Pooled prevalence and risk factors of malaria among children aged 6-59 months in 13 sub-Saharan African countries: A multilevel analysis using recent malaria indicator surveys.

BACKGROUND: Every 75 seconds, a child under five dies of malaria. Mainly children, aged between six months and five years, are at the highest risk for malaria. These children lost maternal immunity and did not yet developed specific immunity to the infection. Under the age of five, children bear the highest burden of malaria in Sub-Saharan Africa (SSA). Many individual and community level factors could contribute to malaria prevalence remaining high among under-five children in the region. Thus, this study aimed to assess the pooled prevalence of malaria among children aged 6-59 months and identify potential factors associated with malaria by using recent Malaria Indicator Surveys in 13 SSA countries. METHODS: Data for this study were drawn from recent 13 Sub-Saharan African countries Malaria Indicator Surveys (MIS). A total weighted sample of 60,541 children aged 6-59 months was included. STATA version 14.2 was used to clean, code and analyze the data. Multilevel logistic regression was employed to identify factors associated with malaria. Adjusted odds ratio with 95% CI and a P value <0.05 was reported to indicate statistical association. Model fitness and comparison were done using Inter cluster correlation coefficient, Median odds ratio, proportional change in variance, and deviance. RESULTS: The pooled prevalence of malaria among children aged 6-59 months was found to be 27.41% (95% CI: 17.94%-36.88%). It ranges from 5.04% in Senegal to 62.57% in Sierra Leone. Aged 36-47 months (AOR = 3.54, 95% CI 3.21-3.91), and 48-59 months (AOR = 4.32, 95% CI 3.91-4.77), mothers attended primary education (AOR = 0.78, 95% CI 0.73-0.84), richer (AOR = 0.35, 95% CI 0.32-0.39), and richest household (AOR = 0.16, 95% CI 0.14-0.19), number of three and more under-five children (AOR = 1.35, 95% CI 1.26-1.45), improved floor material (AOR = 0.65, 95% CI 0.57-0.73), improved wall material (AOR = 0.73, 95% CI 0.64-0.84), improved roof material (AOR = 0.70, 95% CI 0.51-0.93), insecticide-treated bed net (ITN) use (0.56, 95% CI 0.51-0.62), not anemic (AOR = 0.05, 95% CI 0.04-0.06), rural resident (AOR = 2.16, 95% CI 2.06-2.27), high community ITN use (AOR = 0.40, 95% CI 0.24-0.63) and high community poverty (AOR = 2.66, 95% CI 2.53-2.84) were strongly associated with malaria. CONCLUSIONS AND RECOMMENDATIONS: Almost 3 out of 10 children were infected by malaria in 13 SSA countries. Malaria infection remains one of the main killers of children aged 6-59 months in the SSA. This study revealed that older under-five children living in large families with low incomes in rural areas are most vulnerable to malaria infection. Our results clearly indicate that ITN utilization and improved housing are promising means to effectively prevent malaria infection among children aged 6-59 months. It is therefore important to note that households with low wealth quintiles and rural residents should be prioritized in any mass distribution of ITNs. This has to be accompanied by education using mass media to enhance community awareness.

Can angiographic Flat Detector Computed Tomography blood volume measurement be used to predict final infarct size in acute ischemic stroke?

INTRODUCTION AND PURPOSE: Flat detector computed tomography (FD-CT) technology is becoming more widely available in the angiography suites of comprehensive stroke centers. In patients with acute ischemic stroke (AIS), who are referred for endovascular therapy (EVT), FD-CT generates cerebral pooled blood volume (PBV) maps, which might help in predicting the final infarct area. We retrospectively analyzed pre- and post-recanalization therapy quantitative PBV measurements in both the infarcted and hypoperfused brain areas of AIS patients referred for EVT. MATERIALS AND METHODS: We included AIS patients with large vessel occlusion in the anterior circulation referred for EVT from primary stroke centers to our comprehensive stroke center. The pre- and post-recanalization FD-CT regional relative PBV (rPBV) values were measured between ipsilateral lesional and contralateral non-lesional areas based on final infarct area on post EVT follow-up cross-sectional imaging. Statistical analysis was performed to identify differences in PBV values between infarcted and non-infarcted, recanalized brain areas. RESULTS: We included 20 AIS patients. Mean age was 63 years (ranging from 36 to 86 years). The mean pre- EVT rPBV value was 0.57 (±0.40) for infarcted areas and 0.75 (±0.43) for hypoperfusion areas. The mean differences (Δ) between pre- and post-EVT rPBV values for infarcted and hypoperfused areas were respectively 0.69 (±0.59) and 0.69 (±0.90). We found no significant differences (p > 0.05) between pre-EVT rPBV and ΔrPBV values of infarct areas and hypoperfusion areas. CONCLUSION: Angiographic PBV mapping is useful for the detection of cerebral perfusion deficits, especially in combination with the fill run images. However, we were not able to distinguish irreversibly infarcted tissue from potentially salvageable, hypoperfused brain tissue based on quantitative PBV measurement in AIS patients.

Flat Detector CT with Cerebral Pooled Blood Volume Perfusion in the Angiography Suite: From Diagnostics to Treatment Monitoring.

C-arm flat-panel detector computed tomographic (CT) imaging in the angiography suite increasingly plays an important part during interventional neuroradiological procedures. In addition to conventional angiographic imaging of blood vessels, flat detector CT (FD CT) imaging allows simultaneous 3D visualization of parenchymal and vascular structures of the brain. Next to imaging of anatomical structures, it is also possible to perform FD CT perfusion imaging of the brain by means of cerebral blood volume (CBV) or pooled blood volume (PBV) mapping during steady state contrast administration. This enables more adequate decision making during interventional neuroradiological procedures, based on real-time insights into brain perfusion on the spot, obviating time consuming and often difficult transportation of the (anesthetized) patient to conventional cross-sectional imaging modalities. In this paper we review the literature about the nature of FD CT PBV mapping in patients and demonstrate its current use for diagnosis and treatment monitoring in interventional neuroradiology.

Selective Angiographic Flat Detector Computer Tomography Blood Volume Imaging in Pre-Operative Vascular Mapping and Embolization of Hypervascular Intracranial Tumors-Preliminary Clinical Experience.

Pre-operative embolization of hypervascular intracranial tumors can be performed to reduce bleeding complications during resection. Accurate vascular mapping of the tumor is necessary for both the correct indication setting for embolization and for the evaluation of the performed embolization. We prospectively examined the role of whole brain and selective parenchymal blood volume (PBV) flat detector computer tomography perfusion (FD CTP) imaging in pre-operative angiographic mapping and embolization of patients with hypervascular intracranial tumors. Whole brain FD CTP imaging with a contrast injection from the aortic root and selective contrast injection in the dural feeding arteries was performed in five patients referred for tumor resection. Regional relative PBV values were obtained pre- and post-embolization. Total tumor volumes with selective external carotid artery (ECA) supply volumes and post-embolization devascularized tumor volumes were determined as well. In all patients, including four females and one male, with a mean age of 54.2 years (range 44-64 years), the PBV scans were performed without adverse events. The average ECA supply was 54% (range 31.5-91%). The mean embolized tumor volume was 56.5% (range 25-94%). Relative PBV values decreased from 5.75 ± 1.55 before embolization to 2.43 ± 1.70 post-embolization. In one patient, embolization was not performed because of being considered not beneficial for the resection. Angiographic FD CTP imaging of the brain tumor allows 3D identification and quantification of individual tumor feeder arteries. Furthermore, the technique enables monitoring of the efficacy of pre-operative endovascular tumor embolization.

Vessel territory mapping after cerebral revascularization surgery using selective angiographic flat detector perfusion imaging.

The technical feasibility and diagnostic potential of angiographic flat-detector perfusion imaging technique, combining digital subtraction angiography with a flat-detector computed tomography steady-state perfusion imaging, was explored in patients treated with direct or indirect revascularization surgery. This short communication is about an imaging modality with great potential for evaluation, comparison and grading of vascular perfusion territory areas and anatomical location selectively perfused by direct and indirect cerebral bypasses.

Multicenter, retrospective analysis of endovascular treatment for acute ischemic stroke in nonagenarians.

BACKGROUND: With the increasing age of acute stroke patients being admitted to hospitals, more data are needed on indications, complications and outcome of endovascular treatment (EVT) in the very elderly. METHODS: Retrospective observational study with data collection from Belgian, Swiss, Canadian comprehensive stroke centers and Swedish EVT National database. All patients with acute ischemic stroke were eligible if aged older than or ≥90 years and treated with EVT ± pretreatment with intravenous thrombolysis (IVT). Safety assessment comprised presence of periprocedural complications, hemorrhagic transformation or other adverse events (<7days). Efficacy and outcome measures were successful recanalization (modified Treatment In Cerebral Infarction (mTICI) score ≥2b), favorable clinical outcome (modified Rankin Score (mRS) 0-2) and 3-months mortality. RESULTS: Inclusion of 112 nonagenarians (mean age 93.3 ± 2.5 years; 76.8% women; pre-mRS ≤2 in 69.4%). Pretreatment with IVT was performed in 54.7%. In 74.6% successful recanalization (mTICI ≥2b) was achieved. Favorable outcome (mRS ≤2) was seen in 16.4% and 3-months mortality was 62.3%. Multivariate logistic regression analysis showed younger age (odds ratio [OR] 2.99; 1.29-6.95; P = .011) and lower prestroke mRS (OR 13.46; 2.32-78.30; P = .004) as significant predictors for good clinical outcome at 90 days. CONCLUSIONS: Our observational study on EVT in nonagenarians demonstrates the need for careful patient selection. A substantial proportion of nonagenarians shows an unfavorable clinical outcome and high mortality, despite acceptable recanalization rates. A high prestroke disability (mRS) and advancing age predict an unfavorable outcome. Treatment decisions should be made on case-by-case evaluation, keeping in mind limited chances of favorable outcome and high risk of mortality.

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection.

BACKGROUND: Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure. METHODS: Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis. RESULTS: Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector. CONCLUSIONS: Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.

Geniculate Artery Embolization in Patients With Recurrent Hemarthrosis After Knee Arthroplasty: A Retrospective Study.

BACKGROUND: Recurrent hemarthrosis after knee arthroplasty is an uncommon and disabling complication of this frequently performed procedure. Selective endovascular embolization of the geniculate arteries is one of the therapeutic options to manage this complication. The purpose of this study is to analyze the effectiveness of this treatment in patients suffering from recurrent hemarthrosis after knee arthroplasty. METHODS: We performed a retrospective study of 31 patients (39 embolization procedures) with recurrent hemarthrosis after knee arthroplasty. There were 17 men and 14 women with a median age of 67 years (range 48-90). All patients were referred for geniculate artery embolization between January 2007 and November 2016. RESULTS: Twenty-seven procedures were executed on the right side and 12 on the left side. Total knee arthroplasty was performed on 29 patients, only 2 patients underwent unicompartmental knee arthroplasty. Embolization of the superior geniculate arteries was achieved in all patients. In 12 of 39 procedures (31%), at least 1 of the inferior geniculate arteries could not be catheterized, therefore embolization was achieved through collaterals. Symptomatic improvement was observed in 26 of 31 patients (84%). Discomfort or mild postprocedural pain was observed in most patients, needing only minor pain medication, mostly resolving within 24 hours. Two patients presented with a severe complication: a 48-year-old male patient developed septic arthritis and an 85-year-old hypertensive female patient treated with anticoagulants showed aseptic necrosis of the femoral condyles. CONCLUSION: Embolization of geniculate arteries is a safe and effective treatment in recurrent hemarthrosis post knee arthroplasty. Clinical improvement was seen in most patients.

Current concepts in imaging and endovascular treatment of acute ischemic stroke: implications for the clinician.

During the last decade, the management of acute ischemic stroke has changed dramatically, from an expectant bedside "wait and see" attitude towards active treatment, thanks to the continuous improvement of new therapeutic options. In addition to the use of intravenous (IV) thrombolysis in emergent large vessel occlusion (ELVO), endovascular therapy (EVT) has proven to be very efficient in selected acute stroke patients. The indications for EVT have progressed from the era of thrombolysis to individual patient profiling. Recently, several indication parameters, e.g., "treatment time window" or "more distal vessel occlusion," are under debate for adjustment. In this article, we review the imaging strategies in acute stroke and discuss several EVT indication dogmas, which are subject to change.

Miltefosine-resistant Leishmania infantum strains with an impaired MT/ROS3 transporter complex retain amphotericin B susceptibility.

Objectives: Increasing numbers of miltefosine treatment failures in visceral leishmaniasis therapy and reports of miltefosine resistance in the Indian subcontinent resulted in the recommendation to use liposomal amphotericin B as first-line therapy. Cross-resistance between miltefosine and amphotericin B has recently been documented, suggesting a role of mutations in the miltefosine transporter, a complex encoded by the MT and ROS3 genes. This study aimed to further explore the putative role of MT/ROS3 defects in the molecular basis of amphotericin B cross-resistance. Methods: The susceptibility profiles of different miltefosine-resistant Leishmania infantum strains with well-characterized mutations in the transporter complex and the corresponding episomally restored susceptible parasite lines were determined using both the routine extracellular promastigote assay and the intracellular amastigote assay. Results: In vitro amastigote and promastigote susceptibility testing of the two miltefosine-resistant and the episomally reconstituted L. infantum lines revealed full susceptibility to amphotericin B, despite the variable miltefosine susceptibility profile. Conclusions: Mutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier.

Molecular detection of infection homogeneity and impact of miltefosine treatment in a Syrian golden hamster model of Leishmania donovani and L. infantum visceral leishmaniasis.

Control of visceral leishmaniasis caused by Leishmania infantum and Leishmania donovani primarily relies on chemotherapy using an increasingly compromised repertoire of antileishmanial compounds. For evaluation of novel drugs, the Syrian golden hamster is considered as a clinically relevant laboratory model. In this study, two molecular parasite detection assays were developed targeting cathepsin-like cysteine protease B (CPB) DNA and 18S rRNA to achieve absolute amastigote quantification in the major target organs liver and spleen. Both quantitative PCR (qPCR) techniques showed excellent agreement with a strong correlation with the conventional microscopic reading of Giemsa-stained tissue smears. Using multiple single tissue pieces and all three detection methods, we confirmed homogeneity of infection in liver and spleen and the robustness of extrapolating whole organ burdens from a small single tissue piece. Comparison of pre- and post-treatment burdens in infected hamsters using the three detection methods consistently revealed a stronger parasite reduction in the spleen compared to the liver, indicating an organ-dependent clearance efficacy for miltefosine. In conclusion, this study in the hamster demonstrated high homogeneity of infection in liver and spleen and advocates the use of molecular detection methods for assessment of low (post-treatment) tissue burdens.

Genomic and Molecular Characterization of Miltefosine Resistance in Leishmania infantum Strains with Either Natural or Acquired Resistance through Experimental Selection of Intracellular Amastigotes.

During the last decade miltefosine (MIL) has been used as first-line treatment for visceral leishmaniasis in endemic areas with antimonial resistance, but a decline in clinical effectiveness is now being reported. While only two MIL-resistant Leishmania infantum strains from HIV co-infected patients have been documented, phenotypic MIL-resistance for L. donovani has not yet been identified in the laboratory. Hence, a better understanding of the factors contributing to increased MIL-treatment failure is necessary. Given the paucity of defined MIL-resistant L. donovani clinical isolates, this study used an experimental amastigote-selected MIL-resistant L. infantum isolate (LEM3323). In-depth exploration of the MIL-resistant phenotype was performed by coupling genomic with phenotypic data to gain insight into gene function and the mutant phenotype. A naturally MIL-resistant L. infantum clinical isolate (LEM5159) was included to compare both datasets. Phenotypically, resistance was evaluated by determining intracellular amastigote susceptibility in vitro and actual MIL-uptake. Genomic analysis provided supportive evidence that the resistance selection model on intracellular amastigotes can be a good proxy for the in vivo field situation since both resistant strains showed mutations in the same inward transporter system responsible for the acquired MIL-resistant phenotype. In line with previous literature findings in promastigotes, our data confirm a defective import machinery through inactivation of the LiMT/LiRos3 protein complex as the main mechanism for MIL-resistance also in intracellular amastigotes. Whole genome sequencing analysis of LEM3323 revealed a 2 base pair deletion in the LiMT gene that led to the formation an early stop codon and a truncation of the LiMT protein. Interestingly, LEM5159 revealed mutations in both the LiMT and LiRos3 genes, resulting in an aberrant expression of the LiMT protein. To verify that these mutations were indeed accountable for the acquired resistance, transfection experiments were performed to re-establish MIL-susceptibility. In LEM3323, susceptibility was restored upon expression of a LiMT wild-type gene, whereas the MIL-susceptibility of LEM5159 could be reversed after expression of the LiRos3 wild-type gene. The aberrant expression profile of the LiMT protein could be restored upon rescue of the LiRos3 gene both in the LEM5159 clinical isolate and a ΔLiRos3 strain, showing that expression of LdMT is dependent on LdRos3 expression. The present findings clearly corroborate the pivotal role of the LiMT/LiRos3 complex in resistance towards MIL.

Comparative Fitness of a Parent Leishmania donovani Clinical Isolate and Its Experimentally Derived Paromomycin-Resistant Strain.

Paromomycin has recently been introduced for the treatment of visceral leishmaniasis and emergence of drug resistance can only be appropriately judged upon its long term routine use in the field. Understanding alterations in parasite behavior linked to paromomycin-resistance may be essential to assess the propensity for emergence and spread of resistant strains. A standardized and integrated laboratory approach was adopted to define and assess parasite fitness of both promastigotes and amastigotes using an experimentally induced paromomycin-resistant Leishmania donovani strain and its paromomycin-susceptible parent wild-type clinical isolate. Primary focus was placed on parasite growth and virulence, two major components of parasite fitness. The combination of in vitro and in vivo approaches enabled detailed comparison of wild-type and resistant strains for which no differences could be demonstrated with regard to promastigote growth, metacyclogenesis, in vitro infectivity, multiplication in primary peritoneal mouse macrophages and infectivity for Balb/c mice upon infection with 2 x 107 metacyclic promastigotes. Monitoring of in vitro intracellular amastigote multiplication revealed a consistent decrease in parasite burden over time for both wild-type and resistant parasites, an observation that was subsequently also confirmed in a larger set of L. donovani clinical isolates. Though the impact of these findings should be further explored, the study results suggest that the epidemiological implications of acquired paromomycin-resistance may remain minimal other than the loss of one of the last remaining drugs effective against visceral leishmaniasis.