A primate model of severe malarial anaemia: a comparative pathogenesis study.

Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodium falciparum infection in African children. SMA is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including CD35). However, a deeper mechanistic understanding of the pathogenesis requires improved animal models. In this comparative study of two closely related macaque species, we interrogated potential causal factors for their differential and temporal relationships to onset of SMA. We found that rhesus macaques inoculated with blood-stage Plasmodium coatneyi developed SMA within 2 weeks, with no other severe outcomes, whereas infected cynomolgus macaques experienced only mild/ moderate anaemia. The abrupt drop in haematocrit in rhesus was accompanied by consumption of haptoglobin (haemolysis) and poor reticulocyte production. Rhesus developed a greater inflammatory response than cynomolgus macaques, and had lower baseline levels of CD35 on red blood cells (RBCs) leading to a significant reduction in the proportion of CD35+ RBCs during infection. Overall, severe anaemia in rhesus macaques infected with P. coatneyi has similar features to SMA in children. Our comparisons are consistent with an association of low baseline CD35 levels on RBCs and of early inflammatory responses with the pathogenesis of SMA

The project did not come to us with a solution: Perspectives of research teams on implementing a study about electronic health record-embedded individualized pain plans for emergency department treatment of vaso-occlusive episodes in adults with sickle cell disease.

BACKGROUND: This study aimed to capture the implementation process of the ALIGN Study, (An individualized Pain Plan with Patient and Provider Access for Emergency Department care of Sickle Cell Disease). ALIGN aimed to embed Individualized Pain Plans in the electronic health record (E-IPP) and provide access to the plan for both adult patients with sickle cell disease (SCD) and emergency department providers when a person with SCD comes to the emergency department in vaso-occlusive crises. METHODS: Semi-structured interviews were conducted with research teams from the 8 participating sites from the ALIGN study. Seventeen participants (principal investigators and study coordinators) shared their perspectives about the implementation of ALIGN in their sites. Data were analyzed in three phases using open coding steps adapted from grounded theory and qualitative content analysis. RESULTS: A total of seven overarching themes were identified: (1) the E-IPP structure (location and upkeep) and collaboration with the informatics team, (2) the role of ED champion, (3) the role of research coordinators, (4) research team communication, and communication between research team and clinical team, (5) challenges with the study protocol, (6) provider feedback: addressing over-utilizers, patient mistrust, and the positive feedback about the intervention, and (7) COVID-19 and its effects on study implementation. CONCLUSIONS: Findings from this study contribute to learning how to implement E-IPPs for adult patients with SCD in ED. The study findings highlight the importance of early engagement with different team members, a champion from the emergency department, study coordinators with different skills and enhancement of communication and trust among team members. Further recommendations are outlined for hospitals aiming to implement E-IPP for patients with SCD in ED

Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals

A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated ("putative progressors", PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = -0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia

Clinical and immunological characteristics of viremic non-progressors and putative progressors.

<p>(<b>A</b>) Estimated duration of HIV diagnosis based on first HIV+ test. (<b>B</b>) Plasma HIV RNA in VNPs and PPs as measured by RT-PCR. (<b>C</b>) The fraction of CD4+ T cells in VNPs and PPs measured by flow cytometry. (<b>D</b>) Absolute CD4+ T cell count in blood from VNPs and PPs based on CD4+ T cell fraction and lymphocyte count by CBC. <i>p</i> values from Mann Whitney T test. Line reflects median. Circles, VNPs; Squares, PPs.</p

Patient characteristics.

<p>Patient characteristics.</p

T cell proliferation and activation in VNPs and PPs.

<p>(<b>A–B</b>) The frequency of activated CD38+HLA-DR+ T cells in VNPs and PPs by flow cytometry: (<b>A</b>) total CD4+ CD38+HLA-DR+ T cells and (<b>B</b>) CD8+ CD38+HLA-DR+ T cells. (<b>C–D</b>) The frequency of proliferating (Ki67+) VNPs and PPs by flow cytometry: (<b>C</b>) total CD4+Ki67+ T cells and (<b>D</b>) total CD8+Ki67+ T cells. (<b>E–G</b>) The absolute count of Ki67+CD4+ T cell memory subsets measured by flow cytometry and lymphocyte count by CBC for: (<b>E</b>) CD4+Ki67+ T_EM cells; (<b>F</b>) CD4+Ki67+ T_CM cells; (<b>G</b>) and CD4+Ki67+ T_SCM cells. <i>p</i> values from Mann Whitney T test. Line reflects median. Circles, VNPs; Squares, PPs.</p