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Design and synthesis of novel thioether analogs as promising antiviral agents: In vitro activity against enteroviruses of interest
No full textInternational audienc
Mutagenesis to Orient conjugation and preserve self‐adjuvant properties of flagellin in conjugates
No full textInternational audienceBacterial flagellins are unique for their capacity to activate both the innate and the adaptive immune response through a Toll‐like receptor 5 (TLR5) signaling cascade. Used as a carrier protein in conjugate vaccines it is crucial to preserve their self‐adjuvant properties during the conjugation step. Considering the absence of cysteine in the Salmonella enterica flagellin FliC sequence, we have investigated the impact of five mutations (A2C, K180C, T240C, D251C and S306C) alone or in combination on TLR5 activation. The FliC mutated at the four positions K180C, T240C, D251C and S306C displayed much the same activity as native flagellin whether the cysteine residues were free or conjugated. These results pave the way for the preparation of self‐adjuvanting conjugate vaccines based on cysteine‐mutated FliC as a carrier protein
Artemisinin pressure in field isolates can select highly resistant Plasmodium falciparum parasites with unconventional phenotype and no K13 mutation
No full textInternational audienceArtemisinin resistance, which poses a serious threat to malaria control efforts, is monitored in the field by delayed parasite clearance in patients, elevated parasite survival rate in the ring-stage survival assay, and mutations in the Plasmodium falciparum kelch13 gene. However, sporadic cases of artemisinin-resistant malaria do not meet all of these criteria, highlighting that our understanding of artemisinin resistance is still incomplete. Here, we selected for artemisinin resistance in vitro in nine P. falciparum field isolates from Africa, Asia, and South America. Artemisinin pressure selected highly resistant parasites in all lineages, but only one acquired a validated pfkelch13 mutation. Phenotypic tests evidenced an unconventional response of selected parasites that can be artemisinin-resistant only at an advanced ring age, making them undetectable by the standard “0–3 h” test used to monitor resistance. These results highlight the need for broader approaches to artemisinin resistance monitoring
First-line chemotherapy with selective internal radiation therapy for intrahepatic cholangiocarcinoma: The French ACABi GERCOR PRONOBIL cohort
No full textInternational audienceBackground and Aims: Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL. Methods: Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups' similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement >50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups. Results: Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemoSIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 vs. 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, p <0.0001), a trend for longer OS (median = 22.5 vs. 15.1 months, HR 0.76, 95% CI 0.571.01), higher ORR (58.3% vs. 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, p <0.0001), and resection rate (18.7% vs. 8.8%, p = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, p <0,0001), OS (HR 0.70, 95% CI 0.58-0.85, p = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, p <0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, p <0.0001). Conclusions: Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results. Clinical trial number: NCT04935853. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
“They Have to Make an Effort Too”: What Decliners Can Teach Us About HIV Cure/Remission-Related Clinical Trials? Results from a French Qualitative Study
No full textInternational audienceOnly one study to date has focused on people living with HIV (PLWH) who refused to participate in a HIV cure/remission-related clinical trial (HCCT)-"decliners" hereafter-that included analytical treatment interruption (ATI). Exploring why these persons refuse may provide valuable information to ensure more ethical recruitment and support in HCCTs within the bigger picture of improving HIV cure research. The qualitative component of the AMEP-EHVA-T02/ANRS-95052 study, called AMEP-Decliners, documented the experiences of French PLWH who refused to participate in EHVA-T02/ANRS-VRI07, a phase II randomized, placebo-controlled HCCT with ATI. AMEP-Decliners comprised semi-structured individual interviews with six decliners in two HIV care sites in France between September 2022 and March 2023. The interviews documented their expectations regarding HCCTs, reasons for refusal, and perceived factors that might have led them to participate. Audio files were transcribed, and an inductive thematic analysis was performed. Surprisingly, the main reason for refusal was not ATI but the trial monitoring. Besides the frequency of appointments, respondents emphasized the incompatibility with their active life. One underlying reason for refusal was that participating would have meant "break[ing] the carefree attitude about the disease," reflecting the substantial psychological burden associated with participation. Finally, respondents perceived that the trial's clinical team did not sufficiently recognize their "normal life" and the level of commitment required to participate, leading them to call for greater involvement by the team: "they have to make an effort too." Results from decliners' discourses highlighted that two levels of commitment to participation must be considered when developing HCCTs: psychological burden and logistical constraints. We suggest allowing home examinations and flexible appointment times, prioritizing face-to-face invitations in order to address the psychological burden associated with HCCT participation, and explaining the reasons for monitoring constraints when they cannot be alleviated. Further studies are necessary to confirm our results
High versus low dose of 14 days treatment of primaquine in Plasmodium vivax infected patients in Cambodia: a randomised open-label efficacy study
No full textBackground The WHO malaria treatment guidelines recommend a total dose in the range of 3·5 to 7·0 mg/kg of primaquine to eliminate Plasmodium vivax ( P. vivax ) hypnozoites and prevent relapses. There are however indications that for tropical P. vivax isolates, notably from Southeast Asia, the lower dose of 3·5 mg/kg is insufficient. Determining the most effective regimen to eliminate P. vivax hypnozoites is needed to achieve elimination of this malaria parasite. Methods We conducted an open-label randomised controlled trial in Kampong Speu province, Western Cambodia. P. vivax infected patients with uncomplicated malaria, diagnosed at the community level or in health centres of the province, were offered to participate. Patients aged less than 15 years old, and pregnant or breastfeeding women were excluded. Enrolled patients were treated with a blood schizonticidal artesunate regimen of 2 mg/kg/day for 7 days. Upon enrolment, patients’ glucose-6-phosphate dehydrogenase (G6PD) activity was determined. G6PD normal patients were randomly assigned (2:2:1) to receive either (i) 3·5 mg/kg (low dose as 0·25 mg/kg/day) or (ii) 7·0 mg/kg (high dose as 0·5 mg/kg/day) of primaquine over 14 days or (iii) no primaquine as comparator arm. G6PD deficient patients were assigned to the no-primaquine comparator arm. Randomisation was done by blocks of 5 using sealed envelopes. Upon enrolment, patients were relocated to the study site in Aoral town where no malaria transmission occurs to ensure that they were not reinfected during their 90-day follow-up. After 90 days of relocation, G6PD normal patients in the no-primaquine arm were provided 3·5 mg/kg for 14 days of primaquine to be taken unsupervised. At day 90, all the patients returned home and they were further followed monthly for three months until day 180. The primary outcome was the treatment failure rate defined as the proportion of patients with at least one P. vivax recurrence within 90 days of relocated follow-up. All patients that completed treatment and complied with relocation without interruption before any recurrence was detected were included in the primary efficacy analysis. All patients enrolled and assigned to an intervention arm were included in the safety analysis. The study is registered on ClinicalTrials.gov ( NCT04706130 ). Findings Between Nov 10, 2021, and Feb 10, 2024, a total of 160 patients were enrolled and 156 were allocated to one of the three study arms. Of these, 37 G6PD deficient patients were assigned to the no primaquine arm and 119 G6PD normal patients were randomised: 24 in the no primaquine arm, 49 in the primaquine 3·5 mg/kg arm, and 46 in the primaquine 7·0 mg/kg arm. The proportion of participants with at least one P. vivax recurrence within 90 days in the no primaquine arm was 81·4% (95% CI 69·6-89·2). The proportion of participants with recurrence was higher in the low dose primaquine arm (24·4%, 95% CI 14·2-38·7) compared to the high primaquine arm (4·7%, 95% CI 0·8-15·5, p=0·0141) resulting in a hazard ratio of high dose primaquine compared to low dose of 0·17 (95% CI 0·04-0·79, p=0·0229). Both primaquine arms were well tolerated. Interpretation Not providing primaquine to patients led to a considerable rate of P. vivax recurrence. The risk of P. vivax recurrence was 5·9 times lower for the 7·0 mg/kg of primaquine treatment compared to 3·5 mg/kg. Tolerability and safety of both primaquine regimens in G6PD normal individuals was comparable. Policy makers in Cambodia and most likely in other Southeast Asian countries should endorse the 7·0 mg/kg of primaquine regimen to reduce the risk of P. vivax relapses. Funding National Institutes of Health (R01AI146590) Research in context Evidence before this study The WHO treatment guidelines for preventing Plasmodium vivax relapses using primaquine recommend a range of 3·5-7·0 mg/kg. These guidelines mention that for P. vivax infections acquired in Southeast Asia and Oceania, 7·0 mg/kg should be preferred. We searched Pubmed for randomized controlled trials studies containing the terms “vivax” and “primaquine” published between 1990 and November 2024, with no language restrictions, to identify studies comparing primaquine regimen to treat P. vivax infections. Our search retrieved only two studies comparing head-to-head the efficacy of 3·5mg/kg with 7·0 mg/kg primaquine administered over a same duration of 14 days but were both conducted in South Asia and both showed similar efficacy of high dose compared to low dose primaquine. No studies compared 3·5 and 7·0 mg/kg of primaquine administered over 14 days in South East Asian countries. Added value of this study This randomised controlled trial compared the efficacy of a total dose of 3·5 mg/kg and 7·0 mg/kg of primaquine over 14 days to prevent relapses of P. vivax in Cambodia. Our study design minimized confounding factors affecting therapeutic efficacy evaluation. This study confirms that 7·0 mg/kg has greater efficacy to prevent recurrences than the low 3·5mg/kg regimen, with comparable safety and tolerability in G6PD normal patients from Cambodia. Implications of all the available evidence Our results confirm that 7·0 mg/kg of primaquine should be recommended to prevent relapses in P. vivax infections acquired in Cambodia and most likely in South East Asia. National treatment guidelines in those countries should be changed to endorse this regimen rather than the 3·5 mg/kg
Older people predialysis care pathways and early morbidity–mortality upon start of dialysis
No full textInternational audienceBackground: The ageing of the population with advanced chronic kidney disease (CKD) increases the complexity of care pathways. Our aim was to identify subgroups of older people according to predialysis care pathways and describe their association with early morbidity–mortality after transition to dialysis.Methods: This study included 22 128 incident dialysis patients aged ≥75 years during 2009–2017 from the French nationwide registry linked to the National Health Data System. Predialysis care pathways were identified by ascending hierarchical classification based on preselected healthcare use indicators in the previous year. Their association with a composite outcome of death or hospitalization ≥50% of the time off dialysis within the first year of dialysis was studied by multivariable logistic regression accounting for demographics, comorbidities, functional status, conditions of dialysis initiation, socioeconomic deprivation index and home-to-dialysis center travel time.Results: Five care pathway profiles were identified, characterized by limited healthcare use (Cluster 1, 28%), non-nephrology ambulatory care (Cluster 2, 17%), nephrology ambulatory care (Cluster 3, 37%) and a high level of non-nephrology or nephrology hospitalizations (Clusters 4 and 5, both 9%). Profile subgroups did not differ according to patient age and comorbidities, but Clusters 1, 2 and 4 displayed higher levels of social deprivation. Compared with Cluster 3, the odds ratios of primary composite outcome were significantly increased for Clusters 1, 4 and 5 [odds ratio (95% confidence interval) of 1.16 (1.08–1.25), 1.17 (1.05–1.32) and 1.12 (1.01–1.25), respectively]. Moreover, prolonged hospitalizations were also more common in all groups, compared with Cluster 3.Conclusion: Despite a similar comorbidity profile, older people with advanced CKD experience very heterogeneous predialysis care pathways, some of which associated with higher burden of hospitalization after the transition to dialysis
A fully humanized von Willebrand disease type 1 mouse model as unique platform to investigate novel therapeutic options
No full textInternational audiencePatients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD-patients, especially for the large portion of those with VWD-type 1. Due to species differences, the available VWD murine models are not suitable for preclinical studies, making it difficult to test new therapeutic approaches in vivo. With this in mind, we generated mice selectively expressing human von Willebrand factor (VWF) and human GPIbalpha. Because this fully humanized model was found to express low VWF (12%) and FVIII (40%) levels with normal multimer profile and activity/antigen ratio, we repositioned it as a VWD-type 1 model (hVWD1 mice). In depth characterization of this model confirmed VWD-type 1 features with a decrease in platelet adhesion and thrombus formation in vitro. In vivo, a moderate bleeding phenotype was observed which was corrected upon the administration of recombinant-VWF or upon histamine- induced release of endothelial VWF. In search for new therapeutic options for VWD, we designed a bispecific single-domain antibody that bridges VWF to albumin (KB-V13A12). Remarkably, a single subcutaneous administration of KB-V13A12 coincided with a sustained 2-fold increase in VWF antigen levels for up to 10 days and normalized haemostasis in a tail-clip model in hVWD1 mice.We have developed a unique humanized mouse model for VWD-type 1 and a promising new therapeutic that corrected haemostasis in these mice
Systematic analysis of SCN5A variants associated with inherited cardiac diseases
No full textInternational audienceBackground: SCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes, or pleiotropy, which have not been systematically described. Additionally, the involvement of SCN5A in dilated cardiomyopathies (DCM) remains controversial.Objective: We aimed to (1) evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and (2) determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers.Methods: The DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced using a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped.Results: The study included 170 P/LP variants found in 495 patients. Among them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, six with progressive cardiac conduction disease, four with multifocal ectopic Purkinje-related premature contraction, and three with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes and/or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Among those, eight were carried by eight patients presenting with DCM with a debatable causative genotype/phenotype link.Conclusion: Most P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960), if not questionable
Outbreak Caused by Multidrug-Resistant Mycobacterium Tuberculosis with Unusual Combination of Resistance Mutations, Northern Argentina, 2006–2022
No full textInternational audienceArgentina is considered a mid-incidence country for tuberculosis (TB); 1% of multidrug-resistant (MDR) cases persist in Argentina. The northern province of Chaco, a province with a top 5 TB burden (1), had a low number of MDR TB cases and no prior evidence of local transmission (2). MDR TB can affect patients beyond the well-established risk groups, making clinical suspicion essential where universal drug-susceptibility testing (DST) is unavailable. Whole-genome sequencing (WGS) enables timely and precise molecular drug-resistance profiling, but genotype/phenotype correlations need further research, especially for rapidly emerging resistance to second-line drugs (e.g., bedaquiline and linezolid) (3).To reconstruct the transmission chains and drug-resistance profiles, we used WGS to analyze an MDR TB outbreak in Resistencia, Chaco Province, Argentina. The study was performed in accordance with the Helsinki Declaration as revised in 2013. The Research Ethics Committee of the Instituto Nacional de Epidemiologia, ANLIS “Dr. Jara,” Buenos Aires, Argentina, approved the project and waived the informed consent requirement (project code YOKOBORI05/2022)