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A tandem structure efficiently boosts solar cell efficiency because it uses a larger spectrum of solar radiation and minimizes photon energy thermalization. High-performance tandem solar cells have historically been difficult to produce due to a shortage of high-performance, low-bandgap cells. The proposed design is based on the CH3NH3GeI3 (1.9 eV) as a wide band gap absorber layer and FAMASnGeI3 (1.4 eV) as a narrow band gap perovskite layer with CZTSe as HTL. This research investigates the effect of different ETLs, perovskite layer thicknesses and their doping concentration on the device's photovoltaic parameters. Furthermore, the effect of tunnel junction thickness and front contact work function on the solar cell performance has also been simulated. It has been noted that the PCBM presents a better efficiency device than the other ETLs. The Voc of different ETLs has been related to Vbi. Moreover, the optimized thicknesses of both perovskite absorber layers are 450 nm and 400 nm for MAGeI3 and FAMASnGeI3, respectively. The optimal doping density is found to be E14 cm−3. It has been observed that the tunnel junction's thickness and the front contact's work function also play an important role in optimized device efficiency. The tunnel junction thickness is 4 nm for lead-free mixed cation perovskite/CZTSe tandem solar cells. However, the work function of the front electrode of 4.4 eV is optimum for this structure. The proposed lead-free mixed cation perovskite/CZTSe tandem device shows significant performance parameters, i.e., Voc= 0.970 V, Jsc = 28.46 mAcm−2, FF = 84.43 % and PCE= 23.32 %

Railway infrastructure maintenance is critical for ensuring safe and efficient transportation networks. Railway track surface defects such as cracks, flakings, joints, spallings, shellings, squats, grooves pose substantial challenges to the integrity and longevity of the tracks. To address these challenges and facilitate further research, a novel dataset of railway track surface faults has been presented in this paper. It is collected using the EKENH9R cameras mounted on a railway inspection vehicle. This dataset represents a valuable resource for the railway maintenance and computer vision related scientific communities. This dataset includes a diverse range of real-world track surface faults under various environmental conditions and lighting scenarios. This makes it an important asset for the development and evaluation of Machine Learning (ML), Deep Learning (DL), and image processing algorithms. This paper also provides detailed annotations and metadata for each image class, enabling precise fault classification and severity assessment of the defects. Furthermore, this paper discusses the data collection process, highlights the significance of railway track maintenance, emphasizes the potential applications of this dataset in fault identification and predictive maintenance, and development of automated inspection systems. We encourage the research community to utilize this dataset for advancing the state-of-the-art research related to railway track surface condition monitoring.

Purpose: Local tumor progression is a cause of significant morbidity and mortality in patients with pancreatic ductal adenocarcinoma (PDAC) with surgically unresectable disease. Novel and effective approaches to accomplish durable local control are urgently needed. We tested whether CPI-613 (devimistat), a first-in-class investigational small molecule inhibitor of mitochondrial metabolism, was capable of altering cancer cell energy metabolism and sensitizing PDAC cells to radiation therapy (RT). Methods and Materials: The effect of a combined treatment of RT with CPI-613 on the viability of, clonogenic potential of, and cell death induction in PDAC cells (MiaPaCa-2 and Panc-1) was determined using a trypan blue dye exclusion assay, a colony formation assay, and a 7–amino-actinomycin D assay, respectively. The synergistic effects of CPI-613-RT and chemotherapeutic agents (gemcitabine or 5-fluorouracil) were measured in MiaPaCa-2 cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and spheroid formation assay. Changes in energy metabolism were determined by profiling metabolites treated with either RT, CPI-613, or both using liquid chromatography-mass spectrometry. Results: This study demonstrates that a combination of single-fraction RT (2 and 10 Gy) with CPI-613 significantly inhibits PDAC cell growth compared with RT alone. Molecular analysis revealed inhibition of α-ketoglutarate dehydrogenase at the protein level. In addition, we demonstrate enhanced cell death of PDAC cells when treated with RT-CPI-613 combination. Targeted metabolomic analysis on PDAC cells post–CPI-613-RT treatment revealed alterations in key mitochondrial metabolites, with broader target engagement by the combination treatment, indicating the sensitization of CPI-613–treated PDAC cells to RT. Furthermore, a combination treatment of CPI-613 with either gemcitabine or 5-fluorouracil in the presence of 2 Gy RT synergistically inhibits PDAC cell proliferation. Conclusions: Our results support a novel combination of CPI-613-RT that warrants further preclinical and early-phase clinical investigations. A phase 1 trial designed to identify the maximum tolerated dose of CPI-613 in combination with chemo-RT in patients with PDAC was recently initiated (NCT05325281).

Thermogravimetric analysis/differential scanning calorimeter (TGA/DSC) technique along with basic coal characteristics study is carried out for eighty coal samples of Indian coalfields, to determine spontaneous combustion propensity behaviour of coal. TGA study of coal samples indicates that there is an increase in the mass of coal samples in the temperature range 150–350 ℃, which may be due to oxygen adsorption and absorption. The correlation and principal component analysis states that the component of proximate analysis (Mad, VMd, FR, and VR) have an acceptable correlation with the TGA experiments results i.e., Tgsh and Tgign. Multiple fixed nonlinear regression analysis shows that thermogravimetry (TG) experiment results Tgign may be the best index to categorise/classify the coal as per their susceptibility towards spontaneous combustion. The authors proposed four groups of classification as per their propensity towards spontaneous combustion depending upon the moisture (Mad), volatile matter (VMd), and TG ignition temperature from differential thermogravimetric (DTG) curve (Tgign) using hierarchal clustering analysis. The coal samples of different seams from Indian coalfield may be classified into four different clusters, viz. very highly/extremely susceptible (Tgign 320 ℃). The field observations and TGA/DSC experiment results with the following statistical analysis substantiate a similar assessment.

Mine disasters occur predominantly due to methane or coal dust explosion or a combination of both. Among the top ten worst coal mine disasters in India, nine are due to coal dust explosion. The current paper describes a general overview of the parameters causing dispersion leading to coal dust explosion, and computational fluid dynamics (CFD) simulation study to observe the effects of particle size on dispersion in Indian coal mines. Turbulent kinetic energy (TKE) and velocity vector path of dust-air mixture and dust-free air were simulated to understand their effects on coal dust dispersion. The TKE contours and velocity vector paths for dust-free air were uniform and symmetrical due to resistance-free path available. The TKE contours and velocity vector paths for dust-air mixture shows the asymmetrical distribution of contours, due to entrainment of air with dust particles. Vortices were observed in velocity vector paths which gradually diminish on increment of time sequence. These vortices are dead centres where velocity and coal dust particles concentration are both zero.

Autism spectrum disorder (ASD) is a childhood-onset neurodevelopmental disorder characterized by social interaction, behavior, and communication challenges. Here, we generated an induced pluripotent stem cell (iPSC) line, QBRIi013-A using a non-integrating Sendai virus from a 6-year-old female diagnosed with ASD and intellectual disability. The QBRIi013-A cell line was fully characterized and exhibited a pluripotency capacity and trilineage differentiation potential. Furthermore, it showed normal karyotype and genetic identity to the patient’s PBMCs. Consequently, this iPSC line provides a valuable cell model in understanding the molecular mechanism underlying the complexities of ASD pathogenesis.

Background: Waterpipe tobacco smoking (WTS) has increased substantially in the Eastern Mediterranean Region (EMR), affecting young adults who perceive waterpipe as safer than cigarette smoking. Applying pictorial health warning labels (HWLs) on tobacco products has been effective in communicating health risks associated with tobacco smoking. However, there are few experimental studies that examined pictorial HWLs specific to WTS. Methods/design: This report describes the design and protocol of the first factorial experimental study that aims to test the effectiveness of pictorial HWLs based on their placement on waterpipe device, tobacco, and charcoal packages among young adult smokers and non-smokers residing in Lebanon and Tunisia. After completing a baseline assessment, participants will be randomly assigned to 3 experimental conditions in a 3 (HWL: pictorial HWL on tobacco package vs. pictorial HWL on 3 placements [device, tobacco, and charcoal packages] vs. text-only HWL on tobacco package) x 4 (pictorial HWLs) x 2 (waterpipe smokers vs. non-smokers) factorial design. We will use a within/between-subject design, where pictorial HWLs and time (pre vs. post-exposure) are the within-subject factors and waterpipe smoking status as the between-subjects factor. Participants will complete post-exposure measures that include attention, perceived harm, intention to quit (smokers) or initiate smoking (non-smokers). Discussion: This is the first international study examining the placements of pictorial HWLs using efficient within/between subject design. Findings will provide additional evidence to convince policymakers to consider three placements of HWLs specific to WTS as a promising regulatory target to curb WTS.

Approximately 45% of young cancer survivors (18–40 years) are cigarette smokers. Continued smoking after cancer diagnosis leads to lower survival rates. A major logistical problem with smoking cessation efforts in this group is their geographic dispersion which makes them hard to reach. In addition, depression is a major predictor of smoking relapse and its rates are roughly twice as high in cancer survivors as the general population. Smartphone applications (apps) show promise in terms of efficacy, dissemination, and improving access to treatment. Mindfulness training (defined as maintaining attention on one's immediate experience and cultivating an attitude of acceptance toward this experience) is effective in improving smoking cessation outcomes by reducing psychological stress and controlling craving. Given that smartphone apps can address the issues of mobility and remote access, and mindfulness can address the high depression rate among cancer survivors, validating the feasibility and efficacy of a mindfulness-based smoking cessation intervention app in young cancer survivors is a high priority. Thus, the aims of the current study are: (1) test the feasibility, acceptability, and potential efficacy of the mindfulness-based smoking cessation app versus in-person mindfulness or usual care in a 3-arm pilot randomized clinical trial among young cancer survivors (n = 60; 18–40 years); and 2) conduct semi-structured exit interviews with participants in the two mindfulness groups to fine-tune the two active interventions based on feedback from participants. Findings will have implications for the development and dissemination of innovative and highly scalable tobacco cessation interventions designed for young cancer survivors.

Development of acquired resistance to cisplatin (CDDP) is a major obstacle in the treatment of ovarian cancer patients. According to the cancer stem cell (CSC) hypothesis, the recurrence and chemoresistance are presumed to be linked to cancer stem/progenitor cells. Here, we investigated the CSC-like phenotypes and mechanism of chemoresistance in CDDP resistant ovarian cancer cells. A well-established CDDP sensitive ovarian cancer cell line A2780 and its resistant population A2780-Cp were used. We also developed a supra resistant population (SKOV3-Cp) from a naturally CDDP resistant cell line SKOV3. Both resistant/supra resistant cell lines showed significantly higher self-renewal capability than their parental counterparts. They also showed significant resistance to apoptosis and sub-G1 arrest by CDDP treatment. Stem cell marker ALDH1 positivity rates were higher both in A2780-Cp and SKOV3-Cp cell lines than in their counterparts, quantified by Aldefluor assay kit. Hoechst 33342 dye effluxing side populations were increased up to about five folds in A2780-Cp cells and two folds in SKOV3-Cp cells compared to A2780 and SKOV3 cells, respectively. Among major stemness related genes (POU5F1/OCT4, SOX2, NANOG, NES, BMI1, KLF4 and ALDH1A1), ALDH1A1 and KLF4 were significantly overexpressed in both resistant/supra resistant cells. Silencing ALDH1A1 in A2780 and A2780-Cp cells using siRNA greatly reduced the stem cell population and sensitized cells to CDDP. Moreover, silencing of ALDH1A1 reduced the transcript and protein level of its downstream target NEK-2. We also observed the downregulation of ABC transporters (ABCB1/MDR1, ABCG2 and ABCC1/MRP1) either by ALDH1A1 or NEK-2 silencing and upreguation of ABCB1/MDR1 due to the overexpression of NEK-2. Taken together, the present study suggests that stemness gene ALDH1A1 can be involved in CDDP resistance through the upregulation of NEK-2 in ovarian cancer.

In this article, two models of the generalized thermo-elastic theory are used to see the influence on the refraction and reflection of the plane waves at the interface under a constant magnetic field. The elasticity modulus depends on the reference temperature. The elasticity modulus is considered as a linear function of reference temperature. The resulting problem is solved by using the boundary conditions at the interface. The matrix equations have been solved numerically. Keywords: Generalized thermo-elasticity, Refraction, Reflection, Relaxation times

Bruton's Tyrosine Kinase (BTK) is a member of the TEC family and plays a central role in B-cell signaling, activation, proliferation and differentiation. Here we evaluated the impact of BTK inhibitor Ibrutinib on a panel of HL models in vitro and in vivo. Ibrutinib suppressed viability and induced apoptosis in 4 HL cell lines in a dose and time dependent manner. Molecular analysis showed induction of both apoptotic and autophagy markers. Ibrutinib treatment resulted in suppression of BTK and other downstream targets including PI3K, mTOR and RICTOR. Ibrutinib given at 50 mg/kg p.o daily for three weeks caused statistically significant inhibition of HL cell line derived subcutaneous xenografts (p < 0.01) in ICR-SCID mice. Molecular analysis of residual tumor tissue revealed down-regulation of BTK; its related markers and autophagy markers. Our studies are the first showing in vitro and in vivo action of BTK inhibition in classical HL. A phase II study examining the activity of ibrutinib in relapsed or refractory HL is currently enrolling (NCT02824029).

Background: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets., Methods: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed., Findings: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032)., Interpretation: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications., Funding: French Ministry of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Targeted temperature management (TTM) currently is the only treatment with demonstrated efficacy in attenuating the harmful effects on the brain of ischemia-reperfusion injury after cardiac arrest. However, whether TTM is beneficial in the subset of patients with in-hospital cardiac arrest (IHCA) remains unclear., Research Question: Is TTM at 33 °C associated with better neurological outcomes after IHCA in a nonshockable rhythm compared with targeted normothermia (TN; 37 °C)?, Study Design and Methods: We performed a post hoc analysis of data from the published Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm randomized controlled trial in 584 patients. We included the 159 patients with IHCA; 73 were randomized to 33 °C treatment and 86 were randomized to 37 °C treatment. The primary outcome was survival with a good neurologic outcome (cerebral performance category [CPC] score of 1 or 2) on day 90. Mixed multivariate adjusted logistic regression analysis was performed to determine whether survival with CPC score of 1 or 2 on day 90 was associated with type of temperature management after adjustment on baseline characteristics not balanced by randomization., Results: Compared with TN for 48 h, hypothermia at 33 °C for 24 h was associated with a higher percentage of patients who were alive with good neurologic outcomes on day 90 (16.4% vs 5.8%; P = .03). Day 90 mortality was not significantly different between the two groups (68.5% vs 76.7%; P = .24). By mixed multivariate analysis adjusted by Cardiac Arrest Hospital Prognosis score and circulatory shock status, hypothermia was associated significantly with good day 90 neurologic outcomes (OR, 2.40 [95% CI, 1.17-13.03]; P = .03)., Interpretation: Hypothermia at 33 °C was associated with better day 90 neurologic outcomes after IHCA in a nonshockable rhythm compared with TN. However, the limited sample size resulted in wide CIs. Further studies of patients after cardiac arrest resulting from any cause, including IHCA, are needed., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury., Methods: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580., Findings: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089)., Interpretation: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials., Funding: Programme Hospitalier de Recherche Clinique., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients with sepsis-induced cardiomyopathy with cardiogenic shock have a high mortality. This study assessed venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for sepsis-induced cardiogenic shock refractory to conventional treatments., Methods: In this retrospective, multicentre, international cohort study, we compared outcomes of 82 patients (aged ≥18 years) with septic shock who received VA-ECMO at five academic ECMO centres, with 130 controls (not receiving ECMO) obtained from three large databases of septic shock. All patients had severe myocardial dysfunction (cardiac index 3 L/min per m 2 or less or left ventricular ejection fraction [LVEF] 35% or less) and severe haemodynamic compromise (inotrope score at least 75 μg/kg per min or lactic acidaemia at least 4 mmol/L) at time of inclusion. The primary endpoint was survival at 90 days. A propensity score-weighted analysis was done to control for confounders., Findings: At baseline, patients treated with VA-ECMO had more severe myocardial dysfunction (mean cardiac index 1·5 L/min per m 2 vs 2·2 L/min per m 2 , LVEF 17% vs 27%), more severe haemodynamic impairment (inotrope score 279 μg/kg per min vs 145 μg/kg per min, lactataemia 8·9 mmol/L vs 6·5 mmol/L), and more severe organ failure (Sequential Organ Failure Assessment score 17 vs 13) than did controls, with p<0·0001 for each comparison. Survival at 90 days for patients treated with VA-ECMO was significantly higher than for controls (60% vs 25%, risk ratio [RR] for mortality 0·54, 95% CI [0·40-0·70]; p<0·0001). After propensity score weighting, ECMO remained associated with improved survival (51% vs 14%, adjusted RR for mortality 0·57, 95% CI [0·35-0·93]; p=0·0029). Lactate and catecholamine clearance were also significantly enhanced in patients treated with ECMO. Among the 49 survivors treated with ECMO, 32 who had been treated at the largest centre reported satisfactory Short Form-36 evaluated health-related quality of life at 1-year follow-up., Interpretation: Patients with severe sepsis-induced cardiogenic shock treated with VA-ECMO had a large and significant improvement in survival compared with controls not receiving ECMO. However, despite the careful propensity-weighted analysis, we cannot rule out unmeasured confounders., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition., Methods: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099., Findings: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04)., Interpretation: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition., Funding: La Roche-sur-Yon Departmental Hospital and French Ministry of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO 2 ) and fluid resuscitation with hypertonic saline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality., Methods: This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO 2 at 1·0 (hyperoxia) or FiO 2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422., Findings: Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23)., Interpretation: In patients with septic shock, setting FiO 2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival., Funding: The French Ministry of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Numerous papers have been published on the role of H2S during circulatory shock. Consequently, knowledge about vascular sulfide concentrations may assume major importance, in particular in the context of "acute on chronic disease", i.e., during circulatory shock in animals with pre-existing chronic disease. This review addresses the questions (i) of the "real" sulfide levels during circulatory shock, and (ii) to which extent injury and pre-existing co-morbidity may affect the expression of H2S producing enzymes under these conditions. In the literature there is a huge range on sulfide blood levels during circulatory shock, in part as a result of the different analytical methods used, but also due to the variable of the models and species studied. Clearly, some of the very high levels reported should be questioned in the context of the well-known H2S toxicity. As long as "real" sulfide levels during circulatory shock are unknown and/or undetectable "on line" due to the lack of appropriate techniques, it appears to be premature to correlate the measured blood levels of hydrogen sulfide with the severity of shock or the H2S therapy-related biological outcomes. The available data on the tissue expression of the H2S-releasing enzymes during circulatory shock suggest that a "constitutive" CSE expression may play a crucial role of for the maintenance of organ function, at least in the kidney. The data also indicate that increased CBS and CSE expression, in particular in the lung and the liver, represents an adaptive response to stress states., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Given the controversial experimental and clinical data reported in the literature, up to now it is rather difficult to draw a definitive conclusion on the effects of V1 agonists on splanchnic haemodynamics. Nevertheless, it must be underscored that most of the experimental studies assessing the effects of low dose V1 agonist infusion in hyperdynamic models did not demonstrate any detrimental effect on splanchnic haemodynamics both at macro- and microcirculatory levels. Interestingly, all the reported studies focused on macro- and microcirculatory haemodynamics, while only some also addressed the local oxygenation and metabolism. In clinical studies in patients with septic shock, data are accumulating regarding the absence of clinically relevant side effects in the splanchnic region when vasopressin is used, but conversely little is known about the safety of terlipressin, mainly because of the small number of patients studied. Thus, the absence of clinically harmful effect does not exclude covert splanchnic ischaemia, which may counterbalance the beneficial systemic effects.

Human serum albumin (HSA) is used as a resuscitation fluid in sepsis. This study investigated the potential protective properties of HSA on vascular function in a mouse endotoxic model in terms of oxidative and nitrosative stresses. Swiss mice were treated with either lipopolysaccharide (LPS) (50 mg/kg i.p.) or vehicle. One and five hours later, mice were infused with HSA (4%, 10 ml/kg), normal saline (0.9% NaCl, 30 ml/kg), or no fluid. Six hours after treatment, vascular reactivity was assessed on aortae and small mesenteric arteries. Measurements of NO and superoxide anion (O2(-)) by spin trapping and nuclear factor (NF)-kappaB, inducible NO synthase (iNOS), and peroxynitrite by Western blotting and immunohistochemical studies were conducted. HSA partially prevented the reduction of blood pressure induced by LPS and completely prevented both vascular hyporeactivity to phenylephrine and myogenic tone as well as endothelial dysfunction induced by the endotoxin. This was associated with a decreased up-regulation of NF-kappa B, iNOS, and peroxynitrite in the vascular wall. LPS-induced tissue increases in both NO and O2(-) production was decreased by HSA. These data demonstrate the protective effect of HSA treatment in experimental endotoxic shock by reducing the inflammatory process leading to oxidative and nitrosative stresses and vascular hyporeactivity.

Aims: To examine the feasibility of percutaneous radiologic gastrostomy in critically ill patients and to assess the rates of complications, esophagitis and gastroesophageal reflux when compared with nasogastric tube., Method: Sixty patients admitted to a medical intensive care unit and who were supposed to require gastric tubing for at least 14 days were randomized to have a nasogastric tube or a percutaneous radiologic gastrostomy. Patients with gastrostomy contraindication or gastric tubing for more than 2 days were excluded., Results: No major complication requiring invasive treatment was observed. The nasogastric tube was more prone to failure as defined by the impossibility to place or to replace the allocated tube (P = 0.04) and to tube dysfunction (P<0.001), whereas gastrostomy was associated with increased incidence of minor local complications (P<0.001). Ten days after allocation, the rates of esophagitis (15%) and gastroesophageal reflux (24%) were not significantly different between the two groups., Conclusion: In selected critically ill patients, percutaneous radiologic gastrostomy carried a low risk of severe complication but we found no benefit in terms of esophagitis and gastroesphageal reflux between early performed gastrostomy and the nasogastric tube.