Real-life use of letermovir prophylaxis for cytomegalovirus in heart transplant recipients.

INTRODUCTION: Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR). METHODS: In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen. RESULTS: The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir. CONCLUSION: This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study on the behalf of G2I and Intergroupe Francophone du Myélome.

OBJECTIVES: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. METHODS: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. RESULTS: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). DISCUSSIONS: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS.

Intracellular Pseudomonas aeruginosa within the Airway Epithelium of Cystic Fibrosis Lung Tissues.

RATIONALE: Pseudomonas aeruginosa (P.a.) is the major bacterial pathogen colonizing the airways of adult cystic fibrosis (CF) patients and causes chronic infections that persist despite antibiotic therapy. Intracellular bacteria may represent an unrecognized reservoir of bacteria that evades the immune system and antibiotic therapy. While the ability of P.a. to invade and survive within epithelial cells has been described in vitro in different epithelial cell models, evidence of this intracellular lifestyle in human lung tissues is currently lacking. OBJECTIVES: To detect and characterize intracellular P.a. in CF airway epithelium from human lung explant tissues. METHODS: We sampled the lung explant tissues from CF patients undergoing lung transplantation and non-CF lung donor control. We analyzed lung tissue sections for the presence of intracellular P.a. by quantitative culture and microscopy, in parallel to histopathology and airway morphometry. MEASUREMENTS AND MAIN RESULTS: P.a. was isolated from the lungs of 7 CF patients undergoing lung transplantation. Microscopic assessment revealed the presence of intracellular P.a. within airway epithelial cells in 3 out of the 7 patients analyzed, at a varying but low frequency. We observed those events occurring in lung regions with high bacterial burden. CONCLUSION: This is the first study describing the presence of intracellular P.a. in CF lung tissues. While intracellular P.a. in airway epithelial cells are likely relatively rare events, our findings highlight the plausible occurrence of this intracellular bacterial reservoir in chronic CF infections.

Refractory Microascus Bronchopulmonary Infection Treated with Olorofim, France.

We report 3 cases of successful treatment of Microascus spp. bronchopulmonary infection in a multiple-traumatized patient and 2 lung transplant recipients in France. We emphasize the promising use of olorofim antifungal therapy in a rising context of intrinsically less-susceptible respiratory infections caused by mold.

Reliability of QuantiFERON®-CMV in predicting CMV recurrence in heart transplant recipients: A single-center retrospective study.

BACKGROUND: Recurrence after Cytomegalovirus (CMV) infection in heart transplant recipients is difficult to predict, in spite of its high incidence. Secondary prophylaxis could reduce this burden; however, its duration remains unestablished. We evaluated the QuantiFERON®-CMV test to see if it could predict CMV recurrence and help optimize the duration of secondary prophylaxis. METHODS: This observational retrospective single center study included all heart transplant recipients who developed CMV infection between 2019 and 2021, with the CD8+ T-cell-mediated CMV immunity QuantiFERON®-CMV test assessed at the time of (val)ganciclovir curative treatment completion. The main outcomes were CMV recurrence and duration of secondary prophylaxis. Secondary outcomes included immunosuppressive regimen, rejection, lymphocyte count, CMV viral load, infection type, and duration as possible confounding factors for recurrence. RESULTS: Among the 15 patients included, five (33%) experienced recurrence, of whom three (60%) had a positive QuantiFERON®-CMV test. The duration of secondary prophylaxis was similar regardless of QF-CMV positivity. No confounding factor was significantly associated with CMV recurrence; however, it occurred in only 1/7 (14%) of the patients receiving an everolimus-containing immunosuppressive regimen. CONCLUSION: In the population of heart transplant recipients, most of whom received ATG-based induction, the QuantiFERON®-CMV assay may not accurately predict CMV recurrence and would have not helped refining the duration of secondary prophylaxis in our patients. Other cell-mediated immunity tests and strategies in this specific population, including everolimus-containing regimens, may help predict and manage CMV recurrence.

Absence of association between persistent skin lesion and virological replication in severe disseminated monkeypox infection in solid organ transplant recipient.

The Monkeypox (mpox) virus outbreak has been controlled worldwide. We report the case of a combined pancreas-kidney transplant recipient who presented a severe and prolonged cutaneous infection with onset of 3 successive rashes while receiving tecovirimat therapy. During follow-up, skin lesions, blood and throat samples were collected. Viral culture and mpox PCR were performed. No positive viral culture was obtained from blood and throat. The lowest mpox CT-values were obtained early after onset of skin lesions and were more likely to be associated with positive viral cultures. Furthermore, we observed persistent skin lesions up to 3 months. On these persistent lesions, mpox PCR positives were obtained but were not associated with positive viral culture after 23 days. In this immunocompromised host, who was receiving tecovirimat, in accordance with existing recommendations a 21-day isolation period appeared to be adapted. That said, isolation should not be systematically extended if complete healing of skin lesions has not been achieved.

A single oscillating proto-hypothalamic neuron gates taxis behavior in the primitive chordate Ciona.

Ciona larvae display a number of behaviors, including negative phototaxis. In negative phototaxis, the larvae first perform short spontaneous rhythmic casting swims. As larvae are cast in a light field, their photoreceptors are directionally shaded by an associated pigment cell, providing a phototactic cue. This then evokes an extended negative taxis swim. We report here that the larval forebrain of Ciona has a previously uncharacterized single slow-oscillating inhibitory neuron (neuron cor-assBVIN78) that projects to the midbrain, where it targets key interneurons of the phototaxis circuit known as the photoreceptor relay neurons. The anatomical location, gene expression, and oscillation of cor-assBVIN78 suggest homology to oscillating neurons of the vertebrate hypothalamus. Ablation of cor-assBVIN78 results in larvae showing extended phototaxis-like swims, even in the absence of phototactic cues. These results indicate that cor-assBVIN78 has a gating activity on phototaxis by projecting temporally oscillating inhibition to the photoreceptor relay neurons. However, in intact larvae, the frequency of cor-assBVIN78 oscillation does not match that of the rhythmic spontaneous swims, indicating that the troughs in oscillations do not themselves initiate swims but rather that cor-assBVIN78 may modulate the phototaxis circuit by filtering out low-level inputs while restricting them temporally to the troughs in inhibition.

A single oscillating proto-hypothalamic neuron gates taxis behavior in the primitive chordate Ciona.

Ciona larvae display a number of behaviors, including negative phototaxis. In negative phototaxis, the larvae first perform short spontaneous rhythmic casting swims. As larvae cast in a light field, their photoreceptors are directionally shaded by an associated pigment cell, providing a phototactic cue. This then evokes an extended negative taxis swim. We report here that the larval forebrain of Ciona has a previously uncharacterized single slow-oscillating inhibitory neuron (neuron cor-assBVIN78 ) that projects to the midbrain, where it targets key interneurons of the phototaxis circuit known as the photoreceptor relay neurons . The anatomical location, gene expression and oscillation of cor-assBVIN78 suggest homology to oscillating neurons of the vertebrate hypothalamus. Ablation of cor-assBVIN78 results in larvae showing extended phototaxis-like swims, but which occur in the absence of phototactic cues. These results indicate that cor-assBVIN78 has a gating activity on phototaxis by projecting temporally-oscillating inhibition to the photoreceptor relay neurons. However, in intact larvae the frequency of cor-assBVIN78 oscillation does not match that of the rhythmic spontaneous swims, indicating that the troughs in oscillations do not themselves initiate swims, but rather that cor-assBVIN78 may modulate the phototaxis circuit by filtering out low level inputs while restricting them temporally to the troughs in inhibition.

Immersive and interactive visualization of 3D spatio-temporal data using a space time hypercube: Application to cell division and morphogenesis analysis.

The analysis of multidimensional time-varying datasets faces challenges, notably regarding the representation of the data and the visualization of temporal variations. We propose an extension of the well-known Space-Time Cube (STC) visualization technique in order to visualize time-varying 3D spatial data, taking advantage of the interaction capabilities of Virtual Reality (VR). First, we propose the Space-Time Hypercube (STH) as an abstraction for 3D temporal data, extended from the STC concept. Second, through the example of embryo development imaging dataset, we detail the construction and visualization of a STC based on a user-driven projection of the spatial and temporal information. This projection yields a 3D STC visualization, which can also encode additional numerical and categorical data. Additionally, we propose a set of tools allowing the user to filter and manipulate the 3D STC which benefits the visualization, exploration and interaction possibilities offered by VR. Finally, we evaluated the proposed visualization method in the context of 3D temporal cell imaging data analysis, through a user study (n = 5) reporting the feedback from five biologists. These domain experts also accompanied the application design as consultants, providing insights on how the STC visualization could be used for the exploration of complex 3D temporal morphogenesis data.

Oropharyngeal samples versus lesion specimens at diagnosis in patients infected with monkeypox virus in Northern France.

The ongoing outbreak of monkeypox virus (MPXV) is the largest one in historically non-endemic countries. Early reports described atypical epidemiological and clinical presentations. We investigated MPXV DNA detection in oropharyngeal samples (OPS), and compared the viral load to that in lesion samples at diagnosis in patients infected with MPXV. We retrospectively included patients suspected to have monkeypox in Northern France, who underwent a MPXV PCR in the Virology Laboratory, University Hospital of Lille, from May 23 to August 18, 2022. Overall, a total of 228 patients (376 samples) were included. A positive result in at least one sample was found in 138 patients (60.5%). We compared PCR results between OPS and lesion samples (i.e., cutaneous or anal/rectal samples) in patients with both samples. A positive result in OPS was observed in 54 out of 60 patients (90%). The viral load in OPS (median Ct value = 29.5; interquartile range [IQR] = 24.7-34) was significantly lower than that in lesion samples (median Ct  value = 17.8; IQR = 16.3 and 19.7) (p < 0.0001). This report shows that pharyngeal sampling does not bring additional information for the initial diagnosis in patients presenting with typical lesions.

The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients.

Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult patients who are CMV positive undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Because CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. In this single-center study, all consecutive adult patients who were CMV positive and underwent allo-HCT between 2015 and 2021 were included. During period 1 (2015-2017), letermovir was not used, whereas during period 2 (2018-2021), letermovir was used in patients at high risk but not in patients at low risk, except in those receiving corticosteroids. In patients at high risk, the incidence of clinically significant CMV infection (csCMVi) in period 2 was lower than that in period 1 (P < .001) by week 14 (10.5% vs 51.6%) and week 24 (16.9% vs 52.7%). In patients at low risk, although only 28.6% of patients received letermovir in period 2, csCMVi incidence was also significantly lower (P = .003) by week 14 (7.9% vs 29.0%) and week 24 (11.2% vs 33.3%). Among patients at low risk who did not receive letermovir (n = 45), 23 patients (51.1%) experienced transient positive CMV DNA without csCMVi, whereas 17 patients (37.8%) experienced negative results. In both risk groups, the 2 periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and nonrelapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in patients at high risk but allows some patients at low risk to not use letermovir.

Challenges of intracellular visualization using virtual and augmented reality.

Microscopy image observation is commonly performed on 2D screens, which limits human capacities to grasp volumetric, complex, and discrete biological dynamics. With the massive production of multidimensional images (3D + time, multi-channels) and derived images (e.g., restored images, segmentation maps, and object tracks), scientists need appropriate visualization and navigation methods to better apprehend the amount of information in their content. New modes of visualization have emerged, including virtual reality (VR)/augmented reality (AR) approaches which should allow more accurate analysis and exploration of large time series of volumetric images, such as those produced by the latest 3D + time fluorescence microscopy. They include integrated algorithms that allow researchers to interactively explore complex spatiotemporal objects at the scale of single cells or multicellular systems, almost in a real time manner. In practice, however, immersion of the user within 3D + time microscopy data represents both a paradigm shift in human-image interaction and an acculturation challenge, for the concerned community. To promote a broader adoption of these approaches by biologists, further dialogue is needed between the bioimaging community and the VR&AR developers.

SARS-CoV-2 detection using a nanobody-functionalized voltammetric device.

Background: An ongoing need during the COVID-19 pandemic has been the requirement for accurate and efficient point-of-care testing platforms to distinguish infected from non-infected people, and to differentiate SARS-CoV-2 infections from other viruses. Electrochemical platforms can detect the virus via its envelope spike protein by recording changes in voltammetric signals between samples. However, this remains challenging due to the limited sensitivity of these sensing platforms. Methods: Here, we report on a nanobody-functionalized electrochemical platform for the rapid detection of whole SARS-CoV-2 viral particles in complex media such as saliva and nasopharyngeal swab samples. The sensor relies on the functionalization of gold electrode surface with highly-oriented Llama nanobodies specific to the spike protein receptor binding domain (RBD). The device provides results in 10 min of exposure to 200 µL of unprocessed samples with high specificity to SARS-CoV-2 viral particles in human saliva and nasopharyngeal swab samples. Results: The developed sensor could discriminate between different human coronavirus strains and other respiratory viruses, with 90% positive and 90% negative percentage agreement on 80 clinical samples, as compared to RT-qPCR. Conclusions: We believe this diagnostic concept, also validated for RBD mutants and successfully tested on Delta variant samples, to be a powerful tool to detect patients' infection status, easily extendable to other viruses and capable of overcoming sensing-related mutation effects.

Association between acute graft pyelonephritis and kidney graft survival: A single-center observational study.

The association between acute graft pyelonephritis (AGPN) and graft failure in kidney transplant recipients (KTR) remains controversial. In this single-center observational study, we aimed to assess the incidence of AGPN as a time-dependent posttransplantation event. We also examined the association between the diagnosis of AGPN and graft outcomes. In total, we evaluated 1480 patients who underwent kidney transplantation between January 2007 and December 2017. During a median follow-up of 5.04 years, we observed 297 AGPN episodes that occurred in 158 KTR. To evaluate the association between AGPN and clinical outcomes, we performed Cox proportional hazards regression analyses in which AGPN was entered as a time-dependent covariate. AGPN was independently associated with an increased risk of graft loss (hazard ratio = 1.66; 95% confidence interval [CI]: 1.05-2.64, p < .03) and a persistently decreased eGFR (fixed effect on intercept: -2.29 ml/min/1.73 m2 ; 95% CI: from -3.23 to -1.35, p < .01). However, neither mortality nor biopsy-proven acute rejection was found to correlate with AGPN. Moreover, recurrent AGPN episodes did not appear to have an additive detrimental impact on graft loss. These data represent a promising step in understanding whether AGPN prevention may decrease the risk of graft loss in KTR.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Taeniasis: An unexpected variceal hemorrhage trigger.

Here we report a fatal and uncommon case of esophageal variceal bleeding secondary to the presence of a Tapeworm in the upper digestive tract in a patient coming back from North Africa.