Immune-based Machine learning Prediction of Diagnosis and Illness State in Schizophrenia and Bipolar Disorder.

BACKGROUND: Schizophrenia and bipolar disorder frequently face significant delay in diagnosis, leading to being missed or misdiagnosed in early stages. Both disorders have also been associated with trait and state immune abnormalities. Recent machine learning-based studies have shown encouraging results using diagnostic biomarkers in predictive models, but few have focused on immune-based markers. Our main objective was to develop supervised machine learning models to predict diagnosis and illness state in schizophrenia and bipolar disorder using only a panel of peripheral kynurenine metabolites and cytokines. METHODS: The cross-sectional I-GIVE cohort included hospitalized acute bipolar patients (n = 205), stable bipolar outpatients (n = 116), hospitalized acute schizophrenia patients (n = 111), stable schizophrenia outpatients (n = 75) and healthy controls (n = 185). Serum kynurenine metabolites, namely tryptophan (TRP), kynurenine (KYN), kynurenic acid (KA), quinaldic acid (QUINA), xanthurenic acid (XA), quinolinic acid (QUINO) and picolinic acid (PICO) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), while V-plex Human Cytokine Assays were used to measure cytokines (interleukin-6 (IL-6), IL-8, IL-17, IL-12/IL23-P40, tumor necrosis factor-alpha (TNF-ɑ), interferon-gamma (IFN-γ)). Supervised machine learning models were performed using JMP Pro 17.0.0. We compared a primary analysis using nested cross-validation to a split set as sensitivity analysis. Post-hoc, we re-ran the models using only the significant features to obtain the key markers. RESULTS: The models yielded a good Area Under the Curve (AUC) (0.804, Positive Prediction Value (PPV) = 86.95; Negative Prediction Value (NPV) = 54.61) for distinguishing all patients from controls. This implies that a positive test is highly accurate in identifying the patients, but a negative test is inconclusive. Both schizophrenia patients and bipolar patients could each be separated from controls with a good accuracy (SCZ AUC 0.824; BD AUC 0.802). Overall, increased levels of IL-6, TNF-ɑ and PICO and decreased levels of IFN-γ and QUINO were predictive for an individual being classified as a patient. Classification of acute versus stable patients reached a fair AUC of 0.713. The differentiation between schizophrenia and bipolar disorder yielded a poor AUC of 0.627. CONCLUSIONS: This study highlights the potential of using immune-based measures to build predictive classification models in schizophrenia and bipolar disorder, with IL-6, TNF-ɑ, IFN-γ, QUINO and PICO as key candidates. While machine learning models successfully distinguished schizophrenia and bipolar disorder from controls, the challenges in differentiating schizophrenic from bipolar patients likely reflect shared immunological pathways by the both disorders and confounding by a larger state-specific effect. Larger multi-centric studies and multi-domain models are needed to enhance reliability and translation into clinic.

B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Pharmacokinetic Model of Tenofovir and Emtricitabine and Their Intracellular Metabolites in Patients in the ANRS 134-COPHAR 3 Trial Using Dose Records.

Tenofovir (TFV) and emtricitabine (FTC) are part of the recommended highly active antiretroviral therapy (ART). Both molecules show a large interindividual pharmacokinetic (PK) variability. Here, we modeled the concentrations of plasma TFV and FTC and their intracellular metabolites (TFV diphosphate [TFV-DP] and FTC triphosphate [FTC-TP]) collected after 4 and 24 weeks of treatment in 34 patients from the ANRS 134-COPHAR 3 trial. These patients received daily (QD) atazanavir (300 mg), ritonavir (100 mg), and a fixed-dose combination of coformulated TFV disoproxil fumarate (300 mg) and FTC (200 mg). Dosing history was collected using a medication event monitoring system. A three-compartment model with absorption delay (Tlag) was selected to describe the PK of, respectively, TFV/TFV-DP and FTC/FTC-TP. TFV and FTC apparent clearances, 114 L/h (relative standard error [RSE] = 8%) and 18.1 L/h (RSE = 5%), respectively, were found to decrease with age. However, no significant association was found with the polymorphisms ABCC2 rs717620, ABCC4 rs1751034, and ABCB1 rs1045642. The model allows prediction of TFV-DP and FTC-TP concentrations at steady state with alternative regimens.

Intravenous immunoglobulins, cyclosporine, and best supportive care in epidermal necrolysis: Diverse effects on systemic inflammation.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life-threatening cutaneous adverse reactions. There is still no consensus on adjuvant treatments, and little is known about their effects on systemic inflammation in SJS/TEN. Our aim was to characterize the systemic and cutaneous immune profiles of SJS/TEN patients and to investigate whether/how intravenous immunoglobulins (IVIG), cyclosporine A (CSA), and best supportive care only (BSCO) affected the systemic immune signature and clinical outcome (6 week-mortality, complications, hospitalization stay). METHODS: We included 16 patients with SJS/TEN, treated with high-dose IVIG (n = 8), CSA (n = 4) or BSCO (n = 4). Serial serum samples were obtained prior-, 5-7 days, and 21 days after treatment onset. Serum levels of inflammation-/immune response-associated proteins were measured by high-throughput proteomics assay (OLINK) and cytotoxic molecules by ELISA. RNA extracted from skin biopsies collected prior treatment was analyzed by Nanostring. RESULTS: Serum inflammatory profiles in SJS/TEN patients were notably characterized by massive upregulation of type 1 immune response and proinflammatory markers. Surprisingly, there was limited overlap between cutaneous and serum immune profiles. Serial serological measurements of immune response markers showed very diverse dynamics between the different treatment groups. IVIG-treated patients showed completely different dynamics and most significant proteomic changes in an early phase (Day 5-7). In all treatment groups, type 1-/inflammatory response markers were dampened at day 21. Clinically, there were no outcome differences. CONCLUSION: Our study demonstrates that BSCO, CSA, and IVIG have very diverse biological effects on the systemic inflammatory response in SJS/TEN, which may not correlate with clinical outcome differences.

CADPS functional mutations in patients with bipolar disorder increase the sensitivity to stress.

Bipolar disorder is a severe and chronic psychiatric disease resulting from a combination of genetic and environmental risk factors. Here, we identified a significant higher mutation rate in a gene encoding the calcium-dependent activator protein for secretion (CADPS) in 132 individuals with bipolar disorder, when compared to 184 unaffected controls or to 21,070 non-psychiatric and non-Finnish European subjects from the Exome Aggregation Consortium. We found that most of these variants resulted either in a lower abundance or a partial impairment in one of the basic functions of CADPS in regulating neuronal exocytosis, synaptic plasticity and vesicular transporter-dependent uptake of catecholamines. Heterozygous mutant mice for Cadps+/- revealed that a decreased level of CADPS leads to manic-like behaviours, changes in BDNF level and a hypersensitivity to stress. This was consistent with more childhood trauma reported in families with mutation in CADPS, and more specifically in mutated individuals. Furthermore, hyperactivity observed in mutant animals was rescued by the mood-stabilizing drug lithium. Overall, our results suggest that dysfunction in calcium-dependent vesicular exocytosis may increase the sensitivity to environmental stressors enhancing the risk of developing bipolar disorder.

Natural killer cells in first-episode psychosis: an innate immune signature?

Accumulating evidence majorly implicates immune dysfunction in the etiology of psychotic disorders. In particular, altered numbers and functions of natural killer (NK) cells have been described in psychosis, but interpretation has often been confounded by a number of biases, including treatment. Eighty-one first-episode psychosis (FEP) patients who subsequently received a diagnosis of either schizophrenia (SZ; n = 30) or bipolar disorder (BP; n = 31) over a five-year follow-up period were investigated for their NK cell phenotype and compared to 61 healthy controls (HCs). We found a similar proportion of CD3-CD56+ NK cells in FEP patients and HCs. The frequency of NK cells expressing the late cell activation marker HLA-DR was significantly increased in FEP patients compared to HCs, especially in patients with BP (p < 0.0001) and, to a lesser degree, in patients with SZ (p = 0.0128). Interestingly, the expression of the activating NKG2C receptor, known to be associated with infections, was higher in patients with SZ and BP than in HCs (p < 0.0001) and correlated with HLA-DR expression, altogether defining adaptive NK cells. In terms of NK cell function, we observed a suppressed capacity of SZ-derived NK cells to mount cytotoxic responses in the presence of target cells, while NK cells from patients with BP show an inability to produce IFN-γ, a cytokine pivotal to NK function. This study strongly suggests major dysfunction of NK cells in FEP with functioning impairment correlated with psychotic, manic, and depressive symptoms in subsequently diagnosed patients with SZ and BP.

Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures.

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

Cardioprotective Signaling Pathways in Obese Mice Submitted to Regular Exercise: Effect on Oxysterols.

Exercise induces cardioprotection against myocardial infarction, despite obesity, by restoring pro-survival pathways and increasing resistance of mitochondrial permeability transition pore (mPTP) opening at reperfusion. Among the mechanisms involved in the inactivation of these pathways, oxysterols appear interesting. Thus, we investigated the influence of regular exercise on the reperfusion injury salvage kinase (RISK) pathway, oxysterols, and mitochondria, in the absence of ischemia-reperfusion. We also studied 7ß-hydroxycholesterol (7ßOH) concentration (mass spectrometry) in human lean and obese subjects. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise. Exercise significantly increased Akt phosphorylation, whereas 7ßOH concentration was reduced. Moreover, exercise induced the translocation of PKCε from the cytosol to mitochondria. However, exercise did not affect the calcium concentration required to open mPTP in the mitochondria, neither in WT nor in ob/ob animals. Finally, human plasma 7ßOH concentration was consistent with observations made in mice. In conclusion, regular exercise enhanced the RISK pathway by increasing kinase phosphorylation and PKCε translocation and decreasing 7ßOH concentration. This activation needs the combination with stress conditions, i.e., ischemia-reperfusion, in order to inhibit mPTP opening at the onset of reperfusion. The human findings suggest 7ßOH as a candidate marker for evaluating cardiovascular risk factors in obesity.

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation.

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens. 312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman's correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method. We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05). Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.

Impact of renal function on hydroxyurea exposure in sickle-cell disease patients.

AIMS: This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics. METHODS: We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated high-performance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR. RESULTS: The HU PK model was constructed as a 2-compartment model with first-order absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed. CONCLUSION: Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease.

Heritability of fetal hemoglobin, white cell count, and other clinical traits from a sickle cell disease family cohort.

Sickle cell disease (SCD) is the most common monogenic disorder in the world. Notably, there is extensive clinical heterogeneity in SCD that cannot be fully accounted for by known factors, and in particular, the extent to which the phenotypic diversity of SCD can be explained by genetic variation has not been reliably quantified. Here, in a family-based cohort of 449 patients with SCD and 755 relatives, we first show that 5 known modifiers affect 11 adverse outcomes in SCD to varying degrees. We then utilize a restricted maximum likelihood procedure to estimate the heritability of 20 hematologic traits, including fetal hemoglobin (HbF) and white blood cell count (WBC), in the clinically relevant context of inheritance from healthy carriers to SCD patients. We report novel estimations of heritability for HbF at 31.6% (±5.4%) and WBC at 41.2% (±6.8%) in our cohort. Finally, we demonstrate shared genetic bases between HbF, WBC, and other hematologic traits, but surprisingly little overlap between HbF and WBC themselves. In total, our analyses show that HbF and WBC have significant heritable components among individuals with SCD and their relatives, demonstrating the value of using family-based studies to better understand modifiers of SCD.

A Multilevel Functional Study of a SNAP25 At-Risk Variant for Bipolar Disorder and Schizophrenia.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25, rs6039769, that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b/SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala-ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia.SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal-limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Red blood cells free α-haemoglobin pool: a biomarker to monitor the ß-thalassemia intermedia variability. The ALPHAPOOL study.

The severity of ß-thalassaemia (ß-thal) intermedia is mainly correlated to the degree of imbalanced α/non α-globin chain synthesis. The phenotypic diversity of ß-thal depends on this imbalance and reflects all possible combinations of α- and ß-globin genotypes, levels of fetal haemoglobin (HbF) and co-inheritance of other modulating factors. This study aimed to demonstrate the validity of a new surrogate of α/non α-globin biosynthetic ratio by measuring the soluble α-Hb pool in lysed red blood cells. Our results confirm that the α-Hb pool measurement allows a good discrimination between ß-thal intermedia patients, controls and α-thal patients (P < 0·003). Receiver operator characteristic analyses revealed an area under the curve of 0·978 for the α-Hb pool measurement at a threshold of 120 ng free α-Hb/mg of total Hb/ml of haemolysate (ppm) with a sensitivity and specificity of 86% and 100%, respectively, to discriminate between ß-thal and not ß-thal subjects. Significant correlations were observed between the α-Hb pool and biological parameters of ß-thal, the most significant association being observed with red cell hexokinase activity. This study indicates that the α-Hb pool could be a new marker for assistance in diagnostic orientation of ß-thal intermedia patients and may be clinically useful for monitoring the evolution of the disequilibrium of globin synthesis in response to treatments.

Pharmacokinetics of Mycophenolic Acid and Dose Optimization in Children After Intestinal Transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (MPS) is now commonly used in pediatric intestinal transplantation (Tx), but to date, no clear recommendations regarding the dosing regimen have been made in this population. The aim of this study was to determine the MMF/MPS dosage required to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) for mycophenolic acid (MPA) greater than 30 mg·h·L in children after intestinal transplantation. METHODS: A pharmacokinetic study was conducted in 8 children (median, 9.4 years; range, 0.75-15.8 years) at a median time of 113 months (range, 1.5-160 months) after intestinal transplantation. RESULTS: MMF was initially introduced at a low median starting dose of 687 mg·m·d (range, 310-1414 mg·m·d). One of the 3 patients who received MPS and 2 of the 6 patients who received MMF had an MPA AUC0-12 value below 30 mg.h.L. The median MMF dosage had to be increased by 91% (1319 mg·m·d versus 687 mg·m·d) to reach AUC0-12 values above the defined target level of 30 mg·h·L. CONCLUSIONS: When used in combination with tacrolimus and steroids, an initial MMF dose of 600 mg/m twice a day would be recommended to children after intestinal transplantation to achieve MPA exposure similar to those observed in adults and children after the transplantation of other organs. Further studies are required to recommend a suitable dosage for pediatric intestinal transplant recipients who receive MPA.

A Study of Hypermethylated Circulating Tumor DNA as a Universal Colorectal Cancer Biomarker.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a good candidate for tracking tumor dynamics in different cancer types, potentially avoiding repeated tumor biopsies. Many different genes can be mutated within a tumor, complicating procedures for tumor monitoring, even with highly sensitive next-generation sequencing (NGS) strategies. Droplet-based digital PCR (dPCR) is a highly sensitive and quantitative procedure, allowing detection of very low amounts of circulating tumor genetic material, but can be limited in the total number of target loci monitored. METHODS: We analyzed hypermethylation of 3 genes, by use of droplet-based dPCR in different stages of colorectal cancer (CRC), to identify universal markers for tumor follow-up. RESULTS: Hypermethylation of WIF1 (WNT inhibitory factor 1) and NPY (neuropeptide Y) genes was significantly higher in tumor tissue compared to normal tissue, independently of tumor stage. All tumor tissues appeared positive for one of the 2 markers. Methylated ctDNA (MetctDNA) was detected in 80% of metastatic CRC and 45% of localized CRC. For samples with detectable mutations in ctDNA, MetctDNA and mutant ctDNA (MutctDNA) fractions were correlated. During follow-up of different stage CRC patients, MetctDNA changes allowed monitoring of tumor evolution. CONCLUSIONS: These results indicate that MetctDNA could be used as a universal surrogate marker for tumor follow-up in CRC patients, and monitoring MetctDNA by droplet-based dPCR could avoid the need for monitoring mutations.

A Brief Period of Hypothermia Induced by Total Liquid Ventilation Decreases End-Organ Damage and Multiorgan Failure Induced by Aortic Cross-Clamping.

BACKGROUND: In animal models, whole-body cooling reduces end-organ injury after cardiac arrest and other hypoperfusion states. The benefits of cooling in humans, however, are uncertain, possibly because detrimental effects of prolonged cooling may offset any potential benefit. Total liquid ventilation (TLV) provides both ultrafast cooling and rewarming. In previous reports, ultrafast cooling with TLV potently reduced neurological injury after experimental cardiac arrest in animals. We hypothesized that a brief period of rapid cooling and rewarming via TLV could also mitigate multiorgan failure (MOF) after ischemia-reperfusion induced by aortic cross-clamping. METHODS: Anesthetized rabbits were submitted to 30 minutes of supraceliac aortic cross-clamping followed by 300 minutes of reperfusion. They were allocated either to a normothermic procedure with conventional ventilation (control group) or to hypothermic TLV (33°C) before, during, and after cross-clamping (pre-clamp, per-clamp, and post-clamp groups, respectively). In all TLV groups, hypothermia was maintained for 75 minutes and switched to a rewarming mode before resumption to conventional mechanical ventilation. End points included cardiovascular, renal, liver, and inflammatory parameters measured 300 minutes after reperfusion. RESULTS: In the normothermic (control) group, ischemia-reperfusion injury produced evidence of MOF including severe vasoplegia, low cardiac output, acute kidney injury, and liver failure. In the TLV group, we observed gradual improvements in cardiac output in post-clamp, per-clamp, and pre-clamp groups versus control (53 ± 8, 64 ± 12, and 90 ± 24 vs 36 ± 23 mL/min/kg after 300 minutes of reperfusion, respectively). Liver biomarker levels were also lower in pre-clamp and per-clamp groups versus control. However, acute kidney injury was prevented in pre-clamp, and to a limited extent in per-clamp groups, but not in the post-clamp group. For instance, creatinine clearance was 4.8 ± 3.1 and 0.5 ± 0.6 mL/kg/min at the end of the follow-up in pre-clamp versus control animals (P = .0004). Histological examinations of the heart, kidney, liver, and jejunum in TLV and control groups also demonstrated reduced injury with TLV. CONCLUSIONS: A brief period of ultrafast cooling with TLV followed by rapid rewarming attenuated biochemical and histological markers of MOF after aortic cross-clamping. Cardiovascular and liver dysfunctions were limited by a brief period of hypothermic TLV, even when started after reperfusion. Conversely, acute kidney injury was limited only when hypothermia was started before reperfusion. Further work is needed to determine the clinical significance of our results and to identify the optimal duration and timing of TLV-induced hypothermia for end-organ protection in hypoperfusion states.

Pharmacokinetic study of raltegravir in HIV-infected patients with end-stage liver disease: the LIVERAL-ANRS 148 study.

BACKGROUND: The end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hépatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2). METHODS: All patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Ten patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study. CONCLUSIONS: The results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.

[Bridging the gap between the first year of the Health Sciences bachelor's degree and the second year at Ifsi]. / Passerelle entre la première année de licence Sciences pour la santé et la deuxième année d'Ifsi.

Université Paris-Est Créteil offers a gateway to the second year of a nursing training institute after the first year of a Health Sciences degree. Eight students entered the second year of nursing training institute via this gateway. At the end of session 1, seven of them were able to move on to the third year of nursing training institute. The results are encouraging, both in terms of theoretical knowledge acquisition and qualitative feedback from students.

Gastric microbiota in patients with gastric MALT lymphoma according to Helicobacter pylori infection.

BACKGROUND: Gastric Mucosa Associated Lymphoid Tissue lymphoma (GML) development is triggered by Helicobacter pylori (H. pylori) infection. Little is known about the impact of H. pylori infection on gastric microbiota. METHODS: The gastric microbiota was retrospectively investigated using 16S rRNA gene sequencing in 32 patients with untreated GML (10 H. pylori-positive and 22 H. pylori-negative), 23 with remitted and 18 refractory GML and 35 controls. Differences in microbial diversity, bacterial composition and taxonomic repartition were assessed. RESULTS: There was no change in diversity and bacterial composition between GML and control patients taking into account H. pylori status. Differential taxa analysis identified specific changes associated with H. pylori-negative GML: the abundances of Actinobacillus, Lactobacillus and Chryseobacterium were increased while the abundances of Veillonella, Atopobium, Leptotrichia, Catonella, Filifactor and Escherichia_Shigella were increased in control patients. In patients with remitted GML, the genera Haemophilus and Moraxella were significantly more abundant than in refractory patients, while Atopobium and Actinomyces were significantly more abundant in refractory patients. CONCLUSION: Detailed analysis of the gastric microbiota revealed significant changes in the bacterial composition of the gastric mucosa in patients with GML that may have a role in gastric lymphomagenesis but not any new pathobionts.