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BackgroundMalaria continues to pose a significant health challenge, particularly in low-resource settings (LRS), where access to reliable and timely diagnostics is often limited. In this context, point-of-care (POC) in vitro diagnostics (IVDs) play a key role in supporting early detection and treatment. The aim of this scoping review was to better understand the landscape of malaria IVD technologies, with the aim of identifying both their strengths and limitations to guide and accelerate the development of POC diagnostics suitable for endemic regions and LRS. To support this analysis, the ASSURED (Affordability, Sensitivity, Specificity, User-friendliness, Rapidity, Equipment-free, Deliverability) criteria were applied to rank each technology in terms of its potential for POC applications in LRS.MethodsA literature search was conducted in PubMed and Web of Science for original research articles on malaria POC diagnostic devices published in English over the last 20 years (2003–2023). Records were screened based on eligibility criteria. For each paper, we identified biomarkers, biological specimens used, analytical methods, and readout technologies. Each record was ranked from low to high for its compatibility with the seven ASSURED criteria and for the Technology Readiness Level.ResultsThe final dataset included 118 records. Of the methods considered, immunoassays were the most frequently reported (41.5%), followed by loop-mediated isothermal amplification (LAMP, 22.8%), polymerase chain reaction (PCR, 6.7%) and optical microscopy (4.2%). The limit of detection was highest for LAMP and PCR. Biomarkers employed for diagnosis included the Plasmodium parasite, parasite protein antigens and hemozoin. Blood was the most commonly employed biological specimen (76.2%), followed by urine and saliva (5.1%). Despite a focus on malaria IVDs for POC applications, only 8% of the records mentioned ASSURED criteria, with most studies manifesting low compatibility with the criteria.ConclusionsAlthough meeting the ASSURED criteria remains challenging, microscopy is still the gold standard because of its diagnostic accuracy. Recent developments in low-cost, high-magnification lenses and innovative manufacturing techniques have enabled the production of microscopy devices in LRS. Combined with advancements in image processing and shape recognition through machine learning, there is strong potential for intellectual and economic investments to enhance microscopy for POC malaria diagnostics.Graphic abstract

Infection with Schistosoma haematobium causes urogenital disease associated with organ disfunction, bleeding, pain, and higher susceptibility to infections and cancer. Timely and accurate diagnosis is crucial for prompt and appropriate treatment as well as surveillance efforts, and the use of plasma biomarkers offers important advantages over parasitological examination of urine, including increased sensitivity and the possibility to use the same specimen for multiple investigations. The present study aims to evaluate the diagnostic performance of different plasma biomarkers in endemic populations from Burkina Faso, West Africa. Schistosoma spp. Circulating Anodic Antigen (CAA), cell free S . haematobium DNA (cfDNA), class M and G antibodies against S . haematobium Soluble Worm Antigen Preparation (SWAP) and Soluble Egg Antigen (SEA) were measured in 406 plasma samples. Results of each biomarker test were compared to those of CAA, a Composite Reference Standard (CRS) and Latent Class Analysis (LCA). An identical proportion of positive samples (29%) was observed as a result of CAA and cfDNA testing, with a substantial agreement (84%, Cohen k = 0.62) between the results of the two tests, and a comparable agreement with the results of CRS and LCA. A higher positivity was observed, as expected, as a result of specific antibody testing (47%-72%), with IgG showing a higher agreement than IgM with the three references. Also, higher IgG levels were observed in current vs past infection, and ROC analysis identified optimal cutoff values for improved testing accuracy. This study provides compelling evidence that can inform the choice of the most appropriate diagnostic plasma biomarker for urogenital schistosomiasis in endemic areas, depending on the purpose, context, and available resources for testing. Either CAA or cfDNA testing can be used for the diagnosis of patients and for epidemiological investigations, even in absence of urine filtration microscopy, whereas anti-SWAP or anti-SEA IgG can be employed for surveillance and integrated monitoring of control interventions against poverty-associated diseases.

A multi-centre genome-wide association study of severe malaria in African children uncovers a new resistance locus close to a cluster of genes encoding glycophorins, which are receptors used by the malaria-causing parasite to invade red blood cells. Gene variants associated with resistance to malaria This multi-centre genome-wide association study of severe malaria in more than 11,000 African children uncovers a new variant associated with resistance to malaria that is close to a cluster of genes encoding glycophorins — membrane receptors used by the Plasmodium falciparum parasite to invade red blood cells. Interestingly, the variant is linked to polymorphisms previously found to have been maintained for millions of years, based on genome analysis of humans and chimpanzees. The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies 1 , 2 , 3 . To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-threatening Plasmodium falciparum infection (severe malaria) in over 11,000 African children, with replication data in a further 14,000 individuals. Here we report a novel malaria resistance locus close to a cluster of genes encoding glycophorins that are receptors for erythrocyte invasion by P. falciparum . We identify a haplotype at this locus that provides 33% protection against severe malaria (odds ratio = 0.67, 95% confidence interval = 0.60–0.76, P value = 9.5 × 10 −11 ) and is linked to polymorphisms that have previously been shown to have features of ancient balancing selection, on the basis of haplotype sharing between humans and chimpanzees 4 . Taken together with previous observations on the malaria-protective role of blood group O 1 , 2 , 3 , 5 , these data reveal that two of the strongest GWAS signals for severe malaria lie in or close to genes encoding the glycosylated surface coat of the erythrocyte cell membrane, both within regions of the genome where it appears that evolution has maintained diversity for millions of years. These findings provide new insights into the host–parasite interactions that are critical in determining the outcome of malaria infection.

Background Transfusion with Plasmodium -infected blood represents a risk for malaria transmission, a rare but severe event. Several non-endemic countries implement a strategy for the screening of candidate blood donors including questionnaire for the identification of at-risk subjects and laboratory testing of blood samples, often serology-based, with temporary deferral from donation for individuals with a positive result. In Italy, the most recent legislation, issued in November 2015, introduced the use of serological tests for the detection of anti- Plasmodium antibodies. Methods In the absence of a gold standard for malaria serology, the aim of this work was to evaluate five commercial ELISA kits, and to determine their accuracy (sensitivity and specificity) in comparison to immuno-fluorescence antibody test (IFAT), and their agreement (concordance of results). Serum samples from malaria patients or from subjects with malaria history (N = 64), malaria naïve patients with other parasitic infections (N = 15), malaria naïve blood donors (N = 8) and malaria exposed candidate blood donors (N = 36) were tested. Results The specificity of all ELISA kits was 100%, while sensitivity ranged between 53 and 64% when compared to IFAT on malaria patients samples. When tested on candidate blood donors’ samples, ELISA kits showed highly variable agreement (42–94%) raising the possibility that the same individual could be included or excluded from donation depending on the test in use by the transfusion centre. Conclusions These preliminary results indicate how the lack of a gold standard for malaria serology must be taken into account in the application and future revision of current legislation. There is need of developing more sensitive serological assays. Moreover, the adoption of a unique serological test at national level is recommended, as well as the development of screening algorithms based on multiple laboratory tests, including molecular assays.

Structural variants are mapped that are correlated with a reduced risk of severe malaria. Large-scale deletions and duplications of genes, referred to as structural variants (SVs), are common within the human genome and have been linked to disease. Examining a genomic region that appears to confer a selective benefit, Leffler et al. used fine mapping to identify a specific SV that reduces the risk of severe malaria by an estimated 40% (see the Perspective by Winzeler). Data from African individuals revealed that populations harbor different SVs in this region. Furthermore, by dissecting a highly complex genomic region, the authors identified the likely causal element. This element encodes hybrid genes that affect glycophorin proteins, which are used by the malarial parasite in infection and are associated with resistance to severe disease. Science , this issue p. eaam6393 ; see also p. 1122 The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB . We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

Our understanding of the composition of multi-clonal malarial infections and the epidemiological factors which shape their diversity remain poorly understood. Traditionally within-host diversity has been defined in terms of the multiplicity of infection (MOI) derived by PCR-based genotyping. Massively parallel, single molecule sequencing technologies now enable individual read counts to be derived on genome-wide datasets facilitating the development of new statistical approaches to describe within-host diversity. In this class of measures the F(WS) metric characterizes within-host diversity and its relationship to population level diversity. Utilizing P. falciparum field isolates from patients in West Africa we here explore the relationship between the traditional MOI and F(WS) approaches. F(WS) statistics were derived from read count data at 86,158 SNPs in 64 samples sequenced on the Illumina GA platform. MOI estimates were derived by PCR at the msp-1 and -2 loci. Significant correlations were observed between the two measures, particularly with the msp-1 locus (P = 5.92×10(-5)). The F(WS) metric should be more robust than the PCR-based approach owing to reduced sensitivity to potential locus-specific artifacts. Furthermore the F(WS) metric captures information on a range of parameters which influence out-crossing risk including the number of clones (MOI), their relative proportions and genetic divergence. This approach should provide novel insights into the factors which correlate with, and shape within-host diversity.

A man with hepatitis B infection was admitted to Pisa University Hospital for hepatological evaluation, which revealed multiple cystic lesions and suggested a cirrhotic evolution. Treatment with Entecavir 0.5 mg/day was started, resulting in rapid viral load suppression and alanine aminotransferase normalization. After 10 years, imaging documented a single nodule of hepatocellular carcinoma (HCC), and a robot-assisted nodule resection was performed. One year later, HCC recurrence prompted orthotopic liver transplantation, during which the patient died because of the sudden rupture of the donor’s organ and rapid multiorgan deterioration before retransplantation. During post-mortem liver examination, adult worms were evidenced within large biliary ducts, suggesting infection with Opisthorchis or Clonorchis spp. flukes. Sequencing of the ITS2 locus, following PCR amplification of DNA extracted from liver tissue, revealed 100% identity with the reference sequence of O. felineus. Infection of the patient with O. felineus was confirmed by the presence of specific IgG detected by ELISA in the patient’s sera. Two major alkaline phosphatase serum levels peaks observed during the first two years of antiviral therapy support the hypothesis that O. felineus infection worsened liver function. This case report highlights the importance of a very careful screening of parasitic infections in solid organ transplantation candidates.

Although hemoglobin S (HbS) and hemoglobin C (HbC) are well known to protect against severe Plasmodium falciparum malaria, conclusive evidence on their role against infection has not yet been obtained. Here we show, in 2 populations from Burkina Faso (2007-2008), that HbS is associated with a 70% reduction of harboring P. falciparum parasitemia at the heterozygous state (odds ratio [OR] for AS vs AA, 0.27;95% confidence interval [CI], .11-.66; P = .004). There is no evidence of protection for HbC in the heterozygous state (OR for AC vs AA, 1.49; 95% CI, .69-3.21; P= .31), whereas protection even higher than that observed with AS is observed in the homozygous and double heterozygous states (OR for CC + SC vs AA, 0.04; 95% CI, .01-. 29; P = .002). The abnormal display of parasite-adhesive molecules on the surface of HbS and HbC infected erythrocytes, disrupting the pathogenic process of sequestration, might displace the parasite from the deep to the peripheral circulation, promoting its elimination at the spleen level.

The Einstein Telescope is Europe’s next generation gravitational-wave detector. To develop all necessary technology, four research facilities have emerged across Europe: The Amaldi Research Center (ARC) in Rome (Italy), ETpathfinder in Maastricht (The Netherlands), SarGrav in the Sos Enattos mines on Sardinia (Italy) and E-TEST in Liége (Belgium) and its surroundings. The ARC pursues the investigation of a large cryostat, equipped with dedicated low-vibration cooling lines, to test full-scale cryogenic payloads. The installation will be gradual and interlaced with the payload development. ETpathfinder aims to provide a low-noise facility that allows the testing of full interferometer configurations and the interplay of their subsystems in an ET-like environment. ETpathfinder will focus amongst others on cryogenic technologies, silicon mirrors, lasers and optics at 1550 and 2090 nm and advanced quantum noise reduction schemes. The SarGrav laboratory has a surface lab and an underground operation. On the surface, the Archimedes experiment investigates the interaction of vacuum fluctuations with gravity and is developing (tilt) sensor technology for the Einstein Telescope. In an underground laboratory, seismic characterisation campaigns are undertaken for the Sardinian site characterisation. Lastly, the Einstein Telecope Euregio meuse-rhine Site & Technology (E-TEST) is a single cryogenic suspension of an ET-sized silicon mirror. Additionally, E-TEST investigates the Belgian–Dutch–German border region that is the other candidate site for Einstein Telescope using boreholes and seismic arrays and hydrogeological characterisation. In this article, we describe the Einstein Telescope, the low-frequency part of its science case and the four research facilities.

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNγ, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4⁺CD25⁺ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFβ, TGFβRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFβ and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25⁺ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.