Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants: Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions: Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures: The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results: Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

The Trial Innovation Network Liaison Team: building a national clinical and translational community of practice.

In 2016, the National Center for Advancing Translational Science launched the Trial Innovation Network (TIN) to address barriers to efficient and informative multicenter trials. The TIN provides a national platform, working in partnership with 60+ Clinical and Translational Science Award (CTSA) hubs across the country to support the design and conduct of successful multicenter trials. A dedicated Hub Liaison Team (HLT) was established within each CTSA to facilitate connection between the hubs and the newly launched Trial and Recruitment Innovation Centers. Each HLT serves as an expert intermediary, connecting CTSA Hub investigators with TIN support, and connecting TIN research teams with potential multicenter trial site investigators. The cross-consortium Liaison Team network was developed during the first TIN funding cycle, and it is now a mature national network at the cutting edge of team science in clinical and translational research. The CTSA-based HLT structures and the external network structure have been developed in collaborative and iterative ways, with methods for shared learning and continuous process improvement. In this paper, we review the structure, function, and development of the Liaison Team network, discuss lessons learned during the first TIN funding cycle, and outline a path toward further network maturity.

Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41- 0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19.

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

NIH's Helping to End Addiction Long-termSM Initiative (NIH HEAL Initiative) Clinical Pain Management Common Data Element Program.

The Helping to End Addiction Long-term Initiative (NIH HEAL Initiative) is an aggressive trans-NIH effort to speed solutions to stem the national opioid public health crisis, including through improved pain management. Toward this end, the NIH HEAL Initiative launched a common data element (CDE) program to ensure that NIH-funded clinical pain research studies would collect data in a standardized way. NIH HEAL Initiative staff launched a process to determine which pain-related core domains should be assessed by every clinical pain study and what questionnaires are required to ensure that the data is collected uniformly. The process involved multiple literature reviews, and consultation with experts inside and outside of NIH and the investigators conducting studies funded by the initiative. Ultimately, 9 core pain domains, and questionnaires to measure them, were chosen for studies examining acute pain and chronic pain in adults and pediatric populations. These were augmented with dozens of study-specific supplemental questionnaires to enable uniform data collection methods of outcomes outside of the core domains. The selection of core domains will ensure that valuable clinical pain data generated by the initiative is standardized, useable for secondary data analysis, and useful for guiding future research, clinical practice decisions, and policymaking. PERSPECTIVE: The NIH HEAL Initiative launched a common data element program to ensure that NIH-funded clinical pain research studies would collect data in a standardized way. Nine core pain domains and questionnaires to measure them were chosen for studies examining acute pain and chronic pain in adults and pediatric populations.

Empathy in Medical Education: Its Nature and Nurture - a Qualitative Study of the Views of Students and Tutors.

Context: Medical education is committed to teaching patient centred communication and empathy. However, quantitative research suggests empathy scores tend to decline as students progress through medical school. In qualitative terms, there is a need to better understand how students and tutors view the practice and teaching of clinical empathy and the phenomenon of empathic erosion. Methods: Working within a constructivist paradigm, researchers thematically analysed the individual interview data from a purposive sample of 13 senior students and 9 tutors. Results: The four major themes were as follows: (1) 'the nature of empathy', including the concept of the innate empathy that students already possess at the beginning of medical school; (2) 'beyond the formal curriculum' and the central importance of role modelling; (3) 'the formal curriculum and the tick-box influence of assessments'; and (4) the 'durability of empathy', including ethical erosion and resilience. A garden model of empathy development is proposed - beginning with the innate seeds of empathy that students bring to medical school, the flowering of empathy is a fragile process, subject to both enablers and barriers in the formal, informal, and hidden curricula. Conclusion: This study provides insights into empathic erosion in medical school, including the problems of negative role modelling and the limitations of an assessment system that rewards 'tick-box' representations of empathy, rather than true acts of compassion. It also identifies factors that should enable the flowering of empathy, such as new pedagogical approaches to resilience and a role for the arts and humanities.

Platypnoea and orthodeoxia in the hepatopulmonary syndrome.

A 71-year-old female patient with alcohol-induced cirrhosis presented with symptoms of dyspnoea. Previous extensive investigations had detected no apparent cause. Platypnoea and orthodeoxia were observed. A bubble echocardiogram revealed significant intracardiac shunting and a diagnosis of hepatopulmonary syndrome was made. The patient was discharged on home oxygen and referred for liver transplantation.

Twelve tips for the recruitment and retention of general practitioners as teachers of medical students.

BACKGROUND: Primary care physicians have become a fundamental aspect of teaching in modern medical school curricula worldwide with a significant proportion of undergraduate teaching taking place in primary care. There are calls for this to increase with more patient care occurring in the community but teaching capacity in primary care is a potential challenge. Medical schools, therefore, need strategies to be able to increase their primary care physician teaching workforce. METHODOLOGY: We asked all Heads of General Practice Teaching in UK medical schools to share their three top tips for recruiting and retaining GPs to teach undergraduate students. The majority (two-thirds) of medical schools responded and we have summarized the answers into the following twelve tips. RESULTS: Although the twelve tips are varied and comprehensive, including broad topics such as finances and training, one clear theme running through the majority of tips is good communication and relationships between education teams and GPs. CONCLUSIONS: The solutions to recruiting and retaining GPs to teach undergraduate medical students are clearly multifactorial and complex. We hope that by presenting suggestions from UK GP heads of teaching as these twelve tips provides some helpful, thought-provoking ideas and inspiration for both the UK and internationally.

The prevalence of caries and tooth loss among participants in the Hispanic Community Health Study/Study of Latinos.

BACKGROUND: The Hispanic and Latino population is projected to increase from 16.7 percent to 30.0 percent by 2050. Previous U.S. national surveys had minimal representation of Hispanic and Latino participants other than Mexicans, despite evidence suggesting that Hispanic or Latino country of origin and degree of acculturation influence health outcomes in this population. In this article, the authors describe the prevalence and mean number of cavitated, decayed and filled surfaces, missing teeth and edentulism among Hispanics and Latinos of different national origins. METHODS: Investigators in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-a multicenter epidemiologic study funded by the National Heart, Lung, and Blood Institute with funds transferred from six other institutes, including the National Institute of Dental and Craniofacial Research-conducted in-person examinations and interviews with more than 16,000 participants aged 18 to 74 years in four U.S. cities between March 2008 and June 2011. The investigators identified missing, filled and decayed teeth according to a modified version of methods used in the National Health and Nutrition Examination Survey. The authors computed prevalence estimates (weighted percentages), weighted means and standard errors for measures. RESULTS: The prevalence of decayed surfaces ranged from 20.2 percent to 35.5 percent, depending on Hispanic or Latino background, whereas the prevalence of decayed and filled surfaces ranged from 82.7 percent to 87.0 percent, indicating substantial amounts of dental treatment. The prevalence of missing teeth ranged from 49.8 percent to 63.8 percent and differed according to Hispanic or Latino background. Significant differences in the mean number of decayed surfaces, decayed or filled surfaces and missing teeth according to Hispanic and Latino background existed within each of the age groups and between women and men. CONCLUSIONS: Oral health status differs according to Hispanic or Latino background, even with adjustment for age, sex and other characteristics. PRACTICAL IMPLICATIONS: These data indicate that Hispanics and Latinos in the United States receive restorative dental treatment and that practitioners should consider the association between Hispanic or Latino origin and oral health status. This could mean that dental practices in areas dominated by patients from a single Hispanic or Latino background can anticipate a practice based on a specific pattern of treatment needs.

Salivary gland involvement in chronic graft-versus-host disease: prevalence, clinical significance, and recommendations for evaluation.

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Aquaporin-1 gene transfer to correct radiation-induced salivary hypofunction.

Irradiation damage to salivary glands is a common iatrogenic consequence of treatment for head and neck cancers. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective conventional therapy. To address this problem, we developed an in vivo gene therapy strategy involving viral vector-mediated transfer of the aquaporin-1 cDNA to irradiation-damaged glands and successfully tested it in two pre-clinical models (irradiated rats and miniature pigs), as well as demonstrated its safety in a large toxicology and biodistribution study. Thereafter, a clinical research protocol was developed that has received approval from all required authorities in the United States. Patients are currently being enrolled in this study.

Management of oral lesions in HIV-positive patients.

HIV/AIDS is currently the leading cause of death in Africa and the fourth leading cause of death worldwide. This systematic review of the literature was conducted to evaluate the evidence for treatment of the most common oral lesions associated with HIV: oral candidiasis with or without oropharyngeal involvement (OPC), oral hairy leukoplakia (OHL), recurrent aphthous-like ulcerations (RAU), oral Kaposi's sarcoma (OKS), orolabial herpes simplex infection (HSV), oral herpes zoster infection (VZV), intraoral or perioral warts (HPV), and HIV-associated periodontal diseases. Treatment of HIV-associated salivary gland disease is addressed in a different section of this World Workshop. We found the largest body of evidence for treatment of OPC in HIV patients. Future trials will be needed to test drugs currently in development for treatment of Candida strains that are resistant to existing therapies. There were no double blind, placebo-controlled randomized clinical trials (RCT) for topical treatment of OHL, and only one RCT for systemic treatment of the lesion with desciclovir. Systemic thalidomide was the only drug tested in RCT for treatment or prevention of RAU. Only 1 double-blind RCT comparing vinblastine and sodium tetradecyl sulfate was identified for localized treatment of OKS. Three drugs (famciclovir, acyclovir, and valaciclovir) were shown to be effective in randomized, double-blind trials for treatment or suppression of mucocutaneous HSV lesions in HIV patients. In all 3 trials, the effects of these medications on orolabial HSV lesions were not reported separately. There were no double-blind, placebo-controlled RCT testing topical treatments for orolabial HSV lesions in HIV patients. No trials testing treatments of oral VZV were identified. There were no double-blind, placebo-controlled RCT for treatment of HIV-associated intraoral or perioral warts or periodontal diseases. In conclusion, there is a need for well-designed RCTs to assess the safety and efficacy of topical and systemic treatments of most oral mucosal and perioral lesions in HIV patients. There is also a need to develop newer drugs for treatment of resistant fungal and viral microorganisms. Finally, standardized outcome measures should be developed for future clinical trials to allow comparisons of studies using different populations.

Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is frequently complicated by severe infections and graft-vs-host disease (GVHD). Saliva contains many components of adaptive and innate immune response crucial for local host defenses. Changes in salivary constituents could reflect systemic processes such as immune reconstitution and development of GVHD that occur posttransplant. This study was an initial evaluation of salivary protein changes that occur after allo-HCT. PATIENTS AND METHODS: Serially collected saliva samples from 41 patients undergoing allo-HCT were evaluated. Changes in salivary proteome were initially examined by SELDI-TOF mass spectrometry. Individual protein changes were identified by 2-dimensional differential in-gel electrophoresis (2D-DIGE) with subsequent MS/MS sequencing and ELISA. RESULTS: Significant increases and decreases in multiple salivary proteins that lasted at least 2 months posttransplant were detected by SELDI-TOF mass spectrometry. Lactoferrin and secretory leukocyte protease inhibitor demonstrated elevations 1 month post-HCT that persisted at least 6 months. Secretory IgA (sIgA) levels were decreased 1 month posttransplant, with recovery at approximately 6 months. Levels of salivary beta(2)-microglobulin were elevated at 6 months and correlated with sIgA levels. CONCLUSION: Allo-HCT is associated with long-term changes in several salivary proteins important for innate immune responses. These results support further studies on the association of salivary proteins with posttransplant complications including infections and GVHD.

Chronic graft versus host disease of oral mucosa: review of available therapies.

The use of hematopoetic stem cell transplantation (HSCT) has greatly expanded in the recent years for many neoplastic and hematological disorders. Chronic graft versus host disease (cGVHD) is a major complication of allogeneic HSCT and a major cause of morbidity and mortality. Oral mucosal involvement is frequent in cGVHD and contributes significantly to the overall burden of the condition. Oral medicine professionals should be familiar with various treatment options for oral cGVHD. This review discusses treatment modalities available for the management of oral mucosal manifestations of cGVHD. Available evidence for efficacy and safety of various systemic and topical agents, including corticosteroids, calcineurin antagonists, mycophenolate mofetil, and extracorporeal photopheresis, is reviewed.

Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report.

This consensus document provides an update for pathologists and clinicians about the interpretation of biopsy results and use of this information in the management of hematopoietic cell transplantation patients. Optimal sampling and tissue preparation are discussed. Minimal criteria for the diagnosis of graft-versus-host disease (GVHD) are proposed, together with specific requirements for the diagnosis of chronic GVHD. Four final diagnostic categories (no GVHD, possible GVHD, consistent with GVHD, and definite GVHD) reflect the integration of histopathology with clinical, laboratory, and radiographic information. Finally, the Working Group developed a set of worksheets to facilitate communication of clinical information to the interpreting pathologist and to aid in clinicopathologic correlation studies. Forms are available at . The recommendations of the Working Group represent a consensus opinion supplemented by evaluation of available peer-reviewed literature. Consensus recommendations and suggested data-capture forms should be validated in prospective clinicopathologic studies.