Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.

Diabetes constitutes a major public health problem, with dramatic consequences for patients. Both genetic and environmental factors were shown to contribute to the different forms of the disease. The monogenic forms, found both in humans and in animal models, specially help to decipher the role of key genes in the physiopathology of the disease. Here, we describe the phenotype of early diabetes in a colony of NOD mice, with spontaneous invalidation of Akt2, that we called HYP. The HYP mice were characterised by a strong and chronic hyperglycaemia, beginning around the age of one month, especially in male mice. The phenotype was not the consequence of the acceleration of the autoimmune response, inherent to the NOD background. Interestingly, in HYP mice, we observed hyperinsulinemia before hyperglycaemia occurred. We did not find any difference in the pancreas' architecture of the NOD and HYP mice (islets' size and staining for insulin and glucagon) but we detected a lower insulin content in the pancreas of HYP mice compared to NOD mice. These results give new insights about the role played by Akt2 in glucose homeostasis and argue for the ß cell failure being the primary event in the course of diabetes.

Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis.

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1ß (IL-1ß) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1ß release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis.

Pathogen exposure influences immune parameters around weaning in pigs reared in commercial farms.

BACKGROUND: Multiple antigenic stimulations are crucial to immune system training during early post-natal life. These stimulations can be either due to commensals, which accounts for the acquisition and maintenance of tolerance, or to pathogens, which triggers immunity. In pig, only few works previously explored the influence of natural exposition to pathogens upon immune competence. We propose herein the results of a multicentric, field study, conducted on 265 piglets exposed to contrasted pathogen levels in their living environment. Piglets were housed in 15 different commercial farms, sorted in two groups, low (HSLOW)- and high (HSHIGH)-health status farms, depending on their recurrent exposition to five common swine pathogens. RESULTS: Using animal-based measures, we compared the immune competence and growth performances of HSLOW and HSHIGH pigs around weaning. As expected, we observed a rise in the number of circulating leucocytes with age, which affected different cell populations. Monocyte, antigen-experienced and cytotoxic lymphocyte subpopulation counts were higher in piglets reared in HSLOW farms as compared to their HSHIGH homologs. Also, the age-dependent evolution in γδ T cell and neutrophil counts was significantly affected by the health status. With age, circulating IFNα level decreased and IgM level increased while being greater in HSLOW piglets at any time. After weaning, LPS-stimulated blood cells derived from HSLOW piglets were more prone to secrete IL-8 than those derived from HSHIGH pigs did. Monocytes and granulocytes issued from HSLOW pigs also exhibited comparable phagocytosis capacity. Altogether our data emphasize the more robust immunophenotype of HSLOW piglets. Finally, piglets raised under higher pathogen pressure grew less than HSHIGH piglets did and exhibited a different metabolic profile. The higher cost of the immune responses associated with the low farm health status may account for lower HSLOW piglet performances. CONCLUSIONS: Altogether, our data, obtained in field conditions, provide evidence that early exposure to pathogens shapes the immune competence of piglets. They also document the negative impact of an overstimulation of the immune system on piglets' growth.

Necroptosis Blockade Potentiates the Neuroprotective Effect of Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy (NE) caused by hypoxia-ischemia (HI) affects around 1 per 1000 term newborns and is the leading cause of acquired brain injury and neurodisability. Despite the use of hypothermia (HT) as a standard of care, the incidence of NE and its devastating outcomes remains a major issue. Ongoing research surrounding add-on neuroprotective strategies against NE is important as HT effects are limited, leaving 50% of treated patients with neurological sequelae. Little is known about the interaction between necroptotic blockade and HT in neonatal HI. Using a preclinical Lewis rat model of term human NE induced by HI, we showed a neuroprotective effect of Necrostatin-1 (Nec-1: a compound blocking necroptosis) in combination with HT. The beneficial effect of Nec-1 added to HT against NE injuries was observed at the mechanistic level on both pMLKL and TNF-α, and at the anatomical level on brain volume loss visualized by magnetic resonance imaging (MRI). HT alone showed no effect on activated necroptotic effectors and did not preserve the brain MRI volume. This study opens new avenues of research to understand better the specific cell death mechanisms of brain injuries as well as the potential use of new therapeutics targeting the necroptosis pathway.

COVID-19 vaccine humoral response in frequent platelet donors with plateletpheresis-associated lymphopenia.

BACKGROUND: Plateletpheresis involves platelet separation and collection from whole blood while other blood cells are returned to the donor. Because platelets are replaced faster than red blood cells, as many as 24 donations can be done annually. However, some frequent apheresis platelet donors (>20 donations annually) display severe plateletpheresis-associated lymphopenia; in particular, CD4+ T but not B cell numbers are decreased. COVID-19 vaccination thereby provides a model to assess whether lymphopenic platelet donors present compromised humoral immune responses. STUDY DESIGN AND METHODS: We assessed vaccine responses following 2 doses of COVID-19 vaccination in a cohort of 43 plateletpheresis donors with a range of pre-vaccination CD4+ T cell counts (76-1537 cells/µl). In addition to baseline T cell measurements, antibody binding assays to full-length Spike and the Receptor Binding Domain (RBD) were performed pre- and post-vaccination. Furthermore, pseudo-particle neutralization and antibody-dependent cellular cytotoxicity assays were conducted to measure antibody functionality. RESULTS: Participants were stratified into two groups: <400 CD4/µl (n = 27) and ≥ 400 CD4/µl (n = 16). Following the first dose, 79% seroconverted within the <400 CD4/µl group compared to 87% in the ≥400 CD4/µl group; all donors were seropositive post-second dose with significant increases in antibody levels. Importantly differences in CD4+ T cell levels minimally impacted neutralization, Spike recognition, and IgG Fc-mediated effector functions. DISCUSSION: Overall, our results indicate that lymphopenic plateletpheresis donors do not exhibit significant immune dysfunction; they have retained the T and B cell functionality necessary for potent antibody responses after vaccination.

Protective Effects of Interleukin-1 Blockade on Group B Streptococcus-Induced Chorioamnionitis and Subsequent Neurobehavioral Impairments of the Offspring.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. Placental infection due to GBS is a major risk factor for fetal organ injuries, preterm birth, perinatal morbidity and mortality, and life-long multiorgan morbidities. Preclinical and clinical studies have shown that GBS-induced infection drives polymorphonuclear (PMN) cell infiltration within the placenta, the hallmark of human chorioamnionitis. In preclinical and clinical studies, the upregulation of interleukin(IL)-1ß in the placenta and maternal/fetal blood was associated with a high risk of neurodevelopmental impairments in the progeny. We hypothesized that targeted IL-1 blockade administered to the dam alleviates GBS-induced chorioamnionitis and the downstream fetal inflammatory response syndrome (FIRS). IL-1 receptor antagonist (IL-1Ra) improved the gestational weight gain of GBS-infected dams and did not worsen the infectious manifestations. IL-1Ra reduced the IL-1ß titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1ß titer in the fetal sera of GBS-exposed fetuses. IL-1 blockade also alleviated GBS-induced FIRS and subsequent neurobehavioral impairments of the offspring without worsening the outcome of GBS infection. Altogether, these results showed that IL-1 plays a key role in the physiopathology of live GBS-induced chorioamnionitis and consequent neurobehavioral impairments.

Androgens Upregulate Pathogen-Induced Placental Innate Immune Response.

Group B Streptococcus (GBS) is a leading cause of placental infection, termed chorioamnionitis. Chorioamnionitis is associated with an increased risk of neurobehavioral impairments, such as autism spectrum disorders, which are more prominent in males than in female offspring. In a pre-clinical model of chorioamnionitis, a greater inflammatory response was observed in placenta associated with male rather than female fetuses, correlating with the severity of subsequent neurobehavioral impairments. The reason for this sex difference is not understood. Our hypothesis is that androgens upregulate the placental innate immune response in male fetuses. Lewis dams were injected daily from gestational day (G) 18 to 21 with corn oil (vehicle) or an androgen receptor antagonist (flutamide). On G 19, dams were injected with saline (control) or GBS. Maternal, fetal sera and placentas were collected for protein assays and in situ analyses. Our results showed that while flutamide alone had no effect, a decrease in placental concentration of pro-inflammatory cytokines and infiltration of polymorphonuclear cells was observed in flutamide/infected compared to vehicle/infected groups. These results show that androgens upregulate the placental innate immune response and thus may contribute to the skewed sex ratio towards males observed in several developmental impairments resulting from perinatal infection/inflammation.

Comparison of Neutrophil Function in Granulocyte Concentrates From Prednisone- and G-CSF-Treated Donors: Effect of Stimulant, Leukapheresis and Storage.

Transfusion of granulocyte concentrates (GC) is an alternative therapy for neutropenic patients with life-threatening infections. While neutrophils are the main source of antimicrobial activity, only neutrophil numbers are used to certify GCs. The objective of this study was thus to functionally characterize neutrophils in GCs prepared by leukapheresis from G-CSF-stimulated donors and compare to the less characterized prednisone GCs. GCs prepared from healthy donors stimulated with prednisone and then G-CSF after a 6-month washout period were analyzed prior to and after leukapheresis, and after storage. Leukocyte composition, neutrophil viability, calcium mobilization, chemotaxis, phagocytosis, reactive oxygen species, cytokine production and metabolites were determined. G-CSF GCs contained significantly more neutrophils than prednisone GCs of which 40% were immature. In comparison to non-stimulated healthy donor neutrophils, prednisone GC neutrophils exhibited enhanced phagocytosis and G-CSF GC neutrophils showed decreased chemotaxis but increased IL-8 production. Leukapheresis altered prednisone GC neutrophil responses. Storage had a significant, negative impact on G-CSF GC neutrophils compared to prednisone GC neutrophils. G-CSF and prednisone GC neutrophils thus differ in maturity and function, and G-CSF GC neutrophils are more sensitive to storage. Functional testing of GC neutrophils and better storage conditions would improve the quality of this blood product.

Optimization of an O2-balanced bioartificial pancreas for type 1 diabetes using statistical design of experiment.

A bioartificial pancreas (BAP) encapsulating high pancreatic islets concentration is a promising alternative for type 1 diabetes therapy. However, the main limitation of this approach is O2 supply, especially until graft neovascularization. Here, we described a methodology to design an optimal O2-balanced BAP using statistical design of experiment (DoE). A full factorial DoE was first performed to screen two O2-technologies on their ability to preserve pseudo-islet viability and function under hypoxia and normoxia. Then, response surface methodology was used to define the optimal O2-carrier and islet seeding concentrations to maximize the number of viable pseudo-islets in the BAP containing an O2-generator under hypoxia. Monitoring of viability, function and maturation of neonatal pig islets for 15 days in vitro demonstrated the efficiency of the optimal O2-balanced BAP. The findings should allow the design of a more realistic BAP for humans with high islets concentration by maintaining the O2 balance in the device.

Uvaol Prevents Group B Streptococcus-Induced Trophoblast Cells Inflammation and Possible Endothelial Dysfunction.

Group B Streptococcus (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 106 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1ß and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.

Nonhypoalbuminemic Inflammatory Bowel Disease in Dogs as Disease Model.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is increasing worldwide, emphasizing the need of relevant models, as dogs spontaneously affected by IBD may be, for better knowledge of the disease's physiopathology. METHODS: We studied 22 client-owned dogs suffering from IBD without protein loss and 14 control dogs. Biopsies were obtained from the duodenum, ileum, and colon. Inflammatory grade was assessed by histopathology, immunohistochemistry, and chemokine analysis. The expression of Toll-like receptors (TLR) in mucosa was immunohistochemically evaluated. Antibody levels against bacterial ligands (lipopolysaccharide [LPS] and flagellin) were measured in sera using enzyme-linked immunoassay. RESULTS: Dogs with IBD showed low to severe clinical disease. Histopathologically, the gut of dogs with IBD did not exhibit significant alterations compared with controls except in the colon. The number of CD3+ T lymphocytes was decreased in the ileum and colon of dogs with IBD compared with controls, whereas the numbers of Foxp3+, CD20+, and CD204+ cells were similar in the 2 groups. Three chemokines, but no cytokines, were detected at the protein level in the mucosa, and the disease poorly affected their tissue concentrations. Dogs with IBD exhibited higher serum reactivity against LPS and flagellin than controls but similar immunoreactivity against the receptors TLR4 and TLR5. In addition, TLR2 and TLR9 showed similar expression patterns in both groups of dogs. CONCLUSIONS: Our data described dysregulated immune responses in dogs affected by IBD without protein loss. Despite fairly homogeneous dog cohorts, we were still faced with interindividual variability, and new studies with larger cohorts are needed to validate the dog as a model.

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS).

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

Mycophenolic acid drug monitoring in patients with systemic sclerosis associated with diffuse skin and/or pulmonary involvement: A monocentric and retrospective French study.

Objective: To explore pharmacokinetic/pharmacodynamic relationship between mycophenolic acid area under the curve and clinical response at 1 year on skin involvement or interstitial lung disease in patients with systemic sclerosis. Method: Retrospective, monocentric study based on French Scleroderma Database in patients receiving mycophenolate mofetil who experienced a limited sampling strategy to estimate individual mycophenolic acid area under the curve plus two pulmonary function tests and skin evaluation after 1 month and 1 year. Efficacy criterions were variations of modified Rodnan skin score, forced vital capacity, and diffusing lung capacity for carbon monoxide at 1 year. Results: We included 52 patients; mean age was 49 years (range 17-79), and 36 (69%) were females. Fifty patients (96%) had skin sclerosis, 39 (75%) had diffuse skin involvement with a median modified Rodnan skin score of 14 (0-38). Thirty-eight (76%) had interstitial lung disease, with median forced vital capacity and diffusing lung capacity for carbon monoxide of 81% (37-127) and 56% (28-103) from predicted values, respectively. Twenty-five (51%) patients had pulmonary fibrosis. Mycophenolate mofetil was given for 10 months (0-173) at a median dose of 2000 mg/day (500-3000). In the entire population, no relationship was found between area under the curve and modified Rodnan skin score (p = 0.085), forced vital capacity (p = 0.80), or diffusing lung capacity for carbon monoxide (p = 0.72) variations at 1 year. Conclusion: In this retrospective study, we failed to document any relationship between mycophenolic acid area under the curve and skin involvement or interstitial lung disease evolution. Routine monitoring of mycophenolic acid in systemic sclerosis patients treated with mycophenolate mofetil cannot be recommended based on our results.

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

BACKGROUND: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent patients. METHODS: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL. RESULTS: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL). CONCLUSIONS: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

Ampicillin Treatment Increases Placental Interleukin-1 Beta Concentration and Polymorphonuclear Infiltration in Group B Streptococcus-Induced Chorioamnionitis: A Preclinical Study.

BACKGROUND: Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death. OBJECTIVES: Using an established rat model of group B Streptococcus (GBS)-induced chorioamnionitis, we hypothesized that ampicillin treatment increases placental inflammation, as shown in other bacterial infections. METHODS: At gestational day 19, 19 Lewis dams were intraperitoneally (i.p.) inoculated by 108 CFU of ß-hemolytic serotype Ia GBS (strain #16955 susceptible to ampicillin). Dams were treated i.p. with either 200 mg/kg of ampicillin (n = 9) or 0.9% saline (n = 10) at 48 and 60 h post-GBS inoculation. Cesarean sections were performed 72 h post-GBS inoculation. RESULTS: Ampicillin treatment was associated with an increased number of polymorphonuclear cells (PMN) infiltrating the decidua (mean 1,536 vs. 532 PMN/mm2; p < 0.001) and a higher placental concentration of IL-1ß (mean 26.4 vs. 7.9 pg/mg; p < 0.01) compared to saline-treated dams. These effects were observed in dams without GBS bacteremia. Conversely, ampicillin treatment was associated with a decreased placental concentration of proinflammatory cytokines in dams with GBS bacteremia. CONCLUSIONS: Ampicillin increases placental inflammation in a rat model of GBS-induced chorioamnionitis without bacteremia. This proinflammatory effect of ampicillin could be due to bacterial lysis. Our findings do not query the intrapartum antibiotic prophylaxis against GBS disease. They pave the way for future preclinical studies combining anti-inflammatory treatments and antibiotic therapy for GBS-induced chorioamnionitis.

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.

INTRODUCTION: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. PATIENTS AND METHODS: Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). RESULTS: Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 µg/mL and 8.8 ± 2.1 µg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 µg/mL vs. 11.6 ± 2.6 µg/mL, respectively; P = .027). CONCLUSION: The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.

Is there an Exposure-Response Relationship for Nivolumab in Real-World NSCLC Patients?

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small-cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman's rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02-3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78-36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46-27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Paternal support for child sexual abuse victims: A qualitative study.

BACKGROUND: The current state of knowledge regarding the role of non-offending fathers in supporting their sexually abused children is very scarce. OBJECTIVE: The objective of this study is to further our understanding of fathers' roles following disclosure of their children's sexual abuse (SA) by evaluating fathers' perceptions of the impact of disclosure on their involvement and support of their children. PARTICIPANTS AND METHOD: This qualitative study relies on individual semi-structured interviews conducted with 17 fathers of allegedly abused children. RESULTS: Inductive thematic analysis first highlighted that some reported a period of disengagement from the child during which they put into question their role and attitudes, followed by a period of re-involvement. This period of difficulties experienced by some fathers in regard to their involvement towards their children was due to either their own important psychological distress, their ambivalence towards their child or even because of feelings of uneasiness experienced during physical contact with them. Despite this, findings indicate the presence of thoughts and attitudes that suggest children are a source of concern for fathers. The four forms of abuse-specific support previously observed among mothers (believing the child, seeking out professional services, protecting him/her from the offender, supporting him/her emotionally) were also observed among fathers. In accordance with the activation theory, a form of support specific to fathers, namely, encouraging the child to open up to and explore the world outside the family, thereby, fostering the child's self-esteem development, was observed and constitutes a relevant finding. CONCLUSION: Clinical and empirical implications are discussed.

Sex-specific maternofetal innate immune responses triggered by group B Streptococci.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis, which is a major risk factor for premature birth and brain injuries. Males are at greater risk than females for developing lifelong neurobehavioural disorders, although the origins of this sex bias remain poorly understood. We previously showed that end-gestational inflammation triggered by GBS led to early neurodevelopmental impairments mainly in the male rat progeny. Identifying key inflammatory players involved in maternofetal immune activation by specific pathogens is critical to develop appropriate novel therapeutic interventions. We aimed to map out the GBS-induced profile of innate immune biomarkers in the maternal-placental-fetal axis, and to compare this immune profile between male and female tissues. We describe here that the GBS-induced immune signalling involved significantly higher levels of interleukin (IL)-1ß, cytokine-induced neutrophil chemoattractant-1 (CINC-1/CXCL1) and polymorphonuclear cells (PMNs) infiltration in male compared to female maternofetal tissues. Although male - but not female - fetuses presented increased levels of IL-1ß, fetuses from both sexes in-utero exposed to GBS had increased levels of TNF-α in their circulation. Levels of IL-1ß detected in fetal sera correlated positively with the levels found in maternal circulation. Here, we report for the first time that the maternofetal innate immune signalling induced by GBS presents a sexually dichotomous profile, with more prominent inflammation in males than females. These sex-specific placental and fetal pro-inflammatory responses are in keeping with the higher susceptibility of the male population for preterm birth, brain injuries and neurodevelopmental disorders such as cerebral palsy and autism spectrum disorders.