There is a paucity of data concerning the optimal ventilator management in patients with COVID-19 pneumonia; particularly, the optimal levels of positive-end expiratory pressure (PEEP) are unknown. ...We aimed to investigate the effects of two levels of PEEP on alveolar recruitment in critically ill patients with severe COVID-19 pneumonia.
A single-center cohort study was conducted in a 39-bed intensive care unit at a university-affiliated hospital in Genoa, Italy. Chest computed tomography (CT) was performed to quantify aeration at 8 and 16 cmH
O PEEP. The primary endpoint was the amount of alveolar recruitment, defined as the change in the non-aerated compartment at the two PEEP levels on CT scan.
Forty-two patients were included in this analysis. Alveolar recruitment was median interquartile range 2.7 0.7-4.5 % of lung weight and was not associated with excess lung weight, PaO
/FiO
ratio, respiratory system compliance, inflammatory and thrombophilia markers. Patients in the upper quartile of recruitment (recruiters), compared to non-recruiters, had comparable clinical characteristics, lung weight and gas volume. Alveolar recruitment was not different in patients with lower versus higher respiratory system compliance. In a subgroup of 20 patients with available gas exchange data, increasing PEEP decreased respiratory system compliance (median difference, MD - 9 ml/cmH
O, 95% CI from - 12 to - 6 ml/cmH
O, p < 0.001) and the ventilatory ratio (MD - 0.1, 95% CI from - 0.3 to - 0.1, p = 0.003), increased PaO
with FiO
= 0.5 (MD 24 mmHg, 95% CI from 12 to 51 mmHg, p < 0.001), but did not change PaO
with FiO
= 1.0 (MD 7 mmHg, 95% CI from - 12 to 49 mmHg, p = 0.313). Moreover, alveolar recruitment was not correlated with improvement of oxygenation or venous admixture.
In patients with severe COVID-19 pneumonia, higher PEEP resulted in limited alveolar recruitment. These findings suggest limiting PEEP strictly to the values necessary to maintain oxygenation, thus avoiding the use of higher PEEP levels.
Identification of lung parenchyma on computer tomographic (CT) scans in the research setting is done semi-automatically and requires cumbersome manual correction. This is especially true in ...pathological conditions, hindering the clinical application of aeration compartment (AC) analysis. Deep learning based algorithms have lately been shown to be reliable and time-efficient in segmenting pathologic lungs. In this contribution, we thus propose a novel 3D transfer learning based approach to quantify lung volumes, aeration compartments and lung recruitability.
Two convolutional neural networks developed for biomedical image segmentation (uNet), with different resolutions and fields of view, were implemented using Matlab. Training and evaluation was done on 180 scans of 18 pigs in experimental ARDS (
2
) and on a clinical data set of 150 scans from 58 ICU patients with lung conditions varying from healthy, to COPD, to ARDS and COVID-19 (
2
). One manual segmentations (MS) was available for each scan, being a consensus by two experts. Transfer learning was then applied to train
2
on the clinical data set generating
2
. General segmentation quality was quantified using the Jaccard index (
) and the Boundary Function score (
). The slope between
or
and relative volume of non-aerated compartment (
and
, respectively) was calculated over data sets to assess robustness toward non-aerated lung regions. Additionally, the relative volume of ACs and lung volumes (LV) were compared between automatic and MS.
On the experimental data set,
2
resulted in
= 0.892 0.88 : 091 (median inter-quartile range),
= 0.995 0.98 : 1.0 and slopes
= -0.2 {95% conf. int. -0.23 : -0.16} and
= -0.1 {-0.5 : -0.06}.
2
showed similar performance compared to
2
in
,
but with reduced robustness
= -0.29 {-0.36 : -0.22} and
= -0.43 {-0.54 : -0.31}. Transfer learning improved overall
= 0.92 0.88 : 0.94,
< 0.001, but reduced robustness
= -0.46 {-0.52 : -0.40}, and affected neither
= 0.96 0.91 : 0.98 nor
= -0.48 {-0.59 : -0.36}.
2
improved
compared to
2
in segmenting healthy (
= 0.008), ARDS (
< 0.001) and COPD (
= 0.004) patients but not in COVID-19 patients (
= 0.298). ACs and LV determined using
2
segmentations exhibited < 5% volume difference compared to MS.
Compared to manual segmentations, automatic uNet based 3D lung segmentation provides acceptable quality for both clinical and scientific purposes in the quantification of lung volumes, aeration compartments, and recruitability.
Background:
Variable pressure support ventilation (vPSV) is an assisted ventilation mode that varies the level of pressure support on a breath-by-breath basis to restore the physiological variability ...of breathing activity. We aimed to compare the effects of vPSV at different levels of variability and pressure support (Δ
P
S
) in patients with acute respiratory distress syndrome (ARDS).
Methods:
This study was a crossover randomized clinical trial. We included patients with mild to moderate ARDS already ventilated in conventional pressure support ventilation (PSV). The study consisted of two blocks of interventions, and variability during vPSV was set as the coefficient of variation of the Δ
P
S
level. In the first block, the effects of three levels of variability were tested at constant Δ
P
S
: 0% (PSV
0%
, conventional PSV), 15% (vPSV
15%
), and 30% (vPSV
30%
). In the second block, two levels of variability (0% and variability set to achieve ±5 cmH
2
O variability) were tested at two ΔP
S
levels (baseline Δ
P
S
and Δ
P
S
reduced by 5 cmH
2
O from baseline). The following four ventilation strategies were tested in the second block: PSV with baseline Δ
P
S
and 0% variability (PSV
BL
) or ±5 cmH
2
O variability (vPSV
BL
), PSV with ΔP
S
reduced by 5 cmH
2
O and 0% variability (PSV
−5
) or ±5 cmH
2
O variability (vPSV
−5
). Outcomes included gas exchange, respiratory mechanics, and patient-ventilator asynchronies.
Results:
The study enrolled 20 patients. In the first block of interventions, oxygenation and respiratory mechanics parameters did not differ between vPSV
15%
and vPSV
30%
compared with PSV
0%
. The variability of tidal volume (
V
T
) was higher with vPSV
15%
and vPSV
30%
compared with PSV
0%
. The incidence of asynchronies and the variability of transpulmonary pressure (
P
L
) were higher with vPSV
30%
compared with PSV
0%
. In the second block of interventions, different levels of pressure support with and without variability did not change oxygenation. The variability of
V
T
and
P
L
was higher with vPSV
−5
compared with PSV
−5
, but not with vPSV
BL
compared with PSV
BL
.
Conclusion:
In patients with mild-moderate ARDS, the addition of variability did not improve oxygenation at different pressure support levels. Moreover, high variability levels were associated with worse patient-ventilator synchrony.
Clinical Trial Registration:
www.clinicaltrials.gov
, identifier: NCT01683669.
Mechanical ventilation (MV) may initiate or worsen lung injury, so-called ventilator-induced lung injury (VILI). Although different mechanisms of VILI have been identified, research mainly focused on ...single ventilator parameters. The mechanical power (MP) summarizes the potentially damaging effects of different parameters in one single variable and has been shown to be associated with lung damage. However, to date, the association of MP with pulmonary neutrophilic inflammation, as assessed by positron-emission tomography (PET), has not been prospectively investigated in a model of clinically relevant ventilation settings yet. We hypothesized that the degree of neutrophilic inflammation correlates with MP.
Eight female juvenile pigs were anesthetized and mechanically ventilated. Lung injury was induced by repetitive lung lavages followed by initial PET and computed tomography (CT) scans. Animals were then ventilated according to the acute respiratory distress syndrome (ARDS) network recommendations, using the lowest combinations of positive end-expiratory pressure and inspiratory oxygen fraction that allowed adequate oxygenation. Ventilator settings were checked and adjusted hourly. Physiological measurements were conducted every 6 h. Lung imaging was repeated 24 h after first PET/CT before animals were killed. Pulmonary neutrophilic inflammation was assessed by normalized uptake rate of 2-deoxy-2-
Ffluoro-D-glucose (K
), and its difference between the two PET/CT was calculated (ΔK
). Lung aeration was assessed by lung CT scan. MP was calculated from the recorded pressure-volume curve. Statistics included the Wilcoxon tests and non-parametric Spearman correlation.
Normalized
F-FDG uptake rate increased significantly from first to second PET/CT (
= 0.012). ΔK
significantly correlated with median MP (ρ = 0.738,
= 0.037) and its elastic and resistive components, but neither with median peak, plateau, end-expiratory, driving, and transpulmonary driving pressures, nor respiratory rate (RR), elastance, or resistance. Lung mass and volume significantly decreased, whereas relative mass of hyper-aerated lung compartment increased after 24 h (
= 0.012,
= 0.036, and
= 0.025, respectively). Resistance and PaCO
were significantly higher (
= 0.012 and
= 0.017, respectively), whereas RR, end-expiratory pressure, and MP were lower at 18 h compared to start of intervention.
In this model of experimental acute lung injury in pigs, pulmonary neutrophilic inflammation evaluated by PET/CT increased after 24 h of MV, and correlated with MP.
All is fish that comes to the net Russo, Tommaso; Maiello, Giulia; Talarico, Lorenzo ...
Ecological applications,
03/2021, Volume:
31, Issue:
2
Journal Article
Peer reviewed
Open access
Monitoring marine resource exploitation is a key activity in fisheries science and biodiversity conservation. Since research surveys are time consuming and costly, fishery-dependent data (i.e., ...derived directly from fishing vessels) are increasingly credited with a key role in expanding the reach of ocean monitoring. Fishing vessels may be seen as widely ranging data-collecting platforms, which could act as a fleet of sentinels for monitoring marine life, in particular exploited stocks. Here, we investigate the possibility of assessing catch composition of single hauls carried out by trawlers by applying DNA metabarcoding to the dense water draining from fishing nets just after the end of hauling operations (hereafter “slush”). We assess the performance of this approach in portraying β-diversity and examining the quantitative relationship between species abundances in the catch and DNA amount in the slush (read counts generated by amplicon sequencing). We demonstrate that the assemblages identified using DNA in the slush satisfactorily mirror those returned by visual inspection of net content (about 71% of species and 86% of families of fish) and detect a strong relationship between read counts and species abundances in the catch. We therefore argue that this approach could be upscaled to serve as a powerful source of information on the structure of demersal assemblages and the impact of fisheries.
Despite remarkable progress in the last decade, metastatic prostate cancer (mPCa) remains incurable. The approval of PARP inhibitors (PARPis) represents a milestone in this field, which definitively ...enters the era of precision medicine, as mPCa is often enriched for defects of homologous recombination repair genes. PARPis are now used as single agents for patients with metastatic castration-resistant PCa. Moreover, combinations of PARPis plus androgen-receptor targeted agents and immune checkpoint inhibitors, and earlier applications of PARPis in the metastatic hormone-sensitive PCa are under evaluation, representing the possible upcoming applications of these agents. Mechanisms of sensitization and resistance have been only partially elucidated. In our review, we summarize the current clinical evidence regarding PARPis in mPCa and the future directions of these targeted agents.
The highly conserved family of cyclophilins comprises multifunctional chaperones that interact with proteins and RNAs, facilitating the dynamic assembly of multimolecular complexes involved in ...various cellular processes. Cyclophilin A (CypA), the predominant member of this family, exhibits peptidyl–prolyl cis–trans isomerase activity. This enzymatic function aids with the folding and activation of protein structures and often serves as a molecular regulatory switch for large multimolecular complexes, ensuring appropriate inter- and intra-molecular interactions. Here, we investigated the involvement of CypA in the nucleus, where it plays a crucial role in supporting the assembly and trafficking of heterogeneous ribonucleoproteins (RNPs). We reveal that CypA is enriched in the nucleolus, where it colocalizes with the pseudouridine synthase dyskerin, the catalytic component of the multifunctional H/ACA RNPs involved in the modification of cellular RNAs and telomere stability. We show that dyskerin, whose mutations cause the X-linked dyskeratosis (X-DC) and the Hoyeraal–Hreidarsson congenital ribosomopathies, can directly interact with CypA. These findings, together with the remark that substitution of four dyskerin prolines are known to cause X-DC pathogenic mutations, lead us to indicate this protein as a CypA client. The data presented here suggest that this chaperone can modulate dyskerin activity influencing all its partecipated RNPs.
FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with ...metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status.
This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled.
NIVACOR is registered at ClinicalTrials.gov: NCT04072198 , August 28, 2019.
Abstract
Conservation and management of chondrichthyans are becoming increasingly important, as many species are particularly vulnerable to fishing activities, primarily as bycatch, which leads to ...incomplete catch reporting, potentially hiding the impact on these organisms. Here, we aimed at implementing an eDNA metabarcoding approach to reconstruct shark and ray bycatch composition from 24 hauls of a bottom trawl fishing vessel in the central Mediterranean. eDNA samples were collected through the passive filtration of seawater by simple gauze rolls encapsulated in a probe (the “metaprobe”), which already showed great efficiency in detecting marine species from trace DNA in the environment. To improve molecular taxonomic detection, we enhanced the 12S target marker reference library by generating sequences for 14 Mediterranean chondrichthyans previously unrepresented in public repositories. DNA metabarcoding data correctly identifies almost all bycaught species and detected five additional species not present in the net, highlighting the potential of this method to detect rare species. Chondrichthyan diversity showed significant association with some key environmental variables (depth and distance from the coast) and the fishing effort, which are known to influence demersal communities. As DNA metabarcoding progressively positions itself as a staple tool for biodiversity monitoring, we expect that its melding with opportunistic, fishery-dependent surveys could reveal additional distribution features of threatened and elusive megafauna.
The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI ...(fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab.
TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116.
Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio HR 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 17% vs 18 5%), neutropenia (168 50% vs 71 21%), and arterial hypertension (25 7% vs 35 10%) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six 5% of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis).
Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria.
The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.
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