National Institutes Of Health Office Research Articles

A multi-modal framework improves prediction of tissue-specific gene expression from a surrogate tissue

Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC). Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood. MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues. The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes. This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).

Rett syndrome: The Natural History Study journey

AbstractUnderstanding clinical features and disease progression of Rett syndrome (RTT) and establishing clinical trial readiness was enhanced by the RTT Natural History Study (NHS). The NHS benefited from two key developments: one, the Orphan Drug Act passed by Congress in 1983 defining criteria for rare disorders in the United States and creating opportunities for pharmaceutical companies to develop products for individuals with rare disorders, and two, the Rare Diseases Act of 2002, which established the National Institutes of Health Office of Rare Diseases and provided research funding. Funding for the RTT and related disorders NHS was obtained in 2003, creating a broad network of experienced clinical investigators across the United States and producing critical results not only for RTT but also for related disorders: CDKL5 deficiency disorder, FOXG1 disorder, and MECP2 duplication syndrome. Longitudinal information from over 1800 participants (more than 1600 diagnosed with RTT) led to multiple reports describing their clinical features and natural progression and identified putative biomarkers and clinical outcome measures. Establishing clinical trial readiness assisted in evaluating the first FDA‐approved medication for RTT in 2023 and continues to provide opportunities to develop potentially life‐altering therapies. The experiences of the RTT NHS journey provide informative guidance for studying other rare neurological disorders. These lessons include positive features of developing productive collaborations focused on improving lives of people and families with RTT and related disorders, as well as lessons learned through retrospective analysis for improving overall conduct of natural history studies in rare disorders.

The National Institutes of Health Lasker Clinical Research Scholars Program: A Decade of Launching Clinician-Scientist Careers.

In response to the decades-long decrease in U.S. clinician-scientists, the National Institutes of Health (NIH) and the Albert and Mary Lasker Foundation launched the Lasker Clinical Research Scholars Program in academic year 2011 to 2012. The investigators examined the early outcomes of this program. Thirty-nine scholars have matriculated into the program as of May 2023. Productivity was assessed for all scholars who joined the program before October 2020 (n = 31). Extramural early-stage investigators (ESIs) were used as a control group, and coarsened exact matching was used to compare the groups. The scholars were compared with the matched ESIs on 4 productivity metrics: publication count, weighted relative citation ratio, clinical impact, and approximate potential to translate. Publication records for both groups were compiled using the NIH Office of Portfolio Analysis' name disambiguation method and manually curated to ensure integrity of the data set. Of the 39 scholars, 29 were compared with 121 matched extramural ESIs. Five years before matriculation, the 2 groups had comparable numbers of publications, but scholars had a higher median weighted relative citation ratio, clinical impact, and approximate potential to translate score. Five years after matriculation, the scholars had a higher median number of publications than the ESIs, and the gap between scholars and ESIs, with scholars having higher scores, had widened for all metrics except approximate potential to translate scores. Of 10 of the 39 scholars at or approaching tenure eligibility, 6 have attained tenure (3 at NIH and 3 in academic institutions), and 4 are on track to attain tenure at NIH. All the Lasker clinical research scholars are substantially involved in clinical and translational research. Their productivity matches or exceeds that of a matched cohort of ESIs at U.S. academic institutions.

Musculoskeletal health: an ecological study assessing disease burden and research funding

Exacerbated by an aging population, musculoskeletal diseases are a chronic and growing problem in the United States that impose significant health and economic burdens. The objective of this study was to analyze the correlation between the burden of diseases and the federal funds assigned to health-related research through the National Institutes of Health (NIH). An ecological study design was used to examine the relationship between NIH research funding and disease burden for 60 disease categories. We used the Global Burden of Disease (GBD) Study 2019 to measure disease burden and the NIH Research, Condition, and Disease Categories (RCDC) data to identify 60 disease categories aligned with available GBD data. NIH funding data was obtained from the RCDC system and the NIH Office of Budget. Using linear regression models, we observed that musculoskeletal diseases were among the most underfunded (i.e., negative residuals from the model) with respect to disease burden. Musculoskeletal diseases were underfunded, with neck pain being the most underfunded at only 0.83% of expected funding. Low back pain, osteoarthritis, and rheumatoid arthritis were also underfunded at 13.88%, 35.08%, and 66.26%, respectively. Musculoskeletal diseases were the leading cause of years lived with disability and the third leading cause in terms of prevalence and disability-adjusted life years. Despite the increasing burden of these diseases, the allocation of NIH funding to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has remained low compared to other institutes. Despite the increasing health burden and economic cost of $980 billion annually, the allocation of NIH funding to the NIAMS has remained low compared to other institutes. These findings suggest that the NIH may need to reassess its allocation of research funding to align with the current health challenges of our country. Furthermore, these clinically relevant observations highlight the need to increase research funding for musculoskeletal diseases and improve their prevention, diagnosis, and treatment. No funding.

Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic Aging Tenacity ("You are never too old to become younger!") Specialized Center of Research Excellence on Sex Differences Career Enhancement Core: Building the Future.

The objective of the National Institutes of Health Office of Research in Women's Health (NIH/ORWH) Specialized Center of Research and Career Enhancement (SCORE) program is to expedite the development and application of new knowledge that affect women, to learn more about the etiology of these diseases, and to foster improved approaches to treatment and/or prevention. Each SCORE has a Career Enhancement Core (CEC) that serves to meet the career enhancement needs of translational science in the study of sex differences. The Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic aging Tenacity (MAE-WEST) ("You are never too old to become younger!") Specialized Center of Research Excellence (SCORE) on Sex Differences will study pro- and anti-inflammatory responses and small vessel aging traits. As part of our SCORE CEC, we have advanced several initiatives to embed consideration of sex as a biological variable (SABV) into the infrastructure of our two CEC institutions. Unlike other professions, ongoing physician education through continuing medical education (CME) activities is required and embedded in the practice of medicine. The MAE-WEST SCORE in collaboration with the CSMC Clinical Scholars Program, the Center for Research in Women's Health and Sex-differences and the CSMC CME Office requires SABV and as Diversity, Equity, and Inclusion components in all CSMC CME programs. Clinical practice is also increasingly guided by evidence-based guidelines, with Class I recommendations resulting from clinical trials rather than expert consensus. It is essential that women be included in clinical trials proportionate to the prevalence and burden of disease. The MAE-WEST SCORE has developed our own unique CEC for providing novel educational, networking, funding opportunities, and translation to practice support. The developed best practices have found novel ways to enhance studies of women's health and SABV. We welcome visitors on-site and virtual to share with the broader academic and practicing community.

Orphan Drugs in Neurology-A Narrative Review.

Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment. With this paper, we aim to present some of the orphan neurological diseases for which new drugs have been developed lately. We have conducted a literature review of the papers concerning rare diseases and their treatment, and we have analyzed the existing studies for each orphan drug. For this purpose, we have used the Google Scholar search engine and the Orphanet. We have selected the studies published in the last 15 years. Since the formation of the National Organization for Rare Diseases, the Orphan Drug Act, and the National Institutes of Health Office of Rare Diseases, pharmacological companies have made a lot of progress concerning the development of new drugs. Therefore, diseases that until recently were without therapeutic solutions benefit today from personalized treatment. We have detailed in our study over 15 neurological and systemic diseases with neurological implications, for which the last 10-15 years have brought important innovations regarding their treatment. Many steps have been taken towards the treatment of these patients, and the humanity and professionalism of the pharmaceutical companies, along with the constant support of the patient's associations for rare diseases, have led to the discovery of new treatments and useful future findings.

Advice for Early Career Clinical Stroke Researchers Applying for National Institutes of Health Funding.

Advice for Early Career Clinical Stroke Researchers Applying for National Institutes of Health Funding.

Prevention of Laboratory Animal Allergy and Impact of COVID-19 on Prevention Programs in the United States: A National Survey 10-Year Update.

Laboratory animal allergy (LAA) is common and preventable. This study provides a 10-year update on LAA prevention programs in the United States and the effect of COVID-19 on prevention practices. An electronic survey was e-mailed to designated institutional officials at laboratory animal facilities identified by the National Institutes of Health Office of Laboratory Animal Welfare. Results were compared with the prior survey. A total of 141 institutions employing 58,224 laboratory animal workers responded. Results were similar to the prior survey with wide variation in practices. Medical surveillance increased (58%-71%), but N95 respirator use decreased (17%-13%). As before, only 25% of institutions knew their LAA incidence and prevalence rates. COVID-19 had a small time-limited effect on personal protective equipment use. Universal use of evidence-based practices and improved medical surveillance would provide greater worker protection from LAA.

Commentary: Improving the Effectiveness and Utility of the Helping to End Addiction Long-Term (HEAL) Prevention Cooperative: A Full Translational Framework.

The Helping to End Addiction Long-term (HEAL) Prevention Collaborative (HPC) is designed to expedite the development of programs aimed at preventing opioid misuse and opioid use disorder (OUD) in older adolescents and young adults (ages 16-30). Funded by the National Institutes of Health Office of the Director (ODP-NIH), the HPC includes ten outcome studies that focus on distinct interventions to determine their effectiveness and real-world applicability. Also included is a coordinating center at RTI International that supports the individual projects. This commentary highlights the scientific and practical significance of this cooperative and its promise for facilitating the production and implementation of successful interventions. Attributes such as novel program designs, advanced methodologies, addressing unique characteristics of diverse populations, and real-time analysis of data and costs make this cooperative highly innovative. We note, however, that papers in this Supplemental Issue did not specifically address the persistent need to obtain stronger effect sizes than those achieved to date. Existing data captured earlier in development (< 16years of age) are uncovering interactive neurocognitive and social-contextual mechanisms underlying the phenomena we wish to prevent. HPC projects could be guided by this information to incorporate developmentally appropriate measures of mechanisms shown previously to be influential in targeted outcomes and determine how they are impacted by specific components of their interventions. This mechanistic information can provide a roadmap for constructing interventions that are more precision-based and, thus, more likely to yield greater benefits for a larger number of recipients. Furthermore, an understanding of underlying mechanism(s) promises to shed light on the sources of heterogeneity in outcomes for further intervention refinement. It is quite possible, if not probable, that meaningful measures of underlying processes will reveal subtypes-some with very high effect sizes and others that are much lower-directly enabling program refinements to more directly target mechanisms that portend and explain less favorable outcomes. Described herein is a full-spectrum translational approach which promises to significantly boost effect sizes, a key objective that should be reached prior to scaling.

Current gaps and opportunities in screening, prevention, and treatment of cervical cancer.

In their fiscal year 2021 reports, the US House and Senate Appropriations Committees requested that the National Institutes of Health (NIH) evaluate current research related to women's health and topics that include stagnant cervical cancer survival. In response, the NIH Office of Research on Women's Health, with input from women's health experts; members of the public; representatives from NIH institutes, centers, and offices; and members of the NIH Advisory Committee on Research on Women's Health, reviewed the public health needs and current NIH activities on cervical cancer. The Advancing NIH Research on the Health of Women: A 2021 Conference held in October 2021 reviewed these findings and allowed the identification of opportunities to strengthen research. In this review, the authors summarize public health needs related to cervical cancer and NIH activities in this realm. Cervical cancer has become a rare disease in theUnited States, yet significant portions of the US population remain under screened orunscreened for cervical cancer, human papillomavirus vaccination rates remain low, access to high-quality treatment remains a challenge for many, and large inequities by race and ethnicity persist. Novel, inclusive, and intentional research isneeded to produce improvements in cervical cancer survival within the UnitedStates.

Abstracts from the NIH Office of Research on Women's Health 2022 Annual BIRCWH Meeting:Building Interdisciplinary Research Careers in Women's Health November 2, 2022

Abstracts from the NIH Office of Research on Women's Health 2022 Annual BIRCWH Meeting:Building Interdisciplinary Research Careers in Women's Health November 2, 2022

Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial.

In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT). CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation. Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants. Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer. National Cancer Institute and National Institutes of Health Office of Research on Women's Health. For the Spanish translation of the abstract see Supplementary Materials section.

The publication impact of the first 100 THOR Network publications by bibliometric and social network analyses.

A specialized international multidisciplinary group of investigators wanted to determine the performance and impact of publications presented at an annual conference over a 6 year period. Specifically, the group wanted to know if the influence of the conference publications extended beyond conference publication authors and attendees. Bibliometric methods and network analyses were used to evaluate the performance and impact of 100 peer-reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 (published 2013-2018). Further analysis was performed on the affiliations of conference attendees who attended from the years of 2012 to 2017. This project used normative and relative bibliometric measures and social network analysis to evaluate the performance and impact of 100 peer-reviewed publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network RDCR Symposia from 2012 to 2017. Publication and citation data were from Elsevier Scopus, a bibliographic citation database. Metrics from Elsevier SciVal were selected for the project to normalize for group size, year of publication, and document type. A six-year period of publications presented at the Symposia, published from 2013 to 2018, was selected for analysis. The publication and citation data were further analyzed using Elsevier SciVal and the iCite database from the National Institutes of Health Office of Portfolio Analysis. Sci2, VOSviewer, and Gephi were used for social network analyses and visualization. The 100 publications presented at the Trauma Hemostasis and Oxygenation Research (THOR) Network Remote Damage Control Resuscitation (RCDR) Symposia from 2012 to 2017 demonstrate reach and influence beyond the authors of the THOR publications or the THOR attendees. Citations to the THOR publications were published in 10 languages and 313 unique journals, with author affiliations from 62 countries. Citation metrics for the THOR publications exceed global averages with 65% of the THOR publications being in the 25% citation percentiles. When benchmarking the THOR publications using six homogenous comparator groups, the THOR publications demonstrate higher citation metrics than any of the comparator groups with more citations per publication, a higher average of cited publications, higher FWCI and outputs in the top citation percentiles among the six groups. The Office of Portfolio Analysis (OPA) iCite database was used to calculate potential to translate for the THOR publications with 57 of the THOR publications cited by clinical articles with an average approximate potential to translate score of 65.3%. The value of international groups with sharing of research and knowledge are instrumental in enhancing the uptake for best practices for in medicine and treatment of hemorrhagic shock resuscitation. The use of bibliometric methods and network analyses, along with benchmarking, demonstrated reach and impact beyond the THOR Network. Limitations include use of a single source for analysis of publication and citation; and that publication data alone does not provide a full overview of research performance. Despite these limitations, bibliometric methods, social network analyses, and benchmarking can help centers better understand their impact.

Sociodemographic inequalities in uranium and other metals in community water systems across the USA, 2006–11: a cross-sectional study

SummaryBackgroundThe US Environmental Protection Agency (EPA) currently sets maximum contaminant levels (MCLs) for ten metals or metalloids in public drinking water systems. Our objective was to estimate metal concentrations in community water systems (CWSs) across the USA, to establish if sociodemographic or regional inequalities in the metal concentrations exist, and to identify patterns of concentrations for these metals as a mixture.MethodsWe evaluated routine compliance monitoring records for antimony, arsenic, barium, beryllium, cadmium, chromium, mercury, selenium, thallium, and uranium, collected from 2006–11 (2000–11 for uranium; timeframe based on compliance monitoring requirements) by the US EPA in support of their second and third Six-Year Reviews for CWSs. Arsenic, barium, chromium, selenium, and uranium (detectable in >10% records) were included in the main analyses (subgroup and metal mixture analyses; arsenic data reported previously). We compared the mean, 75th percentile, and 95th percentile contaminant concentrations and the percentage of CWSs with concentrations exceeding the MCL across subgroups (region, sociodemographic county-cluster, size of population served, source water type, and CWSs exclusively serving correctional facilities). We evaluated patterns in CWS metal concentration estimate profiles via hierarchical cluster analysis. We created an online interactive map and dashboard of estimated CWS metal concentrations for use in future analyses.FindingsAverage metal concentrations were available for a total of 37 915 CWSs across the USA. The total number of monitoring records available was approximately 297 000 for arsenic, 165 000 for barium, 167 000 for chromium, 165 000 for selenium, and 128 000 for uranium. The percentage of analysed CWSs with average concentrations exceeding the MCL was 2·6% for arsenic (MCL=10 μg/L; nationwide mean 1·77 μg/L; n=36 798 CWSs), 2·1% for uranium (MCL=30 μg/L; nationwide mean 4·37 μg/L; n=14 503 CWSs), and less than 0·1% for the other metals. The number of records with detections was highest for uranium (63·1%). 75th and 95th percentile concentrations for uranium, chromium, barium, and selenium were highest for CWSs serving Semi-Urban, Hispanic communities, CWSs reliant on groundwater, and CWSs in the Central Midwest. Hierarchical cluster analysis revealed two distinct clusters: an arsenic–uranium–selenium cluster and a barium–chromium cluster.InterpretationsUranium is an under-recognised contaminant in CWSs. Metal concentrations (including uranium) are elevated in CWSs serving Semi-Urban, Hispanic communities independent of location or region, highlighting environmental justice concerns.FundingUS National Institutes of Health Office of the Director, US National Institutes for Environmental Health Sciences, and US National Institute of Dental and Craniofacial Research.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

Genome-wide association study meta-analysis identifies three novel loci for circulating anti-Müllerian hormone levels in women.

Translatability Analysis of National Institutes of Health–Funded Biomedical Research That Applies Artificial Intelligence

Despite the rapid growth of interest and diversity in applications of artificial intelligence (AI) to biomedical research, there are limited objective ways to characterize the potential for use of AI in clinical practice. To examine what types of medical AI have the greatest estimated translational impact (ie, ability to lead to development that has measurable value for human health) potential. In this cohort study, research grants related to AI awarded between January 1, 1985, and December 31, 2020, were identified from a National Institutes of Health (NIH) award database. The text content for each award was entered into a Natural Language Processing (NLP) clustering algorithm. An NIH database was also used to extract citation data, including the number of citations and approximate potential to translate (APT) score for published articles associated with the granted awards to create proxies for translatability. Unsupervised assignment of AI-related research awards to application topics using NLP. Annualized citations per $1 million funding (ACOF) and average APT score for award-associated articles, grouped by application topic. The APT score is a machine-learning based metric created by the NIH Office of Portfolio Analysis that quantifies the likelihood of future citation by a clinical article. A total of 16 629 NIH awards related to AI were included in the analysis, and 75 applications of AI were identified. Total annual funding for AI grew from $17.4 million in 1985 to $1.43 billion in 2020. By average APT, interpersonal communication technologies (0.488; 95% CI, 0.472-0.504) and population genetics (0.463; 95% CI, 0.453-0.472) had the highest translatability; environmental health (ACOF, 1038) and applications focused on the electronic health record (ACOF, 489) also had high translatability. The category of applications related to biochemical analysis was found to have low translatability by both metrics (average APT, 0.393; 95% CI, 0.388-0.398; ACOF, 246). Based on this study's findings, data on grants from the NIH can apparently be used to identify and characterize medical applications of AI to understand changes in academic productivity, funding support, and potential for translational impact. This method may be extended to characterize other research domains.

1196. A Multi-faceted, Iterative Program to Increase COVID-19 Vaccine Uptake in a Midwestern HIV Clinic

Abstract Background The National Institutes of Health Office of AIDS Research recommend that patients with HIV be prioritized for COVID-19 vaccination due to high rates of co-morbidities and sociodemographic risk factors that place them at increased risk for severe disease. However, COVID-19 vaccines were not distributed specifically to those in high-risk medical categories in Nebraska, and HIV clinics were not included in the state’s COVID-19 vaccine delivery system. As a result, barriers to vaccine uptake emerged and interventions to mitigate them were needed. Methods A multi-faceted and iterative program aimed at improving COVID-19 vaccine uptake was implemented at the University of Nebraska Medical Center’s (UNMC) HIV clinic in Omaha, Nebraska in January 2021. A multidisciplinary task force was established in late January 2021 and met on a weekly basis to provide staff and patient education, linkage to vaccines, and review and analysis of vaccine completion rates as shown in the figure. Outreach interventions were continuously revised based on patient and staff feedback as well as updated data and vaccine availability. Multidisciplinary COVID-19 Task Force Overview Overview of the outreach interventions and activities conducted by the COVID-19 task force Results All 1188 patients of the UNMC HIV clinic were ultimately eligible for the COVID-19 vaccine, but availability was on a rolling basis by age group, profession, county, and, ultimately, co-morbidities. 76% were male, 45.8% non-white, median age 48, and 73% had income less than 400% of federal poverty level. Of the 1188 eligible patients, 63.1% (n=751) had received at least one dose the COVID-19 vaccine and 59.3% (n=705) had completed the COVID-19 vaccine series by June 4, 2021. In comparison, 49.32% of the population of the state of Nebraska had initiated the COVID-19 vaccine series and 43.12% had completed the vaccine series by that date. Among our clinic patients, 27.9% (n=261) of those who had received at least one vaccine were assisted by our task force. 4.5% were noted to have a potential barrier at the time of outreach and these included hesitancy (3.5%), language (1.2%) and transportation (0.9%). Conclusion A multi-faceted and iterative program to improve COVID-19 vaccine uptake in a high-risk patient population resulted in high rates of vaccine completion. Disclosures Sara H. Bares, MD, Gilead Sciences (Grant/Research Support)Janssen (Grant/Research Support)ViiV Healthcare (Grant/Research Support)

Maternal Morbidity and Mortality.

Maternal Morbidity and Mortality.

Viral Load in Non-Surviving Liberian Ebola Virus Disease Patients Is Underestimated by Diagnostic qRT-PCR: A Retrospective Observational Study

Background: Viral load in Ebola virus disease (EVD) correlates with case fatality rate (CFR) and is an important parameter used for diagnostic cutoffs, stratification in randomized controlled trials, and epidemiologic investigation. However, it is currently only estimated using cycle threshold (Ct) values from diagnostic qRT-PCR tests that were not developed or validated for quantitative purposes. Furthermore, during the 2013-2016 EVD epidemic in west Africa, numerous different diagnostic platforms and protocols were used and yielded inconsistent, often conflicting data. Methods: 727 whole blood samples, both positive and negative for Ebola virus (EBOV), that were collected for diagnostic purposes in Monrovia, Liberia between August 28 and December 18, 2014 were reanalyzed under highly controlled biosafety level 4 laboratory conditions. An optimized TRIzol-based extraction protocol was utilized, followed by a novel semi-strand specific two-step droplet digital PCR assay to quantify viral load as log10 EBOV RNA copies/mL. These data were then compared to the cycle threshold (Ct) values from the original diagnostic qRT-PCR testing, and a subset of the samples was also reanalyzed following re-extraction with the same diagnostic one-step PCR and instruments employed at the Ebola treatment unit for further assessment. Finally, for EBOV-positive patients, correlations between viral load, outcome, time from symptom onset, and other epidemiological parameters were evaluated utilizing a deidentified database. Findings: Survivors had significantly lower mean viral loads at presentation than non-survivors in both the reanalyzed dataset (5.61 [95% CI 5.34 to 5.87] versus 7.19 [95% CI 6.99 to 7.38] log10 EBOV RNA copies/mL, respectively; p < 0.0001) and diagnostic dataset (Ctvalue 28.72 [95% CI 27.97 to 29.47] versus 26.26 [95% CI 25.72 to 26.81], respectively; p < 0.0001). However, receiver operating characteristic curve analysis demonstrated the reanalyzed dataset to be superior to the diagnostic dataset (area under curve 0.80 [95% CI 0.75 to 0.85] versus 0.66 [95% CI 0.59 to 0.72], respectively) in distinguishing between survivors and non-survivors and the prognostic capacity of viral load increased substantially upon reanalysis (odds ratio [OR] of death 8.06, 95% CI 4.81 to 13.53, p < 0.0001 for viral loads above 6.71 log10 EBOV RNA copies/mL versus OR of death 2.02, 95% CI 1.27 to 3.20, p = 0.0028 for Ct values below 27.37). Diagnostic Ct values underestimated viral load in non-survivors by nearly 100-fold on average (mean difference between diagnostic Ct value and reanalyzed Ct value of 5.15 [95% CI 4.43 to 5.87]); substantially less discrepancy was observed for survivors (mean difference between diagnostic Ct value and reanalyzed Ct value of 1.79 [95% CI 1.16 to 2.43]). Six samples that were reported negative by diagnostic testing were found to be positive upon reanalysis, and had high viral loads. Non-survivors presented to the ETU significantly earlier as the epidemic progressed, from 6.8 days following symptom onset (95% CI 5.7 to 7.9), on average, during the first three weeks to 3.7 days (95% CI 2.4 to 5.0) during the last three weeks (p = 0.0006) and had significantly lower viral loads (7.6 log10 EBOV RNA copies/mL [95% CI 7.3 to 7.9] to 6.5 log10 EBOV RNA copies/mL [95% CI 5.8 to 7.2] for the same intervals (p = 0.0046). However, the CFR remained steady at approximately 60% throughout. Interpretation: Inaccurate viral load estimation from diagnostic Ct values is likely multifactorial, but unaddressed PCR inhibition from tissue damage in patients with fulminant EVD may largely account for the discrepancies between the datasets in this study. In light of these findings, testing protocols for EVD require further standardization and validation to produce accurate viral load estimates, minimize false negatives, and allow for reliable epidemiological investigation. Funding Information: This research was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The deidentified samples and data utilized for this study received a determination of ‘not human subjects research’ by the NIH Office of Human Subjects Research Protection and has been approved by the University of Liberia-Pacific Institute for Research and Evaluation IRB.

Developing the Process and Tracking the Implementation and Evaluation of the National Institutes of Health Strategic Plan for Women's Health Research.

BackgroundThe National Institutes of Health (NIH) released Advancing Science for the Health of Women: The Trans-NIH Strategic Plan for Women’s Health Research, 2019–2023 (Strategic Plan) in February 2019. The NIH Office of Research on Women’s Health (ORWH) engaged staff members from across NIH to develop recommendations on the implementation and evaluation of the Strategic Plan. Objective: This paper describes the process used to develop recommendations for tools and approaches that NIH Institutes, Centers, and Offices (ICOs) could apply when implementing and evaluating the Strategic Plan. Methods: A Trans-NIH Strategic Plan Implementation and Evaluation Guidance Development Team conducted meetings and individual interviews with 69 NIH staff members knowledgeable about research on the health of women and sex and gender differences and met with 11 Advisory Committee on Research on Women’s Health Strategic Plan Evaluation Working Group members. The purpose of these stakeholder meetings and interviews was to obtain recommendations for implementing the Strategic Plan and identify measures for evaluating implementation success. A thematic analysis was performed to synthesize and map the recommendations to the Strategic Plan goals and objectives. Results: The process resulted in the Guide for Implementing and Evaluating the 2019–2023 Trans-NIH Strategic Plan for Women’s Health Research Across NIH Institutes, Centers, and Offices (the Guide), which includes both a conceptual and logic model for implementation and evaluation. Conclusions: The Guide offers methods, tools, and suggestions that ICO planning and evaluation staff, as well as national and international entities, can choose from when determining how to implement the Strategic Plan through ICO activities, programs, and research initiatives and how to evaluate their efforts in the context of their unique mission.