Hans Christian Ackerman

Introduction: Sickle cell disease is a monogenic blood disorder prevalent in Africa, where malaria poses a health risk for affected individuals. Individuals with sickle cell disease are susceptible to malaria, which can be complicated by vaso-occlusive episodes, severe anaemia and death. Understanding the intersection of malaria and sickle cell disease in African countries with high co-prevalence is essential for developing effective management and prevention strategies, including clinical guidelines on the use of malaria chemoprophylaxis in this population. This study will determine the monthly incidence of malaria in children living with sickle cell disease in each of two clusters of African countries. Methods and analysis: This 1-year observational study will enrol 2808 children with sickle cell disease, aged 6 months to 17 years, at Sickle Pan-African Research Consortium clinical sites in Ghana, Mali, Nigeria (West), Tanzania, Uganda, Zimbabwe and Zambia (East-South). Malaria infection will be assessed at monthly visits and unscheduled sick visits over 12 months. Data collected will include socio-demographic characteristics, beta-globin genotype, medical history, clinical symptoms and malaria blood smear or rapid diagnostic test results. The primary outcome is monthly incidence of clinical malaria; a secondary outcome is incidence of asymptomatic malaria. Ethics and dissemination: This study was developed with input from patients with sickle cell disease and their caregivers. The study will be conducted according to the principles of the Declaration of Helsinki. Written informed consent from guardians and assent from child participants age 7 or above will be provided before enrolling in the study. This protocol has been reviewed and approved by local and national ethics committees at each study site. The findings of this study will be provided to participants and the general public through presentations at the annual Sickle Cell Day community events at each study site, local media and open access publication in peer-reviewed journals. The full names of the ethics committees are as follows. Ghana: Komfo Anokye Teaching Hospital Institutional Review Board; Mali: Ethics Committee of the University of Sciences, Techniques and Technologies of Bamako; Nigeria: National Health Research Ethics Committee of Nigeria; Tanzania: Muhimbili University of Health and Allied Sciences Research Ethics Committee and National Health Research Ethics Committee; Uganda: Makerere School of Medicine Research and Ethic Committee; Zambia: National Health Research Authority and Excellence in Research Ethics and Science Converge Institutional Review Board; and Zimbabwe: Joint Research Ethics Committee and the Medical Research Council of Zimbabwe.

Background & Purpose: Experimental cerebral malaria (ECM) is associated with abnormalities in cerebral perfusion, yet the mechanisms underlying vascular dysfunction remain incompletely defined. Experimental Approach: Ex vivo pressure myography of middle cerebral arteries (MCAs) was used to assess intrinsic arterial function in control and ECM mice. Mesenteric arteries were used to compare intraluminal perfusion versus abluminal superfusion with healthy plasma or serotonin (5-HT). Wire myography of aortic rings as a biosensor for plasma-derived vasoactive factors was used to investigate circulating modulators of vascular tone. Key Results: MCAs from ECM animals showed preserved constriction to 5-HT, preserved endothelium-dependent relaxation to methacholine (MCh), and intact responses to nitroprusside. MCh relaxation was inhibited by L-NAME, indicating preserved endothelial NO signaling. In aortic rings, ECM plasma produced concentration-dependent vasoconstriction, enhanced by NOS inhibition. Blockade of 5-HT₂A receptors with ketanserin abolished >80% of this constriction in a sex-independent manner, demonstrating that plasma 5-HT is the predominant circulating vasoconstrictor. Plasma or 5-HT induced robust vasoconstriction when applied abluminally, but not intraluminally. Conclusion & Implications: ECM does not cause intrinsic endothelial or smooth muscle dysfunction of the MCA. Vasoconstrictive responses to plasma from ECM or control mice were similar, suggesting no major differences in plasma vasoregulatory molecules. Plasma serotonin exerts a vasoconstrictive effect in the setting of NOS inhibition when plasma contacts the adventitial, but not the luminal, aspect of an artery. Based on these findings, we propose that normal circulating levels of serotonin could potentially have vasoconstrictive effects in disease conditions that compromise vascular barrier integrity.

We developed a noninvasive approach to measure vascular responses to sympathetic stimuli. We hypothesized that standing, handgrip exercise, or cold exposure would raise blood pressure (BP) and lower renal vascular conductance (RVC). BP was recorded continuously and renal arterial velocity was measured using renal Doppler ultrasound. Repeated measures one‐way ANOVA with Dunnett's post hoc test was used to compare BP during stimulation against baseline. Intraclass correlation analysis was used to compare first and second visits. Seven women and four men aged 29.9 ± 4.7 years participated. On first visits, standing from supine raised systolic BP by 11.9 ± 2.6 mmHg ( p = 0.0018) and diastolic BP by 15.0 ± 1.9 mmHg ( p < 0.0001). Handgrip exercise raised systolic BP by 15.9 ± 4.1 mmHg ( p = 0.0146) and decreased systolic RVC by 0.68 ± 0.26 cm/s/mmHg ( p = 0.0049). Cold increased systolic BP by 27.8 ± 3.4 mmHg ( p < 0.0001) and decreased systolic RVC by 0.32 ± 0.07 cm/s/mmHg ( p = 0.0049). BP and RVC responses were similar from visit one to visit two; however, most outcome measurements were not correlated within individuals. These findings expand our understanding of vasoregulation in Black adults and guide studies to characterize vascular function in the future.

Near-infrared spectroscopy with vascular occlusion testing (NIRS-VOT) offers a non-invasive approach for real-time assessment of tissue oxygenation and vascular function. However, its clinical application remains limited, in part due to substantial inter-individual variability in anatomical and physiological characteristics. To identify potential sources of variability, we explored whether incorporating conduit artery size—specifically baseline brachial artery diameter (BrAD)—into the NIRS-VOT data analysis could enhance physiological interpretation and reduce measurement error. We analyzed NIRS-VOT responses from 16 healthy participants recruited to the NIH Clinical Center (NCT06552767 and NCT03538639), incorporating individual BrAD measurements as a covariate. Strong to moderate Spearman’s rank-order correlations were observed between BrAD and dynamic perfusion parameters, including the desaturation rate ( ρ = 0.77, p = 0.0005) and resaturation rate ( ρ = 0.79, p = 0.0003). These findings suggest that larger brachial arteries are associated with greater oxygen extraction during occlusion and faster reoxygenation during reperfusion. Across parameters, BrAD explained a substantial proportion of the variance in NIRS-VOT outcomes. When BrAD was included as a covariate, the unexplained variability in the desaturation and resaturation rates was reduced to 28% and 34% of the total variance, respectively, indicating that accounting for conduit artery size substantially decreases residual variability and enhances the interpretability of these dynamic responses. Visual comparison also indicated that incorporating BrAD helped clarify response patterns and reclassify outliers. By reducing inter-individual variability and explaining a greater share of the physiological response, the BrAD-informed analysis enhances the interpretability and consistency of NIRS-VOT measurements. Integrating vascular anatomy into NIRS-VOT analysis may improve the detection of subtle vascular dysfunction and strengthen its diagnostic utility. Future research involving larger and more diverse cohorts, and additional vascular territories are needed to validate and expand these findings.

Acquired tick resistance (ATR) is well characterized in tick‐exposed animals, compromising tick fitness through antibody‐mediated activation of basophils. Yet, anti‐tick vaccines inducing ATR have had limited success. Here, we describe a neuroimmune event preceding ATR that leads to rapid host‐mediated tick removal. Tick‐sensitized guinea pigs mechanically remove ticks within 3–6 h via an acquired neuroimmune‐induced itch response that correlates with increased dermal expression of itch‐associated genes and skin infiltration by CD3 ⁺ T cells and Iba‐1 ⁺ macrophages, independent of IgG and IgE antibodies. Inhibiting the development of acquired T cell memory by averting naive lymphocyte egress from lymph nodes with the sphingosine‐1‐phosphate receptor modulator FTY720, before tick sensitization, prevents Iba‐1 ⁺ macrophage and CD3 ⁺ T cell infiltration to the tick bite site and abrogates scratching and tick removal. This neuroimmune response is independent of Trpv1 as tick‐sensitized guinea pigs treated with the Trpv1 agonist, resiniferatoxin, remove ticks effectively. Strikingly, prior exposure to a single tick is sufficient to generate a fast and active itch‐induced tick removal (IITR) that is observed even in tick‐attached sites distant from the location of previous tick exposure. IITR represents a novel approach to tick‐borne disease prevention through early tick detection and fast removal.

Resistance arteries, which include small arteries and arterioles, play essential roles in regulating blood pressure and tissue perfusion. Dysfunction in these arteries can lead to various cardiovascular conditions such as hypertension, atherosclerosis, and heart failure, as well as neurovascular conditions. The examination of human resistance arteries is crucial for understanding cardiovascular disease mechanisms and developing targeted therapeutic strategies. This study presents an innovative method for preparing isolated human resistance arteries by infusing a tissue-stabilizing gel into the lumen, preserving their native architecture and cellular integrity. Human omental tissues were obtained from patients undergoing abdominal surgeries, and small resistance arteries (100-300 µm in diameter) were isolated by careful micro-dissection. The arteries were then cannulated, pressurized in a culture myograph chamber, and fixed with 10% neutral buffered formalin. A tissue-stabilizing gel was infused into the lumen of the cannulated artery, which was allowed to solidify to preserve the three-dimensional structure. Histological, immunohistochemical, and gene expression analyses were performed to assess the preservation of the arteries. Histological sections revealed the well-preserved structural integrity and natural architecture of the arteries, maintaining well-defined endothelial and smooth muscle layers. Immunohistochemical staining showed distinct localization of markers such as CD31 and α-smooth muscle actin. In situ hybridization revealed specific gene expression patterns, providing insights into the molecular mechanisms. This advanced method of intraluminal gel infusion offers significant advantages, enabling advanced imaging and comprehensive analysis of arterial structure, remodeling, and cellular interactions in both healthy and diseased states. This method has the potential to improve clinical diagnostics and therapeutic strategies for vascular diseases, thereby providing a valuable tool for advancing vascular biology research.

Resistance arteries, which include small arteries and arterioles, play essential roles in regulating blood pressure and tissue perfusion. Dysfunction in these arteries can lead to various cardiovascular conditions such as hypertension, atherosclerosis, and heart failure, as well as neurovascular conditions. The examination of human resistance arteries is crucial for understanding cardiovascular disease mechanisms and developing targeted therapeutic strategies. This study presents an innovative method for preparing isolated human resistance arteries by infusing a tissue-stabilizing gel into the lumen, preserving their native architecture and cellular integrity. Human omental tissues were obtained from patients undergoing abdominal surgeries, and small resistance arteries (100-300 µm in diameter) were isolated by careful micro-dissection. The arteries were then cannulated, pressurized in a culture myograph chamber, and fixed with 10% neutral buffered formalin. A tissue-stabilizing gel was infused into the lumen of the cannulated artery, which was allowed to solidify to preserve the three-dimensional structure. Histological, immunohistochemical, and gene expression analyses were performed to assess the preservation of the arteries. Histological sections revealed the well-preserved structural integrity and natural architecture of the arteries, maintaining well-defined endothelial and smooth muscle layers. Immunohistochemical staining showed distinct localization of markers such as CD31 and α-smooth muscle actin. In situ hybridization revealed specific gene expression patterns, providing insights into the molecular mechanisms. This advanced method of intraluminal gel infusion offers significant advantages, enabling advanced imaging and comprehensive analysis of arterial structure, remodeling, and cellular interactions in both healthy and diseased states. This method has the potential to improve clinical diagnostics and therapeutic strategies for vascular diseases, thereby providing a valuable tool for advancing vascular biology research.

The regulation of angiotensin-converting enzyme 2 (ACE2) expression by medications such as ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) has raised critical questions regarding their potential benefits and risks during COVID-19. ACE2, a regulator of blood pressure through the renin–angiotensin system (RAS), is the primary receptor for SARS-CoV-2. ACEis and ARBs can modulate ACE2 expression, potentially exacerbating viral load. However, the risks of higher viral load could be mitigated by favorable anti-inflammatory responses associated with ACEi and ARB use, highlighting the complexity of their impact on viral replication and disease outcomes. This study investigates the effects of sustained Losartan monotherapy (ARB) and combination Losartan + Lisinopril (ARB + ACEi) on viral replication, inflammation, lung function, and clinical measures of disease severity in a murine model of severe COVID-19 involving humanized ACE2 transgenic mice infected with SARS-CoV-2 Wuhan strain. Both ARB and ARB + ACEi treatments led to increased ACE2 expression in the lungs and higher viral load post-infection. Despite this, the ARB + ACEi combination improved clinical scores, reduced weight loss and inflammatory cytokine levels, and preserved lung function, though it did not improve survival. Overall, the results of these controlled experiments provide insight into the complex dynamics of ACEi and ARB use in COVID-19; while these drugs induce expression of the ACE2 receptor and increase viral load, they provide compensatory modulation of the inflammatory response that appears to diminish severity of the infection.

Apicomplexan parasite, Babesia rossi, is an Ixodid tick-transmitted pathogen that causes the most severe form of canine babesiosis disease. Compared to other Babesia pathogens of dogs, B. rossi exhibits unique pathophysiology, virulence, and a responsiveness to drugs that differs from the small Babesia parasites. Here we report the first near-complete chromosome-level assembly of Babesia rossi strain PMB – isolated from a sick dog from Pietermaritzburg, South Africa. Assembly with long-read HiFi data yielded 21.06 Mbp genome size, spanning across five gene-dense chromosome-level scaffolds, a single apicoplast scaffold, and a remaining 54 unplaced low gene density scaffolds with 1.32 Mb N50 and 96.6% BUSCO Apicomplexan completeness. The genome annotation identified a total of 3,098 protein-coding genes, 71 tRNA, and 16 rRNA genes. The mitochondrial genome (6.4 Kbp) was also identified. Genome assemblies of two additional field isolates of B. rossi were also reported. Comparative genomic analyses revealed four syntenic genomic inversions and multiple polymorphisms across three B. rossi isolates, although SNP and indel density was higher within the gene desserts of the genomes. Despite these differences, three B. rossi isolates’ genome assemblies showed 99% conserved orthologous gene sets. About 76% of protein-coding genes of Babesia rossi isolate PMB were shared with four other Babesia species. This report provides valuable genomic information that is crucial to comprehend B. rossi evolution, virulence, and potential drug targets for canine babesiosis.