Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice.

Background: Innate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown. Methods: IAV infection was analyzed in global (Par2-/- ), myeloid (Par2fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl ;SPCCre+) mice and their respective controls (Par2+/+ and Par2fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice. Results: After IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl . In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2+/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2+/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice. Conclusion: Global Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology.

Summary of recommendations from the National Institute for Occupational Safety and Health Fire Fighter Fatality Investigation and Prevention Program, 2006-2014.

INTRODUCTION: The NIOSH Fire Fighter Fatality Investigation and Prevention Program (FFFIPP) conducts independent investigations of selected fire fighter line-of-duty deaths (LODD) and offers recommendations to prevent similar deaths. The purpose of the current study was to provide information on more recent FFFIPP recommendations and to determine if recommendations have changed over time. METHODS: Fatality investigations completed from 2006 to 2014 were selected for this study with recommendations being assigned into twelve major categories when possible. The most frequently occurring recommendations were then rank ordered overall and then by medical and traumatic fire fighter LODD. RESULTS: There were 1,067 total recommendations made in the published fire fighter investigative reports for both medical and trauma-related fire fighter fatalities for the period 2006-2014. Of these, 784 (73%) could be placed within one of the 12 categories noted previously. The top 10 recommendation categories overall were: 1. Medical screening, 2. Fitness and wellness program, 3. Training, 4. Medical clearance, 5. Standard Operating Procedures/Standard Operating Guidelines (SOPs/SOGs), 6. Incident command, 7. Strategy and tactics, 8. Communications, 9. Personal protective equipment and 10. Staffing. CONCLUSIONS: The leading recommendations from the NIOSH FFFIPP medical investigations between 2006 and 2014 did not change compared to those made between 1998 and 2005, with the exception of the addition of "medical clearance for duty". There were changes for the traumatic injury leading recommendations for 2006-2014, with the major change being "training", which was the leading FFFIPP recommendation for traumatic injuries for this time period. Practical applications: The intent of the FFFIPP is to influence fire departments and fire fighters to critically assess and evaluate situations/circumstances similar to those identified by NIOSH investigations and implement the recommendations offered to prevent additional fire fighter fatalities.

Efficiency and usability of a near field communication-enabled tablet for medication administration.

BACKGROUND: Barcode-based technology coupled with the electronic medication administration record (e-MAR) reduces medication errors and potential adverse drug events (ADEs). However, many current barcode-enabled medication administration (BCMA) systems are difficult to maneuver and often require multiple barcode scans. We developed a prototype, next generation near field communication-enabled medication administration (NFCMA) system using a tablet. OBJECTIVE: We compared the efficiency and usability of the prototype NFCMA system with the traditional BCMA system. METHODS: We used a mixed-methods design using a randomized observational cross-over study, a survey, and one-on-one interviews to compare the prototype NFCMA system with a traditional BCMA system. The study took place at an academic medical simulation center. Twenty nurses with BCMA experience participated in two simulated patient medication administration scenarios: one using the BCMA system, and the other using the prototype NFCMA system. We collected overall scenario completion time and number of medication scanning attempts per scenario, and compared those using paired t tests. We also collected participant feedback on the prototype NFCMA system using the modified International Business Machines (IBM) Post-Study System Usability Questionnaire (PSSUQ) and a semistructured interview. We performed descriptive statistics on participant characteristics and responses to the IBM PSSUQ. Interview data was analyzed using content analysis with a qualitative description approach to review and categorize feedback from participants. RESULTS: Mean total time to complete the scenarios using the NFCMA and the BCMA systems was 202 seconds and 182 seconds, respectively (P=.09). Mean scan attempts with the NFCMA was 7.6 attempts compared with 6.5 attempts with the BCMA system (P=.12). In the usability survey, 95% (19/20) of participants agreed that the prototype NFCMA system was easy to use and easy to learn, with a pleasant interface. Participants expressed interest in using the NFCMA tablet in the hospital; suggestions focused on implementation issues, such as storage of the mobile devices and infection control methods. CONCLUSIONS: The NFCMA system had similar efficiency to the BCMA system in a simulated scenario. The prototype NFCMA system was well received by nurses and offers promise to improve nurse medication administration efficiency.

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts.

The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.

The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1.

A thiodipeptide carrier system is shown to be effective at enabling a range of covalently bound molecules, including benzyl, benzoyl and ibuprofen conjugates, to be transported via the intestinal peptide transporter PepT1, demonstrating its potential as a rational drug delivery target.

The leadership team: complementary strengths or conflicting agendas?

Senior leadership teams whose members play complementary roles have been chronicled as far back as Homer's account of the Trojan War: Although King Agamemnon commanded the Greek army, Achilles, Odysseus, and Nestor each played a distinct role in defeating Troy. Today, complementary-leadership structures are common and, in some cases, even institutionalized. Think of a CEO concerned mainly with external issues and a COO who focuses internally. The authors describe four kinds of complementarity: task, expertise, cognitive, and role. The two top executives at the software company Adobe Systems, for example, represent the second kind. As CEO, Bruce Chizen draws on his sales and marketing knowledge, while COO Shantanu Narayen adds his engineering and product development expertise. Roberto Goizueta, formerly the CEO of Coca-Cola, and Douglas Ivester, his COO (who later became CEO), were famous examples of the fourth type: Goizueta, the diplomat, maintained good relations with external stakeholders; Ivester, the warrior, drove the company to defeat the competition. Bringing together two or more people with complementary strengths can compensate for the natural limitations of each. But with the benefits comes the risk of confusion, disagreement about priorities, and turf battles. Leadership succession also presents substantial challenges, especially when a COO or president who has worked in a complementary fashion with the CEO moves into the top role. An organization's board of directors and CEO can manage the risks by fostering a shared vision, common incentives, communication, and trust. They can also ensure smooth succession processes in various ways, such as brokering a gradual transfer of responsibilities or allowing the CEO and the COO to share duties as long as they maintain the logic of complementarity.

Factor VIII A1 domain residues 97-105 represent a light chain-interactive site.

Results from a recent study on subunit association in factor VIIIa indicated that the A1 and A3C1C2 domains contribute approximately 90% of the interchain binding energy in factor VIII and that A3 domain residues 1954-1961 participate in the interaction with A1 domain (Ansong, C., and Fay, P. J. (2005) Biochemistry 44, 8850-8857). Enhanced trypsin-accessibility at four sites within residues 89-142 in free A1 compared with that of A3C1C2-bound A1, as determined by mass spectrometry, suggested that residues within this region are interactive with the A3C1C2 domains. A synthetic peptide to A1 domain residues 97-105, predicted to be A3 domain-interactive from molecular modeling, inhibited the formation of a functional A1/A3C1C2 dimer (apparent K(i) = 0.64 +/- 0.21 microM) and reduced the efficiency of energy transfer between a fluorescein-labeled A1 subunit and an acrylodan-labeled A3C1C2 subunit. B-domainless factor VIII point mutants, His99Ala, Val101Ala, and Gly102Ser, exhibited reduced specific activity (32%, 51%, and 45%, respectively) compared with that of factor VIII wild type. Furthermore, the activity of factor VIII His99Ala was less stable (t(1/2) = 2.3 +/- 0.2 min) compared with that of factor VIII wild type (t(1/)(2) = 6.2 +/- 0.7 min) following heat denaturation analysis. This reduced stability appeared to result from an approximately 40% increase in the dissociation rate for the mutant factor VIII heterodimer as judged by solid-phase binding assays. These results indicate that residues within segment 97-105 of the A1 domain interact with residues within the A3C1C2 domains of the light chain and contribute to the interface in the factor VIII heterodimer.

Second in command: the misunderstood role of the chief operating officer.

Asking the question,"What makes a great COO?" is akin to asking "What makes a great candidate for U.S. vice president?" It all depends on the first name on the ticket--the CEO. New research sheds light on this most contingent, and most mysterious, of C-suite jobs. After in-depth conversations with dozens of executives who have held the position and with CEOs who have worked with COOs, the authors have concluded that different views of the COO role arise from the different motives behind creating the position in the first place. There are seven basic reasons why companies decide to hire a COO: to implement the CEO's strategy; to lead a particular initiative, such as a turnaround; to mentor a young, inexperienced CEO; to complement the strengths or make up for the weaknesses of the CEO; to provide a partner to the CEO; to test out a possible successor; or to stave off the defection of a highly valuable executive, particularly to a rival. This tremendous variation implies that there is no standard set of great COO attributes, which makes finding suitable candidates difficult for companies and recruiters alike. Still, certain common success factors came up consistently in the interviews, the most important being building a high level of trust between CEO and COO. Trust comes from meeting obligations on both sides: The COO must truly support the CEO's vision; keep ego in check; and exhibit strong execution, coaching, and coordination skills. The CEO must communicate faithfully, grant real authority and decision rights, and not stymie the COO's career. It's surprising that COOs are not more common. They would be, the authors contend, if there were less confusion surrounding the role. As we continue to demystify that role, more companies will benefit from more effective leadership.

pH-dependent association of factor VIII chains: enhancement of affinity at physiological pH by Cu2+.

Reconstitution of factor VIII from isolated heavy chain (HC) and light chain (LC) shows pH-dependence. In the presence of Ca2+, up to 80% of native factor VIII activity was recovered over a wide range of pH. In contrast, affinity of HC and LC was maximal at pH 6.5-6.75 (Kd approximately 4 nM), whereas a Kd approximately 20 nM was observed at physiological pH (7.25). The effect of Cu2+ (0.5 microM total Cu2+) on maximal activity regenerated was negligible at pH 6.25-8.0. However, this level of Cu2+ increased the inter-chain affinity by approximately 5-fold at pH 7.25. This effect resulted from an approximately 1.5-fold increased association rate constant (k(on)) and an approximately 3-fold reduced dissociation rate constant (k(off)). High affinity (Kd=5.3 fM) of the factor VIII heterodimer for Cu2+ was estimated by increases in cofactor activity. No significant increase in inter-chain affinity was observed when either isolated chain was reacted with Cu2+ followed by addition of the complementary chain. Together, these results suggest that the protonation state of specific residues modulates inter-chain affinity. Furthermore, copper ion contributes to the maintenance of the heterodimer at physiologic pH by a mechanism consistent with bridging the two chains.