Mucorales Rhizopus, Mucor, Rhizomucor, Absidia, Apophysomyces, Cunninghamella,and Saksenaea. The major risk factors for the development of mucormycosis are diabetic ketoacidosis, deferoxamine treatment, cancer, solid organ or bone marrow transplantations, prolonged steroid use, extreme malnutrition, and neutropenia. The common clinical forms of mucormycosis are rhino-orbital-cerebral, pulmonary, cutaneous, and gastrointestinal. During the second wave of COVID-19, there was a rapid increase in mucormycosis with more severity than before. Amphotericin B is currently found to be an effective drug as it is found to have a broad-spectrum activity and posaconazole is used as a salvage therapy. Newer triazole isavuconazole is also found effective against mucormycosis. This study aimed to review various studies on the laboratory diagnosis and treatment of mucormycosisMucormycosis  is a diverse group of increasingly recognized and frequently fatal mycotic diseases caused by members of the class zygomycetes. Mucormycosis is around 80 times more common in India, compared to other developed countries, with a frequency of 0.14 cases per 1,000 population.The most frequent causative agent of mucormycosis is the following genera from the Order  Mucor, Rhizopus, Rhizomucor, Absidia, Apophysomyces, Cunninghamella,and Saksenaea are under the order Mucorales while order Entomophthorales includes Conidiobolus sp. and Basidiobolus sp. that causecutaneous and subcutaneous infections [ The class Zygomycetes includes two orders: Mucorales and Entomophthorales. Common genera that cause mucormycosis,like ections  . Their ections  . ZygomyThe risk factors commonly encountered are diabetic ketoacidosis, deferoxamine treatment, cancer, solid organ or bone marrow transplantations, prolonged usage of steroids, extreme malnutrition, neutropenia, trauma, burns, or neonatal prematurity  - 5. FeThe diagnosis of mucormycosis is difficult, and the main challenge is the identification of zygomycetes to the species level isolated in culture and the direct identification in tissue specimens. However, there have been recent advances in new molecular approaches. Delay in the accurate identification of zygomycete infections can negatively affect patient survival  . TimelyDuring the COVID-19 pandemic, a remarkable increase in the incidence rate of mucormycosis was noted in India. Moreover, zygomycetes show resistance against conventional antifungal agents; therefore, there is a need to study newer antifungal agents for the treatment  . DuringMucor," and "Rhizopus," as well as"CAM risk factors," "Clinical complications in CAM," and "Diagnosis of Mucormycosis and CAM.". The corresponding authors have independently verified the accuracy of the data. A total of 128 works of literature were included in this study.The electronic databases of PubMed, Scopus, and Google Scholar were searched for a structured review of the literature up until January 2023 using theterms "Mucormycosis," "COVID-19," "Zygomycosis," "SARS CoV-2," "Globally, the incidence rate of mucormycosis varies from 0.005 to 1.7 per a million population. The prevalence rate of India is estimated to be 140 per million population, which is about 80 times higher than that of other developed countries  . A systBased on a study performed by Jeong et al., the cases of mucormycosis reported in Europe were higher, compared to Asia. However, results of a recent review of 851 cases reported over a period from 2000 to 2017 were different as the rate of mucormycosis cases was 34% in Europe, 31% in Asia, 28% in North or South America, 3% in Africa followed by 3% in Australia and New Zealand  . The hiRhizopus arrhizus. The variety of agents causing mucormycosis in India is considerably wide.The second most frequently isolated agent is Apophysomyces variabilis. Based on the literature, Apophysomyces species cause necrotizing fasciitis i.e., cutaneous mucormycosis,and are responsible for about 60% of reported cases. In India and throughout the world, the leading cause of mucormycosis is Lichtheimia account for 0.5-13% of cases in India. According to Chander et al., L. ramosa is the cause of the majority of cases in India.Other genera associated with mucormycosis in India are Rhizomucor pusillus, Mucor species Cunninghamella species, Syncephalastrum species,and Saksenaea species [ Species of species   .Saksenaea erythrospora, Mucor irregularis,and Thamnostylum lucknowense [ Mucormycosis is also reported due to rarer organisms, like nowense  . Its innowense  . Duringnowense  . Hussain et al. carried out a meta-analysis on a sample size of 52,196 COVID-19 patients to estimate the global prevalence of CAM. They observed that the CAM incidence rate was 50 times greater (7 cases per 1000 COVID-19 patients) than the highest-incidence rates reported in previously published statistics . Infection with CAM was shown to have a significant death rate (26.9%)  . Nagalli et al. used electronically accessible data to conduct a systematic review. They identified 115 COVID-19 cases who had confirmed infection with mucormycosis. They stated that diabetes mellitus (DM) was the most prevalent co-morbidity for mucormycosis among them (approximately 77.1%) and that 90% of patients took steroids for the treatment of COVID-19. Antifungal therapy was used; however, CAM infection still had a significant death rate (approximately 48.7%)  . Diabetic ketoacidosis, deferoxamine treatment, cancer, solid organ or bone marrow transplantations, prolonged steroid use, extreme malnutrition, and neutropenia are the major risk factors for mucormycosis  . In IndA prevalence of 0.16-1.72% mucormycosis cases from North India was reported in patients with DM  , 22. PDiabetes mellitus is a major risk factor for mucormycosis with 72% cases in Mexico, 75% in Iran, and 52% in the USA, similar to India. In comparison, European countries have a lower prevalence of diabetes among mucormycosis cases 17-23%)  . Patien7-23%  .In light of the rise in mucormycosis cases stimulated by the COVID-19 pandemic, the entity has been termed CAM  . DiabetThe CAM may occur due to COVID-19-induced immune dysregulation or associated treatments with corticosteroids and immunomodulatory drugs  which impair the host defense mechanism against molds  . Owing The increase in mucormycosis cases in India could also be associated with high ferritin levels. In severe COVID-19 cases, there was a change in iron metabolism  . A studSteroids are frequently used for the treatment of pneumonia due to COVID-19. They lessen phagocytic activity which results in pathogen invasion that worsens glycemic control. This is challenging particularly when patients need steroids for the management of severe acute respiratory distress syndrome and COVID-19 pneumonia  . In a sPhysical factors, like frequent nasopharyngeal swab testing (more than twice), for COVID-19, have been an independent factor associated with a higher risk of CAM. It may also induce micro-trauma to the nasal and nasopharyngeal mucosa, leading to angioinvasion. Cutaneous mucormycosis can occur at sites of local trauma, such as contaminated intravenous catheters, bandages, and needles. Similarly, it has been proposed that inhaling steam can lead to thermal damage to the nasal mucosa which can also be one of the risk factors  , 40. TIndirect factors, including interventions associated with the prevention and management of COVID-19, can also be a reason for the increased number of cases during the pandemic  . DuringThe term "breakthrough invasive fungal infection" (bIFI) refers to an infection that develops after exposure to an antifungal agent which involves fungi that are not within the range of activity of antifungals  . Some oAspergillus mold invasive illnesses is associated with breakthrough mucormycosis [ An aspect that contributes to the development of breakthrough invasive candidiasis (bIC) is exposure to two or more antibiotics for at least 14 days. This suggests changes in the endogenous microbiota   . Few stmycosis  . Accordmycosis  . Fusarium spp. than Aspergillus spp. [ A retrospective study performed by Kim et al. reported the prevalence and incidence rates of breakthrough IFDs during VRC treatment for IA to be 2.25% and 0.22 cases per year, respectively  . Two prus spp.   . Cunninghamella spp., and increasing age [ Clinical forms of mucormycosis are classified according to the anatomical site of infection which is as follows: rhino-cerebral or rhino-orbital, pulmonary, cutaneous, gastrointestinal, disseminated, or other uncommon presentations, like endocarditis, osteomyelitis, peritonitis, and renal infection  . The paing age  , 50 . Pulmonary mucormycosis has non-specific clinical signs that make it difficult to distinguish it from pulmonary aspergillosis. Non-productive cough is a common symptom,whereas hemoptysis, pleuritic chest pain, and dyspnea are less common. Rarely, particularly in diabetics, pulmonary mucormycosis may present as an endobronchial or tracheal lesion.A summary of distribution, risk factors,and clinical forms of Mucormycosis is presented in Other uncommon forms include endocarditis, osteomyelitis, peritonitis, and pyelonephritis. Endocarditis of prosthetic or native valves can occasionally be caused by mucormycosis. Aortic thrombosis can be caused by endocarditis, which develops on or near prosthetic valves. Osteomyelitis typically develops following a traumatic inoculation or surgical procedure . Hematogenous osteomyelitis is relatively uncommon, but researchers have described osteomyelitis of the tibia, cuboid, calcaneus, femur, humerus, scapula, metacarpals, and phalanges  - 69. IClinical forms of mucormycosis can be categorized into rhino-orbital-cerebral, pulmonary, cutaneous, gastrointestinal, and disseminated mucormycosis. During the COVID-19 pandemic, complications in clinical presentations were observed in CAM cases. A study conducted by Pruthi et al. described five cases of pulmonary mucormycosis linked to COVID-19 that were complicated by pulmonary artery pseudo-aneurysm. When combined with comparable radiographic findings in mechanically ventilated patients, the detection of a mucormycosis agent from respiratory specimens supports the diagnosis  . Facial pain, facial palsy, headache, loose teeth, black necrotic turbinate, peri-orbital or facial edema, skin induration, and blackish staining are some of the clinical signs of head and neck mucormycosis. Moreover, bloody nasal discharge and palate damage are symptoms associated with nasal and oral cavity invasion. As a result of orbital expansion, the ophthalmic artery, and optic nerves may be destroyed, which could result in eyelid ptosis, proptosis, visual problems, and blindness.A retrospective study performed in India reported vision loss in patients with CAM  . Due topresented information on the provision of invasive or non-invasive mechanical ventilation for patients with pulmonary mucormycosis linked with COVID-19. Fever, dyspnea, cough, chest discomfort, and hemoptysis are signs of pulmonary mucormycosis in non-ventilated individuals. Disseminated mucor-mycosis, which results from bloodstream invasion in highly immunocompromised patients, may damage any organ but primarily the brain and lungs, and causes non-specific symptoms, such as abdominal pain and distension, diarrhea, and gastrointestinal bleeding  .Most of the clinical presentations are similar in CAM and non-CAM infections; however, the percentage of complications encountered during the COVID-19 pandemic was higher which may be attributed to the increased invasiveness of zygomycetes during COVID infection. Rhinocerebral mucormycosis is the common clinical presentation seen in CAM, whereas pulmonary mucormycosis is reported in non-CAM infections. A study conducted by Watanabe et al. in 2022 reported that one-fifth of CAM patients may lose their eyes  .Diagnosis of mucormycosis is challenging as most of the cases are culture-negative and microscopic identification can sometimes miss the fungus due to improper sample processing or lack of expertise. Demand for a quick diagnosis of mucormycosis has been encountered during the COVID-19 pandemic due to its ability to cause infection. Various examinations for the identification of thepathogen are listed in According to previous studies performed by Bonin et al. and Dannaoui et al., the sensitivity of testing fresh tissue was 100% while that of testing formalin-fixed and paraffin-embedded tissue was only 56%. Low sensitivity in formalin-fixed tissue was due to the nucleic acid fragmentation by the extensive cross-linkage of tissue proteins after fixation in formaldehyde which is known to inhibit the polymerase chain reaction (PCR) process and can also give false negative results  , 79. DR. arrhizus WSSA) [ The various serological tests used for the diagnosis of mucormycosis including Enzyme-linked immune-sorbent assay (ELISA) (s WSSA)  , Westers WSSA)  , ELISA s WSSA)  , and ELs WSSA)  . These Mucor circinelloides, M. bainieri, M. mucedo, M. plumbeus,and M. racemosus [ Pulse field gel electrophoresis is a useful tool for molecular typing and revealing the genetic variability at species and intraspecies levels.Karyotypes of several zygomycetes, like cemosus  , have bRhizomucor and Rhizopus species has also been studied by this method asthey are among the clinically important zygomycetes [ Randomly amplified polymorphic DNA analysis uses random oligonucleotide primers for the detection of distinctive amplification patterns.The intraspecies and interspecies genetic variability of mycetes  , 89 Rhizopus microspores, R. arrhizus. var. arrhizus, R. arrhizusvar. delemar, Mucor irregularis, Mucor circinelloides, L. ramosa,and Lichtheimia corymbifera. The RCA is particularly suitable for high-throughput applications. In addition, it is used as a screening tool in view of hospital hygiene and for understanding pathogen population dynamics. The development of a reliable diagnostic tool for the early detection and identification of fungi remains a priority for improving patient outcomes. Given the simplicity and the results, RCA can become a routine test in hospital hygiene when there is a huge number of samples to be screened [ Rolling circle amplification (RCA) is an isothermal amplification method proven to be rapid, cost-effective, and specific for the molecular identification of pathogenic fungi.They have a specific detection limit of a single nucleotide. In Mucorales, there was no cross-reactivity observed within tested strains.The RCA has rapidly identified the following six virulent species: creened  .Aspergillus spp.as well as Fusarium sp., and to a lesser extent, the Mucorales have also been evaluated. The precision and simplicity of this identification method together with its cost-effectiveness and potential for high throughput, are its main advantages over molecular-based identification. The method does have limitations; accordingly, the isolates must be cultivated as pure cultures and direct identification from clinical samples is not feasible. The incubation period, medium choice, and sample preparation could differ and have an impact on the outcomes [ Mass spectroscopy using MALDI-TOF is a good alternative to molecular methods in the setting of a microbiology laboratory due to its numerous benefitsover other identification techniques, including ease of handling, cheap prices, speed, and the potential for high throughput. Filamentous fungi, like utcomes  . Radiological findings of various forms of mucormycosis are shown in Zygomycetes include a diverse group of fungi with variable susceptibilities to antifungals  . Polyenin vitro action and a low minimum inhibitory concentration (MIC) value.The COVID-19 pandemic caused a drug crisis, after which azoles, like posaconazole, which have good in-vitro activity, were employed as the treatment agent [ Amphotericin B is the recommended treatment for mucormycosis since it has significant t agent  , 123. in-vitro activity despite its limited use during the pandemic and can still be used. It is a good treatment option for the management of resistant infections in the future and can be considered for newer azoles,like isavuconazole as it has good in-vitro activity and a low mean MIC. Combination therapy may be used when monotherapy has proven ineffective; however, additional research on the interactions between various drugs is necessary to improve patient care [ Amphotericin B showed good nt care  - 126. Mucorales are intrinsically resistant to azoles and other common antifungal drugs. Members of the ABC transporter superfamily may be in control of thedrug efflux that leads to azole resistance. Drug resistance is most closely related to a subtype of ABC transporters called pleiotropic drug resistance (PDR) transporters. The development of azole resistance in the fungi that cause mucormycosis is poorly understood. Various azoles, such as fluconazole and VRC, can affect how sensitive these fungi are to certain amino acid alterations in one of the Cyp51 enzymes  . Mucor circinelloides. The majority of Mucorales spp. are resistant to fluconazole and VRC,whereas isavuconazole and itraconazole have been shown to have species-specific in vitro actions [ pdr2 had no impact on the susceptibility to isavuconazole despite the fact that it was discovered to be elevated by this drug [ Eight potential PDR-type transporters are encoded in the genome of actions  . The muis drug  .Early identification has become essential due to the significant rise in mortality and morbidity rate of mucormycosis during the pandemic. Due to the deadly nature of zygomycetes, it is crucial to develop a new molecular technique for its early diagnosis. Standardization of a conventional PCR for the detection of zygomycetes directly from patient samples would help in the early diagnosis and can also be performed in a resource-limited laboratory setting. This will also help to overcome the long time required for diagnosis, including the time needed for the culture to grow and the performance of further tests. Hence, the early identification of zygomycetes directly from samples will not only aid in faster diagnosis but also help in the right choice of antifungals. As the antifungals used against Mucorales are slowly developing resistance, further studies on the synergistic effects of drugs can be studied to administer combination therapy rather than monotherapy. The authors would like to thank the management of Sri Ramachandra Institute of Higher Education and Research, Chennai, India for the provision of excellent infrastructure and facilities for research.M. K. contributed to the literature search and draft preparation. P. T., S. P., and A.J. K. contributed to the conceptualization, manuscript editing, and critical review. All authors read and approved the final manuscript.None.Self-funding.


Telemedicine is a method of providing remote healthcare services and consultations to patients using communication technology. Tele-audiology is a sub-branch of telemedicine. It refers to providing audiology services using telehealth strategies. This study aims to compare the satisfaction of patients who come to the hearing aid center and receive device fitting service and patients who have hearing aid fitting using tele-audiology service. For this purpose, hearing aid users were divided into two groups. The study group consisted of 17 participants  who continued fitting appointments remotely after the first clinic application, while the control group consisted of 23 participants  who had all hearing aid fittings performed face-to-face in the clinic. The participant’s satisfaction was assessed with The International Outcome Inventory for Hearing Aids Turkiye (IOI-HA-TR) questionnaire because it is practical and can be administered over the phone.p < 0.05). In addition, most of the participants stated that using Remote Care solved their problems  and they were satisfied with the fitting of their hearing aids with this application . In addition, 13 out of 17 participants stated that they would pay attention to the “remote fitting” feature when purchasing a new hearing aid (76% very good). Moreover, they would like to continue the fitting using the Remote Care application (65% yes).There were no significant differences in hearing aid satisfaction between those who came to the hearing center and filled out the IOI-HA-TR questionnaire personally and those who completed it through the Remote Care application (Remote fitting technology via smartphone applications can facilitate the lives of hearing aid users and improve their quality of life in cases of risky conditions such as pandemics, various diseases, and physical limitations. Telemedicine is a method of providing healthcare services and consultations to patients through the use of telecommunications technology, thus reducing personal contact for both the healthcare professional and the patient . AccordiTele-audiology is a sub-branch of telemedicine. It refers to providing audiology services using telehealth strategies . NowadayTele-audiology was previously used for audiological assessment in rural areas . It gainHearing aids are the most common solution to compensate for hearing problems, except for pathological conditions that can be treated surgically . WirelesAt the present time, many hearing aid manufacturers offer remote, smartphone-based fitting protocols. However, while some users do not prefer to use smartphones, others are unable to use smartphones due to reasons such as vision problems, advanced age and/or inability to adapt to technology . AccordiAs a result, tele-audiology provides convenience to both audiologists and patients. Nevertheless, the future of this technology depends on its adoption by users. It has been increasingly used throughout the world in recent years, but how much of it has been adopted in Turkiye is not known. Our study aimed to compare the satisfaction of patients who came to the hearing aid center for fitting with those who had their hearing aids adjusted using the tele-audiology service in Turkiye. We hope that our research will contribute to the literature on hearing aid users’ usage habits and their satisfaction with this technology.The study was performed with Oticon hearing aid patients using a Remote Care phone application in Turkiye. Hearing aid users were divided into two groups. Control group consisted of participants who had all hearing aid fittings performed face to face in the clinic, while study group consisted of continued fitting appointments remotely after the first clinic application. The inclusion criteria for the study group were as follows: use of Remote Care application at least once in the past 6 months, ≤ 80 years of age, slight to severe hearing loss between 26 and 90 dB HL, smartphone use, and a minimum of 1 year hearing aid experience. Similar inclusion criteria were accepted for control group as well except for Remote Care application use. The exclusion criteria were as follows for both groups: the presence of active ear disease, and cognitive or vision impairment that would preclude participation in the study. In addition, whereas the hearing aid functionality of the control group participants was checked at the hearing center, the study group was questioned on the phone to ensure that all participants are using their devices to fully functionality. A healthy phone conversation was essential for the study. Therefore, individuals with profound hearing loss were also not included in the study because they had lower discrimination scores and needed more visual cues than those with less hearing loss. The demographic information about the participants can be seen in Table see Table First, all of the hearing aid patient database was scanned at the Idea Hearing Systems Industry and Trade Inc (IDIS) hearing center in Turkiye, and 34 Oticon users who experienced remote fitting were identified. These users were called by an audiologist and two questionnaires were administered to those who wanted to participate in the study. Only 17 of the 34 participants agreed to participate . Seventeen users were not included in the study for different reasons. Seven hearing aid users did not agree to participate in the survey, one user died, two users were not available for phone conversation, three users could not be reached with the phone, and four users did not answer their phones. The International Outcome Inventory for Hearing Aids Turkiye (IOI-HA-TR) questionnaire was used as an assessment tool because it is practical and can be administered over the phone. In addition, in order to evaluate the experiences of the participants whose hearing aids were adjusted by remote care, a mini questionnaire consisting of 4 multiple-choice questions was applied to the participants over the phone  who agreed to participate in the study were given an information form, and their consent was obtained. They were then asked to complete the IOI-HA-TR questionnaire.In IDIS hearing aid clinics, the first appointment of all hearing aid users is performed face-to-face. The first fitting is completed with the Real Ear Measurement (REM) verification method according to the NAL-NL 2 prescription formula for all patients. In addition, IDIS clinics have a standard control procedure. If users do not want an additional appointment, routine controls are performed in the 1st month, 3rd month, 6th month, and 1st year. Participants of both groups were followed online or face-to-face similarly in terms of hearing aid satisfaction.U test was used to compare the two groups. In addition, Pearson correlation was used to correlate the questions where necessary.The Statistical Package for the Social Sciences program was used for the analysis. Since the data were not distributed normally, non-parametric test methods were used. The Mann–Whitney This study was approved by the Ethics Committee of Istanbul Medipol University (registration no. 7834E184XA).p < 0.05).Thirty-seven hearing aid users where experts at IDIS made adjustments remotely using Remote Care were contacted, and seventeen of them were provided to answer the surveys. In addition, 23 hearing aid users who have never used Remote Care were included in the study as the control group. When the participants in the two groups were compared in terms of their mean age, no significant difference was found (p < 0.05) (see Table There was no significant difference in the answers to any questions for those who came to the hearing aid center and completed the IOI-HA-TR questionnaire in person or those who completed it with Remote Care (Think about how much you used your present hearing aids over the past two weeks). On an average day, how many hours did you use the hearing aids?) (r (15) =  − 0.436, P = 0.038). However, there was no significant difference in control group (p = 0.395). In question 4, the hearing aid satisfaction of older participants in the study group was lower than that of younger participants  (r (15) =  − 0.421, P = 0.046).Table r (15) =  − 0.509, P = 0.013). In the control group, the short-term users of current hearing aids were using them for longer during the day (r (15) = 0.579, P = 0.015)  (r (15) =  − 0.442, P = 0.035).The average duration of using the last purchased hearing aids of the participants in the study group was 29.9 months while in the control group was 24 months. The long-term users of current hearing aids in the study group were using their hearing aids less during the day than those who purchased their hearing aids recently . Since the app can work with all Oticon hearing aids compatible with 2.4 GHz, we were able to include hearing aids from different segments and models in our study. However, despite the technological development and the negative impact of the COVID-19 pandemic, the use of Remote Care in Turkiye was limited. The database of the IDIS Hearing Center, which has 35 branches in Turkiye, was searched and only 34 users who used Remote Care actively were found. Seventeen of them could be reached by phone and agreed to participate in the study. Due to the small number of Remote Care users in Turkiye, we had to perform our study with a limited study group. In the future, research with larger participants will contribute to the literature.Participants’ hearing aid satisfaction was evaluated with the IOI-HA-TR questionnaire , and no In addition to the online fitting service provided by an audiologist, there are also self-fitting options tried and offered by different manufacturers. In a recent study, it was stated that the digital self-fitting tool enables multiple sessions and easy re-fitting, with the potential to outperform the classical fitting approach. In the following years, in addition to the online fitting method, the self-fitting method may often take place in tele-audiology .Remote Care can install easily on the smartphone and acts as a bridge between the hearing aid and hearing care professional. Despite the easing of the pandemic conditions, this technology continues with 44 active hearing care specialist users in our country. During to study, it was observed that some users who participated this study purchased new smartphones in order to use Remote Care application. On the other hand, this technology also requires a smartphone and a stable Internet connection to work. However, some users, especially elderly users, may not want to use a smartphone. In addition, the use of smartphones can also be restricted by physical disabilities, such as hand tremors and vision difficulties. In our study, no significant difference was found between the Remote Care fitting group and the mean age of the face-to-face fitting group. However, in the remote care group, it was found that older users were less satisfied with their hearing aids and tended to use them less. This may be due to the mental and physical limitations of aging .The long-term users of current hearing aids in Remote Care group were using their hearing aids less during the day than those who purchased their hearing aids recently. This may be due to the fact that individuals with hearing loss express themselves more limitedly on the online platform during the fitting appointment. Obviously, it is known that even individuals with unilateral hearing loss are adversely affected by their expressive language skills . In addiIn our study, we used a short survey to assess the impact of remote fitting technology on users. Because there is no structured, valid-reliable questionnaire on this subject in the literature. A “comprehensive” questionnaire on tele-audiology would be beneficial for future studies. In addition, repeating our research with a larger experimental group will provide more reliable results. Moreover, the longitudinal study design with certain periods can also give information about the adaptation process of Remote Care users. Furthermore, the comparison of the groups with objective measures such as Real Ear Measurement will enable the evaluation of more different variables.There is no significant difference between patients who fitted hearing aids face-to-face and those who received them remotely. Patients can express themselves more clearly when they are face-to-face with an audiologist and can be examined in greater detail. However, it is also possible that hearing aid users could not go to the hearing center due to the risk of COVID-19, rules related to the pandemic or physical limitations. Nonetheless, without remote fitting protocol, these patients may had been completely deprived of functional hearing aids. The possibility of remote hearing aid adjustment with a smartphone application can improve the life quality of hearing aid users in cases of pandemics, various diseases, and physical limitations.


Cochlear implantation (CI) outcomes in patients with auditory neuropathy (AN) are variable, which hampers patients’ decisions on CI.This study aims to assess the outcomes of CI in individuals diagnosed with AN and to examine the various factors that may influence the effectiveness of this intervention.A total of 75 patients diagnosed with AN were included in the study. The hearing threshold, the score of categories of auditory performance (CAP), speech intelligibility rating (SIR), and speech audiometry were tested. Genetic testing was conducted by medical exome sequencing in 46 patients.p < 0.001) and 6.00 ± 0.96 (p < 0.001), respectively; SIR score increased to 3.57 ± 1.22 (p < 0.001) and 4.15 ± 0.95 (p < 0.001), respectively. Maximum speech recognition ranged from 58 to 93% for prelingual onset patients and 43 to 98% for those with post-lingual onset. Speech outcomes of CI in cases with cochlear nerve (CN) deficiency were significantly poorer (p = 0.008). Molecular etiologies, including TWIST1, ACTG1, m.A7445G, and a copy-number variant (CNV) carrying ACTB, were related to AN here.After CI, the average aided hearing threshold for patients with prelingual and post-lingual onset was 38.25 ± 6.63 dB and 32.58 ± 9.26 dB, respectively; CAP score improved to 5.52 ± 1.64 (CI is a viable therapy option for patients with AN; CN deficiency might impact outcomes of CI. Nearly In patients with AN, the degree of hearing loss (HL) varies from mild to profound, and it can occur prelingually or post-lingually. In contrast, the hearing may be affected bilaterally or unilaterally. AN may occur simply or as part of some syndromes. Simultaneously, patients of AN may also have inner-ear malformations. Risk factors, including hyperbilirubinemia, infection, premature, ototoxic drug exposure, cochlear nerve (CN) deficiency, and congenital brain anomalies , are higMany genes have been found as the molecular causes of AN , with heThis study enrolled 75 unrelated patients with AN who received cochlear implantation. Outcomes of CI in patients were evaluated through auditory assessment, speech audiometry, and questionnaires, including categories of auditory performance (CAP) and speech intelligibility rate (SIR). Meanwhile, for 46 patients, medical exome sequencing was performed for genetic testing. The molecular etiology of this specific patient subgroup was thoroughly elucidated. Furthermore, examining candidate factors, including hereditary influences that may affect the IC outcomes of individuals with AN, was also assessed to provide more reliable information for the decision of the rehabilitation approach for AN.2.2.1.In this study, 84 patients diagnosed as AN and received CI in Chinese PLA General Hospital from 2010–08 to 2020–11 were enrolled. Exclusion criteria were: (1) having a tumor , (2) severe cognitive abnormality hampering speech development, (3) otitis media, and (4) loss to follow-up. Finally, 75 subjects were included. The Ethics Committee of Chinese PLA General Hospital approved this study. It was conducted as per the Declaration of Helsinki. Written informed consent was obtained from the participants or the parents of the minors.2.2.Auditory brainstem responses (ABR), distortion-product otoacoustic emissions (DPOAE), cochlear microphonics, and tympanometry were conducted to diagnose AN. Pure tone audiometry (PTA) was used for auditory threshold determination in subjects >5 years old who could complete this testing; behavior audiometry was performed in subjects ≤5 years old, including strength vision audiometer (subjects >1 and ≤ 2.5 years old) and play audiometer (subjects >2.5 and ≤ 5 years old). ABR and auditory steady-state response (ASSR) were measured for patients who could not undergo the aforementioned auditory tests. The degree of hearing loss was determined by the average threshold at frequencies of 0.5, 1, 2, and 4 kHz or response thresholds in ABR. The level of HL was graded as mild (26–40 dB), moderate (41–55 dB), moderately severe (56–70 dB), severe (71–90 dB), and profound (>90 dB). To evaluate the hearing sensitivity pre-operation and post-operation, categories of auditory performance (CAP) were also used.Hierarchic speech audiometry was estimated based on patients’ age and their capability of hearing and speech. The Mandarin Early Speech Perception (MESP) test was performed for patients aged 2 to 5 years to evaluate the children’s recognition of words. The Mandarin Pediatric Speech Intelligibility (MPSI) test was chosen for patients aged 3 to 6 years to assess the children’s perception of sentences . Speech 2.3.In order to assess the condition of the inner ear and auditory nerve, a comprehensive diagnostic approach was employed, which included high-resolution computed tomography (CT) scanning of the temporal bone, magnetic resonance imaging (MRI) of the brain, and magnetic resonance hydrography (MRH) of the inner ear.2.4.The genetic cause of patients was identified through medical exome sequencing (Trio exome sequencing was performed for probands whose parents’ DNA samples were available). The peripheral blood was obtained, and DNA was extracted according to the standard protocol. DNA sequencing , bioinformatics analysis, and variant interpretation were performed following an earlier described protocol . Copy nu2.5.U test in SPSS Statistics 25 was applied for significance analysis. The statistical significance was defined as p < 0.05.Mann–Whitney 3.3.1.Of the 75 patients enrolled here, 61 had prelingual HL with the onset or awareness age ≤ 3 years old, and the remaining 14 subjects had post-lingual HL (>3 years old). Among this subgroup, the onset or awareness age of HL in 13 patients ranged from 3 to 16 years of age. Unilateral AN was identified in three cases, with sensorineural HL determined in the contralateral ear. The average implantation age was 2.67 ± 2.17 years for subjects with prelingual HL and 20.29 ± 8.44 years for patients with post-lingual HL. Bilateral implantation was conducted in eight cases with the same type of device .3.2.n = 3), neonatal hyperbilirubinemia combined with Kawasaki syndrome (n = 1), neonatal hyperbilirubinemia combined with favism (n = 1), neonatal RH hemolysis combined with acute bilirubin encephalopathy (n = 1), meningitis (n = 1), neonatal septicemia combined with intrauterine distress and mixed acidosis (n = 1), hypoxic–ischemic encephalopathy (n = 1), premature (n = 1), trauma (n = 1), expose to ototoxic medicine (n = 1), hydrocephalus (n = 1), and development delay (n = 1)  .Based on imaging results, 10 patients had bilateral cochlear nerve (CN) deficiency, including hypoplastic CN and absent CN; two cases had a bilateral cochlear malformation, and another case had enlarged vestibular aqueduct (EVA) .n = 1) and unilateral renal agenesis (n = 1).Other relevant comorbidities included epilepsy , were normal as A type. For the ABR test, 140 ears had no response to stimulants , while the response threshold of the remaining seven ears ranged from 75 dB to 100 dB. Of 74 left ears, 9, 9, 9, 26, 33, 28, 40, 37, 39, 38 ears passed DPOAE at frequencies 0.125, 0.25, 0.5, 1, 2, 1.5, 3, 4, 6, 8 kHz, respectively, while 7, 7, 8, 26, 34, 33, 39, 38, 38, 35 of 73 right ears passed DPOAE at frequencies as mentioned above, respectively. In 58 left ears and 55 right ears, cochlear microphonics waveforms were detected.3.4.n = 56) are shown in Of the patients with prelingual HL (61 subjects), behavior audiometry was completed in 20 cases, with the average hearing threshold being 98.38 ± 16.28 dB for left ears and 102.56 ± 17.14 dB for right ears ,B. ASSR n = 5) for this subgroup by speech audiometer, indicating profound speech disabilities.For the remaining 14 cases with post-lingual onset, the average hearing threshold through PTA was 79.08 ± 15.11 dB for left ears and 74.83 ± 22.58 dB for right ears ,G. At th3.5.n = 56) improved from 0.29 ± 0.73 to 5.52 ± 1.64 (p < 0.001), and the SIR score (n = 61) increased from 1.00 ± 0.00  to 3.57 ± 1.22 (p < 0.001)  . Five pa< 0.001) .n = 11), the average hearing threshold after CI through pure tone audiometry improved from 78.33 ± 17.34 dB to 32.58 ± 9.26 dB (p < 0.001) (n = 6) was enhanced from 0.50 ± 1.03 to 6.00 ± 0.96 (p < 0.001), and SIR score (n = 13) increased from 1.15 ± 0.48 to 4.15 ± 0.95 (p < 0.001)  . CAP sco< 0.001) . In this< 0.001) .3.6.OTOF in 13 prelingual onset patients and AIFM1 in three cases of post-lingual hearing loss. Genetic testing results are presented in In this study, 46 patients  participated in genetic testing using high throughput sequencing. When only pathogenic or likely pathogenic variants were considered, molecular etiologies were identified in 25 patients , with two leading responsive genes being 3.6.1.OTOF attributed to CI, CAP score (n = 10) improved dramatically from 0.10 ± 0.32 to 6.20 ± 1.32 (p < 0.001), and SIR score (n = 13) increased significantly from 1.00 ± 0.00 to 3.83 ± 1.10 (p < 0.001), while in proband 71, SIR score increased to 2 after the operation, which indicated the poor effect of CI.Of 13 patients caused by mutations in 3.6.2.AIFM1. In case 46, the average hearing threshold improved from 78.25 dB to 40 dB, the CAP score increased from 0 to 3, and the SIR score improved from 1 to 5 after three years of operation. In case 51, the speech recognition score of monosyllables, disyllables, and sentences in quiet was 0, 0, and 0% before implantation. In comparison, the score was 82, 88, and 98%, respectively, after 1.5 years of implantation in the left ear. In patient 68, the CAP score increased from 2 to 5, and the SIR score increased from 1 to 3 after one year of implantation.In three subjects , simple hearing loss was identified to be caused by mutations in 3.6.3.TIMM8A were detected in patients 61 and 70, respectively. Case 61 was found to have progressive hearing impairment at two years old, and he had no other obvious abnormalities until this report. After six months of implantation in the right ear, his average hearing threshold improved from 116.25 dB to 40 dB, his CAP score increased from 0 to 5, and his SIR score increased from 1 to 4. Case 70 was noticed to have hearing loss at two months old, with the molecular diagnosis being established at the age of one year. The maternal aunt of Proband 70 also had hearing loss with the same pathogenic variant as Proband, which was revealed when he was 30. Case 70 and his maternal aunt had no other obvious abnormalities. After one year of implantation in the left ear, the average hearing threshold of case 70 improved from 91.25 dB to 36.25 dB, the CAP score increased from 0 to 6, and the SIR score rose from 1 to 3.Two mutations in 3.6.4.ATP1A3 (p.Glu818Lys)   was foun3.6.5.TWNK gene were detected. He walked unsteadily and fell quickly after three years old; both eyes had strabismus and astigmia when he was four years old and progressive hearing loss at half past five years old. He was later diagnosed as AN with profound hearing impairment. His speech, understanding, emotion management, and body development were delayed. The sibling of Proband had similar clinical manifestations and had the same compound heterozygote variants in TWNK. Accordingly, these two siblings were diagnosed with Perrault syndrome. For the Proband, after one year of implantation, the average hearing threshold improved from 98.75 dB to 38.25 dB, and vowel, consonant, disyllable, and tone recognition scores in the quiet field were 36, 36, 36, and 56%, respectively. In contrast, the speech recognition rate was 0% for all subtests before CI by the MESP test. The CAP score increased from 0 to 6, and the SIR score improved from 1 to 3 after two years of implantation.In case 22, compound heterozygote variants in the TWNK gene were also identified in this patient. The CAP score increased from 1 to 4, and the SIR score rose from 1 to 3 after two years of implantation.Case 30 had congenital hearing loss combined with ovarian dysfunction, manifested as primary amenorrhea and undeveloped mammary gland. Compound heterozygote variants in the 3.6.6.TWIST1 gene (rs104894054). Accordingly, the patient was diagnosed as having Saethre-Chotzen syndrome. The average hearing threshold improved from 102.5 dB to 35 dB, the CAP score increased from 0 to 5, and the SIR score was raised from 1 to 2 after six months of implantation . In addition, three variants with uncertain significance were also detected in this patient, including c.3041C>T in MYO7A (NM_000260.3), c.1007G>T in USH1C (NM_001297764.1), and c.1461G>T in PDZD7 (NM_001195263.1), which was inherited from father, mother, mother of this patient, respectively. Profound hearing loss was observed when case 56 was one year old, and the parents of this case reported no other abnormalities until this report. After four years of implantation, the average hearing threshold improved from 97.75 dB to 30 dB after implantation of half years. The CAP score was increased from 0 to 7, and the SIR score was raised from 1 to 5.Trio exome sequencing found a pathogenic 3.7.n = 74) before and after CI, candidate impact factors on speech performances attributed to CI were analyzed, including the age of onset, age of implantation, with or without risk factors, with or without CN deficiency, bilateral or unilateral implantation, etc. (p = 0.671), subjects with an interval time between onset age and implantation age less or more than three years (p = 0.502), subjects with or without risk factors (p = 0.925), and subjects with bilateral or unilateral implantation (p = 0.394); while speech outcomes of patients with no CN deficiency were better than those of subjects with CN deficiency (p = 0.008). As for subjects with prelingual and post-lingual hearing loss, there was no significant difference in speech outcomes after CI (p = 0.260), but for speech performances before IC, patients with post-lingual onset were better than that of subjects with prelingual onset (p = 0.002).In this study, based on SIR score . Furthermore, there was no significant difference in speech performance for subjects with OTOF variants and subjects with remaining genetic lesions (p = 0.503).Similarly, 46 patients participating in the genetic testing had no significant difference in speech outcomes between subjects with or without positive genetic etiology  was identified. The wild type of this variant was highly conserved among species  is also associated with Baraitser–Winter cerebrofrontofacial syndrome. Clinical presentations of this syndrome identified sensorineural hearing loss . Similarly, it has been reported that two of four CAPOS patients caused by the same mutation as we have identified in this study have markedly benefitted from CI . Other risk factors were identified in 14 patients, and the leading factor was neonatal hyperbilirubinemia. Molecular diagnosis was established in 25 (54.35%) of 46 patients participating in the comprehensive genetic testing.In conclusion, 82.67% (62/75) of enrolled patients in the present study could benefit from CI . Ten patients were CN deficient whose speech performances after CI were poorer than those who were not CN deficient (The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving humans were approved by the Ethics Committee of Chinese PLA General Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.JW: Formal analysis, Investigation, Writing – original draft. JC: Formal analysis, Investigation, Writing – original draft. ZD: Data curation, Writing – original draft. JF: Data curation, Writing – original draft. QW: Formal analysis, Writing – original draft. PD: Conceptualization, Writing – review & editing. DH: Conceptualization, Writing – review & editing.


Learners living with hearing impairment are at a higher risk of visual impairment.To summarise relevant literature investigating the prevalence and causes of visual impairment amongst learners living with hearing impairment in sub-Saharan Africa.A search of nine databases and the reference lists of retrieved studies were conducted using the standard methodology for scoping reviews as described in the PRISMA statement. The databases were MEDLINE, PubMed, EMBASE, the Cochrane Library, Global Health, OVID, Google Scholar, Web of Science, and Science Direct. A scoping review of articles published in the English language from 2000 to 2020 was conducted while considering the study design, sub-Saharan Africa, and school for the deaf. Descriptive statistics was used to analyse the data.The initial search retrieved eight studies, seven of which met the set inclusion criteria. All seven studies included employed a cross-sectional design. The prevalence of visual impairment ranged from 2.2–34.6% with the major cause being uncorrected refractive error (7.9–73.26%). The most common type of refractive error was myopia (42.2%) followed by hyperopia (28.6%) and astigmatism (28.6%).This review has demonstrated that there is a paucity of high-quality and well-designed studies that have investigated the prevalence and causes of visual impairment amongst hearing-impaired children in sub-Saharan Africa suggesting the need for further research in this area. The most significant causes of visual impairment amongst children is uncorrected refractive error accounting for 47 – 92% of all ocular morbidities (any eye condition regardless of resultant vision loss).Reports suggest that the prevalence of ocular morbidities and refractive error amongst children with hearing impairment is 5 - 90.1% and 7.2 - 62.65%, respectively.17There still exists the lack of scientifically rigorous studies that have investigated the prevalence and causes of visual impairment amongst learners living with hearing impairment in sub-Saharan Africa. Therefore, the aim of this scoping review is to evaluate published scientific research studies on the prevalence and causes of visual impairment in children living with hearing impairment in terms of their visual acuity status, causes, interventions provided/suggested and limitations of the studies.This study was conducted using the recommended search strategy as described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Inclusion criteria were based on the PICO tool, articles published in English, date of publication (2000–2020), study design, sub-Saharan Africa and school for the deaf. Unrelated articles, abstract-only papers, duplicates, related studies outside the study setting were excluded.Nine databases were used in this study that met the guidelines of assessment of multiple systematic reviews (AMSTAR). 32The initial search yielded a total of eight records, but seven studies met the inclusion criteria. The study which was excluded was conducted in special schools among participants with intellectual, visual, hearing, physical and multiple disabilities with no distinct classification of visual impairment among the different groups.The analysis was based on the seven studies that met the inclusion criteria see . All theIn Nigeria, Osiayuwu and EbeigbeIn 2013, Ovenseri-Ogbommo et al.,This is the first literature review to report on the causes and prevalence of visual impairment amongst learners with hearing impairment in sub-Saharan Africa. The prevalence of ocular morbidities was high, with the leading cause being refractive error. Allergic conjunctivitis was the second most common cause of ocular morbidities. In sub-Saharan Africa, eye care delivery is unevenly distributed due to inadequate equipment and skilled personnel, with most of the secondary and tertiary eye care institutions located in major urban centres and national capitals.42The prevalence of ocular morbidity was high (20.9–73.26), which can remain undetected and impact the learners' academic pursuits. The high prevalence can be reduced through periodic eye screening, better screening protocols amongst the learners, and awareness of eye health among caretakers such as parents and teachers since these learners rely primarily on visual cues. Furthermore, an increase in the workforce in eye care can reduce the prevalence of ocular problems among these learners. The common ocular disorder was refractive error which is consistent with other reviews among learners with hearing impairment.All the seven studies provided evidence for the type of refractive error. Studies by Osiayuwu and EbeigbeA number of indicative findings and recommendations emerged from this study;1 A recommended definition and classification of visual impairment and refractive error should be used in reporting research findings.2 Researchers should classify the types of hearing impairment  and deaf among learners in the Schools for the Deaf. Knowing the specific impairment will inform stakeholders on the plight of the learners and their management.3 Corresponding authors should be contacted to clarify any inconsistencies in their articles to avoid citing different prevalence rates.4 There is a need for more research involving learners with hearing impairment across sub-Saharan Africa and classifying them according to their impairment to meet their visual needs. Learners with hearing and visual impairment would require special teaching and learning environment to improve their quality of life.This study reflects a high prevalence of avoidable ocular morbidities and visual impairment amongst learners with hearing impairment, with refractive error as the main cause. This information can provide the evidence to justify and inform planning, policies and management strategies amongst learners living with visual and hearing impairment in Ghana and Nigeria. This data also provides evidence from which the priorities and scope for further research amongst learners with hearing impairment in SSA can be planned.


Telocytes are a new type of interstitial cell with a diverse morphology and important functions, such as mechanical support, signal transduction, immune regulation, and tissue repair. In this paper, the origin and physiological and pathological functions of telocytes as well as their role in inflammation will be discussed, and the functions and targets of telocytes in inflammation will be fully reviewed, which may contribute to a new therapeutic strategy for inflammatory diseases in the future. TCs form homocytic or heterocytic contacts through TPs, thereby forming three-dimensional network structures and transmitting signaling molecules through prosecretory and/or paracrine binding to enter the vascular, neural and endocrine systems by the outgrowth and shedding of vesicles. In this interaction, organelles, mRNA, microRNA, long-stranded noncoding RNA and genomic DNA are subsequently transferred to play a role in signal transmission. In addition to signaling, TCs also participate in various physiological and pathological processes, such as the immune response, inflammatory response, angiogenesis and invasion and metastasis of cancer cells. Besides, TCs were shown to function as crucial components of the stem cell niche. Telocytes may become an effective means of clinical treatment of inflammatory diseases, malignant tumors and other diseases.Telocytes (TCs), which are of mesenchymal origin and are resident connective tissue  cells, were first discovered by Prof L.M. Pescu in 2005 under transmission electron microscopy (TEM). Their structures are similar to those of interstitial cells of Cajal (ICCs), and they were called interstitial Cajal-like cells. After further study, researchers found that TC markers were obviously different from ICC molecular markers, so they were renamed telocytes. TCs are widely found in several mammalian tissues and organs, and their cytosomes are diverse, with dendritic, ellipsoidal, pear-shaped and polygonal forms predominating. TEM has revealed TCs with elongated cytoplasmic protrusions called telopods (TPs), and each TC has one or several TPs . The TPs are not uniform in their thickness all along and show narrow zones (podomers) and thickenings (podomes),6 vessels, the trachea and lungs,,9 gallbladder, liver, Intestinal tissues, duodenum, colon, and spleen, and they are also found in the male genitals including the testis, and epididymis,as well as the female genital organs and the uterus,,19 oviduct, and placenta. In addition, TCs are also found in the pleura, skin, parotid glands, skeletal muscle,,25 and epithelium. After more than 20 years of exploration, TCs have been shown to exist in almost all tissues and organs.TCs are widespread in a variety of tissues and organs, such as cardiac tissues, For example, in human myocardial tissue, TCs are negative for nestin, CD13 and S-100 immunohistochemical indicators, but are positive for CD34, CD117, vimentin, and epithelial cell growth factor immunohistochemical indicators. In addition, TCs positive for CD34, C-Kit, and vimentin expression were found in human aortic, mitral, and tricuspid valves, which can form a 3D scaffold network within the heart valves and provide mechanical support. Moreover, as a major component of the endocardial “blood-heart barrier,” TCs participate in the cellular network and play a role in signaling, promoting myocardial repair and regeneration and immune surveillance, in addition to mechanical support.,30 In human bladder tissue, 3 subtypes of TCs are distinguished by immunohistochemistry, and the subtypes differ in their expression of the same immunohistochemical markers in the same tissue. The subtypes of TCs in the submucosa and detrusor of the bladder are positive for CD34 and negative for α-smooth muscle actin, platelet-derived growth factor receptor alpha (PDGFR-α) and CD117. In the respiratory system, TCs are mainly distributed among the basement membrane of the fine bronchial epithelium, clusters of airway smooth muscle cells in the muscular layer, respiratory epithelium at the bronchoalveolar junction, and clusters of peripheral vessels, nerves, and stem cells, and in the above tissues, TCs show positive expression of CD34 and C-Kit and play a role in cellular communication and structural support. In addition, TCs express different positive biomarkers in the reproductive and digestive systems as well as in the skeleton and skin. A study found that miRNA may be a means to differentially discriminate TCs from other cells, and miR-193 was shown to be differentially expressed between TCs and other interstitial cells. In addition, reseachers have found that cardiomyocytes and other muscle cell-specific miRs  are absent in TCs, which confirms the specificity of TCs and may be an important method to differentiate them from other interstitial cells. Although no specific molecular markers for TCs have been identified, the commonly used molecular markers are summarized as follows: C-Kit, CD34, CD117, vimentin, PDGFR-α, caveolin-1, vascular endothelial growth factor, inducible nitric oxide synthase, and so on.–37Although TCs are distributed in the digestive, cardiovascular, respiratory, nervous, reproductive and urinary systems, as well as in the skin and skeletal muscle, there are tissue differences in the molecular markers they express, even within the same tissue and their specific role depends on different tissue distributions. In the cardiovascular system: because of the presence of a specific electrochemical gradient barrier exists in the endocardium, that is, the blood–brain barrier, and TCs are an important component of this barrier and are involved in the formation of a three-dimensional myocardial network and in intercardiac signaling and myocardial repair. TCs are able to support myocardial tissue and adult heart redevelopment as support cells and are the connecting and communicating cells of cardiac myocytes. In the respiratory system, TPs establish interstitial synapses with mast cells and participate in the regulation of tracheal secretion and contraction together with mast cells. In addition, ectopic pacing of the heart mainly originates from the myocardial sleeve of the pulmonary vein (PV), and TCs, as potential mechanoreceptors in the PV, can affect the pacing of the heart by sensing changes in PV pressure that trigger changes in nonselective cation currents and Cl- currents in cardiomyocytes. The number of TCs in the lung is constantly changing during development from the fetal stage to adulthood, during which TCs are involved in lung angiogenesis, the formation of the air-blood barrier and lung tissue growth and development. In the digestive system, TCs not only participate in the construction of the three-dimensional network and the formation of the microenvironment, but also influence the contraction of smooth muscle and the movement of the gallbladder.,45 In the reproductive system, TCs are present in the middle layer of the myometrium, which is considered the regulatory center of the myometrium and is responsible for receiving signals from the autonomic nerves and transmitting them to the cells of the myometrium through TCs; and studies have been performed on the release of certain stimulating factors by TCs that act on the myofibroblasts during the contraction of the uterus, thus causing the ion-activated channels in the myofibroblasts to function and causing muscle contraction, thereby participating in the regulation of blood flow and muscle contraction in the myometrium. In the urinary system, TCs are not only involved in the urinary reflex of the bladder and the dilatory movement of the bladder wall, thereby maintaining the normal three-dimensional structure of the testes, but they are also an important component of the blood-testis barrier and are involved in the regulation of spermatogenesis. In skin and skeletal muscle, TCs can integrate skeletal muscle fiber regulation and affect the regeneration of skin and skeletal muscle.,48,49TCs are involved in tissue renewal, mechanical support, and immune modulation, In the field of oncology research, TCs are involved in the formation of PDGFR-α mutation-associated gastrointestinal tumors. During the formation of these tumors, proteomic methods and gene sequence mutation detection have confirmed that TCs show reduced numbers, morphological changes and even nuclear sequence destruction during the formation of gastrointestinal mesenchymal tumors. Although this study did not find a clear pathogenesis of TCs in the process of tumor formation, it gives us important hints for the next steps in studying tumor formation. In the interstitial matrix between liver parenchymal cells of human liver tissues, TCs are heterogeneous, and alterations in their function are obvious, especially when liver fibrosis, liver tumors and inflammation occur, suggesting that TCs play an important role in the development of liver diseases. In a study on hepatocellular carcinoma (HCC), the expression of matrix metalloproteinase-9 in TCs was found to promote the metastasis of HCC. It was found that PDGF-α secreted by HCC activated the Ras/ERK signaling pathway in TCs and increased the expression of matrix metalloproteinase-9, which in turn accelerated the invasive metastasis of HCC.,54 There is a large distribution of TCs and TPs between the submucosa and smooth muscle cells in bladder cancer. However, TCs and TPs are scarce in the neurogenic bladder. In addition, it was found that TCs in normal tissues with ezrin expression may compete for invasiveness and may be an indicator that can be used to reduce the recurrence rate of bladder cancer. Thus, TCs and ezrin may serve as predictors of bladder cancer invasiveness and recurrence. In fibrosis, when pathological loss occurs, the number of fibroblasts increases, producing large amounts of extracellular matrix (ECM) that disrupts tissue integrity. A study showed that TCs can synthesize ECM in response to hormonal stimulation and can interact with neighboring cells to produce exosomes and transmit intercellular biological signals.,56 TCs have a potential role in the development of systemic fibrotic diseases and are important for improving the therapeutic outcome of related diseases. In a study of lymphedema, transplantation of TCs into lymphedema-damaged tissues promoted regeneration of the damaged tissues. It has been shown that TCs not only promote fibrosis reversal but also increase the number of TCs expressing the immune marker CD34+. Promoting the survival and growth of TCs by stimulating them in new ways or using new drugs may be a therapeutic strategy for the treatment of lymphedema fibrosis. In the field of dermatology, TCs are closely associated with or in contact with fibroblasts, papillary cells, adipocytes, collagen bands and elastic fibers, and their density and distribution are influenced by pathological conditions of the skin, such as psoriasis and systemic sclerosis.,57 In addition, normalization of TC numbers is associated with disease remission and is involved in the process of skin tissue repair and revascularization.,59 In a rat experiment on myocardial infarction, TCs were found to inhibit myocardial microvascular endothelial cell apoptosis by targeting Cdip1 silencing through exosomal miR-21-5p to inhibit myocardial infarction angiogenesis.,61 In addition to affecting angiogenesis, TCs show strong immunoreactivity toward APG5, transforming growth factor beta and nuclear factor erythroid-2-related factor 2; affect phagocytosis and autophagy; and may also be involved in cell differentiation and regeneration. Endometriosis involves the survival and growth of glands and stroma outside the uterine cavity and is a common benign inflammatory gynecological disease. TCs play a potential role in endometriosis by affecting the inflammatory response, invasion and angiogenesis and may be a potential therapeutic option for endometriosis.TCs act as a network organization for building the three-dimensional structure of tissues, providing a “scaffold-like” structure for tissue remodeling, providing mechanical support, mediating cell signaling, directing and caring for immature cells during organogenesis, and serving as a precursor for many mesenchymal-derived cells during adulthood. In addition, TCs are involved in regulating the progression of many diseases and are key players in the regeneration and repair of many organs. A report has found a significant increase in the TC concentration in tissues of chronically injured patients compared to healthy controls, which reduced the delay in wound healing, and the inflammatory response induced by LPS can be mediated by inflammatory inhibition, thereby limiting apoptosis, promoting skin cell proliferation and migration, and accelerating inflammatory repair. The following is a comprehensive description of the inflammatory response involving TCs.TCs are involved in a range of inflammatory responses in addition to a variety of pathological processes, such as cancer cell invasion and metastasis, vascular regeneration, and fibrosis reversal. Evidence has indicated that TCs may help prevent abnormal activation of immune cells and fibroblasts, attenuate changes in stromal tissue during fibrosis, promote regeneration and prevent the evolution of irreversible tissue damage. In the near future, TCs may offer new therapeutic opportunities to control the development of chronic inflammatory and fibrotic diseases.The development and activity of the immune system is coordinated by cytokines, which are small, short-lived proteins necessary for paracrine, autocrine and endocrine signaling. TCs have their own cytokine profile and may influence the secretion of macrophages and B cells. The development of inflammation is the result of complex interactions between immune and nonimmune cells, tissue resident cells, and mesenchymal cells. TCs, as mesenchymal cells newly discovered in recent years, can prevent the abnormal activation of immune cells to control chronic inflammation and are active players in immune regulation and immune surveillance.,68 Moderate exercise in early myocardial infarction increases the number of myocardial TCs in the marginal zone but not in the infarct zone and improves postinfarction angiogenesis, fibrosis, and ventricular remodeling. Therefore, new strategies to effectively limit myocardial cell and TC death in the infarct zone are essential for myocardial infarct regeneration.TCs can affect the activity of immune cells through direct heterocellular connections or indirect paracrine effects and thus participate in local inflammatory processes or immune responses. A study on acute myocardial infarction in rats found severe TC death in the infarcted area of the heart, with a significant reduction in TC numbers.Experimental autoimmune encephalomyelitis (EAE) is a common inflammatory disease of the brain, and the expression of CD34+ in TCs was found to be significantly upregulated in the spleen of mice with EAE, and CD34+ TCs were shown to be involved in the regulation of immune response after spleen injury, specifically by recruiting of macrophages and proliferating stem cells and promotings tissue repair and regeneration in mice with EAE. Therefore, combined transplantation of TCs and stem cells may be a promising therapeutic strategy for the treatment and prevention of multiple autoimmune and chronic inflammatory diseases. TCs may promote the migration of mesenchymal Schwann cells (MSCs) to lung tissue, the survival of MSCs in lung tissue, and the therapeutic effects of MSCs on asthma by altering inflammatory cells and mediators. The treatment of experimental asthma by TCs was found to increase systemic and local transforming growth factor beta production and to alter the ratio of Treg cells. The interaction between TCs and Treg cells may be a key part of the cellular mechanism by which TCs ameliorate allergen-induced airway inflammation and hyperresponsiveness. Intravenously transplanted TCs significantly inhibit airway inflammation and airway hyperresponsiveness.In the lungs, TCs are mainly distributed in the alveolar wall within the capillaries and are partially located in the interstitial space.Th1/Th2 imbalance is thought to be the pathogenesis of asthma. It has been found that TCs can affect the Th1/Th2 balance by downregulating the expressing of the Th2-related cytokines interleukin-4 and GATA binding protein 3 and Th2 cell differentiation and upregulating the expressing of the Th1-related cytokines IFN-γ and T-bet. Experiments have shown that TCs can maintain lung anatomical structure and function and provide a new alternative for the treatment of lung diseases.TCs in the lung have a specific connection with air–liquid epithelial cells, tolerance to movement and pressure, and flexibility among barriers. Dongli Song successfully constructed a mouse lung TC cell line that was clearly able to maintain the biological properties and behavior of primary TCs and to respond to lipopolysaccharide (LPS)-induced inflammatory responses. With LPS as a stimulus for infection and TNFα as an inflammatory mediator, the proliferative capacity of TCs was found to decrease with increasing LPS/TNFα concentration. There is evidence that prolonged exposure of intestinal fibroblasts to inflammatory mediators may contribute to their conversion to activated myogenic cells expressing α-smooth muscle actin, leading to abnormal collagen production and tissue remodeling. However, inflammation also appears to play a secondary role in fibrotic progression, so anti-inflammatory therapy may not limit intestinal fibrosis once the ECM is overdeposited. Notably, the number of TCs and TPs is negatively correlated with the amount of mature fibrillar collagen and is positively correlated with degraded collagen. A significantly reduced TC abundance was found in the mucosal myenteric and submucosal layers of the colonic wall in early and advanced UC. A normal distribution of TCs was observed in the intrinsic muscular layer in early UC, but TCs were reduced or even completely absent in the fibrotic area of the muscular layer and around the myenteric ganglion in advanced UC. Excessive deposition of ECM and the progressive reduction of TCs may alter the spatial relationships of TPs with neighboring immune cells, fibroblasts, smooth muscle cells, and neural structures, impairing intercellular signaling and function. Progressive loss of TCs in the intestinal wall leads to alterations in the three-dimensional organization of the ECM, which may accelerate the fibrotic process. In the intestine, the three-dimensional network of TCs is also thought to play specific mechanical and supportive roles in different layers of the intestinal wall, with resistance and deformability of the network affecting intestinal motility.,76,77 More importantly, in the lamina propria, TCs and ICCs may form interconnected networks around smooth muscle bundles and myenteric plexus ganglia, and the reduction in TC and ICC networks within the neuromuscular compartment of the intestinal wall may largely contribute to the gastrointestinal motility disorders in patients with Crohn disease and UC.Inflammatory bowel disease, including Crohn disease and ulcerative colitis (UC), is a widespread autoimmune disease. In inflammatory bowel disease, inflammation tends to evolve into tissue fibrosis, which is closely related to the distribution and site of inflammation.,80 The late stage of SSc mostly shows severe fibrotic skin changes, irregular tight accumulation of collagen bundles, loss of capillaries, occlusion of small arteries and nerve fiber damage. In a study on the involvement of TCs in skin injury diseases, researchers found that TCs inhibit the release of inflammatory factors and promote the migration of epithelial cells in injured skin tissues, and this effect is achieved by influencing TC tropism through the LPS-related protein signaling pathway.,65 TCs are normally present around perivascular inflammatory infiltrates in the reticular dermis but are absent when these infiltrates are located in the papillary dermis. It is also hypothesized that TCs may be involved in maintaining local tissue homeostasis by controlling fibroblast/myocyte activity. Future studies could focus on typing perivascular and perivascular TCs distributed in the reticular dermis in the disease state and assessing the possible role of TCs in preserving and regulating inflammatory cells in the perivascular space.–83Systemic sclerosis (SSc) is a chronic connective tissue disease. In the early stages of SSc, the main histopathological features of the skin are perivascular inflammatory infiltration, dermal edema, and varying degrees of ECM accumulation in the papillary and reticular dermis. Therefore, it has been suggested that loss of perivascular TCs may be important in the characteristic vascular pathology of psoriasis.Psoriasis is also a common inflammatory skin disease that is mainly considered a keratosis with a genetic predisposition. In psoriasis, TEM shows the presence of apoptotic distal cells with nuclei, dystrophic distal cells with broken TPs, and even TCs with nuclear extrusion, membrane disintegration, and cytoplasmic breakage. It was found that in small vessels that have lost the protective membrane formed by TCs, the phenotype of the vascular smooth muscle cells undergoes profound changes.,86 As novel mesenchymal cells, TCs play a crucial role in promoting angiogenesis and increasing endometrial mesenchymal and inflammatory cell activity. Moreover, TCs can be involved in the structural and functional abnormalities of the fallopian tubes, specifically the changes in diseased tubal tissues, such as those of the aseptic inflammatory disease endometriosis and infectious acute salpingitis. In the tubal tissues of acute salpingitis, multiple ultrastructural impairments in TC bodies and TPs are seen, accompanied by significant TC loss and elevated collagen content. Similarly, TC damage was also found in the tubal tissues of endometriosis. In contrast, TC damage in the fallopian tube may lead to impaired immunomodulation/immunosurveillance, diminished intercellular signaling and tubal constriction.Endometriosis, pelvic inflammatory disease and tubal inflammatory disease are the most common gynecological inflammatory diseases and are important causes of female infertility. Studies have shown that immune cells such as monocytes and macrophages play an important role in the local peritoneal immune response in endometriosis or pelvic inflammatory disease, and their dysfunction or abnormal changes in their numbers may alter smooth muscle movement and the microcirculation in endometriosis, leading to pelvic pain and even infertility.Inflammation and ischemia can cause extensive ultrastructural damage to TC cell bodies and TPs, with significant TC loss and interstitial fibrotic remodeling. Such pathological changes may lead to structural and functional abnormalities of the tubal tissue and even to infertility. In normal and diseased tissues, TCs are linked to various activated immune cells that may be involved in local immune regulation (suppression or activation) and may be a cause of immune-mediated pregnancy failure. An in vitro TC study has shown that TCs can activate peritoneal macrophages in mice and subsequently trigger the secretion of inflammatory cytokines, among other factors, suggesting that TCs are not merely innocent bystanders, but potential participants in local immune regulation and immune surveillance.Telocytes, novel mesenchymal cells, are expressed in almost all tissues and organs. TCs have important functions such as mechanical support, signaling, immune regulation, and tissue repair. They not only participate in the balance of tissue homeostasis, but also participate in the pathophysiological process and tissue repair and regeneration of various diseases. In particular, inflammatory diseases and malignant tumor-related diseases have been widely studied in recent years. TCs play a vital role in some inflammatory diseases and may become a new choice for the treatment of inflammatory diseases. The experimental study of TCs is not yet deep enough and has been almost at a relative standstill in recent years, and many of the functions assigned to TCs do not originate from direct functional experimental validation. It is hoped that future studies will continue to deepen and find specific biological molecular markers of TCs, in order to better investigate its key role in physiopathological processes. In the future, we will explore the role of TCs in the development of ulcerative colitis and its mechanism of action, which may provide new ideas for the treatment of ulcerative colitis.Resources: Hu Tian.Writing – review & editing: Yuhua Zhang.