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Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving >15 mg/kg CQ identifies a 76 kb region in chromosome 1 including pvcrt , an ortholog of the Plasmodium falciparum CQR transporter gene. Transcriptional analysis supports upregulated pvcrt expression as a mechanism of CQR. Here, a cross of Plasmodium vivax malaria parasites links a chloroquine resistance (CQR) phenotype to a 76 kb region of chromosome 1 and greater expression of pvcrt , an ortholog of the Plasmodium falciparum CQR transporter gene.

Sickle trait, the heterozygous state of normal hemoglobin A (HbA) and sickle hemoglobin S (HbS), confers protection against malaria in Africa. AS children infected with Plasmodium falciparum are less likely than AA children to suffer the symptoms or severe manifestations of malaria, and they often carry lower parasite densities than AA children. The mechanisms by which sickle trait might confer such malaria protection remain unclear. We have compared the cytoadherence properties of parasitized AS and AA erythrocytes, because it is by these properties that parasitized erythrocytes can sequester in postcapillary microvessels of critical tissues such as the brain and cause the life-threatening complications of malaria. Our results show that the binding of parasitized AS erythrocytes to microvascular endothelial cells and blood monocytes is significantly reduced relative to the binding of parasitized AA erythrocytes. Reduced binding correlates with the altered display of P. falciparum erythrocyte membrane protein-1 (PfEMP-1), the parasite's major cytoadherence ligand and virulence factor on the erythrocyte surface. These findings identify a mechanism of protection for HbS that has features in common with that of hemoglobin C (HbC). Coinherited hemoglobin polymorphisms and naturally acquired antibodies to PfEMP-1 may influence the degree of malaria protection in AS children by further weakening cytoadherence interactions.

α-Thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α(2)β(2)) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-α/αα) and homozygous (-α/-α) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes--two interactions that are centrally involved in the pathogenesis of severe disease. We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect αα/αα (normal), -α/αα and -α/-α RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized -α/αα, -α/-α and -/-α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-Thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism.

Background. The World Health Organization (WHO) recently recommended that the time to first malaria episode serve as the primary end point in phase III malaria vaccine trials—the first of which will be held in Africa. Although common red blood cell (RBC) polymorphisms such as sickle hemoglobin (HbS) are known to protect against malaria in Africa, their impact on this end point has not been investigated. Methods. A longitudinal study of 225 individuals aged 2–25 years was conducted in Mali. The association between common RBC polymorphisms and the time to first malaria episode was evaluated. Results. Among children aged 2–10 years, sickle cell trait (HbAS) was associated with a 34-day delay in the median time to first malaria episode (P = .017). Cox regression analysis showed that greater age (hazard ratio [HR], 0.87 [95% CI, 0.80–0.94]; P = .001), HbAS (HR, 0.48 [95% CI, 0.26–0.91]; P = .024), and asymptomatic parasitemia at enrollment (HR, 0.35 [95% CI, 0.14–0.85]; P = .021) were associated with decreased malaria risk. Conclusion. Given the delay in the time to first malaria episode associated with HbAS, it would be advisable for clinical trials and observational studies that use this end point to include Hb typing in the design of studies conducted in areas where HbAS is prevalent.

Visible‐light optical coherence tomography (vis‐OCT) is a novel noninvasive retinal imaging system that offers improved resolution compared to conventional near‐infrared (NIR) OCT systems. Here, we utilized vis‐OCT to produce fibergrams (vis‐OCTF) for the first time in human patients, enabling en face visualization and precise quantification of hyperreflective dots in the central fovea in two patients. We also directly compare the imaging qualities of conventional vis‐OCT and NIR‐OCT. Vis‐OCT generated a 3 × 3 mm 2 en face image with an impressive axial resolution of 1.3  μ m, whereas NIR‐OCT produced an en face image with a larger field of view (FOV) (9 × 9 mm 2 ) but a lower resolution of 7.0  μ m. Moreover, vis‐OCTF unveiled clear images of hyperreflective dots in the fovea of both patients, which were not discernible in the NIR‐OCT en face images. Foveal dots have often been linked to several age‐related and pathological conditions. The high‐resolution images generated by vis‐OCTF enable more precise characterization of changes in retinal sublayers within the central fovea.

Sickle hemoglobin (Hb) S and HbC may protect against malaria by reducing the expression of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of parasitized red blood cells (RBCs), thereby weakening their cytoadherence to microvascular endothelial cells (MVECs) and impairing their activation of MVECs to produce pathological responses. Therefore, we hypothesized that parasites causing malaria in HbAS or HbAC heterozygotes have overcome this protective mechanism by expressing PfEMP1 variants which mediate relatively strong binding to MVECs. To test this hypothesis, we performed 31 cytoadherence comparisons between parasites from HbAA and HbAS (or HbAC) Malian children with malaria. Ring-stage parasites from HbAA and HbAS (or HbAC) children were cultivated to trophozoites, purified, and then inoculated in parallel into the same wildtype uninfected RBCs. After one cycle of invasion and maturation to the trophozoite stage expressing PfEMP1, parasite strains were compared for binding to MVECs. In this assay, there were no significant differences in the binding of parasites from HbAS and HbAC children to MVECs compared to those from HbAA children (HbAS, fold-change  = 1.46, 95% CI 0.97-2.19, p = 0.07; HbAC, fold-change  = 1.19, 95% CI 0.77-1.84, p = 0.43). These data suggest that in-vitro reductions in cytoadherence by HbS and HbC may not be selecting for expression of high-avidity PfEMP1 variants in vivo. Future studies that identify PfEMP1 domains or amino-acid motifs which are selectively expressed in parasites from HbAS children may provide further insights into the mechanism of malaria protection by the sickle-cell trait.

To investigate the association between demographic, socioeconomic, and clinical factors and severe vision loss in patients with neovascular glaucoma (NVG). A retrospective chart review of patients referred to the University of Virginia (UVA), diagnosed with NVG, and treated for NVG between January 2010 and December 2020 was performed. Patients were grouped according to vision outcomes after 1 year of treatment: mild - moderate vision loss (best corrected visual acuity [BCVA] > light perception [LP]) and severe vision loss (BCVA ≤ LP). The associations between patient characteristics and BCVA were also examined. Of the 89 patients (99 eyes), those with progression to severe vision loss presented with higher intraocular pressure (IOP) (p < 0.001) and lower visual acuity (p = 0.003) on average. However, there was no difference in IOP between the vision loss groups after one year of treatment. Univariate analysis showed a moderate association between a history of type 2 diabetes mellitus (T2DM) and severe vision loss (p = 0.033). Increasing age was associated with an increased likelihood of progression to severe vision loss (odds ratio [OR] 1.074, p = 0.008). Females were more likely to exhibit severe vision loss (OR 3.281, p = 0.036). Patients with Medicare (OR 0.098, p = 0.005) or private insurance (OR 0.110, p = 0.006) were less likely to progress to severe vision loss than those without insurance. Progression of vision loss in patients with NVG may be influenced by the stage of disease at diagnosis, age, sex, T2DM, and insurance status.

ObjectivesTo characterize the use of virtual visits, as well as compare the characteristics to in-person visits during the pandemic period.MethodsThis retrospective study included patients who had virtual and in-person ophthalmology visits from March 19, 2020, to July 31, 2020, in a large multispecialty ophthalmic center. Exclusion criteria included patients aged less than 18 years old; canceled, incomplete, mislabelled, and duplicated visits. 2943 virtual and 56,174 in-person visits were identified. A random sample of 3000 in-person visits was created. Each visit was analyzed as an individual data point.Results2,266 virtual visits (2,049 patients, 64.3% female, mean [SD] age 64.3 [16.6] years old) and 2590 in-person visits (2509 patients, 59.5% female, 65.9 [15.8] years old) were included. Most virtual visits were classified as comprehensive ophthalmology (34.6%), optometry-related (19.5%), and oculoplastics (13.0%). For in-person visits, the most common specialties were optometry (29.8%), comprehensive ophthalmology (23.9%), and retina and uveitis (17.3%). The most common diagnoses in the virtual group were from the eyelids, lacrimal system, and orbits group (26.9%), while in the in-person groups were choroid and retina conditions (19.3%).ConclusionsNumerous ocular conditions were evaluated and managed through virtual visits, and external complaints and oculoplastic consults appear to be well-suited to the virtual format. Further studies focusing on visual outcomes and patient experience will be beneficial.

Our purpose was to evaluate visual acuity in aniridia subjects and the more severely affected phenotype in WAGR syndrome subjects, and to assess potential impact on visual function. This was a retrospective comparative study of 25 aniridia subjects with nonsense mutations of PAX6 (50 eyes) and 25 WAGR syndrome subjects with large deletion mutations involving PAX6 (50 eyes). Aniridia subjects were age- and gender-matched with WAGR syndrome subjects in the Coordination of Rare Diseases at Sanford (CoRDS) database. Best-corrected ETDRS visual acuity measurements were converted to LogMAR visual acuity values, which were used to perform statistical analyses. The age and gender distribution of the subjects was not statistically significantly different. The mean LogMAR values in aniridia and WAGR syndrome subjects were 0.95±0.53 and 1.51±0.99, respectively (P<0.001). In the better-seeing eye, mean LogMAR values were 0.78±0.15 in aniridia subjects and 1.40±0.88 in WAGR syndrome subjects (P=0.001). The mean LogMAR values for the better-seeing eye corresponded to Snellen visual acuity of 20/125 in aniridia subjects and 20/500 in WAGR syndrome subjects. This average visual acuity was worse than the threshold for profound visual impairment (WHO criteria) and legal blindness (AAO criteria) in WAGR syndrome but not in aniridia subjects. In analysis of both eyes, the visual efficiency was 34% in aniridia subjects and 2% in WAGR syndrome subjects. Visual acuity was significantly worse in WAGR subjects with multi-gene deletion mutations compared with aniridia subjects with nonsense mutations, which corresponded to differences in standard visual function thresholds. Our results suggest that visual acuity may indicate severity of ocular involvement and variability of phenotype in aniridia and WAGR syndrome.

[alpha]-thalassemia results from decreased production of [alpha]-globin chains that make up part of hemoglobin tetramers (Hb; [alpha].sub.2 [beta].sub.2) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-[alpha]/[alpha][alpha]) and homozygous (-[alpha]/-[alpha]) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that [alpha]-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes - two interactions that are centrally involved in the pathogenesis of severe disease. We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect [alpha][alpha]/[alpha][alpha] (normal), -[alpha]/[alpha][alpha] and -[alpha]/-[alpha] RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-[alpha] RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized [alpha][alpha]/[alpha][alpha] RBCs, we found that parasitized -[alpha]/[alpha][alpha], -[alpha]/-[alpha] and -/-[alpha] RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. [alpha]-thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs. Parasitized [alpha]-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which [alpha]-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired [alpha]-globin chains (in the case of [beta]-thalassemia) protect against life-threatening malaria by a similar mechanism.