Online Educational Module Improves Knowledge of Nurses on Bowel Preparation for Colonoscopy.

The effectiveness of colonoscopy is limited by the adequacy of bowel preparation. Nurses are essential in providing bowel cleansing agents and instructions for hospitalized patients before colonoscopy. This study aims to assess and improve the knowledge of nurses on bowel preparation for inpatient colonoscopy. Participants were asked to complete the survey before and after completing an educational module. The module and survey questions were placed in the NetLearning environment of the hospital intranet. A minimum post-test score of 80% was required to pass the course. A total of 1,107 nurses participated in the survey. Overall, the average score improved from 87% to 93% after the module (p < .0495). Knowledge of the different ways of consuming bowel cleansing agents improved from 54.3% to 83.6% (p = .0001). Only 56.2% of nurses knew how to carry out a split-dose bowel preparation regimen, which increased to 80.1% after the educational module (p = .0001). Nurses' knowledge about the different ways of consuming bowel cleansing agents before colonoscopy and the split-dose regimen is inadequate. A simple online educational module significantly improved the knowledge of nurses on bowel preparation for colonoscopy.

Trauma induced heterotopic ossification patient serum alters mitogen activated protein kinase signaling in adipose stem cells.

Post-traumatic heterotopic ossification (HO) is the formation of ectopic bone in non-osseous structures following injury. The precise mechanism for bone development following trauma is unknown; however, early onset of HO may involve the production of pro-osteogenic serum factors. Here we evaluated serum from a cohort of civilian and military patients post trauma to determine early induction gene signatures in orthopaedic trauma induced HO. To test this, human adipose derived stromal/stem cells (hASCs) were stimulated with human serum from patients who developed HO following trauma and evaluated for a gene panel with qPCR. Pathway gene analysis ontology revealed that hASCs stimulated with serum from patients who developed HO had altered gene expression in the activator protein 1 (AP1) and AP1 transcriptional targets pathways. Notably, there was a significant repression in FOS gene expression in hASCs treated with serum from individuals with HO. Furthermore, the mitogen-activated protein kinase (MAPK) signaling pathway was activated in hASCs following serum exposure from individuals with HO. Serum from both military and civilian patients with trauma induced HO had elevated downstream genes associated with the MAPK pathways. Stimulation of hASCs with known regulators of osteogenesis (BMP2, IL6, Forskolin, and WNT3A) failed to recapitulate the gene signature observed in hASCs following serum stimulation, suggesting non-canonical mechanisms for gene regulation in trauma induced HO. These findings provide new insight for the development of HO and support ongoing work linking the systemic response to injury with wound specific outcomes.

Inhibition of Mammalian Target of Rapamycin Signaling with Rapamycin Prevents Trauma-Induced Heterotopic Ossification.

A pressing clinical need exists for 63% to 65% of combat-wounded service members and 11% to 20% of civilians who develop heterotopic ossification (HO) after blast-related extremity injury and traumatic injuries, respectively. The mammalian target of rapamycin pathway is a central cellular sensor of injury. We evaluated the prophylactic effects of rapamycin, a selective inhibitor of mammalian target of rapamycin signaling, on HO formation in a rat model of blast-related, polytraumatic extremity injury. Rapamycin was administered intraperitoneally daily for 14 days at 0.5 mg/kg or 2.5 mg/kg. Ectopic bone formation was monitored by micro-computed tomography and confirmed by histologic examination. Connective tissue progenitor cells, platelet-derived growth factor receptor-α-positive cells, and α-smooth muscle actin-positive blood vessels were assayed at postoperative day 7 by colony formation and immunofluorescence. Early gene expression changes were determined by low-density microarray. There was significant attenuation of 1) total new bone and soft tissue ectopic bone with 0.5 mg/kg (38.5% and 14.7%) and 2.5 mg/kg rapamycin (90.3% and 82.9%), respectively, 2) connective tissue progenitor cells, 3) platelet-derived growth factor receptor-α-positive cells, 4) α-smooth muscle actin-positive blood vessels, and 5) of key extracellular matrix remodeling (CD44, Col1a1, integrins), osteogenesis (Sp7, Runx2, Bmp2), inflammation (Cxcl5, 10, IL6, Ccl2), and angiogenesis (Angpt2) genes. No wound healing complications were noted. Our data demonstrate the efficacy of rapamycin in inhibiting blast trauma-induced HO by a multipronged mechanism.

Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.

The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using postnatal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl ). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and coexpress markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult preinjury restricted cells coexpressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl ), tendons and joints formed HO. Postnatal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl ) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive BMP receptor (e.g., caACVR1) activity. Stem Cells 2017;35:705-710.

Is Smoking Shisha Safer than Cigarettes: Comparison of Health Effects of Shisha and Cigarette Smoking among Young Adults in Kuwait.

OBJECTIVE: The aim of this study was to compare the health effects of shisha smoking with cigarette smoking among male college students in Kuwait. SUBJECTS AND METHODS: This cross-sectional study was conducted on 525 male students in Kuwait from September to October 2013. A pretested questionnaire was used for information on demographics and health complaints. Peak expiratory flow rate (PEFR) was measured using a portable peak flow meter. The outcome variables of health status were compared between smoking shisha, cigarettes, or both, and nonsmoking. RESULTS: The prevalence of current smoking was 243 of the 525 students (46%); of them, 52 (10%) were shisha smokers, 69 were (13%) cigarette smokers and 122 (23%) were both shisha and cigarette smokers. There were significantly fewer shisha smokers than cigarette smokers with symptoms of persistent cough (4 vs. 13% or 2/52 vs. 15/69; p = 0.007), chest pain (4 vs. 23% or 2/52 vs. 16/69; p = 0.004) and rapid heart rate (12 vs. 28% or 6/52 vs. 19/69; p = 0.04). Other complaints, including asthma, respiratory infections, shortness of breath, high blood pressure, increased blood sugar levels and sleep disturbances were similar in the 2 groups. Values of PEFR for shisha smokers and cigarette smokers were not significantly different. CONCLUSION: This study produced evidence suggesting that shisha smoking is not safer than cigarette smoking except with regard to complaints such as cough, chest pain and rapid heart rate, and that people who smoke both experience worse health effects in terms of frequent symptoms of respiratory infections, persistent cough, rapid heartbeat and sleep disturbances.

Evaluation of bone regeneration potential of dental follicle stem cells for treatment of craniofacial defects.

BACKGROUND AIMS: Stem cell-based tissue regeneration offers potential for treatment of craniofacial bone defects. The dental follicle, a loose connective tissue surrounding the unerupted tooth, has been shown to contain progenitor/stem cells. Dental follicle stem cells (DFSCs) have strong osteogenesis capability, which makes them suitable for repairing skeletal defects. The objective of this study was to evaluate bone regeneration capability of DFSCs loaded into polycaprolactone (PCL) scaffold for treatment of craniofacial defects. METHODS: DFSCs were isolated from the first mandibular molars of postnatal Sprague-Dawley rats and seeded into the PCL scaffold. Cell attachment and cell viability on the scaffold were examined with the use of scanning electron microscopy and alamar blue reduction assay. For in vivo transplantation, critical-size defects were created on the skulls of 5-month-old immunocompetent rats, and the cell-scaffold constructs were transplanted into the defects. RESULTS: Skulls were collected at 4 and 8 weeks after transplantation, and bone regeneration in the defects was evaluated with the use of micro-computed tomography and histological analysis. Scanning electron microscopy and Alamar blue assay demonstrated attachment and proliferation of DFSCs in the PCL scaffold. Bone regeneration was observed in the defects treated with DFSC transplantation but not in the controls without DFSC transplant. Transplanting DFSC-PCL with or without osteogenic induction before transplantation achieved approximately 50% bone regeneration at 8 weeks. Formation of woven bone was observed in the DFSC-PCL treatment group. Similar results were seen when osteogenic-induced DFSC-PCL was transplanted to the critical-size defects. CONCLUSIONS: This study demonstrated that transplantation of DFSCs seeded into PCL scaffolds can be used to repair craniofacial defects.

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model.

BACKGROUND: Heterotopic ossification (HO) affects the majority of combat-related lower extremity wounds involving severe fracture and amputation. Defining the timing of early osteogenic-related genes may help identify candidate prophylactic agents and guide the timing of prophylactic therapy after blast and other combat-related extremity injuries. QUESTIONS/PURPOSES: Using a recently developed animal model of combat-related HO, we sought to determine (1) the timing of early chondrogenesis, cartilage formation, and radiographic ectopic bone development; and (2) the early cartilage and bone-related gene and protein patterns in traumatized soft tissue. METHODS: We used an established rat HO model consisting of blast exposure, controlled femur fracture, crush injury, and transfemoral amputation through the zone of injury. Postoperatively, rats were euthanized on Days 3 to 28. We assessed evidence of early ectopic bone formation by micro-CT and histology and performed proteomic and gene expression analysis. RESULTS: All rats showed radiographic evidence of HO within 28 days. Key chondrogenic (collagen type I alpha 1 [COL1α1], p = 0.016) and osteogenic-related genes (Runt-related transcription factor 2 [RUNX-2], p = 0.029; osteoclacin [OCN], p = 0.032; phosphate-regulating neutral endopeptidase, X-linked [PHEX], p = 0.0290, and POU domain class 5 transcription factor [POU5F], p = 0.016) and proteins (Noggin [NOG], p = 0.04, OCN, p = 0.02, RUNX- 2, p = 0.04, and substance P-1 [SP-1], p = 0.01) in the injured soft tissue, normalized to the contralateral limb and/or sham-treated naïve rats, increased on Days 3 to 14 postinjury. By 14 days, foci of hypertrophic chondrocytes, hyaline cartilage, and woven bone were present in the soft tissue surrounding the amputation site. CONCLUSIONS: We found that genes that regulate early chondrogenic and osteogenic signaling and bone development (COL1α1, RUNX-2, OCN, PHEX, and POU5F1) are induced early during the tissue reparative/healing phase in a rat model simulating a combat-related extremity injury. CLINICAL RELEVANCE: The ability to correlate molecular events with histologic and morphologic changes will assist researchers and clinicians to understand HO and hence formulate therapeutic interventions.

Bioburden Increases Heterotopic Ossification Formation in an Established Rat Model.

BACKGROUND: Heterotopic ossification (HO) develops in a majority of combat-related amputations wherein early bacterial colonization has been considered a potential early risk factor. Our group has recently developed a small animal model of trauma-induced HO that incorporates many of the multifaceted injury patterns of combat trauma in the absence of bacterial contamination and subsequent wound colonization. QUESTIONS/PURPOSES: We sought to determine if (1) the presence of bioburden (Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus [MRSA]) increases the magnitude of ectopic bone formation in traumatized muscle after amputation; and (2) what persistent effects bacterial contamination has on late microbial flora within the amputation site. METHODS: Using a blast-related HO model, we exposed 48 rats to blast overpressure, femur fracture, crush injury, and subsequent immediate transfemoral amputation through the zone of injury. Control injured rats (n = 8) were inoculated beneath the myodesis with phosphate-buffered saline not containing bacteria (vehicle) and treatment rats were inoculated with 1 × 10(6) colony-forming units of A baumannii (n = 20) or MRSA (n = 20). All animals formed HO. Heterotopic ossification was determined by quantitative volumetric measurements of ectopic bone at 12-weeks postinjury using micro-CT and qualitative histomorphometry for assessment of new bone formation in the residual limb. Bone marrow and muscle tissue biopsies were collected from the residual limb at 12 weeks to quantitatively measure the bioburden load and to qualitatively determine the species-level identification of the bacterial flora. RESULTS: At 12 weeks, we observed a greater volume of HO in rats infected with MRSA (68.9 ± 8.6 mm(3); 95% confidence interval [CI], 50.52-85.55) when compared with A baumannii (20.9 ± 3.7 mm(3); 95% CI, 13.61-28.14; p < 0.001) or vehicle (16.3 ± 3.2 mm(3); 95% CI, 10.06-22.47; p < 0.001). Soft tissue and marrow from the residual limb of rats inoculated with A baumannii tested negative for A baumannii infection but were positive for other strains of bacteria (1.33 × 10(2) ± 0.89 × 10(2); 95% CI, -0.42 × 10(2)-3.08 × 10(2) and 1.25 × 10(6) ± 0.69 × 10(6); 95% CI, -0.13 × 10(6)-2.60 × 10(6) colony-forming units in bone marrow and muscle tissue, respectively), whereas tissue from MRSA-infected rats contained MRSA only (4.84 × 10(1) ± 3.22 × 10(1); 95% CI, -1.47 × 10(1)-11.1 × 10(1) and 2.80 × 10(7) ± 1.73 × 10(7); 95% CI, -0.60 × 10(7)-6.20 × 10(7) in bone marrow and muscle tissue, respectively). CONCLUSIONS: Our findings demonstrate that persistent infection with MRSA results in a greater volume of ectopic bone formation, which may be the result of chronic soft tissue inflammation, and that early wound colonization may be a key risk factor. CLINICAL RELEVANCE: Interventions that mitigate wound contamination and inflammation (such as early débridement, systemic and local antibiotics) may also have a beneficial effect with regard to the mitigation of HO formation and should be evaluated with that potential in mind in future preclinical studies.

In vitro activity studies of hyperthermal near-infrared nanoGUMBOS in MDA-MB-231 breast cancer cells.

A new kind of material called nanoGUMBOS, comprised entirely of cations and anions, has been developed by pairing various functional ions that exhibit fluorescence activity with biocompatible ions, in a process very much akin to that employed in ionic liquid chemistry. In the present study, spectral and biological properties of NIR absorbing nanoGUMBOS were evaluated using electron microscopy, dynamic light scattering, absorbance, thermal imaging, and live/dead fluorescence assays in conjunction with malignant MDA-MB-231 and non-malignant HS-578-BST epithelial human breast cells. The primary focus of this study was to maximize heat generation using NIR laser irradiation and minimize non-specific cytotoxicity using biocompatible constituent ions (e.g. amino acids, vitamins, or organic acids). Concurrently, in order to generate highly responsive nanomaterials for NIR-laser-triggered hyperthermia, optimization of the nanoparticle size, shape, and uniformity was carried out. Evaluation of data from hyperthermal studies of NIR absorbing nanoGUMBOS shows that these materials can achieve temperatures above the threshold for killing cancerous cells. Additionally, in vitro cell based assays demonstrated their promising hyperthermal effects on cancer derived epithelial cells.

De-implementation of Fecal Occult Blood Testing in the Emergency Department and Hospital Units: A Quality Improvement Project.

Background: Fecal occult blood tests (FOBT) are inappropriately used in patients with melena, hematochezia, coffee ground emesis, iron deficiency anemia, and diarrhea. The use of FOBT for reasons other than screening for colorectal cancer is considered low-value and unnecessary. Methods: Quality Improvement Project that utilized education, Best Practice Advisory (BPA) and modification of order sets in the electronic health record (EHR). The interventions were done in a sequential order based on the Plan-Do-Study-Act (PDSA) method. An annotated run chart was used to analyze the collected data. Results: Education and Best Practice Advisory within the EHR led to significant reduction in the use of FOBT in the ED. The interventions eventually led to a consensus and removal of FOBT from the order set of the EHR for patients in the ED and hospital units. Conclusions: The use of electronic BPA, education and modification of order sets in the EHR can be effective at de-implementing unnecessary tests and procedures like FOBT in the ED and hospital units.

H pylori-Negative MALT-Associated Extranodal Marginal Zone Lymphoma: A Comprehensive Case Report and Literature Review.

Extranodal marginal zone B-cell lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT), a rare subtype of B-cell lymphoma, is typically associated with Helicobacter pylori (H pylori) infection, especially in gastric cases. However, this article presents 2 unique cases of H pylori-negative colonic ENMZL, challenging the conventional understanding of the disease. The first case involves an 80-year-old male diagnosed with Stage 1E ENMZL in the descending colon, and the second describes a 74-year-old male with sigmoid colon ENMZL. Both cases lacked H pylori infection, adding complexity to their management. Accompanying these case studies is a comprehensive literature review, delving into the epidemiology, pathology, clinical features, diagnosis, and treatment of H pylori-negative ENMZL, with a focus on gastrointestinal involvement. This review highlights the importance of considering H pylori-negative cases in ENMZL diagnosis and management, illustrating the need for further research and individualized treatment approaches in this uncommon lymphoma subtype.

Endoscopic Management of Boerhaave Syndrome: Are Outcomes Better Than Surgery? A Case Report and Review of Literature.

Boerhaave syndrome (BS) is a rare clinical diagnosis associated with a high morbidity and mortality rate. Diagnosis of this condition is usually delayed which can lead to a very poor outcome. The timing of presentation and time to management plays a very important role in the prognosis and selection of the management method. With the advances seen in therapeutic endoscopy, many authors have been exploring the possibility of shifting the focus of management from surgery to interventional endoscopy. We present a case report of a patient presenting with BS that was successfully managed endoscopically. We also reviewed the literature on how surgical management compares to endoscopic management and attempted to establish general recommendations from available literature on management of BS.

Survival and Disease Progression in Older Adult Patients With Cirrhosis: A Retrospective Study.

Background: Cirrhosis incidence in older adult patients has been increasing with limited data on their survival. This study is aimed at investigating the survival and disease progression in older adult patients with cirrhosis compared to younger patients. Methods: This is a retrospective single-center study. Patients aged above 50 with a confirmed diagnosis of cirrhosis based on biopsy, FibroSure test, splenomegaly, and low platelets < 120 × 109/L) or imaging findings including FibroScan were included. Patients with active substance abuse, transjugular intrahepatic portosystemic shunt (TIPS), prior spontaneous bacterial peritonitis (SBP), variceal hemorrhage, model for end-stage liver disease-Na (MELD - Na) ≥ 20, had liver transplantation, malignancy except for squamous cell carcinoma, and other comorbidities such as congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and end-stage kidney disease with glomerular filtration rate (GFR) < 30 were excluded. Patients' records from the liver clinic were reviewed and demographics, laboratory, and compensation and decompensation status were collated. Patients were separated into two groups based on age 50-64 years and age ≥ 65. The primary endpoint was death, and the secondary endpoint was disease progression measured by the baseline to 12-month increase in MELD-Na score. The Kaplan-Meier analysis was conducted to compare the survival between the two groups. Cox regression analysis was performed to identify independent risk factors for poor survival. Results: A total of 191 patients diagnosed with cirrhosis met the inclusion and exclusion criteria. There were 80 patients aged 50-64 years and 111 patients aged ≥ 65 years. Significantly shorter survival times were seen among patients aged ≥ 65 years compared to those aged 50-64 years (73.3 ± 4.8 vs. 151.5 ± 22.7; p < .001). Age of diagnosis ≥ 65 years (p < 0.001), male gender (p = .013), body mass index (BMI) < 30 (p = 0.005), and decompensation (p = 0.008) were found to be independent risk factors for poor survival. MELD-Na scores increased significantly in 12 months of follow-up from baseline, but only in patients with decompensated cirrhosis (p = 0.013). Conclusions: Cirrhotic patients aged ≥ 65 years have significantly poor survival compared to younger patients. A prospective study is needed to further investigate the effect of age and obesity on survival and disease progression in older adult patients with cirrhosis.

Evolving therapeutic strategies for advanced hepatocellular carcinoma.

Introduction: While sorafenib dominated the therapeutic arena in advanced hepatocellular carcinoma (HCC) for almost a decade, newer agents and combinations have been changing the therapeutic landscape in the last years.Areas covered: The authors outline the etiopathogenesis and evaluate the diagnostics in HCC, followed by a comprehensive review of the currently approved and experimental treatment approaches, with a focus on various systemic agents and combinations of agents. The manuscript was subdivided into relevant categories, thus making it applicable for both clinical practice and research endeavors.Expert opinion: Recently, combination therapies including immune checkpoint inhibitors with anti-VEGF/R agents have shown superior clinical efficacy in HCC. The Atezolizumab-bevacizumab combination is currently the preferred first-line therapy. Single-agents cabozantinib and regorafenib as well as nivolumab-ipilimumab combination are favored as second-line therapies. Further research is needed to identify the predictors of response to various treatments and establish the distinct patient profiles that will derive most benefit. Tumor mutation analysis and germline mutation testing could identify rational therapeutic targets in HCC in the near future. As the skyline for new therapeutic agents and combinations in HCC continues to expand, the outlook as of today is cautiously optimistic in this still difficult-to-treat malignant neoplastic disease.

Proteomic characterization of a trauma-based rat model of heterotopic ossification identifies interactive signaling networks as potential therapeutic targets.

Heterotopic ossification (HO) is the formation of ectopic bone in soft tissues observed in patients following blast injuries, orthopedic or head trauma, burns, or in the context of inborn mutations of genes involved in osteogenesis. There is no universally accepted therapy for HO. This study has used global unbiased mass spectrometry proteomic approaches, validated by western immunoblots, to interrogate skeletal muscle tissues obtained from a highly reproducible rat model of trauma induced HO. During early the phase of HO development, statistically significant modulation of proteins within the following pathways was identified: coagulation, cyclic AMP, extracellular matrix, immunity/inflammation, NADH metabolism, TGFß. These metabolic proteins and pathways have the potential to serve as diagnostic, prognostic, and therapeutic targets for this devastating orthopedic condition that has considerable impact on the patient's quality of life. Furthermore, the findings confirm and extend previous in vitro stromal/stem cell and clinical studies from the field. SIGNIFICANCE: This study confirms and extends the field's understanding of the protein pathways that are modulated in a rat model of trauma induced heterotopic ossification. The identification of specific proteins such as the AP1 transcription factor as well as protein families such as the complement/coagulation pathway and serine protease inhibitors as biomarkers have potential clinical translational value. These outcomes have relevance to the physiological and pathological mineralization processes contributing to the recovery of orthopedic trauma patients.

Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat-related heterotopic ossification.

Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high-energy penetrating injuries and blast-related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast-related amputation in a rodent model (n = 72 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL-6 (p = 0.01), TNF-α (p = 0.001), and IFN-γ (p = 0.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post-operative day (POD)-7 (p = 0.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP-O) colonies by as much as 98% both in vitro (p = 0.04) and in vivo (p = 0.01). Palovarotene treated animals exhibited significantly decreased expression of osteo- and chondrogenic genes by POD-7, including BMP4 (p = 0.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD-1 (p < 0.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter-related mechanisms including anti-inflammatory, anti-proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135-1144, 2018.

Early local delivery of vancomycin suppresses ectopic bone formation in a rat model of trauma-induced heterotopic ossification.

Heterotopic ossification (HO) is a debilitating sequela of high-energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat-injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast-related, post-traumatic HO. Male Sprague-Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin-resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD-0, n = 34) or on postoperative day-3 (POD-3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12-weeks post-injury by micro-CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post-injury. Vancomycin treatment on POD-0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro-inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2397-2406, 2017.

Hemolytic Potential of Tafenoquine in Female Volunteers Heterozygous for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (G6PD Mahidol Variant) versus G6PD-Normal Volunteers.

Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40-60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose-response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (-2.65 to -2.95 g/dL [N = 3]) and primaquine (-1.25 to -3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61-80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.