Application of Transthoracic Echocardiography for Cardiac Safety Evaluation in the Clinical Development Process of Vaccines Against Streptococcus pyogenes.

Superficial infections with Streptococcus pyogenes (Strep A), pharyngitis and impetigo can induce acute rheumatic fever, an autoimmune sequela manifesting mostly with arthritis and rheumatic carditis. Valvular heart damage can persist or advance following repeated episodes of acute rheumatic fever, causing rheumatic heart disease. Acute rheumatic fever and rheumatic heart disease disproportionately affect children and young adults in developing countries and disadvantaged communities in developed countries. People living with rheumatic heart disease are at risk of experiencing potentially fatal complications such as heart failure, bacterial endocarditis or stroke. Transthoracic echocardiography plays a central role in diagnosing both rheumatic carditis and rheumatic heart disease. Despite the obvious medical need, no licensed Strep A vaccines are currently available, as their clinical development process faces several challenges, including concerns for cardiac safety. However, the development of Strep A vaccines has been recently relaunched by many vaccine developers. In this context, a reliable and consistent safety evaluation of Strep A vaccine candidates, including the use of transthoracic echocardiography for detecting cardiac adverse events, could greatly contribute to developing a safe and efficacious product in the near future. Here, we propose a framework for the consistent use of transthoracic echocardiography to proactively detect cardiac safety events in clinical trials of Strep A vaccine candidates.

Throat and skin infections caused by certain types of bacteria, named Streptococcus pyogenes, are frequent worldwide; however, in many children from less developed countries and disadvantaged communities, infections with S. pyogenes lead to a condition called acute rheumatic fever, which usually affects the joints and the heart. Damage to the heart valves may evolve to rheumatic heart disease, a permanent condition with often life-threatening complications. Rheumatic heart disease is an important health problem in places and communities where S. pyogenes infections occur frequently. A vaccine against these bacteria would help lower the number of people with valvular heart disease; however, no such vaccine exists yet. Research on vaccines against S. pyogenes was on hold for almost 30 years because of initial concerns that vaccinated children might develop acute rheumatic fever more frequently. Recently, researchers started working again on vaccines against S. pyogenes, but concerns about the safety of such vaccines persist. Doctors can reliably use echocardiography to diagnose cases of rheumatic carditis (as a sign of acute rheumatic fever) and rheumatic heart disease. Here, we propose a simple approach for the consistent use of echocardiography in clinical research of vaccines against S. pyogenes that will allow the detection of any potential heart-related side effects of the vaccine.

WORDS: A New Verbal Memory Test to Evaluate Cognitive Health in a Zambian School-aged Population.

Objective: The paucity of psychometric instruments is one of the challenges preventing the effective implementation of child cognitive health testing in Sub-Saharan countries. WORDS is a new memory assessment tool originally validated in a Zambian school-aged population. Design: WORDS involves the standardized administration of a multitrial, verbal, free recall task with acquisition and immediate recall of a structured list of 16 words, followed by a second acquisition and delayed recall after a five-minute interference. A field trial was carried out to evaluate test feasibility of use, reliability, and validity. A total of 448 children, aged 5 to 17 years, were recruited at multiple Zambian clinical sites and schools. Results: WORDS provides a summary score of recall productivity derived from the sum of items correctly retrieved at immediate and delayed recalls. Recall productivity showed a moderate/good reliability at test-retest with alternate forms (N=53, 95% confidence interval of the intraclass correlation [CI-IC]: 0.73, 0.54-0.85). Recall productivity was found to increase with age. Altered memory functioning, as indicated by lower recall productivity, was associated with poor health status resulting from chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation [recall productivity, range: 0-32, healthy mean (standard deviation [SD]): 15.36 (4.7) vs. poor health, mean (SD): 12.62 (4.8); F (1,446)=27.79, p=0.000, d=0.58]. Conclusion: WORDS addresses the need for new psychometric tools to evaluate memory in a school-aged Zambian population. WORDS has the potential for clinical utility to evaluate cognitive development, as well as the effect of different health conditions on memory. Study results warrant research to further validate its use in Sub-Saharan clinical and epidemiological research settings.

WAVES: A Novel Test to Evaluate Visuospatial Construction Ability in a School-aged Population.

Objective: The paucity of valid diagnostic tools is one of the challenges preventing the effective implementation of child cognitive health testing in Sub-Saharan developing countries. WAVES addresses the need for new psychometric tests to evaluate visuospatial construction ability in a school-aged population. WAVES involves the standardized administration of a copy design task that is sequentially repeated by four distinct reproduction modalities: copy design with open eyes (CDO), immediate reproduction from memory with open eyes (IRMO), immediate reproduction from memory with closed eyes (IRMC), and delayed reproduction from memory with closed eyes (DRMC). Design: WAVES reliability and validity were assessed in a field trial using Classical Test Theory or Item Response Theory (IRT) methods. A total of 445 children, aged 5 to 17 years old, were recruited at multiple Zambian clinical sites and schools. Results: WAVES provides a visuographomotor construction processing (VGCP) index and three subscale inaccuracy of reproduction scores: perseveration, decreased spacing, and changing direction difficulty (CDD). WAVES scores depended on age and showed an age-related increase of reproduction accuracy. Altered visuospatial construction, as indicated by higher scores, was associated with poor health status (i.e., chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation). Reliability estimates, expressed as an intraclass correlation coefficient (ICC; 95% confidence interval [CI]), at test-retest (n=86) were: VGCP Index: 0.94 (0.91, 0.96); perseveration: 0.76 (0.62, 0.84); decreased spacing: 0.86 (0.79, 0.91); and CDD: 0.93 (0.89, 0.95). Conclusion: WAVES has potential for clinical utility in evaluating the effect of different health conditions on visuospatial construction ability. Study results warrant further research to validate its use in healthcare and clinical research settings.

Development of a Symbol Cancellation Test to Evaluate Attention in a School-aged Zambian Population.

Objective: The assessment of child cognitive health in Sub-Saharan developing countries poses significant challenges, including the paucity of valid diagnostic tools. We report the development and the initial validation of the Zambia Symbol Cancellation Test (ZSCT), a psychometric test to evaluate selective attention in a pediatric, school-aged population. Design: ZSCT reliability and validity were assessed in a field trial. A total of 409 children, aged 5 to 17 years, were recruited at multiple Zambian clinical sites and schools. The ZSCT provides a visuomotor processing index (VMPI), a measure of effortful processing to deliver accurate task response. Results: The VMPI reliability estimate at test-retest was found to be adequate for a clinical use (intraclass correlation coefficient [ICC]: 0.79, ICC-95% confidence interval [CI]: 0.69-0.86). Age showed a large effect on VMPI (n=323, r=-0.62, p=0.000). Impaired visuo-perceptual-motor processing, as measured by VMPI, was associated with poor health status (i.e., chronic neurologic or medical disease or prolonged exposure to psychosocial stress and deprivation). A two-way ANOVA found significant and small health status and age group effects [F (7, 408): 33.24, p=0.0000, η2=0.367]; the main effect of health status [F (1, 408): 37.79, p=0.000, η2=0.09], age group [F (3, 408): 35.06, p=0.000, η2=0.21], and their interaction was not significant (p=0.364). Conclusion: Study findings indicate that the ZSCT has satisfactory reliability, validity, and clinical utility to evaluate cognitive development and the effect of health conditions on attention. Study results warrant further research to validate its use in healthcare and clinical research settings.

Development of a Cognitive Ability Assessment Tool for a Pediatric School-aged Population.

OBJECTIVE: The assessment of a child's cognitive health in developing countries poses significant challenges, including the paucity of valid diagnostic tools. We report the development and initial psychometric evaluation of a new eight-item cognitive ability assessment tool (CAAT-8) for use in an African Sub-Saharan school-aged population. DESIGN: CAAT-8 reliability and validity were assessed in a field trial. Participants (446 children aged 5-17 years) were recruited at multiple clinical sites and schools. Methods and techniques based on Item Response Theory and Structural Equation Modeling were applied for item analysis and selection, reliability, and validity assessments. RESULTS: CAAT-8 includes eight cognitive tasks and provides a reliable measure of the factor of Knowledge Processing. Knowledge Processing consistently increased over age (simple regression model, R2=0.44). A poorer health status (e.g., due to a neurological or medical condition or chronic exposure to psychosocial stress and deprivation) was associated with lower Knowledge Processing. CONCLUSION: CAAT-8 is a viable methodology for cognitive health assessment in a pediatric school-aged population. The results from this study warrant further research to validate its use in healthcare and clinical research settings.