Our goal is to develop a vaccine that sustainably prevents Plasmodium falciparum (Pf) malaria in ≥80% of recipients. Pf sporozoites (PfSPZ) administered by mosquito bites are the only immunogens ...shown to induce such protection in humans. Such protection is thought to be mediated by CD8⁺ T cells in the liver that secrete interferon-γ (IFN-γ). We report that purified irradiated PfSPZ administered to 80 volunteers by needle inoculation in the skin was safe, but suboptimally immunogenic and protective. Animal studies demonstrated that intravenous immunization was critical for inducing a high frequency of PfSPZ-specific CD8⁺, IFN-γ-producing T cells in the liver (nonhuman primates, mice) and conferring protection (mice). Our results suggest that intravenous administration of this vaccine will lead to the prevention of infection with Pf malaria.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Ventriculitis is a serious complication of intraventricular catheter (IVC) use, with rates of IVC-related infections ranging from 0% to 45% and gram-positive organisms predominating. We prospectively ...analyzed ventriculostomy-related infections occurring among 157 adult neurosurgical patients (mean age, 54.9 years; 90 57% were women) from 1995 through 1998, to determine the incidence of, risk factors for, and organisms that cause ventriculitis. A total of 196 IVC events resulted in 11 infections (5.6%; 9 were caused by gram-negative organisms and 2 by coagulase-negative staphylococci). Independent risk factors for IVC-related infection include length of IVC placement (8.5 days infected vs. 5.1 days uninfected; P = .007) and cerebrospinal fluid leakage about the IVC (P = .003). The length of hospital stay (30.8 days vs. 22.6 days; P = .03) and mean total hospital charges ($85,674.27 vs. $55,339.21; P = .009) were greater for infected patients than for uninfected patients. In addition, a microbiologic shift from gram-positive organisms toward gram-negative organisms was noted. This study suggests that IVC-related infections remain serious infections that increase the length of hospitalization.
Full text
Available for:
BFBNIB, NUK, PNG, UL, UM, UPUK
Plasmodium falciparum rosetting (the spontaneous binding of infected erythrocytes to uninfected erythrocytes) is a well-recognized parasite virulence factor. However, it is currently unclear whether ...rosetting is associated with all clinical forms of severe malaria, or only with specific syndromes such as cerebral malaria. We investigated the relationship between rosetting and clinical malaria in 209 Malian children enrolled in a case-control study of severe malaria. Rosetting was significantly higher in parasite isolates from severe malaria cases compared with non-severe hyperparasitemia and uncomplicated malaria controls (F(2,117) = 8.15, P < 0.001). Analysis of sub-categories of severe malaria (unrousable coma, severe anemia, non-comatose neurological impairment, repeated seizures or a small heterogeneous group with signs of renal failure or jaundice) showed high levels of rosetting in all sub-categories, and no statistically significant differences in rosetting between sub-categories (F(4,67) = 1.28, P = 0.28). Thus rosetting may contribute to the pathogenesis of all severe malaria syndromes in African children, and interventions to disrupt rosetting could be potential adjunctive therapies for all forms of severe malaria in Africa.
Alternaria species are ubiquitous dematiaceous fungi that are increasingly recognized as pathogens in immunocompromised patients or those with significant underlying disease, but they are also ...pathogens in otherwise healthy hosts. We describe a case of dermal cutaneous ulcerative alternariosis in a frail 83-year-old patient with diet-controlled diabetes mellitus. Histological analysis revealed hyphal morphology in tissue sections that was initially confused with that of a zygomycetous fungus, and multiple positive culture results were necessary to identify the organism. Treatment with oral itraconazole and surgical debridement were ineffective; clinical improvement was achieved by means of treatment with intravenous amphotericin B lipid complex. We review the literature regarding the role of diabetes mellitus in cutaneous alternariosis and regarding the efficacy of treatment with itraconazole, which has been used very successfully. To our knowledge, this is only the second case report noting diabetes mellitus uncomplicated by steroid administration as a possible predisposing factor for cutaneous infection.
Full text
Available for:
BFBNIB, NUK, PNG, UL, UM, UPUK
BackgroundTrimethoprim-sulfamethoxazole (TS) prophylaxis is recommended for persons living with human immunodeficiency virus infection and acquired immunodeficiency syndrome in Africa. TS and the ...antimalarial combination sulfadoxine-pyrimethamine (SP) share mechanisms of action and resistance patterns, and concerns about the impact of TS resistance on SP efficacy have contributed to reluctance to implement TS prophylaxis in Africa MethodsTo determine whether TS prophylaxis impairs SP efficacy for treatment of uncomplicated falciparum malaria, we conducted a randomized, controlled, open-label study of TS prophylaxis. Two hundred and forty children 5–15 years old were randomized in a 2:1 fashion to receive either thrice-weekly TS for 12 weeks or no prophylaxis and were treated with SP for subsequent episodes of malaria. The incidence of malaria, SP efficacy, and the prevalence of parasite mutations that confer antifolate drug resistance were measured ResultsTS prophylaxis had a 99.5% protective efficacy against episodes of clinical malaria, with 97% efficacy against infection. Four SP treatment failures occurred in the control group, and none occurred in the TS group. No evidence was seen for selection by TS of antifolate resistance–conferring mutations in parasite dihydrofolate reductase or dihydropteroate synthase during subclinical infections ConclusionsIn this setting of low antifolate resistance, TS was highly effective in preventing falciparum malaria infection and disease and did not appear to select for SP-resistant parasites
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Plasmodium falciparum and Schistosoma haematobium are co-endemic parasitic diseases with worldwide distribution. Evidence suggests interactions occur between helminthic and malaria infections, ...although it is unclear whether this effect is beneficial or harmful to the host. Malian children 4-14 years of age with asymptomatic S. haematobium infection (SP) (n = 338) were prospectively matched by age, sex, and residence to children without schistosomiasis (SN) (n = 338) who were cleared of occult intestinal parasites, and followed-up for one malaria transmission season (25 weeks). The time to the first clinical malaria infection, incidence of malaria episodes, and parasitemia were recorded. Age associated protection from malaria in children with schistosomiasis was observed. SP children (4-8 years of age) compared with SN children demonstrated delayed time to first clinical malaria infection (74 versus 59 days; P = 0.04), fewer numbers of malaria episodes (1.55 versus 1.81 infections; P = 0.03) and lower geometric mean parasite densities (6,359 versus 9,874 asexual forms/mm(3); P = 0.07) at first infection. No association between schistosomiasis and P. falciparum malaria was observed in children 9-14 years of age. We conclude that underlying schistosomiasis is associated with protection against clinical falciparum malaria in an age-dependent manner.
Peripheral parasite density of Plasmodium falciparum is used as an indicator of malaria disease severity, but does not quantify central sequestration, which is important in the pathogenesis of severe ...disease. Malaria pigment, recognizable within the cytoplasm of phagocytic cells by light microscopy may represent a peripheral marker for parasite biomass. One hundred seventy-two index cases of severe malaria and 172 healthy age-, residence-, and ethnicity-matched controls with uncomplicated malaria in Bandiagara, Mali were analyzed prospectively for presence of malaria pigment. The presence of polymorphonuclear cell (PMN) and monocyte pigment was strongly associated with severe disease compared with uncomplicated malaria. Total PMN pigment burden in children with severe malaria was higher in those with cerebral manifestations and with combined cerebral manifestations and severe anemia (hemoglobin < or = 5 g/dL) but was not associated with hyperparasitemia (> 500,000 asexual forms/mm3). Additionally, pigmented PMNs/mm3 was associated with a fatal outcome in patients with severe malaria. This study validates the presence of malaria pigment in monocytes and neutrophils as a marker for disease severity, and demonstrates that pigmented neutrophils are associated with cerebral malaria and with death in children with severe malaria.
The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and ...malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses.
Display omitted
•Single-cell RNA-seq reveals two distinct B cell lineages•An alternative lineage contains CXCR3+ and atypical B cells•Alternative B cells are primed after primary vaccination and respond to boosters•Alternative B cells adopt a more atypical phenotype following repeated antigen exposure
Using single-cell RNA sequencing, Sutton et al. show that a population of “atypical” B cells, normally associated with disease, are part of a wider landscape of alternative B cells that participate in normal responses to vaccination.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The general theory of relativity predicts that a star passing close to a supermassive black hole should exhibit a relativistic redshift. In this study, we used observations of the Galactic Center ...star S0-2 to test this prediction. We combined existing spectroscopic and astrometric measurements from 1995-2017, which cover S0-2's 16-year orbit, with measurements from March to September 2018, which cover three events during S0-2's closest approach to the black hole. We detected a combination of special relativistic and gravitational redshift, quantified using the redshift parameter ϒ. Our result, ϒ = 0.88 ± 0.17, is consistent with general relativity (ϒ = 1) and excludes a Newtonian model (ϒ = 0) with a statistical significance of 5σ.
PDF
