Metabolomics and cytokine profiling of mesenchymal stromal cells identify markers predictive of T-cell suppression.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) have shown great promise in the field of regenerative medicine, as many studies have shown that MSCs possess immunomodulatory function. Despite this promise, no MSC therapies have been licensed by the Food and Drug Administration. This lack of successful clinical translation is due in part to MSC heterogeneity and a lack of critical quality attributes. Although MSC indoleamine 2,3-dioxygnease (IDO) activity has been shown to correlate with MSC function, multiple predictive markers may be needed to better predict MSC function. METHODS: Three MSC lines (two bone marrow-derived, one induced pluripotent stem cell-derived) were expanded to three passages. At the time of harvest for each passage, cell pellets were collected for nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography mass spectrometry (MS), and media were collected for cytokine profiling. Harvested cells were also cryopreserved for assessing function using T-cell proliferation and IDO activity assays. Linear regression was performed on functional data against NMR, MS and cytokines to reduce the number of important features, and partial least squares regression (PLSR) was used to obtain predictive markers of T-cell suppression based on variable importance in projection scores. RESULTS: Significant functional heterogeneity (in terms of T-cell suppression and IDO activity) was observed between the three MSC lines, as were donor-dependent differences based on passage. Omics characterization revealed distinct differences between cell lines using principal component analysis. Cell lines separated along principal component one based on tissue source (bone marrow-derived versus induced pluripotent stem cell-derived) for NMR, MS and cytokine profiles. PLSR modeling of important features predicted MSC functional capacity with NMR (R2 = 0.86), MS (R2 = 0.83), cytokines (R2 = 0.70) and a combination of all features (R2 = 0.88). CONCLUSIONS: The work described here provides a platform for identifying markers for predicting MSC functional capacity using PLSR modeling that could be used as release criteria and guide future manufacturing strategies for MSCs and other cell therapies.

Morphological landscapes from high content imaging reveal cytokine priming strategies that enhance mesenchymal stromal cell immunosuppression.

Successful clinical translation of mesenchymal stromal cell (MSC) products has not been achieved in the United States and may be in large part due to MSC functional heterogeneity. Efforts have been made to identify "priming" conditions that produce MSCs with consistent immunomodulatory function; however, challenges remain with predicting and understanding how priming impacts MSC behavior. The purpose of this study was to develop a high throughput, image-based approach to assess MSC morphology in response to combinatorial priming treatments and establish morphological profiling as an effective approach to screen the effect of manufacturing changes (i.e., priming) on MSC immunomodulation. We characterized the morphological response of multiple MSC lines/passages to an array of Interferon-gamma (IFN-γ) and tumor necrosis factor-⍺ (TNF-⍺) priming conditions, as well as the effects of priming on MSC modulation of activated T cells and MSC secretome. Although considerable functional heterogeneity, in terms of T-cell suppression, was observed between different MSC lines and at different passages, this heterogeneity was significantly reduced with combined IFN-γ/TNF-⍺ priming. The magnitude of this change correlated strongly with multiple morphological features and was also reflected by MSC secretion of immunomodulatory factors, for example, PGE2, ICAM-1, and CXCL16. Overall, this study further demonstrates the ability of priming to enhance MSC function, as well as the ability of morphology to better understand MSC heterogeneity and predict changes in function due to manufacturing.

Implementing an ultrasound-based protocol for diagnosing appendicitis while maintaining diagnostic accuracy.

BACKGROUND: The use of ultrasound to diagnose appendicitis in children is well-documented but not universally employed outside of pediatric academic centers, especially in the United States. Various obstacles make it difficult for institutions and radiologists to abandon a successful and accurate CT-based imaging protocol in favor of a US-based protocol. OBJECTIVE: To describe how we overcame barriers to implementing a US-based appendicitis protocol among a large group of nonacademic private-practice pediatric radiologists while maintaining diagnostic accuracy and decreasing medical costs. MATERIALS AND METHODS: A multidisciplinary team of physicians (pediatric surgery, pediatric emergency medicine and pediatric radiology) approved an imaging protocol using US as the primary modality to evaluate suspected appendicitis with CT for equivocal cases. The protocol addressed potential bias against US and accommodated for institutional limitations of radiologist and sonographer experience and availability. Radiologists coded US reports according to the probability of appendicitis. Radiology reports were compared with clinical outcomes to assess diagnostic accuracy. During the study period, physicians from each group were apprised of the interim US protocol accuracy results. Problematic cases were discussed openly. RESULTS: A total of 512 children were enrolled and underwent US for evaluation of appendicitis over a 30-month period. Diagnostic accuracy was comparable to published results for combined US/CT protocols. Comparing the first 12 months to the last 12 months of the study period, the proportion of children achieving an unequivocal US result increased from 30% (51/169) to 53% (149/282) and the proportion of children undergoing surgery based solely on US findings increased from 55% (23/42) to 84% (92/109). Overall, 63% (325/512) of patients in the protocol did not require a CT. Total patient costs were reduced by $30,182 annually. CONCLUSION: We overcame several barriers to implementing a US protocol. During the study period our ability to visualize the appendix with US increased and utilization of CT decreased. Our overall diagnostic accuracy with the US-based protocol was comparable to other published results and remained unchanged throughout the study.

Chondroitin Sulfate Glycosaminoglycan Scaffolds for Cell and Recombinant Protein-Based Bone Regeneration.

Bone morphogenetic protein 2 (BMP-2)-loaded collagen sponges remain the clinical standard for treatment of large bone defects when there is insufficient autograft, despite associated complications. Recent efforts to negate comorbidities have included biomaterials and gene therapy approaches to extend the duration of BMP-2 release and activity. In this study, we compared the collagen sponge clinical standard to chondroitin sulfate glycosaminoglycan (CS-GAG) scaffolds as a delivery vehicle for recombinant human BMP-2 (rhBMP-2) and rhBMP-2 expression via human BMP-2 gene inserted into mesenchymal stem cells (BMP-2 MSC). We demonstrated extended release of rhBMP-2 from CS-GAG scaffolds compared to their collagen sponge counterparts, and further extended release from CS-GAG gels seeded with BMP-2 MSC. When used to treat a challenging critically sized femoral defect model in rats, both rhBMP-2 and BMP-2 MSC in CS-GAG induced comparable bone formation to the rhBMP-2 in collagen sponge, as measured by bone volume, strength, and stiffness. We conclude that CS-GAG scaffolds are a promising delivery vehicle for controlling the release of rhBMP-2 and to mediate the repair of critically sized segmental bone defects. Stem Cells Translational Medicine 2019;8:575-585.

Acute Bowel Computed Tomography.

Acute abdominal pain is a common presenting complaint in the emergency department. Increasingly, computed tomography is utilized for evaluating these patients. Radiologists are therefore expected to be familiar with the pertinent clinical and radiologic information related to acute bowel pathology. This primer will review the need-to-know and latest updates related to computed tomography evaluation of acute bowel pathology.

Biomechanical consequences of adding plantar fascia release to metatarsal osteotomies: Changes in forefoot plantar pressures.

Destruction of the normal metatarsal arch by a long metatarsal is often a cause for metatarsalgia. When surgery is warranted, distal oblique, or proximal dorsiflexion osteotomies of the long metatarsal bones are commonly used. The plantar fascia has anatomical connection to all metatarsal heads. There is controversial scientific evidence on the effect of plantar fascia release on forefoot biomechanics. In this cadaveric biomechanical study, we hypothesized that plantar fascia release would augment the plantar metatarsal pressure decreasing effects of two common second metatarsal osteotomy techniques. Six matched pairs of foot and ankle specimens were mounted on a pressure mat loading platform. Two randomly assigned surgery groups, which had received either distal oblique, or proximal dorsiflexion osteotomy of the second metatarsal, were evaluated before and after plantar fasciectomy. Specimens were loaded up to a ground reaction force of 400 N at varying Achilles tendon forces. Average pressures, peak pressures, and contact areas were analyzed. Supporting our hypothesis, average pressures under the second metatarsal during 600 N Achilles load were decreased by plantar fascia release following proximal osteotomy (p < 0.05). However contrary to our hypothesis, peak pressures under the second metatarsal were significantly increased by plantar fascia release following modified distal osteotomy, under multiple Achilles loading conditions (p < 0.05). Plantar fasciotomy should not be added to distal metatarsal osteotomy in the treatment of metatarsalgia. If proximal dorsiflexion osteotomy would be preferred, plantar fasciotomy should be approached cautiously not to disturb the forefoot biomechanics. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:800-804, 2017.

Developing a platform system for gene delivery: amplifying virus-like particles (AVLP) as an influenza vaccine.

Delivery of a gene of interest to target cells is highly desirable for translational medicine, such as gene therapy, regenerative medicine, vaccine development, and studies of gene function. Parainfluenza virus 5 (PIV5), a paramyxovirus with a negative-sense RNA genome, normally infects cells without causing obvious cytopathic effect, and it can infect many cell types. To exploit these features of PIV5, we established a system generating self-amplifying, virus-like particles (AVLP). Using enhanced green fluorescent protein (EGFP) as a reporter, AVLP encoding EGFP (AVLP-EGFP) successfully delivered and expressed the EGFP gene in primary human cells, including stem cells, airway epithelial cells, monocytes, and T cells. To demonstrate the application of this system for vaccine development, we generated AVLPs to express the HA and M1 antigens from the influenza A virus strain H5N1 (AVLP-H5 and AVLP-M1H5). Immunization of mice with AVLP-H5 and AVLP-M1H5 generated robust antibody and cellular immune responses. Vaccination with a single dose of AVLP-H5 and M1H5 completely protected mice against lethal H5N1 challenge, suggesting that the AVLP-based system is a promising platform for delivery of desirable genes.

Value Narratives: A Novel Method for Understanding High-Cost Pediatric Hospital Patients.

OBJECTIVES: To delineate the drivers of cost associated with the most-costly inpatients in a tertiary pediatric hospital. METHODS: We identified the 10% most-costly inpatients treated at a large regional children's hospital in 2010. From this group we randomly selected, within representative specialties, 2 groups of 50 inpatients for detailed chart review. By using daily cost data and clinical records, 2 independent reviewers examined the clinical course of each patient to identify events that drove cost beyond that expected for standard of care. By using an iterative process, these events were grouped into themes or "cost drivers." Linear regression was used to measure the association of number of cost drivers and total 2010 inpatient cost. RESULTS: We identified 7 cost drivers: medical complications (49%), futile treatment (6%), failure to identify family care preferences (9%), system errors (65%), preventable admissions (21%), complex family dynamics (11%), and expensive diagnosis with no other cost driver (15%). Cost drivers were associated with increased total costs. CONCLUSIONS: We developed a novel method for understanding high-cost inpatients. This method allowed a more detailed understanding of cost drivers than could be achieved with administrative data alone. Many of these cost drivers were related to problems with communication.

Biomechanical benefits of anterior offsetting of humeral head component in posteriorly unstable total shoulder arthroplasty: A cadaveric study.

Restoration of joint stability during total shoulder arthroplasty can be challenging in the face of severe glenoid retroversion. A novel technique of humeral head component anterior-offsetting has been proposed to address posterior instability. We evaluated the biomechanical benefits of this technique in cadaveric specimens. Total shoulder arthroplasty was performed in 14 cadaveric shoulders from 7 donors. Complementary shoulders were assigned to either 10° or 20° glenoid retroversion, with retroversion created by eccentric reaming. Two humeral head component offset positions were tested in each specimen: The anatomic (posterior) and anterior (reverse). With loads applied to the rotator cuff and deltoid, joint contact pressures and the force and energy required for posterior humeral head translation were measured. The force and energy required to displace the humeral head posteriorly increased significantly with the anterior offset position compared to the anatomic offset position. The joint contact pressures were significantly shifted anteriorly, and the joint contact area significantly increased with the anterior offset position. Anterior offsetting of the humeral head component increased the resistance to posterior humeral head translation, shifted joint contact pressures anteriorly, and increased joint contact area, thus, potentially increasing the joint stability in total shoulder arthroplasty with simulated glenoid retroversion.

A retrospective analysis of treatment-related hospitalization costs of pediatric, adolescent, and young adult acute lymphoblastic leukemia.

This retrospective study examined the longitudinal hospital outcomes (costs adjusted for inflation, hospital days, and admissions) associated with the treatment of pediatric, adolescent, and young adult acute lymphoblastic leukemia (ALL). Patients between one and 26 years of age with newly diagnosed ALL, who were treated at Primary Children's Hospital (PCH) in Salt Lake City, Utah were included. Treatment and hospitalization data were retrieved from system-wide cancer registry and enterprise data warehouse. PCH is a member of the Children's Oncology Group (COG) and patients were treated on, or according to, active COG protocols. Treatment-related hospital costs of ALL were examined by computing the average annual growth rates (AAGR). Longitudinal regressions identified patient characteristics associated with costs. A total of 505 patients (46.9% female) were included. The majority of patients had B-cell lineage ALL, 6.7% had T-ALL, and the median age at diagnosis was 4 years. Per-patient, first-year ALL hospitalization costs at PCH rose from $24,197 in 1998 to $37,924 in 2012. The AAGRs were 6.1, 13.0, and 7.6% for total, pharmacy, and room and care costs, respectively. Average days (AAGR = 5.2%) and admissions (AAGR = 3.8%) also demonstrated an increasing trend. High-risk patients had 47% higher costs per 6-month period in the first 5 years from diagnosis than standard-risk patients (P < 0.001). Similarly, relapsed ALL and stem cell transplantations were associated with significantly higher costs than nonrelapsed and no transplantations, respectively (P < 0.001). Increasing treatment-related costs of ALL demonstrate an area for further investigation. Value-based interventions such as identifying low-risk fever and neutropenia patients and managing them in outpatient settings should be evaluated for reducing the hospital burden of ALL.

Comparison of Proximal and Distal Oblique Second Metatarsal Osteotomies with Varying Achilles Tendon Tension: Biomechanical Study in a Cadaver Model.

BACKGROUND: The optimal surgery for reducing pressure under the second metatarsal head to treat metatarsalgia is unknown. We tested our hypothesis that a proximal oblique dorsiflexion osteotomy of the second metatarsal would decrease second-metatarsal plantar pressures in a cadaver model with varying Achilles tendon tension. We also tested the plantar pressure effects of two popular techniques of distal oblique osteotomy. METHODS: Twelve fresh-frozen feet from six cadavers were randomly assigned to either the distal osteotomy group (a classic distal oblique osteotomy followed by a modified distal oblique osteotomy) or proximal metatarsal osteotomy group. Each specimen was tested intact and then after the osteotomy or osteotomies. The feet were loaded with 0, 300, and 600 N of Achilles tendon tension and a 400-N ground reaction force. Plantar pressures were measured by a pressure sensitive mat and analyzed in sections located under each metatarsal. RESULTS: The proximal metatarsal osteotomy significantly reduced average pressures beneath the second metatarsal head during both 300 and 600 N of Achilles tendon loading by an average of 19.4 and 29.7 kPa, respectively (p < 0.05). The modified distal oblique osteotomy significantly decreased these pressures during 600 N of Achilles tendon loading, by a mean of 20.2 kPa, which was to a lesser extent than the proximal metatarsal osteotomy. Interestingly, the classic distal oblique osteotomy was not found to have significant effects on pressures beneath the second metatarsal head. CONCLUSIONS: The proximal oblique dorsiflexion metatarsal osteotomy may be the most effective procedure for decreasing plantar pressures under the second metatarsal. The modified distal oblique osteotomy may be the second most effective. CLINICAL RELEVANCE: The findings of this biomechanical study help shed light on which of the common second metatarsal osteotomies are best for decreasing plantar pressures.

One hospital, one appendectomy: The cost effectiveness of a standardized doctor's preference card.

PURPOSE: Appendicitis in children provides a unique opportunity to explore changes that reduce variation, reduce cost, and improve value. In this study we sought to evaluate the effectiveness of standardization of surgical technique and intraoperative disposable device utilization for laparoscopic appendectomy among all surgeons at a tertiary children's hospital. METHODS: All 6 surgeons at our tertiary children's hospital agreed to standardize to a single technique of performing a laparoscopic appendectomy. We collected data on all pediatric patients who had a laparoscopic appendectomy following implementation of the uniform doctor's preference card (DPC) (March 1, 2013 to February 28, 2014) and compared them to a historical control group. RESULTS: Implementation of the uniform DPC decreased the device cost per appendectomy from $844.11 to $305.32. Operative times (skin incision to skin closure) were 34.8 minutes prior to the uniform DPC and 37.0 minutes using the uniform DPC. There were no significant differences in postappendectomy outcomes. CONCLUSION: We have demonstrated that implementation of a uniform DPC and technical standardization for laparoscopic appendectomy can significantly reduce cost. Furthermore, this can occur without dramatically increasing operative times, length of stay, or postoperative complications.

A dynamic postoperative protocol provides efficient care for pediatric patients with non-ruptured appendicitis.

PURPOSE: Postoperative management of pediatric patients with non-ruptured appendicitis is highly variable and often includes an overnight stay in the hospital. We implemented a criteria-based postoperative protocol designed to eliminate postoperative antibiotics and facilitate timely discharge by utilizing the bedside nurse to evaluate for readiness for discharge. METHODS: We collected data on all patients with non-ruptured appendicitis at our institution following protocol implementation (May 1, 2012 to April 30, 2013) and compared them to a control group. RESULTS: 580 patients were treated for non-ruptured appendicitis (285 prior protocol, 295 new protocol). Following implementation of our protocol, there was an overall reduction in length of stay from 40.1 (SD 27.5) to 23.5 (SD 20.8)h, and total cost of care per patient also decreased from $5783 (SD $2501) to $4499 (SD $1983) (p<0.001). There was no change in hospital readmission rate (1.1% prior protocol, 1.4% new protocol) or postoperative abscess rate (0.8% prior protocol, 0.3% new protocol). CONCLUSION: Our new protocol reveals the value of eliminating postoperative antibiotics and leveraging the continuous availability of the bedside nurse in the determination of readiness for discharge.

Pediatric palliative care and inpatient hospital costs: a longitudinal cohort study.

BACKGROUND: Pediatric palliative care (PPC) improves the quality of life for children with life-limiting conditions, but the cost of care associated with PPC has not been quantified. This study examined the association between inpatient cost and receipt of PPC among high-cost inpatients. METHODS: The 10% most costly inpatients treated at a children's hospital in 2010 were studied, and factors associated with receipt of PPC were determined. Among patients dying during 2010, we compared 2010 inpatient costs between PPC recipients and nonrecipients. Inpatient costs during the 2-year follow up period between PPC recipients and nonrecipients were also compared. Patients were analyzed in 2 groups: those who died and those who survived the 2-year follow-up. RESULTS: Of 902 patients, 86 (10%) received PPC. Technology dependence, older age, multiple chronic conditions, PICU admission, and death in 2010 were independently associated with receipt of PPC. PPC recipients had increased inpatient costs compared with nonrecipients during 2010. Among patients who died during the 2-year follow-up, PPC recipients had significantly lower inpatient costs. Among survivors, PPC recipients had greater inpatient costs. When controlling for patient complexity, differences in inpatient costs were not significant. CONCLUSIONS: The relationship of PPC to inpatient costs is complex. PPC seems to lower costs among patients approaching death. Patients selectively referred to PPC who survive most often do so with chronic serious illnesses that predispose them to remain lifelong high-resource utilizers.

Causes and costs for ED visits after pediatric adenotonsillectomy.

OBJECTIVE: (1) Review the reasons, timing, and costs for children presenting to the emergency department (ED) after adenotonsillectomy (T&A). STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: A standardized activity-based hospital accounting system was used to identify 437 children from an academic pediatric otolaryngology practice presenting to the ED after T&A from 2009 to 2012. The reason for presentation, timing after surgery, and facility costs were recorded. RESULTS: The study cohort represented 13.3% of the 3198 patients who underwent T&A during that time period. Overall, 133 (4.2%) presented for dehydration, 106 (3.3%) presented for post-tonsillectomy hemorrhage, 65 (2.0%) for poorly controlled pain, 42 (1.3%) for fever, 29 (1.0%) for vomiting/nausea/GI discomfort, 22 (0.7%) for respiratory complications, and 12 (0.4%) for miscellaneous reasons related to the operation; 28 (0.8%) were unrelated to the T&A and excluded. Mean postoperative day at the time of ED presentation was 4.4 (95% CI, 4.1-4.7). The mean cost per patient presenting to the ED was $1420 (95% CI, $1104-$1737), the most costly subgroups being those presenting with respiratory complications ($2855; 95% CI, $1434-$4277), hemorrhage ($1502; 95% CI, $1216-$1787), and dehydration ($1372; 95% CI, $995-$1750). The least costly subgroup was acute postoperative pain ($781; 95% CI, $282-$1200). CONCLUSION: A significant portion of children present to the ED after T&A for poorly controlled pain, dehydration, or fever. The costs from these visits are significant. Accounting for these costs in the global care for pediatric T&A could assist in calculating appropriate reimbursement for bundled payments in this climate of health care reform.

Surgeon dependent variation in adenotonsillectomy costs in children.

OBJECTIVES: To (1) identify the major expenses for same-day adenotonsillectomy (T&A) and the costs for postoperative complication encounters in a children's hospital and (2) compare differences for variations in costs by surgeon. STUDY DESIGN: Observational cohort study. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: A standardized activity-based hospital accounting system was used to determine total hospital costs per encounter (not including professional fees for surgeons or anesthetists) for T&A cases at a tertiary children's hospital from 2007 to 2012. Hospital costs were subdivided into categories, including operating room (OR), OR supplies, postanesthesia care unit (PACU), same-day services (SDS), anesthesia, pharmacy, and other. Costs for postoperative complication encounters were included to identify a mean total cost per case per surgeon. RESULTS: The study cohort included 4824 T&As performed by 14 different surgeons. The mean cost per T&A was $1506 (95% confidence interval, $1492-$1519, with a range of $1156-$1828 for the lowest and highest cost per case per surgeon; P < .01). Including the cost for postoperative complications, the mean cost increased to $1599 ($1570-$1629). The largest cost categories included OR (31.9%), SDS (28.1%), and OR supplies (15.6%). CONCLUSION: A large portion of T&A expenses are due to OR and supply costs. Significant differences in costs between surgeons for outpatient T&A were identified. Studies to understand the reasons for this variation and the impact on outcomes are needed. If this variation does not affect patient outcomes, then reducing this variation may improve health care value by limiting waste.

Response-based therapy for ruptured appendicitis reduces resource utilization.

PURPOSE: We examined the effectiveness of a postoperative ruptured appendicitis protocol that eliminated Pseudomonas coverage and based the duration of IV antibiotic treatment and length of hospital stay on the patient's clinical response. METHODS: In our new protocol, IV antibiotics were administered until the patient met discharge criteria: adequate oral intake, pain control with oral medications, and afebrile for 24h. We collected data on all patients with ruptured appendicitis at our institution following protocol implementation (May 1, 2012, to April 30, 2013) and compared them to a control group. RESULTS: 306 patients were treated (154 prior protocol, 152 new protocol). The new clinical response-based protocol led to a decrease in hospital stay from 134h (SD 66.1) to 94.5h (SD 61.7) (p<0.001) and total cost of care per patient also decreased from $13,610 (SD $6859) to $9870 (SD $5670) (p<0.001). CONCLUSION: Our clinical response-based protocol for pediatric patients with ruptured appendicitis decreased LOS, cost, and IV antibiotics use without significant changes in adverse events.

Decreasing hospital length of stay for bronchiolitis by using an observation unit and home oxygen therapy.

IMPORTANCE: Pediatric observation units (OUs) offer the opportunity to safely and efficiently care for common illnesses previously cared for in an inpatient setting. Home oxygen therapy (HOT) has been used to facilitate hospital discharge in patients with hypoxic bronchiolitis. It is unknown how implementation of a hospitalwide bronchiolitis treatment protocol promoting OU-HOT would affect hospital length of stay (LOS). OBJECTIVE: To test the hypothesis that using OU-HOT for bronchiolitis would decrease LOS. DESIGN AND SETTING: Retrospective cohort study at Primary Children's Medical Center, Salt Lake City, Utah. PARTICIPANTS: Uncomplicated bronchiolitis patients younger than 2 years admitted during the winter seasons of 2005 through 2011. INTERVENTIONS: Implementation of a new bronchiolitis care process encouraging use of an OU-HOT protocol. MAIN OUTCOME MEASURES: Mean hospital LOS, discharge within 24 hours, emergency department (ED) bronchiolitis admission rates and ED revisit/readmission rates, and inflation-adjusted cost. RESULTS: A total of 692 patients with bronchiolitis from the 2010-2011 bronchiolitis season were compared with 725 patients from the 2009-2010 season. Implementation of an OU-HOT protocol was associated with a 22.1% decrease in mean LOS (63.3 hours vs 49.3 hours, P < .001). Although LOS decreased during all 6 winter seasons, linear regression and linear quantile regression analyses for the 2005-2011 LOS data demonstrated a significant acceleration in the LOS decrease for the 2010-2011 season after implementation of the OU-HOT protocol. Discharges within 24 hours increased from 20.0% to 38.4% (P < .001), with no difference in ED bronchiolitis admission or ED revisit/readmission rates. After implementation of the OU-HOT protocol, the total cost per admitted case decreased by 25.4% ($4800 vs $3582, P < .001). CONCLUSIONS AND RELEVANCE: Implementation of an OU-HOT protocol for patients with bronchiolitis safely reduces hospital LOS with significant cost savings. Although widespread implementation has the potential for dramatic cost savings nationally, further studies assessing overall health care use and cost, including the impact on families and outpatient practices, are needed.