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Background: Thoracic endometriosis syndrome gives rise to various clinical and radiological manifestations. We reviewed the records of patients operated for intrathoracic migration of abdominal viscera through a diaphragmatic hernia secondary to thoracic endometriosis. Methods: We retrospectively reviewed the single-center prospective collected database of all patients operated for thoracic endometriosis during the twenty years. All cases in which an abdominal organ was found to be herniated into the thoracic cavity were retrieved. Clinical and pathological data are presented and analyzed. Results: Twenty women of median age 36 (range 25–58) years were operated for endometriosis-related diaphragmatic hernia. The hernia was diagnosed concomitantly with endometriosis-related pneumothorax in 13 cases and during the exploration of catamenial thoracic pain in seven cases. There were 18 cases on the right side and two cases on the left side. The median diameter of the hernia was 8 cm (2.5–20 cm). In seventeen cases, the hernia was repaired by direct suture, and in three cases a heterologous prosthesis was positioned. At follow-up, two patients had an episode of recurrent pneumothorax. Conclusions: Diaphragmatic hernia should be ruled out in the presence of endometriosis-related pneumothorax or catamenial thoracic pain. Surgery is indicated to make a pathological diagnosis, restore anatomy, and prevent recurrence in patients presenting with pneumothorax. [ABSTRACT FROM AUTHOR]

Abstract Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic‐free, conventional wild‐type mice. We found that transferring obese‐mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non‐inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring of obese‐mouse microbiota changes both the gut microbiota and the microbiome of recipient mice. We also found that transferring obese gut microbiota to NC‐fed mice then fed with a high‐fat diet (HFD) acutely impacts hepatic metabolism and prevents HFD‐increased hepatic gluconeogenesis compared to non‐inoculated mice. Moreover, the recipient mice exhibit reduced hepatic PEPCK and G6Pase activity, fed glycaemia and adiposity. Conversely, transfer of lean‐mouse microbiota does not affect markers of hepatic gluconeogenesis. Our findings provide a new perspective on gut microbiota dysbiosis, potentially useful to better understand the aetiology of metabolic diseases.

Purpose: Survivors after acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) are at high risk of developing respiratory sequelae and functional impairment. The healthcare crisis caused by the pandemic hit socially disadvantaged populations. We aimed to evaluate the influence of socio-economic status on respiratory sequelae after COVID-19 ARDS. Methods: We carried out a prospective multicenter study in 30 French intensive care units (ICUs), where ARDS survivors were pre-enrolled if they fulfilled the Berlin ARDS criteria. For patients receiving high flow oxygen therapy, a flow ≥ 50 l/min and an FiO2 ≥ 50% were required for enrollment. Socio-economic deprivation was defined by an EPICES (Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examens de Santé - Evaluation of Deprivation and Inequalities in Health Examination Centres) score ≥ 30.17 and patients were included if they performed the 6-month evaluation. The primary outcome was respiratory sequelae 6 months after ICU discharge, defined by at least one of the following criteria: forced vital capacity < 80% of theoretical value, diffusing capacity of the lung for carbon monoxide < 80% of theoretical value, oxygen desaturation during a 6-min walk test and fibrotic-like findings on chest computed tomography. Results: Among 401 analyzable patients, 160 (40%) were socio-economically deprived and 241 (60%) non-deprived; 319 (80%) patients had respiratory sequelae 6 months after ICU discharge (81% vs 78%, deprived vs non-deprived, respectively). No significant effect of socio-economic status was identified on lung sequelae (odds ratio (OR), 1.19 [95% confidence interval (CI), 0.72–1.97]), even after adjustment for age, sex, most invasive respiratory support, obesity, most severe P/F ratio (adjusted OR, 1.02 [95% CI 0.57–1.83]). Conclusions: In COVID-19 ARDS survivors, socio-economic status had no significant influence on respiratory sequelae 6 months after ICU discharge. [ABSTRACT FROM AUTHOR]

Background: Computed tomography (CT) scan with rectal contrast enema (RCE-CT) could increase the detection rate of anastomotic leaks (AL) in the early postoperative period following colorectal surgery, compared to CT scan without RCE. The aim of this study was to assess the benefit of RCE-CT for the early diagnosis of AL following colorectal surgery. Methods: Patients who had a RCE-CT for suspected AL in the early postoperative period following colorectal surgery with anastomosis between January 2012 and July 2019 at the Dijon University Hospital were retrospectively included. All images were reviewed by two independent observers who were blinded to the original report. The reviewers reported for each patient whether an AL was present or not in each imaging modality (CT scan, then RCE-CT). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were then calculated to determine the diagnostic performance of each modality. Results: One hundred and thirty-nine patients were included. RCE-CT had an increased NPV compared to CT scan (82% vs 77% (p = 0.02) and 84% vs 68% (p < 0.0001) for observers 1 and 2, respectively). RCE-CT had an increased sensitivity compared to CT scan (79% vs 48% (p < 0.0001) for observer 2). RCE-CT had a significant lower false-negative rate for both observers: 18% vs 23% (p = 0.02) and 16% vs 32% (p < 0.0001). Conclusions: RCE-CT improved the detection rates of AL in the early period following colorectal surgery. RCE-CT should be recommended when a CT scan is negative and AL is still suspected. [ABSTRACT FROM AUTHOR]

Background: Few real-world data are available in patients with advanced metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy, particularly in those with brain metastases at treatment initiation. Methods: This was a national, retrospective, multicenter study that consecutively included all patients with PD-L1-positive (tumor proportion score ≥ 50%) advanced NSCLC who initiated first-line treatment with pembrolizumab as a single agent between May 2017 (date of availability of pembrolizumab in this indication in France) to November 22, 2019 (approval of the pembrolizumab-chemotherapy combination). Data were collected from medical records with local response assessment. Results: The cohort included 845 patients and 176 (20.8%) had brain metastases at diagnosis. There were no significant differences in outcomes for patients with and without brain metastases: 9.2 (95% CI 5.6–15) and 8 (95% CI 6.7–9.2, p = 0.3) months for median progression-free survival (PFS) and, 29.5 (95% CI 17.2–NA) and 22 (95% CI 17.8–27.1, p = 0.3) months for median overall survival (OS), respectively. Overall response rates were 47% and 45% in patients with and without cerebral metastases. In multivariate analysis, performance status 2–4 vs. 0–1 and neutrophil-to-lymphocyte ratio ≥ 4 vs. < 4 were the main independent negative factors for OS; brain metastasis was not an independent factor for OS. Conclusion: In this large multicenter cohort, nearly 20% of patients initiating pembrolizumab therapy for advanced NSCLC had cerebral metastases. There was no significant difference in response rates, PFS and OS between patients with and without brain metastases. [ABSTRACT FROM AUTHOR]

Biofilm (BF) growth is believed to play a major role in the development of ventilator-associated pneumonia (VAP) in the intensive care unit. Despite concerted efforts to understand the potential implication of endotracheal tube (ETT)-BF dispersal, clinically relevant data are lacking to better characterize the impact of its mesostructure and microbiological singularity on the occurrence of VAP. We conducted a multicenter, retrospective observational study during the third wave of the COVID-19 pandemic, between March and May 2021. In total, 64 ETTs collected from 61 patients were included in the present BIOPAVIR study. Confocal microscopy acquisitions revealed two main morphological aspects of ETT-deposited BF: (1) a thin, continuous ribbon-shaped aspect, less likely monobacterial and predominantly associated with Enterobacter spp., Streptococcus pneumoniae or Viridans streptococci, and (2) a thicker, discontinuous, mushroom-shaped appearance, more likely characterized by the association of bacterial and fungal species in respiratory samples. The microbiological characterization of ETT-deposited BF found higher acquired resistance in more than 80% of analyzed BF phenotypes, compared to other colonization sites from the patient's environment. These findings reveal BF as a singular microbiological compartment, and are of added clinical value, with a view to future ETT-deposited BF-based antimicrobial stewardship in critically ill patients. Trial registration NCT04926493. Retrospectively registered 15 June 2021. [ABSTRACT FROM AUTHOR]

Purpose: The use of oral cancer drugs (OAD) has increased over the last two decades. The objective of this study was to measure the impact of a nurse-led telephone follow-up in the therapeutic management of patients treated with an OAD regarding toxicity, medication adherence and quality of life. Methods: A randomized, multicenter, controlled trial was conducted. All consecutive over 18-year-old patients, treated in medical oncology, radiotherapy, or hematology departments, receiving OAD for any cancer were invited to participate to the study. A total of 183 patients treated for solid or hematological cancers with an OAD were randomly assigned to receive a nurse-led telephone follow-up or standard care for 24 weeks. Data were collected between 2015 and 2018. Results: Nurse telephone follow-up did not improve the global score toxicity in the intervention group. However, telephone calls directed by trained nurses induced a significant decrease in number of patients with grade 3 adverse events throughout the follow-up [OR 0.45 (IC à 95%) (0.23, 0.9)](P = 0.03). There was no significant difference in quality of life and medication adherence between groups at any follow-up time point. Conclusions: In this first French real-life study, the advice provided by qualified nurses via phone calls improved the management of grade 3 toxicities but failed to demonstrate an improvement of all grades of toxicities. More prospective studies are needed to confirm the impact of telephone calls on the toxicities related to OAD. Trial registration: Clinical trial registration is NCT02459483. Protection committee SUD-ESTI registration is 2015-A00527-42 on 13 April 2015. National Agency for the Safety of Medicines and Health Products registration is 150619-B on the 27 may 2015. [ABSTRACT FROM AUTHOR]

B Correction: Intensive Care Medicine b https://doi.org/10.1007/s00134-023-07180-y When this article was published, some final corrections were accidentally overlooked. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [Extracted from the article]

Background: To assess the ability of procalcitonin (PCT) to distinguish between bacterial and nonbacterial causes of patients with severe acute exacerbation of COPD (AECOPD) admitted to the ICU, we conducted a retrospective analysis of two prospective studies including 375 patients with severe AECOPD with suspected lower respiratory tract infections. PCT levels were sequentially assessed at the time of inclusion, 6 h after and at day 1, using a sensitive immunoassay. The patients were classified according to the presence of a documented bacterial infection (including bacterial and viral coinfection) (BAC + group), or the absence of a documented bacterial infection (i.e., a documented viral infection alone or absence of a documented pathogen) (BAC- group). The accuracy of PCT levels in predicting bacterial infection (BAC + group) vs no bacterial infection (BAC- group) at different time points was evaluated by receiver operating characteristic (ROC) analysis. Results: Regarding the entire cohort (n = 375), at any time, the PCT levels significantly differed between groups (Kruskal–Wallis test, p < 0.001). A pairwise comparison showed that PCT levels were significantly higher in patients with bacterial infection (n = 94) than in patients without documented pathogens (n = 218) (p < 0.001). No significant difference was observed between patients with bacterial and viral infection (n = 63). For example, the median PCT-H0 levels were 0.64 ng/ml [0.22–0.87] in the bacterial group vs 0.24 ng/ml [0.15–0.37] in the viral group and 0.16 ng/mL [0.11–0.22] in the group without documented pathogens. With a c-index of 0.64 (95% CI; 0.58–0.71) at H0, 0.64 [95% CI 0.57–0.70] at H6 and 0.63 (95% CI; 0.56–0.69) at H24, PCT had a low accuracy for predicting bacterial infection (BAC + group). Conclusion: Despite higher PCT levels in severe AECOPD caused by bacterial infection, PCT had a poor accuracy to distinguish between bacterial and nonbacterial infection. Procalcitonin might not be sufficient as a standalone marker for initiating antibiotic treatment in this setting. [ABSTRACT FROM AUTHOR]

Gap junctions are ubiquitous within the retina, but in general, it remains to be determined whether gap junction coupling between specific cell types is sufficiently strong to mediate functionally relevant coupling via electrical synapses. From ultrastructural, tracer coupling and immunolabeling studies, there is clear evidence for gap junctions between cone bipolar cells, but it is not known if these gap junctions function as electrical synapses. Here, using whole-cell voltage-clamp recording in rat (male and female) retinal slices, we investigated whether the gap junctions of bipolar cells make a measurable contribution to the membrane properties of these cells. We measured the input resistance (RN) of bipolar cells before and after applying meclofenamic acid (MFA) to block gap junctions. In the presence of MFA, RN of ON-cone bipolar cells displayed a clear increase, paralleled by block of the electrical coupling between these cells and AII amacrine cells in recordings of coupled cell pairs. For OFF-cone and rod bipolar cells, RN did not increase in the presence of MFA. The results for rod bipolar cells are consistent with the lack of gap junctions in these cells. However, for OFF-cone bipolar cells, our results suggest that the morphologically identified gap junctions between these cells do not support a junctional conductance that is sufficient to mediate effective electrical coupling. Instead, these junctions might play a role in chemical and/or metabolic coupling between subcellular compartments. [ABSTRACT FROM AUTHOR]

Recent applications require vertical chip stacking to increase the performance of many devices without the need of advanced node components. Image sensors and vision systems will embed more and more smart functions, for instance, image processing, object recognition, and movement detection. In this perspective, the combination of Cu-to-Cu direct hybrid bonding technology with Through-Silicon-Via (TSV) will allow 3D interconnection between pixels and the associated computing and memory structures, each function fabricated on a separate wafer. Wafer-to-wafer hybrid bonding was achieved with multi-pitch design—1–4 μm—of single levels of Cu damascene patterned on 300 mm silicon substrates. Defect-free bonding, as far as the extreme edge of the wafer, was demonstrated on a stack with three wafers. Middle wafers thinning was done with grinding only and with a thickness uniformity (TTV) <2 μm to an ultimate thinning as low as 3 μm. Alignment performance was characterized by post-bonding for two superposed hybrid bonding interfaces. In our set of wafers, modeling the alignment with translation, rotation, and scaling components enables us to optimize the residuals down to 3σ < 100 nm. A process flow of thin TSV with a fine pitch of 2 μm for high-density vertical interconnect through a three-wafer stack was developed. Via-last TSV architecture was adopted with 1 μm TSV diameter and 10 μm thickness. Lithography, etching solutions, Ti/TiN barrier deposition, and void-free Cu filling solutions were demonstrated. TSV cross sections after CMP and connections with top and bottom Cu damascene lines show good profile control. Process developments are matured and can be reliably used in the fabrication of an electrical test vehicle including vertical interconnects associating multi-wafers stacking with a hybrid bonding process and high-density thin TSV applicable to low pitches (<5 μm). [ABSTRACT FROM AUTHOR]

Purpose: The widespread use of Nivolumab results in an increasing number of side effects and adverse events. Herein, we evaluated the impact of Nivolumab on crude and normalized pulmonary artery diameter (PAD).Methods: We analyzed clinical, morphometric, pathological and radiological data of lung cancer patients treated by Nivolumab in an 18-month period. Blinded radiological evaluation was performed, by three observers measuring axial PAD and Aorta diameter (AoD) in secondarily matched pre- and post-Nivolumab CT-scans. Correlation between ΔPAD and clinicopathological data was investigated.Results: 59 patients receiving Nivolumab for treatment of advanced lung carcinoma were identified. Pre-and post-Nivolumab comparison of CT-scan measures revealed that mean PAD was 26.3 ± 2.8 mm versus 28.0 ± 3.0 mm (p < 0.001), and mean PAD/AoD ratio was 0.82 ± 0.09 versus 0.87 ± 0.11 (p <  0.001), respectively. Median ΔPAD was 0.05 [0.01-0.122] was significantly higher in hypometabolic patients exhibiting low Rest Energy Expenditure (p = 0.03). Patients exhibiting ΔPAD > 1% had significantly lower serum albumin level (p = 0.03), and higher nutritional risk (p = 0.02), compared to others. Unlike Nivolumab therapy, there was no increase of PAD after chemotherapy in the same cohort of patients with available scans (n = 45, 25.9 ± 2.9 mm pre-chemotherapy versus 25.7 ± 2.4 mm post-chemotherapy, p = 0.51). Anti-PD-1 treatment was associated with immune-related adverse events in 11 (18.6%) cases including 2 cases of life-threatening acute pulmonary hypertension, both exhibiting post-treatment PAD/AoD ratio > 1.Conclusion: Nivolumab is associated to PAD enlargement, a potential marker of pulmonary hypertension, sometimes leading to lethal adverse events. Careful CT-scan and echocardiographic evaluation of PAD should be part of the therapeutic work-up of patients receiving Nivolumab, especially those suffering cancer-associated malnutrition. [ABSTRACT FROM AUTHOR]

Purpose: Gastropleural and gastrobronchial fistulas (GPF/GBFs) are serious but rare complications after bariatric surgery whose management is not consensual. The aim was to establish a cohort and evaluate different clinical presentations and therapeutic options. Materials and Methods: A multicenter and retrospective study analyzing GPF/GBFs after bariatric surgery in France between 2007 and 2018, via a questionnaire sent to digestive and thoracic surgery departments. Results: The study included 24 patients from 9 surgical departments after initial bariatric surgery (21 sleeve gastrectomies; 3 gastric bypass) for morbid obesity (mean BMI = 42 ± 8 kg/m2). The GPF/GBFs occurred, on average, 124 days after bariatric surgery, complicating an initial post-operative gastric fistula (POGF) in 66% of cases. Endoscopic digestive treatment was performed in 79% of cases (n = 19) associated in 25% of cases (n = 6) with thoracic endoscopy. Surgical treatment was performed in 83% of cases (n = 20): thoracic surgery (n = 5), digestive surgery (n = 8), and combined surgery (n = 7). No patient died. Overall morbidity was 42%. The overall success rate of the initial and secondary strategies was 58.5% and 90%, respectively. The average healing time was approximately 7 months. Patients who had undergone thoracic surgery (n = 12) had more initial management failures (n = 9/12) than patients who had not (n = 3/12), p = 0.001. Conclusion: Complex and life-threatening fistulas that are revealed late require a multidisciplinary strategy. Thoracic surgery should be reserved once the abdominal leak heals; otherwise, it is associated with a higher risk of failure. [ABSTRACT FROM AUTHOR]

Background: The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission. Methods: The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score. Results: Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = − 1.85 [95% CI − 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders. Conclusions: Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013 [ABSTRACT FROM AUTHOR]

Background: The resistance mutation T790M is reported in 50-60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare.Objective: The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients.Methods: This retrospective multicentric study included pretreated octogenarian patients with EGFR T790M-mutated advanced non-small cell lung cancer (NSCLC) in the setting of the French early access program for osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation.Results: In total, 43 patients were included (mean age 84.6 years; women 90.7%: adenocarcinoma 100%; never smokers 90.5%; at osimertinib initiation: performance status ≥ 2, 42.4%; stage 4, 93.0%; brain metastases 16.3%). Patients received a median of two lines of treatment before osimertinib initiation, and all received first- or second-generation EGFR TKIs before osimertinib (first line in 79.1%). Osimertinib was used as a second-line treatment in 41.9% of cases and third line or more in 58.1%. Median PFS was 17.5 (95% confidence interval [CI] 12.2-19.0) months for the entire population: 20.6 (95% CI 18.8-not reached) months in patients with brain metastases and 16.7 (95% CI 10.4-18.9) months in patients without (p = 0.1). There was no significant difference for osimertinib treatment as second or third line or more (17.1 vs. 18.6 months, respectively). OS was 22.8 (95% CI 15.7-not reached) months from osimertinib initiation.Conclusion: The efficacy of osimertinib as second-line treatment or more in octogenarian pretreated patients with EGFR T790M-mutated advanced NSCLC in a real-life setting was similar to that in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Purpose: Compare the effectiveness of different cutaneous antiseptics in reducing risk of catheter-related infection in intensive care unit (ICU) patients.Methods: We compared the risk of central venous catheter-related infection according to four-step (scrub, rinse, dry, and disinfect) alcoholic 5 % povidone-iodine (PVI-a, n = 1521), one-step (disinfect) alcoholic 2 % chlorhexidine (2 % CHX-a, n = 1116), four-step alcoholic <1 % chlorhexidine (<1 % CHX-a, n = 357), and four-step aqueous 10 % povidone-iodine (PVI, n = 368) antiseptics used for cutaneous disinfection and catheter care during the 3SITES multicenter randomized controlled trial. Within this cohort, we performed a quasi-experimental study (i.e., before-after) involving the four ICUs which switched from PVI-a to 2 % CHX-a. We used propensity score matching (PSM, n = 776) and inverse probability weighting treatment (IPWT, n = 1592). The end point was the incidence of catheter-related infection (CRI) defined as catheter-related bloodstream infection (CRBSI) or a positive catheter tip culture plus clinical sepsis on catheter removal.Results: In the cohort analysis and compared with PVI-a, the incidence of CRI was lower with 2 % CHX-a [adjusted hazard ratio (aHR), 0.51; 95 % confidence interval (CI) (0.28-0.96), p = 0.037] and similar with <1 % CHX-a [aHR, 0.73; (0.36-1.48), p = 0.37] and PVI [aHR, 1.50; 95 % CI (0.85-2.64), p = 0.16] after controlling for potential confounders. In the quasi-experimental study and compared with PVI-a, the incidence of catheter-related infection was again lower with 2 % CHX-a after PSM [HR, 0.35; 95 % CI (0.15, 0.84), p = 0.02] and in the IPWT analysis [HR, 0.31; 95 % CI (0.14, 0.70), p = 0.005]. The incidence of CRBSI or adverse event was not significantly different between antiseptics in all analyses.Conclusions: In comparison with PVI-a, the use of 2 % CHX-a for cutaneous disinfection of the central venous catheter insertion site and maintenance catheter care was associated with a reduced risk of catheter infection, while the benefit of <1 % CHX-a was uncertain.Clinical Trials Identifier: NCT01479153. [ABSTRACT FROM AUTHOR]

Purpose: To compare the efficacy of an antibiotic protocol guided by serum procalcitonin (PCT) with that of standard antibiotic therapy in severe acute exacerbations of COPD (AECOPDs) admitted to the intensive care unit (ICU).Methods: We conducted a multicenter, randomized trial in France. Patients experiencing severe AECOPDs were assigned to groups whose antibiotic therapy was guided by (1) a 5-day PCT algorithm with predefined cutoff values for the initiation or stoppage of antibiotics (PCT group) or (2) standard guidelines (control group). The primary endpoint was 3-month mortality. The predefined noninferiority margin was 12%.Results: A total of 302 patients were randomized into the PCT (n = 151) and control (n = 151) groups. Thirty patients (20%) in the PCT group and 21 patients (14%) in the control group died within 3 months of admission (adjusted difference, 6.6%; 90% CI - 0.3 to 13.5%). Among patients without antibiotic therapy at baseline (n = 119), the use of PCT significantly increased 3-month mortality [19/61 (31%) vs. 7/58 (12%), p = 0.015]. The in-ICU and in-hospital antibiotic exposure durations, were similar between the PCT and control group (5.2 ± 6.5 days in the PCT group vs. 5.4 ± 4.4 days in the control group, p = 0.85 and 7.9 ± 8 days in the PCT group vs. 7.7 ± 5.7 days in the control group, p = 0.75, respectively).Conclusion: The PCT group failed to demonstrate non-inferiority with respect to 3-month mortality and failed to reduce in-ICU and in-hospital antibiotic exposure in AECOPDs admitted to the ICU. [ABSTRACT FROM AUTHOR]

Direct bonding of PECVD SiO films is of great interest in the field of microtechnologies for applications such as stacked structures, thin film transfers, whose fabrication processes still deserve to be investigated. This work deals with the influence of water diffusion in the SiO films deposited onto 200 mm Si wafers and its impact on adherence of hydrophilic surfaces. The as-deposited film nature induces various stresses. Stresses evolutions and water penetration are characterized and a correlation is made between the kinetics of both stress variations and water diffusion through the oxide thin films. Impacts of room temperature (RT) storage prior to bonding and thermal treatments applied for strengthening the bonding is shown. As direct bonding operates through surface asperities deformation, specific mechanical properties of such contact asperities can lead to a stronger bonding by increasing bonding area (Fournel et al., ECS J Solid State Sci Technol 4(5):124-130, 2015; Rieutord et al., ECS Trans 3(6):205-215, 2006; Ventosa et al., J Appl Phys 104:123524, 2008, Electrochem Solid State Lett 12(10):H373-H375, 2009). As the mechanical properties of silicon oxide material are greatly influenced by internal water concentration, aging and water diffusion on asperity have a real impact in term of direct bonding energy. Moreover at bonding interfaces, it is observed by X-ray reflectivity (XRR) that aging of deposited SiO prior to bonding enables shallower bonding gaps, indicating better bonding interface closure which is coherent with the bonding energy enhancement. All these results confirm the link between water diffusion and hydrophilic surface adherence of deposited SiO films. [ABSTRACT FROM AUTHOR]

This paper deals with the effect of the silicon bonding temperature with thermoplastic adhesive. The bonding temperature exhibits a significant effect on the morphology and on the adherence energy of the bonded stack. A suitable temperature control leads to an excellent homogeneity of the bonded structure and an optimal total thickness variation (TTV) value. Using Brewer Bsi5150 adhesive material, 275 °C appears as the optimal bonding temperature in order to optimize the TTV from 55 µm down to 5 µm. The adherence of the structure is also increased with high bonding temperatures. Indeed, the adherence energy is above 10 J/m when the temperature is above 250 °C. On the contrary, when the temperature is less than 150 °C, the adherence is only around 1 J/m. Noteworthy, this value is suitable for back side processing and a mechanical debonding of the structure without any need of other specific layer which could lead to a very simple temporary bonding process. [ABSTRACT FROM AUTHOR]

Background: Histological subdivision into typical (TC) and atypical (AC) is crucial for treatment and prognosis of lung carcinoids but can be also very challenging, even for experts. In this study, we aimed to strengthen or reduce the prognostic value of several pathological, clinical, or per-operative factors some of which are still controversial. Methods: We retrospectively reviewed clinical records related to 195 patients affected by TC (159) or AC (36) surgically treated between 2000 and 2014, in three different centers. Survival and subtypes comparison analyses were performed to identify potential prognostic factors. Results: TCs showed a lower rate of nodal involvement than ACs ( N0 = 94.9%; N1 = 1.9%; N2 = 3.2% in typical and N0 = 63.8%; N1 = 16.6%; N2 = 19.4% in atypical carcinoids, respectively, p < 0.0001). Long-term oncological results of resected carcinoids were significantly better in TCs than ACs with higher 5- and 10-year overall survival rates (97.2 and 88.2% vs. 77.9 and 68.2%, respectively; p = 0.001) and disease-free survival rates (98.2 and 90.3% in typical and 80.8 and 70.7% atypical carcinoids, respectively; p = 0.001). Risk factors analysis revealed that AC subtype [HR 4.33 (95% CI 1.72-8.03), p = 0.002], pathological nodal involvement [HR 3.05 (95% CI 1.77-5.26), p < 0.0001], and higher SUV [HR 4.33 (95% CI 1.03-7.18), p = 0.002] were independently and pejoratively associated with overall survival. Factors associated with a higher risk of recurrence were AC subtype [HR 6.13 (95% CI 1.13-18.86), p = 0.002]; nodal involvement [HR 5.48 (95% CI 2.85-10.51), p < 0.0001]; higher Ki67 expression level [HR 1.09 (95% CI 1.01-1.20), p = 0.047]; and SUV [HR 1.83 (95% CI 1.04-3.23), p = 0.035]. Conclusion: Surgery for lung carcinoids allows satisfactory oncological results which mainly depend on carcinoid subtype dichotomy, pathological nodal status, and SUV. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma is a rare tumor with a poor prognosis. The only universally recognized pathological prognostic factor is histopathological subtype with a shorter survival in non-epithelioid subtypes. Recently, a grading of epithelioid mesothelioma on surgical resection has been proposed. The aim of our work is to assess the prognostic role of several histopathological factors on a retrospective cohort of 116 patients diagnosed as a pleural mesothelioma for more than 95% of patients on pleural biopsy. Our work shows that mitotic count <3/10 HPF (p < 0.0001), the lack of necrosis (p = 0.0379), mild nuclear atypia (p = 0.0054), the lack of atypical mitoses (p = 0.0265), a nucleoli size <3 μm (p = 0.0139), and a nucleoli absent or visible at 200× or higher magnification (p = 0.0170) are significantly associated with a better median overall survival in epithelioid mesothelioma. The presence of atypical mitoses was found to be related to a worse median survival in non-epithelioid mesothelioma. Mitotic count, necrosis, nuclear atypia, and nucleoli size are not associated with overall survival in non-epithelioid mesothelioma. Our work highlights that histopathological prognostic factors can be assessed on pleural biopsies and can predict reliably median overall survival. This is of interest in order to define subgroups of patients who could benefit of different therapies and select patients who could benefit of surgical excision. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) has a pivotal role in sepsis pathophysiology, but its measurement with limulus amoebocyte lysate (LAL) and other bioassays yielded conflicting results in clinical studies [[1]]. Moreover, 3HM levels were significantly higher in septic shock patients compared to sepsis patients, although they were similar between non-septic patients and controls (Fig. [Extracted from the article]

Unlabelled: Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients.Clinical Trial Information: NCT02293733. [ABSTRACT FROM AUTHOR]

The increasing complexity of multiprocessor system on chip (MPSoC) makes the software developers life harder when chasing bugs. The debugging process is particularly tedious as it involves analyzing parallel execution flows. Executing a program many times is an integral part of the process in conventional debugging, but the non-determinism due to parallel execution often leads to different execution paths and different behaviors. In this paper, we propose an approach based on simulation, as it is nowadays an integral part of the MPSoC design flow, to ease pin-pointing bugs in a parallel execution. To that aim, we collect traces using a virtual platform, and when an execution fails, re-execute the traces, in either forward or reverse direction. We define a trace model suitable for this task, and detail a strategy for providing forward and reverse execution features to avoid long simulation times during a debug session. We demonstrate experimentally that re-execution is a deterministic process which, when debugging using the usual trial and error developer approach, is much faster than simulation. [ABSTRACT FROM AUTHOR]

Copper-copper direct bonding is a fundamental procedure in three-dimensional integration. It has been reported that voiding occurs in bonded copper layers if process temperatures exceed 300°C; this leads to serious reliability issues. However, voiding nucleation and growth mechanisms have not been clearly established. Void characteristics were compared for different bonded structures specifically designed to identify the origin of void formation and its contribution. It seems that mechanical stress caused by different dilatation of silicon substrates and metal thin films leads to metallurgical creep. This stress-driven vacancy diffusion makes a major contribution to the reliability problem. This study provides better understanding of these physical phenomena and can be used as guideline for metal integration. [ABSTRACT FROM AUTHOR]

SOI circuit exhibits excellent performance and rehabilitee but with the component miniaturization trend and the clock frequency increase, the self-heating phenomena that arise from the SOI structure itself must not be underestimated. In order to minimize this problem, several candidates have been identified to replace the buried silicon oxide (SiO) by high thermal conductive dielectric layers such as HfO, SiN, diamond or AlO. In order to elaborate a SOI structure using this kind of innovative buried dielectric, first of all, their direct bonding with silicon has to be studied. In this work, we investigate the bonding thermal behaviour of Si/AlO and AlO/AlO direct bonded structures: bondings are submitted to room temperature up to 900 °C annealing. Amorphous or crystallized AlO thin films were used in this study. Bonding energies are measured in an anhydrous atmosphere and bonding defectivity is analysed using scanning acoustic microscope (SAM). With amorphous a-AlO layer, for T > 200 °C, high bonding energy are obtained even if high defect density appeared when annealing temperature exceeded 400-500 °C. Spontaneous debonding phenomena even occurred for a-AlO/a-AlO direct bonding. This defectivity, unobservable using infrared camera, may be explained by chemical or structural AlO modification such as gases desorption, internal stress or crystallisation state. Bonding with crystallized AlO film has been also characterized by infrared spectroscopy and complementary analysis. No high defect density is observed with crystallized AlO layer. Based on these results, an AlO bonding mechanism is proposed. [ABSTRACT FROM AUTHOR]

This paper deals with the improvement of the TTV values (Total Thickness Variation) of 300 mm silicon wafers thinned down at 100 μm using the ZoneBond (ZoneBond is registred by Brewer Science Inc.) technology. We have demonstrated that the thin film TTV of the film was mainly driven by the bonding process and was very tolerant towards the coating step. It was also shown that, within the experiment precision, the TTV value was not changed by the grinding thinning process. 8 µm was the best TTV value obtained after the optimization of the bonding parameters. [ABSTRACT FROM AUTHOR]

Indium phosphide (InP) and gallium arsenide (GaAs) 100 mm wafers were bonded by direct wafer bonding in a cleanroom environment. Unexpected high bow values measured at room temperature after different thermal annealings are the focus of this study. Various experiments such as in situ bow measurements, surface XPS characterizations and TEM cross section observations highlight the key mechanisms that evolve with temperature. Over 200 °C, gallium oxide is formed at the bonded interface due to the presence of water that is trapped at the InP/GaAs interface during the hydrophilic bonding. These results allow us to explain the heterostructure debonding/re-bonding behavior. [ABSTRACT FROM AUTHOR]

The use of reconstructed silicon wafers obtained after high temperature annealing under H atmosphere was demonstrated as an efficient way for increasing the bonding energy of silicon hydrophobic bonding (Rauer et al. ). Mechanisms occurring in these bondings are the focus of this paper. Si bonding interface closure was analyzed at the nanometer scale using X-Ray Reflectivity and Fourier Transform InfraRed spectroscopy in multiple internal reflexion mode. These two characterization techniques enable one to follow the interface closure taking under consideration mechanical and chemical aspects. We have shown that the terrace morphology and the monohydride surface termination specific to reconstructed Si surfaces both play a role in obtaining an efficient bonding gap closure after annealing at low temperature. [ABSTRACT FROM AUTHOR]

In the field of radiotherapy, there is very little scientific data on the management of nonagenarians, especially in patients aged 90 years or more and with head and neck cancer (HNC). We made one of the first retrospective study of the feasibility and safety of radiotherapy in this population with HNC. Records of radiotherapy coming from four health facilities were studied to include all nonagenarian patients with HNC in the last 10 years and who received radiation therapy. We analyzed patient characteristics and primary cancers, as well as objective of the treatment (curative or palliative), efficacy and toxicity. Twenty patients receiving radiotherapy were identified; mean age was 93.2 years (standard deviation 2.8). Treatment was given with curative and palliative intent in 40 and 60 % of cases, respectively. The most common primary tumors were tumors of the salivary glands (30 % of cases), oral cavity tumors (25 % of cases) and thyroid tumors (15 % of cases). Median total prescribed dose was 47.5 Gy (12-70 Gy). Median number of delivered fractions was 18.5 (2-35 fractions). All patients received intensive supportive care during radiotherapy. Toxicities were mild to moderate. Radiotherapy could not be completed for four patients (20 % of cases). One patient developed grade 1-2 delayed toxicities. At the last follow-up, only four patients (20 % of cases) were alive. Cancer was cause of death in most cases. Radiotherapy may be performed for the nonagenarians with HNC. The total dose and fractionation must be adjusted to optimize the tolerance. However, the prognosis remains very poor, cancer being the main cause of death. Research of geriatric vulnerabilities prior to any treatment, in the context of a comprehensive geriatric assessment, is still recommended to select patients for radiotherapy. [ABSTRACT FROM AUTHOR]

A pre-bond cleaning process was developed utilizing a unique, radially uniform, large area proximity type Megasonic transducer. In prior work this new cleaning method was investigated for PRE (particle removal efficiency) as well as particle neutrality. These tests yielded higher values than those achieved with the processes of record. Subsequently, this process was integrated into an industrial volume low temperature fusion bonding process and enabled higher bonding yields. In the above process flow the process fluid was dispensed to fill the gap between the Megasonic transducer surface and the substrate using an atmospheric free flow stream applied to the substrate. Current work describes development, testing and operational verification of a process fluid management device used in conjunction with the wide area proximity Megasonic transducer. The goals of this development were reduction of process fluid amount required, increase the operating substrate rotation speed, and provide better control of process fluid parameters. The design criteria and process flow as well as test results demonstrating the benefits of the new system are presented. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. Methods: First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg kg day, i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. Results: In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. Conclusions/interpretation: Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice. [ABSTRACT FROM AUTHOR]

The bonding of hydrophobic, reconstructed (001) Si surfaces obtained with high temperature H processes has been studied with atomic force microscopy, low energy electron diffraction spectroscopy, X-ray reflectivity and bonding energy measurements. Surface reconstruction is shown to strongly affect bonding mechanisms. As a consequence, bonding energies of such surfaces are significantly higher, in the room temperature −500 °C range, than those of 'HF-last' surfaces. [ABSTRACT FROM AUTHOR]

Knowledge of the causes of forest fires, and of the main driving factors of ignition, is an indispensable step towards effective fire prevention policies. This study analyses the factors driving forest fire ignition in the Mediterranean region including the most common human and environmental factors used for modelling in the European context. Fire ignition factors are compared to spatial and temporal variations of fire occurrence in the region, then are compared to results obtained in other areas of the world, with a special focus on North America (US and Canada) where a significant number of studies has been carried out on this topic. The causes of forest fires are varied and their distribution differs among countries, but may also differ spatially and temporally within the same country. In Europe, and especially in the Mediterranean basin, fires are mostly human-caused mainly due arson. The distance to transport networks and the distance to urban or recreation areas are among the most frequently used human factors in modelling exercises and the Wildland-Urban Interface is increasingly taken into account in the modelling of fire occurrence. Depending on the socio-economic context of the region concerned, factors such as the unemployment rate or variables linked to agricultural activity can explain the ignition of intentional and unintentional fires. Regarding environmental factors, those related to weather, fuel and topography are the most significant drivers of ignition of forest fires, especially in Mediterranean-type regions. For both human and lightning-caused fires, there is a geographical gradient of fire ignition, mainly due to variations in climate and fuel composition but also to population density for instance. The timing of fires depends on their causes. In populated areas, the timing of human-caused fires is closely linked to human activities and peaks in the afternoon whereas, in remote areas, the timing of lightning-caused fires is more linked to weather conditions and the season, with most such fires occurring in summer. [ABSTRACT FROM AUTHOR]

Granular activated carbon (GAC) and more recently activated carbon fibers (ACF) are used for the treatment of volatile organic compounds (VOC) in industrial processes. The purpose of this study was to investigate the adsorption kinetics of ACF to eliminate VOC from polluted air. This approach is carried out by modeling experimental breakthrough curves with two kinds of models: an equilibrium model and a mass transfer model based on a linear driving force (LDF) in conjunction with the Langmuir equilibrium model. The results show the influence of the intraparticle diffusion on the adsorption kinetics of ACF, in spite of their small fiber diameter. Moreover, external diffusion kinetics is fast because of the influence of the large external surface area of ACF on the VOC mass transfer. [ABSTRACT FROM AUTHOR]

The epitaxial growth of germanium on silicon leads to the self-assembly of SiGe nanocrystals by a process that allows the size, composition and position of the nanocrystals to be controlled. This level of control, combined with an inherent compatibility with silicon technology, could prove useful in nanoelectronic applications. Here, we report the confinement of holes in quantum-dot devices made by directly contacting individual SiGe nanocrystals with aluminium electrodes, and the production of hybrid superconductor–semiconductor devices, such as resonant supercurrent transistors, when the quantum dot is strongly coupled to the electrodes. Charge transport measurements on weakly coupled quantum dots reveal discrete energy spectra, with the confined hole states displaying anisotropic gyromagnetic factors and strong spin–orbit coupling with pronounced dependences on gate voltage and magnetic field. [ABSTRACT FROM AUTHOR]

Lung cancer embodies the conundrum of cancer in general: why some patients with apparently similar tumors respond and others progress. In spite of a plethora of knowledge at the investigational level, in daily practice, the physician is still challenged by the lack both of prognostic markers to identify patients with a high risk of relapse and of predictive markers for customizing chemotherapy and targeted therapy. Multiple microarray studies have deciphered the important network of signaling pathways that can lead to the formation of metastasis, and we are not far from being able to predict the risk of metastasis at a particular site (bone, brain or others) according to specific gene profiles. Quantitative PCR has allowed the assessment of mRNA expression levels of key genes, identified mostly by transcriptome analysis. Growing evidence indicates that three-or five-gene signatures by quantitative PCR are highly predictive of metastasis and survival in early-stage non-small cell lung cancer, including stage IB, paving the way for the selection of high-risk patients for adjuvant chemotherapy and for the customization of treatment. A meaningful proportion of lung cancer patients are EGFR-driven, and abundant knowledge has enabled us to identify extensive networks of downstream signals that collapse when drug treatment is effective. Novel mechanisms of resistance to chemotherapy and targeted therapies can be useful for personalizing treatment and can lead to the implementation of novel targeted therapies. [ABSTRACT FROM AUTHOR]

Since Darwin, long-spurred angraecoid orchids have been known for their fascinating evolutionary relationship with long-tongued hawkmoths (Sphingidae) on Madagascar. We studied the reproductive biology of the long-spurred endemic Jumellea stenophylla on Reunion. Despite the species exhibits flowers with the typical sphingophilous pollination syndrome (i.e. spur length averaged 137.9 mm, mean nectar volume was 6.1 µl, and nectar concentration was 10.7% sugar in sucrose equivalent), it does not require pollinators to achieve fruits. Compared with other hawkmoth-pollinated orchids, flower longevity was very short, lasting less than 5 days, and the species did not emit the characteristic strong and sweet scent at dusk. Fruit set ranged from 66.7 to 83.9% when pollinators were excluded, and 56–77.5% under natural conditions. Auto-pollination is a consequence of structural modifications. On Reunion, such breeding system is not rare within long-spurred species, and seems linked to the absence of specific pollinator during island colonization, and species establishment. [ABSTRACT FROM AUTHOR]

This randomized, open-label, parallel-group, phase II study evaluated the efficacy and safety of gefitinib and docetaxel in combination, as second-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). Eighty-nine patients who had failed first-line, platinum-based chemotherapy were randomly assigned to gefitinib (250 mg/day orally) in combination with docetaxel (75 mg/m2 every 3 weeks) or single-agent docetaxel (75 mg/m2 every 3 weeks). Objective response rates were 6.8% with gefitinib plus docetaxel and 9.1% with docetaxel alone. Disease control was experienced by a higher proportion of patients receiving gefitinib plus docetaxel (59.1%) versus docetaxel alone (34.1%). Median progression-free and overall survival appeared to be longer with gefitinib plus docetaxel (3.9 months [95% CI:2.3–5.4] and 7.6 months [95% CI:5.4–10.4], respectively) than with docetaxel alone (2.1 months [95% CI:2.1–3.7] and 6.2 months [95% CI:5.2–7.2], respectively). The most common non-hematological adverse events were diarrhea, alopecia, rash and dry skin in the combination arm, and vomiting and asthenia with docetaxel alone. Gefitinib and docetaxel combination therapy has antitumor activity and may be a feasible treatment option in patients with advanced NSCLC who have failed platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]