Systematicity and Skepticism

The fact that philosophy is systematic—that philosophical issues are thoroughly interconnected—was a commonplace among nineteenth century idealists, then neglected by analytic philosophers throughout much of the twentieth century, and has now finally started to get some renewed attention. But other than calling attention to the fact, few philosophers have tried to say what it consists in, or what its implications are. I argue that the systematicity of philosophy has disastrous epistemological implications. In particular, it implies philosophical skepticism: philosophers are rationally prohibited from believing any philosophical thesis. The argument goes by way of a new principle that connects inquiry with what is rational to believe. I conclude with a discussion of the relationship between my argument and other, more well-trodden arguments for philosophical skepticism

Crescas, Hard Determinism, and the Need for a Torah

All adherents of hard determinism face a number of steep challenges; those with traditional religious commitments face still further challenges. In this paper I treat one such further challenge. The challenge, in brief, is that given hard determinism, it’s very difficult to say why God couldn’t, and why God wouldn’t, just immediately and directly realize the final end of creation. I  develop the challenge, and a number of solutions, through the work of the medieval Jewish philosopher, Hasdai Crescas. After arguing that Crescas is indeed a hard determinist, and showing that he forecloses all the easy solutions to our challenge, I piece together from his work two solutions. They both start from the assumption that the purpose of creation is creaturely love of God. Each then lays down a constraint on proper love of God, which can be satisfied only if God demands of us to realize some state of affairs other than loving Him

Improving children’s and their visitors’ hand hygiene compliance

Background: Numerous interventions have tried to improve healthcare workers' hand hygiene compliance, however little attention has been paid to children's and their visitors’ compliance.Aim: To increase children’s and visitors’ compliance using interactive educational interventions. Methods: This was an observational study of hand hygiene compliance before and after the introduction of educational interventions. Qualitative data in the form of Questionnaires and interviews was obtained.Findings: Hand hygiene compliance increased by 21.4% (P [less than] 0.001) following the educational interventions, with children's compliance reaching 40.8% and visitors' being 50.8%. Compliance varied depending on which of the five moments of hygiene was observed (P [less than] 0.001), with the highest compliance was ‘after body fluid exposure’ (96%). Responses from questionnaires showed educational interventions raised awareness of the importance of hand hygiene (69%, 57%) compared to those who hadn't experienced the educational intervention (50%). Conclusion: Educational interventions may result in a significant increase in children's and visitors' hand hygiene (P [less than] 0.001)

High-throughput smFRET analysis of freely diffusing nucleic acid molecules and associated proteins

Single-molecule Förster resonance energy transfer (smFRET) is a powerful technique for nanometer-scale studies of single molecules. Solution-based smFRET, in particular, can be used to study equilibrium intra- and intermolecular conformations, binding/unbinding events and conformational changes under biologically relevant conditions without ensemble averaging. However, single-spot smFRET measurements in solution are slow. Here, we detail a high-throughput smFRET approach that extends the traditional single-spot confocal geometry to a multispot one. The excitation spots are optically conjugated to two custom silicon single photon avalanche diode (SPAD) arrays. Two-color excitation is implemented using a periodic acceptor excitation (PAX), allowing distinguishing between singly- and doubly-labeled molecules. We demonstrate the ability of this setup to rapidly and accurately determine FRET efficiencies and population stoichiometries by pooling the data collected independently from the multiple spots. We also show how the high throughput of this approach can be used o increase the temporal resolution of single-molecule FRET population characterization from minutes to seconds. Combined with microfluidics, this high-throughput approach will enable simple real-time kinetic studies as well as powerful molecular screening applications

One Year Out: An Assessment of DADT Repeal’s Impact on Military Readiness

Prior to the repeal of “don’t ask, don’t tell” (DADT) on September 20, 2011, many observers predicted that allowing lesbian, gay and bisexual (LGB) troops to serve openly would harm the military. This study is the first scholarly effort to assess the accuracy of such predictions about the impact of DADT repeal on military readiness. Our conclusions are based on a consideration of all of the evidence that was available to us at the time our research was conducted, the half- year period starting six months after repeal and concluding at the one-year mark. We sought to maximize the likelihood of identifying evidence of damage caused by repeal by pursuing ten separate research strategies, each of which was designed to uncover data indicating that repeal has undermined the military. Our research strategies included outreach to 553 generals and admirals who predicted that repeal would undermine the military, to all major activists and expert opponents of DADT repeal and to 18 watchdog organizations, including opponents and advocates of repeal, who are known for their ability to monitor Pentagon operations. In addition, we conducted in-depth interviews with 18 scholars and practitioners and 62 active-duty heterosexual, lesbian, gay and bisexual troops from every service branch, as well as on-site field observations of four military units. We analyzed relevant media articles published during the research period, administered two surveys and conducted secondary source analysis of surveys independently administered by outside organizations. Our vigorous effort to collect data from opponents of DADT repeal, including anti-repeal generals and admirals, activists, academic experts, service members and watchdog organizations, should sustain confidence in the validity and impartiality of our findings. Our study team includes distinguished scholars from the US Military Academy, US Air Force Academy, US Naval Academy and US Marine Corps War College, as well as scholars with internationally recognized expertise on the issue of gays in the military. Several members advised the Pentagon’s 2010 DADT working group, and one member led the team that drafted the Defense Department’s plan for implementing DADT repeal

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation.

Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.)

High-throughput smFRET analysis of freely diffusing nucleic acid molecules and associated proteins

Single-molecule Förster resonance energy transfer (smFRET) is a powerful technique for nanometer-scale studies of single molecules. Solution-based smFRET, in particular, can be used to study equilibrium intra- and intermolecular conformations, binding/unbinding events and conformational changes under biologically relevant conditions without ensemble averaging. However, single-spot smFRET measurements in solution are slow. Here, we detail a high-throughput smFRET approach that extends the traditional single-spot confocal geometry to a multispot one. The excitation spots are optically conjugated to two custom silicon single photon avalanche diode (SPAD) arrays. Two-color excitation is implemented using a periodic acceptor excitation (PAX), allowing distinguishing between singly- and doubly-labeled molecules. We demonstrate the ability of this setup to rapidly and accurately determine FRET efficiencies and population stoichiometries by pooling the data collected independently from the multiple spots. We also show how the high throughput of this approach can be used o increase the temporal resolution of single-molecule FRET population characterization from minutes to seconds. Combined with microfluidics, this high-throughput approach will enable simple real-time kinetic studies as well as powerful molecular screening applications

A Bayesian Network Driven Approach to Model the Transcriptional Response to Nitric Oxide in Saccharomyces cerevisiae

The transcriptional response to exogenously supplied nitric oxide in Saccharomyces cerevisiae was modeled using an integrated framework of Bayesian network learning and experimental feedback. A Bayesian network learning algorithm was used to generate network models of transcriptional output, followed by model verification and revision through experimentation. Using this framework, we generated a network model of the yeast transcriptional response to nitric oxide and a panel of other environmental signals. We discovered two environmental triggers, the diauxic shift and glucose repression, that affected the observed transcriptional profile. The computational method predicted the transcriptional control of yeast flavohemoglobin YHB1 by glucose repression, which was subsequently experimentally verified. A freely available software application, ExpressionNet, was developed to derive Bayesian network models from a combination of gene expression profile clusters, genetic information and experimental conditions