Do guidelines influence breathlessness management in advanced lung diseases? A multinational survey of respiratory medicine and palliative care physicians

Background: Respiratory medicine (RM) and palliative care (PC) physicians’ management of chronic breathlessness in advanced chronic obstructive pulmonary disease (COPD), fibrotic interstitial lung disease (fILD) and lung cancer (LC), and the influence of practice guidelines was explored via an online survey. Methods: A voluntary, online survey was distributed to RM and PC physicians via society newsletter mailing lists. Results: 450 evaluable questionnaires (348 (77%) RM and 102 (23%) PC) were analysed. Significantly more PC physicians indicated routine use (often/always) of opioids across conditions (COPD: 92% vs. 39%, fILD: 83% vs. 36%, LC: 95% vs. 76%; all p < 0.001) and significantly more PC physicians indicated routine use of benzodiazepines for COPD (33% vs. 10%) and fILD (25% vs. 12%) (both p < 0.001). Significantly more RM physicians reported routine use of a breathlessness score (62% vs. 13%, p < 0.001) and prioritised exercise training/rehabilitation for COPD (49% vs. 7%) and fILD (30% vs. 18%) (both p < 0.001). Overall, 40% of all respondents reported reading non-cancer palliative care guidelines (either carefully or looked at them briefly). Respondents who reported reading these guidelines were more likely to: routinely use a breathlessness score (χ2 = 13.8; p < 0.001), use opioids (χ2 = 12.58, p < 0.001) and refer to pulmonary rehabilitation (χ2 = 6.41, p = 0.011) in COPD; use antidepressants (χ2 = 6.25; p = 0.044) and refer to PC (χ2 = 5.83; p = 0.016) in fILD; and use a handheld fan in COPD (χ2 = 8.75, p = 0.003), fILD (χ2 = 4.85, p = 0.028) and LC (χ2 = 5.63; p = 0.018). Conclusions: These findings suggest a need for improved dissemination and uptake of jointly developed breathlessness management guidelines in order to encourage appropriate use of existing, evidence-based therapies. The lack of opioid use by RM, and continued benzodiazepine use in PC, suggest that a wider range of acceptable therapies need to be developed and trialled

Novel insights into alkaptonuria physiopathology

Alkaptonuria (AKU) is an ultra-rare genetic disease resulting from a deficient activity of the enzyme homogentisate 1,2- dioxygenase (HGD), responsible for the catabolism of the aromatic amino acids Phenylalanine and Tyrosine. This condition leads to the accumulation of a toxic metabolite, HGA and of its product of oxidation BQA, whose polymerization generates melanin-like aggregates, with amyloidogenic properties, leading to the phenomenon of “Ochronosis”. The most affected structures by the deposition of these ochronotic aggregates are joints, which undergo severe arthropathy; therefore, articular cartilage is the main investigated tissue for the comprehension of AKU physiopathology. Articular cartilage homeostasis is maintained by articular chondrocytes, which have an important role in the synthesis and release of extracellular matrix (ECM) components, essential to properly respond to mechanical compression processes the tissue is constantly subjected to. This mechanism is mediated by chondrocyte cytoskeleton, including the microtubule-based organelle primary cilium, which exerts its function through the activation of the Hedgehog (Hh) signaling pathway. On the basis of the previous considerations, for the aims of this thesis, the set-up of in vitro AKU cellular and tissue models, was fundamental to counteract problems related to the collection of AKU samples, due to the rarity of the disease. Both experimental models were properly characterized, by highlighting the role of HGA in mediating pigment deposition and cartilage degradation processes, through histological and cytological analyses and immunofluorescence assays. Results showed that the ochronotic pigment deposits following HGA treatment lead to an oxidative stress status and to the accumulation of serum amyloid A (SAA) protein in the cartilaginous tissue. Another in vitro model was used to analyse the ability of AKU chondrocytes to respond to mechanical loading in terms of production of ECM components, by applying a 10% strain on adherent cell cultures. AKU chondrocytes resulted unable to respond properly to mechanical strain and HGA seemed to be involved in this altered responsiveness. Afterwards, a deep investigation of the cytoskeleton characteristics of AKU chondrocytes was performed, mainly by focusing on the interaction of each cytoskeletal marker with the amyloidogenic protein serum amyloid A (SAA). An in situ proximity ligation assay confirmed the co-localization of cytoskeletal marker with SAA, thus explaining the severe alterations observed in AKU cytoskeleton. Furthermore, another cytoskeletal component was characterized, the primary cilium, both investigating on its structural features and on its function in terms of Hedgehog (Hh) signaling activation. Primary cilia of AKU chondrocytes resulted shorter than normal chondrocytes and HGA treatment led to the same ciliary phenotype. In order to investigate the activation of the Hh pathway, the expression of the constitutive activator of the pathway (Gli-1) was evaluated both at the gene and at the protein level. This protein was found overexpressed in AKU/HGA-treated chondrocytes. Finally, given the role of Hh activation in mediating processes of cartilage degradation in osteoarthritis-like diseases, a therapeutic approach based on the inhibition of the Hh signaling was adopted, by using treatment with lithium chloride and with small molecule antagonists of the Hh receptor Smoothened (Smo). All the testing compounds resulted efficient in inhibiting Hh signal and in restoring cilia lengths, suggesting the use of these compounds as a potential therapeutic approach for the treatment of AKU

Angiogenesis in alkaptonuria

Alkaptonuria (AKU) is a rare genetic disease that affects the entire joint. Current standard of AKU treatment is palliative and little is known about its physiopathology. Neovascularization is involved in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes AKU. Here, we investigated the presence of neoangiogenesis in AKU synovium and healthy controls. Synovium from AKU patients, who had undergone total joint replacement or arthroscopy, or from healthy patients without any history of rheumatic diseases, who underwent surgical operation following sport trauma was subjected to hematoxylin and eosin staining. Histologic grades were assigned for clinical disease activity and synovitis based on cellular content of the synovium. By immunofluorescence microscopy, using different endothelial cell markers, we observed large vascularization in AKU but not in healthy synovium. Moreover, Western blotting and quantification analyses confirmed strong expression of endothelial cell markers in AKU synovial tissues. Importantly, AKU synovium vascular endothelium expressed high levels of β-dystroglycan, a protein previously involved in the regulation of angiogenesis in osteoarthritic synovium. This is the first report providing experimental evidences that new blood vessels are formed in AKU synovial tissues, opening new perspectives for AKU therapy

Chondroptosis in alkaptonuric cartilage

Alkaptonuria (AKU) is a rare genetic disease that affects the entire joint. Current standard of treatment is palliative and little is known about AKU physiopathology. Chondroptosis, a peculiar type of cell death in cartilage, has been so far reported to occur in osteoarthritis, a rheumatic disease that shares some features with AKU. In the present work, we wanted to assess if chondroptosis might also occur in AKU. Electron microscopy was used to detect the morphological changes of chondrocytes in damaged cartilage distinguishing apoptosis from its variant termed chondroptosis. We adopted histological observation together with Scanning Electron Microscopy and Transmission Electron Microscopy to evaluate morphological cell changes in AKU chondrocytes. Lipid peroxidation in AKU cartilage was detected by fluorescence microscopy. Using the above-mentioned techniques, we performed a morphological analysis and assessed that AKU chondrocytes undergo phenotypic changes and lipid oxidation, resulting in a progressive loss of articular cartilage structure and function, showing typical features of chondroptosis. To the best of our knowledge, AKU is the second chronic pathology, following osteoarthritis, where chondroptosis has been documented. Our results indicate that Golgi complex plays an important role in the apoptotic process of AKU chondrocytes and suggest a contribution of chondroptosis in AKU pathogenesis. These findings also confirm a similarity between osteoarthritis and AKU

Combined Aerobic and Resistance Exercises Evokes Longer Reductions on Ambulatory Blood Pressure in Resistant Hypertension: A Randomized Crossover Trial

Aim. The present study compared the acute effects of aerobic (AER), resistance (RES), and combined (COM) exercises on blood pressure (BP) levels in people with resistant hypertension (RH) and nonresistant hypertension (NON-RH). Methods. Twenty patients (10 RH and 10 NON-RH) were recruited and randomly performed three exercise sessions and a control session. Ambulatory BP was monitored over 24 hours after each experimental session. Results. Significant reductions on ambulatory BP were found in people with RH after AER, RES, and COM sessions. Notably, ambulatory BP was reduced during awake-time and night-time periods after COM. On the other hand, the effects of AER were more prominent during awake periods, while RES caused greater reductions during the night-time period. In NON-RH, only RES acutely reduced systolic BP, while diastolic BP was reduced after all exercise sessions. However, the longest postexercise ambulatory hypotension was observed after AER (~11 h) in comparison to RES (~8 h) and COM (~4 h) exercises. Conclusion. Findings of the present study indicate that AER, RES, and COM exercises elicit systolic and diastolic postexercise ambulatory hypotension in RH patients. Notably, longer hypotension periods were observed after COM exercise. In addition, NON-RH and RH people showed different changes on BP after exercise sessions, suggesting that postexercise hypotension is influenced by the pathophysiological bases of hypertension

A machine-learning parsimonious multivariable predictive model of mortality risk in patients with Covid-19

The COVID-19 pandemic is impressively challenging the healthcare system. Several prognostic models have been validated but few of them are implemented in daily practice. The objective of the study was to validate a machine-learning risk prediction model using easy-to-obtain parameters to help to identify patients with COVID-19 who are at higher risk of death. The training cohort included all patients admitted to Fondazione Policlinico Gemelli with COVID-19 from March 5, 2020, to November 5, 2020. Afterward, the model was tested on all patients admitted to the same hospital with COVID-19 from November 6, 2020, to February 5, 2021. The primary outcome was in-hospital case-fatality risk. The out-of-sample performance of the model was estimated from the training set in terms of Area under the Receiving Operator Curve (AUROC) and classification matrix statistics by averaging the results of fivefold cross validation repeated 3-times and comparing the results with those obtained on the test set. An explanation analysis of the model, based on the SHapley Additive exPlanations (SHAP), is also presented. To assess the subsequent time evolution, the change in paO2/FiO2 (P/F) at 48 h after the baseline measurement was plotted against its baseline value. Among the 921 patients included in the training cohort, 120 died (13%). Variables selected for the model were age, platelet count, SpO2, blood urea nitrogen (BUN), hemoglobin, C-reactive protein, neutrophil count, and sodium. The results of the fivefold cross-validation repeated 3-times gave AUROC of 0.87, and statistics of the classification matrix to the Youden index as follows: sensitivity 0.840, specificity 0.774, negative predictive value 0.971. Then, the model was tested on a new population (n=1463) in which the case-fatality rate was 22.6%. The test model showed AUROC 0.818, sensitivity 0.813, specificity 0.650, negative predictive value 0.922. Considering the first quartile of the predicted risk score (low-risk score group), the case-fatality rate was 1.6%, 17.8% in the second and third quartile (high-risk score group) and 53.5% in the fourth quartile (very high-risk score group). The three risk score groups showed good discrimination for the P/F value at admission, and a positive correlation was found for the low-risk class to P/F at 48 h after admission (adjusted R-squared=0.48). We developed a predictive model of death for people with SARS-CoV-2 infection by including only easy-to-obtain variables (abnormal blood count, BUN, C-reactive protein, sodium and lower SpO2). It demonstrated good accuracy and high power of discrimination. The simplicity of the model makes the risk prediction applicable for patients in the Emergency Department, or during hospitalization. Although it is reasonable to assume that the model is also applicable in not-hospitalized persons, only appropriate studies can assess the accuracy of the model also for persons at home

Asthma in patients admitted to emergency department for COVID-19: prevalence and risk of hospitalization

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