Airways Type-2 Related Disorders: Multiorgan, Systemic or Syndemic Disease?

Chronic rhinosinusitis (CRS) has recently undergone a significant paradigm shift, moving from a phenotypical classification towards an "endotype-based" definition that places more emphasis on clinical and therapeutic aspects. Similar to other airway diseases, like asthma, most cases of CRS in developed countries exhibit a dysregulated type-2 immune response and related cytokines. Consequently, the traditional distinction between upper and lower airways has been replaced by a "united airway" perspective. Additionally, type-2 related disorders extend beyond respiratory boundaries, encompassing conditions beyond the airways, such as atopic dermatitis. This necessitates a multidisciplinary approach. Moreover, consideration of possible systemic implications is crucial, particularly in relation to sleep-related breathing diseases like Obstructive Sleep Apnoea Syndrome (OSAS) and the alteration of systemic inflammatory mediators such as nitric oxide. The trends in epidemiological, economic, and social burden are progressively increasing worldwide, indicating syndemic characteristics. In light of these insights, this narrative review aims to present the latest evidence on respiratory type-2 related disorders, with a specific focus on CRS while promoting a comprehensive perspective on the "united airways". It also introduces a novel concept: viewing these conditions as a multiorgan, systemic, and syndemic disease.

The effect of drug-induced sleep endoscopy on surgical outcomes for obstructive sleep apnea: a systematic review.

PURPOSE: Drug-induced sleep endoscopy (DISE) is the most widespread diagnostic tool for upper-airway endoscopic evaluation of snoring and obstructive sleep apnea (OSA). However, a consensus on the effectiveness of DISE on surgical outcomes is still lacking. This study aimed to quantify the effect of DISE on surgical outcomes and to compare DISE with awake examination using the Müller Maneuver (MM). METHODS: This systematic review was performed according to the PRISMA guidelines. Published studies from the last 30 years were retrieved from the Cochrane Library, MEDLINE, SCOPUS, and PubMed databases. Studies comparing DISE with awake examination, or MM were included. Surgical success rate was defined according to Sher's criteria, achieving a postoperative apnoea-hypopnea index (AHI) value < 20 events per hour and a 50% improvement from preoperative AHI. Outcomes are presented in terms of surgical success, pre- and postoperative AHI, Epworth sleepiness score (ESS), oxygen desaturation index (ODI) and lowest oxygen saturation (LOS). RESULTS: This review included 8 studies comprising 880 patients. DISE group showed a higher LOS increase, ODI decrease, ESS decrease than non-DISE group (6.83 ± 3.7 versus 3.68 ± 2.9, p<0.001; 19.6 ± 11.2 versus 12.6 ± 10.4, p<0.001; 6.72 ± 4.1 versus 3.69 ± 3.1, p<0.001). Differences in surgical success rate were significant only between DISE and MM (64.04% versus 52.48%, p = 0.016). AHI decrease resulted higher in non-DISE than in DISE group (39.92 ± 24.7 versus 30.53 ± 21.7, p<0.001). CONCLUSION: Results of this systematic review suggest that the evidence is mixed regarding a positive effect of DISE on surgical outcomes.

Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.

Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.

Matrix metalloproteinases, purinergic signaling, and epigenetics: hubs in the spinal neuroglial network following peripheral nerve injury.

Activation of glial cells (reactive gliosis) and the purinergic pathway, together with metalloproteinase (MMP)-induced remodeling of the neural extracellular matrix (nECM), drive maladaptive changes in the spinal cord following peripheral nerve injury (PNI). We evaluated the effects on spinal maladaptive plasticity through administration of oxidized ATP (oxATP), an antagonist of P2X receptors (P2XR), and/or GM6001, an inhibitor of MMPs, in rats following spared nerve injury (SNI) of the sciatic nerve. With morpho-molecular techniques, we demonstrated a reduction in spinal reactive gliosis and changes in the neuro-glial-nECM crosstalk via expression remodeling of P2XR, nerve growth factor (NGF) receptors (TrkA and p75), and histone deacetylase 2 (HDAC2) after treatments with oxATP/GM6001. Altogether, our data suggest that MMPs and purinergic inhibition have a modulatory impact on key proteins in the neuro-glial-nECM network, acting at different levels from intracellular signaling to epigenetic modifications.

The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence.

Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.

Effects of glove finger- versus lidocaine-soaked nasal packing after endoscopic nasal surgery: a prospective randomized controlled trial.

PURPOSE: Nasal packing is a common but unpleasant procedure in patients who undergo endoscopic sinus surgery (ESS). The aim of this study was to assess whether a glove-finger pack strategy would reduce pain compared to lidocaine-soaked packs after ESS. METHODS: A prospective randomized controlled trial enrolling 120 consecutive patients affected by chronic rhinosinusitis, who underwent bilateral ESS. At the end of surgery 62 subjects received 10 cm non-absorbable pack soaked with 5 mL of 2%-lidocaine solution and 58 received a 10 cm non-absorbable pack coated with a latex free glove finger soaked with saline solution. Data concerning pain were collected using a 0 to 10 visual analogue scale at post-operative hours 1, 4, 8, and 16 and at pack removal (24 h ± 15 min). All post-operative analgesic rescue doses were registered. Also, bleeding was reported. RESULTS: The mean VAS score during pack-removal was significantly lower in glove-finger group than in the lidocaine group (3.22 ± 2.16 vs 4.89 ± 2.90, p = 0.0012). There was no statistically significant difference between re-soaking lidocaine-soaked-packs with saline solution or lidocaine at pack removal time (p = 0.42). CONCLUSION: Glove-finger nasal pack seems to provide better pain control after ESS, when compared with lidocaine-soaked pack, especially at pack removal time.

[Effectiveness of school-based interventions to prevent traffic accidents: an overview of secondary literature]. / Efficacia degli interventi scolastici per la prevenzione degli incidenti stradali: una overview della letteratura secondaria.

INTRODUZIONE: gli incidenti stradali sono l'ottava causa di morte al mondo e la prima tra i giovani di 15-29 anni. In Italia il Piano nazionale sicurezza stradale raccomanda l'educazione scolastica per la prevenzione degli incidenti stradali; ad oggi non esistono documenti che raccolgano evidenze di efficacia sugli interventi educativi stradali e le rapportino al contesto italiano. OBIETTIVI: riassumere e discutere ciò che è noto in letteratura riguardo agli interventi scolastici per la prevenzione degli incidenti stradali. METODI: sono state ricercate linee guida e revisioni sistematiche usando i seguenti criteri di inclusione: popolazione di età inferiore ai 25 anni di entrambi i sessi; interventi scolastici di educazione stradale; effetti su indicatori primari di esito come riduzione degli incidenti stradali, astinenza dalla guida sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol; effetti su indicatori secondari di esito come conoscenze e competenze sui comportamenti di guida sicura. RISULTATI: sono state identificate due revisioni sistematiche. L'educazione stradale nelle scuole non mostra evidenza di efficacia (rischio relativo 1,03; IC95% 0,98-1,08) nel ridurre gli incidenti. Programmi scolastici più specifici mostrano risultati solo in parte convincenti per l'adozione di comportamenti sicuri come l'astinenza dal guidare sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol. DISCUSSIONE: le revisioni incluse non hanno trovato programmi efficaci nella riduzione degli incidenti stradali o dei fattori che possano determinarli. Nell'attesa di studi più recenti, appare opportuno promuovere l'implementazione di interventi misti, scolastici e di comunità, che hanno mostrato maggiori prove di efficacia.

Psychiatric Burden in Chronic Sinonasal Diseases: A Single-Center Cross-Sectional Observational Study.

BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis (CRS) and nasal septum deviation (SD) are two widely diffused clinical conditions in otorhinolaryngology clinical practice. Albeit nasal symptoms are the most commonly referred by patients affected by both conditions, recent evidence has explored the impairment of nasal function beyond its local implication. Indeed, the prevalence of psychiatric disorders, specifically anxiety and depression, was found higher in patients suffering from SD or CRS than in the general population. The aim of this study was to evaluate the psychiatric burden of these conditions in terms of anxiety and depression and to assess its relationship with clinical phenotype and age. METHODS: Monocentric cross-sectional observational study. Consecutive patients affected by CRS with or without nasal polyps or by SD were considered eligible. At referral, each patient underwent nasal endoscopy for clinical diagnosis and had to fill in the Hospital Anxiety and Depression Scale (HADS), the Sinonasal Outcome Test-22 (SNOT-22), and the Visual Analogue Scale (VAS) for global nasal symptoms. The population was grouped according to disease and age. RESULTS: One hundred fifty patients were enrolled. We observed a statistically significant difference in mean HADS score between patients affected by CRS with nasal polyps and those suffering from CRS without nasal polyps or SD both in the overall population and by age groups. Nevertheless, there was no significant difference in the HADS score between younger patients affected by CRS and SD. The mean HADS score was significantly higher in younger patients affected by SD compared to older. Furthermore, we observed an inverse correlation between age and HADS score in each disease group, statistically significant for SD. On the contrary, in the overall population, HADS score and patient-related outcomes (PROs) were directly correlated.  Conclusions: In the era of personalized medicine, our work remarks on the critical impact of anxiety and depression on the quality of life (QoL) of patients affected by sinonasal conditions. According to our results, age affects patient-reported outcomes (PROs) and should, therefore, be enhanced in the therapeutic decision process.

Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.

Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid ß (Aß) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid ß (Aß) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.

ENT Referral From Emergency Department During COVID-19: A Single-Center Experience.

PURPOSE: COVID-19 pandemic transformed the health system response worldwide. The aim of this study is to report changes about numbers and reason for ENT consultations in emergency department (ED) during COVID-19 pandemic comparing with those occurred the previous year (2019). METHODS: Data about patients admitted to adult and pediatric ED were collected from March 1 to May 31, 2019 and 2020. Patients referred for urgency from general practitioners were excluded from the study. RESULTS: Global ED admission (except for dyspnea or COVID-19-related symptoms) dramatically decreased during pandemic (-50.9% among adults and -71.4% among pediatrics). At the same time, ENT consultancy significantly reduced too, by 71.5% (P < .01) among adults and 45.1% (P < .01) for pediatrics. Among adults, it was reported a statistically significant decrease in consultation for ear problems (-88.5%, P = .0146). Reduction in ENT referral for bone fracture (-40%, P = .059), vertigo (-77.8%, P = .637), and tonsillitis (-87.5%, P = .688) was consistent, but not significant. Among pediatric patients, it was observed an increase by 25% about foreign bodies (12 vs 15, P < .01). A reduction in numbers of consults for ear problem (-90.8%; P = .045), epistaxis (-80%; P = .196), and nasal fracture (-70%; P = .36) was also observed. CONCLUSION: Fear of infection and the forced lock down caused a significant decrease in the number of ED accesses and in ENT consultancy. These data may suggest that some ED referral usually could be deferred, but on the other hand, pandemic will cause a great diagnostic delay.

Care for Patients with Type-2 Chronic Rhinosinusitis.

In the last 20 years, growing interest in chronic rhinosinusitis (CRS) has become evident in medical literature; nevertheless, it is still difficult to identify the real prevalence of the disease. Epidemiological studies are few and focused on heterogeneous populations and diagnostic methods. Recent research has contributed to identifying CRS as a disease characterized by heterogeneous clinical scenarios, high impact on quality of life, and elevated social costs. Patient stratification with phenotypes and identification of the pathobiological mechanism at the origin of the disease (endotype) and its comorbidities are pivotal in the diagnostic process, and they should be addressed in order to properly tailor treatment. A multidisciplinary approach, shared diagnostic and therapeutic data, and follow-up processes are therefore necessary. Oncological multidisciplinary boards offer models to imitate in accordance with the principles of precision medicine: tracing a diagnostic pathway with the purpose of identifying the patient's immunological profile, monitoring therapeutical processes, abstaining from having only a single specialist involved in treatment, and placing the patient at the center of the therapeutic plan. Awareness and participation from the patient's perspective are fundamental steps to optimize the clinical course, improve quality of life, and reduce the socioeconomic burden.

Image-Guided Intraoperative Assessment of Surgical Margins in Oral Cavity Squamous Cell Cancer: A Diagnostic Test Accuracy Review.

(1) Background: The assessment of resection margins during surgery of oral cavity squamous cell cancer (OCSCC) dramatically impacts the prognosis of the patient as well as the need for adjuvant treatment in the future. Currently there is an unmet need to improve OCSCC surgical margins which appear to be involved in around 45% cases. Intraoperative imaging techniques, magnetic resonance imaging (MRI) and intraoral ultrasound (ioUS), have emerged as promising tools in guiding surgical resection, although the number of studies available on this subject is still low. The aim of this diagnostic test accuracy (DTA) review is to investigate the accuracy of intraoperative imaging in the assessment of OCSCC margins. (2) Methods: By using the Cochrane-supported platform Review Manager version 5.4, a systematic search was performed on the online databases MEDLINE-EMBASE-CENTRAL using the keywords "oral cavity cancer, squamous cell carcinoma, tongue cancer, surgical margins, magnetic resonance imaging, intraoperative, intra-oral ultrasound". (3) Results: Ten papers were identified for full-text analysis. The negative predictive value (cutoff < 5 mm) for ioUS ranged from 0.55 to 0.91, that of MRI ranged from 0.5 to 0.91; accuracy analysis performed on four selected studies showed a sensitivity ranging from 0.07 to 0.75 and specificity ranging from 0.81 to 1. Image guidance allowed for a mean improvement in free margin resection of 35%. (4) Conclusions: IoUS shows comparable accuracy to that of ex vivo MRI for the assessment of close and involved surgical margins, and should be preferred as the more affordable and reproducible technique. Both techniques showed higher diagnostic yield if applied to early OCSCC (T1-T2 stages), and when histology is favorable.

Paraganglioma of the Thyroid Gland: A Case Report and a Review of the Literature.

Paragangliomas of the thyroid gland are rare and usually they originate from the inferior laryngeal paraganglia. In this case report, we describe the case of a 78-year-old woman who presented with an incidental finding of thyroid nodule dislocating the trachea. After a systemic and radiological evaluation, right lobo-isthmectomy was performed, and the definitive diagnosis of paraganglioma was reached. Diagnosis of these thyroidal lesions could be difficult due to their rarity, to their specific radiological aspects and the need of employing specific histological staining techniques. Once the definitive diagnosis is reached, patients should undergo a systemic and genetic evaluation. Surgery is the gold standard treatment; radiotherapy should be considered when aggressive behavior is suspected. Regular long-lasting follow-up should be proposed to these patients considering the unpredictable behavior of these lesions.

Frozen Section Analysis and Real-Time Magnetic Resonance Imaging of Surgical Specimen Oriented on 3D Printed Tongue Model to Assess Surgical Margins in Oral Tongue Carcinoma: Preliminary Results.

BACKGROUND: A surgical margin is the apparently healthy tissue around a tumor which has been removed. In oral cavity carcinoma, a negative margin is considered ≥ 5 mm, a close margin between 1 and 5 mm, and a positive margin ≤ 1 mm. Currently, the intraoperative surgical margin status is based on the visual inspection and tissue palpation by the surgeon and intraoperative histopathological assessment of the resection margins by frozen section analysis (FSA). FSA technique is limited and susceptible to sampling errors. Definitive information on the deep resection margins requires postoperative histopathological analysis. METHODS: We described a novel approach for the assessment of intraoperative surgical margins by examining a surgical specimen oriented through a 3D-printed specific patient tongue with real-time Magnetic Resonance Imaging (MRI). We reported the preliminary results of a case series of 10 patients, prospectively enrolled, with oral tongue carcinoma who underwent surgery between February 2020 and April 2021. Two radiologists with 5 and 10 years of experience, respectively, in Head and Neck radiology in consensus evaluated specimen MRI and measured the distance between the tumor and the specimen surface. We performed intraoperative bedside FSA. To compare the performance of bedside FSA and MRI in predicting definitive margin status we computed the weighted sensitivity (SE), specificity (SP), accuracy (ACC), area under the ROC curve (AUC), F1-score, Positive Predictive Value (PPV), and Negative Predictive Value (NPV). To express the concordance between FSA and ex-vivo MRI we reported the jaccard index. RESULTS: Intraoperative bedside FSA showed SE of 90%, SP of 100%, F1 of 95%, ACC of 0.9%, PPV of 100%, NPV (not a number), and jaccard of 90%, and ex-vivo MRI showed SE of 100%, SP of 100%, F1 of 100%, ACC of 100%, PPV of 100%, NPV of 100%, and jaccard of 100%. These results needed to be validated in a larger sample size of 21- 44 patients. CONCLUSION: The presented method allows a more accurate evaluation of surgical margin status, and the first clinical experiences underline the high potential of integrating FSA with ex-vivo MRI of the fresh surgical specimen.