Search

Cell fate is determined by specific transcription programs that are essential for tissue homeostasis and regeneration. The E3-ligases RING1A and B represent the core activity of the Polycomb repressive complex 1 (PRC1) that deposits repressive histone H2AK119 mono-ubiquitination (H2AK119ub1), which is essential for mouse intestinal homeostasis by preserving stem cell functions. However, the specific role of different PRC1 forms, which are defined by the six distinct PCGF1–6 paralogs, remains largely unexplored in vivo. We report that PCGF6 regulates mouse intestinal Tuft cell differentiation independently of H2AK119ub1 deposition. We show that PCGF6 chromatin occupancy expands outside Polycomb repressive domains, associating with unique promoter and distal regulatory elements. This occurs in the absence of RING1A/B and involves MGA-mediated E-BOX recognition and specific H3K9me2 promoter deposition. PCGF6 inactivation induces an epithelial autonomous accumulation of Tuft cells that was not phenocopied by RING1A/B loss. This involves direct PCGF6 association with a Tuft cell differentiation program that identified Polycomb-independent properties of PCGF6 in adult tissues homeostasis.

Introduction: The improvement in oxygenation after helmet application in hypoxemic patients may be explained by the alveolar recruitment obtained with positive end expiratory pressure (PEEP) or by the administration of a more accurate inspiratory fraction of oxygen (FiO2). We have designed the “ZEEP-PEEP test”, capable to distinguish between the FiO2-related or PEEP-related oxygenation improvement. Our primary aim was to describe the use of this test during helmet CPAP to assess the oxygenation improvement attributable to PEEP application. Material and methods: We performed a prospective physiological study including adult critically ill patients. Respiratory and hemodynamic parameters were recorded before helmet application (PRE step), after helmet application without PEEP (ZEEP step) and after the application of the PEEP valve (PEEP step), while maintaining a constant FiO2. We defined as “PEEP responders” patients showing a PaO2/FiO2 ratio improvement ≥10% after PEEP application. Results: 93 patients were enrolled. Compared to the PRE step, PaO2/FiO2 ratio was significantly improved during helmet CPAP both at ZEEP and PEEP step (189 ± 55, 219 ± 74 and 241 ± 82 mmHg, respectively, p < 0.01). Both PEEP responders (41%) and non-responders showed a significant improvement of PaO2/FiO2 ratio after the application of helmet at ZEEP, PEEP responders also showed a significant improvement of oxygenation after PEEP application (208 ± 70 vs 267 ± 85, p < 0.01). Conclusions: Helmet CPAP improved oxygenation. This improvement was not only due to the PEEP effect, but also to the increase of the effective inspired FiO2. Performing the ZEEP-PEEP test may help to identify patients who benefit from PEEP.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. Methods: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. Results: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). Conclusions: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management.

Background Appropriate levels and patterns of sound and light in an intensive care room help to maintain the patient's normal physiological functions. High sound levels can disrupt the patient's normal sleep architecture, cause hearing deficits, and induce the onset of delirium. Intensive care unit patients frequently report poor sleep, partly due to the environment. Objectives An observational pilot prospective study was designed to record sound pressure and light pollution levels in an Italian intensive care unit, without windows to provide natural light. Method Sound levels were measured in decibel A (dBA) every 10 seconds. Sound data were analyzed for sound peak, defined as the number of times sound levels exceeded 45, 50, 60, 65, 70, 75, 80, and 85 dBA. Light measures were taken every 10 seconds on a continuous basis. Light data were analyzed for light "peaks,"defined as the number of times light levels exceeded 100, 200, 300, 400, and 500 lux. Results The overall median sound level during the study period was equal to 54.60 (interquartile range [IQR], 51.70-57.70) dBA. The daytime median sound level was 56.00 (IQR, 53.00-59.50) dBA, and the nighttime median was 53.00 (IQR, 49.50-55.20) dBA (P <.001). The overall median light level was equal to 114 (IQR, 0-225) lux. The daytime median light level was 184 (IQR, 114-293) lux, and the nighttime median was 0 (IQR, 0-50) lux (P [removed]45 dBA during daytime and nighttime are, respectively, equal to 99.9% and 98.6% of all readings. The Environmental Protection Agency/World Health Organization recommended thresholds for both day (45 dBA) and night (35 dBA). Sound levels reached "toxic levels"when sound-generating activities were performed by nurses and physicians.

In spite of being a process that exploits a renewable source of energy, the combustion of wood-based biomass contributes to deteriorate outdoor and indoor air quality. Critical situations for human exposure may occur in mountainous areas, where wood-based biomass is usually abundant and the complex morphology may favour the stagnation of air pollutants in valleys. Replacing wood/pellet stoves with centralised systems would reduce the impact, but the construction of district heating systems may not be convenient in areas with low density of houses. A possible solution could rely on direct electrical heating (DEH) systems, preferably fed by thermochemical processes that help achieve environmental goals for the local community, like the reduction of waste landfilling and the valorisation of the energy content of waste. This paper aims at presenting a comparison between the impacts expected by household wood/pellet stoves and by a modern waste-to-energy (WtE) plant, in terms of emissions of air pollutants into the atmosphere, when replacing wood stoves with a DEH system fed by the electric energy generated by the WtE plant. The comparison shows that the replacement of household stoves with an equivalent DEH system would be beneficial in terms of impacts on the local air quality. Such an approach could be considered to reduce the health impacts from biomass burning in critical areas like the Alpine region.