Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice

Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis

A Broadly Implementable Research Course in Phage Discovery and Genomics for First-Year Undergraduate Students

Engaging large numbers of undergraduates in authentic scientific discovery is desirable but difficult to achieve. We have developed a general model in which faculty and teaching assistants from diverse academic institutions are trained to teach a research course for first-year undergraduate students focused on bacteriophage discovery and genomics. The course is situated within a broader scientific context aimed at understanding viral diversity, such that faculty and students are collaborators with established researchers in the field. The Howard Hughes Medical Institute (HHMI) Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) course has been widely implemented and has been taken by over 4,800 students at 73 institutions. We show here that this alliance-sourced model not only substantially advances the field of phage genomics but also stimulates students’ interest in science, positively influences academic achievement, and enhances persistence in science, technology, engineering, and mathematics (STEM) disciplines. Broad application of this model by integrating other research areas with large numbers of early-career undergraduate students has the potential to be transformative in science education and research training

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

A Broadly Implementable Research Course in Phage Discovery and Genomics for First-Year Undergraduate Students

Engaging large numbers of undergraduates in authentic scientific discovery is desirable but difficult to achieve. We have developed a general model in which faculty and teaching assistants from diverse academic institutions are trained to teach a research course for first-year undergraduate students focused on bacteriophage discovery and genomics. The course is situated within a broader scientific context aimed at understanding viral diversity, such that faculty and students are collaborators with established researchers in the field. The Howard Hughes Medical Institute (HHMI) Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) course has been widely implemented and has been taken by over 4,800 students at 73 institutions. We show here that this alliance-sourced model not only substantially advances the field of phage genomics but also stimulates students’ interest in science, positively influences academic achievement, and enhances persistence in science, technology, engineering, and mathematics (STEM) disciplines. Broad application of this model by integrating other research areas with large numbers of early-career undergraduate students has the potential to be transformative in science education and research training

A Broadly Implementable Research Course in Phage Discovery and Genomics for First-Year Undergraduate Students

Engaging large numbers of undergraduates in authentic scientific discovery is desirable but difficult to achieve. We have developed a general model in which faculty and teaching assistants from diverse academic institutions are trained to teach a research course for first-year undergraduate students focused on bacteriophage discovery and genomics. The course is situated within a broader scientific context aimed at understanding viral diversity, such that faculty and students are collaborators with established researchers in the field. The Howard Hughes Medical Institute (HHMI) Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) course has been widely implemented and has been taken by over 4,800 students at 73 institutions. We show here that this alliance-sourced model not only substantially advances the field of phage genomics but also stimulates students’ interest in science, positively influences academic achievement, and enhances persistence in science, technology, engineering, and mathematics (STEM) disciplines. Broad application of this model by integrating other research areas with large numbers of early-career undergraduate students has the potential to be transformative in science education and research training. IMPORTANCE: Engagement of undergraduate students in scientific research at early stages in their careers presents an opportunity to excite students about science, technology, engineering, and mathematics (STEM) disciplines and promote continued interests in these areas. Many excellent course-based undergraduate research experiences have been developed, but scaling these to a broader impact with larger numbers of students is challenging. The Howard Hughes Medical Institute (HHMI) Science Education Alliance Phage Hunting Advancing Genomics and Evolutionary Science (SEA-PHAGES) program takes advantage of the huge size and diversity of the bacteriophage population to engage students in discovery of new viruses, genome annotation, and comparative genomics, with strong impacts on bacteriophage research, increased persistence in STEM fields, and student selfidentification with learning gains, motivation, attitude, and career aspirations

Reconnaissance hydrogeologic investigation of the Defense Waste Processing Facility and vicinity, Savannah River Plant, South Carolina /

Includes bibliographical references (p. 69-74).Mode of access: Internet

I CASE REPORTS Sildenafil Can Increase the Response to Inhaled Nitric Oxide

INHALED nitric oxide (NO) reduces pulmonary artery pressure and increases arterial oxygen tension (Pao2) in many patients with pulmonary hypertension',* and acute respiratory failure.' Not all patients, however, manifest an equally effective r e~p o n s e ,~ and investigators have sought to enhance the physiologic effects of inhaled NO.5 One possible strategy is to increase the availability of cyclic guanosine monophosphate (cGMP), an intracellular messenger of NO, by blocking its degradation by cGMP-specific phosphodiesterase (PDE-5). Dipyridamole, a PDE-5 inhibitor, has been used in combination with inhaled NO to decrease pulmonary artery pressure in patients with pulmonary hypertension of various etiologies."~' However, the results of these small series have been inconsistent, possibly because of the multiple pharmacologic actions of this drug. ' Sildenafil is a newer PDE-5 inhibitor used in the management of erectile dysfunction" that acts by increasing the local availability of endogenous NO. Sildenafil has a higher PDE-5 selectivity than dipyridamole and a predict- [email protected] able gastrointestinal absorption,9 which make it an attractive complement to inhaled NO for the management of acute pulmonary hypertension in critically ill patients. Rather than simply adding the effect of a second vasodilator, sildenafil may enhance the selective pulmonary vasodilator effect of inhaled NO by making more messenger cGMP available locally. For example, the administration of sildenafil was recently reported to attenuate the acute pullnonary hypertension associated with the withdrawal of inhaled NO in two infants treated for pulmonary hypertension. lo We report the case of a patient with severe hypoxemia caused by pulmonary hypertension and venous blood shunting through a patent foramen ovale (PFO) that was reversed using inhaled NO in association with systemic sildenafil administration. Case Report A 52-yr-old woman with severe interstitial piilmonary fibrosis, Crohn disease, and previous pulmonary thromboembolism developed acute respiratory failure while being evaluated for a living related-donor lung transplant. The likely cause of her exacerbation was infectious. Chest radiograms showed her chronic diffuse pattern of pulmonary infiltrates and a new parenchymal consolidation iit the right lung base. Gram stains of bronchial secretions showed abundant neutrophils without predominant organisms. She was administered broad-spectrum antibiotics, her trachea was intubated, and mechanical ventilation was begun. A norepinephrine infusion (1-3 pg/min) was used to treat hypotension. Pulmonaiy artery (PA) catheterization revealed a niran PA pressure of 50 mmHg, a cardiac output of 4.8 I/min with a stroke volume of 47 ml, a pulmonary artery occlusion pressure of 14 nimHg, and a central venous pressure of 9 mmHg. An echocardiogram showed normal left ventricular function, mild right ventricular (RV) dilation, mild tricuspid regurgitation, and a PFO. The latter was not present in a study performed a year earlier, when the systolic RV pressure had been estimated at 41 mmHg. To confirm the presence of a hemodynamically significant shunt, an indocyanine dilution study was performed, which showed a pattern of early dye recirculation compatible with a right-to-left intracardiac shunt

Surgical Care and Career Opportunities in a Changing Practice Paradigm

The American health care system is changing rapidly and radically. The Patient Protection and Affordable Care Act (P.L.111-148) was set in motion by an unsustainable growth in medical expenditures that eventually consumed 16% of our gross domestic product or nearly $3 million annually. Left unattended, this would nearly bankrupt our economy.1 In addition, the Affordable Care Act will allow the enrollment of nearly 20 to 30 million currently uninsured Americans into expanded Medicaid and Medicare programs. Coverage to many additional patients will become more marketplace driven through the establishment of health insurance exchanges.2 These expanded programs, in concert with the rapid increase of Americans that are older than 65 year of age, and the now 13-year freeze of Medicare support for graduate medical education, are expected to produce a projected shortfall of some 91,000 physicians by 2020, including a nearly 7% decrease in such critical surgical subspecialties as urology, thoracic surgery, and rural general surgery.3 and