Clinical perspectives of emerging pathogens in bleeding disorders.

As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be anticipated, but the processes of zoonotic transmission and genetic selection or modification ensure that plasma-derived products will continue to be subject to infectious concerns. Manufacturers of plasma-derived CFC have addressed the issue of emerging infectious agents by developing recombinant products that limit the need for human plasma during production. Such recombinant products have extended the safety profile of their predecessors by ensuring that all reagents used for cell culture, purification steps, and stabilisation and storage buffers are completely independent of human plasma

The use of live attenuated influenza vaccine (LAIV) in healthcare personnel (HCP): Guidance from the society for healthcare epidemiology of America (SHEA)

Because of the live viral backbone of live attenuated influenza vaccine (LAIV), questions have arisen regarding infection control precautions and restrictions surrounding its use in healthcare personnel (HCP). This document provides guidance from the Society for Healthcare Epidemiology of America regarding use of LAIV in HCP and the infection control precautions that are recommended with its use in this population. Infect Control Hosp Epidemiol 2012;33(10):981-98

Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with α4 nicotinic subunits containing a single point mutation, Leu^(9′) → Ala^(9′) in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization

Revised SHEA Position Paper: Influenza Vaccination of Healthcare Personnel

Executive Summary This document serves as an update and companion piece to the 2005 Society for Healthcare Epidemiology of America (SHEA) Position Paper entitled “Influenza Vaccination of Healthcare Workers and Vaccine Allocation for Healthcare Workers During Vaccine Shortages.” In large part, the discussion about the rationale for influenza vaccination of healthcare personnel (HCP), the strategies designed to improve influenza vaccination rates in this population, and the recommendations made in the 2005 paper still stand. This position paper notes new evidence released since publication of the 2005 paper and strengthens SHEA's position on the importance of influenza vaccination of HCP. This document does not discuss vaccine allocation during times of vaccine shortage, because the 2005 SHEA Position Paper still serves as the Society's official statement on that issue

Report from the American Society of Transplantation on frailty in solid organ transplantation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148387/1/ajt15198_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148387/2/ajt15198.pd

Inherited variation in immune genes and pathways and glioblastoma risk

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel–Haenzel P values = 1 × 10−5 to 4 × 10−3), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion–extravasation–migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk

Antibodies against a Surface Protein of Streptococcus pyogenes Promote a Pathological Inflammatory Response

Streptococcal toxic shock syndrome (STSS) caused by Streptococcus pyogenes is a clinical condition with a high mortality rate despite modern intensive care. A key feature of STSS is excessive plasma leakage leading to hypovolemic hypotension, disturbed microcirculation and multiorgan failure. Previous work has identified a virulence mechanism in STSS where M1 protein of S. pyogenes forms complexes with fibrinogen that activate neutrophils to release heparin-binding protein (HBP), an inducer of vascular leakage. Here, we report a marked inter-individual difference in the response to M1 protein–induced HBP release, a difference found to be related to IgG antibodies directed against the central region of the M1 protein. To elicit massive HBP release, such antibodies need to be part of the M1 protein–fibrinogen complexes. The data add a novel aspect to bacterial pathogenesis where antibodies contribute to the severity of disease by promoting a pathologic inflammatory response

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies