Effect of mechanical ventilation versus spontaneous breathing on abdominal edema and inflammation in ARDS: an experimental porcine model.

BACKGROUND: Mechanical ventilation (MV), compared to spontaneous breathing (SB), has been found to increase abdominal edema and inflammation in experimental sepsis. Our hypothesis was that in primary acute respiratory distress syndrome (ARDS) MV would enhance inflammation and edema in the abdomen. METHODS: Thirteen piglets were randomized into two groups (SB and MV) after the induction of ARDS by lung lavage and 1 h of injurious ventilation. 1. SB: continuous positive airway pressure 15 cmH2O, fraction of inspired oxygen (FIO2) 0.5 and respiratory rate (RR) maintained at about 40 cycles min- 1 by titrating remifentanil infusion. 2. MV: volume control, tidal volume 6 ml kg- 1, positive end-expiratory pressure 15 cmH2O, RR 40 cycles min- 1, FIO2 0.5. MAIN OUTCOMES: abdominal edema, assessed by tissues histopathology and wet-dry weight; abdominal inflammation, assessed by cytokine concentration in tissues, blood and ascites, and tissue histopathology. RESULTS: The groups did not show significant differences in hemodynamic or respiratory parameters. Moreover, edema and inflammation in the abdominal organs were similar. However, blood IL6 increased in the MV group in all vascular beds (p < 0.001). In addition, TNFα ratio in blood increased through the lungs in MV group (+ 26% ± 3) but decreased in the SB group (- 17% ± 3). CONCLUSIONS: There were no differences between the MV and SB group for abdominal edema or inflammation. However, the systemic increase in IL6 and the TNFα increase through the lungs suggest that MV, in this model, was harmful to the lungs.

Sovereign rating after private and official restructuring.

This paper studies the relationship between sovereign debt (final) restructuring and sovereign ratings, by distinguishing between commercial and official debt and by considering the creditors' loss (haircut). Institutional Investor's index is taken as a measure of a country's creditworthiness. We find that while a restructuring with private creditors seems to involve some reputational costs, "official defaulters" are not affected (or may even benefit) by the restructuring episodes. Using the Synthetic Control Method, we find further evidence for the heterogeneity of the economic impact of debt restructurings, confirming that official and private restructurings may have different costs and then induce selective defaults.

Abdominal organ perfusion and inflammation in experimental sepsis: a magnetic resonance imaging study.

Diffusion-weighted magnetic resonance imaging (DW-MRI) uses water as contrast and enables the study of perfusion in many organs simultaneously in situ. We used DW-MRI in a hypodynamic sepsis model, comparing abdominal organ perfusion with global hemodynamic measurements and inflammation. Sixteen anesthetized piglets were randomized into 3 groups: 2 intervention (sepsis) groups: HighMAP (mean arterial pressure, MAP > 65 mmHg) and LowMAP (MAP between 50 and 60 mmHg), and a Healthy Control group (HC). Sepsis was obtained with endotoxin and the desired MAP maintained with norepinephrine. After 6 h, DW-MRI was performed. Acute inflammation was assessed with IL-6 and TNFα in abdominal organs, ascites, and blood and by histology of intestine (duodenum). Perfusion of abdominal organs was reduced in the LowMAP group compared with the HighMAP group and HC. Liver perfusion was still reduced by 25% in the HighMAP group compared with HC. Intestinal perfusion did not differ significantly between the intervention groups. Cytokine concentrations were generally higher in the LowMAP group but did not correlate with global hemodynamics. However, cytokines correlated with regional perfusion and, for liver and intestine, also with intra-abdominal pressure. Histopathology of intestine worsened with decreasing perfusion. In conclusion, although a low MAP (≤60 mmHg) indicated impeded abdominal perfusion in experimental sepsis, it did not predict inflammation, nor did other global measures of circulation. Decreased abdominal perfusion partially predicted inflammation but intestine, occupying most of the abdomen, and liver were also affected by intra-abdominal pressure. NEW & NOTEWORTHY The study increases the knowledge of abdominal perfusion during sepsis. We used diffusion weighted imaging to assess perfusion simultaneously and noninvasively in different abdominal organs. The technique has not been used in a sepsis model before. Cytokine concentrations were measured in different abdominal organs and vascular beds and related to regional perfusion. Decreased abdominal perfusion, but not global measures of circulation, predicted inflammation. Intestine, occupying most of the abdomen, and liver were also affected by intra-abdominal pressure.

Continuous chest compressions are associated with higher peak inspiratory pressures when compared to 30:2 in an experimental cardiac arrest model.

BACKGROUND: Ventilation during cardiopulmonary resuscitation (CPR) has long been a part of the standard treatment during cardiac arrests. Ventilation is usually given either during continuous chest compressions (CCC) or during a short pause after every 30 chest compressions (30:2). There is limited knowledge of how ventilation is delivered if it effects the hemodynamics and if it plays a role in the occurrence of lung injuries. The aim of this study was to compare ventilation parameters, hemodynamics, blood gases and lung injuries during experimental CPR given with CCC and 30:2 in a porcine model. METHODS: Sixteen pigs weighing approximately 33 kg were randomized to either receive CPR with CCC or 30:2. Ventricular fibrillation was induced by passing an electrical current through the heart. CPR was started after 3 min and given for 20 min. Chest compressions were provided mechanically with a chest compression device and ventilations were delivered manually with a self-inflating bag and 12 l/min of oxygen. During the experiment, ventilation parameters and hemodynamics were sampled continuously, and arterial blood gases were taken every five minutes. After euthanasia and cessation of CPR, the lungs and heart were removed in block and visually examined followed by sampling of lung tissue which were examined using microscopy. RESULTS: In the CCC group and the 30:2 group, peak inspiratory pressure (PIP) was 58.6 and 35.1 cmH2O (p < 0.001), minute volume (MV) 2189.6 and 1267.1 ml (p < 0.001), peak expired carbon dioxide (PECO2) 28.6 and 39.4 mmHg (p = 0.020), partial pressure of carbon dioxide (PaCO2) 50.2 and 61.1 mmHg (p = 0.013) and pH 7.3 and 7.2 (p = 0.029), respectively. Central venous pressure (CVP) decreased more over time in the 30:2 group (p = 0.023). All lungs were injured, but there were no differences between the groups. CONCLUSIONS: Ventilation during CCC resulted in a higher PIP, MV and pH and lower PECO2 and PaCO2, showing that ventilation mode during CPR can affect ventilation parameters and blood gases.

Case report: Successful use of mepolizumab for immune checkpoint inhibitors-induced hypereosinophilic syndrome in two patients with solid malignancies.

Hypereosinophilic syndrome (HES) represents a group of blood disorders characterized by an absolute eosinophil count (AEC) > 1.5 × 103/µl in the peripheral blood, which eventually extravasate and cause organ damage. It can be primary or secondary to infections or tumors. The infiltration of eosinophils in tissue and organs is associated with different disorders and, in some cases, with life-threatening manifestations. Albeit the pathogenesis of HES in patients with solid tumo\rs is not yet clarified; recently, HES has also been described as an immune-related adverse event in patients with solid tumors receiving immune checkpoint inhibitors. Treatment of HES is still debated, especially in patients with concomitant solid tumors, and different drugs including imatinib, hydroxyurea, interferon-ɑ, glucocorticoids, and the monoclonal antibody targeting circulating IL-5 mepolizumab have been proposed according to the underlying cause and the severity of HES. Herein, we describe, for the first time, the successful use of mepolizumab for the treatment of immune checkpoint-induced HES in two patients with metastatic solid tumor.

Immunotherapy in Early-Stage Non-Small Cell Lung Cancer (NSCLC): Current Evidence and Perspectives.

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

Effect of a quality improvement program on compliance to the sepsis bundle in non-ICU patients: a multicenter prospective before and after cohort study.

Objective: Sepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a "simplified 1-h bundle" (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU). Methods: Emergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort). Measurements and main results: The effect of QIP on bundle compliance and hospital mortality was evaluated in a before-after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the "simplified rapid (1 h) intervention bundle" (the Sepsis 6 bundle - S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p < 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients' cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate <4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality. Conclusion: A multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality.

Suction cup on a piston-based chest compression device improves coronary perfusion pressure and cerebral oxygenation during experimental cardiopulmonary resuscitation.

Introduction: The presented study aimed to investigate whether a mechanical chest compression piston device with a suction cup assisting chest recoil could impact the hemodynamic status when compared to a bare piston during cardiopulmonary resuscitation. Methods: 16 piglets were anesthetized and randomized into 2 groups. After 3 minutes of induced ventricular fibrillation, a LUCAS 3 device was used to perform chest compressions, in one group a suction cup was mounted on the device's piston, while in the other group, compressions were performed by the bare piston. The device was used in 30:2 mode and the animals were manually ventilated. Endpoints of the study were: end tidal carbon dioxide, coronary and cerebral perfusion pressures, and brain oxygenation (measured using near infrared spectroscopy). At the end of the protocol, the animals that got a return to spontaneous circulation were observed for 60 minutes, then euthanized. Results: No difference was found in end tidal carbon dioxide or tidal volumes. Coronary perfusion pressure and cerebral oxygenation were higher in the Suction cup group over the entire experiment time, while cerebral perfusion pressure was higher only in the last 5 minutes of CPR. A passive tidal volume (air going in and out the airways during compressions) was detected and found correlated to end tidal carbon dioxide. Conclusions: The use of a suction cup on a piston-based chest compression device did not increase end tidal carbon dioxide, but it was associated to a higher coronary perfusion pressure.

Duodenum edema due to reduced lymphatic drainage leads to increased inflammation in a porcine endotoxemic model.

BACKGROUND: Interventions, such as mechanical ventilation with high positive end-expiratory pressure (PEEP), increase inflammation in abdominal organs. This effect could be due to reduced venous return and impaired splanchnic perfusion, or intestinal edema by reduced lymphatic drainage. However, it is not clear whether abdominal edema per se leads to increased intestinal inflammation when perfusion is normal. The aim of the presented study was to investigate if an impaired thoracic duct function can induce edema of the abdominal organs and if it is associated to increase inflammation when perfusion is maintained normal. In a porcine model, endotoxin was used to induce systemic inflammation. In the Edema group (n = 6) the abdominal portion of the thoracic duct was ligated, while in the Control group (7 animals) it was maintained intact. Half of the animals underwent a diffusion weighted-magnetic resonance imaging (DW-MRI) at the end of the 6-h observation period to determine the abdominal organ perfusion. Edema in abdominal organs was assessed using wet-dry weight and with MRI. Inflammation was assessed by measuring cytokine concentrations in abdominal organs and blood as well as histopathological analysis of the abdominal organs. RESULTS: Organ perfusion was similar in both groups, but the Edema group had more intestinal (duodenum) edema, ascites, higher intra-abdominal pressure (IAP) at the end of observation time, and higher cytokine concentration in the small intestine. Systemic cytokines (from blood samples) correlated with IAP. CONCLUSIONS: In this experimental endotoxemic porcine model, the thoracic duct's ligation enhanced edema formation in the duodenum, and it was associated with increased inflammation.

Delegation of implementation in project aid.

In this paper we explore the factors that determine delegation of implementation in project aid. In particular, focusing on the importance of informational asymmetry between levels of government, we empirically assess whether this choice is influenced by the relative importance of the local information at the recipient country level. Moreover, we test whether this choice can in turn influence project performance. Using information on more than 5800 World Bank projects for the period 1995-2014, and controlling for characteristics at both country and project level, we find that transparency does influence the probability that a project is implemented locally rather than nationally. More specifically, a one standard deviation decline in transparency increases the probability of a locally implemented project by three percentage points. We also find that a local implementing agency may increase the probability of a successful project only up to a certain level of a country's transparency.

A context-sensitive technique robust to registration noise for change detection in VHR multispectral images.

This paper presents an automatic context-sensitive technique robust to registration noise (RN) for change detection (CD) in multitemporal very high geometrical resolution (VHR) remote sensing images. Exploiting the properties of RN in VHR images, the proposed technique analyzes the distribution of the spectral change vectors (SCVs) computed according to the change vector analysis (CVA) in a quantized polar domain. The method studies the SCVs falling into each quantization cell at different resolution levels (scales) to automatically identify the effects of RN in the polar domain. This information is jointly exploited with the spatial context information contained in the neighborhood of each pixel for generating the final CD map. The spatial context information is modeled through the definition of adaptive regions homogeneous both in spatial and temporal domain (parcels). Experimental results obtained on real VHR remote sensing multitemporal images confirm the effectiveness of the proposed technique.