Upregulation of the Adhesin Gene EPA1 Mediated by PDR1 in Candida glabrata Leads to Enhanced Host Colonization.

Candida glabrata is the second most common Candida species causing disseminated infection, after C. albicans. C. glabrata is intrinsically less susceptible to the widely used azole antifungal drugs and quickly develops secondary resistance. Resistance typically relies on drug efflux with transporters regulated by the transcription factor Pdr1. Gain-of-function (GOF) mutations in PDR1 lead to a hyperactive state and thus efflux transporter upregulation. Our laboratory has characterized a collection of C. glabrata clinical isolates in which azole resistance was found to correlate with increased virulence in vivo. Contributing phenotypes were the evasion of adhesion and phagocytosis by macrophages and an increased adhesion to epithelial cells. These phenotypes were found to be dependent on PDR1 GOF mutation and/or C. glabrata strain background. In the search for the molecular effectors, we found that PDR1 hyperactivity leads to overexpression of specific cell wall adhesins of C. glabrata. Further study revealed that EPA1 regulation, in particular, explained the increase in adherence to epithelial cells. Deleting EPA1 eliminates the increase in adherence in an in vitro model of interaction with epithelial cells. In a murine model of urinary tract infection, PDR1 hyperactivity conferred increased ability to colonize the bladder and kidneys in an EPA1-dependent way. In conclusion, this study establishes a relationship between PDR1 and the regulation of cell wall adhesins, an important virulence attribute of C. glabrata. Furthermore, our data show that PDR1 hyperactivity mediates increased adherence to host epithelial tissues both in vitro and in vivo through upregulation of the adhesin gene EPA1. IMPORTANCE Candida glabrata is an important fungal pathogen in human diseases and is also rapidly acquiring drug resistance. Drug resistance can be mediated by the transcriptional activator PDR1, and this results in the upregulation of multidrug transporters. Intriguingly, this resistance mechanism is associated in C. glabrata with increased virulence in animal models and also with increased adherence to specific host cell types. The C. glabrata adhesin gene EPA1 is a major contributor of virulence and adherence to host cells. Here, we show that EPA1 expression is controlled by PDR1 independently of subtelomeric silencing, a known EPA1 regulation mechanism. Thus, a relationship exists between PDR1, EPA1 expression, and adherence to host cells, which is critical for efficient virulence. Our results demonstrate that acquisition of drug resistance is beneficial for C. glabrata in fungus-host relationships. These findings further highlight the challenges of the therapeutic management of C. glabrata infections in human patients

Competency, Proficiency, and Mastery: Learning Curves for Robotic Distal Pancreatectomy at 16 International Expert Centers

Objective: The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers. Summary background data: RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve. Methods: Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared. Results: The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications. Conclusion: Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP

Competency, Proficiency, and Mastery: Learning Curves for Robotic Distal Pancreatectomy at 16 International Expert Centers

OBJECTIVE The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers. SUMMARY BACKGROUND DATA RDP is an emerging minimally invasive approach; however, only limited, mostly single center data are available on its safe implementation, including the learning curve. METHODS Consecutive patients undergoing elective RDP from 16 expert centers across three continents were included to assess the learning curve. Based on the first 100 RDPs at each center, three cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade ≥III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared. RESULTS The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P=0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P=0.012), and mastery was associated with a higher proportion of patients with textbook outcome (71% vs. 63%; P=0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications. CONCLUSION Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Évaluation des greffons rénaux avant la transplantation; une mise au point sur la situation actuelle et les méthodes émergentes

Le manque de greffons rénaux adéquats amène à une augmentation du nombre de patients sur liste d’attente de transplantation. A ce jour, aucun processus d’évaluation universel ne permet de prédire avec une fiabilité suffisante l’issue favorable de ces transplants. Les méthodes établies comme l’évaluation histologique, les scores cliniques et les techniques de perfusion offrent une prédiction relativement fiable du retard du fonctionnement du greffon, mais ne sont pas systématiquement capables de prédire la survie d’un greffon. Les techniques émergentes comme les marqueurs moléculaires, les nouvelles techniques d’imagerie et la perfusion des organes normothermique offrent des approches innovatrices tout en permettant d’identifier des cibles d’interventions thérapeutiques. Cependant, les études rigoureuses sur le sujet font défauts et ces nouvelles méthodes nécessitent d’être validées. Le but ultime étant que ces nouvelles approches permettent de diminuer le taux d’organes non-utilisés tout en améliorant la finesse dans l’établissement d’un pronostic pour les greffons rénaux

Impact of maternal obesity on the gut microbiome, chronic liver disease and hepatocellular carcinoma in the offspring

L’épidémie d’obésité représente un enjeu de santé majeur. Les femmes en âge de procréer sont particulièrement touchées. L’objectif de cette thèse est de comprendre l’impact de l’obésité maternelle sur le risque de développer une maladie hépatique. Nous avons démontré que l’obésité maternelle entraînait de profonds changements de l’expression des gènes hépatiques. Nous avons constaté une association entre l’obésité maternelle et des taux plus élevés de stéatose, fibrose et d’inflammation. La descendance des mères obèses présente également un risque plus élevé de développer des tumeurs hépatiques. Les modifications du microbiome intestinal de la progéniture des souris obèses sont conservées à l’âge adulte. En restaurant un microbiome normal, nous avons pu réduire le risque de développer un cancer du foie. Ces observations mettent en évidence le rôle clé du microbiome intestinal dans la transmission des maladies du foie de la mère à l’enfant, et ouvrent la voie vers le développement de thérapies.The obesity epidemic represents a major challenge to our health systems. Women of childbearing age are particularly affected. Overweight and obesity have a multitude of adverse health effects and can lead to chronic liver disease and liver cancer. In addition, maternal obesity is associated with metabolic disorders in children, and an increased rate of childhood cancers. Obesity alters the composition of the gut microbiome, which contributes to the progression of chronic liver disease and is passed on to the next generation. The objective of this thesis is to understand the impact of maternal obesity on the risk of developing chronic liver disease and liver cancer in children, and the role of the microbiome in this context. We have demonstrated, in a mouse model, that maternal obesity leads to profound changes in gene expression in their offspring. We observed that signaling pathways of the innate immune system and the cell cycle are altered, and that genes important for the development of chronic liver diseases are dysregulated. In addition, we found that maternal obesity leads to higher rates of steatosis, fibrosis and inflammation in adult offspring of obese mothers. The offspring of obese mothers also have a significantly higher risk of developing liver tumors. The gut microbiome of offspring of obese mouse mothers is altered and these alterations are retained into adulthood. By restoring a normal microbiome, we were able to normalize the next generation's risk of developing liver cancer. This highlights the key role of the gut microbiome and its alterations in the transmission of liver disease from mother to child, and paves the way for the development of a future therapy

Commentary: Insulin-Producing Organoids Engineered From Islet and Amniotic Epithelial Cells to Treat Diabetes

A Commentary on : "Insulin-Producing Organoids Engineered from Islet and Amniotic Epithelial Cells to Treat Diabetes" By Lebreton F, Lavallard V, Bellofatto K, Bonnet R, Wassmer CH, Perez L, Kalandadze V, Follenzi A, Boulvain M, Kerr-Conte J, Goodman DJ, Bosco D, Berney T, Berishvili E. Nat Commun. (2019). 10(1):4491. doi: 10.1038/s41467-019-12472-3