IVIg therapy in the management of BK virus infections in pediatric kidney transplant patients.

BK virus-associated nephropathy (BKPyVAN) induces kidney allograft dysfunction. Although decreasing immunosuppression is the standard for managing BK virus (BKPyV) infection, this strategy is not always effective. The use of polyvalent immunoglobulins (IVIg) may be of interest in this setting. We performed a retrospective single-center evaluation of the management of BKPyV infection in pediatric kidney transplant patients. Among the 171 patients who underwent transplantation between January 2010 and December 2019, 54 patients were excluded (combined transplant n = 15, follow-up in another center n = 35, early postoperative graft loss n= 4). Thus, 117 patients (120 transplants) were included. Overall, 34 (28%) and 15 (13%) transplant recipients displayed positive BKPyV viruria and viremia, respectively. Three had biopsy-confirmed BKPyVAN. The pre-transplant prevalence of CAKUT and HLA antibodies was higher among BKPyV-positive patients compared to non-infected patients. After the detection of BKPyV replication and/or BKPyVAN, the immunosuppressive regimen was modified in 13 (87%) patients: either by decreasing or changing the calcineurin inhibitors (n = 13) and/or switching from mycophenolate mofetil to mTor inhibitors (n = 10). Starting IVIg therapy was based on graft dysfunction or an increase in the viral load despite reduced immunosuppressive regimen. Seven of 15(46%) patients received IVIg. These patients had a higher viral load (5.4 [5.0-6.8]log vs. 3.5 [3.3-3.8]log). In total, 13 of 15 (86%) achieved viral load reduction, five of seven after IVIg therapy. As long as specific antivirals are not available for the management of BKPyV infections in pediatric kidney transplant patients, polyvalent IVIg may be discussed for the management of severe BKPyV viremia, in combination with decreased immunosuppression.

Androgen therapy does not prevent bone loss and arterial calcifications in male rats with chronic kidney disease.

Patients suffering from chronic kidney disease (CKD) often experience bone loss and arterial calcifications. It is unclear if hypogonadism contributes to the development of these complications and whether androgen therapy might prevent them. Male adult rats were randomized into four groups. The first group received standard chow (control), while three other groups were fed a 0.25% adenine/low vitamin K diet (CKD). Two CKD groups were treated with testosterone or dihydrotestosterone (DHT), whereas the control group and one CKD group received vehicle (VEH). CKD animals had 10-fold higher serum creatinine and more than 15-fold higher parathyroid hormone levels compared to controls. Serum testosterone levels were more than two-fold lower in the CKDVEH group compared to control + VEH and CKD + testosterone groups. Seminal vesicle weight was reduced by 50% in CKDVEH animals and restored by testosterone and DHT. CKD animals showed a low bone mass phenotype with decreased trabecular bone volume fraction and increased cortical porosity, which was not rescued by androgen treatment. Aortic calcification was much more prominent in CKD animals and not unequivocally prevented by androgens. Messenger RNA expression of the androgen receptor-responsive genes Acta1 and Col1a1 was reduced by CKD and stimulated by androgen treatment in levator ani muscle but not in the bone or aortic tissue. We conclude that adenine-induced CKD results in the development of hypogonadism in male rats. Androgen therapy is effective in restoring serum testosterone levels and androgen-sensitive organ weights but does not prevent bone loss or arterial calcifications, at least not in the presence of severe hyperparathyroidism.

Adverse events during nursing care procedure in intensive care unit: The PREVENIR study.

OBJECTIVES: Intensive care unit patients undergo several nursing care procedures (NCP) every day. These procedures involve a risk for adverse events (AE). Yet, their prevalence, intensity, and predisposing risk factors remain poorly established. The main objective of the study was to measure the incidence and severity of NCP related AE. DESIGN: This prospective observational multicentre study was conducted in 9 ICUs. All NCP were recorded for four consecutive weeks. For each NCP, the following were collected: patients' baseline characteristics, type of NCP, characteristics of the NCP, AE and therapeutic responses. RESULTS: 5849 NCP occurred in 340 patients. Among the 340 patients included, 292 (85.9%) were affected by at least one AE, and 141 (41.5%) by an SAE during a NCP. Thirty % of NCP were associated with at least one AE: hemodynamic AE in 17.1%, respiratory AE in 13.6%, agitation and pain (3.7% and 3.3%). Eight invasive devices were accidentally removed. Severe Adverse Events (SAE) occurred in 5.5% of NCP. The main risk factor associated with SAE was pain/agitation at the beginning of the NCP. CONCLUSION: AE are frequent during NCP in ICU. We identified several risk factors, some of them preventable, that could be considered for the development of recommendations for the nursing care of critically ill patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02881645.

Exogenous acquisition of Pseudomonas aeruginosa in intensive care units: a prospective multi-centre study (DYNAPYO study).

BACKGROUND: Pseudomonas aeruginosa remains one of the most common nosocomial pathogens in intensive care units (ICUs). Although exogenous acquisition has been widely documented in outbreaks, its importance is unclear in non-epidemic situations. AIM: To elucidate the role of exogenous origin of P. aeruginosa in ICU patients. METHODS: A chronological analysis of the acquisition of P. aeruginosa was performed using samples collected in 2009 in the DYNAPYO cohort study, during which patients and tap water were screened weekly. Molecular relatedness of P. aeruginosa isolates was investigated by pulsed-field gel electrophoresis. Exogenous acquisition was defined as identification of a P. aeruginosa pulsotype previously isolated from another patient or tap water in the ICU. FINDINGS: The DYNAPYO cohort included 1808 patients (10,402 samples) and 233 water taps (4946 samples). Typing of 1515 isolates from 373 patients and 375 isolates from 81 tap water samples identified 296 pulsotypes. Analysis showed exogenous acquisition in 170 (45.6%) of 373 patients. The pulsotype identified had previously been isolated from another patient and from a tap water sample for 86 and 29 patients, respectively. The results differed according to the ICU. CONCLUSION: Exogenous acquisition of P. aeruginosa could be prevented in half of patients. The overall findings of this survey support the need for studies on routes of transmission and risk assessment approach to better define how to control exogenous acquisition in ICUs.

Statistical analysis of the effluent quality of 231 on-site sanitation facilities in France monitored during a 6-year period.

On-site wastewater treatment systems are approved by the French regulation based on the results of platform tests following the European standard NF EN 12566-3. In addition to this approval for the treatment system, at least 90% of outlet concentrations have to be below 30 mg L-1 for total suspended solids (TSS) and 35 mg L-1 for biochemical oxygen demand. The aim of this study is to evaluate the effluent quality of these treatment systems on site, i.e. under real operating conditions, and to assess their performances. Between 2011 and 2016, 1,286 treated wastewater samples were taken from 231 on-site sanitation facilities in France. Data collected are heterogeneous and a robust statistical methodology (using a generalized log-linear model) was used to study the effects of four explanatory variables (treatment systems, loading rate, aging and sampling methods) on the distribution of treated wastewater concentrations. The model calculates median outlet concentrations depending on the effects identified. Its application allowed studying and comparing the outlet median concentrations of 21 on-site sanitation systems classified into nine categories and three groups. Four treatment systems out of the 21 monitored showed TSS median outlet concentrations below 10 mg L-1 and four treatment systems have TSS medians higher than the regulatory threshold of 30 mg L-1.

Antibiotics associated with acquisition of carbapenem-resistant Pseudomonas aeruginosa in ICUs: a multicentre nested case-case-control study.

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains are involved in severe infections, mostly in ICUs. Exposure to antibiotics other than carbapenems may be associated with isolation of CRPA; therefore, we aimed to identify those antibiotics using the case-case-control study design. Methods: A case-case-control study was conducted in 2015 in a prospective multicentre cohort that included 1808 adults hospitalized in 2009 in 10 French ICUs. Patients were screened for P. aeruginosa at admission to the ICU and then weekly. Cases were patients with CRPA and patients with carbapenem-susceptible P. aeruginosa (CSPA) isolation. Controls were patients without P. aeruginosa isolation, matched with each case according to centre, length of stay and hospitalization period. Effects of antibiotic exposure were explored, after adjusting for prior treatment with carbapenems and confounding factors comprising colonization pressure with two logistic regression models. The two models were compared to identify specific risk factors for CRPA isolation. Results: Fifty-nine CRPA, 83 CSPA and 142 controls were compared. In adjusted multivariable analyses, exposure to carbapenems and to antibiotics belonging to the group of ß-lactams inactive against P. aeruginosa were independent risk factors for CRPA isolation (OR, 1.205; 95% CI, 1.079-1.346 and OR, 1.101; 95% CI, 1.010-1.201, respectively). Conversely, exposure to ß-lactams active against P. aeruginosa was an independent protective factor for CSPA isolation (OR, 0.868; 95% CI, 0.772-0.976). Conclusions: Besides carbapenem exposure, exposure to ß-lactams inactive against P. aeruginosa was a specific risk factor for CRPA isolation. Clinicians should counterweigh the potential benefits of administering these antibiotics against the increased risk of CRPA infection.

On-site single-stage constructed wetland fed by raw wastewater: performances and resilience of the system.

On-site sanitation systems in Europe are evaluated through a CE marked procedure done on a platform test under a specific schedule of loads. Nevertheless, the test procedure conditions do not represent the real conditions of treatment systems in terms of wastewater characteristics and loads. On another angle, in France, systems implemented for capacities above 20 p.e. do not need the CE marked procedure but have to comply with performance requirements. French on-site treatment regulations lead to a paradoxical situation where constructed wetlands (CW) designed for 21 p.e. can be more compact than for 15 p.e. Here we focus on a single-stage vertical flow CW treating raw wastewater from a six-person house. Working with a (compact) community CW design, the objectives were to evaluate, in real-world conditions, the limits of the system and its ability to handle the high hydraulic and organic load variations found in on-site sanitation. Concentrations and fluxes showed high inter-day and intra-day variability, confirming the necessity for treatment systems to be robust enough for on-site sanitation. The compact CW appeared very efficient and stable for organic pollutants and nitrification (average removal rates of more than 98%, 99%, 94% and 97% for TSS, BOD5, COD and TKN, respectively). Denitrification has been optimized to reach 70% of TN removal, but seems unable to go higher due to a lack of carbon.

Comparison of methods for detection of plasmid-mediated and chromosomally encoded colistin resistance in Enterobacteriaceae.

OBJECTIVES: Because of the emergence of plasmid-mediated (mcr-1 and mcr-2 genes) and chromosomally encoded colistin resistance, reliable methods for detecting colistin resistance/susceptibility in routine laboratories are required. We evaluated the respective performances of the BD Phoenix automated system, the newly developed Rapid Polymyxin NP test and the broth microdilution (BMD) reference method to detect colistin resistance in Enterobacteriaceae, and particularly those producing mcr-1 and mcr-2. METHODS: Colistin susceptibility of 123 enterobacterial clinical isolates (40 colistin-susceptible and 83 colistin-resistant isolates) was tested with the BD Phoenix automated system, the Rapid Polymyxin NP test and the BMD method. Molecular mechanisms responsible for plasmid-mediated and chromosomally encoded colistin resistance mechanisms were investigated by PCR and sequencing. RESULTS: Considering BMD as a reference method, the BD Phoenix system failed to detect ten colistin-resistant isolates (one Escherichia coli, one Klebsiella pneumoniae, seven Enterobacter species and one Salmonella enterica). The Rapid Polymyxin NP test failed to detect the same single E. coli isolate. Those two latter methods detected the 16 E. coli, K. pneumoniae and S. enterica isolates producing the plasmid-encoded mcr-1 and mcr-2. CONCLUSIONS: The BD Phoenix system and the Rapid Polymyxin NP test are reliable techniques for detecting plasmid-mediated mcr-1 and mcr-2-related colistin resistance. However, a high rate of false susceptibility was observed with the BD Phoenix system, indicating that susceptibility results obtained with that system should be confirmed by BMD method. By contrast, the Rapid Polymyxin NP test showed a good agreement with the BMD method, and results were obtained rapidly (within 2 hours). The BMD method should be performed if minimum inhibitory concentration values are needed.

Comparison of the design criteria of 141 onsite wastewater treatment systems available on the French market.

New EC standards published in 2009 led to a surge in onsite wastewater treatment systems reaching the European market. Here we summarize their technical aspects and compare them to known values used in centralized wastewater treatment. The paper deals with two types of processes: attached-growth systems (AGS) on fine media and suspended-growth systems (SGS). Covering 141 technical approvals and 36 manufacturers, we compare onsite design criteria against the centralized wastewater design criteria for each process. The systems use a wide range of materials for bacterial growth, from soil, sand or gravel to zeolite, coconut shavings or rockwool cubes, with a huge range of variation in useful surface, from 0.26 m2/PE for one rockwool cube filter to 5 m2/PE for a (traditional system) vertical sand filter. Some rockwool can handle applied daily surface load of 160 g BOD5/m2. SGS design parameters range from 0.025 to 0.34 kg BOD5 per kg MLVSS/d with hydraulic retention times of 0.28-3.7 d. For clarifier design, water velocity ranges from 0.15 to 1.47 m/h. In the sludge line, sludge storage volume ranges from 0.125 down to just 0.56 m3/PE.

Face Transplantation: Partial Graft Loss of the First Case 10 Years Later.

Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis. Microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. Flow magnetic resonance imaging of the facial graft showed a decrease of the distal right facial artery flow. Three steroid pulses of 500 mg each, followed by intravenous immunoglobulins (2 g/kg), five sessions of plasmapheresis, and three cycles of bortezomib 1.3 mg/m2 , were administered. Despite rescue therapy with eculizumab, necrosis of the lips and the perioral area occurred, which led to surgical removal of the lower lip, labial commissures, and part of the right cheek in May 2015. In January 2016, the patient underwent conventional facial reconstruction because during the retransplantation evaluation a small-cell lung carcinoma was discovered, causing the patient's death in April 2016.

Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function.

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Inventory of Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae in France as Assessed by a Multicenter Study.

The objective of this study was to perform an inventory of the extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae isolates responsible for infections in French hospitals and to assess the mechanisms associated with ESBL diffusion. A total of 200 nonredundant ESBL-producing Enterobacteriaceae strains isolated from clinical samples were collected during a multicenter study performed in 18 representative French hospitals. Antibiotic resistance genes were identified by PCR and sequencing experiments. The clonal relatedness between isolates was investigated by the use of the DiversiLab system. ESBL-encoding plasmids were compared by PCR-based replicon typing and plasmid multilocus sequence typing. CTX-M-15, CTX-M-1, CTX-M-14, and SHV-12 were the most prevalent ESBLs (8% to 46.5%). The three CTX-M-type EBSLs were significantly observed in Escherichia coli (37.1%, 24.2%, and 21.8%, respectively), and CTX-M-15 was the predominant ESBL in Klebsiella pneumoniae (81.1%). SHV-12 was associated with ESBL-encoding Enterobacter cloacae strains (37.9%). qnrB, aac(6')-Ib-cr, and aac(3)-II genes were the main plasmid-mediated resistance genes, with prevalences ranging between 19.5% and 45% according to the ESBL results. Molecular typing did not identify wide clonal diffusion. Plasmid analysis suggested the diffusion of low numbers of ESBL-encoding plasmids, especially in K. pneumoniae and E. cloacae However, the ESBL-encoding genes were observed in different plasmid replicons according to the bacterial species. The prevalences of ESBL subtypes differ according to the Enterobacteriaceae species. Plasmid spread is a key determinant of this epidemiology, and the link observed between the ESBL-encoding plasmids and the bacterial host explains the differences observed in the Enterobacteriaceae species.

Disordered eating in French high-level athletes: association with type of sport, doping behavior, and psychological features.

PURPOSE: Over the last few years, disordered eating in athletes has received increasing attention. According to several studies, athletes could be more vulnerable to disordered eating and some characteristics specific to the athletic community could be in favour of an increased risk of poor body image and disturbed eating habits in athletes. However, the literature is sparse and some methodological issues in studies have been pointed out. In this context, we aimed at determining the prevalence of disordered eating in French high-level athletes using clinical interviews of three different clinicians and identifying what are the factors associated with disordered eating in athletes. METHODS: In France, all athletes registered on the French high-level list have to undergo a yearly evaluation. Data collected during the somatic assessment, the dietary consultation, and the psychological of the yearly evaluation were used. Multivariate analysis was performed for identification of factors associated with disordered eating. RESULTS: Out of the 340 athletes included, 32.9% have been detected with a disordered eating. They were difficult to detect by clinicians, as usual criteria did not seem to be reliable for athletes. Competing in sports emphasizing leanness or low body weight was associated with disordered eating; however, gender was not. CONCLUSION: These results highlight the need for the development of specific screening tools for high-level athletes. Furthermore, the identification of factors associated with disordered eating could improve early detection and prevention program effectiveness.

Pharmacokinetic-pharmacodynamic modelling of drug-induced QTc interval prolongation in man: prediction from in vitro human ether-à-go-go-related gene binding and functional inhibition assays and conscious dog studies.

BACKGROUND AND PURPOSE: Functional measures of human ether-à-go-go-related gene (hERG; Kv 11.1) channel inhibition have been prioritized as an in vitro screening tool for candidate molecules. However, it is unclear how these results can be translated to humans. Here, we explore how data on drug binding and functional inhibition in vitro relate to QT prolongation in vivo. Using cisapride, sotalol and moxifloxacin as paradigm compounds, we assessed the relationship between drug concentrations, binding, functional measures and in vivo effects in preclinical species and humans. EXPERIMENTAL APPROACH: Pharmacokinetic-pharmacodynamic modelling was used to characterize the drug effects in hERG functional patch clamp, hERG radio-labelled dofetilide displacement experiments and QT interval in conscious dogs. Data were analysed in parallel to identify potential correlations between pharmacological activity in vitro and in vivo. KEY RESULTS: An Emax model could not be used due to large variability in the functional patch clamp assay. Dofetilide displacement revealed that binding curves are unrelated to the in vivo potency estimates for QTc prolongation in dogs and humans. Mean in vitro potency estimates ranged from 99.9 nM for cisapride to 1030 µM for moxifloxacin. CONCLUSIONS AND IMPLICATIONS: The lack of standardized protocols for in vitro assays leads to significant differences in experimental conditions, making the assessment of in vitro-in vivo correlations unreliable. Identification of an accurate safety window during the screening of candidate molecules requires a quantitative framework that disentangles system- from drug-specific properties under physiological conditions, enabling translation of the results to humans. Similar considerations will be relevant for the comprehensive in vitro pro-arrhythmia assay initiative.

Risk factors and outcome of graft failure after HLA matched and mismatched unrelated donor hematopoietic stem cell transplantation: a study on behalf of SFGM-TC and SFHI.

Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly involved in graft failure, for the others their role was more questionable. Second HSCT exhibited a protective although not statistically significant effect on OS (hazard ratio=0.57 [0.32-1.02]). In conclusion, only one parameter (disease status before graft) remains risk factor for graft failure in this recent cohort.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

Performances and mechanistic investigations of a triphosphine trioxide/ionic liquid system for rare earth extraction.

The extraction of rare earth elements (REEs) from nitric acid solution with a triphosphine trioxide (TPO) is presented. Performances of such a ligand in ionic liquids vs. a classical solvent (benzyl ether) are compared. TPO seems to be 10 to 100 times more efficient when it is dissolved in ionic media whatever the concentration of nitric acid involved. Mechanistic investigations reveal that cation exchange classically observed in ionic liquids is not consistent with the experimental data. Moreover, clear differences in the TPO/Ln complexes between classical and ionic media are highlighted. A stable complex of 1 lanthanide for 3 TPO is formed in an ionic liquid whereas a complex of 1 lanthanide for 6 to 9 TPO is formed in benzyl ether. Back extraction is also studied and good recovery of REEs could be obtained. The TPO/ionic liquid system shows remarkable performances i.e. efficiency and selectivity towards lanthanides in a simulated leaching solution of a Nd/Fe/B/Dy magnet.

Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.

BACKGROUND AND PURPOSE: The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. EXPERIMENTAL APPROACH: Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect. KEY RESULTS: For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 µM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 µM vs 2.0 µM for monkeys and humans, respectively. CONCLUSIONS AND IMPLICATIONS: Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans.