Readmission for infection after blunt splenic injury: A national comparison of management techniques.

BACKGROUND: As nonoperative management (NOM) of blunt splenic injury (BSI) increases, understanding risks, especially infectious complications, becomes more important. There are no national studies on BSI outcomes that track readmissions across hospitals. Prior studies demonstrate that infection is a major cause of readmission after trauma and that a significant proportion is readmitted to different hospitals. The purpose of this study was to compare nationwide outcomes of different treatment modalities for BSI including readmissions to different hospitals. METHODS: The Nationwide Readmissions Database for 2010 to 2014 was queried for patients 18 years to 64 years old admitted nonelectively with a primary diagnosis of BSI. Organ space infection; a composite infectious incidence of surgical site infection (SSI), urinary tract infection, and pneumonia; and sepsis were identified in three groups: NOM, splenic artery embolization (SAE), and operative management (OM). Rates of infection were quantified during index admission and 30-day and 1-year readmission. Multivariable logistic regression was performed. Results were weighted for national estimates. RESULTS: Of the 37,986 patients admitted for BSI, 54.1% underwent NOM, 12.2% SAE, and 33.7% OM. Compared with OM and NOM, SAE had the highest rates of organ space SSI at 1 year (3.9% vs. 2.2% vs. 1.7%, p < 0.001). Compared with NOM, at 1 year, SAE had higher rates of infection (17.2% vs. 8.1%, p < 0.001) and sepsis (3.2% vs. 1.1%, p < 0.001). Compared with NOM, SAE had an increased risk of infection (odds ratio [OR], 1.24; 95 confidence interval [95% CI], 1.10-1.39; p < 0.001) and sepsis (OR, 1.37; 95% CI, 1.06-1.76; p < 0.001) at 1 year. At 1 year, SAE had increased risk of organ space SSI (OR, 1.99; 1.60-2.47; p < 0.001) but OM did not. CONCLUSION: Blunt splenic injury treated with SAE is at increased risk of both immediate and long-term infectious complications. Despite being considered splenic preservation, surgeons should be aware of these risks and incorporate such knowledge into their practice accordingly. LEVEL OF EVIDENCE: Epidemiological study, level IV.

Underestimation of Unplanned Readmission after Colorectal Surgery: A National Analysis.

BACKGROUND: A significant proportion of postoperative readmission occurs at a different hospital and is therefore missed by current benchmarking. There are no national studies tracking readmission at different hospitals after colorectal surgery. This study aimed to determine the national burden of postoperative colorectal readmission, including readmission to a different hospital. STUDY DESIGN: The 2013 to 2014 Nationwide Readmissions Database was queried for adults undergoing colorectal surgery. The outcome of interest was 30-day unplanned readmission. Risk factors were identified. RESULTS: There were 79,098 patients admitted during the study period, with 7.1% (n = 5,591) readmitted and of those, 10.2% (n = 569) readmitted to a different hospital. Risk factors for readmission to a different hospital included admission to a high-volume hospital (odds ratio [OR] 1.49 [95% CI 1.17 to 1.91], p < 0.01), teaching hospital (OR 1.26 [95% CI 1.01 to 1.59], p = 0.04), nonmetropolitan hospital (OR 2.75 [95% CI 1.95 to 3.89], p < 0.01), hospitalization more than 7 days (OR 1.67 [95% CI 1.33 to 2.10], p < 0.01), and elective admission (OR 1.57 [95% CI 1.22 to 2.02], p < 0.01). Predictors of readmission to a different hospital were different than predictors of readmission. The most common reason for readmission was infection (28.4%). CONCLUSIONS: The burden of readmission to a different hospital after colorectal surgery is significant and disproportionately affects high-volume hospitals. Current quality metrics underestimate readmission, failing to capture the subpopulation readmitted to a different hospital. Interventions designed to prevent readmission need to be tailored to the unique risk factors described for different hospital readmission. Benchmarking not measuring different hospital readmission is inaccurate and should be modified.

Hypothalamic Leptin Gene Therapy Reduces Bone Marrow Adiposity in ob/ob Mice Fed Regular and High-Fat Diets.

Low bone mass is often associated with elevated bone marrow adiposity. Since osteoblasts and adipocytes are derived from the same mesenchymal stem cell (MSC) progenitor, adipocyte formation may increase at the expense of osteoblast formation. Leptin is an adipocyte-derived hormone known to regulate energy and bone metabolism. Leptin deficiency and high-fat diet-induced obesity are associated with increased marrow adipose tissue (MAT) and reduced bone formation. Short-duration studies suggest that leptin treatment reduces MAT and increases bone formation in leptin-deficient ob/ob mice fed a regular diet. Here, we determined the long-duration impact of increased hypothalamic leptin on marrow adipocytes and osteoblasts in ob/ob mice following recombinant adeno-associated virus (rAAV) gene therapy. Eight- to 10-week-old male ob/ob mice were randomized into four groups: (1) untreated, (2) rAAV-Lep, (3) rAAV-green fluorescent protein (rAAV-GFP), or (4) pair-fed to rAAV-Lep. For vector administration, mice were injected intracerebroventricularly with either rAAV-leptin gene therapy (rAAV-Lep) or rAAV-GFP (9 × 10(7) particles) and maintained for 30 weeks. In a second study, the impact of increased hypothalamic leptin levels on MAT was determined in mice fed high-fat diets; ob/ob mice were randomized into two groups and treated with either rAAV-Lep or rAAV-GFP. At 7 weeks post-vector administration, half the mice in each group were switched to a high-fat diet for 8 weeks. Wild-type (WT) controls included age-matched mice fed regular or high-fat diet. High-fat diet resulted in a threefold increase in MAT in WT mice, whereas MAT was increased by leptin deficiency up to 50-fold. Hypothalamic leptin gene therapy increased osteoblast perimeter and osteoclast perimeter with minor change in cancellous bone architecture. The gene therapy decreased MAT levels in ob/ob mice fed regular or high-fat diet to values similar to WT mice fed regular diet. These findings suggest that leptin plays an important role in regulating the differentiation of MSCs to adipocytes and osteoblasts, a process that may be dysregulated by high-fat diet. However, the results also illustrate that reducing MAT by increasing leptin levels does not necessarily result in increased bone mass.

The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton.

Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of endoxifen on bone and our results demonstrate that endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.

Acute exposure to high dose γ-radiation results in transient activation of bone lining cells.

The present studies investigated the cellular mechanisms for the detrimental effects of high dose whole body γ-irradiation on bone. In addition, radioadaptation and bone marrow transplantation were assessed as interventions to mitigate the skeletal complications of irradiation. Increased trabecular thickness and separation and reduced cancellous bone volume fraction, connectivity density, and trabecular number were detected in proximal tibia and lumbar vertebra 14days following γ-irradiation with 6Gy. To establish the cellular mechanism for the architectural changes, vertebrae were analyzed by histomorphometry 1, 3, and 14days following irradiation. Marrow cell density decreased within 1day (67% reduction, p<0.0001), reached a minimum value after 3days (86% reduction, p<0.0001), and partially rebounded by 14days (30% reduction, p=0.0025) following irradiation. In contrast, osteoblast-lined bone perimeter was increased by 290% (1day, p=0.04), 1230% (3days, p<0.0001), and 530% (14days, p=0.003), respectively. There was a strong association between radiation-induced marrow cell death and activation of bone lining cells to express the osteoblast phenotype (Pearson correlation -0.85, p<0.0001). An increase (p=0.004) in osteoclast-lined bone perimeter was also detected with irradiation. A priming dose of γ-radiation (0.5mGy), previously shown to reduce mortality, had minimal effect on the cellular responses to radiation and did not prevent detrimental changes in bone architecture. Bone marrow transplantation normalized marrow cell density, bone turnover, and most indices of bone architecture following irradiation. In summary, radiation-induced death of marrow cells is associated with 1) a transient increase in bone formation due, at least in part, to activation of bone lining cells, and 2) an increase in bone resorption due to increased osteoclast perimeter. Bone marrow transplantation is effective in mitigating the detrimental effects of acute exposure to high dose whole body γ-radiation on bone turnover.

Peripheral leptin regulates bone formation.

Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild-type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice, and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity.