Plasma kininogen and kininogen fragments are biomarkers of progressive renal decline in type-1 diabetes

The ability of microalbuminuria to predict early progressive renal function decline in type-1 diabetic patients has been questioned. To resolve this, we determined the plasma proteome differences between microalbuminuric patients with type-1 diabetes and stable renal function (controls) and patients at risk for early progressive renal function decline (cases) and asked whether these differences have value as surrogate biomarkers. Mass spectrometry was used to analyze small (less than 3 kDa) plasma peptides isolated from well-matched case and control plasma obtained at the beginning of an 8-12 year follow-up period. Spearman analysis of plasma peptide abundance and the rate of renal function decline during follow-up identified seven masses with a significant negative correlation with early progressive renal function decline. Tandem mass spectrometry identified three fragments of high molecular weight kininogen. Increased plasma high molecular weight kininogen in the cases was confirmed by immunoblot. One peptide, des-Arg9-BK(1-8), induced Erk1/2 phosphorylation when added apically to two proximal tubular cell lines grown on permeable inserts. Thus, we have identified plasma protein fragments, some of which have biological activity with moderate to strong correlation, with early progressive renal function decline in microalbuminuric patients with type-1 diabetes. Other peptides are candidates for validation as candidate biomarkers of diabetes-associated renal dysfunction

The same but different: Understanding entrepreneurial behaviour in disadvantaged communities

While entrepreneurship is widely viewed as being equally accessible in all contexts, it could be questioned if potential or nascent entrepreneurs from minority and disadvantaged communities experience entrepreneurship in a similar manner to the mainstream population. This chapter examines immigrant, people with disability, youth, gay and unemployed communities to explore how their entrepreneurial behaviour might differ from the practices of mainstream entrepreneurs. What emerges is that marginalised communities can frequently find it difficult to divorce business from social living. This can have both positive and negative connotations for an entrepreneur, plus they face additional and distinctive challenges that mainstream entrepreneurs do not experience. The chapter concludes by proposing a novel ‘funnel approach’ that policymakers might adopt when seeking to introduce initiatives targeted at these disadvantaged communities

Book reviews

<p><span>Title:</span></p><p>(1) The Library and Information Professional’s Guide to the Internet. (2) Reinvention of the Public Library for the 21st Century. (3) Public Library Collection Development in the Information Age. (4) Making Sense of Journals in the Life Science: From Specialty Origins to Contemporary Assortment. (5) The Holocaust: Memories, Research, Reference. (6) How to Index Your Local Newspaper Using WordPerfect or Microsoft Word for Windows. (7) Effective Utilization and Management of Emerging Information Technologies. (8) Information Technology and Organizations: Challenges of New Technologies. (9) Facilities Planning for School Media and Technology Centers. (10) Libraries Without Walls 2: The Delivery of Library Services to Distance Users. (11) New International Directions in HIV Prevention for Gay and Bisexual Men. (12) Soaring to Excellence Videos: Tools of Our Trade III: Books, the Internet, and Beyond.</p><p>Author:</p><p>(1)Reviewed by Teresa Abdel-Motey. (2)Review by Claire Urfels. (3)Reviewed by Dr. Ketty Rodriguez. (4)Reviewed by Jackie Mardikian. (5)Reviewed by John A. Drobnicki.(6)Reviewed by Dr. Virgil Diodato. (7)Reviewed by Dr. Lisa M. Covi. (8)Reviewed by Tom Zillner. (9)Reviewed by Dr. W. Bernard Lukenbill. (10)Reviewed by Dr. Elizabeth Buchanan. (11)Reviewed by Aisha White. (12)Reviewed by Phyllis Tragash</p

Defining Central Line-Associated Blood Stream Infections Following Hematopoietic Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

Abstract Abstract 3042 Central line-associated blood stream infection (CLABSI) surveillance is increasingly utilized as an objective measure of quality of care provided by individual hospitals. CLABSI is defined by the National Healthcare Safety Network (NHSN) as a primary bloodstream infection (BSI) in a patient with a central line within the 48-hour period before the development of the BSI (NHSN CLABSI). This traditional definition of CLABSI includes pathogens better described as hospital-acquired blood stream infections (HABSI), such as enteric gram-negative bacilli (GNB) and streptococcus viridans - pathogens inherently more common in patients undergoing hematopoietic cell transplantation (HCT) due to the resultant neutropenia and disruption of mucosal barriers, and unlikely to be line-related. To avoid this misclassification, we have developed a modified CLABSI definition (MCLABSI) which excludes HABSI (DiGiorgio, Infect Control Hosp Epidemiol. 33: 865–8, 2012). MCLABSI includes all of the pathogens under the NHSN definition of CLABSI except Viridans group streptococci species in patients with mucositis, and Enterococcus, Enterobacteriaceae, or Candida species in patients with neutropenia or graft-vs-host disease of the gut. We compared the incidence of CLABSI and its impact on survival using both definitions in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients undergoing SCT. AML and MDS patients undergoing HCT between August 2009 and December 2011 were identified from the Cleveland Clinic Unified Transplant Database, and NHSN CLABSI and MCLABSI rates were obtained from the infection control database. CLABSI incidence was estimated using Kaplan-Meier method, and risk factors for mortality were identified using stepwise Cox proportional hazards analyses. Of the 73 patients identified (median age 52, range 16–70), 48 were male, 44 had AML, and 29 MDS. Patients received a median of 2 prior chemotherapy regimens (range 0–6), 3 had prior radiation, and 6 had prior transplant. 54 underwent myeloablative and 19 reduced-intensity preparative regimens; stem cell source included bone marrow (BM, n=34), peripheral stem cells (PSC, n=24), and cord blood cells (CBC, n=15). The median CD34+ count was 2.42 × 106/kg and median time to neutrophil recovery (absolute neutrophil count > 500/μL) was 14 days (range 6–24) with BM/PSC and 28 days (range 19–77) with CBC. Most (88%) had mucositis, including 17 (28%) with grade 3 or 4. Twenty-three (31.5%) developed NHSN CLABSI, compared to 8 (11.0%) who developed MCLABSI following HCT, of whom 16 (69.6%) and 7 (87.5%) died, respectively. The majority (16/23) of NHSN CLABSI occurred within 14 days (median 9 days, range 2–211 days) of HCT (Figure), varying from a median of 5 days (range 2–12 days) for CBC and 78 days for BM/PSC (range 7–211 days, p<.001). Pathogens in NHSN CLABSI included 11 enteric Gram-negative bacilli, 7 Streptococcus viridans group, 6 enterococcus (3 vancomycin resistant), 5 Staphylococcus (3 methicillin resistant), 2 fungal species, 2 Gram-positive bacilli, 1 Pseudomonas, 1 other Streptococcus species, and 1 Stenotrophomonas. MCLABSI occurred a median of 12 days (range 5–176 days) from HCT (Figure), 7 days for CBC (range 5–12 days) compared to 77 days (range 13–176 days) for BM/PSC (p<.001). Pathogens isolated in MCLABSI included 5 Staphylococcal species (3 MRSE), 2 Streptococcus viridans group, 2 GPB, 1 VRE, and 1 Pseudomonas. 4 NHSN CLABSI and 2 MCLABSI were polymicrobial, and 4 patients had recurrent CLABSI (all of whom died, including 3 MCLABSI). When NHSN CLABSI was analyzed as a time-varying covariate in univariable analysis, it was associated with an increased risk of mortality (HR 3.72, 95% CI 1.88 – 7.36, p<.001), as was MCLABSI (HR 2.96, CI 1.27–6.89, p=.012). CLABSI remained a significant risk factor for mortality in multivariable analysis, by both the NHSN (HR 7.14, CI 3.31 – 15.31, p<.001) and MCLABSI (HR 6.44, CI 2.28–18.18, p<.001) definitions. CLABSI is a common complication in AML and MDS patients undergoing SCT, and is associated with decreased survival. CLABSI is identified less commonly with the exclusion of HABSI in the modified definition, which more precisely identifies patients with BSI related to their central lines. The distinction between these definitions is important to guide preventative infectious control measures, particularly given CLABSI's role as a quality measure influencing reimbursement. Disclosures: Hill: Teva Pharmaceuticals: Honoraria, Speakers Bureau

Defining Incidence, Risk Factors, and Impact on Survival of Central Line-Associated Blood Stream Infections Following Hematopoietic Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome

AbstractCentral line-associated blood stream infections (CLABSI) commonly complicate the care of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic stem cell transplantation (HCT). We developed a modified CLABSI (MCLABSI) definition that attempts to exclude pathogens usually acquired because of disruption of mucosal barriers during the vulnerable neutropenic period following HCT that are generally included under the original definition (OCLABSI). We conducted a retrospective study of all AML and MDS patients undergoing HCT between August 2009 and December 2011 at the Cleveland Clinic (N = 73), identifying both OCLABSI and MCLABSI incidence. The median age at transplantation was 52 years (range, 16 to 70); 34 had a high (≥3) HCT comorbidity index (HCT-CI); 34 received bone marrow (BM), 24 received peripheral stem cells (PSC), and 15 received umbilical cord blood cells (UCB). Among these 73 patients, 23 (31.5%) developed OCLABSI, of whom 16 (69.6%) died, and 8 (11%) developed MCLABSI, of whom 7 (87.5%) died. OCLABSI was diagnosed a median of 9 days from HCT: 5 days (range, 2 to 12) for UCB and 78 days (range, 7 to 211) for BM/PSC (P < .001). MCLABSI occurred a median of 12 days from HCT, with similar earlier UCB and later BM/PSC diagnosis (P = .030). Risk factors for OCLABSI in univariate analysis included CBC (P < .001), human leukocyte antigen (HLA)-mismatch (P = .005), low CD34+ count (P = .007), low total nucleated cell dose (P = .016), and non-Caucasian race (P = .017). Risk factors for OCLABSI in multivariable analysis were UCB (P < .001) and high HCT-CI (P = .002). There was a significant increase in mortality for both OCLABSI (hazard ratio, 7.14; CI, 3.31 to 15.37; P < .001) and MCLABSI (hazard ratio, 6.44; CI, 2.28 to 18.18; P < .001). CLABSI is common and associated with high mortality in AML and MDS patients undergoing HCT, especially in UCB recipients and those with high HCT-CI. We propose the MCLABSI definition to replace the OCLABSI definition, given its greater precision for identifying preventable infection in HCT patients

Central Line-Associated Blood Stream Infections Following Hematopoietic Cell Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: Incidence, Risk Factors, and Impact On Survival

Abstract Abstract 4481 Patients undergoing hematopoietic cell transplantation (HCT) require central venous access during treatment, predisposing this inherently susceptible population to infection. Central line-associated blood stream infection (CLABSI) is defined by the National Healthcare Safety Network as a primary bloodstream infection (BSI) in a patient with a central line within the 48-hour period before the development of the BSI. CLABSI surveillance is being increasingly used as an objective measure of quality of care delivered at individual hospitals. The Centers for Disease Control and Prevention have developed guidelines for the insertion, surveillance, and timely removal of these lines to prevent CLABSI, of which approximately 10% are fatal, and the Centers for Medicare & Medicaid will adjust reimbursement for CLABSI. The incidence, risk factors, and impact on survival of CLABSI in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients undergoing HCT has not been reported. AML or MDS patients undergoing HCT between August 2009 and December 2011 were identified from the Cleveland Clinic Unified Transplant Database, and occurrence of CLABSI was determined from the infection control database. Variables analyzed included occurrence of CLABSI, as well as patient demographics, disease type, prior treatment, HCT comorbidity index, transplant type/HLA-match, CD34+ count, and time to neutrophil recovery (absolute neutrophil count >500). CLABSI incidence was estimated using Kaplan-Meier method, and univariable and multivariable risk factors were identified by Cox proportional hazards analyses. Of the 73 patients identified, 48 were male; 68 were Caucasian; 44 had AML, and 29 MDS. The median age at transplant was 52 (range 16–70), and 39 had a low to intermediate HCT comorbidity index (0–2), while 34 had a high index (≥3). Patients received a median of 2 prior chemotherapy regimens (range 0–6), 3 had prior radiation, and 6 had prior transplant. Preparative regimen was myeloablative (n=54) or reduced-intensity (n=19); 34 received bone marrow (BM), 24 peripheral stem cells (PSC), and 15 cord blood cells (CBC). The median CD34+ count was 2.42 × 106/kg and median time to neutrophil recovery was 14 days (range 6–24) with BM/PSC compared to 28 days with CBC (range 19–77). Among these 73 patients, 23 (31.5%) developed CLABSI, of whom 16 (69.6%) died. The majority (16/23) of CLABSI occurred within 14 days (median 9 days, range 2–211 days) from HCT (Figure 1), but timing of CLABSI was highly associated with cell source: median of 5 days (range 2–12 days) for CBC and 78 days (range 7–211 days) for BM/PSC (p<.001). Etiologies of CLABSI included 11 enteric Gram-negative bacilli, 7 Streptococcus viridans group, 6 enterococcus (3 vancomycin resistant), 5 Staphylococcus (3 methicillin resistant), 2 fungal species, 2 Gram-positive bacilli, 1 Pseudomonas, 1 other Streptococcus species, and 1 Stenotrophomonas. 4 patients had polymicrobial infections, and 5 (all of whom died) had more than one separately documented CLABSI. Univariable risk factors for CLABSI included cord blood transplant (p<.001), HLA-mismatch (p=.005), low CD34+ count (p=.007), and non-Caucasian race (p=.017). Risk factors for CLABSI in multivariable analysis were CBC (p<.001) and high comorbidity index (p=.002); 4 distinct populations of patients were created based on this data, ranging from a high comorbidity index/cord blood cohort to a low to intermediate co-morbidity index/marrow cohort (Figure 2). When CLABSI was analyzed as a time-varying covariate in univariable analyses, it was associated with an increased risk of mortality (HR 3.17, 95% CI 1.61–6.22, p<.001). Multivariable risk factors for mortality included CLABSI (HR 7.14, CI 3.31 – 15.37, p<.001), MDS diagnosis (HR 5.21, CI 2.40–11.33, p<.001), and age (HR 1.81, CI 1.21–2.71, p=.004). CLABSI is a common complication in AML and MDS patients undergoing HCT, and is associated with remarkably decreased survival. Cord blood, perhaps related to the extent and duration of severe immune deficiency, and high HCT comorbidity index place patients at higher risk of CLABSI. Efforts to identify patients at high risk of CLABSI, careful adherence to preventative infectious control measures, and design of methods to enhance immune reconstitution post-transplant in the high risk population could improve outcome in a substantial portion of patients. Disclosures: No relevant conflicts of interest to declare