Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p \u3c 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p \u3c 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p \u3c 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p \u3c 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored

Transcranial Doppler ultrasound velocities in a population of unstudied African children with sickle cell anemia

Abstract The greatest burden of sickle cell anemia (SCA) globally occurs in sub‐Saharan Africa, where significant morbidity and mortality occur secondary to SCA‐induced vasculopathy and stroke. Transcranial Doppler ultrasound (TCD) can grade the severity of vasculopathy, with disease modifying therapy resulting in stroke reduction in high‐risk children. However, TCD utilization for vasculopathy detection in African children with SCA remains understudied. The objective was to perform a prospective, observational study of TCD findings in a cohort of children with SCA from the Democratic Republic of the Congo, Zambia, and Malawi. A total of 770 children aged 2–17 years without prior stroke underwent screening TCD. A study was scored as low risk when the time‐averaged maximum of the mean (TAMMX) in the middle cerebral artery or terminal internal carotid artery was 50 cm/s, conditional risk when 170–200 cm/s, and high risk when >200 cm/s. Low‐risk studies were identified in 604 children (78%), conditional risk in 129 children (17%), and high risk in three children (0.4%). Additionally, 34 (4%) were scored as having an unknown risk study (TAMMX <50 cm/s). Over the course of 15 months of follow‐up, 17 children (2.2%) developed new neurologic symptoms (six with low‐risk studies, seven with conditional risk, and four with unknown risk). African children with SCA in this cohort had a low rate of high‐risk TCD screening results, even in those who developed new neurologic symptoms. Stroke in this population may be multifactorial with vasculopathy representing only one determinant. The development of a sensitive stroke prediction bundle incorporating relevant elements may help to guide preventative therapies in high‐risk children

Transcranial doppler velocities in a large healthy population of African children

Background and purpose: Transcranial doppler ultrasound (TCD) is a tool that diagnoses and monitors pathophysiological changes to the cerebrovasculature. As cerebral blood flow velocities (CBFVs) increase throughout childhood, interpretation of TCD examinations in pediatrics requires comparison to age matched normative data. Large cohorts of healthy children have not been examined to develop these reference values in any population. There is a complete absence of normative values in African children where, due to lack of alternate neuroimaging techniques, utilization of TCD is rapidly emerging. Materials and methods: A prospective study of 710 healthy African children 3 months-15 years was performed. Demographics, vital signs, and hemoglobin values were recorded. Participants underwent a complete, non-imaging TCD examination. Systolic (Vs), diastolic (Vd), and mean (Vm) flow velocities and pulsatility index (PI) were calculated by the instrument for each measurement. Results: Vs, Vd, and Vm increased through early childhood in all vessels, with the highest CBFVs identified in children 5–5.9 years. There were few significant gender differences in CBFVs in any vessels in any age group. No correlations between blood pressure or hemoglobin and CBFVs were identified. Children in the youngest age groups had CBFVs similar to those previously published, whereas nearly every vessel in children ≥3 years had significantly lower Vs, Vd, and Vm. Conclusions: For the first time, reference TCD values for African children are established. Utilization of these CBFVs in the interpretation of TCD examinations in this population will improve the overall accuracy of TCD as a clinical tool on the continent