Mucormycosis is an invasive fungal infection caused by fungi belonging to order Mucorales. Recently, with the increase in COVID-19 infections, mucormycosis infections have become a matter of concern globally, because of the high morbidity and mortality rates associated with them. Due to the association of mucormycosis with COVID-19 disease, it has been termed COVID-19-associated mucormycosis (CAM). In the present review, we focus on mucormycosis incidence, pathophysiology, risk factors, immune dysfunction, interactions of Mucorales with endothelial cells, and the possible role of iron in Mucorales growth. We review the limitations associated with current diagnostic procedures and the requirement for more specific, cost-effective, convenient, and sensitive assays, such as PCR-based assays and monoclonal antibody-based assays for the effective diagnosis of mucormycosis. We discuss the current treatment options involving antifungal drug therapies, adjunctive therapy, surgical treatment, and their limitations. We also review the importance of nutraceuticals-based therapy for the prevention as well as treatment of mucormycosis. Our review also highlights the need to explore the potential of novel immunotherapeutics, which include antibody-based therapy, cytokine-based therapy, and combination/synergistic antifungal therapy, as treatment options for mucormycosis. In summary, this review provides a complete overview of COVID-19-associated mucormycosis, addressing the current research gaps and future developments required in the field. Fungal infections have been often neglected, despite their high morbidity and mortality rates worldwide . Fungal Rhizopus, Apophysomyces, Rhizomucor, Lichtheimia, Cunninghamella, Mucor, and Saksenaea [Rhizopus arrhizus [Rhizopus species involved in causing mucormycosis infection are R. homothallicus and R. microsporus [Rhizopus species that are involved in causing rhino-orbital-cerebral mucormycosis have been reported in abundance in the environment [Rhizopus, Apophysomyces is considered as the second most common fungal Genus causing mucormycosis infection in Asia. The fungal species A. variabilis, which causes cutaneous mucormycosis, accounts for 60% of mucormycosis cases in India [Lichtheimia ramosa, Thamnostylum lucknowense, and Mucor irregularis, have also been reported in India [Mucormycosis is an angioinvasive fungal infection caused by fungal species belonging to different genera, which include aksenaea . Globallarrhizus ,5. Otherrosporus ,7. Varioironment ,9. In adin India . Variousin India ,12,13. A. elegans has been reported to be present in soil from tropical climates [Mucorales spp., particularly Rhizopus spp., require a high moisture content for growth and are considered as hydrophilic. Mucorales tend to settle down with liquid droplets present in the air, which could be a probable reason why Mucorales are not detected in the air samples obtained from indoor habitats [Rhizopus, Rhizomucor, and Mucor spp. has been reported in air-conditioning filters, which indicates the persistence of Mucorales spp. in settled dust particles [Mucorales spp.  has also been reported in food sources. As such, Mucorales-contaminated food items may also be a risk factor for acquiring mucormycosis in immunocompromised individuals [Many biotic environments, such as outdoor and indoor habitats, along with various food items, may contribute to the growth and persistence of Mucorales in a wide range of environmental conditions . Soil isclimates . Mucoralhabitats . A predoarticles . A varieividuals .Mucorales spores dispersed in dust particles gain entry into a human host via the respiratory tract and skin or a breach in mucosal barrier/traumatized sites, and fungal spore germination and proliferation lead to cutaneous necrotizing fasciitis and/or disseminated mucormycosis infections ,18. In iMucormycosis infection is mainly associated with diabetic and immunocompromised patients ,24. OtheMucorales spp. are identified by a direct microscopy examination and fungal cell culture. Mucorales specimen are cultured on Sabouraud dextrose agar at a 30–37 °C temperature that forms grayish or black colonies [colonies . Other dcolonies ,33. In rcolonies . Althougcolonies , this apcolonies . Most lacolonies ,35. Duricolonies .During the recent SARS-CoV-2 pandemic, an increase in mucormycosis cases has been reported, causing severe infections in COVID-19 patients . MucormyThe major risk factors of CAM include corticosteroid therapy, DM, DKA, and hyperglycemia, which are presented in Due to the immense burden of CAM, the identification of risk factors, understanding Mucorales pathophysiology, and development of effective diagnostics and therapeutics against mucormycosis is the need of the hour. In the current article, we review information obtained from various multicenter and meta-analysis studies, systematic reviews, narrative reviews, and recent research articles on CAM from various electronic platforms, such as PubMed, Google Scholar, Research Gate, and Scopus. We discuss several case reports of CAM based on various parameters, such as the number of patients, age, gender, associated co-morbidity, involvement of COVID-19, and treatment option used. Furthermore, this review also summarizes the current and updated information on the incidence, risk factors , pathophysiology and immune dysfunctions, role of iron metabolism in Mucorales growth, diagnostics, and possible treatment options for mucormycosis. According to few previous estimates, the prevalence of mucormycosis in the U.S. and Europe was 0.01–0.02 per 100,000 people . HoweverRecently, for estimating the global prevalence of CAM, Hussain et al. conducted a meta-analysis by pooling a sample size of 52,196 COVID-19 patients. They reported that CAM incidence was 50 times higher (7 per 1000 COVID-19 cases) than the previously available highest-incidence data (0.14 per 1000 population). A high mortality rate (26.9%) was found to be associated with CAM infection . In anotFrom the above description, it can be concluded that both immunocompetent and immunocompromised patients were affected by mucormycosis infection ,66,69. DRhizopus spp. is associated with the majority of CAM infections [Mucor spp. [Lichtheimia spp [It is evident from fections ,68,69,74cor spp. ,67,70,71imia spp ,49. For imia spp ,66,67,69The risk factors that contribute to mucormycosis are uncontrolled DM, uncontrolled use of corticosteroids, obesity, DKA, neutropenia, trauma, allogenic hematopoietic stem cell transplant, hematological malignancies, cytokine storm, and solid organ transplant . VariousCorticosteroids are effective in the early management of COVID-19 infection ,89. HoweDM is one of the factors contributing to mucormycosis infection. In a recent study, 57% of total mucormycosis patients had DM, and 18% of patients were diagnosed with DKA . DM is aFurthermore, a recently conducted study reported DM as the most common risk factor in 86.6% of mucormycosis-affected patients . UncontrDKA is associated with autoimmune DM that may cause the destruction of the β cells of pancreatic islets and may lead to insulin deficiency . AnotherSARS-CoV-2 may cause insulin resistance and damage to β cells, which increases blood glucose level ,104. HypA recently conducted study reported that the use of steroids, hyperglycemia, and COVID-19 infection may contribute to neutrophil dysfunction and endothelial damage during CAM. Avoiding the use of steroids in mild COVID-19 infections may prove to be helpful in reducing the risk of mucormycosis infection . FurtherMucorales spp. due to inadequate hygienic practices. Identifying the source of Mucorales contamination is a major challenge, which leads to the delayed employment of preventive measures. Due to inadequate environmental-based studies in developing countries, the exact cause(s) of the higher risk of developing mucormycosis is not yet identified [Rhizopus species was found to be the most frequently present species in a hospital environment [Environmental risk factors can be a major cause of mucormycosis infection. Prolonged hospital stays, used face masks, unhygienic conditions, air-conditioning vents, and oxygen cylinders (with leaky humidifiers) can create a favorable environment for Mucorales growth and can further enhance the risk for contracting mucormycosis infection ,107. Hosentified . Recentlironment . During the SARS-CoV-2 pandemic, the use of industrial oxygen cylinders could be a probable risk factor for rising mucormycosis infections in COVID-19 patients. The industrial oxygen cylinders are different from medical oxygen cylinders. The use of industrial oxygen cylinders is associated with a risk of contamination and infection . The usein vitro study conducted by Muthu et al. reported that zinc-enriched media supported the better growth of R. arrhizus species, which indicates that the use of zinc supplements as immunity boosters could be a risk factor of mucormycosis infection [A higher risk of CAM infection has been reported in people who had repeated (more than twice) nasopharyngeal swab testing for COVID-19 . Self-menfection . Recentlnfection . In another study, Bilgic et al. hypothesized that the excessive use of antibiotics for the treatment of COVID-19 pneumonia may interfere with natural and protective microflora in the human body and make conditions favorable for Mucorales invasion . Therefoin vitro study showed that Mucorales interact with TLR-2 (Toll-like receptor) on the cell surface of phagocytes, that lead to the activation of the downstream signaling pathway, which involves NF-κB activation and the release of various cytokines, such as IL-6 (interleukin) and TNF-α  [Mucorales produce spores that are responsible for the initiation of infection. If a person inhales fungal spores through the nostrils from the atmosphere, then mucus and cilia help to clear the spores from the nasal cavity and windpipe. However, when spores gain entry into the sinus and pulmonary tract, they may germinate and proliferate inside the lungs when they find favorable conditions . An in vr-alpha) . In DM pr-alpha) . COVID-1r-alpha) ,32. Althr-alpha) . COVID-19 infection causes severe damage to lung tissue and the alveolar region, which provides an opportunity to other pathogens for causing infection. Furthermore, critically ill patients with severe COVID-19 pneumonia require mechanical ventilation, in which the proper flow of gases and airway pressure has to be maintained for individual patients. Improper mechanical ventilation can lead to lung injuries. Therefore, it is essential to understand the duration of symptoms, lung mechanics, and underlying pathophysiology to prevent lung injury during the mechanical ventilation of COVID-19 patients . Fungal infections, such as mucormycosis, are mostly involved in causing damage to the pulmonary tract, so COVID-19 patients may be more prone to such infections ,63. In aThe mechanism of a platelet-mediated antifungal response may be due to the production of anti-inflammatory cytokines, such as TGF-β (transforming growth factor-beta), which activate other immune cells by interacting through their cell surface receptors, which further facilitate fungal clearance ,123. A dMucorales spores may invade the endothelium of blood vessels by interacting with endothelial cell receptors through surface proteins. After invading the endothelial lining of blood vessels, Mucorales leads to the thrombosis of blood vessels by the occlusion of the blood supply, and ultimately causes severe tissue necrosis . The intGRP78 is a heat-shock protein that is produced by endothelial cells in stressed conditions. The ER (endoplasmic reticulum) of endothelial cells releases the GRP78 protein in response to stress . ER streRhizopus oryzae infection, the attenuation of CotH3 protein expression led to decreased tissue invasion and endothelium damage, indicating its possible role in the pathogenesis of mucormycosis [There are some other factors, such as the increased concentration of ketone bodies and blood glucose levels, which contribute to fungal invasion by enhancing GRP78 expression . Studiesrmycosis . R. oryzae to grow in iron-deficient media, which indicates the significance of iron in fungal growth and metabolism [In humans, iron is present in a sequestered form with some proteins, such as ferritin and transferrin. This leads to the unavailability of free iron that is required by fungus for growth . Varioustabolism . SARS-CoV-2 infection dysregulates iron homeostasis and increases the concentration of free iron in the blood. Usually, ferritin protects the body’s cells from free iron by storing it, but due to COVID-19-induced iron dysregulation, excessive free iron accumulates in the blood and sends signals to the liver to produce more ferritin ,136. FreBhadania et al. reported the extent of mucormycosis infection in COVID-19 patients by assessing serum ferritin levels. They reported that hyperferritinemia enhances the extent of Mucorales invasion. The serum ferritin levels were much higher in COVID-19 patients suffering from DM and hypertension . Furtherin vitro studies found a direct relationship between the presence of iron and the growth of R. oryzae [Iron transporters, such as ferroportin and hepcidin, play an important role in iron homeostasis . The spi. oryzae . The vir. oryzae . The hig. oryzae . The sur. oryzae . R. oryzae cell surface during murine infection. These high-affinity iron permeases are responsible for iron uptake in Mucorales, which leads to fungal growth and proliferation [2+ complex. R. oryzae also expresses heme oxygenases, which aid in the intracellular degradation of the heme molecule and generation of free iron [Another study reported that the FTR1 gene is associated with the overexpression of high-affinity iron permeases on the feration . FTR1 ovree iron . In thisFurthermore, there could be a correlation between COVID-19 infection and high-free-iron concentration in serum, which contribute to CAM pathogenesis. In a recent study, a significant correlation was reported between CAM infection and elevated serum iron levels. Therefore, patients suffering from severe COVID-19 infection and with increased serum iron levels may be more susceptible to mucormycosis infection .A direct microscopic examination is performed by staining specimens with H&E, methenamine silver, or an optical brightener . The fragile nature of Mucorales makes this identification difficult; therefore, it should be performed carefully . HoweverComputed tomography can be used to for the early detection of pulmonary mucormycosis in cancer patients . AntibodPCR/ESI-MS (PCR–Electrospray Ionization Mass Spectrometry) is a good option for Mucorales hyphae identification within 6 h . FormaliThe limitations associated with the currently available diagnostics, such as high cost, non-specificity, lack of serological assays, and inability to identify novel species, make it challenging to diagnose mucormycosis at an early stage. The identification of fungal species at their species level is a prerequisite for a proper prognosis of infection ,159.For the management of mucormycosis, the treatment options may be divided into different categories, which include first-line therapy, salvage therapy, adjunctive therapy, surgical treatment, and nutraceutical-based therapy. First-line therapy involves high doses of liposomal amphotericin-B. Treatment with liposomal amphotericin-B should be initiated at an earlier stage of infection . In a stDuring the COVID-19 pandemic, a sudden increase in the demand for amphotericin B resulted in a shortage of the amphotericin-B drug . Althougin vitro study, isavuconazole, a triazole drug, exhibited inhibitory effect against Mucorales spp. at a minimum inhibitory concentration: MIC: 1–4 mg/L [In salvage therapy, posaconazole may be used, which acts effectively against Mucorales. Some studies reported better survival rates in mucormycosis patients after using posaconazole via oral-route (200 mg 4 times per day) treatment ,165. In 1–4 mg/L . It was 1–4 mg/L . In comb1–4 mg/L . in vitro study [in vitro antifungal activity of isavuconazole against Mucor species [Salvage therapy involving echinocandins, along with polyene, may be used if first-line therapy fails to control mucormycosis . It was ro study . Another species . Mucorales spp., namely, Mucor circinelloides and Rhizopus delemar [A separate study reported the use of L-AMB/isavuconazonium sulphate (MIC: 0.125–4.0 mg/L) combination therapy against experimental mucormycosis. L-AMB/isavuconazonium sulphate therapy was found to be effective against two  delemar . DespiteR. oryzae and also induced its apoptosis [Adjunctive therapy is not recommended for the treatment of mucormycosis due to the lack of evidence-based studies. Some researchers conducted studies by using hyperbaric oxygen and Deferasirox against Mucorales. In the case of hyperbaric oxygen, survival rates were better in only DM patients, but other than diabetic patients, the survival rates were very low. It was reported that Deferasirox increased the mortality rates in mucormycosis patients ,172. Anopoptosis .Mucor sporangia, and it has been reported that anti-inflammatory drugs selectively target the Mucor sporangia having high mitochondrial activity [It has already been discussed that iron helps in fungal growth and development. A recent study showed that lactoferrin, which acts as an iron chelator, may prove to be an adjunctive treatment option against mucormycosis . Furtheractivity . R. arrhizus. The oral administration of SSKI in mucormycosis patients reduced the dose and duration of amphotericin-B treatment [in silico study evaluated the potential antifungal compounds obtained from marine sponges against CAM, and reported that antifungal compounds belonging to different classes, such as alkaloids, tetratomic glycosides, sesquiterpene phenols, and macrolides, could be used as promising therapeutic candidates against CAM [In a recently conducted study, Mrig et al. reported the use of a saturated solution of potassium iodide (SSKI) with liposomal amphotericin-B as an adjunctive therapy against reatment . An in sinst CAM . As suchSince the treatment of mucormycosis is challenging due to poor drug penetration of necrotic tissues, surgical treatment is associated with better survival rates. In one study, surgical treatment lowered the risk of mortality in mucormycosis-infected patients . In rhinThe Barrier draping technique may be used by surgeons to perform surgical operations on SARS-CoV-2-infected patients . In a reFor the early management of COVID-19 infection, nutraceuticals may prove to be useful, which may further reduce the risk of CAM infection. Maurya et al. found that nutraceuticals, such as curcumin, zingiberene, theaflavin, berberine, resveratrol, and nimbin, showed a binding affinity to the ACE-2 receptor, which may impair the binding of the SARS-CoV-2 virus to the surface of host cells . in vitro inhibition of R. oryzae [Boesenbergia pandurata (fingerroot) presented antifungal properties. It was found to be effective against Mucor species at an MIC of 0.63 g/L [Another study evaluated the potential of curcumin (800 μg/mL) for the . oryzae . It was 0.63 g/L . Novel t0.63 g/L . Nutrace0.63 g/L . in silico study, a phytocompound, namely, quercetin obtained from Azadirachta indica and Curcuma longa, was found to be a promising therapeutic candidate against CAM infection [in vivo studies may be required to strengthen the in vitro research findings. Various treatment options against CAM are also described in In a recent nfection . AlthougThe Directorate General of Health Services (DGHS) has provided guidelines for the management of CAM in India. Mucormycosis treatment should be initiated at an early/initial stage to reduce mortality rates. Treatment options include a combination of antifungal therapy and surgical debridement of infected tissue, although amphotericin B (1–1.5 mg/kg) may be used if liposomal formulations of amphotericin B are not available. However, the treatment of choice is liposomal formulations of amphotericin B at a dose of 5 mg/kg. Furthermore, in the case of CNS involvement, a dose of 10 mg/kg of body weight can be used. The amphotericin-B dose should be diluted in 5–10% of dextrose. Treatment using amphotericin B should be continued until a positive response is observed in terms of disease stabilization/resolution. Treatment monitoring may take several weeks. Following amphotericin-B therapy, salvage therapy with oral posaconazole (300 mg/day) or isavuconazole (200 mg/day) can be initiated. Antifungal therapy should be continued until a resolution of mucormycosis symptoms and disappearance of radiological signs of mucormycosis are observed . The potMucor racemosus. It was reported that such a monoclonal antibody could be used in the detection of pathogenic Mucor species in humans [Rhizopus, Mucor, Fusarium, Candida, and Aspergillus. It was reported that the detection of such conserved antigens using immunoassays could aid in the diagnosis of a broad range of fungi [In immunocompromised hosts, the immune system becomes less functional, which may further enhance host susceptibility to fungal infections. Mucor species are highly pathogenic fungal species causing necrotizing lung infection and, in many cases, can affect host brain tissue. There are limited therapeutics for invasive fungal infections . Mucormyn humans . In anotof fungi . Aspergillus and Mucor species [The identification of fungal antigenic components may prove to be beneficial in the early diagnosis of mucormycosis infection. A monoclonal antibody, MUC5B, was used in the immunohistochemistry-based detection of fungal pathogens. It was reported that the MUC5B antibody could be used to distinguish between  species . Since h species . In recent decades, no significant improvement has been observed in the prognosis of mucormycosis, due to the challenges associated with its early diagnosis and the limited availability of antifungal agents. The hematopoietic stem cell transplant is associated with a high risk of mucormycosis, accounting for almost 90% of mortalities. Schmidt et al. reported that the reconstitution of host immunity following a hematopoietic stem cell transplant may be essential to combat fungal infections. They demonstrated that IL-2 pre-stimulated NK cells could kill mucormycetes, and the early administration of human NK cells was found to be more effective in killing mucormycetes . Although few studies that support the use of combinatorial immunotherapies have been conducted, further research is required in this area. One study demonstrated the feasibility of using combinatorial immunotherapy against mucormycosis. They treated three children having invasive fungal infections and hematological malignancies with combination antifungal therapy along with granulocyte colony-stimulating factor (G-CSF)-mobilized granulocyte transfusions. The immunotherapeutic approaches effectively improved the survival rate of high-risk patients . Treatment monitoring can be a used as a tool to monitor the host’s response to antifungal treatment. Cytokines act as immunological biomarkers, which aids in the diagnosis as well as treatment monitoring of invasive fungal infection. A cytokine-based diagnosis of invasive fungal infection is cost effective and rapid, which may result in the early and effective management of mucormycosis . A separR. delemar. Furthermore, the anti-CotH3 monoclonal antibody exerted a synergistic effect with antifungal drugs against R. delemar spp. This study indicated the role of anti-CotH3 antibodies in adjunctive/combination/antibody-mediated antifungal therapies [R. delemar spores contain the CotH7 antigen, which is involved in the invasion of alveolar epithelial cells via an interaction with β1-integrin receptors. Alqarihi et al. reported that anti-β1 integrin antibodies bind to β1-integrin receptors and inhibit the invasion of R. delemar through alveolar epithelial cells, and conferred protection in a mice model of pulmonary mucormycosis [In another recent study, the anti-CotH3 antibody was found to be protective in a murine model of mucormycosis. The mechanism of protection was reported as antibody-mediated opsonophagocytic activity against herapies . Additiormycosis . M. circinelloides as vaccine candidates. Fungal protein antigens, such as enolase, triosephosphate isomerase, and heat-shock protein HSS1, were tested in a mice model of mucormycosis. It has been reported that these protein antigens may prove to be useful for future vaccine development against mucormycosis infection [For long-term protection against mucormycosis infection, vaccines are urgently required. In this regard, Areitio et al. identified immunoreactive protein antigens from nfection . R. oryzae-mediated mucormycosis in a mice model of DKA [Mucorales spp.  targeting the FTR1 protein. A detailed in silico analysis has shown that this anti-fungal vaccine could prove to be an effective therapeutic agent against CAM infection [Another study conducted by Ibrahim et al. reported that several vaccine compositions, including the FTR (high-affinity iron permease) polypeptide, antibody inhibitor of FTR, and small interfering RNA, could confer protection against l of DKA . In anotnfection . R. delemar using immunoinformatics and reverse vaccinology approaches. In brief, they selected four genome-derived predicted antigens and four experimentally reported antigens, which were then subjected to B- and T-cell epitope predictions. They reported that both vaccine candidates could induce innate and adaptive immune responses against R. delemar [in silico study, Naveed et al. designed a vaccine construct against CAM infection, targeting GRP78 and TLR2 proteins from two Mucorales spp., namely, R. oryzae and M. circinelloides [in vitro and in vivo pre-clinical studies are required to evaluate the efficacy and safety of such vaccine constructs. Although few studies are available, more evidence-based studies are required to assess the potential of immunotherapy against mucormycosis. Owing to its specificity and effectiveness, this area of immunotherapeutics needs to be explored in the future. More recently, Pritam et al. designed two multi-epitope vaccine candidates against  delemar . In anotelloides . FurtherMucorales spp. are performed using expensive and high-end or advanced techniques, such as MALDI-TOF, which are not feasible for middle-income countries, there is an urgent need for the development of cost-effective diagnostics for the precise identification of patients suffering from mucormycosis. Further studies need to be conducted for the identification of early biomarkers of mucormycosis. To date, surgery on infected tissue followed by antifungal therapy is the only recommended treatment option. Critical research gaps still exist, regarding the treatment of mucormycosis, including the use of salvage therapy, adjunctive therapy, combination antifungal drug-based therapy, and the evaluation of treatment responses in patients. The development of animal-based experimental models of mucormycosis for conducting pre-clinical studies may fill these research gaps. Furthermore, little is known about the use of nutraceutical-based therapy and immunotherapy against mucormycosis. Further research is required to resolve the global threat associated with CAM infection amid the SARS-CoV-2 pandemic.Although various population-based studies were conducted in Western countries, which helped in the estimation of mucormycosis incidence, due to the lack of population-based studies and insufficient number of sophisticated laboratories for fungal diagnosis in developing countries, it has been very difficult to estimate the exact incidence of mucormycosis. Additionally, there is a considerable difference between risk factors that contribute to mucormycosis infection in developed and developing countries. For instance, in developing countries, COVID-19 infection, along with the presence of various co-morbidities, such as chronic renal failure, orbital infarction syndrome, post-tuberculosis, long-term ICU stays, self-medication, used masks, use of industrial oxygen cylinders, oxygen cylinders with leaky humidifiers, and air-conditioning vents, represent major risk factors that may lead to alarmingly high rates of mucormycosis infection. On the other hand, patients with COVID-19-induced immunosuppression; hematological malignancies, such as neutropenia; and organ transplant recipients represent the main risk factors that may be responsible for mucormycosis incidence in developed countries. Notably, corticosteroid therapy, DM, DKA, and hyperglycemia are common and major risk factors of mucormycosis among COVID-19 patients in both developed and developing countries. The uncontrolled use of steroids and self-medication must be discontinued to tackle rising incidences of CAM. Moreover, the maintenance of low blood glucose levels in diabetic patients can prove to be a key approach for controlling hyperglycemia. The use of zinc supplements should be initiated only after a consultation with a physician to minimize the probable risk of mucormycosis. Since fungal culture-based identification assays usually produce incorrect results, and diagnostics for Non-reporting of many cases leading to incomplete incidence rates.Lack of awareness leading to delay in seeking healthcare.Lack of knowledge among physicians.Financial constraints restricting the use of surgeries/other costly options in LLMICS.Use of improper antifungals and steroids in CAM.Research on overcoming drug resistance and improving the efficacy of antifungal drugs.Mucor spp. sources.Lack of environmental assessment studies for the identification of Identification of clinical biomarkers for assessing the risk of mucormycosis in high-risk populations and to enable early antifungal prophylaxis and therapy.Lack of research for developing rapid and cost-effective methods for early diagnosis.Lack of research for developing specific therapeutic strategies.Novel immunotherapies, such as antibody therapy; immunomodulators; adjunctive therapy, including cytokines; and combination therapy, including drugs and antibodies; are needed urgently.Need for vaccine development, which can prevent mucormycosis.Lack of studies on the genetic aspects of mucormycosis for understanding virulence.in vivo studies for studying various aspects of CAM.Need for more Development of animal models for mucormycosis.To date, there are no standard protocols that can be implemented to treat mucormycosis in COVID-19 patients. Therefore, there is an overwhelming need to formulate a standard protocol for treating mucormycosis infections in COVID-19 patients. In addition to the development of new treatment options, there is an emergent need for developing rapid, cost-effective, and specific methods to enable the early diagnosis of COVID-19-associated mucormycosis. Novel immunotherapies that can be used in immunosuppressive conditions are required, using cytokines and/or antibodies. The research should also focus on deciphering the mechanisms that confer resistance to various antifungal drugs. Furthermore, it is necessary to perform and validate novel treatment options in all fungal species causing mucormycosis infections. In light of these associated challenges, it is essential that large-scale clinical trials are designed and conducted in mucormycosis patients globally, in order to identify all the associated factors between COVID-19 and mucormycosis and the ways to control them, which can result in reduced morbidity and mortality rates.


Often, individuals with hearing loss have difficulties understanding speech in noisy environments.It was the aim of this study to assess the performance of adult individuals with sensorineural hearing loss, associated with speech perception using digital hearing aids with a sound reduction algorithm called Speech Sensitive Processing, on and off, in the presence of noise.This case study was performed with 32 individuals with sensorineural hearing loss of mild, moderate or mild to moderate level. Our evaluation involved a speech perception test, where we investigated the recognition of sentences in noise, in order to get a signal/noise ratio, with a digital hearing aid.The algorithm provided a benefit for most hearing impaired individuals, in the investigation of signal/noise ratio and the results pointed to a statistically significant difference when the algorithm was on, compared to when the algorithm was off.The use of a sound reduction algorithm must be considered as a clinical alternative - since we observed an efficacy in noise reduction and heightened speech perception. Understanding speech requires anatomical and functional integrity of the peripheral and central auditory system and an acoustically appropriate communication context. However, noise is present in most communication situations, which may decrease the probability of acoustic information being available. AgnewNoise affects understanding of speech in every person. This issue is compounded in patients with hearing loss when speech and noise compete at the same time. Loss of acoustic information is compensated by other non-auditory cues during silence. Noise may be compensated by controlling its environmental intensity or by using strategies such as directional microphones and acoustic filters in personal sound amplification products (PSAPs), which may improve speech understanding.PSAPs with digital technology apply digital circuits for processing signals and for controlling its functions as an alternative for dealing with problems such as speech understanding within noise, a difficult issue for previous technologies  algorithm, found in the Prisma digital PSAP, analyses the input signal envelope in four frequency bands. If it detects speech characteristics and modulation frequencies, it increases acoustic gain to amplify speech according to the degree of hearing loss. Acoustic gain is decreased if the signal does not contain speech characteristics and modulation frequencies.A sinusoidal signal is detected when the maximum sinusoid curve has the same amplitude throughout. The resulting signal is called a modulated signal when the maximum sinusoid varies with time. The maximum points of the modulated signal form a curve named the envelope, which provides the signal modulation frequency and depth. Modulation frequency is the extent by which signal amplitude varies in time (modulation velocity) and is lower than the signal frequency and the modulation depth, which refer to the maximum and minimum envelopes values.The speech modulation spectrum (slow variation with no high modulation frequencies) and the noise spectrum  are different and may be used to differentiate speech from noise. Speech contains a high modulation depth because the envelope is minimal during pauses. Speech may be described n terms of its time structure or its frequency distribution in the spectrum. The speech spectrum contains frequency components from 100 Hz to 8 kHz and an envelope with higher energy at 4 kHz . The speech envelope has a typical time behavior.Boymans and DreschlerThe purpose of this study was to evaluate the performance of adult subjects with sensorineural hearing loss relative to speech perception by using a digital PSAP with an active and inactive SSP noise reduction algorithm in the presence of competing noise.This study was presented to the Institutional Review Board of the graduate course on human communication and was accepted (number 168/99-UEP-CEP).The series consisted of 32 male and female subjects with bilateral sensorineural hearing loss, aged from 21 to 64 years. Subjects had mild, moderate or mild to moderate post-lingual hearing loss in both ears, a symmetrical or asymmetrical flat or descending configuration, speech recognition indices over 70%, no ear mold acoustic changes, audiometric threshold fluctuation, recruitment or cognitive conditions.Programming and fine tuning of a binaurally adapted digital PSAP was carried out in an acoustic booth to investigate the free field speech recognition threshold.A digital PSAP with an adaptation area for mild to profound hearing loss and a speech recognition algorithm in the presence of noise was used. The tools consisted of the CONNEXX software, an SD 50 audiometer and a CD player to play the List of Portuguese Sentences and noise elaborated by Costa,The 1A list was used for training, the 2B list was used for obtaining the sentence recognition threshold in noise for the condition in which the SSP algorithm was active, and the 3B list was used for obtaining the sentence recognition threshold in noise for the condition in which the SSP algorithm was inactive.Audibility thresholds were entered in the CONNEXX software followed by programming with the desired signal level input/output gain prescription method for calibrating the PSAP. Program 1 only was used, as other noise reduction strategies were used in program 2.Subjects were asked to assess the sound quality of the PSAP; if needed, fine tuning was done using the adaptation assistant.Channels 1 and 4 were adjusted to the maximum position and channels 2 and 3 were adjusted to the medium position in the active algorithm condition. A dual slow type curvilinear compression was applied and used with an omnidirectional microphone. In the second condition, the algorithm was inactive in all four frequency channels.Subjects were exposed to noise for 30 seconds before sentences were presented to make sure that the algorithm carried out the spectral analysis of the sound wave and made the appropriate adjustments; the position was 0° azimuth and 1 m distance from the speaker. Subjects were told that lists of sentences would be presented together with noise, and that they should repeat the sentences as understood.The first sentence and noise were presented at 65 dBA ; the noise level was then set at 65 dBA and the sentence level was changed. The signal to noise ratio was obtained using an adaptive strategy with 4 dB intervals until the response changed, after which 2 dB steps were used.The sentence presentation level was noted and the mean values in which the types of responses changed were calculated, which resulted in the sentence recognition threshold in noise. This vale was subtracted from the noise intensity level to obtain the signal to noise ratio.The same method was employed to investigate sentence recognition threshold in noise to obtain the signal to noise ratio in both conditions; subjects were not told when noise suppression was active.PSAP programming and investigation of sentence recognition threshold in noise were done in the same day; the procedure lasted one hour and subjects were observed for fatigue to avoid loss of performance.Student's T test was applied for the statistical analysis; the mean was the central tendency measure and the significance level was 5%.There were 32 subjects with hearing loss that used a digital PSAP bilaterally. The best signal to noise ratio was obtained with the algorithm in the active condition in 22 subjects; the best signal to noise ratio was obtained with the algorithm in the inactive condition in 8 subjects. Two subjects had equal results in the active and inactive condition of the algorithm .Figure 1Descriptive statistics showed that the mean signal to noise ratio values for both variables  were −5.6 and −4.4, and −5.2 e −4.0 for the median .Chart 1SThe standard deviation value was 3.31 for the active algorithm, and 2.79 for the inactive algorithm.Student's test applied to these data resulted in a 0.0021 probability, which was statistically significant.Student's T test for paired samples, with the mean as a measure of central tendency, showed a statistically significant difference (p = 0.0021) between the active and inactive algorithm condition. These findings suggest that technological developments have led to innovations, such as increasing the flexibility by using noise reduction algorithms, which benefit hearing loss patients and debunking the belief that hearing aids are ineffective in some noisy ambiences , which benefited understanding of speech and the auditory performance of adult subjects with sensorineural hearing loss; it is thus, an alternative for speech perception difficulties in the presence of background noise.


Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, heterogeneous, but treatable autoimmune-mediated peripheral neuropathy characterized by demyelination. CIDP can occur independently or simultaneously with a variety of diseases such as diabetes, monoclonal gammopathy of undetermined significance (MGUS), connective tissue disease, and HIV. It is important to identify CIDP and specific peripheral neuropathies caused by these diseases; this review aims to summarize the CIDP literatures related to diabetes, MGUS, SLE, and HIV, and to be helpful for the management of such patients. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, heterogeneous, but treatable autoimmune-mediated peripheral neuropathy, resulting from a synergistic interaction of cellular and humoral immune responses. Although the etiology and exact pathogenesis remain elusive, it is well known that CIDP is characterized by a symmetric distal and proximal weakness, from distal to proximal extremities mostly, often with sensory disorder and the absence of or reduced tendon reflexes, and develops over at least 8 weeks –3. It waDiabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia; it can be associated with a number of peripheral nerve disorders, which include some inflammatory neuropathies . MonocloThere are many articles or reviews about the subtypes, antibody-related pathogenesis, diagnosis, and treatment of CIDP. Previous guidelines have highlighted CIDP in association with concomitant diseases that include diabetes, as well as other disorders such as IgG or IgA monoclonal gammopathy of unknown significance, IgM monoclonal gammopathy without anti-MAG (myelin associated glycoprotein) antibodies, connective tissue diseases, and human immunodeficiency virus (HIV) infection . DonedduThe course of CIDP can be varied from gradually progressive, stepwise progressive, to relapsing–remitting . Both thThere are currently many studies about the pathogenesis of CIDP; since the recognition of neurofascin-155 (NF-155), neurofascin-140 (NF-140), neurofascin-186 (NF-186), contactin-1 (CNTN-1), contactin-associated protein 1 (CASPR1), and other autoantibodies against the node of Ranvier or paranodal protein, we now have a better understanding of CIDP and promote the progress of diagnosis and treatment of CIDP , 12, 13.The prevalence and incidence of CIDP vary in different countries and regions. Merel et al. conducted a systematic review and meta-analysis to estimate the prevalence and incidence of CIDP worldwide, and reported prevalence to range from 0.67 to 10.3 cases per 100,000 population and incidence to range from 0.15 to 1.6 cases per 100,000 person-years . FurtherThe cause of CIDP is still uncertain, although it is mainly attributed to an autoimmune reactivity against nerves. A previous preliminary study indicated that antecedent events, more specifically, antecedent infections or vaccinations, are more associated with an acute onset of CIDP and with cranial nerve involvement . BecauseThe diagnosis of CIDP is challenging; in addition to the typical symmetric, sensorimotor CIDP phenotype, there are many CIDP variants such as sensory CIDP, motor CIDP, distal CIDP, multifocal CIDP, and focal CIDP . The cliCurrently, there are new nerve imaging methods available for auxiliary diagnosis of CIDP under study, particularly of suspected CIDP, including nerve magnetic resonance imaging (MRI) and nerve ultrasound –21. TheyThe current first-line treatment of CIDP includes intravenous immunoglobulin (IVIG), corticosteroids, and plasma exchange (PE) , 2, 27, Diabetes mellitus (DM) is a group of metabolic diseases caused by genetic and environmental factors with chronic hyperglycemia as the main clinical manifestation. Diabetic patients with poor control of blood glucose commonly occur with a wide variety of peripheral neuropathies , 34, sucCIDP is the most common treatable inflammatory neuropathy in diabetic patients, and is often compared with other diabetic peripheral neuropathies.The possible relationship between DM and CIDP, as well as its clinical significance, has been a controversial topic. This review will summarize previous literature and hopes to be helpful for the clinical identification and management of DM-CIDP.From previous preliminary studies, we can conclude that CIDP and diabetes may co-occur. The prevalence of CIDP tends to be higher in diabetic patients than in non-diabetic patients, especially in those of older age –39. FromHowever, some studies have found many contradictory results. An epidemiological study on CIDP in two Italian regions was performed by Chio et al. ; they foSome patients with diabetic peripheral neuropathy may have CIDP-like electrophysiological manifestation such as demyelination. There is still no consensus on whether these patients have DM-CIDP or another demyelinating peripheral neuropathy caused by diabetes , 39. DunAs mentioned above, typical idiopathic CIDP is mainly characterized by varying degrees of limb weakness, most of which are symmetrical, with both proximal and distal involvement, accompanied by paresthesia, without or with reduced tendon reflexes. In a study comparing 14 patients with DM-CIDP  and 60 patients with idiopathic CIDP , Gorson Diabetic peripheral neuropathy is a chronic, progressive, distal symmetric axonal polyneuropathy affecting small fibers only or both small and large fibers. Insidious onset and characteristic features such as progressive exacerbation of numbness and paresthesia of distal extremities are mostly manifested as stocking-like or glove-like distribution, as well as neuropathic pain and autonomic dysfunction  . Its patStewart et al.  collecteAlthough there is still no clear correlation between CIDP and DM, the coexistence of both diseases increases the challenge of treatment . Glycemip < 0.001). However, further controlled trials are still needed to confirm this. Furthermore, the efficacy of IVIG in DM-CIDP patients is in keeping with other studies  in the serum, including various anti-myelin antibodies. The interaction of these antibodies with specific antigenic targets on peripheral nerves or deposition of immunoglobulins will lead to neuropathy, also known as paraproteinemic neuropathy . The assByun et al.  retrospeSome patients with atypical CIDP may coexist with MGUS (CIDP-MGUS) , 66–68. The clinical and electrophysiological characteristics of CIDP-MGUS are very similar to some paraproteinemic demyelinating neuropathies (PDNs). They may have the same pathophysiological mechanisms and are difficult to identify . NotermaMGUS associated with demyelinating neuropathy is the most common PDN. It is mainly divided into two types according to the type of paraprotein: PDN associated with IgM MGUS and PDN associated with IgG/IgA MGUS .IgM PDN is a chronic progressive disease with clinical manifestations of distal, symmetrical sensory involvement and ataxia, without or with minimal motor involvement. In addition, about 50% patients have anti-myelin-associated glycoprotein (anti-MAG) IgM antibodies in the serum or biopsies, and may have a different pathogenesis to CIDP . The folIgG/IgA PDN is a more progressive disease than IgM PDN, often with a relapsing–remitting course. It is characterized by the weakness of proximal and distal muscles of the extremities, the simultaneous involvement of motor and sensory nerves, the absence of specific antibodies, and difficulty in distinguishing from CIDP in terms of clinical and electrophysiological aspects. The treatment principle is the same as that of CIDP , 74. TheThe responsiveness of CIDP-MGUS to immunotherapy is different depending on the types of monoclonal gammopathy. The use of steroids, immunosuppressive agents, PE, or IVIG alone or combined can be considered for the treatment of CIDP-MGUS , 76. TheJann et al.  comparedPosa et al.  reportedCIDP is rarely reported in connective tissue diseases; the most common concomitant disease is SLE. About 10%–20% of patients with SLE can be associated with peripheral neuropathy , and morThe pathogenesis of SLE-associated peripheral nervous system diseases may be related to ischemia, immune complex deposition, antibody-mediated reactions, demyelination or abnormal metabolism, or autoimmune response-like vasculitis caused by connective tissue diseases , 81. NeuCIDP can appear before, after, or at the same time as SLE, and the causes of the disease are varied and are not clear. In addition to the typical clinical manifestations of CIDP, SLE patients with CIDP may also present recurrent episodes of Guillain–Barré syndrome-like symptoms , 86, whiA variety of immunomodulatory therapies can be selected for the treatment of SLE with CIDP. A study from Abraham et al.  reportedHowever, there are a few studies on the treatment options for CIDP with SLE, and only a few case reports; thus, more multicenter cohort studies are needed. When CIDP patients with SLE show disease activity, corticosteroids or immunosuppressive drugs should be actively used, and IVIG can be considered when they are not effective . In the Various peripheral neuropathies can be caused by HIV infection and peripheral neuropathy is probably the most common neurological complication associated with HIV infection . Clinica3.The clinical and electrophysiological manifestations of HIV-positive CIDP patients were not significantly different from those of HIV-negative patients, showing a similar degree of demyelination, and there is a predominance of T lymphocyte or macrophage infiltration with CD8-positive cytotoxic/suppressor cells. CIDP may occur during late infection, often with a CD4 count of less than 50 cells/mmp = 0.007).In a prospective case series analysis of CIDP patients from Johannesburg, South Africa, Mochan et al.  found thMoodley et al.  performeTo the best of our knowledge, there are very limited reports on CIDP complicated by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin change (POEMS) syndrome, multiple myeloma , amyloidCIDP can coexist with a variety of diseases such as diabetes, MGUS, SLE, and other connective tissue diseases such as Sjogren’s syndrome, active hepatitis, HIV, thyroid disease, inflammatory bowel disease, kidney disease, and others. Clinicians should pay attention to the difference between CIDP in concomitant diseases and idiopathic CIDP or other similar neuropathy; early identification can assist clinicians in their therapeutic decision, so that patients can reduce their pain and get the maximum benefit. There must be co-association between diabetes and CIDP to some extent. The occurrence of CIDP in DM patients may be related to antibodies against the common autoantigens of the peri-islet Schwann cells and peripheral nerve Schwann cells. It is particularly important to identify patients with DM-CIDP in DM with peripheral neuropathy, which is challenging despite the combined clinical, electrophysiological, pathological, and nerve imaging. The preferred treatment for patients with DM-CIDP is still immunotherapy, such as IVIG, steroids, PE, and immunosuppressive agents. Moreover, monoclonal antibodies like rituximab may have an active effect on DM-CIDP patients, but still need to be further determined. Furthermore, patients with DM-CIDP may have poorer response to IVIG resulting from more axonal injuries.Paraproteinemia patients have a variety of antibodies on the serum against the myelin sheath or axonal membrane of nerves; thus, there is a possibility of CIDP-MGUS, which is difficult to distinguish from other demyelinating peripheral neuropathies. Attention should be paid to the identification of different types of immunoglobulin-related demyelinating peripheral neuropathies. At present, the primary treatment remains immunotherapy of CIDP-MGUS, and patients with IgG/IgA have a better response to IVIG than patients with IgM.Reports about the connective tissue disease SLE coexisting with CIDP are very rare, and such occurrences are more frequent in antibody-positive SLE patients, which could be associated with autoantibodies or abnormal immunoreactions. Immunotherapy is the primary mode of treatment (IVIG is preferred) of SLE-CIDP patients. The typical CIDP features and SLE-related visceral involvement or autoantibodies may predict a good therapeutic response.Peripheral neuropathy is probably the most common neurological complication associated with HIV infection, and CIDP mostly occurs in the later stages of HIV infection. Currently, limited studies have found that compared with HIV-negative patients, CIDP-HIV patients have no significant difference in clinical and electrophysiological manifestations, which can be manifested as monophasic progressive disease and CSF lymphocytic pleocytosis. The preferred treatment remains corticosteroid therapy, and further studies are needed.The current evidence-based data on CIDP with concurrent illness are still very limited, especially in the differential diagnosis and treatment of some rare concomitant diseases; more large studies are thus still needed.YC contributed to manuscript preparation and wrote the manuscript. XT helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


E. coli infection. In this work, 2,36,345 Arbor acres broiler chickens from the same breeder flock were placed equally in four pens, where two pens were vaccinated against LPAIV of subtype H9N2 virus, and the other two pens served as non-vaccinated controls. All were placed on the same farm under the same management conditions. A total of twenty birds from each pen were moved to biosafety level−3 chicken isolators (BSL-3) on days 21 and 28 of life and challenged with LPAIV-H9N2 or E. coli. Seroconversion for H9N2 was evaluated before and after the challenge. The recorded results revealed a significant decrease in clinical manifestations and virus shedding in terms of titers of shedding virus and number of shedders in vaccinated compared to non-vaccinated chickens. In groups early infected with LPAIV-H9N2 virus either vaccinated or not vaccinated, there was no significant difference in clinical sickness or mortalities in both groups, but in late infection groups with H9N2 alone, non-vaccinated infected group showed significantly higher clinical sickness in comparison with infected vaccinated group but also without mortality. In groups co-infected with E. coli (I/M) and H9N2, it showed 100% mortalities either in vaccinated or non-vaccinated H9N2 groups and thus reflect the high pathogenicity of used E. coli isolates, whereas in groups co-infected with E. coli  and LPAIV-H9N2, mortality rates were significantly higher in non-vaccinated groups than those vaccinated with H9N2 vaccine (15 vs. 5%). In conclusion, the use of the LPAIV H9N2 vaccine has significantly impacted the health status, amount of virus shed, and mortality of challenged commercial broilers, as it can minimize the losses and risks after co-infection with E. coli  and LPAIV-H9N2 virus under similar natural route of infection in commercial broilers.In the last 40 years, low pathogenic avian influenza virus (LPAIV) subtype H9N2 has been endemic in most Middle Eastern countries and of course Egypt which is one of the biggest poultry producers in the middle east region. The major losses with the H9N2 virus infections come from complicated infections in commercial broiler chickens, especially  E. coli (APEC) is the most common infectious pathogen of all poultry species, resulting in multiple diseases in commercial poultry flocks. The most common disease is colibacillosis, which results in severe economic losses , innate immunity associated protein , and cell proliferation, differentiation and apoptosis , and the upregulation processes enhance the bacterial pathogenicity and pathological effect, as a result of the pathological effect of the bacterial, it increases the level of protease-like enzymes in the respiratory and digestive tract tissues, which enhance the cleavability of LPAIV-H9N2 and the immunosuppressive effect of E.coli infection decrease the birds response to the virus infection, so the virus replicates much higher and potentiates its pathological picture (E.coli and AIV-H9N2 virus can elevate the inflammatory mediators (TNF-α and INF-γ), and the immunosuppressive effect of E.coli infection decreases the birds response to the virus infection and potentiates the losses from the co-infection process (E. coli (APEC) and LPAIV H9N2.Low pathogenic avian influenza virus (LPAIV) subtype H9N2 virus infection is an endemic disease in nearly all Middle Eastern countries including Egypt, Iran, Israel, Saudi Arabia, Jordan, Kuwait, Lebanon, and the United Arab Emirates . LPAIV-HPAI H9N2 . No effiPAI H9N2 . Infectich alone . Likewisortality . The co- picture –18. Also process , 18–20. Animal studies were approved by the Animal Welfare and Research Ethics Committee of Benha University by approval no. BU2019421PX23, and all procedures were conducted strictly following the Guidelines for Care and Use of Laboratory Animals. Every effort was made to minimize animal suffering.A total of 2,36,345 1-day-old Arbor Acres broiler chicks from vaccinated broiler breeders' flocks  were obtained from the same breeder flock and placed in two closed broiler system farms in Elsaff, Giza Governorate. All were kept under commercial field conditions with proper biosecurity measures and received the same management standards. Farm A contained 117,170 birds and was vaccinated with MEFLUVAC H5+H9+ND7 combined vaccine “consist of H5N1 clade 2.2.1.2, H5N8 clade 2.3.4.4., NDV genotype-II, NDV-genotype-VII, and H9N2 inactivated vaccine seeds”  at 10th day of age. Farm B was harbored 119,175 birds and vaccinated with MEFLUVAC H5+ND7 combined vaccine “containing H5N1 clade 2.2.1.2, H5N8 clade 2.3.4.4, NDV-genotype-II and NDV-Genotype-VII inactivated vaccine seeds”  at 10th day of age. The birds also received vaccines for IBD (Univax BD “a live virus vaccine containing a mild strain (ST-12) of Infectious Bursal Disease,” MSD company, USA on day one of life then Bursine plus “Live freeze-dried intermediate plus IBD virus, Lukert strain,” Zoetis company, USA at day 13 of life), MEFLUVAC H5+ND7 combined vaccine , and live bivalent ND-IB vaccine , Volvac LaSota , Vaxsafe ND “ND V4 strain”  as the part of routine vaccination program of commercial broilers in Egypt. All vaccines were used according to the manufacturer's recommendations.Birds kept under field conditions underwent regular monitoring by RT-PCR on days 2, 4, 18, 21, 25, 27, and 31 of life for the detection of common circulating pathogens in the region, including AIV-H5, AIV-H9N2, NDV velogenic, IBV, IBD, avian nephritis virus, and chicken astrovirus using primer sets developed by Cairo Poultry Group diagnostic lab  and AgPath-ID™ One-Step RT-PCR Reagents Thermo Fisher Scientific Inc., Massachusetts, USA), according to the manufacturer's instructions  using Applied Biosystem 7500 RT-PCR engine, according to the manufacturer's instructions .The main objective of this work was to evaluate the effect of LPAIV-H9N2 vaccination (using inactivated vaccine) on the broiler chicks and response following challenge with LPAIV-H9N2 virus alone or combined with avian pathogenic E. coli under laboratory and commercial field conditions. The infection was applied in two stages, an early challenge on 21 days of life, 120 birds moved to BSL-3  and grouped as G-1-3(a-b), and for late challenge applied on day 28 of life, another 120 birds moved to BSL-3 and grouped as G-3-5(a-b) , birds in G3a/b were challenged on day 21 of life with E. coli per os and kept under monitoring for 7 days (till 28 day of life) and challenged on day 28 of life with LPAIV-H9N2 via IN route to evaluate the effect of infection of H9N2 following E. coli infection. All birds kept in commercial farms from 1 day of life and moved to the BSL-3, 48 h before the challenge date, and every 12 h, cloacal and tracheal swabs were collected and checked with RT-PCR for AIV-matrix gene, NDV velogenic virus, and IBV using specific primer for each disease, to ensure that it is free from any infection before conducting the experimental infection on BSL-3 according to the experimental design.E. coli intramuscularly. G-3a and G-3b were challenged with E. coli per the oropharyngeal route and then challenged 7 days later with H9N2 intranasally at 28th day of age.On the 19th day of life, 60 birds from each of Farms A and B were moved to BSL-3 isolators at the animal house of Mevac laboratories to conduct the challenge at 21st day of age  as described in E. coli intramuscularly. Birds in G-3a/b were previously challenged with E. coli per the oropharyngeal route in the first challenge “early challenge” (at 21st day of life) and kept under observation for 7 days and then challenged intranasally with LPAIV-H9N2 (at 28th day of life).On day 26th of life, 30 birds from each of Farms A and B were moved to BSL-3 isolators at the animal house of Mevac laboratories to conduct the challenge at 28th day of age as described in Hemagglutination inhibition (HI) test was used to monitor the humoral immune response of each vaccine against the antigens of avian influenza H9N2, H5N1 (clade 2.2.1.1), H5N1 (clade 2.2.1.2), H5N8, and ND, which represents the circulating viruses in Egypt. HI test was performed according to the OIE manual , 22. Ser10 embryo infective dose 50 (EID50) of previously isolated and identified LPAI-H9N2 virus (A/chicken/Egypt/Elfeil-26/2017(H9N2), with GenBank accession number: MF620130, kindly provided by Dr. Wael Elfeil, Suez Canal University, Egypt  was applied either by oral or intramuscular route with 100 μl of 106 cfu/ml, this isolation previously evaluated its pathogenicity and showed 80% mortalities by IM injection in specific pathogen free chicks, and this bacterial isolate generously provided by Mevac bacteriology laboratory (Avian pathogenic boratory .10 EID50/ml as described previously (6 EID50/ml) was used to generate a standard curve using stock virus dilutions from 101 to 106. Since PCR cycle threshold “(CT.)” is defined as the point at which the curve crosses the horizontal threshold line, virus log10 titers of a specimen were plotted against the CT value, and the best fit line was constructed. The linear range of the assay was from 1 to 106 EID50/ml, with a correlation coefficient of 0.99. System detection limit was 0.5 EID50/ml as has been standardized and described previously , and the RT-PCR showed its negative with AIV-H5, AIV-H9N2, and velogenic NDV primers, which declare that the birds did not expose to infection before moving from farms or during transportation process from farm to BSL-3 units either groups moved on day 21 or 28 of life.Random serum samples were collected from different farms at 4, 7, 14, 21, and 28 days of life for monitoring antibody titers for ND using LaSota, and ND Genotype VII antigens, AIV H5 antibodies against AIV (H5N1 clade 2.2.1.1), AIV (H5N1 clade 2.2.1.2), and AIV (H5N8 clade 2.3.4.4) antigens, and results did not show any significant difference between different field groups in titers for different antigens used compared to the significant difference observed in H9N2 titers as shown in The results of the early challenge in different laboratory groups on the 21st day indicated the presence of clinical signs, clinical protection, mortality, and total protection as shown in percentages in The results of the challenge on the 28th day of different laboratory groups indicated the presence of clinical signs, clinical protection percentage, mortality percentage, and total protection percentage as shown in Shedding was evaluated at 3, 5, and 7 days post-challenge for different groups in early and late challenge experiments  as shown in Serum samples were collected from different groups at 10 days post-challenge for monitoring antibody titers for AIV H9N2, ND using LaSota antigen, AIV-H5 using AIV (H5N1 clade: 2.2.1.1), AIV (H5N1 clade: 2.2.1.2), and AIV (H5N8 clade: 2.3.4.4) antigens as shown in E. coli was isolated from groups 2a and 2b following the challenge at 21 days of life, E. coli was isolated from groups 3a/b and 5a/b following challenge at 28 days of life as shown in E. coli (APEC) and LPAIV-H9N2. Co-infection of LPAIV-H9N2  with E-coli O157 (intramuscular injection) either on days 21 or 28 of life showed 100% mortalities in both vaccinated and non-vaccinated groups (2a/b and 5a/b) due to a septicemic reaction following the parenteral infection of the avian pathogenic E.coli (APEC), which is supported by the previous findings of El-Sawah et al.  followed by intranasal infection with LPAIV-H9N2 7 days later  resulted in significantly higher clinical protection in vaccinated birds (G3a) than non-vaccinated birds (G3b) , thus agreeing with the previous report of Wang et al.  showed relatively higher mortality  in non-vaccinated birds (G3b) compared to the birds received H9N2-inactivated vaccine (G3a) , and this difference may be associated with the damage of internal tissues and accumulated protease enzymes after E. coli infection, in addition to increase in the level of invasion and adherence protein transcription rate following H9N2 replication in intestinal and respiratory tissues, which potentiate the replication and pathological picture of APEC and thus increase the level of trypsin-like enzyme in the respiratory and GIT tissues, which later support and exaggerate the cleavability of H9N2 virus and intern the replication rate and thus may reflect the significant higher effect of the co-infection of H9N2 with APEC in non-vaccinated birds over-vaccinated  better clinical protection against chicken sickness and developing clinical manifestations (93.3%) after the challenge compared to the non-vaccinated group ; this is in agreement with the previous report of Talat et al. , may be the actual cause for the exaggerated losses associated with H9N2 infections in commercial broilers in endemic countries. The application of the LPAI-H9N2-inactivated vaccine strategy in commercial broilers may aid in controlling the complications associated with both LPAI-H9N2 and oral E. coli infections, by significant reduction the mortalities and clinical sickness. H9N2 vaccination should be associated with strict farm biosecurity measure to maintain superior clinical protection and minimize the bacterial co-infections especially with E. coli.Co-infection with LPAI-H9N2 and The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Animal Welfare and Research Ethics Committee of Benha University by approval No. BU2019421PX23.SM, KZ, and WE: conceptualization. SM, EK, KZ, MH, and WE: methodology. SM, MH, KZ, and WE: software. SM, MH, and WE: validation, writing—original draft preparation, writing—review and editing, visualization, supervision, project administration, and funding acquisition. SM, EK, and WE: formal analysis and investigation resources. SM, MH, SD, RK, and WE: resources. SM, MH, EK, SD, and WE: data curation. All authors contributed efficiently in this work. All authors have read and agreed to the published version of the manuscript.This research was funded by the Benha University, grant number EGBEN2019421P27.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P = 0.026], while that of tau exhibited an increase of 0.026  per mean pure-tone increase by 10 dB (worsening). Likewise, per mean word-recognition score increase by 10%, the SUVR of β-amyloid showed an increase of 0.060 , while that of tau exhibited an increase of 0.059 . Taken together, our data demonstrates that hearing worsening was related to the increased burdens of β-amyloid as well as tau detected by PET, which were the AD pathological markers.Age-related hearing loss (ARHL) represents the frequently occurring disability that affects the elderly worldwide. The recent evidence has calculated ARHL to be most potential risk factor to predict dementia. β-amyloid plaques and tau accumulation in brain are hallmarks pathologic feature of Alzheimer’s disease (AD), which is a leading cause resulting in dementia. However, the potential mechanistic associations between ARHL and dementia remains unknown. We performed the present cross-sectional cohort study by enrolling 72 patients from research on hearing as well as the pathologic hallmarks of AD in brain. The exposure of hearing was measured by either word recognition score or mean pure-tone of the superior ear. The brain β-amyloid and tau standardized uptake value ratio (SUVR) were measured by positron emission tomography (PET). The covariates included gender, age, cardiovascular disease, education and hearing aid use. To analyze the association between hearing and β-amyloid/tau, linear regression was used and adjusted for potentially confounding covariates. Our data showed that the mean age was 67.1 ± 2.9 years. After adjusted for all the covariates, SUVR of β-amyloid showed an increase of 0.028 [95% confidence interval (CI) 0.004–0.061;  The ARHL impairs more than sensory situations as it is difficult for people with ARHL to understand and process speech. Greater efforts should be made for compensating auditory input reduction, and this may show adverse outcomes3. Recent evidence from a prominent study determines ARHL to be the only most potential risk factor that predicts dementia5. The recent longitudinal studies support this relationship between ARHL and cognitive decline7.Presbycusis or age-related hearing loss (ARHL) refers to hearing loss, which impacts nearly 2/3 elderly people aged > 70 years9 (AD). Countless studies have proved that the elevated level of β-amyloid plaques and tau accumulation in brain are hallmarks pathologic feature of AD12. Several studies have linked ARHL specifically to AD14. The theoretical model suggested that ARHL may change the brain structure and lead to AD15. The magnetic resonance imaging (MRI) also showed that ARHL patients are associated with reduced whole-brain and regional volumes17. The longitudinal and cross-sectional research adjusted for possible confounding factors also links the ARHL to AD18. There are rare studies associating ARHL with specific AD biomarkers.Dementia causes great burden on public health globally, and it is frequently caused by Alzheimer’s disease21. In this study, we design the novel cohort study for clarifying the possible relation of ARHL with dementia. This study explored the relation of audiometric ARHL with typical tau and β-amyloid burdens in AD, thus clarifying the relation of ARHL with AD.Positron emission tomography (PET) for β-amyloid and tau made it possible to noninvasively measure the β-amyloid plaques and tau accumulation in brainParticipants were recruited through Ningbo Medical Center Lihuili Hospital from February 2018 to October 2021. Inclusion criteria of this work were as follows, patients aged 52–74 years, being able to receive neuropsychological assessments, PET/MRI examinations, phlebotomy, and no open wounds surrounding auricle. Patients conforming to the following criteria were excluded, existing neurological or psychiatric diseases. All subjects were right-handed. Ethics Committee of Ningbo Medical Center Lihuili Hospital approved this work. All participants were paid for participation and provided the informed consent. Our work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans.0.5–4.0 kHz ≤ 25 dB) and subjects had HL (average of pure-tone thresholds 0.5–4.0 kHz > 25 dB) and the average of pure-tone refers to the mean value in the right and left ears.Prior to hearing test, patients were inquired of ear disease history, hearing device wearing, ear surgery and perceived ARHL. The subjects with history of common ear diseases include tinnitus, otitis media, tympanic membrane perforation, external auditory canal inflammation were excluded in the hearing test. A clinically validated ipad-based portable audiometer  was used to assess hearing. Each participant was in the tranquil room that had < 45 dB environment noise, asked to wear professional sound-attenuating headphones after calibration and remove any hearing device. Later, the thresholds of air-conduction pure-tone were determined. We calculated the mean pure-tone (in dB hearing level) by the mean hearing threshold at 500/1000/2000/4000 Hz. In addition, we detected word recognition by percentage of Chinese words that were repeated accurately and displayed in the suprathreshold loudness . Just immediate word repeating was required during word recognition test, with no requirement of memory-based word recalling. The pure-tone average in the better hearing ear was the primary exposure variable and the word recognition score was the secondary exposure variable. Subjects had normal hearing  represents the normalized absorption value in every voxel relative to standard gray matter absorption value in the epencephalon. The burden of β-amyloid served as the dependent variable, which was verified to be global SUVR detected using 18F-florbetaben PET. The lateral temporal cortex, cingulate cortex, parietal cortex and frontal cortex were included in the calculation of the overall mean β-amyloid in separate region of interest (ROI) based on different vortexes. In the sensitivity analysis, high and low levels of β-amyloid were binarized according to median SUVR.For β-amyloid, 18F-florbetaben PET/computed tomography (CT) scans  were used. Images were collected within 20 min from 90 min after injection. For tau,  for every 10 dB increase (worsening) in pure-tone average on average  Fig. , while a53) Fig. . When thP = 0.007)   while that of tau showed an increase of 0.059  , the SUVR of β-amyloid showed an increase of 0.0054  Fig.  and that05) Fig. . When thWe later conducted binary regression on the SUVR of β-amyloid (high and low classified according to the median 1.22 ± 0.14) as well as tau  in the sensitivity analysis, as completely adjusted model outcomes. Per 10 dB mean pure-tone increase, the SUVR of β-amyloid showed an increase of 2.09-fold, while that of tau showed an increase of 1.97-fold. No significance was observed between word recognition score and binary β-amyloid/tau SUVR and there were no influential outliers on regression diagnostics.23, this study posed the question regarding the mechanical relation between ARHL and AD. The present work has first displayed the relation between ARHL and the two hallmarks pathologic feature of AD.In our cross-sectional study, audiometric ARHL has significant relationship with β-amyloid and tau measured on PET scan. The above relation was good for adjusting several covariates, such as CVD, education and hearing aid use. Furthermore, it also helped to measure hearing, either via word-recognition score or mean pure-tone. It is widely accepted that β-amyloid and tau accumulation are hallmarks pathologic feature of AD25, and its underlying mechanism should be explored. There are 3 mechanistic pathways put forward, including a confounding, causal pathway, and reverse causal pathway, which may be closely interlinked27. Firstly, ARHL would lead to social isolation and this in turn may reduce cognitive stimulating input and lead to dementia. Secondly, ARHL may induce cognitive load. Because most efforts, which are normally used to create working memories, are instead diverted to decoding speech. Finally, ARHL may lead to unpredictable changes in brain structure through its efferent connections. The accelerated volume declines in whole brain have been observed in individuals with audiometric ARHL. Since ARHL may increase the long-term risk of dementia, the participants in our study may also have cognitive decline.Growing evidence suggests that ARHL is related to cognitive impairment and dementia28. Such discrepancy may be because that the objective hearing measure is lacking in their work, which has limited sensitivity of the study. As suggested by Wei Xu et al.29, ARHL was related to tau in cerebrospinal fluid (CSF) using MRI, which supported our research. Similarly, one research adopts the distinct 18F-florbetapir in PET among the elderly but discovers that ARHL is not related to β-amyloid, but the cause of such discrepancy remains unknown30.A recent study on brain autopsies suggested that ARHL was not related to AD neuropathologic resultsP = 0.047) and a near-significant relationship between pure-tone average and tau SUVR (P = 0.053), When the covariate word recognition score was controlled in multivariable regression, connection of mean pure-tone-detected hearing with SUVR of tau/β-amyloid  became less significant. While included mean pure-tone as a covariate in the Table P = 0.12; P = 0.37) became less significant.There were significant associations between hearing, whether by mean pure-tone or word recognition score, and amyloid/tau SUVR. When included word recognition score as a covariate in the Table  P = 0.05, When thCertain limitations should be noted. Since small effect size of SUVRs changes were observed, larger scale data sets should be examined to further explore the relation between ARHL and the SUVR change of two hallmarks pathologic feature of AD. Just insufficient data were available in the present longitudinal study, making it impossible to conduct the causal inference or cross-sectional research. The population in this study were largely from southeast China, and the generalizability of our cohort remains to be further verified. Therefore, further research is needed to replicate our findings. In our study, most participants showed normal hearing, and they stood for community-based middle-aged population. However, the relations of ARHL with cognitive impairment and brain volumes in such age population are discovered in previous studies. This opposes the necessity of oversampling ARHL subjects. As moderate-severe ARHL patients are lacking, it is difficult to extend our results to this group. This study has strengths. Our research is the first to show the association between ARHL and the two hallmarks pathologic feature of AD. The binary and continuous results were examined, meanwhile, 2 distinct hearing measuring approaches were adopted. As a result, hearing worsening related to the increased burdens of β-amyloid and tau.Supplementary Information.


In most cases, the valuation of the investments characterized by various stages with a high level of uncertainty is done through the compound real option valuation (ROV). This decision making support can consider various types of uncertainty that can affects these investment phases, such as that linked to technology. Specifically, within the category of uncertain investments there are the broadband opportunities that can be valued as real options in order to quantify the risks associated with the investment. However, since ROV theory has no definitive way to determine model parameters based on market information, we propose one that can adjust them dynamically. In this paper, to include this aspect in the project valuation, we have unified the ROV with the sentiment analysis, a natural language processing technique that allows us to quantify the polarity of expressions in natural language numerically. In particular, the inherent risks related to the different phases of the project can be extracted from the information present in the surrounding environment and published in newspapers. From there, we obtain a sentiment score which, through appropriate manipulations, manages to modify the evaluation of the success probabilities of each stage. Then, we embed these success probabilities in the ROV in order to provide a valuation methodology that includes the impact of information on the investment decision. There is no doubt that smart cities are, nowadays, the new frontier for public administration to improve citizens’ quality of life. Sometimes, the smart city concept can be embedded in a wider framework related to the sustainable development goals (SDGs) of the United Nations (UN). The improvements made by smart city projects can happen in different ways . A smart city is a place where traditional networks and services are made more efficient with the use of digital and telecommunication technologies for the benefit of its residents, and businesses.The conception of a smart city may change according to the vision of researchers that apply this concept to lead some specific studies. For example, Caragliu et al.  identifiSmart city renewable projects are comfortably evaluated with this approach. For example, Ha and Fujiwara  used theGenerally, sentiment analysis is applied to financial options theory, as evidenced by Han  analyzinIn this section, we provide a methodology suitable for the characteristics of broadband investments. We proceed, first, by explaining the sequential nature and risks of a broadband project in Sect. T.Broadband projects are characterized by sequential steps that start with a broadband plan. In the first step, the sponsor needs to think strategically about the project; therefore, there is a first overall assessment. We can include various activities such as mapping infrastructure needs, making a possible financial plan and a business model, developing deployment planning, and procurement preparation in this phase. The broadband plan is a relevant point to make an overview of the socioeconomic and demographic features of the territory. Moreover, it contains information regarding the definition of the project’s goals in terms of the demand for high-speed broadband by the population. However, the market’s real conditions during the project’s lifetime can change drastically from the prevision made in this first general assessment. After this step, if the conditions appear favorable, the manager should decide to undertake the first real investment phase related to the building of the network and seek funding from potential investors. Successively, the investment process proceeds with the operation and management stage.Considering the sequential nature of these investments, it is easy to understand the need to embed the managerial flexibility insight in their valuation to allow investors to continue in the following stages only if the previous stages are profitable. This approach reduces the risk of huge losses and makes the project realistically attractive.Regarding the broadband risks, we can divide them into operational, market, financial, and political risks (see Feasibility Report for a Community Network ). The opp of passing from stage What we do, at this point, is to link the value of the sentiment score to the probability of success present in each stage. So, for example, considering the mentclass2pt{minimmentclass2pt{minimCisco Broadband, the first sentence consists of the following sentence: “La crescita sociale ed economica di un Paese è legata a doppio filo con un accesso universale, affidabile e veloce a internet.", whose polarity is positive with “E’ questo il principale dato che emerge dall’edizione 2022 del Broadband Index di Cisco, uno studio condotto ogni anno su quasi 60.000 lavoratori di trenta Paesi  chiamati a rispondere sulla qualità della banda larga domestica." has a neutral polarity with The average sentiment (polarity) score, entclass1pt{minimaThe choice of articles was made randomly, and to avoid news polarization, different journals were considered. However, since there is not much specific news on the broadband sector, we have limited ourselves to considering articles that allow us to extrapolate helpful information on the future of a broadband system. Observing how all the articles have a positive score, we infer that the broadband infrastructure sector is undergoing strong development and is encouraged by institutions and companies.learning measure) that takes into account the possible information revealed , and how this can eliminate part of the uncertainty, modifying the probability of success. Returning to the case of a single firm characterized by a multistage project  and At this point, to understand how to use the sentiment score to adjust the probability of passing from one stage to another, we must refer to the theory introduced by Dias , who modInvesting in information (information revelation process) to reduce uncertainty corresponds, in this case, to study the relationship between the two previous variables and, therefore, the correlation of a bivariate Bernoulli variable. As defined by Dias , revelathat Dias  always ep, q, and the joint probability of success q). Considering exchangeable Bernoulli variables , it is possible to simplify the Fréchet-Hoeffding bounds to q.To study the effect of performance in one stage on the next, we consider the joint distribution between ich Dias  indicatem 4 Dias , for whi Villani , we can The valuation of smart city projects, specifically broadband projects, can be viewed as a series of sequential investments related to different stages in their lifetime period. These stages are not independent of each other but, quite the opposite, the investment process is not able to proceed in the following stage if the previous stage presents a kind of failure. This logic can be captured by compound ROV. Previous studies used this approach to valuate sequential investments. For example, Cassimon et al.  used comPV) that acts as the underlying asset of the compound option, as shown in Eq. PV is equal to the net value given by the discounted difference between revenues (Rev) and operating costs (OC). Considering the volatility (u) and down (d) that are calculated as follows  or negative (neg) information revelation regarding the project value evolution. This information can influence the following investment stages by increasing or decreasing the project value. The inclusion of information revelation into ROV has been made by Di Bari and Villani  is equal to € 11.94 million which acts as the underlying asset. This value has been calculated considering the difference between the revenues and operating costs values  on the basis of the Feasibility Report for a Community Network,r) of The data that we use, related to a consultancy and engineering Feasibility Report for a Community Network, is dated November 2020, during the pandemic period. We provide a simplification using likely data related to a broadband structure to implement a multi-stage ROV modeled as compound options. The data are chosen considering the Feasibility Report for a Community Networknd Gupta . So, theWe hypothesize that the initial investment pursued at time Broadband projects are risky investments as we have shown in Sect. rmantzis  and Di Brmantzis . To calcp and q both equal to 0.7, and PV) from 2020 to 2030, as shown in Fig. Applying a value of entclass1pt{minimaentclass1pt{minimaAll the parameters needed to pursue compound ROV are summarized in Table Results show that the broadband projects evaluated through our methodology are financially attractive since the RO value is positive . On the one hand, thanks to the ROV, the proposed method can embed the riskiness in the project valuation. On the other hand, thanks to the use of AlBERTino, we can identify possible risks coming from the outside world  and, consequently, evaluate whether or not a specific phase has been overcome. Our methodology allows to improve previous models and overcome some limitations concerning previous literature. For example, Burger-Helmchen  determinApplying this methodology has implications for policymakers, given that funding must be gathered from public and private sources to implement broadband. Governments need to make public and private investors aware of the complexity embedded in these smart city projects so that they base their investment decisions on the outcome of assessment analyses that properly valuate these investments without underestimating them. This is a relevant point considering that public administrations often lack financial resources and need private support to pursue long-term investments associated, among others, with several of the 17 UN Sustainable Development Goals (SDGs). Specifically, UN Sustainable Development Goal 11 means to “make cities and human settlements inclusive, safe, resilient, and sustainable”. In particular, broadband investments are part of sustainable cities and human settlements since they can improve the performance of various technologies that make a city smart: smart traffic, safety, smart grid, and city intranet. The improvements happen through an optimization of the processes. People need a smart city to speed up their processes and their communication and live in a safe community. In this sense, broadband projects represent a good alternative to ride the digital era considering that two-thirds of the world population is expected to live in urban areas by 2050. This ongoing process started in 2008 when the global urban population exceeded the rural population for the first time in history. Moreover, the need for innovative broadband investments to increase the speed of navigation on the internet is emphasized by the Covid-19 pandemic since it has significantly increased the number of people working from home. In this sense, to maintain this drastic change in their habits and extend other smart city initiatives, broadband implementation becomes essential and an appropriate assessment of this type of smart city project. Moreover, throughout the result findings regarding the polarity scores on ROV, the organizations, such as the telecommunications industry, can benefit from our methodology to provide a reliable valuation tool for interested public or private investors and to encourage them to invest in telecommunications projects. This is because the results of the case study proposed in this work tend to appreciate the telecommunications projects highlighting their financial profitability for potential investors.The valuation of risky investments characterized by a high level of novelty and sequential nature is still an open issue in financial literature.In most cases, the valuation of the uncertain projects is done through the compound Real Option Valuation (ROV), which can consider various types of uncertainty that can affect each investment stage. In particular, within the uncertain investments category, broadband project opportunities can be valued as real options to quantify the risks associated with the investment.However, the compound ROV could be incomplete decision-making support to make an ex-ante valuation about the future project performance. If the investor should decide whether to invest in the future, s/he should also consider the market information (that can be extrapolated by newspapers or other sources) about the broadband market.Considering their valuation difficulties, we propose a reliable methodology to price a typical broadband project that combines the ROV with sentiment analysis in this article. In this way, we can incorporate into the analysis part of what happens outside the company in the different investment phases and, on this basis, modify the probability of success. The information revealed was obtained by analyzing the news from some newspaper articles through AlBERTino, which produced a sentiment score that, through appropriate manipulations, was integrated into determining the probability of success.We apply this methodology to a hypothetical case study based on likely data to show how to implement the model we proposed in this paper.Moreover, our model could be helpful in public administrations because the valuation process followed stresses the managerial flexibility of broadband projects in an obvious way, something that can contribute to attracting more interest for innovative broadband projects, increasing their number and, consequently, raising the number of smart city initiatives, a target consistent with pursuing UN Sustainable Development Goal 11.