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Prevention and management of syphilis in pregnant and perinatal women
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Urine PCR testing as an effective method for early diagnosis of leptospirosis
No full textInternational audienceThe role of urine PCR for leptospirosis diagnosis in the first week is controversial due to assumed limited urine excretion. This study analyzed the prescribing practices and sensitivity of blood and urine Leptospira PCR, particularly in early stages of infection. A study was conducted on adult patients diagnosed with leptospirosis in French Guiana between 2016 and 2022 by positive Leptospira PCR, or titer of Micro-Agglutination Test > 1/200, or positive IgM with no alternative diagnosis. The timing of PCR tests and their sensitivity were analyzed. A multivariate logistic regression was performed to identify the factors associated with the sensitivity and predict the probability of having a positive result. Among 188 analyzed patients, 137 (73%) and 61 (32%) underwent blood and urine PCR tests with a median (IQR) delay since symptoms onset of 5 (3–7) and 6 (5–8) days, respectively. The overall sensitivity of urine PCR was 84% (vs 70% for blood PCR, P = 0.04). Of the 25 patients sampled the same day in the first week, eight had negative blood PCR but positive urine PCR. Contrary to urine, the sensitivity of blood PCR significantly decreased with time since symptom onset (aOR 0.56 per day, 95% CI [0.44–0.73]). The predicted probability of positive urine PCR appeared higher than that of blood PCR as soon as 4 days after symptom onset. Urine PCR should be considered at the first consultation, alongside blood PCR.IMPORTANCEThe study investigates the utility of urinary PCR for diagnosing leptospirosis, focusing on its early sensitivity. Conducted in French Guiana between 2016 and 2022, the research analyzed prescribing practices and the sensitivity of blood and urine PCR tests in adult patients. Results indicated that while underutilized, urinary PCR demonstrated high sensitivity from the early days of symptom onset, achieving 84% sensitivity compared to 70% for blood PCR. The sensitivity of blood PCR decreased over time, whereas that of urinary PCR remained stable. The study advocates for the routine inclusion of urinary PCR in the diagnostic workup from the first week of illness to enhance early leptospirosis detection
Exposure Perception and Symptom Reporting in Idiopathic Environmental Intolerance Attributed to Electromagnetic Fields Using a Co‐Designed Provocation Test
No full textInternational audienceIdiopathic Environmental Intolerance Attributed to Electromagnetic Fields (IEI‐EMF) is a syndrome that defines people who report symptoms that they attribute to their exposure to EMF sources, without any identified underlying medical condition to explain these symptoms. To date, provocation protocols have failed to demonstrate a consistent relationship between EMF exposure and reported symptoms, raising questions among some researchers and individuals with IEI‐EMF about the relevance of these protocols for studying the syndrome. To address these criticisms, a provocation protocol was co‐designed in collaboration with individuals with IEI‐EMF. This study presents the results of the tests, with a focus on exposure perception and symptom reporting among IEI‐EMF volunteers. A total of 47 IEI‐EMF volunteers were enrolled and participated in an open‐field habituation session. Of these, 27 completed the first double‐blind controlled exposure session, while 26 and 16 volunteers, respectively, participated in three sessions for collective analyses and 12 sessions for individual‐level analyses. At the individual level, no consistent association was found between exposure perception certainty level and exposure status, except for one volunteer whose perception was mostly consistent with exposure status. Similarly, symptom reporting did not align with exposure status, except for the same volunteer, whose symptom reporting showed a borderline significant result with exposure status. However, for half of the volunteers, symptom reporting was significantly correlated with exposure perception certainty level, supporting a nocebo hypothesis. At the collective level, no consistency was observed between exposure perception certainty level, symptom reporting, and exposure status. This study discusses the conditions necessary for future provocation protocols to enhance their relevance, acceptability, and potential utility in a possible care‐oriented approach. It also considers criticisms of using exposure perception and symptom reporting as outcomes in provocation protocols, despite their central role in how individuals identify themselves as individuals with IEI‐EMF
A Multi-Host Approach to Quantitatively Assess the Role of Dogs as Sentinels for Rift Valley Fever Virus (RVFV) Surveillance in Madagascar
No full textInternational audienceSentinel animals may play a key role in the surveillance of arbovirus circulation, particularly in developing countries. This study aimed to assess the relevance of using dogs as sentinel animals for Rift Valley fever virus (RVFV) surveillance in Madagascar. Serological surveys were conducted on 513 dogs and 135 cattle in the Ifanadiana district, southeastern Madagascar. In addition, 486 human dry blood samples available from the same area were used. Antibodies against RVFV were detected in 23 of 513 dogs, in 86 of 486 humans, and in 33 of 135 cattle. Serocatalytic models fitted to age-stratified serological data were developed to estimate the RVFV force of infection (FOI) under several hypotheses, ranging from no relationship to proportional RVFV FOIs between humans, cattle, and dogs. The best supported model indicated that RVFV FOI in humans and cattle was proportional to RVFV FOI in dogs. Proportionality parameters were estimated at 2.6 (95% credible interval: [1.4–5.1]) for humans and 3.5 (95% credible interval: [1.3–6.4]) for cattle. Our findings suggested that dog blood samples could be used to identify RVFV circulation in RVF endemic areas and infer the exposure of humans and cattle in these areas in Madagascar
Left and Right Atrioventricular Coupling: state-of-the-art review
No full textInternational audienceThe coordinated interaction between atria and ventricles, termed atrioventricular (AV) coupling, is essential for maintaining efficient cardiac performance. The left/right atrium (LA/RA) modulates left/right ventricular (LV/RV) filling through its reservoir, conduit, and booster pump functions, while the LV/RV in turn determines atrial pressures and compliance. Disruption of this finely balanced interplay leads to impaired filling dynamics, abnormal pressure–volume relationships, and progressive remodeling. Mechanisms of uncoupling include mechanical dysfunction from atrial dilatation and fibrosis, ventricular diastolic stiffness, and loss of atrial contractile reserve, as well as electromechanical desynchrony due to conduction abnormalities such as AV block or prolonged PR interval. The concept of quantifying AV coupling has been formalised through the left/right atrioventricular coupling index (LACI/RACI), defined as the ratio of LA/RA end-diastolic volume to LV/RV end-diastolic volume. LACI/RACI can be noninvasively derived across imaging modalities—including echocardiography, computed tomography, and cardiovascular magnetic resonance—without requiring specific acquisition protocols. First described in large population cohorts, LACI has demonstrated independent and incremental prognostic value for heart failure, atrial fibrillation and mortality, outperforming isolated atrial or ventricular parameters. Moreover, its ability to capture dynamic remodeling make it a promising biomarker for risk stratification across a broad spectrum of cardiovascular diseases. This review synthesises current knowledge on left and right AV coupling, outlines the physiological and pathophysiological mechanisms of uncoupling, and highlights the role of LACI/RACI as both a diagnostic and prognostic tool. Standardisation of assessment strategies and reference values will be essential to facilitate clinical translation and precision cardiology
Extracellular microbes are required for mosquito development even in the presence of Wolbachia
No full textInternational audienceWolbachia, an endosymbiotic bacterium infecting a wide array of invertebrates, has gained attention for its potential in vector control. Its capacity to colonise host populations primarily relies on vertical transmission and reproductive manipulation in arthropods. This endosymbiont is additionally mutualistic in some hosts, across several Wolbachia supergroups; notably, in nematodes and, as recently demonstrated, in planthoppers and bedbugs, it functions as an essential nutritional symbiont by providing vitamins to its host. Since mosquito larvae require microbe-derived nutrients for development, we investigated whether Wolbachia alone can support larval development in Culex quinquefasciatus mosquitoes. Our findings reveal that Wolbachia alone is insufficient to support larval development. Using transient colonisation with Escherichia coli , we developed a protocol to produce adult Culex quinquefasciatus mosquitoes harbouring Wolbachia only (germ-free Wol+ ). These results suggest that E. coli can support larval development in this species, which typically thrives in murky water; they also underscore the importance of extracellular microbes in larval growth. Furthermore, when Wolbachia infection was suppressed in germ-free Wol+ larvae using tetracycline treatment, we observed enhanced larval development, suggesting that Wolbachia acts as a metabolic parasite. In summary, this study opens the way for gnotobiology research in Culex quinquefasciatus and highlights the intricate interactions between Wolbachia and other members, which collectively influence mosquito development
Derepression of the epithelial transcription factor GRHL2 promotes direct hepatocyte-to-cholangiocyte transdifferentiation
No full textInternational audienceThe liver's regenerative capacity is underscored by the plasticity potential of adult hepatocytes. In this context, hepatocyte-to-cholangiocyte transdifferentiation (HCT) has been ascribed with pro-regenerative functions in animal models and is a feature of end-stage human chronic liver diseases. While dampened activities of hepatocyte identity transcription factors (TFs) underlay HCT, how the cholangiocyte transcriptional program is implemented is poorly defined. Here, we identify that HCT does not involve transitioning through a hepatoblast-like transcriptional program. Furthermore, we show that HCT primarily involves induction of the archetypal transcriptional program of monopolarized epithelial cells initially repressed in hepatocytes. Indeed, HCT requires relieving H3K27me3-mediated and polycomb-dependent epigenetic silencing of epithelial TF encoding genes including Grainyhead Like Transcription Factor 2 (GRHL2). Ectopic expression of GRHL2 in hepatocytes, including in vivo in the adult mouse liver, induces epithelial genes reminiscent of those activated during HCT.Finally, GRHL2 is detected in human hepatocytes undergoing HCT as evidenced using samples from end-stage chronic liver diseases. Hence, HCT is a process chiefly characterized by induction of a conventional epithelial transcriptional program originally lacking in hepatocytes promoted by derepression of the master epithelial TF GRHL2.</p
SHERLOCK4AAT, a new molecular method for highly sensitive and specific detection of animal African trypanosomes
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Comprehensive mutational profiling and clinical outcome of adults AML with NUP98 rearrangement
No full textInternational audienceAcute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r) is recognized as a distinct entity in the 2022 WHO classification; however, it is not as a prognostic factor within the ELN 2022 classification. We report a large cohort of 95 adult patients with NUP98r AML. Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41y vs 61y), had more de novo AML (94% vs 64%), higher rates of normal karyotypes (56% vs 4.5%), FLT3-ITD (76% vs 18%) and WT1 mutations (50% vs 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 14.8 months (95% CI, 11.9–20.8) and event-free survival was 3.3 months (2-7.5). Among patients treated intensively (n=73), age (HR = 1.04) and FLT3 inhibitor therapy (HR = 0.45) influenced OS in univariate analysis, while leukocytosis, partner type, ELN classification, presence of a FLT3-ITD or WT1 mutation or hematopoietic stem cell transplant did not. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with OS approaching that of intermediate-risk AML patients (33.3 months [11.9–not reached])
Treatments and outcomes of adult patients with TP53-mutated acute myeloid leukemia (AML) in the real-life –Report of the prospective french observational ALFA-PPP study.
No full textInternational audienceIntroduction The prognosis of AML harboring TP53 mutations remains exceptionally poor. Clinical trials specifically designed for TP53-mutated AML are scarce and fail to represent real-world patient populations. Furthermore, most outcome data for TP53-mutated AML come from retrospective studies, where therapeutic decisions are frequently made without prior knowledge of molecular results. To address these gaps, we used data from the prospective ALFA-PPP registry (NCT04777916) to investigate the real-world management of patients with TP53-mutated AML. Methods We report the observations of the first 1,108 newly diagnosed adult AML patients (April 2022-August 2024) who had a centralized genomic profiling at diagnosis (50-gene NGS panel), focusing on the presence of TP53 mutation. Kaplan-Meier methodology was applied to estimate overall survival (OS). Multivariable analyses were performed using logistic regression or Cox regression, where appropriate. Results One hundred and sixty-five patients harbored at least one TP53 mutation at diagnosis. There were 89 males and 76 females (median age 72y [IQR, 64-77]; ECOG-PS 0-1/2/3-4, 98/42/21; median WBC 3.1 G/L [IQR, 1.7-7.3]; median marrow blast 31% [IQR, 22-54]). The numbers of patients with de novo, secondary and therapy-related AML (t-AML) were 90 (54%), 26 (16%) and 49 (30%), respectively. ELN-2022 cytogenetic risk was intermediate in 20 (12%), adverse in 137 (83%), and unclassifiable in 8 (5%). Median TP53 variant allele frequency was 44% (IQR 23-73), and 121 (74%) patients were classified as having bi-allelic TP53 mutations. In the full cohort, in multivariable analysis, older age (OR, 1.28 [95%CI, 1.09-1.52]; p=0.003), lower blast count (OR, 0.82 [95%CI, 0.75-0.90]; p<0.001), and adverse cytogenetic risk (OR, 30.98 [95%CI, 18.74-53.85]; p<0.001) were predictive of the presence of TP53 mutations. Secondary AML (OR, 0.88 [95%CI, 0.45-1.70]; p=0.714) or t-AML (OR, 1.39 [95%CI, 0.82-2.34]; p=0.217) were not significantly associated with TP53 mutation status. In the TP53-mutated cohort, treatment decision was intensive in 37 (22%) (median age, 63 years [56-66]; including 17 CPX-351), less intensive in 106 (64%) (median age, 75 years [68-79]; 78 AZA-VEN, 10 AZA, 18 unknown), and best supporting care in 16 (10%) patients, while the 5/6 remaining patients died before treatment decision. A total of 22/165 (13%) patients received an allogeneic stem cell transplant (HSCT) including 17 intensively and 5 less-intensively treated patients. With a median follow-up of 24 months (95% CI, 17-28), the median OS of intensively and less intensively treated patients was 11.7 (95% CI, 7.6-15.7) and 4.8 (95% CI, 3.6-6.2) months, respectively. The 12-month OS rates of intensively and less intensively treated patients were 48% (95%CI, 34-67%) and 19% (95% CI, 13-28%), respectively. The median OS of patients who underwent HSCT was 17.2 months (95% CI, 2.8-12.9). In these patients, multivariable Cox analysis evidenced older age (HR, 1.3 [95%CI 1.1-1.5]), higher ECOG (HR, 1.7 [95%CI, 1.2-2.5]; p=0.004), higher medullary blasts count (HR, 1.1 [95%CI, 1.01-1.2]; p= 0.03), t-AML (HR 1.7, [95%CI, 1.2-2.5]; p=0.006) and adverse ELN-2022 cytogenetic risk (HR, 2.5 [95%CI, 1.2-5.1]; p=0.02) as predictors of shorter OS. TP53 bi-allelic status had no impact on OS (HR 1.07, [95%CI, 0.66-1.7]; p=0.7). Finally, we assess the objective factors independently associated with the choice of a less intensive treatment option in the full cohort. Interestingly, the presence of TP53 mutations was strongly associated with a less intensive treatment option (OR, 6.5 [95%CI, 3.3-13.1]; p<0.001) while an adverse-risk cytogenetics was not (OR, 1.7 [95%CI, 0.98-2.8]; p=0.06), suggesting that the knowledge of the mutation may have influenced the treatment choice. The other factors associated with less intensive therapy were older age (OR, 8.2 [95%CI, 6.2-11.2]; p<0.001), higher ECOG (OR, 2.6 [95%CI 1.5-4.6]), AML type (OR, 2.5 [95%CI, 1-4-4.7]; p=0.003 for secondary AML, and OR, 2.6 [95%CI, 1.5-4.7]; p<0.001 for t-AML), and, unexpectedly, male sex (OR 1.8, [95%CI, 1.2-2.8]; p=0.004). Conclusion This prospective real-life AML patient cohort confirms that patients with TP53 mutations display distinct features and face a nearly incurable disease course, even when intensively treated. In absence of effective therapies, the knowledge of TP53 status at diagnosis appears to influence the decision to pursue less intensive treatment options