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Diabetes mellitus prevalence is increasing among women of child-bearing age. Diabetic pregnancy is associated with major maternal and fetal risks, and these can be reduced by preconception care. Pregnancy can be planned using appropriate effective contraception. The objective of this study was to assess diabetic patients' knowledge about pregnancy and to describe their contraceptive use.An observational study was conducted from February to July 2020 at Reims University Hospital, France. Inclusion criteria were: women aged 18 to 40years, with type 1 (T1D) or type 2 diabetes (T2D). Patients filled out a survey about contraceptive use and knowledge regarding diabetic pregnancy and data were completed from medical records.Eighty-nine T1D and 33 T2D patients were included, with mean ages of 27.9±6.3 and 32.6±4.6years, respectively. Seventy-five percent reported that they had been informed about pregnancy-related risks and 67% about the need to plan pregnancy. The preconception HbA1c target was known by 33% of patients. Appropriate knowledge about pregnancy was greater in T1D patients (65.9%, versus 36.4% in T2D patients; P=0.003). The rate of patients using an effective contraceptive method was 66.4%. Fifteen percent patients for whom contraception was recommended reported having no contraceptive method; 12.5% of contraception users were using a contraindicated method.A large majority of diabetic women were aware of pregnancy-related risks and the importance of pregnancy planning, but there are still gaps, especially in T2D patients. We need to improve our practices by providing more information and better access to appropriate effective contraception.NCT04350879.

OBJECTIVE: To test the hypothesis that telomere shortening and/or loss are risk factors for infertility.DESIGN: Retrospective analysis of the telomere status in patients with infertility using conventional cytogenetic data collected prospectively.SETTING: Academic centers.PATIENT(S): Cytogenetic slides with cultured peripheral lymphocytes from 50 patients undergoing fertility treatment and 150 healthy donors, including 100 donors matched for age.INTERVENTION(S): Cytogenetic slides were used to detect chromosomal and telomere aberrations.MAIN OUTCOME MEASURE(S): Telomere length and telomere aberrations were analyzed after telomere and centromere staining.RESULT(S): The mean telomere length of patients consulting for infertility was significantly less than that of healthy donors of similar age. Moreover, patients with infertility showed significantly more extreme telomere loss and telomere doublet formation than healthy controls. Telomere shortening and/or telomere aberrations were more pronounced in patients with structural chromosomal aberrations. Dicentric chromosomes were identified in 6/13 patients, with constitutional chromosomal aberrations leading to chromosomal instability that correlated with chromosomal end-to-end fusions.CONCLUSION(S): Our findings demonstrate the feasibility of analyzing telomere aberrations in addition to chromosomal aberrations, using cytogenetic slides. Telomere attrition and/or dysfunction represent the main common cytogenetic characteristic of patients with infertility, leading to potential implications for fertility assessment. Pending further studies, these techniques that correlate the outcome of assisted reproduction and telomere integrity status may represent a novel and useful diagnostic and/or prognostic tool for medical care in this field.

Background There is still limited evidence from prospective high-risk research on the evolution of specific disorders that may emerge early in the development of mood disorders. Moreover, few studies have examined the specificity of mood disorder subtypes among offspring of parents with both major subtypes of mood disorders and controls based on prospective tracking across the transition from childhood to adulthood. Our specific objectives were to (a) identify differences in patterns of psychopathological precursors among youth with (hypo)mania compared to MDD and (b) examine whether these patterns differ by subtypes of parental mood disorders. Methods Our data stem from a prospective cohort study of 449 directly interviewed offspring (51% female, mean age 10.1 years at study intake) of 88 patients with BPD, 71 with MDD, 30 with substance use disorders and 60 medical controls. The mean duration of follow-up was 13.2 years with evaluations conducted every three years. Results Within the whole cohort of offspring, MDE (Hazard Ratio = 4.44; 95%CI: 2.19-9.02), CD (HR = 3.31;1.55-7.07) and DUD (HR = 2.54; 1.15-5.59) predicted the onset of (hypo)manic episodes, whereas MDD in offspring was predicted by SAD (HR = 1.53; 1.09-2.15), generalized anxiety (HR = 2.56; 1.05-6.24), and panic disorder (HR = 3.13; 1.06-9.23). The early predictors of (hypo)mania in the whole cohort were also significantly associated with the onset of (hypo)mania among the offspring of parents with BPD. Conclusions The onset of mood disorders is frequently preceded by identifiable depressive episodes and nonmood disorders. These precursors differed by mood subtype in offspring. High-risk offspring with these precursors should be closely monitored to prevent the further development of MDD or conversion to BPD.

BACKGROUND Renal failure is predictive of mortality in the early postliver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim is to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on chronic kidney disease (CKD)-free 1-year-survival. METHODS Retrospective data of consecutive patients transplanted between 2011 and 2016 and treated with tacrolimus were collected. TLE and all relevant pre- and post-liver transplantation (LT) predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m2 at least for the last 3 months before M12 post-LT. RESULTS Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at 1-month post-LT (eGFRM1)

Background Recently a peripheral blood 8-gene expression assay was developed for non-invasive detection of antibody-mediated rejection (ABMR) after kidney transplantation. Its value has not yet been evaluated in detail in clinical scenarios with different baseline disease probability [human leucocyte antigen donor-specific antibodies (HLA-DSA)-positive versus HLA-DSA-negative cases at the time of stable graft function versus graft dysfunction]. Methods Here we investigated the diagnostic accuracy of the 8-gene expression assay for histology of ABMR (ABMRh) with or without HLA-DSA in a cross-sectional cohort study of 387 blood samples with a concomitant graft biopsy. Results In patients with HLA-DSA (n = 64), the 8-gene expression assay discriminated DSA-positive ABMRh (DSAposABMRh) cases (n = 16) with good diagnostic performance {area under the receiver operating characteristic curve [AUROC] 83.1% [95% confidence interval (CI) 70.8–95.3]}. Also, in HLA-DSA-negative samples (n = 323), a clinically relevant diagnostic performance for DSAnegABMRh cases was found (n = 30) with an AUROC of 75.8% (95% CI 67.4–84.4). The 8-gene assay did not discriminate DSAposABMRh cases from DSAnegABMRh cases. There was a net benefit for clinical decision-making when adding the 8-gene expression assay to a clinical model consisting of estimated glomerular filtration rate, proteinuria, HLA-DSA and age. Conclusion The 8-gene expression assay shows great potential for implementation in the clinical follow-up of high-risk HLA-DSA-positive patients and clinical relevance in HLA-DSA-negative cases.

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism., Gut microbial metabolism of nutrients contributes to metabolic diseases, and the histidine metabolite imidazole propionate (ImP) is produced by type 2 diabetes (T2D) associated microbiome. Here the authors report that circulating ImP levels are increased in subjects with prediabetes or T2D in three European populations, and this increase associates with altered gut microbiota rather than dietary histidine.

International audience; Significance: The vast majority of autoimmune diseases are polygenic, and causal loci uncovered by genetic-mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this missing heritability include rare meaningful variants, rare copy number variations or deletions, epistasis, epigenetics, disease heterogeneity, and rare or infrequent variants that segregate within individual families (even within monozygotic twins). Here we demonstrate that experimental models of spontaneous autoimmune diseases may be invaluable tools to map rare germline variants impacting disease susceptibility traits. We identified a variant of the dual-specificity phosphatase 10 encoding gene that accelerates disease in an autoimmune type 1 diabetes model, the nonobese diabetic mouse.Abstract: Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.

Aims Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies to allow for individual dose adjustment of intravenous mycophenolate mofetil administered by infusion in haematopoietic stem cell transplant patients. Methods Sixty-three MPA concentration-time profiles (median [min-max] = 6 [4-7] samples) were collected from 34 HCT recipients transplanted for 14 (1-45) days and administered IV MMF every 8 hours, concomitantly with cyclosporine. The database was split into development (75%) and validation (25%) datasets. Pharmacokinetic models characterized by a single compartment with first-order elimination, combined with two gamma distributions to describe the transformation of MMF into mycophenolic acid, were developed using in parallel nonparametric (Pmetrics) and parametric (ITSIM) approaches. The performances of the models and the derived Bayesian estimators were evaluated in the validation set. Results The best limited sampling strategy led to a bias (min, max), root mean square error between observed and modeled interdose areas under the curve in the validation dataset of -11.72% (-31.08%, 5.00%), 14.9% for ITSIM and -2.21% (-23.40%, 30.01%), 12.4% for Pmetrics with three samples collected at 0.33, 2 and 3 hours post dosing. Conclusion Population pharmacokinetic models and Bayesian estimators for IV MMF in HCT have been developed and are now available online (https://pharmaco.chu-limoges.fr) for individual dose adjustment based on the interdose area under the curve.

BACKGROUND The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is uncertain. METHODS We performed a 5-year retrospective single-center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB-/FC- (75.6%), BMB+/FC+ (13.4%), and BMB-/FC+ (11%). RESULTS Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event-free survival (EFS) after 18 months was 82, 23, and 27% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p

Background Since its introduction in 2006, SOPARC (Systematic Observation of Play and Recreation in Communities) has become a fundamental tool to quantify park visitor behaviors and characteristics. We tested SOPARC reliability when assessing race/ethnicity, physical activity, contextual conditions at the time of observation, and settings of target areas to understand its utility when trying to account for individual characteristics of users. Methods We used 4725 SOPARC observations completed simultaneously by two independent observers to evaluate intraclass correlation and agreement rate between the two observers when trying to assess sex, age group, race/ethnicity, and level of physical activity of urban park users in different park settings. Observations were in 20 New York City parks during Spring and Summer 2017 within the PARC3 project. Results Observers counted 25,765 park users with high interobserver reliability (ICC = .94; %Agreement.75). Reliability scores were negatively affected by the population being observed, the intensity of physical activity, and the contextual conditions and settings of the target area at the time of observation. Specific challenges emerged when assessing the combination of physical activity and race/ethnicity. Conclusions SOPARC training should aim to improve reliability when assessing concurrent measures such as physical activity, race/ethnicity, age, and sex. Similarly, observing crowded park areas with many active users areas may require more observation practice hours.

Background: Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure. Methods: Tacrolimus whole blood trough levels ( C 0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C 0 < 20 ng/mL) or toxic concentrations ( C 0 ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients. Results: In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C 0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C 0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. Conclusions: Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.

Physical activity typically declines between childhood and adolescence. Despite urban parks being a great venue for physical activity, children change both the frequency of park use and their park use habits as they age into adolescence. However, little is known about how these differences vary by gender and how distinct race/ethnicity groups differentially change their park habits. This study analyzed the differences in park use and per capita energy expenditure between children and teenagers of different gender and race/ethnicity backgrounds. Using the System for Observing Play and Recreation in Communities (SOPARC), systematic observations were conducted in 20 New York City parks in 2017, located in low-income areas with high presence of Latino or Asian residents. A total of 9963 scans in 167 distinct target areas counted 16,602 children (5-10 years old) and 11,269 teenagers (11 or older). Using adjusted marginal means, we estimated the number of park users of each age range, gender, and race/ethnicity expected to be found in each park activity setting. Teenagers of both genders and most race/ethnicity groups were less likely to be in a park and had lower per capita energy expenditure, compared with children. The difference in park attendance was greater than the difference in per capita energy expenditure. Dissimilarities were clearly gendered and race/ethnicity dependent. Asian and Latino females showed the greatest divergence between childhood and adolescence. African American boys were the only group to show a positive age contrast in park attendance and per capita energy expenditure.

BACKGROUND: Antibody-mediated rejection, a leading cause of renal allograft graft failure, is diagnosed by histological assessment of invasive allograft biopsies. Accurate non-invasive biomarkers are not available. METHODS: In the multicentre, prospective BIOMARGIN study, blood samples were prospectively collected at time of renal allograft biopsies between June 2011 and August 2016 and analyzed in three phases. The discovery and derivation phases of the study (N = 117 and N = 183 respectively) followed a case-control design and included whole genome transcriptomics and targeted mRNA expression analysis to construct and lock a multigene model. The primary end point was the diagnostic accuracy of the locked multigene assay for antibody-mediated rejection in a third validation cohort of serially collected blood samples (N = 387). This trial is registered with ClinicalTrials.gov, number NCT02832661. FINDINGS: We identified and locked an 8-gene assay (CXCL10, FCGR1A, FCGR1B, GBP1, GBP4, IL15, KLRC1, TIMP1) in blood samples from the discovery and derivation phases for discrimination between cases with (N = 49) and without (N = 134) antibody-mediated rejection. In the validation cohort, this 8-gene assay discriminated between cases with (N = 41) and without antibody-mediated rejection (N = 346) with good diagnostic accuracy (ROC AUC 79·9%; 95% CI 72·6 to 87·2, p

In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4–5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives. This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated. A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively. This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.

Aims Tacrolimus is a narrow therapeutic range drug that requires fine dose adjustment, for which pharmacokinetic (PK) models have been amply proposed in renal, but not in liver, transplant recipients. This study aimed to build population PK models and Bayesian estimators (BEs) in adult de novo liver transplant patients receiving either the immediate-release (Prograf, twice daily, TD) or prolonged-release (Advagraf, once daily, OD) forms to help PK-guided dose individualization. Methods In total, 160 tacrolimus concentration-time profiles (1654 samples) were collected from 80 patients, at day 7 (D7) and week 6 (W6) post-transplant. Four population PK models were developed using in-parallel parametric and nonparametric approaches for each formulation and period post-transplant. The best limited sampling strategies for estimating the area-under-the-curve (AUC) were selected by comparing predicted values to an independent dataset. Finally, the doses required to reach AUC targets were estimated using each BE and compared to the doses obtained using the trapezoidal AUC. Results Tacrolimus PK was best described using a 1-compartmental model with first-order elimination and 2 γ-distributions to describe the absorption. In the validation datasets, Bayesian AUC estimates yielded mean bias/root mean squared prediction error of −5.06%/13.43% (OD D7), 2.25%/8.51% (OD W6), −2.36%/7.27% (TD D7) and 0.87%/9.07% (TD W6) for the in-parallel parametric approach; and 8.95%/17.84% (OD D7), −0.11%/10.13% (OD W6), 3.57%/18.40% (TD D7) and 4.48%/12.59% (TD W6) for the nonparametric approach. Conclusion The BEs and limited sampling strategies proposed here are able to predict accurately and precisely tacrolimus AUC in liver patients using only 3 plasma concentrations. The dosing methods are available on our ImmunoSuppressive Bayesian dose Adjustment website (www.pharmaco.chu-limoges.fr).

Summary The 6p terminal deletions are rare and usually early diagnosed because of their association with eye and cranio-facial anomalies, particularly as part of Axenfeld-Rieger syndrome in relation with the haploinsufficiency of FOXC1 gene. Deletions in the 22q11 region are frequent, highly correlated with DiGeorge syndrome also named CATCH22, and may be associated with many clinical features of various severities. We report a 31-year-old man with an unbalanced 45,XY,der(6)t(6;22)(p25;q11.2),-22 karyotype leading to monosomies in both 6p25 and 22q11 regions, confirmed by FISH and array-CGH. The length of the deletions was respectively 770 Kb for 6pter and 2.9 Mb for 22q11. This karyotype was discovered at adult age following problems of fertility. The chromosomal formula was unexpected, regarding the patient's medical history and clinical features. This case makes a great example of the difficulties to correlate genotype and phenotype, and furthermore demonstrates the complexity of genetic counselling even in a case with two different chromosomal unbalances.

Objective The objective of this study was to develop a physiologically based pharmacokinetic model for meropenem using a retrograde approach, which could serve as a basis for prediction of the systemic and infection-site drug exposures in different populations and indications. We intended this model to be a useful tool to inform (local) pharmacokinetic-based optimal dosing of meropenem in different settings. Methods We developed a reduced physiologically based pharmacokinetic model with NONMEM software using a top-down approach. We used historical (previously published) data for model development and qualification. We used steady-state systemic and infection-site concentrations from 60 adult patients diagnosed with severe lung infection for model development and internal evaluation. The data included rich plasma and sparse epithelial lining fluid samples. We based the internal validation of the model on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness-of-fit plot with no indication of bias, and acceptable performance of visual predictive checks. We performed external validation by fitting the model to independent data from five previously published studies: four studies in patients with pneumonia, with different grades of renal impairment, and one study in morbidly obese patients. Results We successfully fitted a reduced physiologically based pharmacokinetic model with six compartments (arterial and venous pools, infection site [lungs], liver, kidneys and rest of the body) to the data and adequately estimated model parameters. We successfully qualified the model (internally and externally) using established methods. Estimated values for tissue-to-plasma partition coefficients were 0.2629 and 0.1946 for lungs and non-fat tissues (kidneys and liver), respectively. Estimated total clearance was 8.174 L/h for a typical patient with a glomerular filtration rate of 65 mL/min. Consistent with the known mechanism of meropenem elimination and previously published models, renal clearance accounted for 70% of total clearance. The model had good predictive performances on data from five different sources including populations with different characteristics with regard to body size, renal function and morbidity. Conclusions We successfully developed a physiologically based pharmacokinetic model for meropenem in adult patients to be used as a basis for prediction of concentrations in different groups of patients, and eventually for effective dose individualisation in different subgroups of the population. Electronic supplementary material The online version of this article (10.1007/s40268-019-0268-x) contains supplementary material, which is available to authorized users.

International audience; BACKGROUND AND OBJECTIVES:A new once-daily formulation of tacrolimus (Envarsus®) has recently been developed, with alleged different pharmacokinetics from previous tacrolimus formulations. The objectives of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies for Envarsus® in kidney and liver transplant recipients.MATERIALS AND METHODS:Full tacrolimus concentration-time profiles (13 samples) were drawn from 57 liver (113 profiles) and 49 kidney (97 profiles) graft recipients transplanted for at least 6 months and switched from Prograf® to Envarsus®. The two databases were split into a development (75%) and a validation (25%) dataset. Pharmacokinetic models characterised by a single compartment with first-order elimination and absorption in two phases described by a sum of two gamma distributions were developed using non-parametric (Pmetrics) and parametric (ITSIM) approaches in parallel. The best limited sampling strategy for each patient group was determined using the multiple model optimal algorithm. The performance of the models and derived Bayesian estimators was evaluated in the validation set.RESULTS:The best limited sampling strategy was 0, 8 and 12 h post-dose, leading to a relative bias ± standard deviation (root-mean-square error) between observed and modelled inter-dose area under the curve in the validation dataset of: 0.32 ± 6.86% (6.87%) for ITSIM and 3.4 ± 13.4% (13.2%) for Pmetrics in kidney transplantation; and 0.89 ± 7.32% (7.38%) for ITSIM and -2.62 ± 8.65% (8.89%) for Pmetrics in liver transplantation.CONCLUSION:Population pharmacokinetic models and Bayesian estimators for Envarsus® in kidney and liver transplantation were developed and are now available online for area under the curve-based tacrolimus dose adjustment.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related – most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01000-y.

Background Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax). Methods Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real‐life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020. Results Severe infections incidence was 23% during 17‐month median follow‐up; cumulative incidence was higher in the first 3–6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3–1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1–4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05–3.3). Infection‐related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed. Conclusion A high proportion of patients presented severe infections during follow‐up, with non‐negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered., Our data describe the infection risk associated with the use of targeted drugs in the treatment of lymphoproliferative diseases in real‐life setting and suggest some infection risk factors that could identify the need for antimicrobial prophylaxis in a selected group of patients.

Therapeutic drug monitoring of mycophenolic acid (MPA) based on area under the curve (AUC) is well-established and machine learning (ML) approaches could help to estimate AUC. The aim of this work is to estimate the AUC of MPA in organ transplant patients using extreme gradient boosting (Xgboost R package) ML models. A total of 12,877 MPA AUC from 0 to 12 hours (AUC0-12 h ) requests from 6,884 patients sent to our Immunosuppressant Bayesian Dose Adjustment expert system (https://abis.chu-limoges.fr) for AUC estimation and dose recommendation based on MPA concentrations measured at least at three sampling times (~ 20 minutes, 1 and 3 hours after dosing) were used to develop two ML models based on two or three concentrations. Data were split into a training set (75%) and a test set (25%) and the Xgboost models in the training set with the lowest root mean squared error (RMSE) in a 10-fold cross-validation experiment were evaluated in the test set and in 4 independent full-pharmacokinetic (PK) datasets from renal or heart transplant recipients. ML models based on two or three concentrations, differences between these concentrations, relative deviations from theoretical times of sampling, presence of a delayed absorption peak, and five covariates (dose, type of transplantation, associated immunosuppressant, age, and time between transplantation and sampling) yielded accurate AUC estimation performances in the test datasets (relative bias < 5% and relative RMSE < 20%) and better performance than MAP Bayesian estimation in the four independent full-PK datasets. The Xgboost ML models described allow accurate estimation of MPA AUC0-12 h and can be used for routine exposure estimation and dose adjustment and will soon be implemented in a dedicated web interface.

Background & Aims Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions. Methods Liver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches. Results Deletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001). Conclusions Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation., Graphical abstract

Background Circulating donor-specific anti-HLA antibodies (HLA-DSAs) are often absent in serum of kidney allograft recipients whose biopsy specimens demonstrate histology of antibody-mediated rejection (ABMR). It is unclear whether cases involving ABMR histology without detectable HLA-DSAs represent a distinct clinical and molecular phenotype. Methods In this multicenter cohort study, we integrated allograft microarray analysis with extensive clinical and histologic phenotyping from 224 kidney transplant recipients between 2011 and 2017. We used the term ABMR histology for biopsy specimens that fulfill the first two Banff 2017 criteria for ABMR, irrespective of HLA-DSA status. Results Of 224 biopsy specimens, 56 had ABMR histology; 26 of these (46.4%) lacked detectable serum HLA-DSAs. Biopsy specimens with ABMR histology showed overexpression of transcripts mostly related to IFNγ-induced pathways and activation of natural killer cells and endothelial cells. HLA-DSA-positive and HLA-DSA-negative biopsy specimens with ABMR histology displayed similar upregulation of pathways and enrichment of infiltrating leukocytes. Transcriptional heterogeneity observed in biopsy specimens with ABMR histology was not associated with HLA-DSA status but was caused by concomitant T cell-mediated rejection. Compared with cases lacking ABMR histology, those with ABMR histology and HLA-DSA had higher allograft failure risk (hazard ratio [HR], 7.24; 95% confidence interval [95% CI], 3.04 to 17.20) than cases without HLA-DSA (HR, 2.33; 95% CI, 0.85 to 6.33), despite the absence of transcriptional differences. Conclusions ABMR histology corresponds to a robust intragraft transcriptional signature, irrespective of HLA-DSA status. Outcome after ABMR histology is not solely determined by the histomolecular presentation but is predicted by the underlying etiologic factor. It is important to consider this heterogeneity in further research and in treatment decisions for patients with ABMR histology.

To increase the knowledge about S. capitis in the neonatal setting, we conducted a nationwide 3-month survey in 38 neonatal intensive care units (NICUs) covering 56.6% of French NICU beds. We demonstrated 14.2% of S. capitis BSI (S.capBSI) among nosocomial BSIs. S.capBSI incidence rate was 0.59 per 1000 patient-days. A total of 55.0% of the S.capBSIs were late onset catheter-related BSIs. The S. capitis strains infected preterm babies (median gestational age 26 weeks, median birth weight 855 g). They were resistant to methicillin and aminoglycosides and belonged to the NRCS-A clone. Evolution was favorable in all but one case, following vancomycin treatment.

The toxicokinetics of N-ethyl-2-pyrrolidone (NEP), an embryotoxic organic solvent, has been studied in Sprague-Dawley rats after oral exposure. NEP and its metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were measured in plasma of pregnant and non-pregnant rats, and fetuses after NEP administration by gavage for 14 consecutive days at 50 mg/kg/day, and in plasma of non-pregnant rats after a single NEP administration. Additionally, amniotic fluid and 24-h urine samples of the pregnant rats were analyzed for NEP metabolites. Furthermore, 24-h urine samples from a repeated dose 28-day oral toxicity study in female (non-pregnant) and male rats administered developmentally non-toxic (0, 5, and 50 mg/kg/day) or toxic (250 mg/kg/day) doses of NEP were analyzed. Median peak plasma concentrations in non-pregnant rats after a single dose and repeated doses were 551 and 611 (NEP), 182 and 158 (5-HNEP), and 63.8 and 108 µmol/L (2-HESI), respectively; whereas in pregnant rats and fetuses 653 and 619 (NEP), 80.5 and 91.7 (5-HNEP) and 77.3 and 45.7 µmol/L (2-HESI) were detected. Times to reach maximum plasma concentrations for NEP, 5-HNEP, and 2-HESI were 1, 4, and 8 h, respectively, and were comparable to N-methyl-2-pyrrolidone (NMP) and its corresponding metabolites. In pregnant rats, plasma elimination of NEP and metabolite formation/elimination was much slower compared to non-pregnant rats and efficient placental transfer of NEP was observed. Our data, overall, suggest differences in the toxicokinetics of chemicals between pregnant and non-pregnant rats which need to be addressed in risk assessment, specifically when assessing developmental toxicants such as NEP.

Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p &lt, 10&minus, 4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.

Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients. Full whole blood and PBMC concentration–time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set. A structural two-compartment model with first-order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 haplotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration–time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = − 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively). The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials.

Background Multidrug resistance protein-2 encoded by the ABCC2 gene (MRP2/ABCC2), an efflux transporter expressed at the proximal renal tubule, is rate-limiting for urine excretion of coproporphyrin (UCP) isomers I and III, translating in high UCP [I/(I + III)] ratio in MRP2-deficient patients presenting with the Dubin-Johnson Syndrome. MRP2 is also a major contributor to methotrexate (MTX) clearance. As MTX is both a substrate and an inhibitor of MRP2, time course of the concentrations of MTX in blood could induce functional modification of MRP2 over time, which in turn can modify its own elimination rate. Methods A 3-parameter time-dependent MTX population pharmacokinetic (PK) model based on a power function accounting for nonlinearity in its clearance was developed using Pmetrics in a first cohort of 41 patients (76 PK profiles) and compared with a previously published 2-compartment model developed with NONMEM and a 3-compartment model developed with ITSIM. In a second cohort (62 patients and 62 PK profiles), the association between the UCP [I/(I + III)] ratio at 3 periods [before MTX administration (P1), at the end of infusion (P2), and at hospital discharge (P3)] and the time-dependent PK parameters of MTX was investigated. Effects of genetic polymorphisms and of coadministered drugs were also studied. Results The model developed tightly fitted the data in both cohorts. A significant inverse correlation was found between log (k1) (ie, the rate constant explaining MTX concentration decrease) and the difference in UCP [I/(I + III)] ratio between P3 and P2 (DP3) (β ± SD = -0.025 ± 0.008, P = 0.00443). Conclusions Self-inhibition of the MRP2-dependent secretion of MTX is a plausible explanation for the time-dependent PKs of this drug. Additional studies specifically designed to evaluate this hypothesis are required.

Contraception is needed to prevent overpopulation and inbreeding in highly fecund captive bat colonies. Reports on surgical contraception in bats are limited. The objective of this study was to describe surgical castration techniques in a megachiropteran and a microchiropteran fruit bat species. Open orchiectomy by transfixing ligation of the spermatic cord was performed in 14 Ruwenzori long-haired fruit bats (

International audience; INTRODUCTION:Although thioredoxin-interacting protein (TXNIP) is involved in a variety of biological functions, the contribution of endothelial TXNIP has not been well-defined in regards to endothelial and vascular function or in post-ischemic revascularisation. We postulated that inhibition of endothelial TXNIP with siRNA or in a Cre-LoxP system could be involved in protection from high fat, high protein, low carbohydrate (HFHPLC) diet-induced oxidative stress and endothelial dysfunction, leading to vascular damage and impaired revascularisation in vivo.METHODS AND RESULTS:To investigate the role of endothelial TXNIP, the TXNIP gene was deleted in endothelial cells using anti-TXNIP siRNA treatment or the Cre-LoxP system. Murine models were fed a HFHPLC diet, known to induce metabolic disorders. Endothelial TXNIP targeting resulted in protection against metabolic disorder-related endothelial oxidative stress and endothelial dysfunction. This protective effect mitigates media cell loss induced by metabolic disorders and hampered metabolic disorder-related vascular dysfunction assessed by aortic reactivity and distensibility. In aortic ring cultures, metabolic disorders impaired vessel sprouting and this alteration was alleviated by deletion of endothelial TXNIP. When subjected to ischemia, mice fed a HFHPLC diet exhibited defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. However, reducing endothelial TXNIP rescued metabolic disorder-related impairment of ischemia-induced revascularisation.CONCLUSION:Collectively, these results show that targeting endothelial TXNIP in metabolic disorders is essential to maintaining endothelial function, vascular function and improving ischemia-induced revascularisation, making TXNIP a potential therapeutic target for therapy of vascular complications related to metabolic disorders.

Introduction Crime and the fear of crime can be a barrier to park use, and locations of crimes can have varied effects. Unsafe areas in or around the park, around the residence, or along the route to the park can alter park use behavior. Our study aimed to examine associations between objective measures of types and location of crimes and park use behaviors. Methods In 2013 we surveyed a sample (N = 230) of residents in Greensboro, North Carolina, about park use, with responses matched to objective crime and spatial measures. We measured all crimes and violent crimes near home, near the closest park, and along the shortest route between home and park. By using ordered and binary logistic modeling, we examined the relationships between the locations of crime and park use and duration of park visit, park rating, and never visiting parks. Additional models included distance to the closest park. Results Increased crime in parks and near home was associated with fewer park visits. Greater violent crime in all locations was related to fewer park visits. Park ratings were lower for parks with high violent crime rates. Conclusion Given the importance of parks as settings for outdoor recreation and physical activity, crime may have a detrimental effect on physical activity and, therefore, public health.

ObjectivesThe predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.MethodsTo characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5−; n = 190/201) based on selected variables, collected retrospectively, without any missing data.ResultsWithin anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5− patients with myositis.ConclusionAnti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Altres ajuts: Fundació "la Caixa" ID 100010434 Unidad de excelencia María de Maeztu CEX2019-000940-M Walking is the most accessible form for seniors to engage in daily light or moderate physical activity. Walking activity depends on both individual and environmental factors, the latter including how walkable a given setting is. Recent papers have pointed at the relevance of also considering meteorological conditions in relation to the walking behavior of older adults. This paper explores the combined effect of neighborhood walkability, temperature and rain on daily walking time among seniors residing in Barcelona. Daily walking time was extracted from 7-day GPS (Global Positioning System) devices and accelerometer data of 227 seniors residing in the Barcelona Metropolitan Region (Spain). Temperature and rain data were extracted from official governmental weather stations. Mixed-effects linear regression models were adjusted to test the combined association between weather and walkability on daily walking time. Neighborhood walkability is positively associated with walking time among seniors, while rain generally deters it. Additionally, this study demonstrates that temperature and rain modify the effect of residential walkability on senior walking activity: low temperatures are particularly associated with lower walking activity among those residing in low walkable areas, while the presence of rain presents a negative association with walking time in high walkable environments. The combined effect of walkability and weather should be considered both in design actions that aim at improving walking infrastructure and also in prevention programs aimed at encouraging daily walking among seniors.

Describe clinical, histological and molecular charatcteristics and prognosis values of the serrated candidate markers AnnexinA10 and Gremlin1 in colon adenocarcinomas. Immunohistochemical expression of AnnexinA10 and Gremlin1 was evaluated on 346 colonic adenocarcinomas. Clinicopathological, molecular features and prognostic characteristics were then evaluated. A total of 40 colonic adenocarcinomas expressed AnnexinA10 (11.6%) and, 115 expressed Gremlin1 (40.4%). AnnexinA10 expression was significantly associated, on univariate analyses, with female gender (p = 0.03), right tumor location (p

The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations.In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak 8*MIC and a trough 1 mg/L for MIC values between 0.25 and 4 mg/L.A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak 8*MIC for 90% of the simulations and a trough concentration 1 mg/L at 96 h for 92% and 34% respectively.The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8 mg/kg/day just before dialysis, taking into account the type of infection.

Unidad de excelencia María de Maeztu MdM-2015-0552 This project was funded by the RecerCaixa research fund in the 2016 call, under the original title of Ciudad, calidad de vida y movilidad activa en la tercera edad: Un análisis multimetodológico a través de Tracking Living Labs. Urban green spaces (UGS) have been linked with a series of benefits for the environment, and for the physical health and well-being of urban residents. This is of great importance in the context of the aging of modern societies. However, UGS have different forms and characteristics that can determine their utilization. Common elements in UGS such as the type of vegetation and the type of surface are surprisingly understudied in regard to their relationship with the type of activity undertaken in UGS. This paper aims to explore the relationship between landscape diversity and the type of surface with the time spent and the physical activity intensity performed by seniors. To do so, this study uses GPS tracking data in combination with accelerometer data gathered from 63 seniors residing in Barcelona, Spain. Results showed that senior participants spent little time inside the analyzed UGS and sedentary behaviors (SBs) were more common than physical activities (PAs). The presence of pavement surfaces positively influenced the total time spent in UGS while gravel surfaces were negatively associated with time spent in active behaviors. The provision of well-defined and maintained paved areas and paths are some key infrastructures to be considered when designing UGS for overall urban residents and, especially, when aiming to potentiate the access for senior visitors.

Background and Purpose Disability and sensory impairment are particularly pronounced among the oldest old population (80 years and older). Considering these specificities, we analyzed the association of such parameters with subjective age, a strong predictor of health-related outcomes. We assumed that greater disability and sensory impairment (hearing and visual) would be linked with an older subjective age. Research Design Prospective population-based study. Study Sample Data were gathered from the 27th year follow-up of the PAQUID cohort, visit where the question on subjective age was collected. Our sample included 75 participants older than 93 years, with a mean age of 96 years. Data Collection and Analysis Disability was assessed with Activities of Daily Living and sensory impairments by asking participants if they have visual or hearing difficulties. A multiple linear regression model was performed with subjective age as the dependent variable. Independent variables were functional disability and visual and hearing impairments. Results On average, the participants felt 12 years younger than their actual age. Multiple regression analyses controlled for age, gender, education, depression, and dementia indicated that self-reported hearing loss (p = 0.03) was associated with an older subjective age, whereas no significant associations were observed for disability (p = 0.42) and self-reported visual loss (p = 0.18). Conclusions Hearing impairment, in contrast to visual impairment and disability, is associated with feeling older. These results are discussed in light of health consequences and age stigma carried by hearing impairment.

Small mammals present in areas where hantavirus cardiopulmonary syndrome (HCPS) cases had occurred in central and southern Chile were captured and analyzed to evaluate the abundance of rodents and seroprevalence rates of antibodies to Andes orthohantavirus (ANDV). Sampling areas ranged from the Coquimbo to Ays&eacute, n regions (30&ndash, 45&deg, S approx.) regions. Ninety-two sites in peridomestic and countryside areas were evaluated in 19 years of sampling. An antibody against ANDV was detected by strip immunoassay in 58 of 1847 specimens captured using Sherman traps. Of the eleven species of rodents sampled, Abrothrix olivacea, Oligoryzomys longicaudatus and Abrothrix hirta were the most frequently trapped. O. longicaudatus had the highest seropositivity rate, and by logistic regression analysis, O. longicaudatus of at least 60 g had 80% or higher probability to be seropositive. Sex, age and wounds were significantly related to seropositivity only for O. longicaudatus. Across administrative regions, the highest seropositivity was found in the El Maule region (34.8&ndash, 36.2&deg, S), and the highest number of HCPS cases was registered in the Ays&eacute, n region. Our results highlight the importance of long term and geographically extended studies, particularly for highly fluctuating pathogens and their reservoirs, to understand the implications of the dynamics and transmission of zoonotic diseases in human populations.

Urban parks provide spaces and facilities for children's physical activity (PA) and can be a free resource in low-income communities. This study examined whether neighborhood characteristics were associated with children's park use and park-based moderate-to-vigorous PA (MVPA) in low-income diverse communities and how associations differed between ethnic groups. Data on park visits and MVPA came from 16,402 children 5-10-years old directly observed using the System for Observing Play and Recreation in Communities in 20 parks in low-income neighborhoods with majority Latino or Asian populations in New York City. Neighborhood characteristics included land use mix (LUM), street audits, crime rates, and an area deprivation index. We employed Poisson and negative binomial models to estimate effects of neighborhood-level variables on the number of children observed in parks and engaging in MVPA, overall and by ethnicity. Results for Asian, Latino, and African American children indicated that higher levels of LUM and pedestrian-friendly streets were associated with greater numbers of children in parks and higher MVPA across all three groups. For Asian and Latino children only, quality of environment was positively associated with MVPA, whereas level of deprivation and crime rates in the surrounding neighborhood were negatively associated with children's park-based MVPA. In contrast, a park's access to public transportation was negatively associated with number of all children observed and engaging in MVPA. Study findings suggest that park-based MVPA interventions can be informed by understanding how neighborhood characteristics facilitate and constrain park use and park-based MVPA.

Adverse drug events (ADEs) are a worldwide concern, particularly when leading to a higher level of care. This study defines a higher level of care as an unplanned (re)admission to an intensive care unit or an intervention by a Medical Emergency Team. The objectives are to describe the incidence and preventability of ADEs leading to a higher level of care, to assess the types of drug involved, and to identify the risk factors.A three-stage retrospective review was performed in six Belgian hospitals. Patient records were assessed by a trained clinical team consisting of a nurse, a physician, and a clinical pharmacist. Descriptive statistics, univariate, and multiple logistic regressions were used.In this study, 830 patients were detected for whom a higher level of care had been needed. In 160 (19.3%) cases, an ADE had occurred; 134 (83.8%) of these were categorized as preventable adverse drug events (pADEs). The overall incidence rate of patients transferred to a higher level of care because of a pADE was 33.9 (95% CI: 28.5-39.3) per 100,000 patient days at risk. Antibiotics and antithrombotic agents accounted both for one-fifth of all pADEs. Multivariate analysis indicated American Society of Anaesthesiologists physical status score as a risk factor for pADEs.The high number of pADE with patient harm shows that there is a need for structural improvement of pharmacotherapeutic care. Detection of these pADEs can be the basis for the implementation of these improvements.

International audience; Cerebral malaria, a reversible encephalopathy affecting young children, is a medical emergency requiring urgent clinical assessment and treatment. We performed a whole-transcrip-tomic analysis of blood samples from Malian children with cerebral or uncomplicated malaria. We focused on transcripts from pathways for which dysfunction has been associated with neurodegenerative disorders. We found that SNCA, SIAH2, UBB, HSPA1A, TUBB2A, and PINK1 were upregulated (fold-increases , ≥2.6), whereas UBD and PSMC5 were downregulated (fold-decreases, ≤4.39) in children with cerebral malaria, compared with those with uncomplicated malaria. These findings provide the first evidence for pathogenic mechanisms common to human cerebral malaria and neurodegenerative disorders.

International audience; Most predictive models and scores of graft survival in renal transplantation include factors known before transplant or at the end of the first year. They cannot be updated thereafter, even in patients developing donor-specific anti-HLA antibodies and acute rejection.We developed a conditional and adjustable score for prediction of graft failure (AdGFS) up to 10 years post-transplantation in 664 kidney transplant patients. AdGFS was externally validated and calibrated in 896 kidney transplant patients.The final model included five baseline factors (pretransplant non donor-specific anti-HLA antibodies, donor age, serum creatinine measured at 1 year, longitudinal serum creatinine clusters during the first year, proteinuria measured at 1 year), and two predictors updated over time (de novo donor-specific anti-HLA antibodies and first acute rejection). AdGFS was able to stratify patients into four risk-groups, at different post-transplantation times. It showed good discrimination (time-dependent ROC curve at ten years: 0.83 (CI95% 0.76-0.89).

The solvent N-ethyl-2-pyrrolidone (NEP) was evaluated in a 4-week repeated dose study in rats. NEP diluted in distilled water was orally administered by gavage to male and female Sprague-Dawley rats at doses of 0 (vehicle control), 5, 50, and 250 mg/kg/day for 28 consecutive days. Transient decreases in the body weight and in the body weight gain of the males was observed during the first days of treatment at the 50 and 250 mg/kg/day doses. There was a marked increase in urine volume at the beginning of treatment in males and female rats at doses of 50 and 250 mg/kg/day. No biologically significant differences were observed in hematological and clinical chemistry values in males and females at necropsy. Histological examination revealed an increase in hyaline droplets in the renal tubules of the kidneys and hepatocellular centrilobular hypertrophy in the liver of males at 250 mg/kg/day. Cytochrome P450 concentration in liver microsomes was slightly increased at 250 mg/kg/day in males. The results of this study demonstrate that NEP has mild to no effects at doses up to 250 mg/kg/day when administered orally to rats for 28 days with males being more susceptible than females.

Objectives Anti-Mullerian hormone (AMH) measurement is useful as an aid in the evaluation of ovarian reserve. In the past, its conventional use was restricted by the low-throughput and variability of existing manual AMH assays. We developed the automated Access AMH assay for the quantitative determination of AMH levels on the Access family of immunoassay systems. The analytical performance of this new assay was evaluated. Design and methods Sensitivity, dilution linearity, assay imprecision, AMH sample stability, lot-to-lot comparison and correlation with AMH Gen II assay (Beckman Coulter, Inc.) were evaluated. Reference intervals for Access AMH were established in healthy females, males, newborns (≤ 60 days) and pediatric males classified by Tanner stages. Results The limit of blank and limit of detection were below 0.0077 and 0.0098 ng/mL, respectively. The limit of quantitation was 0.010 ng/mL. The total imprecision ranged from 2.4 to 5.2%. Linearity was observed up to 24 ng/mL. Sample storage at room temperature up to 48 h, at 2–8 °C up to 7 days and at − 20 °C up to 15 months had no impact on measured AMH. The correlation study gave a coefficient between 0.99 and 1 and a regression slope between 0.89 and 0.92. Excellent lot-to-lot comparability was observed on controls and patient samples with a maximum bias of 3.7% between 2.81 and 15.03 ng/mL. Conclusions The fully automated Access AMH immunoassay demonstrates excellent analytical performance. As a consequence, the availability of this assay will represent a robust, fast and precise alternative to manual AMH assay testing.

Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention and treatment in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the replication of viral DNA. Its intracellular accumulation might favor host DNA polymerase inhibition, hence toxicity. Following this hypothesis, we investigated the association between a selected panel of membrane transporter polymorphisms and the evolution of neutrophil counts in n=174 renal transplant recipients. An independent population of n=96 renal transplants served as a replication and experiments using HEK293T-transfected cells were performed to validate the clinical findings. In both cohorts, we found a variant in ABCC4 (rs11568658) associated with decreased neutrophil counts following valganciclovir (GCV prodrug) administration (exploratory cohort: β±SD=-0.68±0.28, p=0.029; replication cohort: β±SD=-0.84±0.29, p=0.0078). MRP4-expressing cells showed decreased GCV accumulation as compared to negative control cells (transfected with an empty vector) (-61%; p