Screening for small for gestational age infants in early vs late third-trimester ultrasonography: a randomized trial.

BACKGROUND: Recent studies have demonstrated that a routine third-trimester ultrasound scan may improve the detection of small for gestational age infants when compared with clinically indicated ultrasound scans but with no reported reduction in severe perinatal morbidity. Establishing the optimal gestational age for the third-trimester examination necessitates evaluation of the ability to detect small for gestational age infants and to predict maternal and perinatal outcomes. Intrauterine growth restriction most often corresponds with small for gestational age infants associated with pathologic growth patterns. OBJECTIVE: This study aimed to assess the performance of routine early ultrasound scans vs late ultrasound scans during the third trimester of pregnancy to identify small for gestational age infants and fetuses with intrauterine growth restriction. STUDY DESIGN: This was an open-label, randomized, parallel trial conducted in Upper Normandy, France, from 2012 to 2015. The study eligibility criteria were heathy, nulliparous women older than 18 years with gestational age determined using the crown-rump length at the first trimester routine scan and with no fetal malformation or suspected small for gestational age fetus at the routine second trimester scan. Pregnant women were randomly assigned to a third-trimester scan group at 31 weeks gestational age ±6 days (early ultrasound scan) or at 35 weeks gestational age ±6 days (late ultrasound scan). The primary outcome of this trial was the ability of a third trimester scan to predict small for gestational age infants (customized birth weight <10th percentile) and intrauterine growth restriction (customized birth weight

Prognostic relevance of sarcopenia, geriatric, and nutritional assessments in older patients with diffuse large B-cell lymphoma: results of a multicentric prospective cohort study.

This prospective study aimed to investigate the prognostic effect of sarcopenia, geriatric, and nutritional status in older patients with diffuse large B-cell lymphoma (DLBCL). Ninety-five patients with DLBCL older than 70 years who were treated with immunochemotherapy were included. The lumbar L3 skeletal muscle index (L3-SMI) was measured by computed tomography at baseline, and sarcopenia was defined as low L3-SMI. Geriatric assessment included G8 score, CIRS-G scale, Timed Up and Go test, and instrumental activity of daily living. Nutritional status was assessed using the Mini Nutritional Assessment and the body mass index, and several scores used in the literature incorporating nutritional and inflammatory biomarkers, namely the Nutritional and inflammatory status (NIS), Geriatric Nutritional Risk Index, Prognostic Nutritional Index, and Glasgow Prognostic Score.Fifty-three patients were considered sarcopenic. Sarcopenic patients displayed higher levels of inflammation markers and lower levels of prealbumin than non-sarcopenic patients. Sarcopenia was associated with NIS, but was not associated with severe adverse events and treatment disruptions. They were, however, more frequent among patients with elevated NIS. Sarcopenia did not appear in this study as a prognostic factor for progression-free survival (PFS) or overall survival (OS). However, NIS emerged as predictive of the outcome with a 2-year PFS rate of 88% in the NIS ≤ 1 group and 49% in the NIS > 1 group and a significant effect in a multivariate analysis for both PFS (p = 0.049) and OS (HR = 9.61, CI 95% = [1.03-89.66], p = 0.04). Sarcopenia was not associated with adverse outcomes, but was related to NIS, which appeared to be an independent prognostic factor.

The priming effect of repetitive transcranial magnetic stimulation on clinical response to electroconvulsive therapy in treatment-resistant depression: a randomized, double-blind, sham-controlled study.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression (TRD). However, due to response delay and cognitive impairment, ECT remains an imperfect treatment. Compared to ECT, repetitive transcranial magnetic stimulation (rTMS) is less effective at treating severe depression, but has the advantage of being quick, easy to use, and producing almost no side effects. In this study, our objective was to assess the priming effect of rTMS sessions before ECT on clinical response in patients with TRD. METHODS: In this multicenter, randomized, double-blind, sham-controlled trial, 56 patients with TRD were assigned to active or sham rTMS before ECT treatment. Five sessions of active/sham neuronavigated rTMS were administered over the left dorsolateral prefrontal cortex (20 Hz, 90% resting motor threshold, 20 2 s trains with 60-s intervals, 800 pulses/session) before ECT (which was active for all patients) started. Any relative improvements were then compared between both groups after five ECT sessions, in order to assess the early response to treatment. RESULTS: After ECT, the active rTMS group exhibited a significantly greater relative improvement than the sham group [43.4% (28.6%) v. 25.4% (17.2%)]. The responder rate in the active group was at least three times higher. Cognitive complaints, which were assessed using the Cognitive Failures Questionnaire, were higher in the sham rTMS group compared to the active rTMS group, but this difference was not corroborated by cognitive tests. CONCLUSIONS: rTMS could be used to enhance the efficacy of ECT in patients with TRD. ClinicalTrials.gov: NCT02830399.

Soluble RAGE as a Prognostic Marker of Worsening in Patients Admitted to the ICU for COVID-19 Pneumonia: A Prospective Cohort Study.

Background: The different waves of SARS-CoV-2 infection have strained hospital resources and, notably, intensive care units (ICUs). Identifying patients at risk of developing a critical condition is essential to correctly refer patients to the appropriate structure and to spare limited resources. The soluble form of RAGE (sRAGE), the endoplasmic stress response and its surrogates, GRP78 and VEGF-A, may be interesting markers. Methods: This was a prospective monocenter cohort study of adult patients admitted to the ICU for severe COVID-19 pneumonia. The plasma levels of sRAGE, GRP78 and VEGF-A were measured within the first 24 h. Patients were classified as critical if they further needed vasopressor therapy, renal replacement therapy, or invasive mechanical ventilation, or died during their ICU stay, and were otherwise classified as not critical. Results: A total of 98 patients were included and 39 developed a critical condition. Critical patients presented higher sRAGE (626 [450−1043] vs. 227 [137−404] pg/mL, p < 0.0001), interleukin-6 (43 [15−112] vs. 11 [5−20] pg/mL, p < 0.0001), troponin T (17 [9−39] vs. 10 [6−18] pg/mL, p = 0.003) and NT-pro-BNP (321 [118−446] vs. 169 [63−366] pg/mL, p = 0.009) plasma levels. No difference was observed for VEGF-A and GRP78. The variables independently associated with worsening in the ICU were sRAGE (1.03 [1.01−1.05] per 10 pg/mL) and age (1.7 [1.2−2.4] per 5 years). An sRAGE value of 449.5 pg/mL predicted worsening with a sensitivity of 77% and a specificity of 80%. Conclusion: sRAGE may allow the identification of patients at risk of developing a critical form of COVID-19 pneumonia, and thus may be useful to correctly refer patients to the appropriate structure of care.

Reliability of the Minto model for target-controlled infusion of remifentanil during cardiac surgery with cardiopulmonary bypass.

BACKGROUND: The Minto pharmacokinetic model is used for target-controlled infusion of remifentanil. The reliability of this model has never been evaluated during normothermic cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study was to assess the predictive performance of the model during CPB to determine its reliability during cardiac surgery. METHODS: This was a single-centre observational study. Arterial blood samples were drawn at five time points: T1, after tracheal intubation; T2, immediately before CPB; T3, 10 min after starting CPB; T4, 45 min after starting CPB; T5, 10 min after weaning off CPB. Prediction error (PE) and absolute prediction error (APE) were calculated for each sample and used to determine median prediction error (MDPE) and median absolute prediction error (MDAPE) per patient. Risk factors for APE >30% were assessed using multivariable analysis. Results are presented as medians with inter-quartile ranges. RESULTS: Fifty-eight patients with 283 blood samples (110 during CPB) were included. In the pre-CPB period, MDPE and MDAPE were -17.3 [-32.9 to 2.3] and 24.6 [12-37.7]%, whereas during CPB, they were -1.8 [-15.6 to 11.1] and 14.0 [6.74-27.1]%, respectively. There was no statistically significant difference between measured and predicted remifentanil plasma concentrations during CPB. Age, preoperative albumin concentrations, temperature, and haemodilution were not independently associated with MDAPE >30%. CONCLUSIONS: The Minto model accurately predicts plasma remifentanil concentrations during cardiac surgery with CPB. CLINICAL TRIAL REGISTRATION: 2017-A03153-50.

Routine and Advanced Laboratory Tests for Hemostasis Disorders in COVID-19 Patients: A Prospective Cohort Study.

BACKGROUND: Thrombosis is frequent during COVID-19 disease, and thus, identifying predictive factors of hemostasis associated with a poor prognosis is of interest. The objective was to explore coagulation disorders as early predictors of worsening critical conditions in the intensive care unit (ICU) using routine and more advanced explorations. MATERIALS: Blood samples within 24 h of ICU admission for viscoelastic point-of-care testing, (VET), advanced laboratory tests: absolute immature platelet count (A-IPC), von Willebrand-GPIb activity (vWF-GpIb), prothrombin fragments 1 + 2 (F1 + 2), and the thrombin generation assay (TGA) were used. An association with worse outcomes was explored using univariable and multivariable analyses. Worsening was defined as death or the need for organ support. RESULTS: An amount of 85 patients with 33 in critical condition were included. A-IPC were lower in worsening patients (9.6 [6.4-12.5] vs. 12.3 [8.3-20.7], p = 0.02) while fibrinogen (6.9 [6.1-7.7] vs. 6.2 [5.4-6.9], p = 0.03), vWF-GpIb (286 [265-389] vs. 268 [216-326], p = 0.03) and F1 + 2 (226 [151-578] vs. 155 [129-248], p = 0.01) were higher. There was no difference observed for D-dimer, TGA or VET. SAPS-II and A-IPC were independently associated with worsening (OR = 1.11 [1.06-1.17] and OR = 0.47 [0.25-0.76] respectively). The association of a SAPS-II ≥ 33 and an A-IPC ≤ 12.6 G/L predicted the worsening of patients (sensitivity 58%, specificity 89%). CONCLUSIONS: Immature platelets are early predictors of worsening in severe COVID-19 patients, suggesting a key role of thrombopoiesis in the adaption of an organism to SARS-CoV-2 infection.

Adaptation of Arterial Wall Viscosity to the Short-Term Reduction of Heart Rate: Impact of Aging.

Background Changes in arterial wall viscosity, which dissipates the energy stored within the arterial wall, may contribute to the beneficial effect of heart rate (HR) reduction on arterial stiffness and cardiovascular coupling. However, it has never been assessed in humans and could be altered by aging. We evaluated the effect of a selective HR-lowering agent on carotid arterial wall viscosity and the impact of aging on this effect. Methods and Results This randomized, placebo-controlled, double-blind, crossover study performed in 19 healthy volunteers evaluated the effects of ivabradine (5 mg BID, 1-week) on carotid arterial wall viscosity, mechanics, hemodynamics, and cardiovascular coupling. Arterial wall viscosity was evaluated by the area of the hysteresis loop of the pressure-lumen cross-sectional area relationship, representing the energy dissipated (WV), and by the relative viscosity (WV/WE), with WE representing the elastic energy stored. HR reduction by ivabradine increased WV and WE whereas WV/WE remained stable. In middle-aged subjects (n=11), baseline arterial stiffness and cardiovascular coupling were less favorable, and WE was similar but WV and therefore WV/WE were lower than in youth (n=8). HR reduction increased WV/WE in middle-aged but not in young subjects, owing to a larger increase in WV than WE. These results were supported by the age-related linear increase in WV/WE after HR reduction (P=0.009), explained by a linear increase in WV. Conclusion HR reduction increases arterial wall energy dissipation proportionally to the increase in WE, suggesting an adaptive process to bradycardia. This mechanism is altered during aging resulting in a larger than expected energy dissipation, the impact of which should be assessed. Registration URL: https://www.clinicaltrials.gov; Unique identifier: 2015/077/HP. URL: https://www. eudract.ema.europa.eu; Unique identifier: 2015-002060-17.

CEA, CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC).

BACKGROUND: We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics. METHODS: Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle. RESULTS: A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001). CONCLUSIONS: CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC. TRIAL REGISTRATION NUMBER: NCT01212510.

Tacrolimus 0.1% versus ciclopiroxolamine 1% for maintenance therapy in patients with severe facial seborrheic dermatitis: A multicenter, double-blind, randomized controlled study.

BACKGROUND: No long-term maintenance therapy has been tested in patients with seborrheic dermatitis (SD). OBJECTIVE: We sought to compare the efficacy and tolerance of tacrolimus 0.1% ointment versus ciclopiroxolamine 1% cream as maintenance therapy for severe SD. METHODS: This double-blind randomized controlled study was conducted from 2014 to 2017 in 5 Dermatology Departments and 15 dermatology practices in France. Consecutive patients with severe and chronic facial SD were included. Patients were initially treated with desonide 0.05% cream twice daily for 7 days. Patients cleared after this open phase were randomized to receive tacrolimus 0.1% or ciclopiroxolamine 1% cream 2 times a week 24 weeks. The primary endpoint was disease-free-duration, defined as the time from randomization to first relapse. RESULTS: One hundred fourteen patients were randomized (tacrolimus, n = 57; ciclopiroxolamine, n = 57). Twelve patients relapsed in the tacrolimus group after a median delay of 91.5 days (range 15-195 days) versus 23 patients in the ciclopiroxolamine group (median delay, 27 days [range 13-201 days]). Comparison of disease-free duration curves showed that patients in the tacrolimus group had a longer duration of complete remission than those in the ciclopiroxolamine group (P = .018), corresponding to a hazard ratio of relapse of 0.44 (95% confidence interval 0.22-0.89; P = .022). LIMITATIONS: The theoretical sample size was not reached. CONCLUSION: Tacrolimus 0.1% is more effective than ciclopiroxolamine 1% as maintenance therapy for patients with facial SD.

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass.

Introduction: Endoplasmic reticulum stress (ERS) is involved in inflammatory organ failure. Our objective was to describe ERS, its unfolded protein response (UPR) expression/kinetics during cardiac surgery with cardiopulmonary bypass (CPB) and its association with postoperative organ failure (OF). Methods: Prospective study conducted on patients undergoing cardiac surgery with CPB. Blood samples were taken before (Pre-CPB), 2 h (H2-CPB) and 24 h (H24-CPB) after CPB. Plasma levels of 78 kDa Glucose- Regulated Protein (GRP78, final effector of UPR) were evaluated by ELISA. The expression of genes coding for key elements of UPR (ATF6, ATF4, sXBP1, CHOP) was evaluated by quantitative PCR performed on total blood. OF was defined as invasive mechanical ventilation and/or acute kidney injury and/or hemodynamic failure requiring catecholamines. Results: We included 46 patients, GRP78 was decreased at H2-CPB [1,328 (878-1,730) ng/ml vs. 2,348 (1,655-3,730) ng/ml Pre-CPB; p < 0.001] but returned to basal levels at H24-CPB [2,068 (1,436-3,005) ng/ml]. The genes involved in UPR had increased expression at H2 and H24. GRP78 plasma levels in patients with OF at H24-CPB (n = 10) remained below Pre-CPB levels [-27.6 (-51.5; -24.2)%] compared to patients without OF (n = 36) in whom GRP78 levels returned to basal levels [0.6 (-28.1; 26.6)%; p < 0.01]. H24-CPB ATF6 and CHOP expressions were lower in patients with OF than in patients without OF [2.3 (1.3-3.1) vs. 3.0 (2.7-3.7), p < 0.05 and 1.3 (0.9-2.0) vs. 2.2 (1.7-2.9), p < 0.05, respectively]. Conclusions: Low relative levels of GRP78 and weak UPR gene expression appeared associated with postoperative OF. Further studies are needed to understand ERS implication during acute organ failure in humans.

In vivo probe-based confocal laser endomicroscopy in chronic interstitial lung diseases: Specific descriptors and correlation with chest CT.

BACKGROUND AND OBJECTIVE: Probe-based confocal laser endomicroscopy (pCLE) enables in vivo microimaging of the distal lung, during bronchoscopy. This study aims at identifying pCLE descriptors of chronic interstitial lung diseases (ILD), their correlations with chest HRCT and assessing inter-observer agreement. METHODS: pCLE was performed in 21 healthy volunteers (HV) and 59 non-smoking ILD patients, including 19 patients with idiopathic pulmonary fibrosis (IPF) or asbestosis, 15 with connective tissue disease-associated ILD (CTD-ILD), 17 with sarcoidosis and 8 with hypersensitivity pneumonitis (HP). pCLE descriptors were identified in ILD on the basis of comparison with HV. RESULTS: Nine pCLE descriptors were more frequent in ILD compared to HV, with good inter-observer agreement, including fluorescent bronchiolar cells (sarcoidosis, CTD-ILD and HP), fluorescent alveolar cells (CTD-ILD and HP), small alveolar entrance rings (IPF or asbestosis and CTD-ILD), enlarged axial elastic fibres (IPF or asbestosis), septal fibres (IPF or asbestosis, CTD-ILD and HP), disorganized acinar network and rigid acinar network (IPF or asbestosis and CTD-ILD), dense elastic network (IPF or asbestosis) and alveolar fluorescent nodular structures (in sarcoidosis) (P < 0.01, Fisher's exact test, all comparisons). The distribution of nodules on computed tomography (CT) appeared to correlate with pCLE alveolar nodular structures, rigid acinar network and septal fibres, while reticulations were associated with septal fibres and disorganized or dense acinar network; ground-glass opacities on CT with small alveolar entrances, rigid elastic network and septal fibres; and honeycombing with septal fibres. CONCLUSION: In the four groups of ILD studied, 9 pCLE descriptors are described, which appear specific and reproducible, and correlate with chest HRCT patterns.

Outcome at Two Years of Very Preterm Infants Born after Rupture of Membranes before Viability.

PURPOSE: To compare the respiratory and neurological outcomes at two years of age of preterm children born before 33 weeks of gestation (WG) after early preterm premature rupture of membranes (EPPROM) between 14 and 24 WG with preterm children without EPPROM. DESIGN AND PATIENTS: This single-center case-control retrospective study was conducted at Rouen University Hospital between 1st January 2000 and 31st December 2010. All the cases with EPPROM born from 26WG to 32WG were included. Each newborn was matched by sex, gestational age (GA) and year of birth to two very preterm children, born without EPPROM. At two years of corrected age, motor and cognitive abilities were assessed by routine score based on the Amiel-Tison and Denver developmental scales. RESULTS: Ninety-four cases with EPPROM before 24WG have been included. The 31 children born from 26WG to 32WG were matched with 62 controls. The EPPROM group had poorer clinical evaluation at one year for motor (p = 0.003) and cognitive developmental scores (p = 0.016). Neuromotor rehabilitation was performed more often (p = 0.013). However, there was no difference at 2 years of age. Children born after EPPROM were hospitalized more often for bronchiolitis (p<0.001) during their first 2 years, which correlates with increased incidence of pneumothorax (p = 0.017), pulmonary hypoplasia (p = 0.004) and bronchopulmonary dysplasia (p = 0.005) during neonatal period. CONCLUSION: At two years, despite an increase in severe bronchiolitis and the need for more neuromotor rehabilitation during the first month of the life after discharge, there was no difference in neurological outcomes in the very preterm children of the EPPROM group compared to those born at a similar GA without EPPROM.

Invasive aspergillosis in neutropenic patients during hospital renovation: effectiveness of mechanical preventive measures in a prospective cohort of 438 patients.

BACKGROUND: Aspergillus species are the main cause of invasive fungal disease for patients with severe and prolonged neutropenia. Building or renovation works have been shown as one of the major causes of outbreaks of aspergillosis. OBJECTIVES: This study aimed to assess the effectiveness of introduction and adaptation by air sampling of mechanical preventive measures on the incidence of invasive pulmonary aspergillosis in neutropenic patients during hospital renovation. PATIENTS: All of the patients admitted for prolonged and severe neutropenia during a renovation period from 2003 to 2008 were prospectively enrolled. Invasive pulmonary aspergillosis (IPA) cases were classified as possible, probable, and proven, according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group criteria. The effectiveness of preventive measures was determined by air sampling. RESULTS: We recorded 705 hospitalizations for neutropenia concerning 438 patients. The majority of hospitalized neutropenic patients was treated for acute leukemia (38.3 %), followed by patients suffering from non-Hodgkin and Hodgkin lymphomas (33 %). The total cumulative incidence of probable and proven IPA was 4.1 %. Risk factors for developing IPA were underlying disease, treatment course at the time of hospitalization, and the mean duration of hospitalization and of neutropenia. CONCLUSIONS: In this prospective study, the incidence of invasive pulmonary aspergillosis did not increase in neutropenic patients during a renovation period because of efficient mechanical preventive measures systematically adjusted using the results of air sampling.