Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin.

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

Biomarkers in Systemic Sclerosis: An Overview.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor ß (TGF-ß) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Tidal lung hysteresis to interpret PEEP-induced changes in compliance in ARDS patients.

BACKGROUND: In ARDS, the PEEP level associated with the best respiratory system compliance is often selected; however, intra-tidal recruitment can increase compliance, falsely suggesting improvement in baseline mechanics. Tidal lung hysteresis increases with intra-tidal recruitment and can help interpreting changes in compliance. This study aims to assess tidal recruitment in ARDS patients and to test a combined approach, based on tidal hysteresis and compliance, to interpret decremental PEEP trials. METHODS: A decremental PEEP trial was performed in 38 COVID-19 moderate to severe ARDS patients. At each step, we performed a low-flow inflation-deflation manoeuvre between PEEP and a constant plateau pressure, to measure tidal hysteresis and compliance. RESULTS: According to changes of tidal hysteresis, three typical patterns were observed: 10 (26%) patients showed consistently high tidal-recruitment, 12 (32%) consistently low tidal-recruitment and 16 (42%) displayed a biphasic pattern moving from low to high tidal-recruitment below a certain PEEP. Compliance increased after 82% of PEEP step decreases and this was associated to a large increase of tidal hysteresis in 44% of cases. Agreement between best compliance and combined approaches was accordingly poor (K = 0.024). The combined approach suggested to increase PEEP in high tidal-recruiters, mainly to keep PEEP constant in biphasic pattern and to decrease PEEP in low tidal-recruiters. PEEP based on the combined approach was associated with lower tidal hysteresis (92.7 ± 20.9 vs. 204.7 ± 110.0 mL; p < 0.001) and lower dissipated energy per breath (0.1 ± 0.1 vs. 0.4 ± 0.2 J; p < 0.001) compared to the best compliance approach. Tidal hysteresis ≥ 100 mL was highly predictive of tidal recruitment at next PEEP step reduction (AUC 0.97; p < 0.001). CONCLUSIONS: Assessment of tidal hysteresis improves the interpretation of decremental PEEP trials and may help limiting tidal recruitment and energy dissipated into the respiratory system during mechanical ventilation of ARDS patients.

Will the last be the first? School closures and educational outcomes.

Governments have implemented school closures and online learning as one of the main tools to reduce the spread of Covid-19. Despite the potential benefits in terms of containment of virus diffusion, the educational costs of these policies may be dramatic. This work identifies these costs, expressed as decrease in test scores, for the whole universe of Italian students attending the 5th, 8th and 13th grade of the school cycle during the 2021/22 school year. The analysis is based on a difference-in-difference model in relative time, where the control group is the closest generation before the Covid-19 pandemic. Results suggest a national average loss between 1.8-4.0% in Mathematics and Italian test scores. After collecting the precise number of school closure days for the universe of students in Sicily, this work also estimates that the average days of closure decrease the test score by 2.4%. In this context, parents appear to have a partial compensatory effect, but only when holding higher levels of education and when their children are attending low and middle schools. This is likely explained by the lower relevance of parental inputs and higher reliance on other inputs, such as peers, for the higher grades. Finally, the effects are also heterogeneous across class size, parents' country of birth and job conditions, pointing towards potential growing inequalities driven by the lack of frontal teaching.

School-age vaccination, school openings and Covid-19 diffusion.

This article investigates the relationship between school openings and Covid-19 diffusion when school-age vaccination becomes available. The analysis relies on a unique geo-referenced high frequency database on age of vaccination, Covid-19 cases and hospitalization indicators from the Italian region of Sicily. The study focuses on the change of Covid-19 diffusion after school opening in a homogeneous geographical territory (i.e., with the same control measures and surveillance systems, centrally coordinated by the Regional Government). The identification of causal effects derives from a comparison of the change in cases before and after school opening in the school year 2020/21, when vaccination was not available, and in 2021/22, when the vaccination campaign targeted individuals of age 12-19 and above 19. Results indicate that, while school opening determined an increase in the growth rate of Covid-19 cases in 2020/2021, this effect has been substantially reduced by school-age vaccination in 2021/2022. In particular, we find that an increase of approximately 10% in the vaccination rate of school-age population reduces the growth rate of Covid-19 cases after school opening by approximately 1%.

Waveforms-guided cycling-off during pressure support ventilation improves both inspiratory and expiratory patient-ventilator synchronisation.

OBJECTIVE: To test the performance of a software able to control mechanical ventilator cycling-off by means of automatic, real-time analysis of ventilator waveforms during pressure support ventilation. DESIGN: Prospective randomised crossover study. SETTING: University Intensive Care Unit. PATIENTS: Fifteen difficult-to-wean patients under pressure support ventilation. INTERVENTIONS: Patients were ventilated using a G5 ventilator (Hamilton Medical, Bonaduz, Switzerland) with three different cycling-off settings: standard (expiratory trigger sensitivity set at 25% of peak inspiratory flow), optimised by an expert clinician and automated; the last two settings were tested at baseline pressure support and after a 50% increase in pressure support. MEASUREMENTS AND MAIN RESULTS: Ventilator waveforms were recorded and analysed by four physicians experts in waveforms analysis. Major and minor asynchronies were detected and total asynchrony time computed. Automation compared to standard setting reduced cycling delay from 407 ms [257-567] to 59 ms [22-111] and ineffective efforts from 12.5% [3.4-46.4] to 2.8% [1.9-4.6]) at baseline support (p < 0.001); expert optimisation performed similarly. At high support both cycling delay and ineffective efforts increased, mainly in the case of expert setting, with the need of reoptimisation of expiratory trigger sensitivity. At baseline support, asynchrony time decreased from 39.9% [27.4-58.7] with standard setting to 32% [22.3-39.4] with expert optimisation (p < 0.01) and to 24.4% [19.6-32.5] with automation (p < 0.001). Both at baseline and at high support, asynchrony time was lower with automation than with expert setting. CONCLUSIONS: Cycling-off guided by automated real-time waveforms analysis seems a reliable solution to improve synchronisation in difficult-to-wean patients under pressure support ventilation.

The Role of Lung Ultrasound Monitoring in Early Detection of Ventilator-Associated Pneumonia in COVID-19 Patients: A Retrospective Observational Study.

Specific lung ultrasound signs combined with clinical parameters allow for early diagnosis of ventilator-associated pneumonia in the general ICU population. This retrospective cohort study aimed to determine the accuracy of lung ultrasound monitoring for ventilator-associated pneumonia diagnosis in COVID-19 patients. Clinical (i.e., clinical pulmonary infection score) and ultrasound (i.e., presence of consolidation and a dynamic linear−arborescent air bronchogram, lung ultrasound score, ventilator-associated lung ultrasound score) data were collected on the day of the microbiological sample (pneumonia-day) and 48 h before (baseline) on 55 bronchoalveolar lavages of 33 mechanically-ventilated COVID-19 patients who were monitored daily with lung ultrasounds. A total of 26 samples in 23 patients were positive for ventilator-associated pneumonia (pneumonia cases). The onset of a dynamic linear−arborescent air bronchogram was 100% specific for ventilator-associated pneumonia. The ventilator-associated lung ultrasound score was higher in pneumonia-cases (2.5 (IQR 1.0 to 4.0) vs. 1.0 (IQR 1.0 to 1.0); p < 0.001); the lung ultrasound score increased from baseline in pneumonia-cases only (3.5 (IQR 2.0 to 6.0) vs. −1.0 (IQR −2.0 to 1.0); p = 0.0001). The area under the curve for clinical parameters, ventilator-associated pneumonia lung ultrasound score, and lung ultrasound score variations were 0.472, 0.716, and 0.800, respectively. A newly appeared dynamic linear−arborescent air bronchogram is highly specific for ventilator-associated pneumonia in COVID-19 patients. A high ventilator-associated pneumonia lung ultrasound score (or an increase in the lung ultrasound score) orients to ventilator-associated pneumonia.

Schools opening and Covid-19 diffusion: Evidence from geolocalized microdata.

Are schools triggering the diffusion of the Covid-19? This question is at the core of an extensive debate about the social and long-run costs of stopping the economic activity and human capital accumulation from reducing the contagion. In principle, many confounding factors, such as climate, health system treatment, and other forms of restrictions, may impede disentangling the link between schooling and Covid-19 cases when focusing on a country or regional-level data. This work sheds light on the potential impact of school opening on the upsurge of contagion by combining a weekly panel of geocoded Covid-19 cases in Sicilian census areas with a unique set of school data. The identification of the effect takes advantage of both a spatial and time-variation in school opening, stemming from the flexibility in opening dates determined by a Regional Decree, and by the occurrence of a national referendum, which pulled a set of poll-station schools towards opening earlier or later September 24th. The analysis finds that census areas where schools opened earlier observed a significant and positive increase in the growth rate of Covid-19 cases between 2.5-3.7%. This result is consistent across several specifications, including accounting for several determinants of school opening, such as the number of temporary teachers, Covid-19 cases in August, and pupils with special needs. Finally, the analysis finds lower effects in more densely populated areas, on younger population, and on smaller class size. The results imply that school reopening generated an increase of one third in cases.

Cutaneous Metastasis from Colorectal Cancer: Making Light on an Unusual and Misdiagnosed Event.

Cutaneous metastasis from solid tumors is a rare event and usually represents a late occurrence in the natural history of an advanced visceral malignancy. Rarely, cutaneous metastasis has been described in colorectal cancer patients. The most frequent cutaneous site of colorectal metastasis is the surgical scar in the abdomen following the removal of the primary malignancy, followed by the extremities, perineum, head, neck, and penis. Metastases to the thigh and back of the trunk are anecdotical. Dermatological diagnosis of cutaneous metastasis can be quite complex, especially in unusual sites, such as in the facial skin or thorax and in cases of single cutaneous lesions since metastasis from colorectal cancer is not usually the first clinical hypothesis, leading to misdiagnosis. To date, due to the rarity of cutaneous metastasis from colorectal cancer, little evidence, most of which is based on case reports and very small case series, is currently available. Therefore, a better understanding of the clinic-pathological characteristics of this unusual metastatic site represents an unmet clinical need. We present a large series of 29 cutaneous metastases from colorectal cancer with particular concerns regarding anatomic localization and the time of onset with respect to primitive colorectal cancer and visceral metastases.

Lung Ultrasound in Patients with Acute Respiratory Failure Reduces Conventional Imaging and Health Care Provider Exposure to COVID-19.

Lung ultrasound gained a leading position in the last year as an imaging technique for the assessment and management of patients with acute respiratory failure. In coronavirus disease 2019 (COVID-19), its role may be of further importance because it is performed bedside and may limit chest X-ray and the need for transport to radiology for computed tomography (CT) scan. Since February 21, we progressively turned into a coronavirus-dedicated intensive care unit and applied an ultrasound-based approach to avoid traditional imaging and limit contamination as much as possible. We performed a complete daily examination with lung ultrasound score computation and systematic search of complications (pneumothorax, ventilator-associated pneumonia); on-duty physicians were free to perform CT or chest X-ray when deemed indicated. We compared conventional imaging exams performed in the first 4 wk of the COVID-19 epidemic with those in the same time frame in 2019: there were 84 patients in 2020 and 112 in 2019; 64 and 22 (76.2% vs. 19.6%, p < 0.001) had acute respiratory failure, respectively, of which 55 (85.9%) were COVID-19 in 2020. When COVID-19 patients in 2020 were compared with acute respiratory failure patients in 2019, the median number of chest X-rays was 1.0 (1.0-2.0) versus 3.0 (1.0-4.0) (p = 0.0098); 2 patients 2 (3.6%) versus 7 patients (31.8%) had undergone at least one thoracic CT scan (p = 0.001). A self-imposed ultrasound-based approach reduces the number of chest X-rays and thoracic CT scans in COVID-19 patients compared with patients with standard acute respiratory failure, thus reducing the number of health care providers exposed to possible contamination and sparing personal protective equipment.

Pediatric Laparoscopy and Adaptive Oxygenation and Hemodynamic Changes.

Adaptive changes in oxygenation and hemodynamics are evaluated during pediatric laparoscopy. The children underwent laparoscopy (LAP Group, n=20) or open surgery (Open Group, n=10). Regional cerebral (rScO2) and peripheral oxygen saturation (SpO2), heart rate (HR), diastolic (DP) and systolic pressure (SP) were monitored at different intervals: basal (T0); anesthesia induction (T1); CO2PP insufflation (T2); surgery (T3); CO2PP cessation (T4); before extubation (T5). At T1, in both the LAP and Open groups significant changes in rScO2, DP and SP were recorded compared with T0; a decrease in SatO2 was also observed at T5. In the LAP group, at T2, changes in HR related to CO2PP pressure and in DP and SP related to IAP were noted; at T4, a SP change associated with CO2PP desufflation was recorded. Open group, at T3 and T5 showed lower rScO2 values compared with T1. Pneuperitoneum and anesthesia are influent to induce hemodynamics changes during laparoscopy.

Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis.

BACKGROUND: The biological role of adrenomedullin (ADM), a hormone involved in hemodynamic homeostasis, is controversial in sepsis because administration of either the peptide or an antibody against it may be beneficial. METHODS: Plasma biologically active ADM (bio-ADM) was assessed on days 1, 2, and 7 after randomization of 956 patients with sepsis or septic shock to albumin or crystalloids for fluid resuscitation in the multicenter Albumin Italian Outcome Sepsis trial. We tested the association of bio-ADM and its time-dependent variation with fluid therapy, vasopressor administration, organ failures, and mortality. RESULTS: Plasma bio-ADM on day 1 (median [Q1-Q3], 110 [59-198] pg/mL) was higher in patients with septic shock, associated with 90-day mortality, multiple organ failures and the average extent of hemodynamic support therapy (fluids and vasopressors), and serum lactate time course over the first week. Moreover, it predicted incident cardiovascular dysfunction in patients without shock at enrollment (OR [95% CI], 1.9 [1.4-2.5]; P < .0001, for an increase of 1 interquartile range of bio-ADM concentration). bio-ADM trajectory during the first week of treatment clearly predicted 90-day mortality after adjustment for clinically relevant covariates (hazard ratio [95% CI], 1.3 [1.2-1.4]; P < .0001), and its reduction below 110 pg/mL at day 7 was associated with a marked reduction in 90-day mortality. Changes over the first 7 days of bio-ADM concentrations were not dependent on albumin treatment. CONCLUSIONS: In patients with sepsis, the circulating, biologically active form of ADM may help individualizing hemodynamic support therapy, while avoiding harmful effects. Its possible pathophysiologic role makes bio-ADM a potential candidate for future targeted therapies. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00707122.

Laparoscopy in children and its impact on brain oxygenation during routine inguinal hernia repair.

BACKGROUND: The systemic impact of intra-abdominal pressure (IAP) and/or changes in carbon dioxide (CO2) during laparoscopy are not yet well defined. Changes in brain oxygenation have been reported as a possible cause of cerebral hypotension and perfusion. The side effects of anaesthesia could also be involved in these changes, especially in children. To date, no data have been reported on brain oxygenation during routine laparoscopy in paediatric patients. PATIENTS AND METHODS: Brain and peripheral oxygenation were investigated in 10 children (8 male, 2 female) who underwent elective minimally invasive surgery for inguinal hernia repair. Intraoperative transcranial near-infrared spectroscopy to assess regional cerebral oxygen saturation (rScO2), peripheral oxygen saturation using pulse oximetry and heart rate (HR) were monitored at five surgical intervals: Induction of anaesthesia (baseline T1); before CO2insufflation induced pneumoperitoneum (PP) (T2); CO2PP insufflation (T3); cessation of CO2PP (T4); before extubation (T5). RESULTS: rScO2decreases were recorded immediately after T1 and became significant after insufflation (P = 0.006; rScO2decreased 3.6 ± 0.38%); restoration of rScO2was achieved after PP cessation (P = 0.007). The changes in rScO2were primarily due to IAP increases (P = 0.06). The HR changes were correlated to PP pressure (P < 0.001) and CO2flow rate (P = 0.001). No significant peripheral effects were noted. CONCLUSIONS: The increase in IAP is a critical determinant in cerebral oxygenation stability during laparoscopic procedures. However, the impact of anaesthesia on adaptive changes should not be underestimated. Close monitoring and close collaboration between the members of the multidisciplinary paediatric team are essential to guarantee the patient's safety during minimally invasive surgical procedures.

Volcano seismicity and ground deformation unveil the gravity-driven magma discharge dynamics of a volcanic eruption.

Effusive eruptions are explained as the mechanism by which volcanoes restore the equilibrium perturbed by magma rising in a chamber deep in the crust. Seismic, ground deformation and topographic measurements are compared with effusion rate during the 2007 Stromboli eruption, drawing an eruptive scenario that shifts our attention from the interior of the crust to the surface. The eruption is modelled as a gravity-driven drainage of magma stored in the volcanic edifice with a minor contribution of magma supplied at a steady rate from a deep reservoir. Here we show that the discharge rate can be predicted by the contraction of the volcano edifice and that the very-long-period seismicity migrates downwards, tracking the residual volume of magma in the shallow reservoir. Gravity-driven magma discharge dynamics explain the initially high discharge rates observed during eruptive crises and greatly influence our ability to predict the evolution of effusive eruptions.

The need for inotropic drugs in anesthesiology and intensive care.

The management of the failing heart represents an increasingly frequent challenge to both anesthesiologists and intensive care physicians, due to the increased prevalence of ventricular dysfunction in the population and to the ever-expanding indications for the surgical treatment of cardiac disease. Inotropic drugs are nowadays invaluable therapeutic tools in the treatment of perioperative heart failure and of the different forms of heart failure found in intensive care unit clinical practice. Postoperative myocardial dysfunction is a major concern in the setting of cardiac surgery since it is extremely frequent and is related to a greater morbidity and mortality. The different forms of heart failure, the rationale and the indications for the use of inotropic drugs in anesthesiology and intensive care are discussed in this review.