Clinical impact and cost-consequence analysis of ePlex® blood culture identification panels for the rapid diagnosis of bloodstream infections: a single-center randomized controlled trial.

To assess clinical impact and perform cost-consequence analysis of the broadest multiplex PCR panels available for the rapid diagnosis of bloodstream infections (BSI). Single-center, randomized controlled trial conducted from June 2019 to February 2021 at a French University hospital with an institutional antimicrobial stewardship program. Primary endpoint was the percentage of patients with optimized antimicrobial treatment 12 h after transmission of positivity and Gram stain results from the first positive BC. This percentage was significantly higher in the multiplex PCR (mPCR) group (90/105 = 85.7% %, CI95% [77.5 ; 91.8] vs. 68/107 = 63.6%, CI95% [53.7 ; 72.6]; p < 10- 3) at interim analysis, resulting in the early termination of the study after the inclusion of 309 patients. For patients not optimized at baseline, the median time to obtain an optimized therapy was much shorter in the mPCR group than in the control group (6.9 h, IQR [2.9; 17.8] vs. 26.4 h, IQR [3.4; 47.5]; p = 0.001). Early optimization of antibiotic therapy resulted in a non-statistically significant decrease in mortality from 12.4 to 8.8% (p = 0.306), with a trend towards a shorter median length of stay (18 vs. 20 days; p = 0.064) and a non-significant reduction in the average cost per patient of €3,065 (p = 0.15). mPCR identified all the bacteria present in 88% of the samples. Despite its higher laboratory cost, the use of multiplex PCR for BSI diagnosis leads to early-optimised therapy, seems cost-effective and could reduce mortality and length of stay. Their impact could probably be improved if implemented 24/7.

[Systematic preoperative SARS-CoV-2 screening by chest CT before urological surgery]. / Dépistage préopératoire systématique du SARS-CoV-2 par scanner thoracique avant chirurgie urologique.

Due to COVID-19 outbreak, the Belgian Association of Urology recommended limiting non-emergency surgical care. The aim of this study was to analyze if a preoperative screening for COVID-19 was key to select optimal operative candidates and its impact on surgical outcomes. MATERIAL AND METHODS: we present a retrospective analysis of all consecutive patients who underwent oncological high-risk and emergency urological surgeries in a Belgium tertiary center from March 30 to April 30, 2020. The screening protocol was based on clinical assessment and chest-CT to identify COVID-19-positive patients. RESULTS: a total of 32 patients underwent elective oncologic (n = 17; 53 %) and emergency (n = 15; 47 %) operations. Screening by chest-CT revealed three cases of COVID-19 (9 %) having led to postpone two interventions. The third positive COVID-19 patient died of respiratory complications after bladder perforation urgent procedure. Two patients developed compatible post-operatively symptoms with one positive chest-CT but no positive RT-PCR and successful recovery. Adapted safety measures were followed to mitigate in-hospital transmission. CONCLUSION: this report suggests feasibility and efficacy of systematic, preoperative screening for COVID-19 by chest computed tomography only. This strategy could allow to perform the majority of scheduled high-risk oncologic interventions safely for both the patients and the surgical staff.

Avec l'épidémie de COVID-19, l'Association Belge d'Urologie a recommandé de limiter les soins chirurgicaux non urgents. Le but de cette étude était d'analyser si un dépistage préopératoire de la COVID-19 était essentiel pour sélectionner les candidats opératoires optimaux et son impact sur les résultats chirurgicaux. Matériel et méthodes : nous présentons une analyse rétrospective des patients qui ont subi des chirurgies urologiques oncologiques à haut risque et d'urgence dans un centre tertiaire belge du 30 mars au 30 avril 2020. Le protocole de dépistage était une évaluation clinique plus CT thoracique pour identifier les patients COVID-19 positifs. Résultats : 32 patients ont bénéficié d'opérations oncologiques (n = 17; 53 %) et urgentes (n = 15; 47 %). Le dépistage par CT thoracique a révélé trois cas de COVID-19 (9 %) conduisant à deux reports de la chirurgie. Le troisième est décédé de complications respiratoires après procédure urgente pour perforation vésicale. Deux patients ont développé des symptômes postopératoires compatibles avec la COVID-19. Un CT thoracique était suspect, les RT-PCR négatives et les récupérations favorables. Des mesures de sécurité ont été instaurées pour atténuer la transmission intra-hospitalière. Conclusion : nous rapportons la faisabilité et l'efficacité du dépistage systématique préopératoire de la COVID-19 uniquement par CT thoracique. Cette stratégie pourrait permettre d'effectuer la majorité des interventions oncologiques à haut risque en toute sécurité pour les patients et le personnel chirurgical.

When residents work less, they feel better: Lessons learned from an unprecedent context of lockdown.

INTRODUCTION: With the COVID-19 outbreak activities of urology departments have been limited to non-deferrable procedures impacting the daily program of residents in urology. We assessed the psychological impact of the lockdown on Belgian residents in urology and their resounding on the quality of the training. MATERIAL AND METHODS: A self-administered anonymous questionnaire assessing the risk of burnout in a pandemic situation and its impact on the quality of the training was e-mailed to the members of the European Society of Residents in Urology of Belgium (ESRU-B). We used the Copenhagen Burnout Inventory score which assesses the different dimensions of burnout (personal (CBIP), professional (CBIPro), relational (CBIR)). Several questions evaluating impact on residents' health and apprehension of the future were included. The survey lasted for 5 days. Comparison of parameters before and during the coronavirus crisis was made using paired samples t-test or Chi2 test were. RESULTS: Fifty percent (62/126) of the ESRU-B members replied to the questionnaire. If 93% of the responders reported a negative impact on the quality of their practical training (CI95=[0.07-1.10]; P=0.83), 56% and 61.7% reported a positive impact of the crisis on their life and on their theoretical training respectively. Burnout risk scores were significantly reduced (P<0.001) for each dimension 7.26 to 3.40 (CBIP), 9.02 to 4.35 (CBIPro) and 4.42 to 3.03 (CBIR) respectively. CONCLUSION: Despite a negative impact on the daily work quality, the decrease in activity induced by the lockdown did not have a negative psychological impact on Belgian residents in urology but stress the opportunity to review the current training system to be better balanced between practice and theoretical formation.

Food allergy phenotypes: The key to personalized therapy.

Food allergies (FAs) are of increasing public health concern and are characterized by a large spectrum of diseases. Their diversity is well known for immunologic pathways (IgE, non-IgE-mediated FAs) and natural history. Many other factors and patient characteristics are involved including type of food, exposure route, allergic comorbidities, gender, racial and ethnic backgrounds, cofactors and health conditions. Food allergen components and sensitization profiles are also involved in FA phenotypes. A new approach to chronic disorders based on the identification of phenotypes through extensive knowledge of all the complex components is also applicable to FAs and could lead towards integrative care management. Diagnostic biomarkers for FAs are emerging which also contribute to better care modalities. The aim of this article was to highlight current knowledge regarding the phenotypic diversity of FA. This review will focus on IgE-mediated FAs and how identifying phenotypes may help to better understand the pathophysiological complexity, improve diagnosis and lead to personalized treatment strategies.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Evaluation of a new panel of six mononucleotide repeat markers for the detection of DNA mismatch repair-deficient tumours.

BACKGROUND: Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI. METHODS: We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS. RESULTS: We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%). CONCLUSION: The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS.

[Family impact of FXTAS diagnosis: genetic counseling for at-risk relatives]. / Conséquences familiales du diagnostic de FXTAS: le conseil génétique aux apparentés à risque.

INTRODUCTION: Fragile X associated Tremor/Ataxia Syndrome (FXTAS) is related to premutation expansions of the FMR1 gene, including 55 to 200 CGG repeats, whereas full expansions, over 200 repeats, cause Fragile X mental retardation. FXTAS is observed in about one-third of men with premutation, generally in their 1950s and over, and less commonly in women. It is characterized by action tremor, ataxia, cognitive, parkinsonism, behavioral difficulties, autonomic dysfunction and peripheral neuropathy. Brain magnetic resonance imaging (MRI) often shows symmetric increases in T2-weighted signal intensity in the middle cerebellar peduncles. The diagnosis of FXTAS in a patient raises important family issues. CASE REPORT: A 47-year-old male patient complained of an abnormal hearing sensation and dizziness for several months. Neurological examination was normal. Brain MRI showed the common signal intensity in middle cerebellar peduncles and bilateral punctual increases in T2-weighted signal intensity in the cerebral white matter. Genetic analysis showed 87CGG repeats, in favor of a possible FXTAS. At the time of diagnosis, fragile X syndrome was subsequently suspected and confirmed in his 10-month-old grandson. DISCUSSION: Due to X-linked inheritance and to the specific related mutational mechanism, the diagnosis of FXTAS in a patient raises major issues for relatives over several generations, including males and females, who should be considered as obligate or potential premutation carriers. Premutated females are not only at risk of transmitting a full mutation to their children but also of developing Fragile X related premature ovarian failure (FXPOI) that may influence their choices in family planning. CONCLUSION: The diagnosis of FXATS in a patient should induce delivery of extensive information and genetic counseling for potential carrier relatives.

[Constrictive pericarditis and disseminated nocardiosis]. / Péricardite constrictive et la nocardiose disséminée.

Human nocardiosis usually involves the respiratory tract or the skin but may disseminate to virtually any organ, it occurs in immunocompromised hosts as well as individuals with no apparent predisposition. Involvement of the pericardium is uncommon, having been reported infrequently in the past, but mandates a special management. This report describes the first case in Europe of a patient with chronic constrictive pericarditis from nocardia brasiliens, successfully treated with pericardiectomy and appropriate antibiotic therapy.

High airborne level of Aspergillus fumigatus and presence of azole-resistant TR34/L98H isolates in the home of a cystic fibrosis patient harbouring chronic colonisation with azole-resistant H285Y A. fumigatus.

Azole-resistant Aspergillus fumigatus (ARAF) has been reported in the domestic environment of patients at risk for aspergillosis. Here, we assessed the mother's and father's homes of an 18-year-old cystic fibrosis patient harbouring chronic colonisation with H285Y CYP51A azole-resistant isolate, in order to explore the link between environmental exposure and ARAF infection. In one dwelling, a very high overall contamination level was found (710-7.240 CFU/m3), with a predominance of A. fumigatus (640-6.490 CFU/m3), and ARAF showing the TR34/L98H mutation was isolated. Mycological follow-up of the patient showed the persistence of H285Y isolates, but no acquisition of TR34/L98H isolates was observed. This could be due to the low proportion of TR34/L98H isolates (<3%), or the establishment of preventative measures and dwelling remediation taken after the environmental investigation. Our data underlines the value of an environmental assessment to establish preventative measures and limit the risk of A. fumigatus exposure and ARAF acquisition.

A drop does not fall in a straight line: a rationale for the width of stalagmites.

Drops loaded in calcium ions detach from stalactites and impact the underlying stalagmites, thereby allowing these latter to grow through calcite precipitation. Nevertheless, little is known about the influence of the drop free fall and splash dynamics on stalagmite shape and width. Through high-speed imaging of impacting drops on stalagmites from several caves, we observed that the impact point position of the drops is scattered, sometimes over several centimetres. We show that this dispersal has no external cause and must, therefore, be self-induced. Using a Langevin-like equation, we then propose a prediction of the impact point dispersal as a function of the falling height travelled by the drops. We finally show that measured stalagmite widths are correlated to the dispersal in the impact point position of the drop.

[Metabolic syndrome: epidemiology and its risks]. / Le syndrome métabolique : son épidémiologie et ses risques.

The prevalence of the metabolic syndrome is rising, particularly in developed countries, and this is largely driven by increasing obesity and sedentarity rates. Regardless of the definition, the prevalence found in France was lower than in North America and in other European countries; it varied from 11.7 p. cent in men and 7.5 p. cent in women according to the National Cholesterol Education Program (NCEP) definition to 26 p. cent in men and 18.4 p. cent in women according to the International Diabetes Federation (IDF) definition. The presence of the metabolic syndrome promotes the occurrence of type 2 diabetes and clinical atherosclerosis. Relative risk of cardiovascular morbidity and mortality is close to 2 in subjects with metabolic syndrome. The informative value of identifying metabolic syndrome has been demonstrated in the general population as well as in hypertensive subjects. However, it could provide only limited clinical value for cardiovascular disease risk stratification in type 2 diabetes mellitus.

TuBaFrost 3: regulatory and ethical issues on the exchange of residual tissue for research across Europe.

The regulatory regimes for research with residual tissue and accompanying data differ widely between countries in the European Union (EU): from specific consent to opt-out or even no consent at all. This could greatly hamper research where the exchange of tissue and accompanying data has become the gold standard, like in TubaFrost. Instead of adhering to international guidelines, which have a democratic deficit, or an attempt for a new set of possible harmonising rules, TubaFrost chose to create a coordinating rule: if tissue may legitimately be used for a certain kind of research in the country where it was taken and under whose jurisdiction the patient falls, it may also be used for such research in the country where it is sent to in the context of a scientific program even if in that other country other regulations would apply for research with residual tissue taken from patients under their jurisdiction. This coordinating rule has a sound basis in EU law in general and will solve the problems related to diverging national regulatory regimes in the case of cross national research with residual tissue.

TuBaFrost 6: virtual microscopy in virtual tumour banking.

Many systems have already been designed and successfully used for sharing histology images over large distances, without transfer of the original glass slides. Rapid evolution was seen when digital images could be transferred over the Internet. Nowadays, sophisticated Virtual Microscope systems can be acquired, with the capability to quickly scan large batches of glass slides at high magnification and compress and store the large images on disc, which subsequently can be consulted through the Internet. The images are stored on an image server, which can give simple, easy to transfer pictures to the user specifying a certain magnification on any position in the scan. This offers new opportunities in histology review, overcoming the necessity of the dynamic telepathology systems to have compatible software systems and microscopes and in addition, an adequate connection of sufficient bandwidth. Consulting the images now only requires an Internet connection and a computer with a high quality monitor. A system of complete pathology review supporting bio-repositories is described, based on the implementation of this technique in the European Human Frozen Tumor Tissue Bank (TuBaFrost).

TuBaFrost 1: Uniting local frozen tumour banks into a European network: an overview.

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

TuBaFrost 2: Standardising tissue collection and quality control procedures for a European virtual frozen tissue bank network.

Tumour Bank Networking presents a great challenge for oncological research as in order to carry out large-scale, multi-centre studies with minimal intrinsic bias, each tumour bank in the network must have some fundamental similarities and be using the same standardised and validated procedures. The European Human Frozen Tumour Tissue Bank (TuBaFrost) has responded to this need by the promotion of an integrated platform of tumour banks in Europe. The operational framework for TuBaFrost has drawn upon the best practice of standard workflows and operating procedures employed by members of the TuBaFrost project and key initiatives worldwide.

TuBaFrost 4: access rules and incentives for a European tumour bank.

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.