Zygomycoses caused by fungi of the mucorales order (mucormycoses) are emerging                    fungal diseases with a high fatality rate. The most important risk factors                    include neutropenia or functional neutropenia, diabetic ketoacidosis, iron                    overload, major trauma, prolonged use of corticosteroids, illicit intravenous                    drug (ID) use, neonatal prematurity, malnourishment, and maybe a previous                    exposure to antifungal agents with no activity against zygomycetes, such as                    voriconazole and echinocandins.A high index of suspicion is crucial for the diagnosis, as prompt and appropriate                    management can considerably reduce morbidity and mortality. Suspicion index can                    be increased through recognition of the differential patterns of clinical                    presentation. In the non- haematological immunocompromised patients,                    mucormycosis can manifest in various clinical forms, depending on the underlying                    condition: mostly as rhino-orbital or rhino-cerebral in diabetes patients,                    pulmonary infection in patients with malignancy or solid organ transplantation,                    disseminated infection in iron overloaded or deferoxamine treated patients,                    cerebral - with no sinus involvement - in ID users, gastrointestinal in                    premature infants or malnourishment, and cutaneous after direct inoculation in                    immunocompetent individuals with trauma or burns.Treating a patient’s underlying medical condition and reducing                    immunosuppression are essential to therapy. Rapid correction of metabolic                    abnormalities is mandatory in cases such as uncontrolled diabetes, and                    corticosteroids or other immunosuppressive drugs should be discontinued where                    feasible. AmphotericinB or its newer and less toxic lipid formulations are the                    drugs of choice regarding antifungal chemotherapy, while extensive surgical                    debridement is essential to reduce infected and necrotic tissue. A high number                    of cases could be prevented through measures including diabetes control                    programmes and proper pre- and post-surgical hygiene. The term ‘Zygomycosis’ refers to a group of rare infections caused by                hyaline filamentous fungi belonging to the class of Zygomycetes. This class is                subdivided in two orders, Mucorales and Entomophthorales, both involved in human                    disease.1Rhizopus, Mucor, Lichtheimia                (formerly known as Absidia corymbifera or                    Mycocladus), Rhizomucor,                    Apophysomyces, Saksenaea, and                    Cunninghamella.1Mucorales are saprobiotic organisms ubiquitous in nature; some members of this order                are weak plant parasites or plant pathogens and opportunistic pathogens for                    man.For Mucorales the portals of entry in the human body are the respiratory tract                through inhalation of fungal spores, the skin and less frequently the gut. They grow                rapidly and produce wide hyaline, aseptate or poorly septated ribbon-like hyphae in                tissues. They invade blood vessels and cause thrombosis and necrosis of the infected                tissues. Disease in humans is limited to severely immunocompromised individuals,                those with diabetic ketoacidosis, or those with burns or trauma. Infection usually                progresses rapidly and the case fatality rate is very high. Depending on the                underlying condition and the portal of entry they can cause rhinocerebral,                pulmonary, cutaneous, gastrointestinal or even disseminated infection.1Conidiobolus and                    Basidiobolus. They affect mainly immunocompetent individuals,                are prevalent in the tropics and do not disseminate.Human infections caused by Entomophthorales, which are mainly insect pathogens,                constitute a completely different clinical entity (entomopfthoramycoses). Genera                involved in human disease are The most important risk factors for mucormycosis include prolonged neutropenia,                diabetic ketoacidosis, iron overload and major trauma. Other important predisposing                factors of mucormycosis include prolonged use of corticosteroids, illicit                intravenous drug use, neonatal prematurity, malnourishment and broad-spectrum                antimicrobial agents, as well as antifungal agents with no activity against                zygomycetes, such as voriconazole and caspofungin.The recent years, mucormycosis incidence is seemingly increasing, particularly in                patients with haematological malignancies or haematopoietic stem cell                transplantation, at least in western countries.Diabetes mellitus as a predisposing factor has been reported in                        36–88% of all mucormycosis cases.26neutrophils are chemotactically attracted to the hyphae,they attach andspread on the hyphae and finally,using their oxidative cytotoxic system, neutrophils damage and                                    kill the fungal elements without accompanying phagocytosis.In the normal host protection from mucormycosis is provided by macrophages.                        They prevent the initiation of infection by phagocytosis and oxidative                        killing of the fungal spores. In case infection is established, neutrophils                        are activated and play a pivotal role in fungal killing. Activation happens                        in four phases: In diabetes, each of the four phases of neutrophil activation is                            impaired.29The most common clinical presentation of mucormycosis in patients with                        diabetes mellitus is sinus disease 66%).6%.6 Diab30Disease in diabetics can also present as pulmonary mucormycosis, a clinical                        presentation more common in neutropenic patients with malignancies or                            HSCT.6The epidemiology in diabetic patients is variable. Roden et al.The overall mortality of diabetic patients with mucormycosis who undergo                        treatment is approximately 44%, and this is lower compared to other                        immunocompromising conditions.37Besides diabetic ketoacidosis, chronic metabolic acidosis due to other                        causes, such as chronic renal failure with uremia,Many microorganisms require iron to grow, and conditions of iron excess have                        been known to predispose to infection with certain bacteria.43et                            al,48Therapy with DFO, an iron chelator used for the treatment of iron and/or                        aluminum overload in dialysis patients, was found paradoxically to be a risk                        factor for angioinvasive mucormycosis.Rhizopus spp. In a                        study reviewing a series of five cases of invasive mucormycosis among 263                        allogeneic bone marrow transplant recipients,Besides DFO, iron overload per se, either transfusional or due to                        dyserythropoiesis has also been recognized as a risk factor for                            mucormycosis.Patients with diabetic ketoacidosis have elevated levels of available serum                        iron, likely due to the release of iron from binding proteins in the                        presence of low pH. Iron is then internalized by the zygomycetes with the                        help of copper oxidase (Cu-oxidase) and the high affinity iron permease                        rFTR1. Therefore, the increased susceptibility of patients with diabetic                        ketoacidosis to mucormycosis is likely due, at least in part, to an                        elevation in available serum iron during diabetic ketoacidosis following                        proton-mediated dissociation of iron from transferrin.43The most common presentation of mucormycosis in patients receiving DFO                        appears to be the disseminated form (44%) and is associated with                        high mortality, reaching 80%.47In contrast to DFO, two other iron chelators, deferiprone and deferasirox, do                        not supply iron to the fungus. This could be either because of their                        different structures and smaller size, rendering them inaccessible to fungal                        iron uptake systems, or because they share higher affinity constants for                            iron.43The incidence of mucormycosis in transplant recipients, including both                        hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT)                        patients has increased. Although global surveys of the incidence of                        mucormycosis are still lacking, data from individual countries and                        institutions show that mucormycosis in SOT is rare, but seems to be a                        concern because of the high mortality rate.The estimated incidence ranges from 0.4–16%.Mycocladus (Lichtheimia)                            corymbifer as causative pathogen appeared to be                        associated with a higher risk for dissemination in SOT with pulmonary                        mucormycosis in one study.55The lung seems to be the most common site of infection in SOT recipients with                            mucormycosis.In a matched case-controlled studyMucormycosis in HIV/AIDS patients is very rare. Antinori et al.57Recently, human immunodeficiency virus (HIV) infection has been recognized as                        a risk factor for mucormycosis, but most cases in HIV-infected patients are                        also associated with intravenous drug abuse.Endocarditis as well as the rhinocerebral form can also occur. Merchant et                            al.Mucormycosis in the HIV+ can also present in the kidneys, the skin,                        the gastrointestinal tract, the respiratory tract, or may be                            disseminated.1Corticosteroid therapy is another primary risk factor that enhances a                        patient’s susceptibility to mucormycosis by causing either defects                        in macrophages and neutrophils or steroid-induced diabetes.1Corticosteroids have a wide range of complex immunosuppressive effects,                        mainly by affecting cellular immunity, and increase host susceptibility to                        invasive fungal infections.34Of the few cases of mucormycosis in patients with lupus erythematosus (SLE)                        reported in English language literature78Mucormycosis in other autoimmune diseases are scarce, but in cases such as in                        Wegener’s granulomatosis it may mimic disease relapse and remain                            underdiagnosed.94A considerable proportion of patients with mucormycosis have no apparent                        immune deficiency.Infection usually occurs through direct inoculation. It can be very invasive                        locally, penetrating the cutaneous and subcutaneous tissues into the                        adjacent fat, muscle, fascia and bone. In rare cases it can even disseminate                        to deep organs. Road traffic accidents, crush injuries, but also minor                        traumas such as those caused by plant thorns or insect bites, can lead to                        traumatic implantation of contaminated soil and subsequent mucormycosis.                        Major burn injury is another well described cause of cutaneous mucormycosis.                        An increased risk for developing mucormycosis in burn patients is the                        development of a condition called “burned stressed                        pseudodiabetes”, which is marked by hyperglycemia and                            glycosuria.97In a new PubMed search from 2008 – 2010, we found 27 additional cases                        of cutaneous mucormycosis occurring in non immunocompromised hosts.Pseudomonas, Aspergillus,                            Histoplasma etc. Biopsy specimens for histology and                        cultures are necessary to establish diagnosis.The clinical presentation is variable. The clinical signs initially are non                        specific, consisting of erythema and induration. Eventually the lesions may                        form blisters, pustules, or necrotic ulcerations. Cotton wool-like material                        may also be observed on the margins of the wound. The lesions may mimic                        pyoderma gangrenosum, bacterial synergistic gangrene or infections produced                        by Rhizopus spp. (the majority),                            Lichtheimia corymbifera , Apohysomyces elegans,                            Mucor spp., Cunninghamella                            bertholetiae and Saksenaea vasiformis. In the                        cases reported after 2008 the cultured species were R.                            arrhizus in 3 cases,Lichtheimia spp.in 5,A. elegans in 4,S. vasiformis in 3,Rhizomucor                            variabilis in 7.Rhizomucor, in contrast to other                        mucorales can cause large but slowly progressing opportunistic infections of                        the skin in immune-competent individuals. These fungi seem to have an                        increasing incidence in farmers from China.Strains involved are usually The prognosis of mucormycosis in the immunocompetent is better than that in                        other patient groups but mortality remains high depending on the site,                        extension of infection and time of initiation of antifungal therapy.                        Iatrogenic cutaneous mucormycosis could easily be prevented with proper                        preoperative preparation and postoperative dressing of the surgical                        sites.The clinical diagnosis of mucormycosis among non haematological immunocompromised                patients is notoriously difficult because of the similarity with aspergillosis or                other mycoses caused by filamentous fungi. Diagnosis is usually delayed, as the                majority of the physicians are not so much familiar with the disease. The leading                signs and symptoms of mucormycosis are presented in When clinical presentation may suggest mucormycosis, imaging techniques are helpful,                but cultures and histopathology are required for confirmation.In case of rhinocerebral involvement, CT and particularly MRI are helpful in enabling                an early detection of orbital, sinus, meningeal, bone, and cerebral lesions as well                as intracranial vascular occlusion even before clinical signs develop. In pulmonary                mucormycosis, lung biopsies  should be performed,                depending on the radiological findings obtained by CT scans. CT guided percutaneous                lung biopsy has been found highly efficient to early differentiate aspergillosis                from mucormycosis in haematological patients. Whatever the initial clinical site                involved, a sinus and chest CT are mandatory in addition to brain imaging. This is                of major importance for the indicated therapeutic approach.112The laboratory diagnosis of mucormycosis is challenging and requires expertise and                proper sampling. Proper clinical samples include scrapings and aspirates from                sinuses, nasal discharges, BAL, needle biopsies from pulmonary lesions, skin                scrapings from cutaneous lesions and biopsy tissues. Zygomycetes are almost never                isolated from blood and very rarely isolated from cultures of cerebrospinal fluid,                sputum, urine or faeces, or swabs of infected areas.113The significance of the isolates grown in cultures may be doubtful, especially when                grown from samples of non sterile sites, as they are commonly encountered as                contaminants. Histopathologic evidence of fungal invasion of tissue is required to                confirm clinical or radiological diagnosis and/or reliability of culture.Aspergillus spp. Histopathologic sections occasionally show                folded, twisted, and compressed hyphae, which may be mistaken for septated hyphae.                Sporangia, the reproductive hyphal structures that contain spores, are seen rarely                in tissue in patients infected with zygomycetes. These hyphae are poorly stained                with PAS and Gram stains but are very well seen by H&E, GMS, or                Periodic-acid Schiff stain. Hyphae may be observed within necrotic tissue and signs                of angioinvasion and infarction; neutrophilic infiltrates or granuloma formation may                be present in patients who are not granulocytopenic or with more chronic infection,                    respectively.114The direct microscopic examination of biopsy material in                10%–20% KOH and/or calcofluor-white wet mount shows                characteristic broad (6–15 μm in diameter), thin walled, mostly                aseptate, ribbon-like hyaline hyphae with almost right –angle branching at                irregular intervals. In tissue, Zygomycetes hyphae can be distinguished from the                regularly septated hyphae of more common opportunistic molds such as                    A. elegans. If all other media fail, sterile                bread without preservatives in a test tube may recover zygomycetes from clinical                samples, since these fungi are commonly associated with bread.Identification of zygomycetes at the genus and species levels requires culture                studies, because all members of this group are morphologically similar in tissue.                Poor recovery of Zygomycetes may reflect limited septation of the hyphae, making the                fungi more liable to damage resulting from tissue excessive grinding. Samples should                be kept at room temperature until culture plating, as these fungi may not survive                refrigerator temperatures, and excessive grinding should be avoided. The zygomycetes                can be easily grown on conventional media like SDA with antibiotics, at temperatures                25° C to 37°C, without cycloheximide as this substance is inhibitory                to most of them except There are no reliable serologic or skin tests for mucormycosis and the recently                introduced antigen tests for Aspergillus  and other fungal species                (b-D-glucan) do not detect Zygomycetes because of the limited amount of                galactomannan and glucan in their cell walls.116When cultures are negative, molecular identification of zygomycetes from fresh frozen                or paraffin embedded tissue can help to confirm diagnosis and identify the fungus to                the genus and species level. Different techniques have been reported: DNA probes                targeting the ribosomal 18S subunit, ITS1 sequencing after PCR with pan-fungal                primers, 18S-targeted semi-nested PCR and real-time PCR targeting cytochrome b                    gene.Sequencing of PCR products leads to a presumptive identification of the Zygomycetes,                which provides some guidance in selecting antifungal therapy that would not have                been available using histopathology alone. Molecular typing is most useful for                characterizing zygomycete epidemiology in the setting of a cluster of nosocomial                cases, outbreaks, or pseudo-outbreaks, in order to rule out clonal spread or a                common infecting source.The prognosis of patients with zygomycosis due to Mucorales without treatment is very                poor approaching 100%, depending on the underlying condition and form of                    mucormycosis.124The therapeutic approach to mucormycosis is multimodal, with an equally important                three-point strategy that includes (a) antifungal therapy, (b) surgical debridement                and (c) correction of the underlying condition predisposing the patient to the                disease. Moreover, management of co-morbid factors and adjunctive treatments may                improve host response.Because of the relative rarity of mucormycosis, prospective, comparative studies of                antifungal agents and strategies have not been conducted. Therefore, the management                of mucormycosis is so far based on the results of case series and case reports,                animal model studies and in vitro susceptibility data.The most frequently used antifungal agents to treat mucormycosis are listed in Amphotericin B has the most significant in-vitro activity against Zygomycetes and has                been successfully used to treat mucormycosis for many years. Amphotericin B                deoxycholate (d-AmB) is the only antifungal agent that has been approved by the US                Food and Drug Administration for primary treatment of mucormycosis. However, this                formulation has significant toxicity. The newer lipid formulations of amphotericin B                that include liposomal AmB (L-AmB), AmB lipid complex (ABLC), and AmB colloidal                dispersion (ABCD) are less nephrotoxic and have almost completely replaced                amphotericin B deoxycholate in the recent years. It seems reasonable to recommend                either L-AmB or ABLC as first-line treatment for mucormycosis.129Of the azoles only posaconazole has in vitro activity against Zygomycetes and has                been shown to be active as salvage therapy.Rhizomucor and                    LichtheimiaZygomycetes are resistant to caspofungin and 5-flucytosine in vitro.There is some evidence that combination of amphotericin B with caspofungin may be                active, but these results are preliminary.139Certain Mucorales species have however variable susceptibilities to amphotericin,                with MICs ranging from <1 to 100 μg/ml and treatment may be                unsuccessful. Moreover, the drug may not reach the target because of tissue                infarction and thrombosis.141Another option for the treatment of mucormycosis is the adjunctive use of                iron-chelators deferasirox and deferiprone. A clinical trial is currently underway,                testing the combination of deferasirox with liposomal amphotericin B.Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage                colony-stimulating factor (GM-CSF), G-CSF and GM-CSF are routinely given to                neutropenic patients with mucormycosis or another invasive fungal disease. These two                cytokines have also be used in a limited number of cases of mucormycosis in                non-neutropenic patients as adjunctive treatment with favorable outcomes.143Treating a patient’s underlying medical condition and reducing                immunosuppression are essential to therapy. Rapid correction of metabolic                abnormalities is mandatory in uncontrolled diabetes. Corticosteroids should be                discontinued, if feasible, and other immunosuppressive drugs should be tapered as                much as possible.Diabetics may have a more favourable outcome than non-diabetics. An overall survival                rate of 60–77% for rhino-orbito-cerebral mucormycosis has been                reported in diabetics, versus 20–34% in non-diabetics.146Despite the progress in the treatment of mucormycosis, many problems are yet unsolved                and the mortality of the disease is still high.Depending on the underlying condition of immunocompromised non- haematological                patients, mucormycosis can manifest in various clinical forms: mostly as                rhino-orbital or rhino-cerebral in diabetes patients, pulmonary infection in                patients with malignancy or solid organ transplantation, disseminated infection in                iron overloaded or deferoxamine treated patients, cerebral - with no sinus                involvement - in ID users, gastrointestinal in premature infants, and cutaneous                after direct inoculation in the immunocompetent.Although there are many unresolved issues concerning the epidemiology, diagnosis and                treatment of mucormycosis, advances have been made. Knowledge of the differential                patterns of clinical presentation can raise the suspicion index for these rare but                highly lethal infections. This is very important since prompt and appropriate                management can reduce mortality and morbidity considerably.


A new cell type named telocyte (TC) has recently been identified in various stromal tissues, including skeletal muscle interstitium. The aim of this study was to investigate by means of light  and electron microscopy the presence of TCs in adult human neuromuscular spindles (NMSs) and lay the foundations for future research on their behaviour during human foetal development and in skeletal muscle pathology. A large number of TCs were observed in NMSs and were characterized ultrastructurally by very long, initially thin, moniliform prolongations (telopodes – Tps), in which thin segments (podomeres) alternated with dilations (podoms). TCs formed the innermost and  the outermost layers of the external NMS capsule and the entire NMS internal capsule. In the latter, the Tps were organized in a dense network, which surrounded intrafusal striated muscle cells, nerve fibres and vessels, suggesting a passive and active role in controlling NMS activity, including their participation in cell-to-cell signalling. Immunohistochemically, TCs expressed vimentin, CD34 and occasionally c-kit/CD117. In human foetus , TCs and perineural cells formed a sheath, serving as an interconnection guide for the intrafusal structures. In pathological conditions, the number of CD34-positive TCs increased in residual NMSs between infiltrative musculoaponeurotic fibromatosis and varied in NMSs surrounded by lymphocytic infiltrate in inflammatory myopathy. We conclude that TCs are numerous in NMSs , which provide an ideal microanatomic structure for TC study. Formerly called interstitial-like  cells, TCs have been observed in several tissues and organs, including skin, respiratory tract, cardiovascular system, gastrointestinal tract, liver, gallbladder, pancreas, parotid gland, female reproductive system, breast, placenta, urinary tract and meninges and choroid plexus A peculiar type of interstitial  cells named telocytes  In skeletal muscle interstitium, TCs have recently been identified close to myocytes, satellite cells, nerve endings and capillaries, suggesting a role in muscle regeneration and repair, and in intercellular signalling The archives of the Department of Anatomical Pathology of the University Hospital of the Canary Islands were searched for histopathological specimens containing areas with normal skeletal muscle of random position in the muscular system. In specimens embedded in paraffin, histological serial sections were again made and 16 NMSs were observed from these areas. The specimens were studied by means of conventional and immunohistochemical procedures. In specimens processed for electron microscopy, four new NMSs were obtained. Six NMSs were also studied from specimens, showing skeletal muscle with histological modifications (in two cases of musculoaponeurotic fibromatosis and in one case of inflammatory myopathy). Five NMSs were examined in skeletal muscle obtained from foetal autopsy . NMSs from pathological-modified skeletal muscle and foetus were only processed for light microscopy studies . All protocols were performed in accordance with international ethical guidelines.For light microscopy, specimens were fixed in a buffered neutral 4% formaldehyde solution, embedded in paraffin and cut into 4-μm thick sections, which were stained with haematoxylin & eosin and PAS-Alcian Blue.For immunohistochemical procedures, in all the specimens with NMSs under conventional light microscopy, 3-μm thick sections were cut and attached to silanized slides. After pre-treatment for enhancement of labelling , the sections were blocked with 3% hydrogen peroxide and then incubated with primary antibodies (10–40 min.).The primary antibodies (Dako) used in this study were CD34 (dilution 1:50), code no. M-7168; CD31 (dilution 1:50), code no. M-0823; CD117 , code no. A-4502; α-smooth muscle actin , code no. M-0851; desmin (dilution 1:50), code no. M-0760; h-caldesmon (dilution 1:50), code no. M-3557; vimentin (dilution 1:100), code no. M-0725; S-100 protein (dilution 1:100), code no. H-0066; epithelial membrane antigen , code no. M-0613; cytokeratin (CK) AE1/AE3 (dilution 1:100), code no. N-1590; neurofilament protein (dilution 1:50), code no. M-0762; collagen IV (dilution 1:50), code no. M-0785 and laminin (dilution 1:20), code no. M-0638. The immunoreaction was developed in a solution of diaminobenzidine and the sections were then briefly counterstained with hematoxylin, dehydrated in ethanol series, cleared in xylene and mounted in Eukitt®. Positive and negative controls were used.For electron microscopy, specimens were fixed in a glutaraldehyde solution, diluted in 2% with sodium cacodylate buffer, pH 7.4 for 6 hrs at 4°C, washed in the same buffer, post-fixed for 2 hrs in 1% osmium tetroxide, dehydrated through a graded acetone series and embedded in epoxy resin. Semi-thin sections (1.5 μm) were mounted on acid-cleaned slides, and stained with 1% Toluidine blue. Ultrathin sections were double stained with uranyl acetate and lead citrate. The grids were examined at 60 kV with a JEOL 100B electron microscope.Normal human NMSs A, with bThe perineural cells, which made up most of the external capsule , expressed EMA immunohistochemically B and, unThe intrafusal striated muscle fibres, including the two major types: ‘nuclear chain fibres’  and ‘nuclear bag fibres’  were easily identified under light microscopy by their typical morphology and desmin immunopositivity G.The nerve intrafusal fibres showed immunohistochemical positivity for anti-neurofilament protein in their axons H, S-100 Sensory nerve terminals J, mainlyIn the capillaries, the continuous endothelium was heavily immunostained with anti-CD34 and anti-CD31. The latter only stained endothelial cells in NMSs K.Telocytes expressing vimentin and CD34, and with characteristic ultrastructural findings, were an important component of NMSs B. TCs shThe cellular body or nuclear region of TCs in the intrafusal connective tissue showed either triangular or spindle morphology B and C. The extracellular matrix was stained by PAS in the capsule and mainly by Alcian Blue in intrafusal areas , residual NMSs were observed. The latter appeared embedded within the lesion, which was composed of proliferating myofibroblasts  and their characteristic components was established by the authors who described this new cell type see , 2, 29.Telocytes were mainly distinguished from other types of cells in NMSs by their distribution (location), relationship, morphology, immunohistochemical profile and ultrastructural characteristics . TCs located in the inner and outermost layer of the capsule were CD34-positive and EMA-negative, whereas another cell type in the capsule  was EMA-positive and CD34-negative. Moreover, perineural cells did not present a moniliform aspect and were surrounded by a basement membrane. The intrafusal TCs were distinguished from: (a) Schwann cells, which were located around nerve fibres, showed S-100 positivity and were surrounded by a basement membrane, (b) pericytes, which were located around endothelial cells, with which they shared a basement membrane Neuromuscular spindle is an encapsulated proprioceptor, in which TCs form the innermost and  the outermost layers of the NMS capsule, and the internal capsule. In the latter, TCs surround NMS intrafusal components, which comprise striated muscle fibres, nerves and blood vessels, adopting a special organization in these microanatomic structures. TCs have previously been identified in striated muscle, nerves and vessels found in several locations other than in NMSs. Thus, in rat, mouse and human skeletal muscle, TCs are arranged in a 3D network distribution of their Tps, which are in close vicinity to myocytes, satellite cells, capillaries and nerve endings e.g. miR-193), which regulates c-kit, differentiates TCs from other stromal cells Immunohistochemically, no single marker specific for TCs has been found Several roles for NMS TCs may be postulated: guide during NMS development, mechanical support with passive control of NMS activity and active involvement in the control of muscle tone and motor activity.e.g. semaphorin III and neurotrophin responsive cells – Telocytes may participate in NMS development. Together with the action of axon guidance molecules (Telocytes and perineural cells may provide mechanical support and, together with their special microenvironment, participate in the control of muscle tone and motor activity. Indeed, the Tp network delimits subcapsular and intrafusal spaces where there is a specific microenvironment, which shows an alcianophylic reaction characteristic of glycosaminoglycans In NMSs, TCs may be actively involved in controlling muscle tone and motor activity. Indeed, TC location is strategic and the interconnected TCs form a continuous network, which could act in cell-to-cell signalling. Thus, a paracrine and/or juxtacrine intercellular modulation between TCs and cardiomyocytes has been proposed Telocytes have been involved in the pathogenesis of several pathological processes. They have, for example, been considered a common origin of both PEComas and GISTs


Streptococcus pneumoniae and ataxia. Validation helps to evaluate whether the model has potential in clinical practice.This study aimed external validation of a formerly developed prediction model identifying children at risk for hearing loss after bacterial meningitis (BM). Independent risk factors included in the model are: duration of symptoms prior to admission, petechiae, cerebral spinal fluid (CSF) glucose level, 116 Dutch school-age BM survivors were included in the validation cohort and screened for sensorineural hearing loss (>25 dB). Risk factors were obtained from medical records. The model was applied to the validation cohort and its performance was compared with the development cohort. Validation was performed by application of the model on the validation cohort and by assessment of discrimination and goodness of fit. Calibration was evaluated by testing deviations in intercept and slope. Multiple imputation techniques were used to deal with missing values.Risk factors were distributed equally between both cohorts. Discriminative ability  of the model was 0.84 in the development and 0.78 in the validation cohort. Hosmer-Lemeshow test for goodness of fit was not significant in the validation cohort, implying good fit concerning the similarity of expected and observed cases. There were no significant differences in calibration slope and intercept. Sensitivity and negative predicted value were high, while specificity and positive predicted value were low which is comparable with findings in the development cohort.Performance of the model remained good in the validation cohort. This prediction model might be used as a screening tool and can help to identify those children that need special attention and a long follow-up period or more frequent auditory testing. Neisseria meningitidis serogroup B infections, the incidence of bacterial meningitis (BM) in childhood is decreasing in the Western world. Still, BM ranks among the top ten causes of death in children younger than 14 years in high-income countries. Further, developing countries account for 98% of the estimated 5.6 million disability-adjusted life years attributed to meningitis globally Due to successful vaccination programs, and to spontaneous decline in Especially in (young) children even mild impairment in hearing abilities may impair auditory, linguistic, communication and learning skills. Early identification of hearing loss is indispensable for effective treatment resulting in the acquisition of normal linguistic development The actual incidence of post-meningitis hearing loss is probably underestimated because audiometric testing is only performed in clinical suspected cases. Many cases are late or never diagnosed et al. developed a clinical prediction rule  were included and a prediction model was developed using multivariable logistic regression. Five risk factors for hearing loss were found to be independent determinants: duration of symptoms prior to admission longer than two days, the absence of petechiae, CSF glucose level ≤0.6 mmol/L, S. pneumoniae as causative pathogen and the presence of ataxia during the illness. After internal validation using bootstrapping techniques and shrinkage of regression coefficients this model was transformed into a clinical prediction rule as presented in Sixteen hundred and five children were eligible for inclusion and their pediatricians were approached to send the parents a letter requesting participation. Six hundred and twenty-eight children were included, and their medical records were investigated for risk factors and for perceptive hearing loss of >25 dB. Hearing loss was found in forty-three children (7%) and by reviewing medical records; information was collected on all potential risk factors for this hearing loss. Predictors univariably associated with the outcome (Haemophilus influenzae type b (Hib) BM between January 1997 and December 2001. The exclusion criteria were identical to those used in the original study et al. in which a prediction rule for academic and behavioral problems after BM was constructed, a nested cohort approach was used In 2005, the files of the NRLBM were searched again for Dutch children born between January 1993 and December 1999 who suffered from non-In the total cohort of 358 children a nested cohort of 160 children were randomly selected and invited to visit our department for academic and neuropsychological testing and for the completion of questionnaires regarding behavior and health. Forty-four of the invited children did not participate in this part of the study.Again, the outcome measure “hearing loss” was defined as a unilateral or bilateral perceptive loss of >25 dB and was based on findings in these records and on parental information provided in the questionnaires about the children’s health  and the Health Utilities Index (HUI) mark 2&3) The risk factors evaluated for this study were the five aforementioned independent predictors included in the original model.2-tests for nominal data. Fisher’s Exact test was used if the data did not meet the criteria for a χ2-test. Statistical significance was considered with 2-tailed p-values of ≤0.05.Univariate comparison of the distribution of patient characteristics and clinical data in the development and the validation cohort was performed by independent sample t-tests for continuous and χIn both the development and the validation cohort multiple imputation techniques were used for substitution of missing variables. In the development cohort a maximum of 20% of the data was missing per variable 2-tests. The five results of these χ2-tests of the imputated datasets were pooled For external validation the discriminative ability of the model in both cohorts was compared. In all sets the model with the original regression coefficients was applied on the data of each individual child. Receiver operating characteristic (ROC) curves of all imputated datasets were constructed for these results predicting the outcome measure “hearing loss”. An average area under the curve (AUC) was calculated and compared with the average AUC of the ROC curves of the development cohort. The fit of the model in the validation cohort was tested with the Hosmer-Lemeshow test for goodness of fit. For this test the patients were grouped by decile of predicted probability and differences between expected and observed outcome in the ten groups were tested using χThe intercept in a logistic regression model results in equal averages of the predicted probabilities and the outcomes when the model is applied in the validation cohort . The slope reflects that the regression coefficients are correctly estimated and that they yield the correct predictions in the validation cohort. We also assessed more specifically whether calibration was successful by separately testing deviations in the intercept and calibration slope when the model was applied in the validation cohort For each child in the validation cohort the individual risk score was calculated. The distribution of the number of subjects across categories according to these scores were compared between the development and the validation cohort. Positive and negative predictive value, sensitivity and specificity were calculated for different cut-off points and were compared for their clinical value with those composed with the original prediction model.All data was analyzed using SPSS Statistics 18.0  and R .p-value 0.10), indicating good fit of the model in the validation cohort concerning the similarity of expected and observed cases of hearing loss. When the original model was applied in the validation cohort there was no significant deviation in intercept (p = 0.07–0.11) and calibration slope (p = 0.14–0.34).The average AUC of the ROC curves of the validation cohort was 0.78 (95% CI 0.64–0.92). In the development cohort, the reported AUC was 0.84 (95% CI 0.78–0.91) In this study, the prediction model for hearing loss after childhood BM was validated successfully in a new independent cohort of school-age children. This is the first validated model for the identification of children at high risk for hearing loss after BM. Our recommendation is that at least the patients who are positive at one or more risk score should achieve timely and frequent hearing evaluation. It is not a replacement for standard hearing tests, but an addition to these tests, to estimate the risk for hearing loss in an early stage of disease.Despite increasing awareness and recommendation of routine hearing evaluation in the standard follow-up of childhood BM, the amount of children whom hearing is not tested or hearing loss is even missed could be up to 25–30% et al. we state that hearing loss should not be missed at all and therefore propose a low cut-off value of zero points For clinical practice the optimal cut-off point of the risk score has to be defined. Conform Koomen Further, BM and subsequent morbidity is considerably more prevalent in developing countries where adequate follow-up, hearing tests, financial resources and support in case of auditory deficits are scarcely available This study has several strengths. This is the first model developed and externally validated that predicts hearing loss after BM in childhood. In the last decade, many prediction models have been designed and presented in literature. Before implementation in practice is possible, external validation is an essential step In general, the discrimination of a prediction model is interpreted to be fair, good or excellent when the AUC is or 0.7–0.8, 0.8–0.9 or 0.9–1.0, respectively. This model has an AUC of 0.84 in the development cohort and an AUC of 0.78 in the validation cohort, thus can be at least considered as fair.Further, state of the art methodology is used and described clearly. Therefore it may be easily to reproduce in a wide range of future studies.p-value = 0.052). This difference may be explained by the fact that in the development cohort 27% of the children were not tested for hearing loss, resulting in underestimation of the incidence The validation cohort was constructed using the nested cohort approach while in the development of the rule the total initial cohort was used Case mix differences were also found in patient characteristics and risk factors, such as: duration of symptoms >2 days, meningeal irritation, dexamethasone therapy, mechanical ventilation, duration of anti-epileptic therapy and focal neurological deficits. These differences could have been responsible for a smaller spread in the risk of hearing loss . This may in turn be responsible for the small drop in discrimination of the model in the validation cohort. Because the differences in case mix may partly be explained by the selection processes, we must be careful to draw conclusions from the comparison of the incidence of hearing loss and risk factors, while some selection bias may have occurred.Though, for the external validation selection bias is not a major issue: the development cohort appeared to be a representative sample of the pediatric BM population of that time: The NRLBM receives approximately 90% of the isolates of Dutch BM patients, and the 628 children included where very similar compared with the 1605 eligible children regarding, sex, age, and causative pathogens Validation samples may differ from development samples in predictor (patient) characteristics and in outcome frequency. These differences may, as we discussed, also occur during the selection of patients in the development sample and not only depend on selection of patients in the validation sample. Differences between samples may be caused by sampling variability or true differences, and not by selection bias per se. The goal of external validation is to investigate to what extend these differences influence the generalizability of the prediction model. Sampling variability  will often show a small influence on the performance of the prediction model. We showed that at low and high risk score categories, which are most important for clinical practice, the model performed equally well in the validation as in the development sample Information bias may have occurred. Risk factors and the outcome were determined retrospectively, with a risk of bias and missing data. To minimize the chance of bias, collection and interpretation of clinical data from the medical files was performed in a standardized w ay, and consensus meetings were held when there was any doubt about how to interpret the medical files. The diagnosis “perceptive hearing loss of >25 dB” is made in the Netherlands by clinicians or audiologists by standard tests. Multiple imputation techniques were used for substitution of missing data, which is currently the most reliable strategy to deal with missing information on covariates Further, sample size of the validation cohort was small. A frequently used general rule in the development of clinical prediction models is that the ratio events per variable (EVP) should be approximately 10 N. meningitidis serogroup C and high frequency serotypes of S. pneumoniae were introduced in the Netherlands and other western countries: Accompanied by a spontaneous decrease of N. meningitidis serogroup B infections this resulted in a dramatic decrease in incidence of BM. Serotype replacement with increasing incidence of infections has not yet occurred for N. meningitidis, but new outbreaks with non-vaccine-serotypes are possible and have occurred in history S. pneumoniae there is a net reduction of invasive infections but an increase in infections with non-vaccine-serotypes is observed S. pneumoniae included in the vaccine, and showed that the model remains stable in this situation It is hypothesized that the distribution of BM pathogens has changed since the introduction of these vaccines and therefore the model will not perform well in the contemporary population. Since the development of the prediction rule two new vaccines against et al. described a strong association between host genetic polymorphisms in pathogen recognition receptors and hearing loss after BM extracted from both development and validation cohort described in this study Another important development is the rapidly increasing knowledge on the influence of genetics on the course of diseases. This also applies for BM and hearing loss, and in recent publications an effort was made to disclose the influence of genetic variation in the immune response and the course of the disease in children. Van Well We conclude that we created and externally validated a clinical useful tool in addition to regular auditory testing for the identification of children at high risk for hearing loss after BM. In the future larger development and validation studies must be performed, in which hearing loss is measured prospectively and genetic risk factors are included in the construction of the prediction model. In our opinion, international cooperation is the answer to the problem of decreasing incidence in the development of prediction models.


The objective of this study was to further develop the Ida Institute model on communication partners' (CPs) journey through experiences of person with hearing impairment (PHI), based on the perspectives of CPs. Nine CPs of hearing aid users participated in this study, recruited through the Swansea hearing impaired support group. Semi-structured interviews were conducted, the data were analysed using qualitative thematic analysis and presented with the use of process mapping approach. Seven main phases were identified in the CP journey which includes: (1) contemplation, (2) awareness, (3) persuasion, (4) validation, (5) rehabilitation, (6) adaptation, and (7) resolution. The Ida Institute model  was compared with the new template developed (based on CPs' perspectives). The results suggest some commonalities and differences between the views of professionals and CPs. A new phase, adaptation, was identified from CPs reported experiences, which was not identified by professionals in the Ida Institute model. The CP's journey model could be a useful tool during audiological enablement/rehabilitation sessions to promote discussion between the PHI and the CP. In addition, it can be used in the training of hearing healthcare professionals. Communication partners (CPs) are those with whom the person with hearing impairment (PHI) communicates on a regular basis. The term communication partner has been used to refer to the significant others which may include their spouse, siblings, children, friends, relatives, colleagues, and carers. Hearing impairment is a communication problem which affects everyone in the communication situation, not only the PHI . It can Ida Institute at Denmark is a non-profit organisation with a mission to foster better understanding of human dynamics of hearing loss. The institute conducts various activities to create and share innovative, actionable knowledge to help hearing care professionals address the psychological and social challenges of hearing loss and implement patient-centered care practices. The institute with collaborative effort from hearing healthcare professionals around the world developed the possible CP journey model . HoweverIn a recent international study that focused on exploring the perspectives of the PHI, it was highlighted that PHI use their life experiences rather than clinical encounters to describe the hearing help-seeking and hearing rehabilitation process . In addiIn our previous studies, we have explored the journey of PHI , 11.  FiThe aim of the current study was to further develop the Ida Institute model on the CP journey through their partner's hearing impairment, based on the perspectives of CPs and to examine the relationship between the perspectives of hearing healthcare professionals and of CPs.Ethical clearance was obtained from Departmental Research Ethics Committee, College of Human and Health Sciences, Swansea University. A purposeful sampling strategy  . Initially, CPs were asked to narrate their journey (tell their story) through their partner's/friend's/father's hearing loss. This was followed by some general questions  to explore the CPs' experiences broadly. In addition, more directed questions based on their reports during the interview were asked to obtain an in-depth understanding of their experiences. Interviews typically lasted for about 60–90 minutes. The interviews were recorded using portable digital recorders to recheck the notes taken by the researcher. It was noticed that many CPs had prepared notes about their experiences before the interview, even though it was not requested in the information sheet. The data collection and the data analysis were conducted by the first author. Thematic analysis which involves identifying, analyzing, and reporting patterns within the data was employed to analyse the data . The maiThe main steps in data analysis included: familiarization with the data by repeated reading of notes and by listening to the voice recordings repeatedly, generating the initial codes , categorising the data and searching for subthemes and themes, ongoing review, defining and naming of themes and subthemes (the Ida model acted as an inspiration for naming the themes), and identifying some extracts which could be used in reporting the data. The subthemes were categorised into most , many , several, and/or few  based on how frequently they were reported by the participants. Moreover, the rule of most of participants reporting was considered for a theme  and many participants reporting for a subtheme . The working model with seven main phases was developed with the interview data of seven participants. Two new participants were interviewed to check for data saturation, and the data collection was stopped as there were no new themes  being identified  , 21.A total of 58 unique subthemes that were related to the study were identified through 9 interviews. However, only 31 of them that were reported by most and many participants were considered for the development of CP's journey model. An ongoing matching of subthemes was done with Ida Institute model to see if the same code names can be assigned. However, where new subthemes  were identified, new names were assigned to reflect the meaning and essence of the reported experiences. The subthemes were grouped together to identify themes, and the themes were further confirmed by repeatedly listening to participants' interviews to check if the identified themes capture the reported experiences. The process mapping  was used to define these themes in appropriate phases to represent the CP's journey model . ProcessSeven main phases and various stages were identified. In this phase, CPs may start noticing the PHI's communication difficulties and reduced social interactions. This may sometimes result in feeling embarrassed, angry, and frustrated. Initially, the CPs might attribute some of the problems noticed to possible cognitive impairments, attentions and concentration. Moreover, the CPs may also start making some accommodation, to the PHI's hearing loss. Initially I thought a lot of it was due to his attention…! I could say something to him and if it was not of his interest, I could see that he has not heard it, or he will repeat what I said five minutes later, and I would say…..I just told you that..! …. Even though I had experience with deafness due to others in the family, I could not realise he had problem straightaway. The following statement made by the CP of a PHI shows how, in the initial phase of the PHI's hearing loss, the CP may think that the communication difficulties noticed were due to attention and concentration rather than to poor hearing. This highlights the fact that the identification of hearing loss is not straightforward. In this phase, CPs become aware that the PHI has genuine difficulties with their hearing. This may be by noticing clear changes in the PHI's communication behaviour, PHI's dependency on other senses, noticing that PHI was not hearing the smoke alarm, telephone, and so forth, and more importantly, by noticing changes in the family dynamics. They may start nagging the PHI (or indirectly persuading the PHI to seek help) or provide support and encouragement, and they may start acting as an interpreter for the PHI. However, this new role of acting as an interpreter may become overwhelming. I can remember a few things which can put the picture together…The first thing I noticed was that he was shouting on the telephone. I could be in there with the doors shut and could hear him. I say to him, do you realise that you were shouting on the telephone?, I do not think I was.. You cannot say anything to that one…… and the other thing is shouting at public places, for example, shouting in the restaurant. ….after it was confirmed to me with these observations, I told my children what I noticed and they agreed, especially the elder daughter, and she started making some adjustments… This description below shows how a CP confirmed their speculation about the PHI's hearing loss (elements of contemplation and awareness phases). It also highlights how this awareness may change the family dynamics. After I started noticing his difficulties…I almost started acting like his secretary…it could be very tiring sometimes…especially later in the day…!!The following statement made by a CP highlights the change in their communication roles, a change in family dynamics and the dependency of the PHI on the CP for everyday activities in relation to communication.After CPs become aware of the PHIs hearing loss, they often start making attempts to make the PHI aware of their communication problems. In addition, they may also start searching for information related to hearing loss and start persuading them to seek help. In the initial stages, this could be indirect. However, there could be some triggering factors for the CPs which make them start directly persuading the PHI to seek help. I have to be very diplomatic you know. ….. [Chuckle]…. I got a bit of adverse reaction on one occasion. He said to me speak up you are mumbling, and I said to him you are not hearing me properly and asked him to get his hearing checked. ….. [Chuckle]…. He said to me ‘you get your hearing checked', you don't hear something that I say to you… Once he said that I have to back off for a while obviously….work with it for a while and then change my approach……….I think I nagged him to such an extent that he went to get a hearing test… he was not hearing the telephone, once he did not hear the alarm and ……once it got to that stage I have to tell him..!!The following quote confirms that the CPs could act as drivers (or facilitators) to the PHI seeking help. The CP's expression in this makes it clear that this task is not always straightforward. They may start with indirect persuasion and move to more direct persuasion as time progresses. This phase was not widely discussed by the CPs. However, in this phase, CPs mainly confirm whether or not the PHI had hearing loss. The results of hearing assessment of the PHIs may or may not surprise the CPs. Even though most CPs were not very keen about the hearing assessment, some accompanied the PHI for hearing assessment and made an attempt to understand the hearing test results and what they may indicate. However, almost all of them made commitments to support the PHIs. After the hearing test, the realisation made him do something about it….after he consulted he started wearing hearing aids, getting them fixed regularly, adjusts them, and it has made a great difference to us.In this statement, the CP talks about the PHI's reaction to the hearing test and acceptance of hearing loss. However, this also indirectly implies that the CP confirmed that their assessment was correct. There are also elements of later stages being mentioned, for example, the rehabilitation phase . In this phase, most CPs were relieved that the PHIs were seeking help. However, they started realising that they also have an important role to play in the rehabilitation process, mainly in supporting the PHI . They soon realised that hearing instrument may not solve all the problems, which made them feel sympathy for the PHI's difficulties. He wears hearing aids, but I still have to shout and I say things six times….oh….I have to say six times very often..! You hear what I said then?….He will say no.. oh….right….I will start again then. So, it's again my temperament….I don't get cross over him… I would say…oh… for goodness sake…you listening now?….[chuckle]…watch my lips….[chuckle]…The following description highlights that soon after the PHI is fitted with hearing aids, they will start realising that they may not solve all the problems. In addition, the coping strategies used and the way in which the CP would support the PHI are evident. I feel a bit guilty sometime….Everyone having a conversation…having a laugh and everything….I feel guilty sometime if he can't join in sometime, and if he is sitting in the corner…and everyone don't realise that.The following statement made by a CP is an example of what may happen at a dinner table when they have big family dinner. This may suggest that they feel sorry for the PHI as they feel helpless in some occasions. This was a new phase identified from CP's reports when compared to the Ida Institute professionals' perspectives of the communication partners' journey . This phI do repeat things for him, yes, he said such and such…sometime he will ask to me what did he say, when he misses a bit…the other day I repeated three times and eventually I say, I spell it out…because if they don't get it after three times….then we just spell it out.The spouse of a PHI made the following statement in relation to how they started exploring new ways of communication after he was confirmed as having hearing loss. It's not like he is missing a lot, because we talk after the meeting, what is been said, and it's not like he is missing anything. In fact, there is another person in the office who just can't be bothered, who goes to meeting and ….dreams. Whereas he [name of PHI] is different, he concentrates on what is being said and pays attention. Maybe it's been a benefit to him in that respect, because, he is hard of hearing he got to concentrate on hearing it.The following quote was made while the CP was talking about how he adapted to dealing with the PHI which demonstrates that the CP is able to identify some positive aspects of hearing loss. This was a more stable phase which most of the CPs reported during the course of the interview. In this phase, CPs started noticing continued difficulties experienced by the PHI in social situations and started realising that crisis may not necessarily hearing related. They also gradually started noticing the increasing difficulties of the PHI, possibly due to the worsening of their hearing loss. Some CPs had positive temperaments and reported satisfactory outcomes. However, others reported frustrating and disappointing outcomes. Changes in family dynamics (more of relationship dynamics) seemed like a dynamic process which was noticed even in this phase. Moreover, in this phase, most CPs were more stable, and hearing loss had just become a way of life compared to the earlier phase  in which they were exploring new ways of communication to improve the situation. We have a way of talking to him now. We have a certain way. We sometime do it with normal hearing people when I talk to them, and they say why are you speaking to me like this? I am so used to being around dad. It does change our lives. The following statement shows that the CP has started using a certain way of communicating rather than exploring new ways of communication. It's our responsibility now…because, we can't expect him to do everyday things now. He will pick up the phone and ring me. Nine out of ten times he does not understand what we say. Few times now, since my mother has died and he lives on his own, if we don't get a response from him on the telephone we have to go there to check if he's alright.A daughter of a PHI made this statement indicating how her life had changed, and the crisis was not only hearing related. A few interesting observations were made while analysing the data. The progression of CPs from one phase to other phase varied in terms of time scale . For example, in the case of a carer, there was very limited time between the contemplation and adaptation phase. Moreover, each CP had different expectations of their PHI and most CPs reported that they had taken additional responsibilities after their partner developed hearing impairment . Whilst CPs may need to continually adapt to life situations , in the initial phases of the journey, CPs reported having explored ways to improve their communication behaviour . However, as time progressed, they became used to dealing with the PHI rather than finding new ways to improve their communication. Such observations also acted as the key difference between adaptation and resolution phase.CPs, who reported less psychosocial consequences and who were coping well, appeared to have had a positive temperament (or attitude) towards life and also had some experience of dealing with other chronic conditions. However, this was not measured using any standard scale but only a subjective interpretation of the researcher. More research is needed to understand the relationship between such factors as CP temperament and personality and their influence on the success of audiological rehabilitation of the PHI. CPs referred more to the initial and later phases in their journey through their partner's hearing loss. Similar results have also been found in studies focusing on experiences of PHI , 12. TheThe study highlights the fact that the professionals failed to identify an important phase adaptation of the CPs' journey. Possible reasons for this may be that the professionals paid less attention to the subjective experiences of the PHI and CP during the rehabilitation process and/or professionals not being able to differentiate between adaptation and resolution phases. Similar results were seen in our previous study on the patient's journey of adults with gradual-onset acquired hearing impairment where professionals did not identify the self-evaluation phase . In addiThe current study has number of clinical and research implications. This is because the model helps to see the bigger picture about experiences of CPs and how they change over time, which is the most important in managing chronic conditions such as hearing impairment. Considering most of the research focuses on specific question (which may only provide fragments of information about CPs experiences), this innovative approach may help organising such information using the proposed model. Whilst the way in which the data presented in this study is quite unique to qualitative research, it appears to be a format which is relatively easy for both professionals and nonprofessionals to understand and remember . Furthermore, the study highlights that it is important to understand the perspectives of both professionals and CPs as there are differences and commonalities. More specifically, in this study, the data reflected personal stories of CPs through PHI's hearing loss which was used to develop typical journey model of CPs. This may suggest that the narrative  approach appeared to be a simple and useful way to gather data from CPs (similar to our previous study findings on PHIs) . We suggAspects such as the frequency of communication and emotional closeness played an important role in the extent to which the CP was affected by the person's hearing impairment. For example, three of the participants  reported very few psychological consequences on them. In addition, three of the CPs (two daughters and a friend) talked about the impact of the PHI on their spouse and expressed the fact that the spouses of PHI were most affected in communication, social, and emotional aspects. This identifies the need for understanding more about the social networks of the PHI and their communication behaviour with CPs. For this purpose, tools such as “communication world” and/or “communication rings” could be helpful , 29. In addition, the identification of a new phase   is signiIn general, the intensity of psychological, emotional, and social consequences reported by each CP varied. For example, to what degree the CPs experienced communication difficulties during social situations. Whilst the CP's journey model represents the main experience of CPs through their partner's hearing loss  over a period of time, it may not clearly differentiate to what extent individual CPs were affected. This may suggest that this model provides us with an understanding of CPs experiences over time. For this reason, informal questioning, use of open-ended questionnaires, and use of structured questionnaires such as Significant Other Assessment of Communication (SOAC), Hearing Handicap Inventory for Elderly for Spouses (HHIE-SP), and the Significant Other Scale for Hearing Disability (SOS-HEAR) can be useful during clinical encounters to gather information about the effect of the PHI's hearing loss on CPs in different dimensions –35. It iThe study's methodology has some advantages and drawbacks which may have influenced the results and the development of the model. For example, whilst thematic analysis offers theoretically flexible approach to the analysis of the data, other approaches such as narrative or other biographical approaches may have tapped into different aspects of the data  . HoweverConsidering the nature of the study, the data collection and analysis were conducted by the first author, and the analyses was discussed with other two authors. This allowed consistency in the method but may have failed to provide multiple perspectives and rechecking the coding. In addition, using notes and voice recordings for data analysis when compared to transcribing the recordings may have some advantages and disadvantages. For example, having the transcription of the interviews may have made the process of coding the data into themes and subthemes easier. However, considering that the data were collected and analysed by the same researcher, we would argue that the researcher was sufficiently familiarised to establish themes and subthemes. Moreover, listening to voice recordings repeatedly rather than looking at the transcriptions allowed the researchers to rethink and reperform parts of the analysis and helped in identifying the differences in intensity of reported psychological, emotional, and social consequences at different points which are not clearly reflected in the proposed model. The reported experience of CPs may vary, based on differences in cultural aspects, social structures, healthcare structures, educational background, and so on. For this reason, it would be interesting to study the CP's journey from other social and cultural backgrounds. Furthermore, an important question would be to explore how PHI's and their CPs' interactions may influence each other's journey. In the current study, most of the CPs were in the resolution stage and the journey reported was retrospectively based on what they could remember. However, it would be important to investigate the CP's journey longitudinally, by interviewing the CPs at different points of time. More importantly, whilst this exploratory study provides a model of CPs' journey, it should be validated using appropriate quantitative methods on a large sample size. The study highlighted commonalities and differences in perspectives of CPs and professionals. The CP's journey model could be a useful tool during audiological enablement/rehabilitation sessions to promote the discussion between PHI and CPs. In addition, it can be used in training the hearing healthcare professionals. The CP's model was developed from a relatively small sample and may not represent the diverse group of CPs' experiences. Moreover, even though the CP's journey model illustrates CPs' experience through their partner's hearing loss, it may not cover all the complex dimensions. For this reason, the model should be used as a starting point to explore the CP's journey further in clinical situations.


Resources for rare diseases are lacking. Patients do not have the information and support that they need, and researchers struggle to make progress due to a shortage of skills and collaborations within the field. One way to overcome these hurdles is to host annual Symposia, focused on a specific rare disease. Here, we use the example of Birt-Hogg-Dubé Symposia to discuss the practical issues of such meetings, including the importance of timing and the choice of invited speakers. We highlight the ways in which rare disease symposia can create a single community, removing barriers between patients, clinicians and researchers. There are estimated to be around 7,000 rare diseases, with 6% of the global population affected by one at some stage in their life . DespiteWith the necessary skills and resources missing, how can we advance rare disease research and support? One method is to host scientific and patient meetings. Scientific meetings are an excellent opportunity for researchers working in a similar field to come together, learn about recent advances in the area, foster new collaborations and stimulate new ideas. Here, we discuss the ways in which such symposia can contribute to and increase the pace of rare disease research, by using the example of the BHD Symposia, an annual global meeting organized by the Myrovlytis Trust.Birt-Hogg-Dubé (BHD) Syndrome is a rare genetic disorder characterized by benign skin tumors, lung cysts leading to pneumothorax and an increased risk for renal cell carcinoma ,3. PatieAs with all scientific meetings, sharing unpublished data and discussing ideas is key to making rapid progress in the field. However, for rare diseases, the importance of symposia extends beyond that of standard scientific meetings. With so few individuals studying the disease, symposia are important for generating a community feel. Researchers are often geographically isolated and find it difficult to form strong collaborations. Symposia are the perfect opportunity for scientists from across disciplines to meet and share their skills.BHD researchers are located all across the world, but often with only one or two institutions in each country involved in BHD research. BHD Symposia mitigate the feeling of isolation for these researchers, and provide sources of help and motivation. The Symposia also allow BHD researchers to meet, discuss challenges and ideas and form new collaborations.As many BHD patients do not know anyone else with BHD outside their own family, it is valuable to bring patients together to share stories, ask advice and jumpstart peer support. The BHD Symposia are joint meetings for researchers and patients, with both mixed and separate sessions. The aim of the Symposia is to generate the sense of a single BHD community, removing barriers between patients, family members, scientists and clinicians.Awareness of BHD amongst the wider research community is central to making progress in understanding the disease. Attracting new researchers to the field would bring in new skills and resources, as well as a fresh perspective on research. Awareness can be achieved through widely advertising the symposium, but also by careful selection of the invited speakers and the timing of the meeting.As well as inviting experts from within the BHD field to speak at the BHD Symposia, other world-class researchers are also invited who could speak on a broader topic. This may attract scientists who would not normally have considered attending and thereby raise awareness of BHD. Holding the Symposium adjacent to another scientific meeting may also help to attract attendees as it would save on travelling time and cost. For the BHD Symposia, previous meetings have been held adjacent to a related rare disease symposium  and, in 2010 and 2012, the American Association for Cancer Research (AACR) Annual Meeting.The BHD Symposia is the only meeting anywhere in the world dedicated entirely to BHD Syndrome, and as such, all researchers who work on BHD are likely to attend. This contributes significantly to the success of the symposia and helps to stimulate research. The format described here for BHD Symposia can be replicated for any rare disease and we hope, with time, that more rare diseases can be represented by such meetings. There is currently an increasing interest into rare diseases, with charities such as Findacure being launched in the UK this year. Now is an exciting time to push rare disease research forward and get more people involved in the field.The authors declare that they have no competing interests.All the listed authors: 1) have made substantial contributions to the conception and design of this letter; 2) have been involved in drafting the manuscript or revising it critically for important intellectual content; and 3) have given final approval of the version to be published.