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Daniel Negrini,1,2,* Andrew Wu,1 Atsushi Oba,1,3 Ben Harnke,4 Nicholas Ciancio,1 Martin Krause,5 Claudia Clavijo,6 Mohammed Al-Musawi,7 Tatiana Linhares,1 Ana Fernandez-Bustamante,6 Sergio Schmidt8,* 1Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; 2Department of Anesthesiology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 3Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; 4Strauss Health Sciences Library, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; 5Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA; 6Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; 7Department of Surgery-Division of Cardiothoracic Surgery, School of Medicine, University of Colorado, Aurora, CO, USA; 8Department of Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil*These authors contributed equally to this workCorrespondence: Sergio Schmidt, Department of Neurology, Federal University of the State of Rio de Janeiro, Rua Mariz e Barros 775, Maracanã, Rio de Janeiro, RJ, 22270-004, Brazil, Email slschmidt@terra.com.brAbstract: Postoperative cognitive dysfunction (POCD) has been increasingly recognized as a contributor to postoperative complications. A consensus-working group recommended that POCD should be distinguished between delayed cognitive recovery, ie, evaluations up to 30 days postoperative, and neurocognitive disorder, ie, assessments performed between 30 days and 12 months after surgery. Additionally, the choice of the anesthetic, either inhalational or total intravenous anesthesia (TIVA) and its effect on the incidence of POCD, has become a focus of research. Our primary objective was to search the literature and conduct a meta-analysis to verify whether the choice of general anesthesia may impact the incidence of POCD in the first 30 days postoperatively. As a secondary objective, a systematic review of the literature was conducted to estimate the effects of the anesthetic on POCD between 30 days and 12 months postoperative. For the primary objective, an initial review of 1913 articles yielded ten studies with a total of 3390 individuals. For the secondary objective, four studies with a total of 480 patients were selected. In the first 30 days postoperative, the odds-ratio for POCD in TIVA group was 0.46 (95% CI = 0.26– 0.81; p = 0.01), compared to the inhalational group. TIVA was associated with a lower incidence of POCD in the first 30 days postoperatively. Regarding the secondary objective, due to the small number of selected articles and its high heterogeneity, a metanalysis was not conducted. Given the heterogeneity of criteria for POCD, future prospective studies with more robust designs should be performed to fully address this question.Keywords: postoperative cognitive dysfunction, POCD, total intravenous anesthesia, TIVA, inhalational anesthesia, postoperative complications, psychometric tests

The article presents a study which analyzes of the role of X-ray repair cross-complementing group 1 (XRCC1) in the DNA base excision repair mechanism and in the development of cervical cancer in Argentine women. Based on the 217 samples gentotyped for two XRCC1 single nucleotide polymorphisms (SNPs), samples carrying heterozygous SNP had a reduced risk of cervical cancer development. It concludes that XRCC1 genotypes and haplotypes contribute to mitigating the risk of cervical cancer.

Abstract A 70-year-old man was admitted for severe hypoxia, haemoptysis and cough. Chest-X-ray and CT-scan indicated a right-lower-lobe collapse. Bronchoscopy showed its occlusion by whitish dense mucus. Aspiration revealed a Bronchial Cast (BC) and a stenotic and inflamed orifice of the right-lower-lobe-bronchus which was biopsied. Histopathologic examination of BC showed fibrin with lymphocytes and neutrophils, and, surprisingly, also the presence of lung cancer. Although the association between BC and benign, myxoid-soft-tissue, tracheobronchial tumors has been described, the association with lung cancer has not previously been reported, and it remains unclear whether it is causal or casual.

Abstract Background Overexpression of the tumor suppressor gene p53 and the marker for cellular proliferation Ki67 in open lung biopsies are indicated as predictor factors of survival of patients with lung cancer. However, the prognostic value of p53 and Ki67 in fiberoptic bronchial biopsies (FBB) has not been fully investigated. We evaluated p53 and Ki67 immunostaining in FBB from 19 with Non Small-Cell Lung Cancer (NSCLC: 12 adenocarcinomas, 5 squamous cell carcinomas and 2 NSCLC-NOS). Methods FBB specimens were fixed in formalin, embedded in paraffin, and immunostained using anti-p53 and anti-Ki67 antibodies. Slides were reviewed by two independent observers and classified as positive (+ve) when the number of cells with stained nuclei exceeded 15% for p53 or when >25% positive cells were observed throughout each section for Ki67. Results Positive (+ve) immunostaining was found in 9 patients for p53 (47.37%) and 8 patients for Ki67 (42.10%). We examined overall survival curves of the patients with Mantel's logrank test, both p53 -ve and Ki67 -ve patients had significantly higher survival rates than p53 + ve (p Conclusion This study suggests that negative immunostaining of fiberoptic bronchial biopsies for p53 and Ki67 could represent a better prognostic factor for patients with NSCLC.

Remdesivir is one of the most attractive options for patients with hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). The aim of our study was to evaluate the effect of remdesivir on the hypoxic and inflammatory state in patients with moderate to severe COVID-19. We retrospectively enrolled 112 patients admitted for COVID-19 pneumonia, requiring low-flow oxygen, 57 treated with remdesivir plus standard of care (SoC) and 55 treated only with SoC that were similar for demographic and clinical data. We evaluated changes in hypoxemia and inflammatory markers at admission (Day 0) and after 5 days of treatment (Day 5) and the clinical course of the disease. From Day 0 to Day 5, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) increased from 222 ± 62 to 274 ± 97 ( p < 0.0001) in the remdesivir group and decreased from 223 ± 62 to 183 ± 76 ( p < 0.05) in the SoC group. Interleukine-6 levels decreased in the remdesivir (45.9 to 17.5 pg/mL, p < 0.05) but not in the SoC group. Remdesivir reduced the need for ventilatory support and the length of hospitalization. In conclusion, compared to standard care, remdesivir rapidly improves hypoxia and inflammation, causing a better course of the disease in moderate to severe COVID-19.

Background: Coronavirus-19 Disease (COVID-19) may cause persistent symptoms and functional respiratory impairment, known as long COVID. Determinants of long COVID are unclear. Although males experience more severe acute illness, the impact of sex on the occurrence of long-term sequelae is unknown. The aim of this study was to establish whether sex affects pulmonary function, exercise capacity, and clinical outcomes in patients recovered from COVID-19 pneumonia. Materials and Methods: We performed a retrospective analysis on patients evaluated in our "Post-COVID Clinic" after a median follow-up of 128 days from the acute disease. Tests performed included standard spirometry, diffusion capacity of the lung for carbon monoxide (DLCO), and 6-minute walk test (6-MWT). Results: A total of 157 patients (mean age 59.9 ± 12, 91 males) recovered from mild to severe pneumonia, without previous respiratory disease, were included. No differences in demographic data and in the severity of the acute illness were observed between the two study groups, males and females. Abnormal alveolar diffusion was more common and severe among females (DLCO <80% in 31% of males vs. 53% of females, p  < 0.01; DLCO <70%, in 20% of males vs. 40% of females, p  < 0.01). Severe reduction in 6-MWT was observed in 20% of males versus 46% of females ( p  < 0.01). Multiple logistic regression showed that female sex was an independent predictor of abnormal DLCO and 6-MWT. The prevalence of symptoms and radiological abnormalities was similar in the two groups. Conclusions: These data show that at 4 months follow-up women recovered from COVID-19 pneumonia are more likely to exhibit a reduced alveolar diffusion capacity and exercise tolerance than men, although a similar severity of the acute disease.

Introduction: Connective Tissue Diseases (CTDs) are systemic autoimmune conditions characterized by frequent lung involvement. This usually takes the form of Interstitial Lung Disease (ILD), but Obstructive Lung Disease (OLD) and Pulmonary Artery Hypertension (PAH) can also occur. Lung involvement is often severe, representing the first cause of death in CTD. The aim of this study is to highlight the role of Pulmonary Function Tests (PFTs) in the diagnosis and follow up of CTD patients., Main Body: Rheumatoid Arthritis (RA) showed mainly an ILD with a Usual Interstitial Pneumonia (UIP) pattern in High-Resolution Chest Tomography (HRCT). PFTs are able to highlight a RA-ILD before its clinical onset and to drive follow up of patients with Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DL CO ). In the course of Scleroderma Spectrum Disorders (SSDs) and Idiopathic Inflammatory Myopathies (IIMs), DL CO appears to be more sensitive than FVC in highlighting an ILD, but it can be compromised by the presence of PAH. A restrictive respiratory pattern can be present in IIMs and Systemic Lupus Erythematosus due to the inflammatory involvement of respiratory muscles, the presence of fatigue or diaphragm distress., Conclusions: The lung should be carefully studied during CTDs. PFTs can represent an important prognostic tool for diagnosis and follow up of RA-ILD, but, on their own, lack sufficient specificity or sensitivity to describe lung involvement in SSDs and IIMs. Several composite indexes potentially able to describe the evolution of lung damage and response to treatment in SSDs are under investigation. Considering the potential severity of these conditions, an HRCT jointly with PFTs should be performed in all new diagnoses of SSDs and IIMs. Moreover, follow up PFTs should be interpreted in the light of the risk factor for respiratory disease related to each disease., Competing Interests: Not applicable.Not applicable.CV is part of the F. Hoffmann-La Roche Ltd. Scientific board. He has received consulting fees and/or speaker fees from AstraZeneca, BoehringerIngelheim, Chiesi, F. Hoffmann-La Roche Ltd. and Menarini. FDM has participated as a lectures, speaker, and/or advisor in scientific meetings and courses under the sponsorhip of Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompè, Guidotti/Malesci, GlaxoSmithKline, Menarini Group, Novartis, and Zambon, and has received financial suppor for research from Novartis. The authors NC, GS, DS, MP, AV, SET declare that they have no conflict of interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The sustained imbalance between oxidant and antioxidant species contributes to lung damage in patients with cystic fibrosis (CF). Glutathione (GSH) is an important component of the antioxidant defense in the airways epithelial lining fluid and its transportation out of the cells may be altered in CF. The aim of this study was to assess the oxidants/antioxidants balance in the airways of patients with CF. We measured the concentrations of GSH, the total antioxidant capacity and the concentration of 8-iso-prostaglandin F 2α (8-isoprostane), a marker of oxidative stress, in the exhaled breath condensate of 17 non-smoking patients with CF, in stable phase, and in 17 age-matched healthy subjects. The levels of GSH and total antioxidant capacity in patients with CF were significantly lower than in healthy subjects (0.66 ± 0.07 μM versus 1.30 ± 0.08 μM, p < 0.001, respectively for GSH; 0.157 ± 0.02 mM and 0.32 ± 0.01 mM, p < 0.05, respectively for antioxidant capacity). The concentration of 8-isoprostane was higher in CF than in healthy controls (26.5 ± 0.1 pg ml -1 versus 10.8 ± 0.1 pg ml -1 ; p < 0.05). A low concentration of antioxidant agents, particularly glutathione, and increased levels of 8-isoprostane in the exhaled breath suggest an altered oxidizing environment in the airways of patients with CF. This altered redox environment in the epithelial liquid surface may contribute to progressive lung disease.

Background: The present study reports the results of a survey jointly carried out by three Italian respiratory scientific associations (AIMAR, AIPO, SIMeR) together with an important Federation of elderly patients (FederAnziani) during the National Conference of Italian Court for Health Right held in Rimini from November 29(th) to December 1(st), 2013. The survey, based on a spirometric examination preceded by a questionnaire on respiratory health, was conducted on elderly people coming from all Italian regions to attend the Conference., Methods: Nine hundred forty-nine subjects (574 females and 375 males), mean age 66.2 ± 10.1 years, were interviewed and performed spirometric examination. There were 137 smokers (14.4 %). Mean value of Body Mass Index (BMI) was significantly higher in males (27.6 ± 6.6) than in females (26.3 ± 4.3)., Results: 17.1 % (N = 143) of the studied subjects reported to be suffering from respiratory disease and the prevalent illnesses were asthma (31.5 %) and COPD/emphysema (24.5 %), but only 3.3 % of the whole surveyed group was able to identify COPD as a pulmonary disease, however without knowing its characteristics, while these were known by 0.5 % of the interviewed subjects only. A high number of subjects, 22 % of whom were smokers, declared chronic sputum production. 10.2 % of the study group showed an obstructive defect at spirometry when the criterium of lower limit of the normal (LLN) was considered, whereas it was 12.4 % if the fixed limit of 0.70 was chosen. 64 % of the obstructed people thought they did not have any respiratory disease., Conclusions: The results of this survey, able to spread the knowledge of respiratory diseases and spirometry in a wide sample of subjects for the most part scarcely aware of them, emphasize the need for a greater divulgation of respiratory issues among the general population.

Background: Kartagener Syndrome (KS) is a rare autosomal recessive genetic disorder, resulting in a group of clinical manifestations, including bronchiectasis, chronic pansinusitis and situs inversus., Methods: We hereby reviewed eight cases of this rare entity selected from patients attending our outpatients Respiratory Unit since 2006. Samples of respiratory epithelium were obtained with the method of nasal brushing and sent to a specialized center in order to be studied with electron microscopy. At least 50 cross sections of different cilia from different cells were observed in each specimen to study the axonemal structure. Electron micrographs were taken at a magnification of X 50,000 to determine the orientation of the cilia and at a magnification of X 110,000 to study the axonemal pattern. The incidence of abnormal cilia was expressed as a percentage., Results: We observed different ultrastructural defects in our KS patients, including absence of outer dynein arms, absence of outer and inner dynein arms, and absence of the central pair with transposition of a peripheral doublet into the central position. Patient's follow up lasted till 2014, however two patients with more severe clinical behavior died before., Conclusions: This is a review of a case series, yet our data has shown that nasal brushing with ultrastructural pathological differentiation may be useful to identify patients with high risk and to develop more complex clinical presentations.

Cytoreductive surgery and hyperthermic-intraoperative-intrapleural-chemotherapy (HITHOC) is a known approach for malignant pleural diseases (MPD). This study was started to clarify the role of cytoreductive surgery and HITHOC in MPD. Criteria of inclusion were early-stage disease in malignant pleural mesothelioma (MPM), young age, good condition and selected stage-M1a lung cancer. Six patients with MPM and two patients with lung cancer were enrolled. After surgical debulking, intrapleural cisplatin was administered for 60 min at 42.5°C. Wedge, rib resection and repaired diaphragm were added in three, one and one patient, respectively. Morbidity, toxicity and mortality was nil. Hospital stay was 8 days. Mean survival is 13.6 months. This experience confirms that cytoreductive surgery and HITHOC is a good option in the treatment of MPD. A randomized controlled trial is necessary.

Lung metastasectomy is considered a safe and potentially curative procedure despite there is not a strong evidence that metastasectomy prolongs long-term survival in patients with lung metastases. Moreover, the debate is open regarding the best approach for lung metastasectomy, video-assisted thoracic surgery versus open approach. A systematic review of literature to clarify what is the best approach to prolong survival in patients with lung metastases was performed. Our study confirms that overall survival is equivalent for video-assisted thoracic surgery and thoracotomy, therefore the 'gold standard' surgical treatment for lung metastases remains a point of debate. The choice of the surgical approach still depends more on the single center or surgeon practice than on strong scientific evidence. A prospective randomized trial could clarify the question.

Cytoreductive surgery and hyperthermic intraoperative intrapleural chemotherapy (HITHOC) are a known option for malignant pleural mesothelioma (MPM). This prospective study was started to prove that pleurectomy/decortication and HITHOC could be successfully performed in a low volume center. Criteria of inclusion were a proven diagnosis of MPM, early-stage disease and good performance status. Six consecutive patients were enrolled. After pleurectomy/decortication, intrapleural cisplatin was administered for 60 min at 42.5 °C. Wedge resections and diaphragmatic reconstruction were added in two and one patient, respectively. Morbidity was 16.6%. Mortality was nil. Hospital stay was 7.8 days. Mean survival was 21.5 months (range: 6-30). This small experience confirms that pleurectomy/decortication and HITHOC are a good therapeutic option in the multimodality treatment of MPM. A randomized controlled trial is necessary.

Background: Mount Etna, located in the eastern part of Sicily (Italy), is the highest and most active volcano in Europe. During the sustained eruption that occurred in October-November 2002 huge amounts of volcanic ash fell on a densely populated area south-east of Mount Etna in Catania province. The volcanic ash fall caused extensive damage to infrastructure utilities and distress in the exposed population. This retrospective study evaluates whether or not there was an association between ash fall and acute health effects in exposed local communities., Methods: We collected the number and type of visits to the emergency department (ED) for diseases that could be related to volcanic ash exposure in public hospitals of the Province of Catania between October 20 and November 7, 2002. We compared the magnitude of differences in ED visits between the ash exposure period in 2002 and the same period of the previous year 2001., Results: We observed a significant increase of ED visits for acute respiratory and cardiovascular diseases, and ocular disturbances during the ash exposure time period., Conclusions: There was a positive association between exposure to volcanic ash from the 2002 eruption of Mount Etna and acute health effects in the Catania residents. This study documents the need for public health preparedness and response initiatives to protect nearby populations from exposure to ash fall from future eruptions of Mount Etna.

Background: The increase in peripheral chemoreflex sensitivity in patients with obstructive sleep apnea (OSA) is associated with activation of autonomic nervous system and hemodynamic responses. Nasal CPAP (nCPAP) is an effective treatment for OSA, but little is known on its effect on chemoreflex sensitivity., Objectives: To assess the effect of nCPAP treatment or placebo (sham nCPAP) on ventilatory control in patients with OSA., Setting: Sleep laboratory of Azienda Ospedaliera Garibaldi., Patients: Twenty-five patients with moderate-to-severe OSA., Design and Measurements: Patients were randomly assigned to either therapeutic nCPAP (use of optimal pressure, n = 15) or sham nCPAP (suboptimal pressure of 1 to 2 cm H2O, n = 10) in a double-blind fashion and treated for 1 month. A rebreathing test to assess ventilatory response to normocapnic hypoxia and normoxic hypercapnia was performed at basal condition and after 1 month of treatment., Results: The use of therapeutic nCPAP or sham nCPAP did not affect daytime percentage of arterial oxygen saturation (SaO2%) or end-tidal P(CO2). The normocapnic hypoxic ventilatory response was reduced after 1 month of treatment with nCPAP (the slope was 1.08 +/- 0.02 L/min/SaO2% at basal condition and 0.53 +/- 0.07 L/min/SaO2% after 1 month of treatment, p = 0.008) [mean +/- SD], but not in patients treated with sham nCPAP (slope, 0.83 +/- 0.09 L/min/SaO2% and 0.85 +/- 0.19 L/min/SaO2% at basal condition and after 1 month, respectively). The normoxic hypercapnic ventilatory response remained unchanged after 1 month in both groups. No changes in ventilatory response to either hypoxia or hypercapnia were observed after a single night of nCPAP treatment., Conclusion: The ventilatory response to hypoxia is reduced during regular treatment, but not after short-term treatment, with nCPAP. Readjusted peripheral oxygen chemosensitivity during nCPAP treatment may be a side effect of both reduced sympathetic activity and increased baroreflex activity, or a possible continuous positive airway pressure-related mechanism leading to a reduced activation of autonomic nervous system per se.

In some asthmatics deep inspiration causes a sustained bronchoconstration, which is dependent on Ca2+ uptake. Inhaled diuretics protect against bronchoconstriction induced by a variety of indirect stimuli, by inhibiting the ionic fluxes involving Ca2+ uptake across the cell membrane of airway epithelium. The aim of this study was therefore to investigate the protective effect of inhaled furosemide on the bronchoconstriction induced by deep inspiration in asthma and to compare it with the effect of acetazolamide, an inhibitor of carbonic anhydrase devoid of effect on ion cotransport but possessing inhibitory effects on chloride ion influx and Na+/K+ exchange. The study was carried out on three different study days according to a randomized, double-blind, placebo-controlled, crossover design. Nine non smoking asthmatic subjects first performed a series of 9 controlled deep inspirations to TLC followed by forced expirations to RV within 20 min, which caused a decrease of FEV1 > 20% from baseline. Two hours later, the subjects inhaled either furosemide (40 mg), or acetazolamide (500 mg), or saline (placebo) in random order, and then two more deep-inspiration challenges were performed after 30 and 140 mins. The progressive percent decrement of FEV1 caused by deep-inspiration challenge was taken as an index of bronchoconstriction. Bronchoconstriction was significantly blunted at 30 mins, but not 140 mins, after inhaling furosemide (p < 0.01) or acetazolamide (p < 0.05) compared to control. We interpret these results as due to a modulation of ionic fluxes across the smooth muscle cell membrane afforded by inhaled furosemide and acetazolamide.

To examine the effect of inhaled platelet-activating factor (PAF) on airway sensitivity and on maximal airway narrowing, we measured airway response to doubling concentrations of methacholine (MCh) 48 h before and 48 h after inhalation of 10, 50 and 100 micrograms of PAF in six nonatopic, nonasthmatic subjects. The forced expiratory volume in one second (FEV1) and airflow at 30 percent of vital capacity (V30) from partial forced expiration were used to assess changes in airway calibre. Inhalation of PAF caused only minor changes in FEV1. In contrast, inhalation of 100 micrograms of PAF caused a significant fall in V30 from 2.64 +/- 0.35 to 1.35 +/- 0.43 l.min-1 (p < 0.05). Two days after PAF inhalation a leftward shift of the concentration-response curve to MCh was observed. The MCh concentration causing a 20% fall in FEV1 (PC20FEV1) was 11.25 +/- 1.78 and 2.38 +/- 1.29 mg.ml-1 (geometric mean +/- GSEM; p < 0.05) before and after PAF inhalation, respectively. PAF did not affect the maximal airway response to MCh. The maximum percentage fall in FEV1 was 36.2 +/- 1.9% at baseline and 37.6 +/- 1.8% after PAF inhalation. Likewise, maximum percentage change in V30 was 72.8 +/- 3.7% at baseline and 73.6 +/- 3.4% after PAF inhalation. The results of this study show that PAF inhalation increases airway sensitivity without altering the maximal bronchoconstrictive response to MCh in normal subjects.

To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.