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.

Does DDI-Predictor Help Pharmacists to Detect Drug-Drug Interactions and Resolve Medication Issues More Effectively?

The characterization of drug-drug interactions (DDIs) may require the use of several different tools, such as the thesaurus issued by our national health agency (i.e., ANSM), the metabolic pathways table from the Geneva University Hospital (GUH), and DDI-Predictor (DDI-P). We sought to (i) compare the three tools' respective abilities to detect DDIs in routine clinical practice and (ii) measure the pharmacist intervention rate (PIR) and physician acceptance rate (PAR) associated with the use of DDI-P. The three tools' respective DDI detection rates (in %) were measured. The PIRs and PARs were compared by using the area under the curve ratio given by DDI-P (RAUC) and applying a chi-squared test. The DDI detection rates differed significantly: 40.0%, 76.5%, and 85.2% for ANSM (The National Agency for the Safety of Medicines and Health Products), GUH and DDI-P, respectively (p < 0.0001). The PIR differed significantly according to the DDI-P's RAUC: 90.0%, 44.2% and 75.0% for RAUC ≤ 0.5; RAUC 0.5-2 and RAUC > 2, respectively (p < 0.001). The overall PAR was 85.1% and did not appear to depend on the RAUC category (p = 0.729). Our results showed that more pharmacist interventions were issued when details of the strength of the DDI were available. The three tools can be used in a complementary manner, with a view to refining medication adjustments.

[Congenital hyperinsulinism revealed by sudden infant death]. / Hyperinsulinisme congénital révélé par une mort inattendue de l'enfant.

We report the case of a girl of 5 and a half months admitted for discomfort and consciousness loss at home and supported on sudden infant death protocol. Workup was negative. Autopsy showed only signs of asphyxia. Microscopic examination of the pancreas showed hypertrophic beta cells of Langerhans islets, explaining death linked to severe hypoglycemia by inappropriate insulin hypersecretion. This observation highlights the importance of the management of sudden infant unexpected death according to the protocol of the National Health Authority, which includes an autopsy with complete sampling, which in this case resulted in a diagnosis of unknown disease the lifetime of the child.

The Myb-domain protein ULTRAPETALA1 INTERACTING FACTOR 1 controls floral meristem activities in Arabidopsis.

Higher plants continuously and iteratively produce new above-ground organs in the form of leaves, stems and flowers. These organs arise from shoot apical meristems whose homeostasis depends on coordination between self-renewal of stem cells and their differentiation into organ founder cells. This coordination is stringently controlled by the central transcription factor WUSCHEL (WUS), which is both necessary and sufficient for stem cell specification in Arabidopsis thaliana ULTRAPETALA1 (ULT1) was previously identified as a plant-specific, negative regulator of WUS expression. However, molecular mechanisms underlying this regulation remain unknown. ULT1 protein contains a SAND putative DNA-binding domain and a B-box, previously proposed as a protein interaction domain in eukaryotes. Here, we characterise a novel partner of ULT1, named ULT1 INTERACTING FACTOR 1 (UIF1), which contains a Myb domain and an EAR motif. UIF1 and ULT1 function in the same pathway for regulation of organ number in the flower. Moreover, UIF1 displays DNA-binding activity and specifically binds to WUS regulatory elements. We thus provide genetic and molecular evidence that UIF1 and ULT1 work together in floral meristem homeostasis, probably by direct repression of WUS expression.

Is it worth carrying out determination of N-butane in postmortem samples? A case report and a comprehensive review of the literature.

The aim of this article is to illustrate the importance of N-butane determination in postmortem samples through a case report and to propose actions and precautions to be taken into consideration when butane is suspected to be involved in cases of death. The case concerns a 15-year-old boy found dead after sniffing a cigarette lighter refill. Toxicological investigation revealed the presence of butane in the heart and femoral blood (1280 and 1170 µg/L, respectively), in the gastric contents (326 µg/L), and in the liver (1010 µg/kg) and lung tissues (210 µg/kg). Propane was present only in the blood samples at concentrations tenfolds lower.Butane can be involved in three kinds of fatalities: deliberate inhalations including volatile substance abuse (VSA), involuntary exposure, and homicides. A fatal outcome of butane inhalation can be caused by asphyxia and/or cardiac arrhythmia. In the context where butane exposure is evidenced by non-toxicological investigations, the usefulness of the determination of butane in postmortem samples is often questionable. However, it is admitted that butane-related deaths are generally underreported. Several difficulties including sample handling and storage, substantial variation in tissue concentrations, and lack of a lethal threshold make the interpretation of butane results challenging. In our opinion, systematic toxicological methods should be developed in order to analyze butane, at least when it concerns a typical VSA victim, even when butane is not actually suspected to be the cause of death.

ULTRAPETALA1 and LEAFY pathways function independently in specifying identity and determinacy at the Arabidopsis floral meristem.

BACKGROUND AND AIMS: The morphological variability of the flower in angiosperms, combined with its relatively simple structure, makes it an excellent model to study cell specification and the establishment of morphogenetic patterns. Flowers are the products of floral meristems, which are determinate structures that generate four different types of floral organs before terminating. The precise organization of the flower in whorls, each defined by the identity and number of organs it contains, is controlled by a multi-layered network involving numerous transcriptional regulators. In particular, the AGAMOUS (AG) MADS domain-containing transcription factor plays a major role in controlling floral determinacy in Arabidopsis thaliana in addition to specifying reproductive organ identity. This study aims to characterize the genetic interactions between the ULTRAPETALA1 (ULT1) and LEAFY (LFY) transcriptional regulators during flower morphogenesis, with a focus on AG regulation. METHODS: Genetic and molecular approaches were used to address the question of redundancy and reciprocal interdependency for the establishment of flower meristem initiation, identity and termination. In particular, the effects of loss of both ULT1 and LFY function were determined by analysing flower developmental phenotypes of double-mutant plants. The dependency of each factor on the other for activating developmental genes was also investigated in gain-of-function experiments. KEY RESULTS: The ULT1 and LFY pathways, while both activating AG expression in the centre of the flower meristem, functioned independently in floral meristem determinacy. Ectopic transcriptional activation by ULT1 of AG and AP3, another gene encoding a MADS domain-containing flower architect, did not depend on LFY function. Similarly, LFY did not require ULT1 function to ectopically determine floral fate. CONCLUSIONS: The results indicate that the ULT1 and LFY pathways act separately in regulating identity and determinacy at the floral meristem. In particular, they independently induce AG expression in the centre of the flower to terminate meristem activity. A model is proposed whereby these independent contributions bring about a switch at the AG locus from an inactive to an active transcriptional state at the correct time and place during flower development.

The ERECTA receptor kinase regulates Arabidopsis shoot apical meristem size, phyllotaxy and floral meristem identity.

In plants, the shoot apical meristem (SAM) serves as a reservoir of pluripotent stem cells from which all above ground organs originate. To sustain proper growth, the SAM must maintain homeostasis between the self-renewal of pluripotent stem cells and cell recruitment for lateral organ formation. At the core of the network that regulates this homeostasis in Arabidopsis are the WUSCHEL (WUS) transcription factor specifying stem cell fate and the CLAVATA (CLV) ligand-receptor system limiting WUS expression. In this study, we identified the ERECTA (ER) pathway as a second receptor kinase signaling pathway that regulates WUS expression, and therefore shoot apical and floral meristem size, independently of the CLV pathway. We demonstrate that reduction in class III HD-ZIP and ER function together leads to a significant increase in WUS expression, resulting in extremely enlarged shoot meristems and a switch from spiral to whorled vegetative phyllotaxy. We further show that strong upregulation of WUS in the inflorescence meristem leads to ectopic expression of the AGAMOUS homeotic gene to a level that switches cell fate from floral meristem founder cell to carpel founder cell, suggesting an indirect role for ER in regulating floral meristem identity. This work illustrates the delicate balance between stem cell specification and differentiation in the meristem and shows that a shift in this balance leads to abnormal phyllotaxy and to altered reproductive cell fate.

Integration of stress-related and reactive oxygen species-mediated signals by Topoisomerase VI in Arabidopsis thaliana.

Environmental stress often leads to an increased production of reactive oxygen species that are involved in plastid-to-nucleus retrograde signaling. Soon after the release of singlet oxygen ((1)O(2)) in chloroplasts of the flu mutant of Arabidopsis, reprogramming of nuclear gene expression reveals a rapid transfer of signals from the plastid to the nucleus. We have identified extraplastidic signaling constituents involved in (1)O(2)-initiated plastid-to-nucleus signaling and nuclear gene activation after mutagenizing a flu line expressing the luciferase reporter gene under the control of the promoter of a (1)O(2)-responsive AAA-ATPase gene (At3g28580) and isolating second-site mutations that lead to a constitutive up-regulation of the reporter gene or abrogate its (1)O(2)-dependent up-regulation. One of these mutants, caa39, turned out to be a weak mutant allele of the Topoisomerase VI (Topo VI) A-subunit gene with a single amino acid substitution. Transcript profile analysis of flu and flu caa39 mutants revealed that Topo VI is necessary for the full activation of AAA-ATPase and a set of (1)O(2)-responsive transcripts in response to (1)O(2). Topo VI binds to the promoter of the AAA-ATPase and other (1)O(2)-responsive genes, and hence could directly regulate their expression. Under photoinhibitory stress conditions, which enhance the production of (1)O(2) and H(2)O(2), Topo VI regulates (1)O(2)-responsive and H(2)O(2)-responsive genes in a distinct manner. These results suggest that Topo VI acts as an integrator of multiple signals generated by reactive oxygen species formed in plants under adverse environmental conditions.