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Background Ultrasound (US) evaluation of diaphragmatic dysfunction (DD) has proved to be a reliable technique in critical care. In this single-center prospective study, we investigated the impact of US-assessed DD on noninvasive ventilation (NIV) failure in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and its correlation with the transdiaphragmatic pressure assessed using the invasive sniff maneuver (Pdi sniff). Methods A population of 75 consecutive patients with AECOPD with hypercapnic acidosis admitted to our respiratory intensive care unit (RICU) were enrolled. Change in diaphragm thickness (ΔTdi) < 20% during tidal volume was the predefined cutoff for identifying DD+/− status. Correlations between ΔTdi < 20% NIV failure and other clinical outcomes were investigated. Correlation between ΔTdi and Pdi sniff values was analyzed in a subset of ten patients. Results DD+ patients had a higher risk for NIV failure than DD− patients (risk ratio, 4.4; p  <  0.001), and this finding was significantly associated with higher RICU, in-hospital, and 90-day mortality rates; longer mechanical ventilation duration; higher tracheostomy rate; and longer RICU stay. Huge increases in NIV failure (HR, 6.2; p  < 0.0001) and 90-day mortality (HR, 4.7; p  = 0.008) in DD+ patients were found by Kaplan-Meier analysis. ΔTdi highly correlated with Pdi sniff (Pearson’s r  = 0.81; p  = 0.004). ΔTdi < 20% showed better accuracy in predicting NIV failure than baseline pH value and early change in both arterial blood pH and partial pressure of carbon dioxide following NIV start (AUCs 0.84 to DTdi < 20%, 0.51 to pH value at baseline, 0.56 to early change in arterial blood pH following NIV start, and 0.54 to early change in partical pressure of carbon dioxide following NIV start, respectively; p  < 0.0001). Conclusions Early and noninvasive US assessment of DD during severe AECOPD is reliable and accurate in identifying patients at major risk for NIV failure and worse prognosis.

Background Diaphragmatic assessment by ultrasound (US) is a non-invasive and useful method in the clinical management of patients with Amyotrophic Lateral Sclerosis (ALS). The aim of our observational study was to evaluate the impact of serial assessment of the diaphragmatic function by US on long-term outcomes in a series of patients suffering from ALS and to correlate US indices of diaphragmatic function and respiratory function tests with these outcomes. Methods A cohort of 39 consecutive patients has been followed up to 24 months. Both lung volume (forced vital capacity, FVC) and diaphragmatic pressure generating capacity (by sniff inspiratory nasal pressure (SNIP) and by both US thickening fraction, ΔTdi, and the ratio of the thickening fraction between tidal volume and maximal lung capacity, ΔTmax) were recorded at baseline and every 3 months. Parameters were then correlated with outcomes (nocturnal hypoventilation, daily hypercapnia, start of ventilatory support (NIV), and death at 1 year) over time. Results The occurrence of ΔTmax > 0.75 increased the risk to start NIV (HR = 5.6, p  = 0.001) and to die (HR = 3.7, p  = 0.0001) compared with patients maintaining lower values. Moreover, compared with the occurrence of FVC < 50% of predicted, ΔTmax > 0.75 appeared slightly better correlated with NIV commencement within 6 months. Conclusions Serial diaphragmatic assessment by ultrasound is a useful and accurate method to predict the initiation of NIV earlier in patients with ALS.

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). ClinicalTrials.gov NCT01125098.

Background: Studies have highlighted long-term respiratory muscle dysfunction in COVID-19 survivors, although the underlying risk factors remain unclear. This single-centre study assessed respiratory muscle function and individual associated factors at follow-up in patients hospitalised with COVID-19 and related acute respiratory failure. Methods: Data were collected for consecutive patients, aged ≥ 18 years, at the post-COVID outpatient service of Hospital Policlinico in Modena (Italy) in the time frame of 3 to 6 months after discharge. Data were analysed using single and multiple logistic regression models. Correlations among MIP/MEP, hand-grip values, and lung function were further explored. Results: Out of 223 patients (mean age 67 years, 69% male) 121 (54.3%) exhibited MIP or MEP dysfunction, which was found to be associated with the use of non-invasive ventilation (aOR = 1.91 [1.07–3.49], p = 0.04) and female gender (aOR = 1.76 [1.09–4.16], p = 0.03) as independent risk factors. A positive correlation was observed between MIP dysfunction and hand-grip strength (p = 0.03 and 0.01), whereas both MIP and MEP were significantly associated with FEV1, FVC, TLC, and DLCO. Conclusions: Respiratory muscle dysfunction is consistently prevalent and parallels peripheral muscle weakness and the lung function level in patients at follow-up after severe COVID-19. The need for non-invasive ventilation during the acute phase and female gender might represent risk factors. MIP/MEP assessment should be recommended to observe respiratory muscle dysfunction in severe post-COVID survivors.

Background: The molecular pathways involved in the onset and progression of idiopathic pulmonary fibrosis (IPF) still need to be fully clarified as some are shared with lung cancer development. HOXB7, a member of the homeobox (Hox) gene family, has been found involved in various cancers. Methods: Immunohistochemical (IHC) analysis was run on lung tissue samples from surgical lung biopsy (SLB) of 19 patients with IPF, retrospectively selected from the IPF database of the University Hospital of Modena. HOXB7 expression was analyzed and compared with that of five patients with no evidence of pulmonary fibrosis as controls. Results: The semi-quantitative analysis of IHC showed that HOXB7 protein expression was higher in IPF patients compared to controls (difference between means = 6.2 ± 2.37, p = 0.0157). Further, HOXB7 expression was higher in IPF patients with a higher extent of fibrosis (50–75%)—measured with high-resolution computer tomography—compared to those with a lower extent (0–25%) (difference between means = 25.74 ± 6.72, p = 0.004). Conclusions: The expression of HOXB7 is higher in the lung of IPF patients compared to controls, and was represented in different cellular compartments within the lung niche. Further investigations are needed to clarify its role in the pathogenesis and progression of IPF.

Chronic obstructive pulmonary disease (COPD) is a common comorbidity of heart failure (HF), but remains often undiagnosed, and we aimed to identify symptoms predicting COPD in HF. As part of an observational, prospective study, we investigated stable smokers with a confirmed diagnosis of HF, using the 8-item COPD-Assessment-Test (CAT) questionnaire to assess symptoms. All the items were correlated with the presence of COPD, and logistic regression models were used to identify independent predictors. 96 HF patients were included, aged 74, 33% with COPD. Patients with HF and COPD were more symptomatic, but only breathlessness when walking up a hill was an independent predictor of COPD (odds ratio = 1.33, p  = 0.0484). Interestingly, COPD-specific symptoms such as cough and phlegm were not significant. Thus, in elderly smokers with stable HF, significant breathlessness when walking up a hill is most indicative of associated COPD, and may indicate the need for further lung function evaluation.

Although non-invasive mechanical ventilation (NIV) is the gold standard treatment for patients with acute exacerbation of COPD (AECOPD) developing respiratory acidosis, failure rates still range from 5% to 40%. Recent studies have shown that the onset of severe diaphragmatic dysfunction (DD) during AECOPD increases risk of NIV failure and mortality in this subset of patients. Although the imbalance between the load and the contractile capacity of inspiratory muscles seems the main cause of AECOPD-induced hypercapnic respiratory failure, data regarding the influence of mechanical derangement on DD in this acute phase are lacking. With this study, we investigate the impact of respiratory mechanics on diaphragm function in AECOPD patients experiencing NIV failure. Twelve AECOPD patients with respiratory acidosis admitted to the Respiratory ICU of the University Hospital of Modena from 2017 to 2018 undergoing mechanical ventilation (MV) due to NIV failure were enrolled. Static respiratory mechanics and end-expiratory lung volume (EELV) were measured after 30 mins of volume control mode MV. Subsequently, transdiaphragmatic pressure (Pdi) was calculated by means of a sniff maneuver (Pdisniff) after 30 mins of spontaneous breathing trial. Linear regression analysis and Pearson's correlation coefficient served to assess associations. Average Pdisniff was 23.3 cmH O (standard deviation 29 cmH O) with 3 patients presenting bilateral diaphragm palsy. Pdisniff was directly correlated with static lung elastance (r=0.69, p=0.001) while inverse correlation was found with dynamic intrinsic PEEP (r=-0.73, p=0.007). No significant correlation was found with static intrinsic PEEP (r=-0.55, p=0.06), EELV (r=-0.4, p=0.3), airway resistance (r=-0.2, p=0.54), chest wall, and total elastance (r=-0-01, p=0.96 and r=0.3, p=0.36, respectively). Significant linear inverse correlation was found between Pdisniff and the ratio between Pdi assessed at tidal volume and Pdi sniff (r=-0.82, p=0.02). The causes of extreme DD in AECOPD patients who experienced NIV failure might be predominantly mechanical, driven by a severe dynamic hyperinflation that overlaps on an elastic lung substrate favoring volume overload.

Introduction The present study was designed to assess the antidepressant effects of UFP-101, a selective nociceptin/orphanin FQ peptide (NOP) receptor antagonist, in a validated animal model of depression: the chronic mild stress (CMS). Materials and methods and Results UFP-101 (5, 10 and 20 nmol/rat; i.c.v., once a day for 21 days) dose- and time-dependently reinstated sucrose consumption in stressed animals without affecting the same parameter in non-stressed ones. In the forced swimming test, UFP-101 reduced immobility of stressed rats from day 8 of treatment. After a 3-week treatment, rats were killed for biochemical evaluations. UFP-101 abolished increase in serum corticosterone induced by CMS and reverted changes in central 5-HT/5-HIAA ratio. The behavioural and biochemical effects of UFP-101 mimicked those of imipramine, the reference antidepressant drug, administered at the dose of 15 mg/kg (i.p.). Co-administration of nociceptin/orphanin FQ (5 nmol/rat, from day 12 to 21) prevented the effects of UFP-101. Brain-derived neurotrophic factor mRNA and protein in hippocampus were not reduced by CMS nor did UFP-101 modify these parameters. Discussion and Conclusion This study demonstrated that chronic treatment with UFP-101 produces antidepressant-like effects in rats subjected to CMS supporting the proposal that NOP receptors represent a candidate target for the development of innovative antidepressant drugs.

Background: In elderly smokers, chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) usually present with dyspnoea. COPD and CHF are associated ­almost invariably with concomitant chronic diseases, which contribute to severity and prognosis. Objectives: We investigated similarities and differences in the clinical presentation, concomitant chronic diseases and risk factors for ­mortality and hospitalization at 3-year follow-up in elderly smokers/ex-smokers with a primary diagnosis of COPD or CHF recruited and followed in specialized centers. Methods: We examined 144 patients with COPD and 96 with CHF, ≥65 years, ≥20 pack/years, and measured COPD Assessment Test (CAT) score, modified Medical Research Council, NYHA, and Charlson Index, routine blood test, estimated glomerular filtration rate, HRCT scan, 6-min walk test. In addition, in each patient we actively searched for CHF, COPD, peripheral vascular disease, and metabolic syndrome. Results: COPD and CHF patients had mild to moderate disease, but the majority was symptomatic. Comorbidities were highly prevalent and often unrecognized in both groups. COPD and CHF patients had a similar risk of hospitalization and death at 3 years. Lower glomerular filtration rate, shorter 6MWT, and ascending aorta calcification score ≥2 were independent predictors of mortality in COPD, whereas previous 12 months hospitalizations, renal disease, and heart diameter were in CHF patients. Lower glomerular filtration rate value, higher CAT score, and lower FEV 1 /FVC ratio were associated with hospitalization in COPD, while age, lower FEV 1 % predicted, and peripheral vascular disease were in CHF. Conclusions: There are relevant similarities and differences between patients with COPD and CHF even when admitted to specialized outpatient centers, suggesting that these patients should be manage in multidisciplinary units.

It is recognized that paracetamol undergoes a metabolic transformation to N -arachydonylphenolamine (AM404), a CB 1 receptor ligand and anandamide uptake inhibitor. Using hot-plate and paw pressure tests, we decided to establish whether AM404 may act through opioidergic and serotonergic mechanisms. Thus, we pretreated rats with opioid μ 1 (naloxonazine) and κ (MR2266) or 5-HT 1A (NAN-190), 5-HT 2 (ketanserin), and 5-HT 3 (ondansetron) receptor antagonists. We investigated the possible changes in 5-hydroxyindoleacetic acid/serotonin ratio in the frontal cortex and pons. The antinociceptive effect of AM404 (10 mg/kg, intrapertoneally) or paracetamol (400 mg/kg, intrapertoneally) in either test was abolished by naloxonazine or MR2266. Ondansetron prevented AM404 activity; NAN-190 and ketanserin were ineffective. Ketanserin antagonized paracetamol activity; NAN-190 and ondansetron were inactive. AM404 did not change serotonergic activity, while paracetamol decreased serotonin turnover. The diverse antinociceptive potency of the compounds might be explained by the different influence on the serotonergic system, despite a similar involvement of opioidergic one.