assessed by MTS assay. Finally, VSMCs were exposed to TSP-1, TSP-2, TSP-5 or SFM for 3, 6 or 24 h. Quantitative real-time PCR was performed on 96 genes using a microfluidic card. Statistical analysis was performed by ANOVA or t-test, with p < 0.05 being significant. RESULTS: TSP-1, TSP-2 and TSP-5 at 20 µg/mL all induce chemotaxis 3.1 fold compared to serum-free media. TSP-1 and TSP-2 induced proliferation 53% and 54% respectively, whereas TSP-5 did not. In the gene analysis, overall, cardiovascular system development and function is the canonical pathway most influenced by TSP treatment, and includes multiple growth factors, cytokines and proteases implicated in cellular migration, proliferation, vasculogenesis, apoptosis and inflammation pathways. CONCLUSIONS AND RELEVANCE: The results of this study indicate TSP-1, -2, and -5 play active roles in VSMC physiology and gene expression. Similarly to TSP-1, VSMC chemotaxis to TSP-2 and -5 is dose-dependent. TSP-1 and -2 induces VSMC proliferation, but TSP-5 does not, likely due conservation of N-terminal domains in TSP-1 and -2. In addition, TSP-1, -2 and -5 significantly affect VSMC gene expression; however, little overlap exists in the specific genes altered. This study further delineates TSP-1, -2 and -5's contributions to processes related to VSMC physiology.

Esophageal reflux disease proton pump inhibitor therapy impact on sleep disturbance: a systematic review.

OBJECTIVE: To perform a systematic literature review that evaluates the impact of proton pump inhibitor treatment of gastroesophageal reflux disease on sleep disturbance-related outcomes. DATA SOURCES: PubMed, Web of Science, and Cochrane databases were searched from 1989 (when omeprazole became available) to present; additional references gleaned from citations. REVIEW METHODS: The search strategy identified all randomized placebo-controlled clinical trials published in English; both proton pump inhibitor use and outcome measures of sleep disturbance were reported for esophageal reflux disease patients. Using a preestablished systematic review protocol and data extraction format, 4 coauthors independently reviewed all articles. RESULTS: The original search identified 20 articles; 9 were not directly relevant, and 3 were not placebo controlled. Sample sizes varied from 15 to 642; mean age was 47.4 ± 4.56 years; mean body mass index was 29.4 ± 2.9; the proportion of women varied widely across studies. Esomeprazole was studied most frequently. More than 50% of publications permitted rescue antacids. Two studies reported polysomnography outcomes, without statistically significant improvement. All studies reported non-polysomnography outcomes; 7 identified statistically significant improvements demonstrating drug treatment superiority over placebo. CONCLUSION: The existing evidence supports the use of proton pump inhibitors as a treatment for esophageal reflux disease to improve quality-of-life sleep disturbance-related outcomes. Given the wide variability in proton pump inhibitor treatments and sleep disturbance-related outcomes reported, however, study-specific results cannot be directly compared or aggregated. This conclusion appears robust not only for 7 of 8 studies included but also for the 3 highest quality studies.