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There has been an erosion of trust in medical care and clinical research, and this has raised issues about whether institutions and investigators conducting clinical research are worthy of trust. We review recent literature on research on trust and trustworthiness in the clinical research enterprise and identify opportunities to enhance trustworthiness, which will likely increase participant trust in clinical research. In addition, we review materials reporting the results of national polls related to the public's trust in different occupations. The literature on trustworthiness and trust is complex and suffers from a lack of agreement on definitions of trust and trustworthiness and actions to enhance trustworthiness. Nonetheless, institutions need to take action to address the many elements that contribute to being perceived as trustworthy. As a complementary approach, since nurses have consistently ranked highest on trust by the public for twenty-two straight years, we analyze the features that likely account for the public's uniform high regard for nurses. We propose specific actions to enhance the role of research nurses in the research enterprise, without compromising their primary role as participant advocates, that we have adopted at Rockefeller University to gain the benefits of the public's trust in nurses in building trustworthiness., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2024.)

Introduction: Latinx populations are underrepresented in clinical research. Asking Latinx research participants about their research experiences, barriers, and facilitators could help to improve research participation for these populations., Methods: The Salud Estres y Resilencia (SER) Hispano cohort study is a longitudinal cohort study of young adult Latinx immigrants whose design and conduct were tailored for their study population. We administered the Research Participant Perception Survey (RPPS) to SER Hispano participants to assess their experiences in the study. We describe overall results from the RPPS and compare results of surveys administered to SER Hispano participants via email versus telephone., Results: Of 340 participants who were contacted with the RPPS, 142 (42%) responded. Among respondents, 53 (37%) responded by initial email contact; and 89 (63%) responded by subsequent phone contact. The majority of respondents were between 35 and 44 years of age (54%), female (76%), and of Cuban origin (50%). Overall, research participants expressed high satisfaction with their research experience; 84% stated that they would "definitely" recommend research participation to friends and family, with no significant difference by method of survey administration ( P = 0.45). The most common factor that was chosen that would influence future research participation was having summary results of the research shared with them (72%)., Conclusion: We found that culturally tailored studies can be good experiences for Latinx research participants; and we found that use of the RPPS can be administered successfully, particularly when administered by more than one method, including telephone, to evaluate and to improve research experiences for this population., Competing Interests: None., (© The Author(s) 2024.)

Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Rockefeller University holds the copyright for the Research Participant Perception Survey(s), which it shares, free of charge for to not-for-profit institutions for research or quality improvement, non-commercial purposes.

The dietary approach to stop hypertension (DASH) diet combines the antihypertensive effect of a low sodium and high potassium diet. In particular, the potassium component of the diet acts as a switch in the distal convoluted tubule to reduce sodium reabsorption, similar to a diuretic but without the side effects. Previous trials to understand the mechanism of the DASH diet were based on animal models and did not characterize changes in human ion channel protein abundance. More recently, protein cargo of urinary extracellular vesicles (uEVs) has been shown to mirror tissue content and physiological changes within the kidney. We designed an inpatient open label nutritional study transitioning hypertensive volunteers from an American style diet to DASH diet to examine physiological changes in adults with stage 1 hypertension otherwise untreated (Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group. N Engl J Med 344: 3-10, 2001). Urine samples from this study were used for proteomic characterization of a large range of pure uEVs (small to large) to reveal kidney epithelium changes in response to the DASH diet. These samples were collected from nine volunteers at three time points, and mass spectrometry identified 1,800 proteins from all 27 samples. We demonstrated an increase in total SLC12A3 [sodium-chloride cotransporter (NCC)] abundance and a decrease in aquaporin-2 (AQP2) in uEVs with this mass spectrometry analysis, immunoblotting revealed a significant increase in the proportion of activated (phosphorylated) NCC to total NCC and a decrease in AQP2 from day 5 to day 11 . This data demonstrates that the human kidney's response to nutritional interventions may be captured noninvasively by uEV protein abundance changes. Future studies need to confirm these findings in a larger cohort and focus on which factor drove the changes in NCC and AQP2, to which degree NCC and AQP2 contributed to the antihypertensive effect and address if some uEVs function also as a waste pathway for functionally inactive proteins rather than mirroring protein changes. NEW & NOTEWORTHY Numerous studies link DASH diet to lower blood pressure, but its mechanism is unclear. Urinary extracellular vesicles (uEVs) offer noninvasive insights, potentially replacing tissue sampling. Transitioning to DASH diet alters kidney transporters in our stage 1 hypertension cohort: AQP2 decreases, NCC increases in uEVs. This aligns with increased urine volume, reduced sodium reabsorption, and blood pressure decline. Our data highlight uEV protein changes as diet markers, suggesting some uEVs may function as waste pathways. We analyzed larger EVs alongside small EVs, and NCC in immunoblots across its molecular weight range.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise., (© The Author(s) 2024.)

(1) Background: With increasing international travel and mass population displacement due to war, famine, climate change, and immigration, pathogens, such as Staphylococcus aureus ( S. aureus ), can also spread across borders. Methicillin-resistant S. aureus (MRSA) most commonly causes skin and soft tissue infections (SSTIs), as well as more invasive infections. One clonal strain, S. aureus USA300, originating in the United States, has spread worldwide. We hypothesized that S. aureus USA300 would still be the leading clonal strain among US-born compared to non-US-born residents, even though risk factors for SSTIs may be similar in these two populations (2) Methods: In this study, 421 participants presenting with SSTIs were enrolled from six community health centers (CHCs) in New York City. The prevalence, risk factors, and molecular characteristics for MRSA and specifically clonal strain USA300 were examined in relation to the patients' self-identified country of birth. (3) Results: Patients born in the US were more likely to have S. aureus SSTIs identified as MRSA USA300. While being male and sharing hygiene products with others were also significant risks for MRSA SSTI, we found exposure to animals, such as owning a pet or working at an animal facility, was specifically associated with risk for SSTIs caused by MRSA USA300. Latin American USA300 variant (LV USA300) was most common in participants born in Latin America. Spatial analysis showed that MRSA USA300 SSTI cases were more clustered together compared to other clonal types either from MRSA or methicillin-sensitive S. aureus (MSSA) SSTI cases. (4) Conclusions: Immigrants with S. aureus infections have unique risk factors and S. aureus molecular characteristics that may differ from US-born patients. Hence, it is important to identify birthplace in MRSA surveillance and monitoring. Spatial analysis may also capture additional information for surveillance that other methods do not.

Introduction: Clinical trials are a vital component of translational science, providing crucial information on the efficacy and safety of new interventions and forming the basis for regulatory approval and/or clinical adoption. At the same time, they are complex to design, conduct, monitor, and report successfully. Concerns over the last two decades about the quality of the design and the lack of completion and reporting of clinical trials, characterized as a lack of "informativeness," highlighted by the experience during the COVID-19 pandemic, have led to several initiatives to address the serious shortcomings of the United States clinical research enterprise., Methods and Results: Against this background, we detail the policies, procedures, and programs that we have developed in The Rockefeller University Center for Clinical and Translational Science (CCTS), supported by a Clinical and Translational Science Award (CTSA) program grant since 2006, to support the development, conduct, and reporting of informative clinical studies., Conclusions: We have focused on building a data-driven infrastructure to both assist individual investigators and bring translational science to each element of the clinical investigation process, with the goal of both generating new knowledge and accelerating the uptake of that knowledge into practice., Competing Interests: A dedicated university counsel oversees clinical trial contracting, material transfer agreements, and the university’s conflict of interest program. She serves on both the ACCTS and the IRB, facilitating the flow of information on both topics to the appropriate committees.The authors have no disclosures to declare., (© The Author(s) 2023.)

Low-income, minority seniors face high rates of hypertension that increase cardiovascular risk. Senior centers offer services, including congregate meals, that can be a valuable platform to reach older adults in underserved communities. We implemented two evidence-based interventions not previously tested in this setting: DASH-aligned congregate meals and Self-Measured Blood Pressure (SMBP), to lower blood pressure (BP) at two senior centers serving low-income, racially diverse communities. The study enrolled congregate meal program participants, provided training and support for SMPB, and nutrition and BP education. DASH-aligned meals delivered 40% (lunch) or 70% (breakfast and lunch) of DASH requirements/day. Primary outcomes were change in BP, and BP control, at Month 1. Implementation data collected included client characteristics, menu fidelity, meal attendance, SMBP adherence, meal satisfaction, input from partner organizations and stakeholders, effort, and food costs. We used the RE-AIM framework to analyze implementation. Study Reach included 94 older, racially diverse participants reflecting neighborhood characteristics. Effectiveness: change in systolic BP at Month 1 trended towards significance (-4 mmHg, p = 0.07); change in SMBP reached significance at Month 6 (-6.9 mmHg, p = 0.004). We leveraged existing community-academic partnerships, leading to Adoption at both target sites. The COVID pandemic interrupted Implementation and Maintenance and may have attenuated BP effectiveness. DASH meals served were largely aligned with planned menus. Meal attendance remained consistent; meal satisfaction was high. Food costs increased by 10%. This RE-AIM analysis highlights the acceptability, feasibility, and fidelity of this DASH/SMBP health intervention to lower BP at senior centers. It encourages future research and offers important lessons for organizations delivering services to older adults and addressing cardiovascular risk among vulnerable populations.

Background and Aims: Cardiovascular Disease (CVD) poses significant health risks for seniors, especially among low-income and minority communities. Senior centers offer multiple services. We tested whether implementing two evidence-based interventions- DASH-aligned meals provided through an existing congregate meal program, and support for home Self-Measured Blood Pressure (SMBP) monitoring-lowers blood pressure among participants at two senior centers serving low-income, racially diverse communities., Methods and Results: Open-label study, enrolling clients aged ≥60, eating ≥4 meals/week at two NYC senior centers. Participants received DASH-aligned congregate meals, and training in nutrition, BP management education, and personal SMBP device. Co-Primary outcomes: a) change in systolic BP measured by independent health professionals, and b) change in percent with "controlled BP" (Eighth Joint National Committee (JNC-8) Guidelines), at Month 1 compared to Baseline., Secondary Outcomes: Changes in BP at Months 3 and 5/6 (last measure). We enrolled 94 participants; COVID closures interrupted implementation mid-study. Mean systolic BP at Month-1 changed by -4.41 mmHg (n = 61 p = 0.07) compared to Baseline. Participants with controlled BP increased (15.7%) at Month 1. Change in mean BP at Month 1 was significantly correlated with BMI (p = 0.02), age (p = 0.04), and baseline BP (p < 0.001). Mean systolic SMBP changed by -6.9 mmHg (p = 0.004) at Months 5/6., Conclusions: Implementing an evidence-based multi-component BP-lowering intervention within existing congregate meal programs at senior centers serving minority and low-income communities is feasible, and early findings show promising evidence of effectiveness. This approach to cardiovascular risk reduction should be further tested for widespread adoption and impact. Registered on ClinicalTrials.gov NCT03993808 (June 21st, 2019)., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Obesity is more prevalent among African American individuals, increasing the risk for cardiorenal morbidity. We explored interactions between race, BMI, and the risk of hyperfiltration associated with obesity-related glomerulopathy (ORG)., Methods: We created a cohort of female adolescents from electronic health records. Glomerular filtration rate (GFR) was estimated in two ways: (A) using standard age recommended formulae and (B) absolute eGFR - adjusted to individual body surface area (BSA). Multivariate logistic regression was used to analyze the contribution of risk factors for ORG-associated hyperfiltration defined as 135 mL/min/1.73 m2 or 135 mL/min, according to BMI group. Pearson's coefficient was used to assess correlation with creatinine clearance (CrCl)., Results: The final cohort included 7,315 African American and 15,102 non-African American adolescent females, with CrCl available for internal validation in 207 non-African American and 107 African American individuals. Compared with non-African American ethnicity, African American ethnicity was independently associated with a lower risk of hyperfiltration with standard eGFR calculations (odds ratio [OR] = 0.57, 95% confidence intervals [CIs] 0.45-0.71), associations were enhanced for absolute eGFR (OR = 0.81, 95% CI 0.69-0.95). Absolute eGFR values agreed better with CrCl (r = 0.63), compared to standard indexed eGFR formulae. Proportions classified as hyperfiltration changed with standard versus absolute eGFR; they were similar across BMI groups with the first and reflected obesity with the later., Conclusion: Adjusting to individual BSA improves estimation of GFR and identification of obesity-related hyperfiltration. More accurate and earlier ascertainment of obesity-related hyperfiltration may have important consequences for preservation of kidney function., (© 2022 S. Karger AG, Basel.)

Background: Methicillin-resistant or methicillin-sensitive Staphylococcus aureus skin and soft tissue infections pose serious clinical and public health challenges. Few protocols exist for outpatient education, decolonization and decontamination., Objectives: This trial implemented infection prevention protocols in homes via community health workers/Promotoras., Methods: We engaged clinicians, patient stakeholders, clinical and laboratory researchers, New York-based federally qualified health centers and community hospital emergency departments. The Clinician and Patient Stakeholder Advisory Committee (CPSAC) convened in person and remotely for shared decision-making and trial oversight., Results: The intervention trial consented participants with skin and soft tissue infections from Methicillin-resistant Staphylococcus aureus or methicillin-sensitive Staphylococcus aureus, completed home visits, obtained surveillance cultures from index patients and household members and sampled household environmental surfaces at baseline and three months., Lessons Learned: The retention of the CPSAC during the trial demonstrated high levels of engagement., Conclusions: CPSAC was highly effective throughout design and execution by troubleshooting recruitment and home visit challenges.

Background: Adolescent obesity, a risk factor for cardiorenal morbidity in adulthood, has reached epidemic proportions. Obesity-related glomerulopathy (ORG) has an early reversible stage of hyperfiltration. Age-appropriate formulae for eGFR, which are standardized to ideal body surface area (BSA) and provide assessment of kidney function in ml/min/1.73 m 2 , may underestimate prevalence of early ORG. We investigated whether adjusting eGFR to actual BSA more readily identifies early ORG., Methods: We studied a cohort of 22,417 young individuals, aged 12-21 years, from a New York metropolitan multi-institutional electronic health records clinical database. eGFR was calculated in two ways: BSA-standardized eGFR, and absolute eGFR. Hyperfiltration was defined above a threshold of 135 ml/min per 1.73 m 2 or 135 ml/min, respectively. The prevalence of hyperfiltration according to each formula was assessed in parallel to creatinine clearance., Results: Serum creatinine values and hyperfiltration prevalence according to BSA-standardized eGFR were similar, 13%-15%, across body mass index (BMI) groups. The prevalence of hyperfiltration determined by absolute eGFR differed across BMI groups: underweight, 2%; normal weight, 6%; overweight, 17%; and obese, 31%. This trend paralleled the rise in creatinine clearance across BMI groups., Conclusions: Absolute eGFR more readily identifies early ORG than the currently used formulae, which are adjusted to a standardized BSA and are not representative of current population BMI measures. Using absolute eGFR in clinical practice and research may improve the ability to identify, intervene, and reverse early ORG, which has great importance with increasing obesity rates., Competing Interests: O.S. Bentur reports receiving research funding from Celecor Therapeutics/Pulmoquine Therapeutics and having ownership interest in Karyopharm Therapeutics. D.M. Charytan reports having consultancy agreements with Allena Pharmaceuticals (data safety monitoring board), Amgen, AstraZeneca, CSL Behring, Eli Lilly/Boehringer Ingelheim, Fresenius, Gilead, GlaxoSmithKline, Janssen (steering committee), PLC Medical (clinical events committee), Novo Nordisk, Medtronic, and Merck; receiving research funding from Amgen, Bioporto (for clinical trial support), Gilead, Medtronic (for clinical trial support), and Novo Nordisk; serving as a scientific advisor for, or member of, CJASN; and receiving expert witness fees related to proton pump inhibitors. J.N. Tobin reports receiving payments, remuneration, reimbursement, or sponsored travel from AstraZeneca (via board of directors), Bio-Ascend LLC/Regional Cancer Care Associates, and Clinical Directors Network Inc. (via board of directors); and receiving payments or remuneration from National Institutes of Health National Cancer Institute. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Recurrent skin and soft tissue infections (SSTI) caused by Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) or Methicillin-Sensitive Staphylococcus aureus (CA-MSSA) present treatment challenges. This community-based trial examined the effectiveness of an evidence-based intervention (CDC Guidelines, topical decolonization, surface decontamination) to reduce SSTI recurrence, mitigate household contamination/transmission, and improve patient-reported outcomes. Participants (n = 186) were individuals with confirmed MRSA(+)/MSSA(+) SSTIs and their household members. During home visits; Community Health Workers/Promotoras provided hygiene instructions; a five-day supply of nasal mupirocin; chlorhexidine for body cleansing; and household disinfecting wipes (Experimental; EXP) or Usual Care Control (UC CON) pamphlets. Primary outcome was six-month SSTI recurrence from electronic health records (EHR). Home visits (months 0; 3) and telephone assessments (months 0; 1; 6) collected self-report data. Index patients and participating household members provided surveillance culture swabs. Secondary outcomes included household surface contamination; household member colonization and transmission; quality of life; and satisfaction with care. There were no significant differences in SSTI recurrence between EXP and UC in the intent-to-treat cohort (n = 186) or the enrolled cohort (n = 119). EXP participants showed reduced but non-significant colonization rates. EXP and UC did not differ in household member transmission, contaminated surfaces, or patient-reported outcomes. This intervention did not reduce clinician-reported MRSA/MSSA SSTI recurrence. Taken together with other recent studies that employed more intensive decolonization protocols, it is possible that a promotora-delivered intervention instructing treatment for a longer or repetitive duration may be effective and should be examined by future studies.

Clinical trials continue to face significant challenges in participant recruitment and retention. The Recruitment Innovation Center (RIC), part of the Trial Innovation Network (TIN), has been funded by the National Center for Advancing Translational Sciences of the National Institutes of Health to develop innovative strategies and technologies to enhance participant engagement in all stages of multicenter clinical trials. In collaboration with investigator teams and liaisons at Clinical and Translational Science Award institutions, the RIC is charged with the mission to design, field-test, and refine novel resources in the context of individual clinical trials. These innovations are disseminated via newsletters, publications, a virtual toolbox on the TIN website, and RIC-hosted collaboration webinars. The RIC has designed, implemented, and promised customized recruitment support for 173 studies across many diverse disease areas. This support has incorporated site feasibility assessments, community input sessions, recruitment materials recommendations, social media campaigns, and an array of study-specific suggestions. The RIC's goal is to evaluate the efficacy of these resources and provide access to all investigating teams, so that more trials can be completed on time, within budget, with diverse participation, and with enough accrual to power statistical analyses and make substantive contributions to the advancement of healthcare., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Introduction: Prior to the COVID pandemic, many CTSAs employed face-to-face interactions to conduct most of their community engagement (CE) activities. During the COVID pandemic, such engagement had to be curtailed and alternatives needed to be formulated. In addition, Community Engaged Research (CEnR) teams refocused their efforts to address this public health crisis., Methods: To obtain a general understanding of how CTSAs have conducted CE and CEnR during the COVID pandemic, we invited seven CTSA CE leaders to provide brief field reports of their activities during the pandemic. This included how their approaches to CE and CEnR were modified during the COVID-19 pandemic and key lessons learned., Results: We found that despite numerous challenges, all seven CTSAs CE cores were able to successfully carry out CE and CEnR. We also found that the fundamental principles of meaningful and authentic stakeholder engagement were of paramount importance during the pandemic. Through virtual approaches, all sites had considerable success in maintaining CE in during the COVID pandemic. They also leveraged existing bi-directional community partnerships to carry out meaningful and impactful research. This included both new COVID CEnR and also innovative approaches to sustain prior non-COVID research., Conclusions: These findings suggest that academic-community partnerships must be fostered and sustained over the many years so that when such crises emerge, all partners can build on existing trust and mutual respect. The lessons learned and the new tools and approaches developed would be key in addressing any such future public health emergencies., Competing Interests: EEM is a consultant for Myovant Sciences. The other authors have conflicts of interest., (© The Association for Clinical and Translational Science 2021.)

The recipients of NIH's Clinical and Translational Science Awards (CTSA) have worked for over a decade to build informatics infrastructure in support of clinical and translational research. This infrastructure has proved invaluable for supporting responses to the current COVID-19 pandemic through direct patient care, clinical decision support, training researchers and practitioners, as well as public health surveillance and clinical research to levels that could not have been accomplished without the years of ground-laying work by the CTSAs. In this paper, we provide a perspective on our COVID-19 work and present relevant results of a survey of CTSA sites to broaden our understanding of the key features of their informatics programs, the informatics-related challenges they have experienced under COVID-19, and some of the innovations and solutions they developed in response to the pandemic. Responses demonstrated increased reliance by healthcare providers and researchers on access to electronic health record (EHR) data, both for local needs and for sharing with other institutions and national consortia. The initial work of the CTSAs on data capture, standards, interchange, and sharing policies all contributed to solutions, best illustrated by the creation, in record time, of a national clinical data repository in the National COVID-19 Cohort Collaborative (N3C). The survey data support seven recommendations for areas of informatics and public health investment and further study to support clinical and translational research in the post-COVID-19 era., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Background: The Rockefeller University Center for Clinical and Translational Science (RU-CCTS) and Clinical Directors Network (CDN), a Practice-Based Research Network (PBRN), fostered a community-academic research partnership involving Community Health Center (CHCs) clinicians, laboratory scientists, clinical researchers, community, and patient partners. From 2011 to 2018, the partnership designed and completed Community-Associated Methicillin-Resistant Staphylococcus Aureus Project (CAMP1), an observational study funded by the National Center for Advancing Translational Sciences (NCATS), and CAMP2, a Comparative Effectiveness Research Study funded by the Patient-Centered Outcomes Research Institute (PCORI). We conducted a social network analysis (SNA) to characterize this Community-Engaged Research (CEnR) partnership., Methods: Projects incorporated principles of Community-Based Participatory Research (CAMP1/2) and PCORI engagement rubrics (CAMP2). Meetings were designed to be highly interactive, facilitate co-learning, share governance, and incentivize ongoing engagement. Meeting attendance formed the raw dataset enriched by stakeholder roles and affiliations. We used SNA software (Gephi) to form networks for four project periods, characterize network attributes (density, degree, centrality, vulnerability), and create sociograms. Polynomial regression models were used to study stakeholder interactions., Results: Forty-seven progress meetings engaged 141 stakeholders, fulfilling 7 roles, and affiliated with 28 organizations (6 types). Network size, density, and interactions across organizations increased over time. Interactions between Community Members or Recruiters/Community Health Workers and almost every other role increased significantly across CAMP2 ( P < 0.005); Community Members' centrality to the network increased over time., Conclusions: In a partnership with a highly interactive meeting model, SNA using operational attendance data afforded a view of stakeholder interactions that realized the engagement goals of the partnership., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2020.)

During the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has led to the infection of millions of people and has claimed hundreds of thousands of lives. The entry of the virus into cells depends on the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2. Although there is currently no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1-5 . Here we report on 149 COVID-19-convalescent individuals. Plasma samples collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres; titres were less than 50 in 33% of samples, below 1,000 in 79% of samples and only 1% of samples had titres above 5,000. Antibody sequencing revealed the expansion of clones of RBD-specific memory B cells that expressed closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on the RBD neutralized the virus with half-maximal inhibitory concentrations (IC 50 values) as low as 2 ng ml -1 . In conclusion, most convalescent plasma samples obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1-5 . Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC 50 s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective., Competing Interests: Declaration of conflict: In connection with this work The Rockefeller University has filed a provisional patent application on which D.F.R. and M.C.N. are inventors.

Introduction: Although the science of team science is no longer a new field, the measurement of team science and its standardization remain in relatively early stages of development. To describe the current state of team science assessment, we conducted an integrative review of measures of research collaboration quality and outcomes., Methods: Collaboration measures were identified using both a literature review based on specific keywords and an environmental scan. Raters abstracted details about the measures using a standard tool. Measures related to collaborations with clinical care, education, and program delivery were excluded from this review., Results: We identified 44 measures of research collaboration quality, which included 35 measures with reliability and some form of statistical validity reported. Most scales focused on group dynamics. We identified 89 measures of research collaboration outcomes; 16 had reliability and 15 had a validity statistic. Outcome measures often only included simple counts of products; publications rarely defined how counts were delimited, obtained, or assessed for reliability. Most measures were tested in only one venue., Conclusions: Although models of collaboration have been developed, in general, strong, reliable, and valid measurements of such collaborations have not been conducted or accepted into practice. This limitation makes it difficult to compare the characteristics and impacts of research teams across studies or to identify the most important areas for intervention. To advance the science of team science, we provide recommendations regarding the development and psychometric testing of measures of collaboration quality and outcomes that can be replicated and broadly applied across studies., (© The Association for Clinical and Translational Science 2019.)

Introduction: The patient portal may be an effective method for administering surveys regarding participant research experiences but has not been systematically studied., Methods: We evaluated 4 methods of delivering a research participant perception survey: mailing, phone, email, and patient portal. Participants of research studies were identified (n=4013) and 800 were randomly selected to receive a survey, 200 for each method. Outcomes included response rate, survey completeness, and cost., Results: Among those aged <65 years, response rates did not differ between mail, phone, and patient portal (22%, 29%, 30%, p >0.07). Among these methods, the patient portal was the lowest-cost option. Response rates were significantly lower using email (10%, p <0.01), the lowest-cost option. In contrast, among those aged 65+ years, mail was superior to the electronic methods ( p <0.02)., Conclusions: The patient portal was among the most effective ways to reach research participants, and was less expensive than surveys administered by mail or telephone.

Introduction: The validated Research Participant Perception Survey (RPPS-Long) elicits valuable data at modest response rates., Methods: To address this limitation, we developed shorter RPPS-Ultrashort and RPPS-Short versions, fielded them with the RPPS-Long to a random sample of a national research volunteer registry, and assessed response and completion rates, test/retest reliability, and demographics., Results: 2228 eligible registry members received survey links. Response rates were 64% (RPPS-Ultrashort), 63% (RPPS-Short), and 51% (RPPS-Long), respectively (P<0.001). Completion rates were 63%, 54%, and 37%, respectively (p<0.001). All surveys were reliable with Cronbach's alpha = 0.81, 0.84, and 0.87, respectively. Retest reliability was highest for RPPS-Short (Kappa=0.85). Provision of compensation increased RPPS-Short completion rate from 54% to 71% (p<0.001). Compensated respondents were younger (p<0.001), with greater minority representation (p=0.03)., Conclusions: Shorter surveys were reliable and produced higher response and completion rates then long surveys. Compensation further increased completion rates and shifted sample age and race profiles., Competing Interests: Conflict of Interest/Disclosure The authors have no conflicts of interest to disclose.

Introduction and Methods: The Rockefeller Clinical Scholars (KL2) Program began in 1976 and transitioned into a 3-year Master's degree program in 2006 when Rockefeller joined the NIH Clinical and Translational Science Award (CTSA) program. The program consists of ~15 trainees supported by the CTSA KL2 award and University funds. It is designed to provide an optimal environment for junior translational investigators to develop team science and leadership skills by designing and performing a human subjects protocol under the supervision of a distinguished senior investigator mentor and a team of content expert educators. This is complemented by a tutorial focused on important translational skills., Results: Since 2006, 40 Clinical Scholars have graduated from the programs and gone on to careers in academia (72%), government service (5%), industry (15%), and private medical practice (3%); two (5%) remain in training programs. 39/40 remain in translational research careers with 23 NIH awards totaling $23 million, foundation and philanthropic support of $20.3 million, and foreign government and foundation support of $6 million. They have made wide ranging scientific discoveries and have endeavored to translate those discoveries into improved human health., Conclusion: The Rockefeller Clinical Scholars (KL2) program provides one model for translational science training., Competing Interests: The authors reported no conflicts of interest related to this study.

Introduction: Obtaining informed consent from prospective participants for research studies that include next-generation nucleotide sequencing (NGS) presents significant challenges because of the need to explain all the potential implications of participating, including the possible return of "incidental" findings, in easy-to-understand language., Methods and Results: After reviewing the consent processes at other institutions, we decided to supplement the protocol-specific informed consent form with the following: (1) a short pamphlet for the prospective participant that includes a series of questions that she or he is encouraged to ask the investigator, and (2) a more detailed companion guide for investigators to help them develop simple-language answers to the questions. Both documents are available to use or modify., Conclusions: We propose an approach to obtaining informed consent for NGS studies that encourages discussion of key issues without creating a complex, comprehensive document for participants; it also maximizes investigator flexibility. We also suggest mechanisms to return restricted information to participants.

Problem: Engaging basic scientists in community-based translational research is challenging but has great potential for improving health., Approach: In 2009, The Rockefeller University Center for Clinical and Translational Science partnered with Clinical Directors Network, a practice-based research network (PBRN), to create a community-engaged research navigation (CEnR-Nav) program to foster research pairing basic science and community-driven scientific aims. The program is led by an academic navigator and a PBRN navigator. Through meetings and joint activities, the program facilitates basic science-community partnerships and the development and conduct of joint research protocols., Outcomes: From 2009-2014, 39 investigators pursued 44 preliminary projects through the CEnR-Nav program; 25 of those became 23 approved protocols and 2 substudies. They involved clinical scholar trainees, early-career physician-scientists, faculty, students, postdoctoral fellows, and others. Nineteen (of 25; 76%) identified community partners, of which 9 (47%) named them as coinvestigators. Nine (of 25; 36%) included T3-T4 translational aims. Seven (of 25; 28%) secured external funding, 11 (of 25; 44%) disseminated results through presentations or publications, and 5 (71%) of 7 projects publishing results included a community partner as a coauthor. Of projects with long-term navigator participation, 9 (of 19; 47%) incorporated T3-T4 aims and 7 (of 19; 37%) secured external funding., Next Steps: The CEnR-Nav program provides a model for successfully engaging basic scientists with communities to advance and accelerate translational science. This model's durability and generalizability have not been determined, but it achieves valuable short-term goals and facilitates scientifically meaningful community-academic partnerships.

Background: Staphylococcus aureus is the most common cause of Skin and Soft Tissue Infections (SSTIs) in the community in the United States of America. Community Health Centers (CHC) serve as primary care providers for thousands of immigrants in New York., Methods: As part of a research collaborative, 6 New York City-area CHCs recruited patients with SSTIs. Characterization was performed in all S. aureus isolates from wounds and nasal swabs collected from patients. Statistical analysis examined the differences in wound and nasal cultures among immigrant compared to native-born patients., Results: Wound and nasal specimens were recovered from 129 patients and tested for antibiotic susceptibility. 40 patients were immigrants from 15 different countries. Although not statistically significant, immigrants had lower rates of MRSA infections (n = 15) than did native-born participants, and immigrants showed significantly higher rates of MSSA wound cultures (n = 11) (OR = 3.5, 95% CI: 1.3, 9.7)., Conclusions: In our study, immigrants were more likely to present with SSTIs caused by MSSA than US-born patients. Immigants also reported lower frequencies of antibiotic prescription or consumption in the months prior to SSTI infection. This suggests that antibiotic resistance may vary regionally and that immigrants presenting with SSTIs may benefit from a broader range of antibiotics., Competing Interests: CONFLICTING AND COMPETING INTERESTS The authors do not have financial or other relationships with the manufacturer(s) of any commercial product(s) or provider(s) of any commercial service(s) discussed in this case report., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Infectious diseases, such as hepatitis C and community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), are emerging health issues., Objectives: The CA-MRSA Project (CAMP1) extended its learning collaborative to the barbershop/hair salon settings to increase awareness and prevention of CA-MRSA and hepatitis C infections., Methods: Education sessions on CA-MRSA and hepatitis C were conducted with 43 estheticians at nine barbershop/hair salons in New York City. All completed pre-post intervention knowledge tests. Low-cost primary care referral cards were also distributed in the CA-MRSA education project., Results: Knowledge about CA-MRSA risks (p < .0003) and infection prevention measures (p < .0001), as well as hepatitis C knowledge and prevention (both p < .0001) increased. Nine shops received referral cards (n = 500) and 4% of the cards (n = 19) were distributed to clients. No self-referrals were reported., Conclusions: CAMP1 successfully recruited and trained a cadre of estheticians on CA-MRSA and hepatitis C prevention increasing their health knowledge deepening our engagement with the community.

Background: Achieving timely accrual into clinical research studies remains a challenge for clinical translational research. We developed an evaluation measure, the Accrual Index (AI), normalized for sample size and study duration, using data from the protocol and study management databases. We applied the AI retrospectively and prospectively to assess its utility., Methods: Accrual Target, Projected Time to Accrual Completion (PTAC), Evaluable Subjects, Dates of Recruitment Initiation, Analysis, and Completion were defined. AI is (% Accrual Target accrued/% PTAC elapsed). Changes to recruitment practices were described, and data extracted from study management databases., Results: December 2014 (or final) AI was analyzed for 101 studies initiating recruitment from 2007 to 2014. Median AI was ≥1 for protocols initiating recruitment in 2011, 2013, and 2014. The AI varied widely for studies pre-2013. Studies with AI > 4 utilized convenience samples for recruitment. Data-justified PTAC was refined in 2013-2014 after which the AI range narrowed. Protocol characteristics were not associated with study AI., Conclusion: Protocol AI reflects the relative agreement between accrual feasibility assessment (PTAC), and accrual performance, and is affected by recruitment practices. The AI may be useful in managing accountability, modeling accrual, allocating recruitment resources, and testing innovations in recruitment practices., (© 2015 Wiley Periodicals, Inc.)

In November 2011, The Rockefeller University Center for Clinical and Translational Science (CCTS), the Laboratory of Microbiology and Infectious Diseases, and Clinical Directors Network (CDN) launched a research and learning collaborative project with six community health centers in the New York City metropolitan area to determine the nature (clonal type) of community-acquired Staphylococcus aureus strains causing skin and soft tissue infections (SSTIs). Between November 2011 and March 2013, wound and nasal samples from 129 patients with active SSTIs suspicious for S. aureus were collected and characterized by molecular typing techniques. In 63 of 129 patients, the skin wounds were infected by S. aureus: methicillin-resistant S. aureus (MRSA) was recovered from 39 wounds and methicillin-sensitive S. aureus (MSSA) was recovered from 24. Most-46 of the 63-wound isolates belonged to the CC8/Panton-Valentine leukocidin-positive (PVL(+)) group of S. aureus clone USA300: 34 of these strains were MRSA and 12 were MSSA. Of the 63 patients with S. aureus infections, 30 were also colonized by S. aureus in the nares: 16 of the colonizing isolates were MRSA, and 14 were MSSA, and the majority of the colonizing isolates belonged to the USA300 clonal group. In most cases (70%), the colonizing isolate belonged to the same clonal type as the strain involved with the infection. In three of the patients, the identity of invasive and colonizing MRSA isolates was further documented by whole-genome sequencing., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: A 24-year-old female with recurrent skin and soft tissue infections (SSTI) was enrolled as part of a multicenter observational cohort study conducted by a practice-based research network (PBRN) on community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)., Methods: Strains were characterized by pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing. MRSA strains were analyzed for SCCmec type and the presence of the Panton-Valentine leukocidin (PVL) and arginine catabolic mobile element (ACME) using PCR., Results: In the first episode, S. aureus was recovered from the wound and inguinal folds; in the second, S. aureus was recovered from a lower abdomen furuncle, inguinal folds, and patellar fold. Molecular typing identified CA-MRSA clone USA300 in all samples as spa-type t008, ST8, SCCmecIVa, and a typical PFGE pattern. The strain carried virulence genes pvl and ACME type I. Five SSTI episodes were documented despite successful resolution by antibiotic treatment, with and without incision and drainage., Conclusions: The source of the USA300 strain remains unknown. The isolate may represent a persistent strain capable of surviving extensive antibiotic pressure or a persistent environmental reservoir may be the source, possibly in the patient's household, from which bacteria were repeatedly introduced into the skin flora with subsequent infections.

Background: Underenrollment of clinical studies wastes resources and delays assessment of research discoveries. We describe the organization and impact of a centralized recruitment core delivering comprehensive recruitment support to investigators., Methods: The Rockefeller University Center for Clinical and Translational Science supports a centralized recruitment core, call center, Research Volunteer Repository, data infrastructure, and staff who provide expert recruitment services to investigators. During protocol development, consultations aim to optimize enrollment feasibility, develop recruitment strategy, budget, and advertising. Services during study conduct include advertising placement, repository queries, call management, prescreening, referral, and visit scheduling. Utilization and recruitment outcomes are tracked using dedicated software., Results: For protocols receiving recruitment services during 2009-2013: median time from initiation of recruitment to the first enrolled participant was 10 days; of 4,047 first-time callers to the call center, 92% (n = 3,722) enrolled in the Research Volunteer Repository, with 99% retention; 23% of Repository enrollees subsequently enrolled in ≥1 research studies, with 89% retention. Of volunteers referred by repository queries, 49% (280/537) enrolled into the study, with 92% retained., Conclusions: Provision of robust recruitment infrastructure including expertise, a volunteer repository, data capture and real-time analysis accelerates protocol accrual. Application of recruitment science improves the quality of clinical investigation., (© 2014 Wiley Periodicals, Inc.)

Background: Although research participation is essential for clinical investigation, few quantitative outcome measures exist to assess participants' experiences. To address this, we developed and deployed a survey at 15 NIH-supported clinical research centers to assess participant-centered outcomes; we report responses from 4,961 participants., Methods: Survey questions addressed core aspects of the research participants' experience, including their overall rating, motivation, trust, and informed consent. We describe participant characteristics, responses to individual questions, and correlations among responses., Results: Respondents broadly represented the research population in sex, race, and ethnicity. Seventy-three percent awarded top ratings to their overall research experience and 94% reported no pressure to enroll. Top ratings correlated with feeling treated with respect, listened to, and having access to the research team (R(2) = 0.80-0.96). White participants trusted researchers more (88%) than did nonwhite participants collectively (80%; p < 0.0001). Many participants felt fully prepared by the informed consent process (67%) and wanted to receive research results (72%)., Conclusions: Our survey demonstrates that a majority of participants at NIH-supported clinical research centers rate their research experience very positively and that participant-centered outcome measures identify actionable items for improvement of participant's experiences, research protections, and the conduct of clinical investigation., (© 2014 Wiley Periodicals, Inc.)

Purpose: To respond to increased public and programmatic demand to address underenrollment of clinical translational research studies, the authors examined participant recruitment practices at Clinical and Translational Science Award (CTSA) sites and make recommendations for performance metrics and accountability., Method: The CTSA Recruitment and Retention taskforce in 2010 invited representatives at 46 CTSAs to complete an online 48-question survey querying accrual and recruitment outcomes, practices, evaluation methods, policies, and perceived gaps in related knowledge/practice. Descriptive statistical and thematic analyses were conducted., Results: Forty-six respondents representing 44 CTSAs completed the survey. Recruitment conducted by study teams was the most common practice reported (78%-91%, by study type); 39% reported their institution offered recruitment services to investigators. Respondents valued study feasibility assessment as a successful practice (39%); desired additional resources included feasibility assessments (49%) and participant registries (44%). None reported their institution systematically required justification of feasibility; some indicated relevant information was considered prior to institutional review board (IRB) review (30%) or contract approval (22%). All respondents' IRBs tracked study progress, but only 10% of respondents could report outcome data for timely accrual. Few reported written policies addressing poor accrual or provided data to support recruitment practice effectiveness., Conclusions: Many CTSAs lack the necessary frame work to support study accrual. Recom men dations to enhance accrual include articulating institutional expectations and policy for routine recruitment plan ning; providing recruitment expertise to inform feasibility assessment and recruit ment planning; and developing interdepartmental coordination and integrated informatics infrastructure to drive the conduct, evaluation, and improvement of recruitment practices.

The development of translational clinical research protocols is complex. To assist investigators, we developed a structured supportive guidance process (Navigation) to expedite protocol development to the standards of good clinical practice (GCP), focusing on research ethics and integrity. Navigation consists of experienced research coordinators leading investigators through a concerted multistep protocol development process from concept initiation to submission of the final protocol. To assess the effectiveness of Navigation, we collect data on the experience of investigators, the intensity of support required for protocol development, IRB review outcomes, and protocol start and completion dates. One hundred forty-four protocols underwent Navigation and achieved IRB approval since the program began in 2007, including 37 led by trainee investigators, 26 led by MDs, 9 by MD/PhDs, 57 by PhDs, and 12 by investigators with other credentials (e.g., RN, MPH). In every year, more than 50% of Navigated protocols were approved by the IRB within 30 days. For trainees who had more than one protocol navigated, the intensity of Navigation support required decreased over time. Navigation can increase access to translational studies for basic scientists, facilitate GCP training for investigators, and accelerate development and approval of protocols of high ethical and scientific quality., (© 2014 Wiley Periodicals, Inc.)

Introduction: Clinical research participants' perceptions regarding their experiences during research protocols provide outcome-based insights into the effectiveness of efforts to protect rights and safety, and opportunities to enhance participants' clinical research experiences. Use of validated surveys measuring patient-centered outcomes is standard in hospitals, yet no instruments exist to assess outcomes of clinical research processes., Methods: We derived survey questions from data obtained from focus groups comprised of research participants and professionals. We assessed the survey for face/content validity, and privacy/confidentiality protections and fielded it to research participants at 15 centers. We conducted analyses of response rates, sample characteristics, and psychometrics, including survey and item completion and analysis, internal consistency, item internal consistency, criterion-related validity, and item usefulness. Responses were tested for fit into existing patient-centered dimensions of care and new clinical research dimensions using Cronbach's alpha coefficient., Results: Surveys were mailed to 18,890 individuals; 4,961 were returned (29%). Survey completion was 89% overall; completion rates exceeded 90% for 88 of 93 evaluable items. Questions fit into three dimensions of patient-centered care and two novel clinical research dimensions (Cronbach's alpha for dimensions: 0.69-0.85)., Conclusions: The validated survey offers a new method for assessing and improving outcomes of clinical research processes., (© 2012 Wiley Periodicals, Inc.)

Purpose: In 2000, the National Center for Research Resources mandated that general research centers create a research subject advocate (RSA) position. In 2008, the Clinical and Translational Science Award (CTSA) consortium endorsed a new advocacy model based on four RSA Best Practice Functions. The authors surveyed CTSA centers to learn about their implementation of programs to fulfill the RSA functions., Method: In 2010, the RSA taskforce developed a two-part online survey to examine leadership, organizational structure, governance, scope, collaboration and integration, and funding and evaluation of RSA activities implemented at CTSA centers., Results: Respondents from 45 RSA programs at 43 CTSA centers completed the survey. Senior university or CTSA officials led all programs. Ninety-six percent (43/45) of programs were funded by a CTSA core. Eighty percent (36/45) designated an individual "RSA." Ninety-eight percent (44/45) provided diverse services either in collaboration with or complementary to other departments, including development of data and safety monitoring plans (16/45; 36%), informed consent observation (10/45; 22%), training responsive to audit findings (12/45; 27%), and direct advocacy services to participants (11/45; 24%). Eighty-six percent (24/28) reported qualitative evaluation methods for these activities., Conclusions: RSA programs conduct both collaborative and unique research protection activities. This survey, an initial step in developing a more robust mechanism for evaluating RSA programs, collected valuable feedback. The authors recommend defining and developing outcome-based evaluation measures that take the heterogeneity of the individual RSA programs into account while advancing their value and effectiveness in protecting human research subject participants.

Community engagement is increasingly becoming an integral part of research. "Community-engaged research" (CEnR) introduces new stakeholders as well as unique challenges to the protection of participants and the integrity of the research process. We--a group of representatives of CTSA-funded institutions and others who share expertise in research ethics and CEnR--have identified gaps in the literature regarding (1) ethical issues unique to CEnR; (2) the particular instructional needs of academic investigators, community research partners, and IRB members; and (3) best practices for teaching research ethics. This paper presents what we know, as well as what we still need to learn, in order to develop quality research ethics educational materials tailored to the full range of stakeholder groups in CEnR.

Introduction: Participants' perceptions of their research experiences provide valuable measures of ethical treatment, yet no validated instruments exist to measure these experiences. We conducted focus groups of research participants and professionals as the initial step in developing a validated instrument., Methods: Research participants enrolled in 12 focus groups, consisting of: (1) individuals with disorders undergoing interventions; (2) in natural history studies; or (3) healthy volunteers. Research professionals participated in six separate groups of: (1) institutional review board members, ethicists, and Research Subject Advocates; (2) research nurses/coordinators; or (3) investigators. Focus groups used standard methodologies., Results: Eighty-five participants and 29 professionals enrolled at eight academic centers. Altruism and personal relevance of the research were commonly identified motivators; financial compensation was less commonly mentioned. Participants were satisfied with informed consent processes but disappointed if not provided test results, or study outcomes. Positive relationships with research teams were valued highly. Research professionals were concerned about risks, undue influence, and informed consent., Conclusions: Participants join studies for varied, complex reasons, notably altruism and personal relevance. They value staff relationships, health gains, new knowledge, and compensation, and expect professionalism and good organization. On the basis of these insights, we propose specific actions to enhance participant recruitment, retention, and satisfaction., (© 2011 Wiley Periodicals, Inc.)

Objective: To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood., Design: Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-gamma ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV)., Methods: Peripheral blood-derived monocytes were cultured for 5-6 days in the presence of IL-4 and granulocyte macrophage colony-stimulating factor, then matured in monocyte-conditioned medium. MDC were infected with r-VV and co-cultured in an ELISPOT assay with autologous monocyte-depleted PBMC., Results: Relative to autologous monocytes, MDC amplified detection of antigen-specific CD8 T cells by 2-30-fold in response to antigens from HIV-1, Epstein-Barr virus and cytomegalovirus. Furthermore, antigenic specificities were revealed that had not been detected using standard ELISPOT of PBMC., Conclusion: This assay will prove useful for the detection of memory T cells present at low frequency, and may be of interest for identifying subdominant cytotoxic T lymphocyte epitopes. This method may have broad applications for the detection of antiviral CD8 T cell responses in patient populations in whom such responses have been difficult to detect, including HIV-1-seropositive individuals with advanced disease or undergoing HAART.

A Phase II clinical trial was designed to evaluate the efficacy and tolerability of twice-daily abacavir, amprenavir, and zidovudine (ZDV)/lamivudine (3TC) in HIV-1-infected study subjects naive to protease inhibitors and 3TC. Plasma and cerebrospinal fluid (CSF) HIV-1 RNA levels and T-cell subsets were measured. In all, 27 newly diagnosed and 12 chronically HIV-1-infected study subjects are included in the analysis. Week 48 plasma HIV-1 RNA levels were <500 copies/ml in 100% of study subjects, and <50 copies/ml in 80% of chronically infected and 100% of newly infected study subjects. The mean change in CD4 was (+)150 cells/microl (newly infected, p <.001), and (+)155 cells/microl (chronically infected, p <.001). At Week 48, evidence of cellular activation persisted in both cohorts. A twice-daily regimen of amprenavir, abacavir, and ZDV/3TC affords potent viral suppression and significant increases in total CD4(+) cells in HIV-1--infected study subjects. Patient intolerance may limit the efficacy of this combination.

To determine the safety, immunogenicity, and efficacy of a recombinant herpes simplex virus type 2 glycoprotein D and B vaccine in the treatment of recurrent genital herpes, a randomized, placebo-controlled trial was held at two referral centers. Healthy patients with 4-14 recurrences per year received injections of both glycoproteins in MF59 adjuvant or of MF59 alone at 0, 2, 12, and 14 months. For 18 study months, the rate and number of recurrences, the duration and severity of the first confirmed recurrence, vaccine immunogenicity, and rates of local and systemic reactions were determined. The monthly rate of recurrences was not significantly improved, but the duration and severity of the first study outbreak was reduced significantly by vaccination. Glycoprotein-specific and neutralizing antibodies were boosted by vaccination for the duration of the study. This vaccine is safe and immunogenic and ameliorated an observed first postvaccination genital recurrence, but it does not reduce recurrence frequency.

Pain typically accompanies acute herpes zoster and, in a proportion of patients, it persists well beyond rash healing. Pain must therefore be analyzed in trials of antiviral agents in herpes zoster, but different methods have been used to analyze pain in recent published trials. These reports are reviewed and their methodological strengths and weaknesses examined. Based on this review, recommendations for the design and analysis of future trials of antiviral agents in herpes zoster are proposed. The principal recommendation is that antiviral efficacy should be evaluated both by distinguishing post-herpetic neuralgia from acute pain and by considering pain as a continuum. The primary endpoint should address both the prevalence and duration of post-herpetic neuralgia and should be examined in those patients who have post-herpetic neuralgia. Adopting the proposed recommendations in design and analysis of future trials should facilitate comparison across trials of the efficacy of antiviral agents in the treatment of herpes zoster.

The varicella-zoster virus (VZV) putative immediate-early (IE) protein encoded by ORF63 is the homolog of HSV-1 ICP-22. To further characterize ORF63 and its function, Northern analysis, primer extension, and S1 nuclease assays were used to map its transcripts, and transient transfection assays were performed with constructs containing ORF63 or its promoter region. Two transcripts were identified: a 0.9-kb transcript spans ORF63 alone, and a 1.8-kb transcript reads through ORF64. Two prominent transcription start sites were identified at -88 and -157 relative to the ORF63 ATG, and two potential TATA elements were identified. In transient transfection assays, the 63 promoter was weakly activated by VZV ORF4 and ORF62 under their homologous promoters, was more strongly activated by ORF62 under the control of a constitutive CMV promoter, and was synergistically activated by ORFs 4 and 62 together. ORF63, driven by its own or by a heterologous SV40 promoter, exerted minimal effects on diverse VZV putative IE and early promoters, showed no clear evidence of autoregulation, and did not directly inhibit the ORF62 promoter as had been reported previously. ORF63's behavior in transient assays suggests that it plays only a limited regulatory role in modulating VZV gene expression.

Immunotherapy of chronic viral diseases with vaccines is an important but unproven concept. We investigated the effect of a vaccine containing recombinant glycoprotein D (gD2) of herpes simplex virus type 2 (HSV-2) on the frequency of symptomatic outbreaks in patients with genital herpes. 98 patients with documented genital herpes who reported 4-14 recurrences per year were enrolled in a double-blind, placebo-controlled trial. Subjects received injections of either 100 micrograms gD2 in alum or alum alone (placebo) at 0 and 2 months, and recurrences were documented for 1 year. The vaccine was well tolerated. gD2 recipients reported fewer recurrences per month than placebo recipients (mean 0.42 [SE 0.05] vs 0.55 [0.05]; p = 0.055), had fewer virologically confirmed recurrences per month (0.18 [0.03] vs 0.28 [0.03]; p = 0.019), and had a lower median number of recurrences for the study year (4 [range 0-17] vs 6 [0-15]; p = 0.039). Neither genital recurrence nor the placebo vaccine had any discernible effect on HSV-2-specific antibody responses, but gD2 vaccine boosted neutralising antibodies to HSV-2 fourfold and gD2-specific titres sevenfold over baseline levels. These results inspire optimism about the potential use of vaccine for the treatment of chronic, recurring viral diseases.