CD138 as a Specific CSF Biomarker of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The aim of this study was to identify novel biomarkers for multiple sclerosis (MS) diagnosis and prognosis, addressing the critical need for specific and prognostically valuable markers in the field. METHODS: We conducted an extensive proteomic investigation, combining analysis of (1) CSF proteome from symptomatic controls, fast and slow converters after clinically isolated syndromes, and patients with relapsing-remitting MS (n = 10 per group) using label-free quantitative proteomics and (2) oligodendrocyte secretome changes under proinflammatory or proapoptotic conditions using stable isotope labeling by amino acids in cell culture. Proteins exhibiting differential abundance in both proteomic analyses were combined with other putative MS biomarkers, yielding a comprehensive list of 87 proteins that underwent quantification through parallel reaction monitoring (PRM) in a novel cohort, comprising symptomatic controls, inflammatory neurologic disease controls, and patients with MS at various disease stages (n = 10 per group). The 11 proteins that passed this qualification step were subjected to a new PRM assay within an expanded cohort comprising 158 patients with either MS at different disease stages or other inflammatory or noninflammatory neurologic disease controls. RESULTS: This study unveiled a promising biomarker signature for MS, including previously established candidates, such as chitinase 3-like protein 1, chitinase 3-like protein 2, chitotriosidase, immunoglobulin kappa chain region C, neutrophil gelatinase-associated lipocalin, and CD27. In addition, we identified novel markers, namely cat eye syndrome critical region protein 1 (adenosine deaminase 2, a therapeutic target in multiple sclerosis) and syndecan-1, a proteoglycan, also known as plasma cell surface marker CD138 and acting as chitinase 3-like protein 1 receptor implicated in inflammation and cancer signaling. CD138 exhibited good diagnostic accuracy in distinguishing MS from inflammatory neurologic disorders (area under the curve [AUC] = 0.85, CI 0.75-0.95). CD138 immunostaining was also observed in the brains of patients with MS and cultured oligodendrocyte precursor cells but was absent in astrocytes. DISCUSSION: These findings identify CD138 as a specific CSF biomarker for MS and suggest the selective activation of the chitinase 3-like protein 1/CD138 pathway within the oligodendrocyte lineage in MS. They offer promising prospects for improving MS diagnosis and prognosis by providing much-needed specificity and clinical utility. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CD138 distinguishes multiple sclerosis from other inflammatory neurologic disorders with an AUC of 0.85 (95% CI 0.75-0.95).

A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Clinical predictive factors and trajectories of suicidal remission over 6 weeks following intravenous ketamine for suicidal ideation.

BACKGROUND: Ketamine is efficient for short-term reduction of suicidal ideas. Predictive factors and outcome trajectories are poorly characterized. METHODS: Secondary analyses were conducted on the KETIS study (Abbar et al. BMJ 2022): 156 suicidal patients were randomized to two intravenous infusions of racemic ketamine (0.5 mg/kg) or placebo. Response or remission was assessed over six weeks based on the Beck Scale for Suicidal Ideation (SSI). We calculated i) predictive values of 12 baseline variables on remission ii) outcome courses, and iii) positive (PPV) and negative predictive values. RESULTS: In multivariate analyses, bipolar disorder, lower patient-rated suicidal ideas, and higher physical pain were predictive of suicidal remission at day 3. No clinical factor predicted remission at week 6. Twenty and 24 different clinical courses were identified in early (day 3) and later (week 6) follow-up, respectively, including around 40 % sustained remission, 50 % fluctuating course and 10 % no response. Suicidal remissions at day 1 and day 3 were highly predictive of remissions at day 3 and week 6 (PPV = 96.8 and 92.6 %). LIMITATIONS: SSI may not be adapted for rapid variations and repeated measures. CONCLUSIONS: Clinical factors were poorly predictive of remission. Fluctuations in suicidal ideas were frequent, even after ketamine (although less than placebo), necessitating vigilance and multimodal care. Remission at day 1 after one infusion was highly predictive of future remission. The benefits of a second infusion will have to be tested.

Violence against nurses in the emergency department: an observational study.

OBJECTIVE: This study aimed to evaluate the number and risk factors of violent events encountered in the emergency department. An observation grid was developed following interviews with emergency department staff to target the most pertinent information to collect in a prospective study design. DESIGN: Observational study. SETTING: Emergency department of a tertiary hospital in France. OUTCOME MEASURES: Number of violent events occurring during a single shift, recorded over 6 months by two observers. Information collected included time and date of incident; number of male/female staff; number of patients and accompaniers present in the service and the waiting room and length of staff debriefing. Perpetrator, victim and patient information were collected. Victims were followed-up 72 hours later. RESULTS: Eighty-two periods were observed between November 2015 and April 2016 recording 35 violent incidents affecting 37 perpetrators and 48 victims, equally distributed over the days of the week and months of the year. The median interval until violence was 0 [0-96] min from entry. Eight (23%) events were officially reported, with two (6%) resulting in charges being pressed. No risk factors were significantly associated with violent incidents in multivariate analysis, although there was a tendency towards significance for fewer senior female doctors present (p=0.0787) and a resulting longer debriefing session (p=0.0712). CONCLUSIONS: We confirm the high rate of violence in the emergency department and poor level of official reporting. Strategies should be implemented to anticipate and reduce incidence and encourage reporting by affected staff. TRIAL REGISTRATION NUMBER: NCT02116439.

Neurofilament Light Chain Levels Are Predictive of Clinical Conversion in Radiologically Isolated Syndrome.

BACKGROUND AND OBJECTIVES: To evaluate the predictive value of serum neurofilament light chain (sNfL) and CSF NfL (cNfL) in patients with radiologically isolated syndrome (RIS) for evidence of disease activity (EDA) and clinical conversion (CC). METHODS: sNfL and cNfL were measured at RIS diagnosis by single-molecule array (Simoa). The risk of EDA and CC according to sNfL and cNfL was evaluated using the Kaplan-Meier analysis and multivariate Cox regression models including age, spinal cord (SC) or infratentorial lesions, oligoclonal bands, CSF chitinase 3-like protein 1, and CSF white blood cells. RESULTS: Sixty-one patients with RIS were included. At diagnosis, sNfL and cNfL were correlated (Spearman r = 0.78, p < 0.001). During follow-up, 47 patients with RIS showed EDA and 36 patients showed CC (median time 12.6 months, 1-86). When compared with low levels, medium and high cNfL (>260 pg/mL) and sNfL (>5.0 pg/mL) levels were predictive of EDA (log rank, p < 0.01 and p = 0.02, respectively). Medium-high cNfL levels were predictive of CC (log rank, p < 0.01). In Cox regression models, cNfL and sNfL were independent factors of EDA, while SC lesions, cNfL, and sNfL were independent factors of CC. DISCUSSION: cNfL >260 pg/mL and sNfL >5.0 pg/mL at diagnosis are independent predictive factors of EDA and CC in RIS. Although cNfL predicts disease activity better, sNfL is more accessible than cNfL and can be considered when a lumbar puncture is not performed. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in people with radiologic isolated syndrome (RIS), initial serum and CSF NfL levels are associated with subsequent evidence of disease activity or clinical conversion.

A Pilot Study Assessing a Closed-Loop System for Goal-Directed Fluid Therapy in Abdominal Surgery Patients.

Background: This prospective multicentre pilot study of patients scheduled for elective major abdominal surgery aimed to validate the fluid challenge (FC) proposed by the closed-loop (CL) system via anaesthesiologist assessment. Methods: This was a phase II trial consisting of two inclusion stages (SIMON method). Each FC (250 mL saline solution for 10 min) proposed by the CL was systematically validated by the anaesthesiologist who could either confirm or refuse the FC or give FC without the CL system. A ≥ 95% agreement between the CL and the anaesthesiologist was considered acceptable. Results: The study was interrupted after interim analysis of the first 19 patients (10 men, median age = 61 years, median body mass index = 26 kg/m2). The anaesthesiologists accepted 165/205 (80%) of fluid boluses proposed by the CL. Median cardiac index (CI) was 2.9 (interquartile: IQ (2.7; 3.4) L/min/m2) and the median coefficient of variation (CV) for CI was 13% (10; 17). Fifteen out of nineteen patients (79%) had a mean CI > 2.5 L/min/m2 or spent > 85% surgery time with pulse pressure variation < 13%. No adverse events related to the CL were reported. Conclusion: In this study of patients scheduled for elective major abdominal surgery, the agreement between CL and anaesthesiologist for giving fluid challenge was 80%, suggesting that CL cannot replace the physician but could help in decision making.

Sutureless socket technique after removal of third molars: a multicentric, open, randomized controlled trial.

BACKGROUND: Although wisdom-tooth extraction is a routine intervention, the postoperative period remains marked by local inflammation classically manifesting as pain, edema and trismus. Furthermore, there is no consensus on the best operative techniques, particularly for the mucosal closure stage on impacted mandibular wisdom teeth. METHODS: This parallel, randomized, non-blinded study compared pain following removal of impacted third molars, with and without sutures. Patients were electronically allocated 1:1 to extraction with versus without sutures. Patients ≥ 14 years' old scheduled for extraction of four impacted wisdom teeth under general anesthesia at three French hospitals were eligible for inclusion. Exclusion criteria included taking antiplatelet agents or anticoagulants, coagulation disorders or immunosuppression, and planned orofacial surgical procedures or emergency pain/infection. The primary objective was pain evaluated by Visual Analogue Scale on Day 3. Secondary outcomes were edema, trismus, healing, complications, painkiller consumption and quality of life on Day 3 and 31. RESULTS: Between June 2016 and November 2018, 100 patients were randomized. Finally, 44 patients in the Suture group and 50 patients in the Without Suture group were analyzed. Mean age was 16.5 years and 66.6% of patients were female. After adjustment on center, age and smoking, no statistical difference was seen between groups for pain on Day 3 (p = 0.904). No differences were seen for swelling, trismus, consumption of painkillers, healing, complications or quality of life. Smokers had a 3.65 times higher complications rate (p = 0.0244). CONCLUSIONS: Sutureless removal of third molars is thus a reliable technique without negative consequence on outcomes, and allows shorter operating time. Smoking is a risk factor for postoperative complications. Trial registration www. CLINICALTRIALS: gov (NCT02583997), registered 22/10/2015.

Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor.

OBJECTIVE: To explore the regulatory role of soluble CD146 (sCD146) and its interaction with galectin-1 (Gal1) in placenta-mediated complications of pregnancy. DESIGN: Prospective pilot and experimental studies. SETTING: University-affiliated hospital and academic research laboratory. PATIENT(S): One hundred fifteen women divided into three groups: 30 healthy, nonpregnant women, 50 women with normal pregnancies, and 35 with placenta-mediated pregnancy complications. INTERVENTION(S): Wound-healing experiments were conducted to study trophoblast migration. MAIN OUTCOME MEASURE(S): Quantification of sCD146 and Gal1 by enzyme-linked immunosorbent assay. Analysis of trophoblast migration by wound closure. RESULT(S): Concomitant detection of sCD146 and Gal1 showed lower sCD146 and higher Gal1 concentrations in women with normal pregnancies compared with nonpregnant women. In addition, follow-up of these women revealed a decrease in sCD146 associated with an increase in Gal1 throughout pregnancy. In contrast, in women with preeclampsia, we found significantly higher sCD146 concentrations compared with women with normal pregnancies and no modification of Gal1. We emphasize the opposing effects of sCD146 and Gal, since, unlike Gal1, sCD146 inhibits trophoblast migration. Moreover, the migratory effect of Gal1 was abrogated with the use of an anti-CD146 blocking antibody or the use of small interfering RNA to silence VEGFR2 expression. This suggests that trophoblast migration is mediated though the interaction of Gal1 with CD146, further activating the VEGFR2 signaling pathway. Significantly, sCD146 blocked the migratory effects of Gal1 on trophoblasts and inhibited its secretion, suggesting that sCD146 acts as a ligand trap. CONCLUSION(S): Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01736826.

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial.

OBJECTIVE: To confirm the rapid onset anti-suicidal benefits of ketamine in the short term and at six weeks, overall and according to diagnostic group. DESIGN: Prospective, double blind, superiority, randomised placebo controlled trial. SETTING: Seven French teaching hospitals between 13 April 2015 and 12 March 2019. ELIGIBILITY CRITERIA FOR PARTICIPANTS: Aged 18 or older with current suicidal ideation, admitted to hospital voluntarily. Exclusion criteria included a history of schizophrenia or other psychotic disorders, substance dependence, and contraindications for ketamine. PARTICIPANTS: 156 participants were recruited and randomised to placebo (n=83) or ketamine (n=73), stratified by centre and diagnosis: bipolar, depressive, or other disorders. INTERVENTION: Two 40 minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) were administered at baseline and 24 hours, in addition to usual treatment. MAIN OUTCOME MEASURES: The primary outcome was the rate of patients in full suicidal remission at day 3, according to the scale for suicidal ideation total score ≤3. Analyses were conducted on an intention-to-treat basis. RESULTS: More participants receiving ketamine reached full remission of suicidal ideas at day 3 than those receiving placebo: 46 (63.0%) of 83 participants in the ketamine arm and 25 (31.6%) of 73 in the placebo arm (odds ratio 3.7 (95% confidence interval 1.9 to 7.3), P<0.001). This effect differed according to the diagnosis (treatment: P<0.001; interaction: P=0.02): bipolar (odds ratio 14.1 (95% confidence interval 3.0 to 92.2), P<0.001), depressive (1.3 (0.3 to 5.2), P=0.6), or other disorders (3.7 (0.9 to 17.3, P=0.07)). Side effects were limited. No manic or psychotic symptom was seen. Moreover, a mediating effect of mental pain was found. At week 6, remission in the ketamine arm remained high, although non-significantly versus placebo (69.5% v 56.3%; odds ratio 0.8 (95% confidence interval 0.3 to 2.5), P=0.7). CONCLUSIONS: The findings indicate that ketamine is rapid, safe in the short term, and has persistent benefits for acute care in suicidal patients. Comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain might explain the anti-suicidal effects of ketamine. TRIAL REGISTRATION: ClinicalTrials.gov NCT02299440.

Direct Determination rather than Oscillometric Estimation of Systolic Blood Pressure in Patients with Severe Chronic Kidney Disease.

INTRODUCTION: Although arterial hypertension is a major concern in patients with chronic kidney disease (CKD), obtaining accurate systolic blood pressure (SBP) measurement is challenging in this population for whom automatic oscillometric devices may yield erroneous results. METHODS: This cross-sectional study was conducted in 89 patients with stages 4, 5, and 5D CKD, for whom we compared SBP values obtained by the recently described systolic foot-to-apex time interval (SFATI) technique which provides direct SBP determination, the standard technique (Korotkoff sounds), and oscillometry. We investigated the effects of age, sex, diabetes, CKD stage, and pulse pressure to explain measurement errors defined as biases or misclassification relative to the SBP thresholds of 110-130-mm Hg. RESULTS: All 3 techniques showed satisfactory reproducibility for SBP measurement (CCC > 0.84 and >0.91, respectively, in dialyzed and nondialyzed patients). The mean ± SD from SBP as determined via Korotkoff sounds was 1.7 ± 4.6 mm Hg for SFATI (CCC = 0.98) and 5.9 ± 9.3 mm Hg for oscillometry (CCC = 0.88). Referring to the 110-130-mm Hg SBP range outside which treatment prescription or adaptation is recommended for CKD patients, SFATI underestimated SBP in 3 patients and overestimated it in 1, whereas oscillometry underestimated SBP in 12 patients and overestimated it in 3. Higher pulse pressure was the main explanatory factor for measurement and classification errors. DISCUSSION/CONCLUSION: SFATI provides accurate SBP measurements in patients with severe CKD and paves the way for the standardization of automated noninvasive blood pressure measurement devices. Before prescribing or adjusting antihypertensive therapy, physicians should be aware of the risk of misclassification when using oscillometry.

Acute effects of graduated and progressive compression stockings on leg vein cross-sectional area and viscoelasticity in patients with chronic venous disease.

OBJECTIVE: To determine the effects of graduated and progressive elastic compression stockings (ECS) on postural diameter changes and viscoelasticity of leg veins in healthy controls and in limbs with chronic venous disease (CVD). METHODS: In 57 patients whose legs presented with C1s, C3, or C5 CEAP classes of chronic venous disease and were treated primarily with compression, and 54 healthy controls matched for age and body mass index, we recorded interface pressures (IFP) at 9 reference leg levels. Cross-sectional areas of the small saphenous vein (SSV) and a deep calf vein (DCV) were measured with B-mode ultrasound with patients supine and standing, recording the force (PF) applied on the ultrasound probe to collapse each vein with progressive ECS, and with and without graduated 15 to 20 mm Hg and 20 to 36 mm Hg elastic stockings. We chose these veins because they were free of detectable lesion and could be investigated at the same level (mid-height of the calf), and their compression by the ultrasound probe was not hampered by bone structures. RESULTS: IFP decreased from ankle to knee with graduated 15 to 20 and 20 to 36 mm Hg, but increased with progressive ECS, and were 8.4 to 13.8 mm Hg lower for C1s than for control or C3 and C5 limbs. Without ECS, the SSV median [lower-upper quartile] cross-sectional area was 4.9 mm2 [3.6-7.1 mm2] and 7.1 mm2 [3.0-9.9 mm2] in C3 and C5 limbs versus 2.9 mm2 [1.8-5.2 mm2] and 3.8 mm2 [2.1-5.4 mm2] in controls (P < .01), respectively, while supine and standing. It remained greater in C3 and C5 than in C1s and control limbs wearing any ESC. Wearing compression, especially with progressive ECS, decreased the SSV and DCV cross-sectional area only with patients supine, thus decreasing postural changes, which remained highly diverse between individuals. The SSV cross-sectional area versus PF function traced a hysteresis loop of which the area, related to viscosity, was greater in C3 and C5 limbs than controls, even with graduated 15 to 20 or 20 to 36 mm Hg ECS. Progressive ECS decreased vein viscosity in the supine position, whereas 20 to 36 mm Hg and progressive ECS increased distensibility in the standing position. CONCLUSIONS: ECS decrease the cross-sectional area of SSV and DCV with patients supine, but not upright. C1s limbs show distinctive features, especially regarding IFP. Graduated 20 to 36 mm Hg and progressive stockings lower viscosity and increase distensibility of the SSV.

Vital NETosis vs. suicidal NETosis during normal pregnancy and preeclampsia.

Background: NETosis occurs in the context of infection or inflammation and results in the expulsion of decondensed DNA filaments called NETs (Neutrophil Extracellular Traps) into the extracellular environment. NETosis activates coagulation and contributes to the thrombotic risk of inflammatory diseases. To date, two mechanisms of NETosis have been identified: suicidal NETosis, in which neutrophils die after expelling the filaments; and vital NETosis, in which expulsion appears without altering the membrane. Human pregnancy is associated with a mild pro-inflammatory state, which is increased in the event of complications such as preeclampsia (PE). NETosis has been observed in these situations, but the mechanism of its production has not yet been studied. The aim of our study was to evaluate the balance of vital vs. suicidal NETosis in normal pregnancy and in PE. Patients/Methods: Neutrophils from healthy volunteers were stimulated with plasma from normal pregnancies (n = 13) and from women developing preeclampsia (n = 13). Immunofluorescent labelling was performed to determine the percentages and origin of NETs in both groups. Inhibition with suicidal or vital NETosis inhibitors was also performed to validate our results. Results: We found a significant increase in NETs in women with PE compared to women with normal pregnancies. We showed that vital and non-vital NETosis are present in normal and preeclamptic pregnancies. We demonstrated that the higher proportion of NETs observed in PE was due to non-vital NETosis whose main component is represented by suicidal NETosis. Discussion: These results suggest the important part of non-vital NETosis in the pathophysiology of PE.

Pressure ulcers microbiota dynamics and wound evolution.

Bacterial species and their role in delaying the healing of pressure ulcers (PU) in spinal cord injury (SCI) patients have not been well described. This pilot study aimed to characterise the evolution of the cutaneous microbiota of PU in SCI cohort. Twenty-four patients with SCI from a French neurological rehabilitation centre were prospectively included. PU tissue biopsies were performed at baseline (D0) and 28 days (D28) and analysed using 16S rRNA gene-based sequencing analysis of the V3-V4 region. At D0, if the overall relative abundance of genus highlighted a large proportion of Staphylococcus, Anaerococcus and Finegoldia had a significantly higher relative abundance in wounds that stagnated or worsened in comparison with those improved at D28 (3.74% vs 0.05%; p = 0.015 and 11.02% versus 0.16%; p = 0.023, respectively). At D28, Proteus and Morganella genera were only present in stagnated or worsened wounds with respectively 0.02% (p = 0.003) and 0.01% (p = 0.02). Moreover, Proteus, Morganella, Anaerococcus and Peptoniphilus were associated within the same cluster, co-isolated from biopsies that had a poor evolution. This pathogroup could be a marker of wound degradation and Proteus could represent a promising target in PU management.

A prospective cohort study of postpartum glucose metabolic disorders in early versus standard diagnosed gestational diabetes mellitus.

Early gestational diabetes mellitus (eGDM) is diagnosed when fasting plasma glucose before 24 weeks of gestation (WG) is ≥ 5.1 mmol/L, whilst standard GDM is diagnosed between 24 and 28 WG by oral glucose tolerance test (OGTT). eGDM seems to have worse obstetric outcomes than standard GDM. We compared the rates of postpartum glucose metabolism disorders between women with early versus standard GDM in this prospective study on women with GDM from three university hospitals between 2014 and 2016. Patients were included if they were < 24 WG with at least one risk factor for GDM and excluded if they had type 2 diabetes. Patients were assigned to Group 1 (G1) for eGDM according to IADPSG: fasting blood glucose < 24 WG between 5.1 and 7 mmol/L. Group 2 (G2) consisted of patients presenting a standard GDM at 24-28 WG on OGTT results according to IADPSG: T0 ≥ 5.1 mmol/L or T60 ≥ 10.0 mmol g/L or T120 ≥ 8.5 mmol/L. The primary outcome was postpartum OGTT result. Five hundred patients were analysed, with 273 patients undergoing OGTT at 4-18 weeks postpartum: 192 patients in G1 (early) and 81 in G2 (standard). Patients in G1 experienced more insulin therapy during pregnancy than G2 (52.2% versus 32.5%, p < 0.001), but no patients were taking insulin postpartum in either group. G1 patients experienced less preterm labour (2.6% versus 9.1%, p = 0.043), more induced deliveries (38% versus 25%, p = 0.049) and reduced foetal complications (29.2% versus 42.0%, p = 0.048). There was no significant difference in the rate of postpartum glucose metabolism disorders (type 2 diabetes, impaired glucose tolerance, impaired fasting glycaemia) between groups: 48/192 (25%) in G1 and 17/81 (21%) in G2, p = 0.58. Thus the frequency of early postpartum glucose metabolism disorders is high, without difference between eGDM and standard GDM. This supports measurement of fasting plasma glucose before 24 WG and the threshold of 5.1 mmol/L seems appropriate until verification in future studies.Trial registration: NCT01839448, ClinicalTrials.gov on 22/04/2013.

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes.

NETosis is an innate immune response occurring after infection or inflammation: activated neutrophils expel decondensed DNA in complex with histones into the extracellular environment in a controlled manner. It activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild proinflammatory state characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with an increased thrombotic risk. This aberrant activation leads to an increased release of nucleosomes in the blood flow. The aim of our study was to initially quantify nucleosome-bound histones in normal pregnancy and in placenta-mediated complication counterpart. We analyzed the role of histones on extravillous trophoblast function. Circulating nucleosome-bound histones H3 (Nu.QH3.1, Nu.QH3PanCit, Nu.QH3K27me3) and H4 (Nu.QH4K16Ac) were increased in complicated pregnancies. In vitro using the extravillous cell line HTR-8/SVNeo, we observed that free recombinant H2B, H3, and H4 inhibited migration in wound healing assay, but only H3 also blocked invasion in Matrigel-coated Transwell experiments. H3 and H4 also induced apoptosis, whereas H2B did not. Finally, the negative effects of H3 on invasion and apoptosis could be restored with enoxaparin, a low-molecular-weight heparin (LMWH), but not with aspirin. Different circulating nucleosome-bound histones are increased in complicated pregnancy and this would affect migration, invasion, and induce apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, with an effect of LMWH on both.

Prospective ultrasonographic follow-up of transvaginal lightweight meshes: a 1-year multicenter study.

INTRODUCTION AND HYPOTHESIS: The use of new lightweight meshes in pelvic organ prolapse (POP) surgery may reduce complications related to mesh retraction (chronic pain, dyspareunia, and mesh exposure). The aim of this study was to investigate changes in the area and position of Uphold Lite™ mesh 6 weeks and 12 months after anterior and/or apical prolapse repair. METHODS: This observational prospective multicenter study included patients who had undergone transvaginal surgery for symptomatic POP-Q stage ≥ II anterior and/or apical compartment prolapse with placement of Uphold Lite mesh. The dimensions and position of the mesh were evaluated at 6 weeks and 12 months by ultrasonography. Correlations between ultrasonographic mesh characteristics and POP recurrence were analyzed. RESULTS: Fifty evaluable women with an average age of 66.8 years were included. No statistically significant difference in mesh area was found between week 6 and month 12 postoperatively, either at rest (1746.92 vs. 1574.48 mm2; p = 0.15) or on Valsalva (1568.81 vs. 1542.98 mm2; p = 0.65). The ROC-AUC of the distance between the mesh and the bladder neck (M-BN) at 6 weeks for predicting cystocele recurrence at 12 months was 0.764 (95% CI 0.573-0.955) at rest and 0.724 (95% CI 0.533-0.916) on Valsalva. An M-BN distance > 12.5 mm could predict cystocele recurrence at month 12 with a sensitivity of 80% and a specificity of 69%. CONCLUSIONS: Ultrasonographic measurements of the Uphold Lite™ mesh appear to remain stable between 6 weeks and 12 months postoperatively. M-BN distance correlates with cystocele recurrence. These results appear to confirm the value of ultrasound in mesh evaluation.

End Colostomy With or Without Mesh to Prevent a Parastomal Hernia (GRECCAR 7): A Prospective, Randomized, Double Blinded, Multicentre Trial.

OBJECTIVE: To evaluate whether systematic mesh implantation upon primary colostomy creation was effective to prevent PSH. SUMMARY OF BACKGROUND DATA: Previous randomized trials on prevention of PSH by mesh placement have shown contradictory results. METHODS: This was a prospective, randomized controlled trial in 18 hospitals in France on patients aged ≥18 receiving a first colostomy for an indication other than infection. Participants were randomized by blocks of random size, stratified by center in a 1:1 ratio to colostomy with or without a synthetic, lightweight monofilament mesh. Patients and outcome assessors were blinded to patient group. The primary endpoint was clinically diagnosed PSH rate at 24 months of the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01380860. RESULTS: From November 2012 to October 2016, 200 patients were enrolled. Finally, 65 patients remained in the no mesh group (Group A) and 70 in the mesh group (Group B) at 24 months with the most common reason for drop-out being death (n = 41). At 24 months, PSH was clinically detected in 28 patients (28%) in Group A and 30 (31%) in Group B [P = 0.77, odds ratio = 1.15 95% confidence interval = (0.62;2.13)]. Stoma-related complications were reported in 32 Group A patients and 37 Group B patients, but no mesh infections. There were no deaths related to mesh insertion. CONCLUSION: We failed to show efficiency of a prophylactic mesh on PSH rate. Placement of a mesh in a retro-muscular position with a central incision to allow colon passage cannot be recommended to prevent PSH. Optimization of mesh location and reinforcement material should be performed.

Noninvasive measurement of venous wall deformation induced by changes in transmural pressure shows altered viscoelasticity in patients with chronic venous disease.

OBJECTIVE: The noninvasive measurement of venous wall deformation induced by changes in transmural pressure could allow for the assessment of viscoelasticity and differentiating normal from diseased veins. METHODS: In 57 patients with limbs in the C1s (telangiectasia or reticular veins and symptoms), C3 (edema), or C5 (healed venous ulcer) CEAP (clinical, etiologic, anatomic, pathophysiologic) category of chronic venous disease and 54 matched healthy controls, we measured the changes in the cross-sectional area of the small saphenous vein and a deep calf vein in the supine and standing positions and under compression with an ultrasound probe using ultrasonography. RESULTS: The small saphenous vein, but not the deep calf vein, cross-sectional area was smaller in the limbs of the controls than in the limbs with C3 or C5 disease but was not different from that in C1s limbs. When changing from the supine to the standing position, a greater force was required to collapse the leg veins. Their cross-sectional area increased in most subjects but decreased in 31.5% of them as for the small saphenous veins and 40.5% for the deep calf vein. The small saphenous vein area vs compression force function followed a hysteresis loop, demonstrating viscoelastic features. Its area, which represents the viscosity component, was greater (P < .001) in the pooled C3 and C5 limbs (median, 2.40 N⋅mm2; lower quartile [Q1] to upper quartile [Q3], 1.65-3.88 N⋅mm2) than in the controls (median, 1.24 N⋅mm2; Q1-Q3, 0.64-2.14 N⋅mm2) and C1s limbs (median, 1.15 N⋅mm2; Q1-Q3, 0.71-2.97 N⋅mm2). The area increased (P < .0001) in the standing position in all groups. CONCLUSIONS: Postural changes in the cross-sectional area of the leg veins were highly diverse among patients with chronic venous disease and among healthy subjects and appear unsuitable for pathophysiologic characterization. In contrast, small saphenous vein viscoelasticity increased consistently in the standing position and the viscosity was greater in limbs with C3 and C5 CEAP disease than in controls.

Placenta-mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes.

BACKGROUND: Placenta-mediated pregnancy complications generate short- and long-term adverse medical outcomes for both the mother and the fetus. Nucleosomes and free DNA (fDNA) have been described in patients suffering from a wide range of inflammatory conditions. OBJECTIVE: The objective of our study was to compare nucleosomes and fDNA circulating levels during pregnancy and particularly in women developing a placenta-mediated complication according to the subtype (preeclampsia or intrauterine growth restriction) (NCT01736826). PATIENTS/METHODS: A total of 115 women were prospectively included in the study across three groups: 30 healthy non-pregnant women, 50 with normal pregnancy, and 35 with a complicated pregnancy. Blood samples were taken up to every 4 weeks for several women with normal pregnancy and nucleosomes and fDNA were quantified using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. RESULTS: We show that nucleosomes and fDNA concentrations significantly increase during normal pregnancy, with concentrations at delivery differing between the two groups. Interestingly, we show that concentrations differ according to the type of placenta-mediated complications, with higher levels in preeclampsia compared to intrauterine growth restriction. CONCLUSIONS: These data suggest that nucleosomes and fDNA may be additional actors participating in placenta-mediated pregnancy complications.