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BackgroundCongenital toxoplasmosis is a treatable, preventable disease, but untreated causes death, prematurity, loss of sight, cognition and motor function, and substantial costs worldwide.ObjectivesWe asked whether high performance of an Immunochromatographic-test (ICT) could enable accurate, rapid diagnosis/treatment, establishing new, improved care-paradigms at point-of-care and clinical laboratory.MethodsData were obtained in 12 studies/analyses addressing: 1-feasibility/efficacy; 2-false-positives; 3-acceptability; 4-pink/black-line/all studies; 5-time/cost; 6-Quick-Information/Limit-of-detection; 7, 8-acute;-chronic; 9-epidemiology; 10-ADBio; 11,12-Commentary/Cases/Chronology.FindingsICT was compared with gold-standard or predicate-tests. Overall, ICT performance for 1093 blood/4967 sera was 99.2%/97.5% sensitive and 99.0%/99.7% specific. However, in clinical trial, FDA-cleared-predicate tests initially caused practical, costly problems due to false-positive-IgM results. For 58 persons, 3/43 seronegative and 2/15 chronically infected persons had false positive IgM predicate tests. This caused substantial anxiety, concerns, and required costly, delayed confirmation in reference centers. Absence of false positive ICT results contributes to solutions: Lyon and Paris France and USA Reference laboratories frequently receive sera with erroneously positive local laboratory IgM results impeding patient care. Therefore, thirty-two such sera referred to Lyon's Reference laboratory were ICT-tested. We collated these with other earlier/ongoing results: 132 of 137 USA or French persons had false-positive local laboratory IgM results identified correctly as negative by ICT. Five false positive ICT results in Tunisia and Marseille, France, emphasize need to confirm positive ICT results with Sabin-Feldman-Dye-test or western blot. Separate studies demonstrated high performance in detecting acute infections, meeting FDA, CLIA, WHO REASSURED, CEMark criteria and patient and physician satisfaction with monthly-gestational-ICT-screening.Conclusions/significanceThis novel paradigm using ICT identifies likely false positives or raises suspicion that a result is truly positive, rapidly needing prompt follow up and treatment. Thus, ICT enables well-accepted gestational screening programs that facilitate rapid treatment saving lives, sight, cognition and motor function. This reduces anxiety, delays, work, and cost at point-of-care and clinical laboratories.Trial registrationNCT04474132, https://clinicaltrials.gov/study/NCT04474132 ClinicalTrials.gov.

Prenatal systematic screening for congenital toxoplasmosis has been performed in Austria and France since 1975 and neonatal screening for congenital toxoplasmosis has been part of the New England Newborn screening program since 1986.In this narrative review we review the data leading up to the systematic screening programs in Austria and France, highlighting the main finding of the European Union funded research in the 1990s and early 2000s. Different descriptive studies of the effect of pre- or postnatal treatment are discussed. Toxoplasma gondii has different genetic lineages with different pathogenicity in humans. This means that results in areas with a low pathogenic lineage cannot be extrapolated to an area with highly pathogenic lineages. The importance of meat as a source of infection is discussed in the light of an increased prevalence of T.gondii in organic livestock production .

Abstract Background Toxoplasmosis is an infectious disease caused by a protozoan parasite named Toxoplasma gondii (T.gondii). Pregnant women are considered one of the risk groups. The objective of this retrospective study is to provide an updated estimate of the seroprevalence of anti-T. gondii antibodies among a group of Moroccan pregnant women monitored at the Parasitology Laboratory of the National Institute of Hygiene in Rabat in Morocco. Methods Serum samples were tested for the presence of specific anti-T. gondii immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using indirect enzyme-linked immunosorbent assay (ELISA). Anti-Toxoplasma IgM- and IgG-positive cases were also evaluated with the anti-Toxoplasma IgG avidity test. All cases were evaluated according to the age, parity, and historical of abortion. Results Among 677 pregnant women, 94.1% (637/677) were serologically screened for the first time and therefore had no knowledge of their serological status, and only 5.9% (40/677) were screened for the second or third time. The overall anti-T. gondii IgG and IgM seropositivity among the 637 pregnant women included in the study analysis was 43% (274/637) and 3.9% (25/637), respectively. The use of the IgG avidity test allowed excluding recent infection among 83% of cases with IgG and IgM positive sera. The mean age was 29.4 ± 6.3 years. The result of the bivariate analysis revealed that the age influenced significantly the seroprevalence rate, while the parity and the existence of previous spontaneous abortion did not have any significant statistical correlation with seropositivity to T. gondii. Conclusion This study shows that 43% of pregnant women were positive and 57% of them had no antibody against the T. gondii infection. However, the pregnancy follow-up and the counseling of pregnant women remain essential for the prevention of congenital toxoplasmosis.

Point-of-care (POC) testing for Toxoplasma infection has the potential to revolutionize diagnosis and management of toxoplasmosis, especially in high-risk populations in areas with significant environmental contamination and poor health infrastructure precluding appropriate follow-up and preventing access to medical care. Toxoplasmosis is a significant public health challenge in Morocco, with a relatively heavy burden of infection and, to this point, minimal investment nationally to address this infection. Herein, we analyse the performance of a novel, low-cost rapid test using fingerstick-derived whole blood from 632 women (82 of whom were pregnant) from slums, educational centres, and from nomad groups across different geographical regions (i.e. oceanic, mountainous) of Morocco. The POC test was highly sensitive and specific from all settings. In the first group of 283 women, sera were tested by Platelia ELISA IgG and IgM along with fingerstick whole blood test. Then a matrix study with 349 women was performed in which fingerstick – POC test results and serum obtained by venipuncture contemporaneously were compared. These results show high POC test performance (Sensitivity: 96.4% [IC95 90.6–98.9%]; Specificity: 99.6% [IC95 97.3–99.9%]) and high prevalence of Toxoplasma infection among women living in rural and mountainous areas, and in urban areas with lower educational levels. The high performance of POC test confirms that it can reduce the need for venipuncture and clinical infrastructure in a low-resource setting. It can be used to efficiently perform seroprevalence determinations in large group settings across a range of demographics, and potentially expands healthcare access, thereby preventing human suffering.

Even in the absence of manifestations at birth, children with congenital toxoplasmosis (CT) may develop serious long-term sequelae later in life. This systematic review aims to present the current state of knowledge to base an informed decision on how to optimally manage these pregnancies and children. For this, a systematic literature search was performed on 28 July 2022 in PubMed, CENTRAL, ClinicalTrials.gov, Google Scholar and Scopus to identify all prospective and retrospective studies on congenital toxoplasmosis and its long-term outcomes that were evaluated by the authors. We included 31 research papers from several countries. Virulent parasite strains, low socioeconomic status and any delay of treatment seem to contribute to a worse outcome, whereas an early diagnosis of CT as a consequence of prenatal screening may be beneficial. The rate of ocular lesions in treated children increases over time to 30% in European and over 70% in South American children and can be considerably reduced by early treatment in the first year of life. After treatment, new neurological manifestations are not reported, while ocular recurrences are observed in more than 50% of patients, with a mild to moderate impact on quality of life in European cohorts when compared to a significantly reduced quality of life in the more severely affected South American children. Though CT is rare and less severe in Europe when compared with South America, antenatal screening is the only effective way to diagnose and treat affected individuals at the earliest possible time in order to reduce the burden of disease and achieve satisfying outcomes.

Abstract Globally, congenital toxoplasmosis remains a significant cause of morbidity and mortality, and outbreaks of infection with T. gondii represent a significant, emerging public health burden, especially in the developing world. This parasite is a threat to public health. Disease often is not recognized and is inadequately managed. Herein, we analyze the status of congenital toxoplasmosis in Morocco, Colombia, the United States, and France. We identify the unique challenges faced by each nation in the implementation of optimal approaches to congenital toxoplasmosis as a public health problem. We suggest that developed and developing countries use a multipronged approach, modeling their public health management protocols after those in France. We conclude that education, screening, appropriate treatment, and the development of novel modalities will be required to intervene successfully in caring for individuals with this infection. Gestational screening has been demonstrated to be cost-effective, morbidity-sparing, and life-saving. Recognition of the value and promise of public health interventions to prevent human suffering from this emerging infection will facilitate better patient and societal outcomes.

BackgroundCongenital Toxoplasmosis (CT) can have severe consequences. France, Austria, and Slovenia have prenatal screening programs whereas some other countries are considering universal screening to reduce congenital transmission and severity of infection in children. The efficiency of such programs is debated increasingly as seroprevalence among pregnant women and incidence of congenital toxoplasmosis show a steady decrease. In addition, uncertainty remains regarding the effectiveness of pre- and postnatal treatments.MethodTo identify cost-effective strategies, prenatal and neonatal screenings were compared using a decision-analytic model based on French guidelines and current knowledge of long-term evolution of the disease in treated children. Epidemiological data were extracted from the scientific literature and clinical data from the French Lyon cohort. Strategies were compared at one year of age, when infection can be definitively evaluated, and at 15 years of age, after which validated outcome data become scarce. The analysis was performed from the French Health Insurance System perspective and included direct medical costs for pregnant women and their children.ResultsThe 1-year Incremental Cost-Effectiveness Ratio showed that prenatal screening would require investing €14,826 to avoid one adverse event (liveborn with CT, fetal loss, neonatal death or pregnancy termination) compared to neonatal screening. Extra investment increased up to €21,472 when considering the 15-year endpoint.ConclusionsPrenatal screening is cost-effective as compared to neonatal screening in moderate prevalence areas with predominant Type II strains. In addition, prenatal screening, by providing closer follow-up of women at risk increases the number of occasions for education avoiding toxoplasmosis.

BACKGROUND:Congenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved. METHODS:We tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed. RESULTS:We found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM-positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients. CONCLUSIONS:Our work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal-fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries.

Women infected with toxoplasmosis during pregnancy do not present symptoms in most cases, but the consequences of the congenital infection may be severe for the unborn child. Fetal damage can range from asymptomatic to severe neurological alterations to retinal lesions prone to potential flare up and relapses lifelong. Despite the possible severity of outcome, congenital toxoplasmosis (CT) is a neglected disease. There is no consensus regarding screening during pregnancy, prenatal/postnatal treatment or short or medium term follow-up. Since 1992, France has offered systematic serological testing to non-immune pregnant women, monthly until delivery. Any maternal infection is thus detected; moreover, diagnosis of congenital infection can be made at birth and follow-up can be provided. “Guidelines„ drawn up by a multidisciplinary group are presented here, concerning treatment, before and after birth. The recommendations are based on the regular analysis of the literature and the results of the working group. The evaluation of the recommendations takes into account the robustness of the recommendation and the quality of the evidence.

Maternal infection by Toxoplasma gondii during pregnancy may have serious consequences for the fetus, ranging from miscarriage, central nervous system involvement, retinochoroiditis, or subclinical infection at birth with a risk of late onset of ocular diseases. As infection in pregnant women is usually symptomless, the diagnosis relies only on serological tests. Some countries like France and Austria have organized a regular serological testing of pregnant women, some others have no prenatal program of surveillance. Reasons for these discrepant attitudes are many and debatable. Among them are the efficacy of antenatal treatment and cost-effectiveness of such a program. A significant body of data demonstrated that rapid onset of treatment after maternal infection reduces the risk and severity of fetal infection. Recent cost-effectiveness studies support regular screening. This lack of consensus put both pregnant women and care providers in a difficult situation. Another reason why congenital toxoplasmosis is disregarded in some countries is the lack of precise information about its impact on the population. Precise estimations on the burden of the disease can be achieved by systematic screening that will avoid bias or underreporting of cases and provide a clear view of its outcome.

Primary Toxoplasma gondii infection during pregnancy can be transmitted to the fetus. At birth, infected infants may have intracranial calcification, hydrocephalus, and retinochoroiditis, and new ocular lesions can occur at any age after birth. Not all children who acquire infection in utero develop these clinical signs of disease. Whilst severity of disease is influenced by trimester in which infection is acquired by the mother, other factors including genetic predisposition may contribute.In 457 mother-child pairs from Europe, and 149 child/parent trios from North America, we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4. Polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci showed unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers. Modeling suggested either an effect of mother's genotype, or parent-of-origin effects. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting.These associations between clinical outcomes of congenital toxoplasmosis and polymorphisms at ABCA4 and COL2A1 provide novel insight into the molecular pathways that can be affected by congenital infection with this parasite.

Abstract Background Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms. Results Acquired resistance to FK866 was independent of NAMPT mutations but rather was based on a shift towards a glycolytic metabolism and on lactate dehydrogenase A (LDHA) activity. In addition, resistant CCRF-CEM cells, which exhibit high quinolinate phosphoribosyltransferase (QPRT) activity, also exploited amino acid catabolism as an alternative source for NAD+ production, becoming addicted to tryptophan and glutamine and sensitive to treatment with the amino acid transport inhibitor JPH203 and with l-asparaginase, which affects glutamine exploitation. Vice versa, in line with their low QPRT expression, FK866-resistant MDA MB231 did not rely on amino acids for their resistance phenotype. Conclusions Our study identifies novel mechanisms of resistance to NAMPT inhibition, which may be useful to design more rational strategies for targeting cancer metabolism.