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Thrombogenicity poses a challenge to the clinical translation of engineered grafts. Previously, small-diameter vascular grafts (sdVG) composed of fibrin hydrogel microfiber tubes (FMT) with an external poly(ε-caprolactone) (PCL) sheath supported long-term patency in mice. Towards the development of an sdVG with off-the-shelf availability, the FMT's shelf stability, scale-up, and successful conjugation of an antithrombotic drug to the fibrin scaffold are reported here. FMTs maintain mechanical stability and high-water retention after storage for one year in a freezer, in a refrigerator, or at room temperature. Low molecular weight heparin-conjugated fibrin scaffolds enabled local and sustained delivery during two weeks of enzymatic degradation. Upscaled fabrication of sdVGs provides natural biodegradable grafts with size and mechanics suitable for human application. Implantation in a carotid artery interposition porcine model exhibited no rupture with thrombi prevented in all heparinized sdVGs (n = 4) over 4-5 weeks. Remodeling of the sdVGs is demonstrated with endothelial cells on the luminal surface and initial formation of the medial layer by 4-5 weeks. However, neointimal hyperplasia at 4-5 weeks led to the stenosis and occlusion of most of the sdVGs, which must be resolved for future long-term in vivo assessments. The off-the-shelf, biodegradable heparinized fibrin sdVG layer limits acute thrombogenicity while mediating extensive neotissue formation as the PCL sheath maintains structural integrity. STATEMENT OF SIGNIFICANCE: To achieve clinical and commercial utility of small-diameter vascular grafts as arterial conduits, these devices must have off-the-shelf availability for emergency arterial bypass applications and be scaled to a size suitable for human applications. A serious impediment to clinical translation is thrombogenicity. Treatments have focused on long-term systemic drug therapy, which increases the patient's risk of bleeding complications, or coating grafts and stents with anti-coagulants, which minimally improves patient outcomes even when combined with dual anti-platelet therapy. We systematically modified the biomaterial properties to develop anticoagulant embedded, biodegradable grafts that maintain off-the-shelf availability, provide mechanical stability, and prevent clot formation through local drug delivery.

Living organisms are vulnerable to thermal stress which causes a diversity of physiological outcomes. Previous work has shown that the snail vectors (

As one of the most successful human pathogens,Mycobacterium tuberculosis(Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibitsMtbproliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treatedMtb-infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model ofMtbinfection, JHU083 lost its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

Background: Chronic pruritus is a prevalent, multifactorial and debilitating condition that is often underestimated. This article reviews current evidence to evaluate the efficacy of acupuncture for the treatment of itch. Results: Although many researchers have conducted observational studies, clinical trials, and systematic reviews on the subject, the lack of more-robust and well-designed studies to prove the effectiveness of acupuncture in the management of itch is evident. Many published studies are of poor quality, with no clear description of randomization methods, and an absence of control groups and measurable clinical outcomes. In addition, a lack of standardization in methods for assessing pruritus and the acupuncture treatment protocols hinders more-comprehensive and higher-quality pooled data analysis. Conclusions: Current evidence cannot fully support acupuncture for the treatment of itch yet.

In many solid tumors including triple‐negative breast cancer (TNBC), upregulation of the interleukin‐4 receptor (IL‐4R) has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential, and a Th2 response in the tumor microenvironment (TME). Since immunosuppressive cells in the TME and spleen including myeloid‐derived suppressor cells (MDSCs) and tumor‐associated macrophages (TAMs) also express the IL‐4R, we hypothesized that selective depletion of IL‐4R‐bearing cells in TNBC would result in the direct killing of tumor cells and the depletion of immunosuppressive cells and lead to an enhanced antitumor response. To selectively target IL‐4R+ cells, we employed DABIL‐4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL‐4. As anticipated, DABIL‐4 has potent cytotoxic activity against TNBC cells both in vitro and in vivo. We demonstrate in the murine 4T1 TNBC model that DABIL‐4 significantly reduces tumor growth, splenomegaly, and lung metastases. Importantly, we also show that the administration of DABIL‐4 results in the selective depletion of MDSCs, TAMs, and regulatory T cells in treated mice, with a concomitant increase in IFN‐γ+ CD8 effector T cells in the TME. Since the 4T1 antitumor activity of DABIL‐4 was largely diminished in IL‐4R knockout mice, we postulate that DABIL‐4 functions primarily as an immunotherapeutic by the depletion of MDSCs, TAMs, and regulatory T cells. NanoString analysis of control and treated tumors confirmed and extended these observations by showing a marked decline of mRNA transcripts that are associated with tumorigenesis and metastasis. In conclusion, we demonstrate that DABIL‐4 targeting of both tumor and immunosuppressive host cells likely represents a novel and effective treatment strategy for 4T1 TNBC and warrants further study., Treatment with the interleukin‐4 diphtheria fusion toxin protein (DABIL‐4) targeted and killed both tumor cells and the immunosuppressive cell populations of the tumor microenvironment. DABIL‐4 treatment in a murine triple‐negative breast cancer (TNBC) model reduced MDSCs, tumor‐associated macrophages, and Treg cell populations and inhibited both tumor growth and metastasis. DABIL‐4 targeting likely represents a novel and effective treatment strategy for TNBC.

Background: Closed loop (CL) automated insulin delivery systems are demonstrated to be safe and effective in regulating glucose levels and reducing cognitive burden in people with type 1 diabetes (T1D). However, given the limited market options and the do-it-yourself nature of most systems, it can be difficult for potential users to shape their expectations fitting them into daily lives and management routines. As such, we examined the potential feasibility of a virtual reality (VR) intervention. Methods: A four-part VR intervention was created to expose adults with T1D to expected CL system barriers: body image, perceived hassles of using CL, deskilling fears, and unwanted social attention. Goals of the pilot were to assess feasibility and expose patients to CL. Surveys were conducted pre- and postparticipating in the VR experience. Results: A total of 20 adults with T1D completed the pilot. Average time to complete the experience was 14.1 minutes (8.8-39.9). Reported VR sickness was low. Willingness to use VR was maintained in 90% ( n = 18) and did not change expectations of CL in 95% ( n = 19). Virtual reality changed perceived hassles of CL in 25% ( n = 5) with four concerned over alarms and one connectivity issues: positive diabetes technology attitudes, confidence in managing hypoglycemia, overall perceptions of appearance, and positive affect maintained after the VR intervention. Negative affect significantly decreased after exposure and perceptions of being overweight trended toward significance. Conclusion: This pilot VR intervention demonstrated high potential in addressing expected barriers to uptake and usage of CL systems without decreasing enthusiasm or changing expectations of CL.

Introduction: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. Methods: We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. Results: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); over-whelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). Conclusion: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.

Lymphocytic thrombophilic arteritis is a recently described entity, histopathologically characterized by lymphocytic vasculitis that affects the arterioles of the dermo-hypodermic junction, associated with deposition of fibrin and a luminal fibrin ring. A 49-year-old female patient presented with achromic maculae and a well-defined ulcer on the medial aspect of the left lower limb. The biopsy showed intense inflammatory infiltrate in the papillary dermis with a predominance of lymphocytes, and medium-caliber vessels surrounded by mononuclear infiltrates in the deep reticular dermis. Masson’s trichrome staining showed intense destruction of the muscle layer of the vascular wall and a fibrin ring. Good clinical response was attained with azathioprine. The authors believe that the ulceration might be another clinical presentation or represent an atypical progression of this condition.

The use of hyaluronic acid (HA) fillers for facial rejuvenation has grown widely and is now one of the most performed noninvasive cosmetic procedures. Viral infections can occur, albeit rarely. This report describes a 65-year-old female patient with significant fat tissue loss in the malar region who developed herpes zoster after receiving HA filler for facial volumization. We performed volumization with a total of 2mL of HA in one session. Two days after the procedure, the patient began feeling mild pain in the malar region bilaterally and in the right side of the nasolabial fold. Upon physical examination, vesicles and erythema were observed. Due to the possibility of herpes zoster virus (HZV) infection, the patient was treated with valacyclovir. Ultrasonography with arterial and venous Doppler study revealed normal blood flow in the angular artery path and adequate positioning of the filler. After seven days of valacyclovir, the patient had complete resolution of the lesions. Herpes virus reactivation can be caused by direct axon damage by the needle, by tissue manipulation, and by inflammatory reaction. Herpes simplex virus (HSV) is the virus most commonly involved and its incidence does not exceed 1.45 percent of the complication cases, and HZV is even rarer. Reactivation of HZV might mimic tissue ischemia. Ultrasonography is a noninvasive, fast, and useful tool to evaluate vascular impairment and the positioning of the filler.

Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in tuberculosis patients and have been found to be permissive for Mycobacterium tuberculosis proliferation. To determine whether depletion of MDSCs may improve host control of tuberculosis, we used a novel diphtheria toxin-based fusion protein DABIL-4 that targets and depletes interleukin 4 (IL-4) receptor-positive cells. We show that DABIL-4 depletes both polymorphonuclear MDSCs and monocytic MDSCs, increases interferon-γ + T cells, and reduces the lung bacillary burden in a mouse tuberculosis model. These results indicate that MDSC-depleting therapies targeting the IL-4 receptor are beneficial in tuberculosis and offer an avenue towards host-directed tuberculosis therapy.

Background Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection. Clinical application of human G-CSF (hG-CSF) is limited due to its plasma half-life of 4 h. Therefore, novel approaches need to be investigated that would (1) enable prolonged manifestation of hG-CSF and (2) demonstrate G-CSF efficacy from studying the underlying protective mechanisms of hG-CSF. In our previous work, we used the self-complementary adeno-associated virus (stereotype2: scAAV2) as a vector to transfect the hG-CSF gene into the global ischemic brain of a mouse. As an extension of that work, we now seek to elucidate the protective mechanisms of hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia. Method A single drop of either AAV-CMV-hG-CSF or AAV-CMV-GFP was dropped into the conjunctival sac of the Swiss Webster mouse’s left eye, 30–60 min after bilateral common artery occlusion (BCAO). The efficacy of the expressed hG-CSF gene product was analyzed by monitoring the expression levels of endoplasmic reticulum stress (ER), mitochondrial dynamics and autophagic proteins over 4- and 7-days post-BCAO in vulnerable brain regions including the striatum, overlying cortex (frontal brain regions) and the hippocampus (middle brain regions). Statistical analysis was performed using mostly One-Way Analysis of variance (ANOVA), except for behavioral analysis, which used Repeated Measures Two-Way ANOVA, post hoc analysis was performed using the Tukey test. Results Several biomarkers that facilitated cellular death, including CHOP and GRP78 (ER stress) DRP1 (mitochondrial dynamics) and Beclin 1, p62 and LC3-ll (autophagy) were significantly downregulated by hG-CSF gene transfer. hG-CSF gene therapy also significantly upregulated antiapoptotic Bcl2 while downregulating pro-apoptotic Bax. The beneficial effects of hG-CSF gene therapy resulted in an overall improvement in functional behavior. Conclusion Taken together, this study has substantiated the approach of sustaining the protein expression of hG-CSF by eye drop administration of the hG-CSF gene. In addition, the study has validated the efficacy of using hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia.

This multicentre, randomized clinical trial assessed the safety and effectiveness of the EVARREST™ Fibrin Sealant Patch (FP) in treating parenchymal bleeding following anatomic and non-anatomic liver resections.One hundred and two patients were stratified according to the type of hepatic resection (anatomic/non-anatomic), and randomized (1:1) after identification of an appropriate bleeding site, to FP vs Standard of Care (SoC, manual compression ± topical haemostat). The primary endpoint was haemostasis at 4 min from bleeding site identification with no re-bleeding requiring re-treatment.The FP was superior in achieving haemostasis at 4 min (96%, 48/50) to SoC (46%, 24/52; p 0.001). Stratification for resection type showed treatment differences for primary endpoint for anatomic (24/25 FP vs 13/23 SoC; p = 0.001) and non-anatomic liver resections (24/25FP vs 11/29 SoC; p 0.001). Adverse events related to the study procedure were reported in 40/50 patients (80%) in the FP group and 43/52 patients (83%) in the SoC group. One (2%) adverse event (infected intra-abdominal fluid collection) was possibly related to study treatment.This clinical trial confirms that the FP is safe and highly effective in controlling parenchymal bleeding following hepatectomy regardless of the type of resection. ClinicalTrials.gov NCT01993888.

In surgery, rapid hemostasis can be required in various settings and bleeding intensities to minimize complications related to blood loss. While effective hemostats are available for mild-to-moderate surgical bleeding, few are effective against challenging severe hemorrhage. We report the effectiveness and safety of the fibrin pad (FP), a novel combination hemostat (device/human biologic), in controlling severe soft-tissue bleeding as compared to the standard of care (SoC).This randomized, controlled, superiority study enrolled subjects ≥18 years, requiring elective abdominal, retroperitoneal, pelvic, or thoracic (non-cardiac) surgery. A severe target bleeding site (TBS) was identified intra-operatively following which, subjects were randomized to the FP or the SoC group. Hemostatic status was observed at 4 min (primary endpoint) and 10 min post-randomization. Safety variables included TBS-related bleeding and thrombotic events.At 4 min post-randomization, 50/59 (84.7 %) subjects in the FP group and 10/32 (31.3%) [Corrected] subjects in the SoC group achieved hemostasis without needing re-treatment (P0.0001). Compared to the SoC group, the FP group showed better hemostasis at 10 min post-randomization [58/59 (98.3 %) vs. 28/32 (87.5 %); P = 0.01], lower mean time to hemostasis (6.1 ± 13.5 vs. 17.8 ± 32.0 min), and a less frequent need for re-treatment (5.1 vs. 53.1 %). The triangular test for binary response demonstrated the FP to be superior to SoC (95 % CI 1.474-3.290; P0.0001). Safety profiles in both groups were similar to those typically observed after long-duration surgery.The FP is safe and superior to SoC for controlling challenging severe soft-tissue bleeding encountered during intra-abdominal and thoracic surgical procedures.

IntroductionHaemostasis after liver resection may be difficult to achieve as a result of the presence of challenging bleeding, the anatomic landscape of the liver and the quality of tissue making up the hepatic parenchyma. The fibrin pad (FP) is a topical absorbable haemostat designed to be effective in a variety of tissues and across multiple bleeding intensities. This is the first clinical trial to evaluate the hemostat's safety and effectiveness in controlling bleeding during elective hepatic resection.MethodsThis prospective, randomized, controlled superiority trial enrolled 104 subjects undergoing elective hepatectomy in 5 countries. After parenchymal transection, subjects with an appropriately defined target bleeding site (TBS) were stratified according to the type of hepatic parenchyma and immediately randomized 1:1: FP versus Standard of Care (SoC). SoC comprised manual compression with the use of an approved topical absorbable haemostat. The primary endpoint was haemostasis at 4 min from identification of the TBS, with no re‐bleeding requiring re‐treatment prior to abdominal closure. Results were stratified for both normal and abnormal (steatosis or cirrhosis) hepatic parenchyma. All subjects were followed for 60 days post‐operatively.ResultsThe intent‐to‐treat (ITT) analysis showed an overall treatment difference of 53.0% (P < 0.001), 82.5% (33/40 FP) versus 29.5% (13/44 SoC) in achieving haemostasis at 4 min with no re‐bleeding requiring treatment up to wound closure. The per protocol analysis showed an overall treatment difference of 65.7% (P < 0.001), with 33/35 successes (94.3%) in the FP group and 12/42 in the SoC group (28.6%). The stratification results showed treatment differences between the normal parenchyma group, 63.6% (95.8% FP versus 32.3% SoC P < 0.001) and a larger difference of 72.7% in the abnormal parenchyma group (90.9% FP versus 18.2% SoC P = 0.0003). Post‐operative intra‐abdominal fluid collections were less frequent in the FP group (3.4% FP versus 13.3% SoC P = 0.059). There was no difference in the safety profile between the FP or SoC groups.ConclusionsThe FP is safe and effective when used as an adjunct to achieve haemostasis during hepatic surgery. The success rate of achieving haemostasis with a FP remained high compared with the SOC group, especially in steatotic or cirrhotic liver tissue where the control success rates diminish. In addition, FP treatment of hepatic parenchymal surfaces may reduce the risk of post‐operative biliary and fluid collections.

BACKGROUND The pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin). METHODS Spot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity. RESULTS Twenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 --0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11-0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03-0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001). CONCLUSION This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction.

Hodgkin lymphoma (HL) can be aggressive and intractable in some cases. Patients who relapse after autologous HCT (auto-HCT) have limited treatment options. City of Hope reports our experience in the use of reduced intensity allogeneic hematopoietic cell transplantation (allo-HCT) in 24 heavily pretreated patients with relapsed HL, between January 2003 and December 2008. The median number of prior therapies was 5; 20/24 patients had prior auto-HCT. The conditioning regimen for all patients was fludarabine and melphalan. With a median follow-up for living patients of 39.0 months, at 2 years the overall survival (OS) was 60% (95% CI 42, 72) and the progression-free survival was 27% (95% CI 22, 32). Non-relapse mortality was 13.1% (95% CI 5.1, 31.4) at 2 years. The incidence of grade II-IV aGVHD was 45.8% and 8.3% for grade III-IV. Allo-HCT in heavily pretreated relapsed Hodgkin lymphoma is feasible, tolerable, and can induce durable clinical remissions.

This study evaluated the hemostatic effectiveness and safety of Fibrin Pad (Omrix Biopharmaceuticals Ltd.) vs absorbable hemostat in patients undergoing nonemergent surgery. Fibrin Pad is a topical absorbable hemostat designed to be effective in a variety of soft tissues and across multiple bleeding intensities.Patients 18 years and older, requiring abdominal, retroperitoneal, pelvic, or thoracic (noncardiac) surgery and with an appropriate soft-tissue target bleeding site (TBS), were randomized to receive Fibrin Pad or absorbable hemostat (NCT00658723). Patients were stratified by bleeding severity at the TBS. Assessments included percentage of patients achieving hemostasis at 4 minutes after randomization with no rebleeding requiring treatment during the subsequent 6 minutes (primary endpoint), proportion of patients achieving hemostasis at 10 minutes, and incidence of treatment failure.On the primary endpoint, 98.3% of patients with Fibrin Pad and 53.3% with absorbable hemostat achieved hemostasis at 4 minutes (p0.0001). The treatment differential was magnified (efficacy was maintained with Fibrin Pad but decreased with absorbable hemostat) with increasing bleeding intensity: in patients with mild bleeding, 100.0% vs 80.0% achieved hemostasis with Fibrin Pad and absorbable hemostat (p = 0.03), respectively; rates were 96.6% vs 26.7%, respectively (p0.0001) with moderate bleeding. Percentages of patients who achieved hemostasis at 10 minutes were: Fibrin Pad, 98.3% and absorbable hemostat, 73.3% (p0.0001). Incidences of adverse events were comparable between groups.Fibrin Pad is superior to absorbable hemostat (SURGICEL Original Absorbable Hemostat [Ethicon]) in soft-tissue bleeding control and is safe and effective as an adjunct for rapidly and reliably achieving hemostasis for soft-tissue bleeding during surgery.

Background Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages. Methods We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product―fibrin pad―to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level. Results Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3–4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled. Conclusions The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage. Trial registration Phase I/II trial, NCT00598130

Background: This study evaluated the safety and hemostatic effectiveness of a tranexamic acid- and aprotinin-free fibrin sealant versus an absorbable hemostat in soft tissue during elective retroperitoneal or intra-abdominal surgery. Materials and Methods: This randomized, active-controlled, multicenter study enrolled patients who were undergoing elective retroperitoneal or intra-abdominal surgery and required adjunctive hemostatic measures at the target bleeding site (TBS). Patients were randomized (time = 0 minutes) to receive fibrin sealant or absorbable hemostat. The primary endpoint was the absence of bleeding at the TBS at 10 minutes. Secondary endpoints included the absence of bleeding at 4 and 7 minutes and the incidence of treatment failure (bleeding at 10 minutes or brisk bleeding requiring additional hemostatic measures), and the incidence of complications potentially related to bleeding. Adverse events were assessed. Results: Patients (N = 124) were randomized to receive fibrin sealant (n = 62) or absorbable hemostat (n = 62). A higher percentage of patients who received fibrin sealant versus absorbable hemostat achieved hemostasis within 10 minutes (95.2% vs 82.3%; 95% CI, 1.02-1.35) and also at 4 (74.2% vs 54.8%; 95% CI, 1.04-1.80) and 7 (90.3% vs 77.4%; 95% CI, 1.00-1.39) minutes. A lower incidence of treatment failure was observed for patients receiving fibrin sealant. Similar incidences of adverse events and complications potentially related to bleeding were observed. Conclusions: This tranexamic acid- and aprotinin-free fibrin sealant is safe and effective for achieving hemostasis in soft tissue during elective retroperitoneal or intra-abdominal surgery.

The primary objective of this multicenter post-market study was to compare the cosmetic outcome of triclosan-coated VICRYL Plus sutures with Chinese silk sutures for skin closure of modified radical mastectomy. A secondary objective was to assess the incidence of surgical site infection (SSI).Patients undergoing modified radical mastectomy were randomly assigned to coated VICRYL Plus antibacterial (Polyglactin 910) suture or Chinese silk suture. Cosmetic outcomes were evaluated postoperatively at days 12 (± 2) and 30 (± 5), and the evidence of SSI was assessed at days 3, 5, 7, 12 (± 2), 30 (± 5), and 90 (± 7). Cosmetic outcomes were independently assessed via visual analogue scale (VAS) score evaluations of blinded incision photographs (primary endpoint) and surgeon-assessed modified Hollander Scale (mHCS) scores (secondary endpoint). SSI assessments used both CDC criteria and ASEPSIS scores.Six Chinese hospitals randomized 101 women undergoing modified radical mastectomy to closure with coated VICRYL Plus suture (n = 51) or Chinese silk suture (n = 50). Mean VAS cosmetic outcome scores for antibacterial suture (67.2) were better than for Chinese silk (45.4) at day 30 (P0.0001)). Mean mHCS cosmetic outcome total scores, were also higher for antibacterial suture (5.7) than for Chinese silk (5.0) at day 30 (P = 0.002).Patients using coated VICRYL Plus suture had significantly better cosmetic outcomes than those with Chinese silk sutures. Patients using coated VICRYL Plus suture had a lower SSI incidence compared to the Chinese silk sutures, although the difference did not reach statistical significance.

Introduction: Sickle cell disease (SCD) may be associated with iron overload following repeated RBC transfusions. In beta thalassemia major, a disease characterized by hemolysis and ineffective erythropoiesis, iron overload occurs due to both repeated RBC transfusions and hyperabsorption of iron. Hyperabsorption of iron occurs due to ineffective erythropoiesis and subsequent downregulation of hepcidin, the main regulator of systemic iron homeostasis. With the presence of a thalassemia gene, HbSβ-thalassemia patients may have an increased tendency to hyperabsorb iron compared to HbSS patients. The purpose of this exploratory study was to compare hepcidin levels in HbSS and HbSβ-thalassemia as well as the levels of GDF-15 and any associations between hepcidin and ferritin, other measures of iron balance, erythropoietin and markers of inflammation. Methods: Eligible patients with HbSS or HbSβ-thalassemia (HbSβ0-thalassemia or HbSβ+-thalassemia) were evaluated during routine clinic visits. Hepcidin, GDF -15 and erythropoietin were analyzed using commercially available ELISA kits, while plasma cytokines were analyzed by Luminex® multi-analyte profiling technology. Complete blood counts, serum iron, transferrin, transferrin saturation and ferritin, high-sensitivity CRP and routine chemistries were performed at the clinical laboratories of UNC Hospitals. Patients' clinical data, including SCD-related clinical complications and estimates of the number of lifetime RBC transfusions, were obtained at the time of evaluation combined with reviews of their medical records. The levels of hepcidin and GDF-15 were compared in HbSS and HbSβ-thalassemia (and SCD vs. healthy controls) using Wilcoxon rank sum tests, and the association of hepcidin and laboratory covariates was evaluated using Spearman correlation coefficient. Reported p-values are for individual tests, unadjusted for multiple comparisons. Results: Baseline demographic variables were similar in HbSS and HbSβ-thalassemia patients, but platelet counts, lactate dehydrogenase, total bilirubin, direct bilirubin, indirect bilirubin, aspartate transaminase and alkaline phosphatase were significantly higher in HbSS patients (Table 1). No significant differences were observed when hepcidin levels were compared between control subjects (N = 15) and SCD patients (N = 40) (25.2 ± 14.3 ng/mL vs. 19.5 ± 17.3 ng/mL, p = 0.13). In addition, no difference was observed in hepcidin levels (16.1 ± 11.4 ng/mL vs. 23.7 ± 22.2 ng/mL, p = 0.53) or GDF-15 levels (1635.1 ± 1357.7 pg/mL vs. 2051 ± 2385.4 pg/mL, p = 0.9) when HbSS patients were compared with HbSβ-thalassemia. Hepcidin was associated with ferritin (r= 0.57, p = 0.0001) and transferrin (r = -0.46, p = 0.0029) in SCD patients. However, no significant correlations were observed between hepcidin and erythropoietin, high sensitivity CRP, IL-6, IL-8, IL-10 and TNFα. Conclusion: No differences in hepcidin levels were observed in SCD patients compared with healthy controls, and in HbSS patients compared with HbSβ-thalassemia patients. We confirm the association of hepcidin with ferritin, but surprisingly find no association of hepcidin with IL-6. Table 1. Baseline Variables Variable HbSS (N = 22)Mean ± SD (or %) HbSβ-thalassemia (N = 18)Mean ± SD (or %) 95% CI for Mean Difference Age (years) 37.96 ± 12.7 36.4 ± 11.4 (-6.2,9.2) Gender (females) 15 (68.2) 12 (66.7) Weight (kg) 70.8 ± 15.1 74.7 ± 14.8 (-13.7,5.9) Transfusions 0 - 5 6 - 10 11 - 20 21 - 50 9 (23.1) 5 (12.8) 5 (12.8) 2 (5.1) 11 (28.2) 3 (7.7) 3 (7.7) 1 (2.6) White Blood Cell Count (× 109/L) 9.5 ± 3.1 9.4 ± 3.1 (-1.9,2.04) Hemoglobin(g/dL) 9.4 ± 1.7 10 ± 1.99 (-1.7,0.6) Platelet Count (× 109/L) 402.6 ± 134.9 310.1 ± 151.6 (1.8,183.1) Ferritin (ng/mL) 346.3 ± 406.9 174 ± 257.7 (-50.3,395) Reticulocyte Count (× 109/L) 233.5 ± 139.9 215.7 ± 138.9 (-71.8,107.6) Lactate Dehydrogenase (U/L) 954.3 ± 322.95 720.4 ± 174.2 (73.8,394) Total Bilirubin (mg/dL) 3.9 ± 3.1 1.4 ± 0.9 (1.2,3.9) Direct Bilirubin (mg/dL) 0.56 ± 0.5 0.3 ± 0.1 (0.04,0.48) Indirect Bilirubin (mg/dL) 3.3 ± 2.8 1.06 ± 0.8 (1.03,3.5) Aspartate Transaminase (U/L) 46.5 ± 18.8 32.8 ± 11.9 (3.4,23.9) Alanine Transaminase (U/L) 30.7 ± 13.5 28.7 ± 9.7 (-5.6,9.6) Alkaline Phosphatase (U/L) 110.6 ± 45.6 78.1 ± 24.7 (9.7,55.3) Creatinine (mg/dL) 0.67 ± 0.17 1.1 ± 1.25 (-1.07,0.18) Disclosures No relevant conflicts of interest to declare.

Introduction: Endothelin-1 (ET1) is as a potent vasoconstrictor and mediates oxidative stress and inflammatory responses in various disease states. ET1 levels are elevated in individuals with physiologic measures of endothelial dysfunction. Further, urinary ET1 levels correlate with microalbuminuria in patients with sickle cell disease (SCD) suggesting ET1 mediates sickle cell nephropathy. We hypothesized that ET1 would be elevated in SCD patients with albuminuria and would correlate with endothelial dysfunction as measured by ultrasound imaging of the brachial artery. Methods: Subjects with sickle cell anemia (HbSS) were evaluated in non-crisis, “steady-states.” Individuals on hydroxyurea or renin-angiotensin-aldosterone system blocking agents (such as ACE-inhibitors) had to be on stable doses for at least 3 months. Spot urine samples were obtained for albumin-to-creatinine ratio (UACR) over 2-3 visits. Hematologic measures were obtained at baseline. At last visit, plasma ET1 levels were drawn, subjects provided 24hr urine collections, and endothelial function was assessed by brachial artery shear stress methods. We obtained ultrasound measures of flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NTMD), as indices of endothelium-dependent and endothelium-independent vasodilation, respectively. Hyperemic flow was quantified as the velocity-time integral (VTI), a reflection of small vessel endothelial function. ET1 levels were compared by categories of albuminuria (normal, micro- (>=30, =300 mg/g) by Kruskal-Wallis testing. We examined Spearman's correlations for ET1 and covariates of interest. Results: 24 subjects had measures of plasma ET1 available with mean age 43.0 (SD 11.9) years; 11 (45.8%) were male and 17 had albuminuria (9 micro-, 7 macro-). Other covariates are presented in Table 1. Median ET1 levels were significantly higher in micro- (0.69 pg/ml; IQR 0.62, 0.82) and macroalbuminuria (0.67 pg/ml; IQR 0.49, 1.02) subjects compared to normoalbuminuria (0.39 pg/ml; IQR 0.28, 0.58) subjects (p =0.03) (Fig 1). ET1 also correlated with UACR in continuous measures (ρ=0.44; 95% CI 0.05, 0.72; p =0.03). We saw no correlation between ET1 and hematologic indices or hemolysis markers including hemoglobin level, WBC and platelet counts, LDH, indirect bilirubin, or HbS or HbF content. In measures of endothelial dysfunction, ET1 had a negative correlation with FMD (ρ= -0.34, 95% CI -0.65, 0.08; p =0.1) that was not statistically significant. However, there was a strong negative correlation between ET1 and hyperemic VTI (ρ= -0.56, 95% CI -0.80, -0.18; p =0.008). Conclusions: In HbSS subjects, plasma ET1 levels associated with the presence of micro- or macroalbuminuria and also correlated with continuous measures of albuminuria. High ET1 levels correlated strongly with lower values of hyperemic VTI, indicating small vessel endothelial dysfunction. This latter finding may reflect glomerular capillary dysfunction leading to albuminuria. Our findings suggest ET1 plays a role in the pathogenesis of early kidney disease in HbSS as reflected by albuminuria and mediated by endothelial dysfunction. Table 1. Demographic and clinical data in 24 patients with HbSS. Normoalbuminuria (n=8) Microalbuminuria (n=9) Macroalbuminuria (n=7) Age (yrs) 38.8 (9.9) 42 (13.8) 49.1 (10.1) Male (N, %) 2 (25.0) 5 (55.6) 4 (57.1) SBP (mmHg) 107.5 (96, 117) 120 (117, 145) 138 (117, 151) DBP (mmHg) 57 (52, 65) 63 (56, 67) 81 (63, 83) Hemoglobin (g/dl) 9.3 (8.3, 10.0) 8.8 (7.5, 9.2) 8.8 (8, 9.5) WBC (109/L) 6.9 (5.6, 8.5) 7.0 (5.8, 10.6) 8.1 (4.8, 11.2) Platelet (109/L) 351 (306, 556) 288 (224, 374) 356 (253, 445) LDH (U/L) 736 (580, 1031) 1068 (771, 1389) 907 (759, 998) Indirect Bilirubin (g/dl) 2.1 (0.9, 4.8) 2.4 (1.2, 3.1) 2.3 (1.6, 4.1) Creatinine (mg/dl) 0.58 (0.55, 0.76) 0.68 (0.66, 0.98) 0.70 (0.54, 1.35) eGFR (ml/min/1.73m2) 121.9 (109.8, 153.7) 118.6 (78.4, 145.2) 127.4 (63.0, 136.8) 24hr CrCl (ml/min/1.73m2) 129 (89, 203) 101 (77, 116) 80 (53, 124) UACR (mg/g) 8.8 (5.1, 11.2) 95.8 (48.6, 142.7) 518.9 (398.6, 706.7) 24hr Urine Protein (mg) 93 (72.5, 106) 207 (140, 216) 910 (506, 1388) Disclosures Archer: Global Blood Therapeutics: Consultancy.

Introduction: Albuminuria is a common and sensitive marker of glomerular injury in SCD. We and others have previously observed the association of albuminuria with echocardiographically-derived tricuspid regurgitant jet velocity, systolic blood pressure, and history of stroke, suggesting a shared vasculopathic pathophysiology. However, the pathogenesis of albuminuria in SCD remains poorly defined. The purpose of this study was to evaluate the association of albuminuria with endothelial dysfunction, assessed non-invasively using ultrasound imaging of the brachial artery in SCD patients. In addition, we evaluated the association of albuminuria assessed by spot urine collection with 24-hour urine collections for protein. Methods: Spot urine measurements for microalbumin/creatinine ratio (UACR) were obtained during the "non-crisis," steady state over 2-3 visits, with a 24-hour urine collection for assessment of protein at the final visit. We obtained routine laboratory tests, including markers of hemolysis (lactate dehydrogenase, and total and indirect bilirubin) at the baseline visit. Endothelial function was assessed non-invasively at the final visit using a brachial artery shear stress method, with measurements of flow-mediated dilation (FMD), an index of endothelium-dependent vasodilation and nitroglycerin-mediated dilation (NTMD), a measure of endothelium-independent vasodilation. Patients on renin-angiotensin-aldosterone system (RAAS) blocking agents (ACE-inhibitors, angiotensin receptor blockers, direct renin inhibitors and mineralocorticoid receptor blockers), as well as those on hydroxyurea were on a stable dose for at least 3 months prior to enrollment. We evaluated associations between measures of endothelial function and other study covariates using Spearman's correlation coefficient for continuous covariates, and the Kruskal Wallis test for categorical covariates. Linear regression analysis was used to adjust for baseline arterial diameter. Reported p-values are for individual tests, unadjusted for multiple comparisons. Results: Spot urine samples were obtained in 23 subjects with sickle cell anemia (female = 13, male = 10), mean age, 43.3 ± 12.0 years, with normoalbuminuria (UACR < 30 mg/g creatinine) in 7 subjects, microalbuminuria (UACR = 30 - 299mg/g creatinine) in 9 subjects and macroalbuminuria (UACR ³300 mg/g creatinine) in 7 subjects. Albuminuria (assessed by spot microalbumin/creatinine ratio) was significantly correlated with FMD (ρ = -0.45, p = 0.031). However, albuminuria was no longer significantly associated with FMD when controlled for baseline arterial diameter (p = 0.09). Although FMD appeared to be lowest in patients with macroalbuminuria, no significant difference was observed when FMD was evaluated in the 3 albuminuria categories (p = 0.16). No significant correlations were observed between NTMD and albuminuria (ρ = 0.35, p = 0.20). Surprisingly, no significant correlations were observed between FMD and hemoglobin, fetal hemoglobin, lactate dehydrogenase or indirect bilirubin. We observed a strong correlation between albuminuria assessed by spot microalbumin-creatinine ratio and total urinary protein assessed by 24-hour urine collection (ρ = 0.90, p < 0.0001). Furthermore, albuminuria assessed by spot microalbumin-creatinine ratio was strongly correlated with urine aliquots for microalbumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001). Conclusion: In this exploratory study, we found that albuminuria is significantly correlated with FMD in patients with SCD, suggesting that endothelial dysfunction may contribute to the pathogenesis of this complication in SCD. We also find a very strong correlation between spot urine assessments for microalbumin/creatinine ratio and 24-hour urine collections for protein, providing validation for the use of spot urine assessments for the evaluation of albuminuria in patients with SCD. Disclosures Archer: Global Blood Therapeutics: Consultancy.

PAKs are serine/threonine kinases that regulate cytoskeletal dynamics and cell migration. PAK1 is activated by binding to the small EF hand protein, CIB1, or to the Rho GTPases Rac1 or Cdc42. The role of PAK1 in angiogenesis was established based only on in vitro studies and its role in angiogenesis in vivo has never been examined. Here we tested the hypothesis that PAK1 is an essential regulator of ischemic neovascularization (arteriogenesis and angiogenesis) and wound healing using a global PAK1 knockout mouse. Neovascularization was assessed using unilateral hindlimb ischemia. We found that plantar perfusion, limb use and appearance were not significantly different between 6-8 week old PAK1-/- and PAK1+/+ mice throughout the 21-day period following hindlimb ischemia; however a slightly delayed healing was observed in 16 week old PAK1-/- mice. In addition, the wound healing rate, as assessed with an ear punch assay, was unchanged in PAK1-/- mice. Surprisingly, however, we observed a notable increase in PAK2 expression and phosphorylation in ischemic gastrocnemius tissue from PAK1-/- but not PAK1+/+ mice. Furthermore, we observed higher levels of activated ERK2, but not AKT, in ischemic and non-ischemic muscle of PAK1-/- mice upon hindlimb ischemic injury. A group I PAK inhibitor, IPA3, significantly inhibited endothelial cell sprouting from aortic rings in both PAK1-/- and PAK1+/+ mice, implying that PAK2 is a potential contributor to this process. Taken together, our data indicate that while PAK1 has the potential to contribute to neovascularization and wound healing, PAK2 may functionally compensate when PAK1 is deficient.

Abstract 1192 Poster Board I-214 Background: Even though Hodgkin lymphoma (HL) is a curable disease, about, 20-30% patients are either refractory to induction chemotherapy or relapse post treatment. High dose chemotherapy and autologous HCT has been shown to be an effective salvage therapy for patients with relapsed HL. However, relapse continues to occur after auto-HCT, especially in patients with chemoresistant or poor-risk features at relapse. The prognosis of these patients is poor with limited options of treatment. Although allo-HCT offers both cytoreduction and potential graft-versus-tumor effect, its use in relapsed HL has been limited by non-relapse mortality (NRM) and patient co-morbidities induced by numerous prior treatments. To examine the potential impact of allo-HCT on survival and disease outcomes, we performed retrospective analysis of allo-HCT in relapsed/refractory HL to determine if allo-HCT can induce long-term remission in heavily pretreated relapsed HL. Results: Between January 2003 and December 2008, 29 patients with relapsed HL underwent allo-HCT at City of Hope National Medical Center. The median age was 37 (range: 14-63). 20 (69%) patients were chemosensitive at time of allo-HCT. 17 (59%) patients had prior auto-HCT. 16 (55%) patients received matched siblings and 13 (45%) received unrelated donor cells. 20 (69%) patients had prior radiation treatments. The median number of prior regimens was 5 (range: 2-8). 23 (79%) patients underwent a non-myeloablative conditioning regimen while 6 (21%) patients had a myeloablative regimen. 14 (48%) patients received Tacrolimus/Sirolimus as graft versus host disease prophylaxis and 15 (52%) patients received a combination of Cellcept/CsA, Cellcept/CsA/MTX, Tacrolimus/MTX, or Tacrolimus/Sirolimus/MTX. With a median follow up of 31.9 months (range: 9.7-69.1) for surviving patients, the results show: 1) OS 1 year 75.8% (95% CI 61.5, 85.5), 2 year 60.8% (95% CI 48.8, 70.8), Figure 1 2) DFS 1 year 41.4% (95% CI 33.9, 48.7), 2 year 33.9% (95% CI 28.0, 39.8), Figure 2 3) Relapse rate 1 year 50.0% (95% CI 40.8, 60.0), 2 year 59.1% (95% CI 51.2, 67.1) 4) Non-relapse mortality 100 days 6.9% (95% CI 1.9, 22.8), 1 year 14.2% (95% CI 6.4, 29.9), 2 years 16.3% (95% CI 6.4, 29.9) 5) GVHD Grade II-IV aGVHD 51.6%, cGVHD 58.6% 6) Prior radiation showed a trend toward adversely affects OS with a hazard ratio of 4.45 (CI 0.97, 20.47), p=0.056 7) Chemoresistant disease at allo-HCT adversely affecting DFS with a hazard ratio of 2.3 (95% CI 0.9, 5.91), p=0.083 8) The only difference between relapsed group and non-relapse group was the type of donor. Relapse rate is 75% for matched related donor versus 23% for unrelated donor (P=0.005). Conclusion: Allogeneic hematopoietic cell transplantation in heavily pretreated relapsed Hodgkin's lymphoma is feasible, tolerable, and can induce durable clinical remissions. Download : Download high-res image (82KB) Download : Download full-size image Download : Download high-res image (82KB) Download : Download full-size image Disclosures: No relevant conflicts of interest to declare.