Virion glycosylation influences mycobacteriophage immune recognition.

Glycosylation of eukaryotic virus particles is common and influences their uptake, trafficking, and immune recognition. In contrast, glycosylation of bacteriophage particles has not been reported; phage virions typically do not enter the cytoplasm upon infection, and they do not generally inhabit eukaryotic systems. We show here that several genomically distinct phages of Mycobacteria are modified with glycans attached to the C terminus of capsid and tail tube protein subunits. These O-linked glycans influence antibody production and recognition, shielding viral particles from antibody binding and reducing production of neutralizing antibodies. Glycosylation is mediated by phage-encoded glycosyltransferases, and genomic analysis suggests that they are relatively common among mycobacteriophages. Putative glycosyltransferases are also encoded by some Gordonia and Streptomyces phages, but there is little evidence of glycosylation among the broader phage population. The immune response to glycosylated phage virions in mice suggests that glycosylation may be an advantageous property for phage therapy of Mycobacterium infections.

National Institutes of Health research project grant inflation 1998 to 2021.

We analyzed changes in total costs for National Institutes of Health (NIH) awarded Research Project Grants (RPGs) issued from fiscal years (FYs) 1998 to 2021 . Costs are measured in 'nominal' terms, meaning exactly as stated, or in 'real' terms, meaning after adjustment for inflation. The NIH uses a data-driven price index - the Biomedical Research and Development Price Index (BRDPI) - to account for inflation, enabling assessment of changes in real (that is, BRDPI-adjusted) costs over time. The BRDPI was higher than the general inflation rate from FY1998 until FY2012; since then the BRDPI has been similar to the general inflation rate likely due to caps on senior faculty salary support. Despite increases in nominal costs, recent years have seen increases in the absolute numbers of RPG and R01 awards. Real average and median RPG costs increased during the NIH-doubling (FY1998 to FY2003), decreased after the doubling and have remained relatively stable since. Of note, though, the degree of variation of RPG costs has changed over time, with more marked extremes observed on both higher and lower levels of cost. On both ends of the cost spectrum, the agency is funding a greater proportion of solicited projects, with nearly half of RPG money going toward solicited projects. After adjusting for confounders, we find no independent association of time with BRDPI-adjusted costs; in other words, changes in real costs are largely explained by changes in the composition of the NIH-grant portfolio.

Early administration of COVID-19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy.

The efficacy of COVID-19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID-19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7- and 28-day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non-intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7- and 28-day death rates, respectively, compared to those non-intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non-intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

Inequalities in the distribution of National Institutes of Health research project grant funding.

Previous reports have described worsening inequalities of National Institutes of Health (NIH) funding. We analyzed Research Project Grant data through the end of Fiscal Year 2020, confirming worsening inequalities beginning at the time of the NIH budget doubling (1998-2003), while finding that trends in recent years have reversed for both investigators and institutions, but only to a modest degree. We also find that career-stage trends have stabilized, with equivalent proportions of early-, mid-, and late-career investigators funded from 2017 to 2020. The fraction of women among funded PIs continues to increase, but they are still not at parity. Analyses of funding inequalities show that inequalities for investigators, and to a lesser degree for institutions, have consistently been greater within groups (i.e. within groups by career stage, gender, race, and degree) than between groups.

Associations of topic-specific peer review outcomes and institute and center award rates with funding disparities at the National Institutes of Health.

A previous report found an association of topic choice with race-based funding disparities among R01 applications submitted to the National Institutes of Health ('NIH') between 2011 and 2015. Applications submitted by African American or Black ('AAB') Principal Investigators ('PIs') skewed toward a small number of topics that were less likely to be funded (or 'awarded'). It was suggested that lower award rates may be related to topic-related biases of peer reviewers. However, the report did not account for differential funding ecologies among NIH Institutes and Centers ('ICs'). In a re-analysis, we find that 10% of 148 topics account for 50% of applications submitted by AAB PIs. These applications on 'AAB Preferred' topics were funded at lower rates, but peer review outcomes were similar. The lower rate of funding for these topics was primarily due to their assignment to ICs with lower award rates, not to peer-reviewer preferences.

STEM Through Authentic Research and Training Program (START) for Underrepresented Communities: Adapting to the COVID-19 Pandemic.

The STEM Through Authentic Research and Training (START) Program is a new program integrating academic, social, and professional experiences, in the theme of exomedicine, to build a pipeline into college for first generation and traditionally underrepresented students by providing year-round authentic opportunities and professional development for high school students and teachers. In response to the COVID-19 pandemic, the START Program has worked with the local Fayette County public school and community partners to provide content to over 300 students through: virtual laboratory tours with community partner Space Tango, "meet a scientist" discussions, and online near-peer student demonstrations aimed at making the practice of STEM disciplines approachable. Furthermore, the START Program has partnered with Higher Orbits to provide at-home, space-themed learning kits for students to develop teamwork, communication, and STEM principles while engaging in online content with teachers, professionals, and astronauts. Finally, the START Program has moved its training platforms online, including receiving College Reading and Learning Association (CRLA) Peer Educator accreditation for our near-peer mentoring and coaching training. As a result, the START Program is better positioned to address this critical need in STEM education, while reaching more students in the community than possible with face-to-face interactions alone.

National Institutes of Health social and behavioral research in response to the SARS-CoV2 Pandemic.

The COVID-19 pandemic has been mitigated primarily using social and behavioral intervention strategies, and these strategies have social and economic impacts, as well as potential downstream health impacts that require further study. Digital and community-based interventions are being increasingly relied upon to address these health impacts and bridge the gap in health care access despite insufficient research of these interventions as a replacement for, not an adjunct to, in-person clinical care. As SARS-CoV-2 testing expands, research on encouraging uptake and appropriate interpretation of these test results is needed. All of these issues are disproportionately impacting underserved, vulnerable, and health disparities populations. This commentary describes the various initiatives of the National Institutes of Health to address these social, behavioral, economic, and health disparities impacts of the pandemic, the findings from which can improve our response to the current pandemic and prepare us better for future infectious disease outbreaks.

Topic choice contributes to the lower rate of NIH awards to African-American/black scientists.

Despite efforts to promote diversity in the biomedical workforce, there remains a lower rate of funding of National Institutes of Health R01 applications submitted by African-American/black (AA/B) scientists relative to white scientists. To identify underlying causes of this funding gap, we analyzed six stages of the application process from 2011 to 2015 and found that disparate outcomes arise at three of the six: decision to discuss, impact score assignment, and a previously unstudied stage, topic choice. Notably, AA/B applicants tend to propose research on topics with lower award rates. These topics include research at the community and population level, as opposed to more fundamental and mechanistic investigations; the latter tend to have higher award rates. Topic choice alone accounts for over 20% of the funding gap after controlling for multiple variables, including the applicant's prior achievements. Our findings can be used to inform interventions designed to close the funding gap.

Unique Review Criteria and Patient and Stakeholder Reviewers: Analysis of PCORI's Approach to Research Funding.

OBJECTIVE: The Patient-Centered Outcomes Research Institute (PCORI) uses a unique approach to Merit Review that includes patients and stakeholders as reviewers with scientists, and includes unique review criteria (patient-centeredness and active engagement of end users in the research). This study assessed the extent to which different reviewer types influence review scores and funding outcomes, the emphasis placed on technical merit compared to other criteria by a multistakeholder panel, and the impact of the in-person discussion on agreement among different reviewer types. METHODS: Cross-sectional analysis of administrative data from PCORI online and in-person Merit Review (N = 1312 applications from the five funding cycles from November 2013 to August 2015). Linear and logistic regression models were used to analyze the data. RESULTS: For all reviewer types, final review scores were associated with at least one review criterion score from each of the three reviewer types. The strongest predictor of final overall scores for all reviewer types was scientists' prediscussion ratings of technical merit. All reviewers' prediscussion ratings of the potential to improve health care and outcomes, and scientists' ratings of technical merit and patient-centeredness, were associated with funding success. For each reviewer type, overall impact scores from the online scoring were changed on at least half of the applications at the in-person panel discussion. Score agreement across reviewer types was greater after panel discussion. CONCLUSIONS: Scientist, patient, and stakeholder views all contribute to PCORI Merit Review of applications for research funding. Technical merit is critical to funding success but patient and stakeholder ratings of other criteria also influence application disposition.

Researchers, Patients, and Stakeholders Evaluating Comparative-Effectiveness Research: A Mixed-Methods Study of the PCORI Reviewer Experience.

OBJECTIVES: The Patient-Centered Outcomes Research Institute (PCORI) includes patients and stakeholders alongside scientists in reviewing research applications using unique review criteria including patient-centeredness and patient and/or stakeholder engagement. To support extension of this unique collaborative model to other funders, information from the reviewers on the review process is needed to understand how scientists and nonscientists evaluate research proposals together. Thus, this study aimed to describe reviewers' perspectives of the interactions during the in-person review panel; to examine the value and challenges of including scientists, patients, and stakeholders together; and to understand the perceived importance of PCORI's review criteria. METHODS: This study utilized anonymous, cross-sectional surveys (N = 925 respondents from 5 funding cycles: 470 scientists, 217 patients, 238 stakeholders; survey completion rates by cycle: 70-89%) and group interviews (N = 18). RESULTS: Reviewers of all types describe PCORI Merit Review as respectful, balanced, and one of reciprocal influence among different reviewer types. Reviewers indicate strong support and value of input from all reviewer types, receptivity to input from others, and the panel chair's incorporation of all views. Patients and stakeholders provide real-world perspectives on importance to patients, research partnership plans, and study feasibility. Challenges included concerns about a lack of technical expertise of patient/stakeholder reviewers and about scientists dominating conversations. The most important criterion for assigning final review scores was technical merit-either alone or in conjunction with patient-centeredness or patient/ stakeholder engagement. CONCLUSIONS: PCORI Merit Reviewers' self-reports indicate that the perspectives of different reviewer types are influential in panel discussions and Merit Review outcomes.

Working Together to Address Women's Health in Research and Drug Development: Summary of the 2017 Women's Health Congress Preconference Symposium.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

NIH Policies on Experimental Studies with Humans.

The U.S. National Institutes of Health clinical trials policies will apply broadly to studies involving experimental manipulations of humans. These studies will require registration and reporting in ClinicalTrials.gov, grant application submission under a clinical trials funding opportunity announcement, and Good Clinical Practice training for investigators.